A Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) (ENESTnd)

• ClinicalTrials.gov Identifier: NCT00471497
• Recruitment Status: Completed
• First Posted: May 10, 2007
• Results First Posted: June 17, 2013
• Last Update Posted: November 18, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Myelogenous Leukemia, Chronic
• Interventions: Drug: nilotinib; Drug: imatinib
• Enrollment: 846

Participant Flow

Recruitment Details	The study over-enrolled, and 846 patients (283 in the imatinib 400 mg arm, 282 in the nilotinib 300 mg arm and 281 in the nilotinib 400 mg arm) were randomized. DP = disease progression, SOR/TF = Suboptimal response or treatment failure
Pre-assignment Details	Randomization was planned for a total of 771 patients.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Period Title: Core Treatment Phase
Started	283	282	281
Safety Analysis Set	280 [1]	279 [1]	277 [1]
Discon. Core/Did Not Enter Ext.	235	256	278
Discontinued Core/Entered Ext.	48	26	3
Completed [2]	99	107	99
Not Completed	184	175	182
Reason Not Completed
Abnormal Laboratory Values	3	9	9
Abnormal Test Procedures	1	0	1
Condition no longer requires study drug	0	1	0
Withdrawal by Subject	31	29	34
Lost to Follow-up	6	6	3
Death	3	9	3
Disease Progression	10	2	4
Protocol Violation	6	15	11
Sub optimal response or treat. failure	19	11	13
Administrative problems	14	14	12
Adverse Event	43	53	89
Disc. Core/Entered Ext. - DP progression	2	0	0
Disc. Core/Entered Ext.- SOR/TF	46	26	3
[1] Safety set contained patients who received at least one dose of study medication.; [2] Completed = Completed Core phase as per protocol
Period Title: Extension Phase
Started	48	26	3
Completed [1]	21	12	2
Not Completed	27	14	1
Reason Not Completed
Adverse Event	9	5	1
Unsatisfactory therapeutic effect	8	6	0
Withdrawal by Subject	3	1	0
Lost to Follow-up	2	0	0
Death	1	0	0
Disease progression	2	0	0
Protocol Violation	2	2	0
[1] Completed = Completed Ext. phase as per protocol

Baseline Characteristics

Arm/Group Title		Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID	Total
Arm/Group Description		Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Total of all reporting groups
Overall Number of Baseline Participants		283	282	281	846
Baseline Analysis Population Description		Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.
Age, Customized; Measure Type: Number; Unit of measure: Participants
<35 years	Number Analyzed	283 participants	282 participants	281 participants	846 participants
		63	67	65	195
>= 35 - <45 years	Number Analyzed	283 participants	282 participants	281 participants	846 participants
		67	50	59	176
>=45 - <55 years	Number Analyzed	283 participants	282 participants	281 participants	846 participants
		63	72	65	200
>=55 - < 65 years	Number Analyzed	283 participants	282 participants	281 participants	846 participants
		55	57	65	177
>=65 years	Number Analyzed	283 participants	282 participants	281 participants	846 participants
		35	36	27	98
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	283 participants	282 participants	281 participants	846 participants
	Female	125 44.2%	124 44.0%	106 37.7%	355 42.0%
	Male	158 55.8%	158 56.0%	175 62.3%	491 58.0%
Race/Ethnicity, Customized [1]; Measure Type: Number; Unit of measure: Participants
Caucasian	Number Analyzed	283 participants	282 participants	281 participants	846 participants
		187	170	185	542
Black	Number Analyzed	282 participants	281 participants	280 participants	843 participants
		7	12	11	30
Asian	Number Analyzed	283 participants	282 participants	281 participants	846 participants
		71	76	66	213
Native American	Number Analyzed	283 participants	282 participants	281 participants	846 participants
		1	0	2	3
Other	Number Analyzed	283 participants	282 participants	281 participants	846 participants
		17	24	17	58
		[1] Measure Analysis Population Description: Missing patient that cannot be identified

Outcome Measures

1. Primary Outcome

Title	Major Molecular Response Rate (MMR) at 12 Months Between All 3 Arms - With Imputation
Description	MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	22.3; (17.6 to 27.6)	44.3; (38.4 to 50.3)	42.7; (36.8 to 48.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Imatinib 400 mg QD, Nilotinb 300 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	22.1
	Confidence Interval	(2-Sided) 95%; 14.5 to 29.6
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Imatinib 400 mg QD, Nilotinib 400 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	20.4
	Confidence Interval	(2-Sided) 95%; 12.9 to 28.0
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation
Description	MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title		Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:		Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed		283	282	281
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
Sokal risk group = Low	Number Analyzed	104 participants	103 participants	103 participants
		26.0; (17.9 to 35.5)	40.8; (31.2 to 50.9)	53.4; (43.3 to 63.3)
Sokal risk group = Interm.	Number Analyzed	101 participants	101 participants	100 participants
		22.8; (15.0 to 32.2)	50.5; (40.4 to 60.6)	40.0; (30.3 to 50.3)
Sokal risk group = High	Number Analyzed	78 participants	78 participants	78 participants
		16.7; (9.2 to 26.8)	41.0; (30.0 to 52.7)	32.1; (21.9 to 43.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Imatinib 400 mg QD, Nilotinb 300 mg BID
	Comments	(Low)
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	14.8
	Confidence Interval	(2-Sided) 95%; 2.1 to 27.5
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Imatinib 400 mg QD, Nilotinib 400 mg BID
	Comments	(Low)
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	27.4
	Confidence Interval	(2-Sided) 95%; 14.6 to 40.2
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Imatinib 400 mg QD, Nilotinb 300 mg BID
	Comments	(Intermediate)
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	27.7
	Confidence Interval	(2-Sided) 95%; 15.0 to 40.4
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Imatinib 400 mg QD, Nilotinib 400 mg BID
	Comments	(Intermediate)
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	17.2
	Confidence Interval	(2-Sided) 95%; 4.6 to 29.8
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Imatinib 400 mg QD, Nilotinb 300 mg BID
	Comments	(High)
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	24.4
	Confidence Interval	(2-Sided) 95%; 10.7 to 38.1
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Imatinib 400 mg QD, Nilotinib 400 mg BID
	Comments	(High)
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	15.4
	Confidence Interval	(2-Sided) 95%; 2.1 to 28.6
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Rates of Durable MMR at 24 Months Between All 3 Arms
Description	Durable MMR at 24 months is defined as having MMR both at 12 months and at 24 months, and with no documented loss of MMR between these 12 month and 24 month time points.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	20.5; (15.9 to 25.7)	41.8; (36.0 to 47.8)	39.1; (33.4 to 45.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Imatinib 400 mg QD, Nilotinb 300 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	21.3
	Confidence Interval	(2-Sided) 95%; 13.9 to 28.8
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Imatinib 400 mg QD, Nilotinib 400 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	18.7
	Confidence Interval	(2-Sided) 95%; 11.3 to 26.0
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months
Description	CCyR is defined as 0% Ph+ metaphases based on at least 20 metaphases from bone marrow cytogenetics. Patients with no CCyR as the best response by any specific time point, all missing cytogenetic evaluations by that time point or Ph- at baseline are combined as "Nocomplete cytogenetic response".
Time Frame	12, 24, 36, 48, 60, 72 months (M)

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Measure Type: Number; Unit of Measure: Percentage of participants
CCyR at M12	55.5	70.2	68.7
CCyR at M24	61.5	66.0	66.2
CCyR at M36	14.1	9.2	12.8
CCyR at M48	11.3	8.9	13.5
CCyR at M60	2.5	2.8	2.8
CCyR at M72	1.8	1.8	2.8

5. Secondary Outcome

Title	Rate of Major Molecular Response (MMR) at 12 Months Between Two Nilotinib Arms
Description	MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months based on 12-month cut-off interim data.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	282	281
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	44.3; (38.4 to 50.3)	42.7; (36.8 to 48.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nilotinb 300 mg BID, Nilotinib 400 mg BID
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6987
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Absolute difference
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 95%; -9.8 to 6.6
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms
Description	MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 6 months and beyond up to 120 months based on final data.
Time Frame	6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
MMR at M6	12.0; (8.5 to 16.4)	33.0; (27.5 to 38.8)	29.5; (24.3 to 35.2)
MMR at M12	22.3; (17.6 to 27.6)	44.7; (38.8 to 50.7)	43.1; (37.2 to 49.1)
MMR at M24	37.5; (31.8 to 43.4)	61.7; (55.8 to 67.4)	59.1; (53.1 to 64.9)
MMR at M36	38.5; (32.8 to 44.5)	59.2; (53.2 to 65.0)	57.3; (51.3 to 63.2)
MMR at M48	43.8; (38.0 to 49.8)	59.9; (54.0 to 65.7)	55.2; (49.1 to 61.1)
MMR at M60	49.1; (43.2 to 55.1)	62.8; (56.8 to 68.4)	61.2; (55.2 to 66.9)
MMR at M72	41.7; (35.9 to 47.7)	52.5; (46.5 to 58.4)	57.7; (51.6 to 63.5)
MMR at M84	40.3; (34.5 to 46.3)	50.0; (44.0 to 56.0)	50.9; (44.9 to 56.9)
MMR at M96	37.5; (31.8 to 43.4)	46.1; (40.2 to 52.1)	46.3; (40.3 to 52.3)
MMR at M108	37.5; (31.8 to 43.4)	43.3; (37.4 to 49.3)	40.2; (34.4 to 46.2)
MMR at M120	36.4; (30.8 to 42.3)	37.9; (32.3 to 43.9)	39.1; (33.4 to 45.1)

7. Secondary Outcome

Title	Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib
Description	Molecular response of <=0.01% is defined as BCR-ABL ratio (%) on IS <= 0.01% (corresponds to >=4 log reduction of BCR-ABL transcripts from standardized baseline value)
Time Frame	at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
Molecular response of <=0.01% at 6 months	1.1; (0.2 to 3.1)	8.9; (5.8 to 12.8)	5.7; (3.3 to 9.1)
Molecular response of <=0.01% at 12 months	3.9; (2.0 to 6.8)	12.1; (8.5 to 16.4)	8.9; (5.8 to 12.9)
Molecular response of <=0.01% at 24 months	10.2; (7.0 to 14.4)	24.5; (19.6 to 29.9)	22.1; (17.4 to 27.4)
Molecular response of <=0.01% at 36 months	14.1; (10.3 to 18.7)	29.4; (24.2 to 35.1)	23.8; (19.0 to 29.3)
Molecular response of <=0.01% at 48 months	19.8; (15.3 to 24.9)	33.0; (27.5 to 38.8)	29.9; (24.6 to 35.6)
Molecular response of <=0.01% at 60 months	31.1; (25.7 to 36.8)	47.9; (41.9 to 53.9)	43.4; (37.5 to 49.4)
Molecular response of <=0.01% at 72 months	27.2; (22.1 to 32.8)	44.3; (38.4 to 50.3)	45.2; (39.3 to 51.2)
Molecular response of <=0.01% at 84 months	29.0; (23.8 to 34.6)	42.9; (37.1 to 48.9)	40.6; (34.8 to 46.6)
Molecular response of <=0.01% at 96 months	28.3; (23.1 to 33.9)	39.7; (34.0 to 45.7)	38.1; (32.4 to 44.0)
Molecular response of <=0.01% at 108 months	32.2; (26.7 to 37.9)	40.4; (34.6 to 46.4)	34.9; (29.3 to 40.8)
Molecular response of <=0.01% at 120 months	28.3; (23.1 to 33.9)	35.5; (29.9 to 41.4)	33.8; (28.3 to 39.7)

8. Secondary Outcome

Title	Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib
Description	This is the molecular response of <=0.0032% is defined as BCR-ABL ratio (%) on IS <= 0.0032% (corresponds to >=4.5 log reduction of BCR-ABL transcripts from standardized baseline value)
Time Frame	at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
Molecular response of <=0.0032% at 6 months	0.0; (0.0 to 1.3)	3.5; (1.7 to 6.4)	1.4; (0.4 to 3.6)
Molecular response of <=0.0032% at 12 months	0.4; (0.0 to 2.0)	4.6; (2.5 to 7.8)	5.0; (2.8 to 8.2)
Molecular response of <=0.0032% at 24 months	2.8; (1.2 to 5.5)	12.4; (8.8 to 16.8)	7.8; (5.0 to 11.6)
Molecular response of <=0.0032% at 36 months	8.1; (5.2 to 11.9)	13.8; (10.0 to 18.4)	12.1; (8.5 to 16.5)
Molecular response of <=0.01032 at 48 months	10.2; (7.0 to 14.4)	16.3; (12.2 to 21.2)	17.1; (12.9 to 22.0)
Molecular response of <=0.0032% at 60 months	19.8; (15.3 to 24.9)	32.3; (26.8 to 38.1)	29.5; (24.3 to 35.2)
Molecular response of <=0.0032% at 72 months	18.0; (13.7 to 23.0)	31.2; (25.8 to 37.0)	28.8; (23.6 to 34.5)
Molecular response of <=0.0032% at 84 months	19.1; (14.7 to 24.2)	31.6; (26.2 to 37.3)	28.8; (23.6 to 34.5)
Molecular response of <=0.01% at 96 months	23.3; (18.5 to 28.7)	31.9; (26.5 to 37.7)	32.4; (26.9 to 38.2)
Molecular response of <=0.0032% at 108 months	24.0; (19.2 to 29.4)	31.9; (26.5 to 37.7)	28.1; (22.9 to 33.8)
Molecular response of <=0.0032% at 120 months	21.2; (16.6 to 26.4)	27.0; (21.9 to 32.5)	25.6; (20.6 to 31.1)

9. Secondary Outcome

Title	Time to First MMR
Description	Time to MMR is defined as time from date of randomization to the date of the first documented MMR in nilotinib treatment arms, compared to imatinib in adult patients with Ph+ CML in CP.
Time Frame	up to 84 months

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Median (95% Confidence Interval); Unit of Measure: Months
	14.13; (11.60 to 17.31)	8.31; (6.21 to 8.48)	8.53; (8.31 to 11.07)

10. Secondary Outcome

Title	Duration of MMR
Description	Duration of MMR for patients with MMR is defined as the time between date of MMR and the earliest of the following: loss of MMR, CML-related death or progression to AP/BC during study treatment The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported.
Time Frame	approx. 11 years

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA = not enough events to calculate median and CI of duration MMR

11. Secondary Outcome

Title	Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts
Description	Time to BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% is defined as: date of first BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% - date of randomization +1.
Time Frame	up to 84 months

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Median (95% Confidence Interval); Unit of Measure: Months
time to first molecular response of <=0.01%	30.46; (24.11 to 36.01)	19.38; (16.62 to 22.34)	22.70; (19.48 to 27.63)
time to first molecular response of <=0.0032%	37.29; (33.45 to 41.63)	32.46; (23.23 to 38.67)	35.94; (30.39 to 41.00)

12. Secondary Outcome

Title	Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts
Description	It is defined as the time from the date of first documented BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% to the earliest of the following: Loss of BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032%, respectively, CML-related death or progression to AP/BC during study treatment. The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported.
Time Frame	approx. 11 years

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Median (95% Confidence Interval); Unit of Measure: Months
duration of first molecular response of <=0.01%	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)
duration of first molecular response of <=0.0032%	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)

[1]

NA = not enough events to calculate median and CI of this molecular response (BCR-ABL ratio of ≤ 0.01%)

[2]

NA = not enough events to calculate median and CI of this molecular response (BCR-ABL ratio of ≤ 0.0032%)

13. Secondary Outcome

Title	Rate of Hematologic Response
Description	Rate of hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count <10 x 109/L, Platelet count <450 x 109/L, Basophils <5%, No blasts and promyelocytes in peripheral blood, Myelocytes + metamyelocytes < 5% in peripheral blood, No evidence of extramedullary disease, including spleen and liver).
Time Frame	12 months, 24 months, Overall on Core study (approx. 11 years)

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
Complete hematologic response (CHR) by M12	93.3; (89.7 to 95.9)	90.1; (86.0 to 93.3)	89.0; (84.7 to 92.4)
CHR by M24	93.6; (90.1 to 96.2)	90.8; (86.8 to 93.9)	90.4; (86.3 to 93.6)
CHR Overall	94.0; (90.6 to 96.5)	92.2; (88.4 to 95.0)	90.7; (86.7 to 93.9)

14. Secondary Outcome

Title	Time to Complete Cytogenic Response (CCyR)
Description	Time to CCyR is defined as the time from the date of randomization to the date of first documented CCyR
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Median (95% Confidence Interval); Unit of Measure: Months
	8.5; (5.8 to 10.9)	5.7; (5.6 to 5.7)	5.7; (5.7 to 5.8)

15. Secondary Outcome

Title	Duration of CCyR
Description	Duration of CCyR is defined as the time from date of first documented CCyR to the earliest date of loss of CCyR.
Time Frame	up to 72 months

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA = not enough events to calculate median and CI of duration CCyR

16. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of death from any cause occurring in the core or extension study, or during the follow-up period after discontinuation of core or extension study
Time Frame	approx. 11 years

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA = not enough events to calculate median or CI of PFS

17. Secondary Outcome

Title	Event-free Survival (EFS)
Description	Event-free survival is defined as the time from the date of randomization to the date of first occurrence of any of the following: death due to any cause (if death is the primary reason for discontinuation), progression to AP or BC, loss of PCyR, loss of CCyR, loss of CHR
Time Frame	approx. 11 years

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA = not enough events to calculate median and CI of EFS

18. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time from the date of randomization to the date death. Up to 10 calendar years of follow up from the date when the last patient randomized received the first dose of study drug in all active treatment arms of adult patients with Ph+ CML CP.
Time Frame	approx. 11 years

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA = not enough events to calculate median and CI of OS

19. Secondary Outcome

Title	Actual Dose-intensity
Description	Actual dose intensity is defined as total dose over time on treatment
Time Frame	approx. 11 years

Outcome Measure Data

Analysis Population Description

Safety Set: Safety set contained 836 patients who received at least one dose of study medication.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	280	279	277
Median (Full Range); Unit of Measure: mg/day
	400.0; (206 to 800)	591.1; (186 to 699)	758.9; (232 to 800)

20. Secondary Outcome

Title	Time to Progression to AP/BC
Description	Time to progression to AP/BC is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of CML related death.
Time Frame	approx. 11 years

Outcome Measure Data

Analysis Population Description

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	283	282	281
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA = not enough events to calculate median and CI of TTP

21. Secondary Outcome

Title	Pharmacokinetics: Cmax
Description	Cmax is defined as the maximum serum concentration after dose
Time Frame	any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration

Outcome Measure Data

Analysis Population Description

Global Full Pharmacokinetics (PK) set: Full-PK set contained 16 patients who received nilotinib. Full PK profile was meant for nilotinib arms only and included all patients with available Full PK profile at one visit.

Arm/Group Title	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	8	8
Median (Inter-Quartile Range); Unit of Measure: ng/mL
	1555; (1340 to 2300)	1440; (1002 to 2125)

22. Secondary Outcome

Title	Pharmacokinetics: Cmin
Description	Cmin is defined as the minimum serum concentration after dose
Time Frame	any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration

Outcome Measure Data

Analysis Population Description

Global Full Pharmacokinetics (PK) set: Full-PK set contained 16 patients who received nilotinib. Full PK profile was meant for nilotinib arms only and included all patients with available Full PK profile at one visit.

Arm/Group Title	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	8	8
Median (Inter-Quartile Range); Unit of Measure: ng/mL
	1430; (1250 to 1740)	915; (752 to 2080)

23. Secondary Outcome

Title	Pharmacokinetics: Tmax
Description	Tmax is defined as the sampling time when maximum measured serum concentration occurs
Time Frame	any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration

Outcome Measure Data

Analysis Population Description

Global Full Pharmacokinetics (PK) set: Full-PK set contained 16 patients who received nilotinib. Full PK profile was meant for nilotinib arms only and included all patients with available Full PK profile at one visit.

Arm/Group Title	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	8	8
Median (Inter-Quartile Range); Unit of Measure: hour (h)
	1.47; (0.50 to 2.04)	1.50; (0.00 to 2.02)

24. Secondary Outcome

Title	Pharmacokinetics: AUC0-last
Description	AUC0-last is defined as area under concentration-time curve from time zero to the last measurable sample, calculated by log-linear trapezoidal method
Time Frame	any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration

Outcome Measure Data

Analysis Population Description

Global Full Pharmacokinetics (PK) set: Full-PK set contained 16 patients who received nilotinib. Full PK profile was meant for nilotinib arms only and included all patients with available Full PK profile at one visit.

Arm/Group Title	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	8	8
Median (Inter-Quartile Range); Unit of Measure: h.ng/mL
	14446; (12806 to 17411)	11689; (7925 to 18678)

25. Secondary Outcome

Title	Rate of Hematologic Response on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)
Description	Rate of hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count <10 x 109/L, Platelet count <450 x 109/L, Basophils <5%, No blasts and promyelocytes in peripheral blood, Myelocytes + metamyelocytes < 5% in peripheral blood, No evidence of extramedullary disease, including spleen and liver).
Time Frame	Overall for Extension study for approx. 10 years

Outcome Measure Data

Analysis Population Description

Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	48	26	3
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	83.3; (69.8 to 92.5)	84.6; (65.1 to 95.6)	66.7; (9.4 to 99.2)

26. Secondary Outcome

Title	Rate of Complete Cytogenetic Response (CCyR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)
Description	Rate of CCyR is defined as the percentage of participants in complete cytogenetic response (CCyR). CcyR is defined as 0% of Ph+ metaphases in the bone marrow.
Time Frame	Overall for Extension study for approx. 10 years

Outcome Measure Data

Analysis Population Description

Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	48	26	3
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	72.9; (58.2 to 84.7)	73.1; (52.2 to 88.4)	66.7; (9.4 to 99.2)

27. Secondary Outcome

Title	Rate of Major Molecular Response (MMR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)
Description	Rate of MMR is defined as the percentage pf participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR))
Time Frame	Overall for Extension study for approx. 10 years

Outcome Measure Data

Analysis Population Description

Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	48	26	3
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	64.6; (49.5 to 77.8)	73.1; (52.2 to 88.4)	66.7; (9.4 to 99.2)

28. Secondary Outcome

Title	Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)
Description	Molecular response of <=0.01% is defined as BCR-ABL ratio (%) on IS <= 0.01% (corresponds to >=4 log reduction of BCR-ABL transcripts from standardized baseline value)
Time Frame	Overall for Extension study for approx. 10 years

Outcome Measure Data

Analysis Population Description

Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	48	26	3
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	43.8; (29.5 to 58.8)	57.7; (36.9 to 76.6)	33.3; (0.8 to 90.6)

29. Secondary Outcome

Title	Rate of ≥ 4.5 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)
Description	Molecular response of <=0.0032% is defined as BCR-ABL ratio (%) on IS <= 0.0032% (corresponds to >=4.5 log reduction of BCR-ABL transcripts from standardized baseline value)
Time Frame	Overall for Extension study for approx. 10 years

Outcome Measure Data

Analysis Population Description

Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	48	26	3
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	35.4; (22.2 to 50.5)	38.5; (20.2 to 59.4)	33.3; (0.8 to 90.6)

30. Secondary Outcome

Title	Presence of Newly Observed BCR-ABL Mutations in Patients Post-baseline and Correlate With Response to Treatment With Imatinib and Nilotinib (Extension)
Description	This is the percentage of patients with any emergent mutation on extension treatment. The mutation comprised of T315T, less sensitive to nilotinib, unknown and sensitive to nilotinib.
Time Frame	Overall for Extension study for approx. 10 years

Outcome Measure Data

Analysis Population Description

Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	48	26	3
Measure Type: Number; Unit of Measure: Percentage of participants
	20.8	11.5	33.3

31. Post-Hoc Outcome

Title	All Collected Deaths
Description	On treatment deaths were collected from first patient first visit up to 28 days after study treatment discontinuation (approx. 11 years). Patients with cancer were also followed up for overall survival until the end of the trial (to collect any deaths occurring more than 28 days after study drug discontinuation). In this study, one death was collected after randomization but before the participant received study drug.
Time Frame	From FPFV up to 28 days post treatment (approx. 11 years), From FPFV to LPLV (approx. 12 years)

Outcome Measure Data

Analysis Population Description

Safety analysis set consisted of all patients who received at least one dose of study medication.

Arm/Group Title	Imatinib 400 mg QD	Nilotinb 300 mg BID	Nilotinib 400 mg BID
Arm/Group Description:	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Number of Participants Analyzed	280	279	277
Measure Type: Number; Unit of Measure: deaths
On-treatment deaths	4	10	5
Total deaths	29	32	23

Adverse Events

Time Frame	Adverse Event (AE) time frame: Adverse events were collected from first dose of study treatment until end of study treatment plus 28 days post treatment, up to maximum duration of approx. 11 years.
Adverse Event Reporting Description	Adverse Event (AE): Any sign or symptom that occurs during the study treatment plus 28 days post treatment.
Arm/Group Title	Imatinib 400 mg QD	Nilotinib 300 mg BID	Nilotinib 400 mg BID	All Patients
Arm/Group Description	Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	All patients randomized in the study to all 3 arms and received at least one dose of study drug.
All-Cause Mortality
	Imatinib 400 mg QD	Nilotinib 300 mg BID	Nilotinib 400 mg BID	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	4/280 (1.43%)	10/279 (3.58%)	5/277 (1.81%)	19/836 (2.27%)
Serious Adverse Events
	Imatinib 400 mg QD	Nilotinib 300 mg BID	Nilotinib 400 mg BID	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	96/280 (34.29%)	112/279 (40.14%)	126/277 (45.49%)	334/836 (39.95%)
Blood and lymphatic system disorders
Anaemia † 1	4/280 (1.43%)	2/279 (0.72%)	5/277 (1.81%)	11/836 (1.32%)
Anaemia macrocytic † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Febrile neutropenia † 1	0/280 (0.00%)	1/279 (0.36%)	2/277 (0.72%)	3/836 (0.36%)
Hypoplastic anaemia † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Iron deficiency anaemia † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Leukocytosis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Leukopenia † 1	2/280 (0.71%)	1/279 (0.36%)	0/277 (0.00%)	3/836 (0.36%)
Neutropenia † 1	2/280 (0.71%)	3/279 (1.08%)	4/277 (1.44%)	9/836 (1.08%)
Pancytopenia † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Thrombocytopenia † 1	4/280 (1.43%)	5/279 (1.79%)	4/277 (1.44%)	13/836 (1.56%)
Cardiac disorders
Acute coronary syndrome † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Acute myocardial infarction † 1	0/280 (0.00%)	2/279 (0.72%)	5/277 (1.81%)	7/836 (0.84%)
Angina pectoris † 1	1/280 (0.36%)	3/279 (1.08%)	11/277 (3.97%)	15/836 (1.79%)
Angina unstable † 1	2/280 (0.71%)	2/279 (0.72%)	3/277 (1.08%)	7/836 (0.84%)
Arrhythmia † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Atrial fibrillation † 1	0/280 (0.00%)	2/279 (0.72%)	4/277 (1.44%)	6/836 (0.72%)
Atrial thrombosis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Brugada syndrome † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Cardiac arrest † 1	1/280 (0.36%)	2/279 (0.72%)	0/277 (0.00%)	3/836 (0.36%)
Cardiac failure † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Cardiac failure congestive † 1	2/280 (0.71%)	1/279 (0.36%)	1/277 (0.36%)	4/836 (0.48%)
Cardio-respiratory arrest † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Cardiogenic shock † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Cardiomyopathy † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Coronary artery disease † 1	1/280 (0.36%)	4/279 (1.43%)	10/277 (3.61%)	15/836 (1.79%)
Coronary artery stenosis † 1	0/280 (0.00%)	1/279 (0.36%)	3/277 (1.08%)	4/836 (0.48%)
Ischaemic cardiomyopathy † 1	0/280 (0.00%)	2/279 (0.72%)	1/277 (0.36%)	3/836 (0.36%)
Myocardial infarction † 1	2/280 (0.71%)	4/279 (1.43%)	6/277 (2.17%)	12/836 (1.44%)
Myocardial ischaemia † 1	2/280 (0.71%)	1/279 (0.36%)	2/277 (0.72%)	5/836 (0.60%)
Palpitations † 1	1/280 (0.36%)	1/279 (0.36%)	0/277 (0.00%)	2/836 (0.24%)
Pericardial effusion † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Pericarditis † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Pericarditis constrictive † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Right ventricular failure † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Supraventricular tachycardia † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Tachycardia † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Ventricular arrhythmia † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Ventricular extrasystoles † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Ventricular tachycardia † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Congenital, familial and genetic disorders
Cytogenetic abnormality † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Trisomy 8 † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Ear and labyrinth disorders
Otosclerosis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Vertigo † 1	0/280 (0.00%)	2/279 (0.72%)	2/277 (0.72%)	4/836 (0.48%)
Endocrine disorders
Goitre † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Hyperthyroidism † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Hypothyroidism † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Eye disorders
Amaurosis fugax † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Blindness unilateral † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Cataract † 1	0/280 (0.00%)	2/279 (0.72%)	0/277 (0.00%)	2/836 (0.24%)
Macular fibrosis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Photophobia † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Retinopathy † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Visual impairment † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Gastrointestinal disorders
Abdominal pain † 1	2/280 (0.71%)	5/279 (1.79%)	6/277 (2.17%)	13/836 (1.56%)
Abdominal pain lower † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Abdominal pain upper † 1	3/280 (1.07%)	2/279 (0.72%)	4/277 (1.44%)	9/836 (1.08%)
Anal inflammation † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Ascites † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Chronic gastritis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Colitis ischaemic † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Constipation † 1	0/280 (0.00%)	2/279 (0.72%)	1/277 (0.36%)	3/836 (0.36%)
Diarrhoea † 1	1/280 (0.36%)	1/279 (0.36%)	1/277 (0.36%)	3/836 (0.36%)
Duodenal ulcer † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Dyspepsia † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Enteritis † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Faecal vomiting † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Food poisoning † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Gastric mucosa erythema † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Gastritis † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Gastrointestinal disorder † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Gastrointestinal haemorrhage † 1	1/280 (0.36%)	1/279 (0.36%)	2/277 (0.72%)	4/836 (0.48%)
Gastrooesophageal reflux disease † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Haemorrhoidal haemorrhage † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Haemorrhoids † 1	1/280 (0.36%)	1/279 (0.36%)	1/277 (0.36%)	3/836 (0.36%)
Ileus † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Ileus paralytic † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Incarcerated inguinal hernia † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Inguinal hernia † 1	0/280 (0.00%)	0/279 (0.00%)	2/277 (0.72%)	2/836 (0.24%)
Intestinal haemorrhage † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Intestinal obstruction † 1	0/280 (0.00%)	1/279 (0.36%)	3/277 (1.08%)	4/836 (0.48%)
Intestinal perforation † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Intestinal stenosis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Mechanical ileus † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Nausea † 1	1/280 (0.36%)	2/279 (0.72%)	2/277 (0.72%)	5/836 (0.60%)
Oesophageal ulcer † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Oesophagitis † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Pancreatic fistula † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Pancreatitis † 1	0/280 (0.00%)	2/279 (0.72%)	3/277 (1.08%)	5/836 (0.60%)
Pancreatitis acute † 1	1/280 (0.36%)	0/279 (0.00%)	3/277 (1.08%)	4/836 (0.48%)
Peptic ulcer † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Periodontal disease † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Peritoneal haematoma † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Peritoneal haemorrhage † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Rectal haemorrhage † 1	0/280 (0.00%)	3/279 (1.08%)	1/277 (0.36%)	4/836 (0.48%)
Retroperitoneal haematoma † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Small intestinal haemorrhage † 1	2/280 (0.71%)	0/279 (0.00%)	0/277 (0.00%)	2/836 (0.24%)
Small intestinal obstruction † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Subileus † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Toothache † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Upper gastrointestinal haemorrhage † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Vomiting † 1	2/280 (0.71%)	3/279 (1.08%)	4/277 (1.44%)	9/836 (1.08%)
General disorders
Asthenia † 1	0/280 (0.00%)	2/279 (0.72%)	0/277 (0.00%)	2/836 (0.24%)
Chest discomfort † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Chest pain † 1	1/280 (0.36%)	1/279 (0.36%)	0/277 (0.00%)	2/836 (0.24%)
Death † 1	0/280 (0.00%)	1/279 (0.36%)	2/277 (0.72%)	3/836 (0.36%)
Drug interaction † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Fatigue † 1	1/280 (0.36%)	1/279 (0.36%)	1/277 (0.36%)	3/836 (0.36%)
Generalised oedema † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Hernia † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Inflammation † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Multiple organ dysfunction syndrome † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Non-cardiac chest pain † 1	0/280 (0.00%)	0/279 (0.00%)	3/277 (1.08%)	3/836 (0.36%)
Oedema peripheral † 1	1/280 (0.36%)	1/279 (0.36%)	0/277 (0.00%)	2/836 (0.24%)
Performance status decreased † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Peripheral swelling † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Pyrexia † 1	2/280 (0.71%)	6/279 (2.15%)	5/277 (1.81%)	13/836 (1.56%)
Systemic inflammatory response syndrome † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Vascular stent stenosis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Hepatobiliary disorders
Bile duct stone † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Biliary colic † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Cholecystitis † 1	0/280 (0.00%)	2/279 (0.72%)	1/277 (0.36%)	3/836 (0.36%)
Cholecystitis acute † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Cholelithiasis † 1	0/280 (0.00%)	2/279 (0.72%)	1/277 (0.36%)	3/836 (0.36%)
Drug-induced liver injury † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Hepatic function abnormal † 1	0/280 (0.00%)	0/279 (0.00%)	3/277 (1.08%)	3/836 (0.36%)
Hepatic necrosis † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Hepatic steatosis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Hepatitis † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Hepatotoxicity † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Hyperbilirubinaemia † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Infections and infestations
Anal infection † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Appendicitis † 1	1/280 (0.36%)	2/279 (0.72%)	0/277 (0.00%)	3/836 (0.36%)
Bronchitis † 1	3/280 (1.07%)	0/279 (0.00%)	0/277 (0.00%)	3/836 (0.36%)
Campylobacter gastroenteritis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Cellulitis † 1	4/280 (1.43%)	1/279 (0.36%)	2/277 (0.72%)	7/836 (0.84%)
Diverticulitis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Epididymitis † 1	1/280 (0.36%)	1/279 (0.36%)	0/277 (0.00%)	2/836 (0.24%)
Escherichia urinary tract infection † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Gastroenteritis † 1	3/280 (1.07%)	0/279 (0.00%)	2/277 (0.72%)	5/836 (0.60%)
Gastroenteritis salmonella † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Gastrointestinal infection † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Gastrointestinal viral infection † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
H1N1 influenza † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Haematoma infection † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Herpes zoster † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Infected skin ulcer † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Localised infection † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Lower respiratory tract infection † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Measles † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Oral infection † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Osteomyelitis chronic † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Otitis media chronic † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Perihepatic abscess † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Periodontitis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Peritonitis † 1	2/280 (0.71%)	0/279 (0.00%)	1/277 (0.36%)	3/836 (0.36%)
Peritonitis bacterial † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Pilonidal cyst † 1	0/280 (0.00%)	0/279 (0.00%)	2/277 (0.72%)	2/836 (0.24%)
Pneumonia † 1	9/280 (3.21%)	6/279 (2.15%)	6/277 (2.17%)	21/836 (2.51%)
Pneumonia legionella † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Postoperative wound infection † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Pseudomonal sepsis † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Pulpitis dental † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Pyelonephritis acute † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Rectal abscess † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Rhinitis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Salpingitis † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Sepsis † 1	1/280 (0.36%)	0/279 (0.00%)	2/277 (0.72%)	3/836 (0.36%)
Septic shock † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Sinusitis † 1	1/280 (0.36%)	1/279 (0.36%)	1/277 (0.36%)	3/836 (0.36%)
Streptococcal sepsis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Tracheobronchitis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Upper respiratory tract infection † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Urinary tract infection † 1	2/280 (0.71%)	1/279 (0.36%)	3/277 (1.08%)	6/836 (0.72%)
Viral infection † 1	0/280 (0.00%)	2/279 (0.72%)	0/277 (0.00%)	2/836 (0.24%)
Viral rash † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Wound infection † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Injury, poisoning and procedural complications
Abdominal injury † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Alcohol poisoning † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Brain contusion † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Cardiac valve replacement complication † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Chest injury † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Concussion † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Contusion † 1	2/280 (0.71%)	0/279 (0.00%)	0/277 (0.00%)	2/836 (0.24%)
Facial bones fracture † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Fall † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Femoral neck fracture † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Femur fracture † 1	0/280 (0.00%)	1/279 (0.36%)	2/277 (0.72%)	3/836 (0.36%)
Foot fracture † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Gun shot wound † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Hand fracture † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Head injury † 1	2/280 (0.71%)	1/279 (0.36%)	0/277 (0.00%)	3/836 (0.36%)
Heat illness † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Incorrect dose administered † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Intentional overdose † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Jaw fracture † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Joint injury † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Kidney contusion † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Ligament injury † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Ligament sprain † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Limb injury † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Lower limb fracture † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Multiple fractures † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Muscle rupture † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Pneumothorax traumatic † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Procedural pain † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Pubis fracture † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Rib fracture † 1	2/280 (0.71%)	0/279 (0.00%)	0/277 (0.00%)	2/836 (0.24%)
Road traffic accident † 1	3/280 (1.07%)	0/279 (0.00%)	2/277 (0.72%)	5/836 (0.60%)
Skeletal injury † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Skin laceration † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Spinal compression fracture † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Spinal cord injury cervical † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Spinal fracture † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Sternal fracture † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Subdural haematoma † 1	1/280 (0.36%)	1/279 (0.36%)	0/277 (0.00%)	2/836 (0.24%)
Subdural haemorrhage † 1	1/280 (0.36%)	1/279 (0.36%)	0/277 (0.00%)	2/836 (0.24%)
Tendon rupture † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Thoracic vertebral fracture † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Toxicity to various agents † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Traumatic haemothorax † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Upper limb fracture † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Vascular graft occlusion † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Wrist fracture † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Investigations
Alanine aminotransferase increased † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Amylase increased † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Aspartate aminotransferase increased † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Blast cell count increased † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Blood alkaline phosphatase increased † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Blood creatine phosphokinase MB increased † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Blood creatinine increased † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Cardioactive drug level increased † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Electrocardiogram QT prolonged † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Gamma-glutamyltransferase increased † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Lipase increased † 1	0/280 (0.00%)	0/279 (0.00%)	3/277 (1.08%)	3/836 (0.36%)
Troponin I increased † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Troponin T increased † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Urine output decreased † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
White blood cell count increased † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Metabolism and nutrition disorders
Dehydration † 1	2/280 (0.71%)	0/279 (0.00%)	0/277 (0.00%)	2/836 (0.24%)
Diabetes mellitus † 1	1/280 (0.36%)	1/279 (0.36%)	0/277 (0.00%)	2/836 (0.24%)
Diabetes mellitus inadequate control † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Electrolyte imbalance † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Fluid overload † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Gout † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Hyperkalaemia † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Hypoglycaemia † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Hyponatraemia † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Hypophosphataemia † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/280 (0.36%)	0/279 (0.00%)	2/277 (0.72%)	3/836 (0.36%)
Back pain † 1	2/280 (0.71%)	2/279 (0.72%)	6/277 (2.17%)	10/836 (1.20%)
Foot deformity † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Gouty arthritis † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Haematoma muscle † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Intervertebral disc disorder † 1	1/280 (0.36%)	1/279 (0.36%)	1/277 (0.36%)	3/836 (0.36%)
Intervertebral disc protrusion † 1	5/280 (1.79%)	6/279 (2.15%)	0/277 (0.00%)	11/836 (1.32%)
Lumbar spinal stenosis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Muscle spasms † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Muscular weakness † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Musculoskeletal chest pain † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Musculoskeletal pain † 1	1/280 (0.36%)	1/279 (0.36%)	1/277 (0.36%)	3/836 (0.36%)
Myalgia † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Myofascial pain syndrome † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Osteoarthritis † 1	1/280 (0.36%)	1/279 (0.36%)	1/277 (0.36%)	3/836 (0.36%)
Pain in extremity † 1	1/280 (0.36%)	2/279 (0.72%)	1/277 (0.36%)	4/836 (0.48%)
Rheumatoid arthritis † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Rotator cuff syndrome † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Spinal ligament ossification † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Spinal pain † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Spondyloarthropathy † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Spondylolisthesis † 1	0/280 (0.00%)	2/279 (0.72%)	1/277 (0.36%)	3/836 (0.36%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Adenocarcinoma gastric † 1	1/280 (0.36%)	1/279 (0.36%)	0/277 (0.00%)	2/836 (0.24%)
Adenocarcinoma of colon † 1	1/280 (0.36%)	1/279 (0.36%)	0/277 (0.00%)	2/836 (0.24%)
B-cell lymphoma † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Basal cell carcinoma † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Benign uterine neoplasm † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Blast cell crisis † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Blast crisis in myelogenous leukaemia † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Breast cancer † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Chloroma † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Colon adenoma † 1	2/280 (0.71%)	1/279 (0.36%)	0/277 (0.00%)	3/836 (0.36%)
Gastric cancer † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Gastrointestinal stromal tumour † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Glioblastoma † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Hepatocellular carcinoma † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Histiocytosis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Leiomyoma † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Leukaemic retinopathy † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Lipoma † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Liposarcoma † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Malignant melanoma in situ † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Meningioma † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Metastases to abdominal wall † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Metastases to liver † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Metastases to lung † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Metastases to lymph nodes † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Metastatic malignant melanoma † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Metastatic neoplasm † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Ovarian cancer † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Ovarian epithelial cancer † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Pancreatic carcinoma † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Pancreatic neuroendocrine tumour † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Papillary thyroid cancer † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Papilloma † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Paraproteinaemia † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Pituitary tumour benign † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Plasma cell myeloma † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Plasmacytoma † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Prostate cancer † 1	3/280 (1.07%)	2/279 (0.72%)	1/277 (0.36%)	6/836 (0.72%)
Prostatic adenoma † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Rectal cancer † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Rosai-Dorfman syndrome † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Skin cancer † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Squamous cell carcinoma † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Squamous cell carcinoma of skin † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Superficial spreading melanoma stage III † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Thyroid cancer † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Transitional cell carcinoma † 1	0/280 (0.00%)	2/279 (0.72%)	0/277 (0.00%)	2/836 (0.24%)
Uterine leiomyoma † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Nervous system disorders
Basilar artery stenosis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Brain oedema † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Carotid arteriosclerosis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Carotid artery stenosis † 1	0/280 (0.00%)	1/279 (0.36%)	4/277 (1.44%)	5/836 (0.60%)
Central nervous system lesion † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Cerebellar stroke † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Cerebral artery stenosis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Cerebral haemorrhage † 1	0/280 (0.00%)	0/279 (0.00%)	2/277 (0.72%)	2/836 (0.24%)
Cerebral infarction † 1	1/280 (0.36%)	2/279 (0.72%)	0/277 (0.00%)	3/836 (0.36%)
Cerebral ischaemia † 1	0/280 (0.00%)	2/279 (0.72%)	0/277 (0.00%)	2/836 (0.24%)
Cerebrospinal fluid leakage † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Cerebrovascular accident † 1	0/280 (0.00%)	4/279 (1.43%)	3/277 (1.08%)	7/836 (0.84%)
Cerebrovascular disorder † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Cervical radiculopathy † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Demyelination † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Depressed level of consciousness † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Dizziness † 1	1/280 (0.36%)	1/279 (0.36%)	0/277 (0.00%)	2/836 (0.24%)
Epilepsy † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Essential tremor † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Facial paralysis † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Focal dyscognitive seizures † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Head discomfort † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Headache † 1	1/280 (0.36%)	3/279 (1.08%)	1/277 (0.36%)	5/836 (0.60%)
Hemiparesis † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Hypoaesthesia † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Ischaemic stroke † 1	0/280 (0.00%)	2/279 (0.72%)	3/277 (1.08%)	5/836 (0.60%)
Loss of consciousness † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Migraine † 1	0/280 (0.00%)	0/279 (0.00%)	2/277 (0.72%)	2/836 (0.24%)
Miller Fisher syndrome † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Multiple sclerosis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Neuralgia † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Neuropathy peripheral † 1	0/280 (0.00%)	0/279 (0.00%)	2/277 (0.72%)	2/836 (0.24%)
Parkinson's disease † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Parkinsonism † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Polyneuropathy † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Sciatica † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Seizure † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Speech disorder † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Syncope † 1	2/280 (0.71%)	0/279 (0.00%)	1/277 (0.36%)	3/836 (0.36%)
Transient ischaemic attack † 1	0/280 (0.00%)	2/279 (0.72%)	5/277 (1.81%)	7/836 (0.84%)
Vertebral artery stenosis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Pregnancy, puerperium and perinatal conditions
Retained products of conception † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Product Issues
Thrombosis in device † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Psychiatric disorders
Alcohol abuse † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Alcohol withdrawal syndrome † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Anxiety † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Bipolar disorder † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Completed suicide † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Confusional state † 1	0/280 (0.00%)	2/279 (0.72%)	0/277 (0.00%)	2/836 (0.24%)
Depression † 1	2/280 (0.71%)	3/279 (1.08%)	2/277 (0.72%)	7/836 (0.84%)
Mental disorder † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Mental status changes † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Somatic symptom disorder † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Suicidal ideation † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Suicide attempt † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Renal and urinary disorders
Acute kidney injury † 1	3/280 (1.07%)	0/279 (0.00%)	1/277 (0.36%)	4/836 (0.48%)
Anuria † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Azotaemia † 1	0/280 (0.00%)	0/279 (0.00%)	2/277 (0.72%)	2/836 (0.24%)
Bladder obstruction † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Chronic kidney disease † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Nephrolithiasis † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Pelvi-ureteric obstruction † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Renal artery stenosis † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Renal colic † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Renal failure † 1	3/280 (1.07%)	1/279 (0.36%)	2/277 (0.72%)	6/836 (0.72%)
Renal impairment † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Renal infarct † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Ureterolithiasis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Urinary retention † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Reproductive system and breast disorders
Adenomyosis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Adnexa uteri pain † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Benign prostatic hyperplasia † 1	0/280 (0.00%)	0/279 (0.00%)	2/277 (0.72%)	2/836 (0.24%)
Breast swelling † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Endometrial hyperplasia † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Gynaecomastia † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Menorrhagia † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Menstruation irregular † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Metrorrhagia † 1	0/280 (0.00%)	3/279 (1.08%)	0/277 (0.00%)	3/836 (0.36%)
Ovarian cyst † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Ovarian cyst ruptured † 1	2/280 (0.71%)	0/279 (0.00%)	0/277 (0.00%)	2/836 (0.24%)
Scrotal swelling † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Uterine polyp † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Vaginal haemorrhage † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Aspiration † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Atelectasis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Bronchial obstruction † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Dyspnoea † 1	2/280 (0.71%)	5/279 (1.79%)	2/277 (0.72%)	9/836 (1.08%)
Epistaxis † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Haemothorax † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Interstitial lung disease † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Mediastinal cyst † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Nasal septum deviation † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Obstructive airways disorder † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Painful respiration † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Pharyngeal oedema † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Pleural effusion † 1	3/280 (1.07%)	0/279 (0.00%)	1/277 (0.36%)	4/836 (0.48%)
Pneumothorax † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Pneumothorax spontaneous † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Pulmonary haemorrhage † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Pulmonary oedema † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Respiratory failure † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Skin and subcutaneous tissue disorders
Angioedema † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Diabetic foot † 1	1/280 (0.36%)	0/279 (0.00%)	0/277 (0.00%)	1/836 (0.12%)
Psoriasis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Rash † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Urticaria † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Vascular disorders
Angiopathy † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Aortic aneurysm † 1	1/280 (0.36%)	1/279 (0.36%)	0/277 (0.00%)	2/836 (0.24%)
Aortic stenosis † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Arterial occlusive disease † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Arterial stenosis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Arteriosclerosis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Extremity necrosis † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Hypertension † 1	0/280 (0.00%)	1/279 (0.36%)	2/277 (0.72%)	3/836 (0.36%)
Hypertensive crisis † 1	1/280 (0.36%)	0/279 (0.00%)	1/277 (0.36%)	2/836 (0.24%)
Hypotension † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Hypovolaemic shock † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Intermittent claudication † 1	1/280 (0.36%)	2/279 (0.72%)	0/277 (0.00%)	3/836 (0.36%)
Peripheral arterial occlusive disease † 1	0/280 (0.00%)	3/279 (1.08%)	5/277 (1.81%)	8/836 (0.96%)
Peripheral artery occlusion † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Peripheral artery stenosis † 1	0/280 (0.00%)	1/279 (0.36%)	4/277 (1.44%)	5/836 (0.60%)
Peripheral ischaemia † 1	0/280 (0.00%)	1/279 (0.36%)	1/277 (0.36%)	2/836 (0.24%)
Peripheral vascular disorder † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Thrombophlebitis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
Varicose vein † 1	0/280 (0.00%)	1/279 (0.36%)	0/277 (0.00%)	1/836 (0.12%)
Vena cava thrombosis † 1	0/280 (0.00%)	0/279 (0.00%)	1/277 (0.36%)	1/836 (0.12%)
1 Term from vocabulary, MedDRA (22.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Imatinib 400 mg QD	Nilotinib 300 mg BID	Nilotinib 400 mg BID	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	275/280 (98.21%)	276/279 (98.92%)	272/277 (98.19%)	823/836 (98.44%)
Blood and lymphatic system disorders
Anaemia † 1	71/280 (25.36%)	38/279 (13.62%)	45/277 (16.25%)	154/836 (18.42%)
Leukopenia † 1	47/280 (16.79%)	23/279 (8.24%)	22/277 (7.94%)	92/836 (11.00%)
Neutropenia † 1	59/280 (21.07%)	45/279 (16.13%)	30/277 (10.83%)	134/836 (16.03%)
Thrombocytopenia † 1	56/280 (20.00%)	54/279 (19.35%)	58/277 (20.94%)	168/836 (20.10%)
Cardiac disorders
Angina pectoris † 1	3/280 (1.07%)	14/279 (5.02%)	10/277 (3.61%)	27/836 (3.23%)
Palpitations † 1	12/280 (4.29%)	19/279 (6.81%)	19/277 (6.86%)	50/836 (5.98%)
Ear and labyrinth disorders
Vertigo † 1	12/280 (4.29%)	13/279 (4.66%)	14/277 (5.05%)	39/836 (4.67%)
Eye disorders
Conjunctival haemorrhage † 1	26/280 (9.29%)	3/279 (1.08%)	5/277 (1.81%)	34/836 (4.07%)
Dry eye † 1	20/280 (7.14%)	20/279 (7.17%)	21/277 (7.58%)	61/836 (7.30%)
Eyelid oedema † 1	44/280 (15.71%)	3/279 (1.08%)	5/277 (1.81%)	52/836 (6.22%)
Periorbital oedema † 1	45/280 (16.07%)	1/279 (0.36%)	4/277 (1.44%)	50/836 (5.98%)
Gastrointestinal disorders
Abdominal distension † 1	13/280 (4.64%)	12/279 (4.30%)	15/277 (5.42%)	40/836 (4.78%)
Abdominal pain † 1	38/280 (13.57%)	46/279 (16.49%)	48/277 (17.33%)	132/836 (15.79%)
Abdominal pain upper † 1	44/280 (15.71%)	53/279 (19.00%)	61/277 (22.02%)	158/836 (18.90%)
Constipation † 1	30/280 (10.71%)	63/279 (22.58%)	52/277 (18.77%)	145/836 (17.34%)
Diarrhoea † 1	137/280 (48.93%)	60/279 (21.51%)	67/277 (24.19%)	264/836 (31.58%)
Dyspepsia † 1	41/280 (14.64%)	34/279 (12.19%)	36/277 (13.00%)	111/836 (13.28%)
Flatulence † 1	13/280 (4.64%)	12/279 (4.30%)	15/277 (5.42%)	40/836 (4.78%)
Gastritis † 1	13/280 (4.64%)	9/279 (3.23%)	18/277 (6.50%)	40/836 (4.78%)
Gastrooesophageal reflux disease † 1	23/280 (8.21%)	15/279 (5.38%)	17/277 (6.14%)	55/836 (6.58%)
Haemorrhoids † 1	19/280 (6.79%)	9/279 (3.23%)	19/277 (6.86%)	47/836 (5.62%)
Nausea † 1	120/280 (42.86%)	64/279 (22.94%)	89/277 (32.13%)	273/836 (32.66%)
Toothache † 1	20/280 (7.14%)	14/279 (5.02%)	11/277 (3.97%)	45/836 (5.38%)
Vomiting † 1	80/280 (28.57%)	46/279 (16.49%)	61/277 (22.02%)	187/836 (22.37%)
General disorders
Asthenia † 1	42/280 (15.00%)	38/279 (13.62%)	29/277 (10.47%)	109/836 (13.04%)
Chills † 1	9/280 (3.21%)	11/279 (3.94%)	14/277 (5.05%)	34/836 (4.07%)
Face oedema † 1	40/280 (14.29%)	2/279 (0.72%)	7/277 (2.53%)	49/836 (5.86%)
Fatigue † 1	62/280 (22.14%)	69/279 (24.73%)	56/277 (20.22%)	187/836 (22.37%)
Influenza like illness † 1	15/280 (5.36%)	15/279 (5.38%)	14/277 (5.05%)	44/836 (5.26%)
Non-cardiac chest pain † 1	19/280 (6.79%)	17/279 (6.09%)	24/277 (8.66%)	60/836 (7.18%)
Oedema peripheral † 1	64/280 (22.86%)	34/279 (12.19%)	43/277 (15.52%)	141/836 (16.87%)
Pyrexia † 1	43/280 (15.36%)	45/279 (16.13%)	50/277 (18.05%)	138/836 (16.51%)
Hepatobiliary disorders
Hyperbilirubinaemia † 1	14/280 (5.00%)	54/279 (19.35%)	53/277 (19.13%)	121/836 (14.47%)
Infections and infestations
Bronchitis † 1	31/280 (11.07%)	28/279 (10.04%)	19/277 (6.86%)	78/836 (9.33%)
Conjunctivitis † 1	24/280 (8.57%)	21/279 (7.53%)	18/277 (6.50%)	63/836 (7.54%)
Folliculitis † 1	3/280 (1.07%)	15/279 (5.38%)	17/277 (6.14%)	35/836 (4.19%)
Gastroenteritis † 1	30/280 (10.71%)	24/279 (8.60%)	21/277 (7.58%)	75/836 (8.97%)
Herpes zoster † 1	13/280 (4.64%)	15/279 (5.38%)	8/277 (2.89%)	36/836 (4.31%)
Influenza † 1	41/280 (14.64%)	49/279 (17.56%)	51/277 (18.41%)	141/836 (16.87%)
Nasopharyngitis † 1	69/280 (24.64%)	82/279 (29.39%)	67/277 (24.19%)	218/836 (26.08%)
Pharyngitis † 1	19/280 (6.79%)	16/279 (5.73%)	17/277 (6.14%)	52/836 (6.22%)
Sinusitis † 1	23/280 (8.21%)	24/279 (8.60%)	29/277 (10.47%)	76/836 (9.09%)
Upper respiratory tract infection † 1	46/280 (16.43%)	57/279 (20.43%)	67/277 (24.19%)	170/836 (20.33%)
Urinary tract infection † 1	16/280 (5.71%)	17/279 (6.09%)	27/277 (9.75%)	60/836 (7.18%)
Injury, poisoning and procedural complications
Procedural pain † 1	5/280 (1.79%)	12/279 (4.30%)	14/277 (5.05%)	31/836 (3.71%)
Investigations
Alanine aminotransferase increased † 1	39/280 (13.93%)	83/279 (29.75%)	87/277 (31.41%)	209/836 (25.00%)
Amylase increased † 1	10/280 (3.57%)	22/279 (7.89%)	23/277 (8.30%)	55/836 (6.58%)
Aspartate aminotransferase increased † 1	30/280 (10.71%)	51/279 (18.28%)	44/277 (15.88%)	125/836 (14.95%)
Blood alkaline phosphatase increased † 1	12/280 (4.29%)	8/279 (2.87%)	16/277 (5.78%)	36/836 (4.31%)
Blood bilirubin increased † 1	8/280 (2.86%)	37/279 (13.26%)	41/277 (14.80%)	86/836 (10.29%)
Blood cholesterol increased † 1	3/280 (1.07%)	16/279 (5.73%)	15/277 (5.42%)	34/836 (4.07%)
Blood creatinine increased † 1	21/280 (7.50%)	5/279 (1.79%)	10/277 (3.61%)	36/836 (4.31%)
Blood phosphorus decreased † 1	7/280 (2.50%)	10/279 (3.58%)	14/277 (5.05%)	31/836 (3.71%)
Haemoglobin decreased † 1	14/280 (5.00%)	7/279 (2.51%)	15/277 (5.42%)	36/836 (4.31%)
Lipase increased † 1	17/280 (6.07%)	38/279 (13.62%)	38/277 (13.72%)	93/836 (11.12%)
Weight decreased † 1	9/280 (3.21%)	16/279 (5.73%)	13/277 (4.69%)	38/836 (4.55%)
Weight increased † 1	28/280 (10.00%)	24/279 (8.60%)	22/277 (7.94%)	74/836 (8.85%)
Metabolism and nutrition disorders
Decreased appetite † 1	17/280 (6.07%)	29/279 (10.39%)	22/277 (7.94%)	68/836 (8.13%)
Hypercholesterolaemia † 1	12/280 (4.29%)	34/279 (12.19%)	39/277 (14.08%)	85/836 (10.17%)
Hyperglycaemia † 1	12/280 (4.29%)	31/279 (11.11%)	28/277 (10.11%)	71/836 (8.49%)
Hyperlipidaemia † 1	2/280 (0.71%)	19/279 (6.81%)	15/277 (5.42%)	36/836 (4.31%)
Hyperuricaemia † 1	5/280 (1.79%)	12/279 (4.30%)	15/277 (5.42%)	32/836 (3.83%)
Hypokalaemia † 1	19/280 (6.79%)	19/279 (6.81%)	11/277 (3.97%)	49/836 (5.86%)
Hypophosphataemia † 1	52/280 (18.57%)	47/279 (16.85%)	55/277 (19.86%)	154/836 (18.42%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	67/280 (23.93%)	74/279 (26.52%)	65/277 (23.47%)	206/836 (24.64%)
Back pain † 1	61/280 (21.79%)	68/279 (24.37%)	65/277 (23.47%)	194/836 (23.21%)
Bone pain † 1	17/280 (6.07%)	21/279 (7.53%)	29/277 (10.47%)	67/836 (8.01%)
Muscle spasms † 1	99/280 (35.36%)	40/279 (14.34%)	39/277 (14.08%)	178/836 (21.29%)
Musculoskeletal pain † 1	25/280 (8.93%)	27/279 (9.68%)	38/277 (13.72%)	90/836 (10.77%)
Myalgia † 1	57/280 (20.36%)	57/279 (20.43%)	55/277 (19.86%)	169/836 (20.22%)
Neck pain † 1	11/280 (3.93%)	21/279 (7.53%)	11/277 (3.97%)	43/836 (5.14%)
Pain in extremity † 1	52/280 (18.57%)	49/279 (17.56%)	53/277 (19.13%)	154/836 (18.42%)
Nervous system disorders
Dizziness † 1	31/280 (11.07%)	37/279 (13.26%)	34/277 (12.27%)	102/836 (12.20%)
Headache † 1	76/280 (27.14%)	97/279 (34.77%)	105/277 (37.91%)	278/836 (33.25%)
Hypoaesthesia † 1	9/280 (3.21%)	16/279 (5.73%)	11/277 (3.97%)	36/836 (4.31%)
Paraesthesia † 1	15/280 (5.36%)	14/279 (5.02%)	11/277 (3.97%)	40/836 (4.78%)
Psychiatric disorders
Anxiety † 1	28/280 (10.00%)	24/279 (8.60%)	22/277 (7.94%)	74/836 (8.85%)
Depression † 1	21/280 (7.50%)	18/279 (6.45%)	18/277 (6.50%)	57/836 (6.82%)
Insomnia † 1	30/280 (10.71%)	41/279 (14.70%)	37/277 (13.36%)	108/836 (12.92%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	45/280 (16.07%)	59/279 (21.15%)	61/277 (22.02%)	165/836 (19.74%)
Dyspnoea † 1	25/280 (8.93%)	34/279 (12.19%)	31/277 (11.19%)	90/836 (10.77%)
Oropharyngeal pain † 1	25/280 (8.93%)	35/279 (12.54%)	29/277 (10.47%)	89/836 (10.65%)
Skin and subcutaneous tissue disorders
Alopecia † 1	26/280 (9.29%)	43/279 (15.41%)	58/277 (20.94%)	127/836 (15.19%)
Dry skin † 1	18/280 (6.43%)	37/279 (13.26%)	40/277 (14.44%)	95/836 (11.36%)
Eczema † 1	11/280 (3.93%)	17/279 (6.09%)	11/277 (3.97%)	39/836 (4.67%)
Erythema † 1	12/280 (4.29%)	15/279 (5.38%)	18/277 (6.50%)	45/836 (5.38%)
Hyperhidrosis † 1	4/280 (1.43%)	13/279 (4.66%)	16/277 (5.78%)	33/836 (3.95%)
Night sweats † 1	9/280 (3.21%)	10/279 (3.58%)	18/277 (6.50%)	37/836 (4.43%)
Pruritus † 1	27/280 (9.64%)	66/279 (23.66%)	56/277 (20.22%)	149/836 (17.82%)
Rash † 1	70/280 (25.00%)	112/279 (40.14%)	125/277 (45.13%)	307/836 (36.72%)
Vascular disorders
Hypertension † 1	26/280 (9.29%)	46/279 (16.49%)	56/277 (20.22%)	128/836 (15.31%)
1 Term from vocabulary, MedDRA (22.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Principal Investigators are NOT employed by the organization sponsoring the study. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial.

Results Point of Contact

• Name/Title: Study Director
• Organization: Novartis Pharmaceuticals
• Phone: 862-778-8300
• EMail: novartis.email@novartis.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hughes TP, Hochhaus A, Kantarjian HM, Cervantes F, Guilhot F, Niederwieser D, le Coutre PD, Rosti G, Ossenkoppele G, Lobo C, Shibayama H, Fan X, Menssen HD, Kemp C, Larson RA, Saglio G. Safety and efficacy of switching to nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on front-line imatinib or nilotinib 300 mg twice daily. Haematologica. 2014 Jul;99(7):1204-11. doi: 10.3324/haematol.2013.091272. Epub 2014 Feb 14.

Hughes TP, Saglio G, Kantarjian HM, Guilhot F, Niederwieser D, Rosti G, Nakaseko C, De Souza CA, Kalaycio ME, Meier S, Fan X, Menssen HD, Larson RA, Hochhaus A. Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood. 2014 Feb 27;123(9):1353-60. doi: 10.1182/blood-2013-06-510396. Epub 2013 Dec 11.

Hochhaus A, Saglio G, Larson RA, Kim DW, Etienne G, Rosti G, De Souza C, Kurokawa M, Kalaycio ME, Hoenekopp A, Fan X, Shou Y, Kantarjian HM, Hughes TP. Nilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood. 2013 May 2;121(18):3703-8. doi: 10.1182/blood-2012-04-423418. Epub 2013 Mar 15.

Branford S, Kim DW, Soverini S, Haque A, Shou Y, Woodman RC, Kantarjian HM, Martinelli G, Radich JP, Saglio G, Hochhaus A, Hughes TP, Muller MC. Initial molecular response at 3 months may predict both response and event-free survival at 24 months in imatinib-resistant or -intolerant patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase treated with nilotinib. J Clin Oncol. 2012 Dec 10;30(35):4323-9. doi: 10.1200/JCO.2011.40.5217. Epub 2012 Oct 29.

Larson RA, Yin OQ, Hochhaus A, Saglio G, Clark RE, Nakamae H, Gallagher NJ, Demirhan E, Hughes TP, Kantarjian HM, le Coutre PD. Population pharmacokinetic and exposure-response analysis of nilotinib in patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase. Eur J Clin Pharmacol. 2012 May;68(5):723-33. doi: 10.1007/s00228-011-1200-7. Epub 2011 Dec 30.

Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L, Goh YT, Rosti G, Nakamae H, Gallagher NJ, Hoenekopp A, Blakesley RE, Larson RA, Hughes TP. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011 Sep;12(9):841-51. doi: 10.1016/S1470-2045(11)70201-7. Epub 2011 Aug 17. Erratum In: Lancet Oncol. 2011 Oct;12(11):989.

Cortes JE, Hochhaus A, le Coutre PD, Rosti G, Pinilla-Ibarz J, Jabbour E, Gillis K, Woodman RC, Blakesley RE, Giles FJ, Kantarjian HM, Baccarani M. Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib. Blood. 2011 May 26;117(21):5600-6. doi: 10.1182/blood-2010-11-318949. Epub 2011 Apr 5.

Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9. doi: 10.1056/NEJMoa0912614. Epub 2010 Jun 5.

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• ClinicalTrials.gov Identifier: NCT00471497
• Obsolete Identifiers: NCT00718263
• Other Study ID Numbers: CAMN107A2303; 2007-000208-34 ( Registry Identifier: EUDRACT )
• First Submitted: May 7, 2007
• First Posted: May 10, 2007
• Results First Submitted: April 10, 2013
• Results First Posted: June 17, 2013
• Last Update Posted: November 18, 2020