Open-label Phase 3 BTK Inhibitor Ibrutinib vs Chlorambucil Patients 65 Years or Older With Treatment-naive CLL or SLL

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ClinicalTrials.gov Identifier: NCT01722487

Recruitment Status : Completed

First Posted : November 6, 2012

Results First Posted : May 4, 2016

Last Update Posted : November 30, 2017

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Sponsor:

Collaborator:

Janssen Research & Development, LLC

Information provided by (Responsible Party):

Pharmacyclics LLC.

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Conditions	Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Interventions	Drug: Ibrutinib Drug: Chlorambucil
Enrollment	269

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum ...
Arm/Group Description	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Period Title: Overall Study
Started	136	133
Completed	134 ^[1]	126 ^[1]
Not Completed	2	7
[1] Participants who were still on study or died at study closure

Baseline Characteristics

Arm/Group Title		Ibrutinib	Chlorambucil	Total
Arm/Group Description		Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum ...	Total of all reporting groups
Arm/Group Description		Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles	Total of all reporting groups
Overall Number of Baseline Participants		136	133	269
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	136 participants	133 participants	269 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	0 0.0%	0 0.0%	0 0.0%
	>=65 years	136 100.0%	133 100.0%	269 100.0%
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	136 participants	133 participants	269 participants
		73.1 (5.67)	73.4 (5.95)	73.3 (5.81)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	136 participants	133 participants	269 participants
	Female	48 35.3%	52 39.1%	100 37.2%
	Male	88 64.7%	81 60.9%	169 62.8%

Outcome Measures

1.Primary Outcome


Title	PFS (Progression Free Survival)
Description	The primary objective of this study was to evaluate the efficacy of Ib...
Description	The primary objective of this study was to evaluate the efficacy of Ibrutinib compared with Chlorambucil based on the independent review committee (IRC) assessment of PFS Progressive disease according to 2008 IWCLL guidelines was defined as: Group A Lymphadenopathy, increase ≥50% Hepatomegaly, increase ≥50% Splenomegaly, increase ≥50% Blood lymphocytes, increase ≥ 50% over baseline Group B Platelets counts, decrease of ≥ 50% from baseline secondary to CLL Hemoglobin, decrease of > 2 g/dL from baseline secondary to CLL
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Intention to treat


Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum ...
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles.
Overall Number of Participants Analyzed	136	133
Median (95% Confidence Interval) Unit of Measure: Months
	NA ^[1] (NA to NA)	18.9 (14.1 to 22.0)

[1]

IBR: Median PFS was not reached so 95% CI for median PFS is not applicable.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95% 0.09 to 0.28
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Overall Survival (OS)
Description	OS is calculated for all randomized subjects as the duration of time f...
Description	OS is calculated for all randomized subjects as the duration of time from the date of randomization to the date of death due to any cause or the date last known alive for subjects who were not known to have died at study closure.
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Intention to treat


Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum ...
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Overall Number of Participants Analyzed	136	133
Median (95% Confidence Interval) Unit of Measure: Months
	NA ^[1] (NA to NA)	NA ^[2] (NA to NA)

[1]

IBR: Median OS was not reached so 95% CI for median OS is not applicable.

[2]

CHL: Median OS was not reached so 95% CI for median OS is not applicable.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0010
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95% 0.05 to 0.56
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	ORR (Overall Response Rate)
Description	ORR is defined as the proportion of subjects who achieved complete res...
Description	ORR is defined as the proportion of subjects who achieved complete response (CR), complete response with incomplete marrow recovery (CRi), nodule partial response (nPR) or PR per IRC assessment. Response criteria are as outlined in the International Workshop on CLL (iwCLL) 2008 criteria with the 2012 iwCLL modification stating that treatment-related lymphocytosis in the setting of improvement in other parameters was not considered as PD and the 2013 iwCLL clarification of criteria for a partial response to therapy.
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Intention to treat


Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum ...
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Overall Number of Participants Analyzed	136	133
Measure Type: Number Unit of Measure: percentage of participants
	82.4	35.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

4.Secondary Outcome


Title	Proportion of Sustained Hemoglobin Improvement
Description	The proportion of subjects who achieved Hemoglobin >11 g/dL or incr...
Description	The proportion of subjects who achieved Hemoglobin >11 g/dL or increase ≥ 2 g/dL over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Intention to treat


Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum ...
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Overall Number of Participants Analyzed	136	133
Measure Type: Number Unit of Measure: Percentage of Participants
	45.6	20.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

5.Secondary Outcome


Title	Proportion of Sustained Hemoglobin Improvement in Subjects With Baseline Anemia
Description	In randomized subjects with baseline hemoglobin ≤ 11 g/dL, the p...
Description	In randomized subjects with baseline hemoglobin ≤ 11 g/dL, the proportion of subjects who achieved Hemoglobin >11 g/dL or increase ≥ 2 g/dL over baseline persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Subjects with Baseline Anemia


Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum ...
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Overall Number of Participants Analyzed	51	55
Measure Type: Number Unit of Measure: Percentage of Participants
	84.3	45.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

6.Secondary Outcome


Title	Proportion of Sustained Platelet Improvement
Description	The proportion of subjects who achieved platelet >100 x 10^9/L or i...
Description	The proportion of subjects who achieved platelet >100 x 10^9/L or increase ≥50% over baseline and persisted continuously for ≥56 days (8 weeks) without blood transfusion or growth factors.
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with the cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Intention to treat


Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum ...
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Overall Number of Participants Analyzed	136	133
Measure Type: Number Unit of Measure: Percentage of Participants
	27.2	11.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	.0009
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

7.Secondary Outcome


Title	Proportion of Sustained Platelet Improvement in Subjects With Baseline Thrombocytopenia
Description	In randomized subjects with baseline platelet ≤ 100 x 10^9/L, th...
Description	In randomized subjects with baseline platelet ≤ 100 x 10^9/L, the proportion of subjects who achieved platelet >100 x 10^9/L or increase ≥50% over baseline persisted continuously for ≥56 days (8 wee without blood transfusion or growth factors.
Time Frame	Analysis was conducted when 15 months had elapsed after the last subject was randomized with cutoff date of 4 May 2015. The median follow-up time is 18 month.

Outcome Measure Data

Analysis Population Description

Subjects With Baseline Thrombocytopenia


Arm/Group Title	Ibrutinib	Chlorambucil
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum ...
Arm/Group Description:	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
Overall Number of Participants Analyzed	35	28
Measure Type: Number Unit of Measure: Percentage of Participants
	77.1	42.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	.0054
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

Adverse Events

Time Frame	From first dose of study drug to within 30 days of last dose or starting new anti-cancer therapy, whichever occurs earlier, up to 04May2015 ( data cutoff date for final analysis).
Adverse Event Reporting Description	269 subjects were randomized on the study of which 2 subjects withdrew without treatment and were not included in the number of participants at risk. Investigators assess the occurrence of AEs and SAEs at all patient evaluation time points during the study.

Arm/Group Title	PCI-32765	Chlorambucil
Arm/Group Description	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum ...
Arm/Group Description	Ibrutinib 420 mg daily.	Chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles
All-Cause Mortality
	PCI-32765	Chlorambucil
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events Serious Adverse Events
	PCI-32765	Chlorambucil
	Affected / at Risk (%)	Affected / at Risk (%)
Total	55/135 (40.74%)	33/132 (25.00%)
Blood and lymphatic system disorders
Anaemia ^† 1	2/135 (1.48%)	2/132 (1.52%)
Febrile neutropenia ^† 1	2/135 (1.48%)	2/132 (1.52%)
Neutropenia ^† 1	1/135 (0.74%)	2/132 (1.52%)
Autoimmune haemolytic anaemia ^† 1	0/135 (0.00%)	1/132 (0.76%)
Haemolytic anaemia ^† 1	0/135 (0.00%)	1/132 (0.76%)
Lymphadenopathy ^† 1	0/135 (0.00%)	1/132 (0.76%)
Cardiac disorders
Atrial fibrillation ^† 1	2/135 (1.48%)	1/132 (0.76%)
Atrial flutter ^† 1	2/135 (1.48%)	0/132 (0.00%)
Aortic valve disease ^† 1	1/135 (0.74%)	0/132 (0.00%)
Cardiac failure ^† 1	1/135 (0.74%)	0/132 (0.00%)
Cardiac failure congestive ^† 1	1/135 (0.74%)	1/132 (0.76%)
Coronary artery disease ^† 1	1/135 (0.74%)	0/132 (0.00%)
Acute myocardial infarction ^† 1	0/135 (0.00%)	1/132 (0.76%)
Aortic valve disease mixed ^† 1	0/135 (0.00%)	1/132 (0.76%)
Myocardial ischaemia ^† 1	0/135 (0.00%)	1/132 (0.76%)
Eye disorders
Blindness unilateral ^† 1	2/135 (1.48%)	0/132 (0.00%)
Hyphaema ^† 1	1/135 (0.74%)	0/132 (0.00%)
Retinal vascular occlusion ^† 1	1/135 (0.74%)	0/132 (0.00%)
Retinal vein occlusion ^† 1	1/135 (0.74%)	0/132 (0.00%)
Vitreous haemorrhage ^† 1	1/135 (0.74%)	0/132 (0.00%)
Gastrointestinal disorders
Abdominal pain upper ^† 1	1/135 (0.74%)	0/132 (0.00%)
Constipation ^† 1	1/135 (0.74%)	0/132 (0.00%)
Pancreatitis acute ^† 1	1/135 (0.74%)	0/132 (0.00%)
Gastrointestinal haemorrhage ^† 1	0/135 (0.00%)	1/132 (0.76%)
General disorders
Death ^† 1	2/135 (1.48%)	0/132 (0.00%)
Oedema peripheral ^† 1	1/135 (0.74%)	1/132 (0.76%)
Pyrexia ^† 1	1/135 (0.74%)	5/132 (3.79%)
Chills ^† 1	0/135 (0.00%)	1/132 (0.76%)
Pain ^† 1	0/135 (0.00%)	1/132 (0.76%)
Hepatobiliary disorders
Bile duct stone ^† 1	1/135 (0.74%)	0/132 (0.00%)
Cholangitis ^† 1	1/135 (0.74%)	0/132 (0.00%)
Cholecystitis ^† 1	0/135 (0.00%)	1/132 (0.76%)
Hepatitis toxic ^† 1	0/135 (0.00%)	1/132 (0.76%)
Immune system disorders
Immunodeficiency ^† 1	1/135 (0.74%)	0/132 (0.00%)
Infections and infestations
Pneumonia ^† 1	5/135 (3.70%)	2/132 (1.52%)
Bronchopneumonia ^† 1	2/135 (1.48%)	0/132 (0.00%)
Escherichia sepsis ^† 1	2/135 (1.48%)	0/132 (0.00%)
Lower respiratory tract infection ^† 1	2/135 (1.48%)	1/132 (0.76%)
Urinary tract infection ^† 1	2/135 (1.48%)	0/132 (0.00%)
Abscess limb ^† 1	1/135 (0.74%)	0/132 (0.00%)
Anal abscess ^† 1	1/135 (0.74%)	0/132 (0.00%)
Arthritis bacterial ^† 1	1/135 (0.74%)	0/132 (0.00%)
Cellulitis ^† 1	1/135 (0.74%)	0/132 (0.00%)
Clostridium difficile infection ^† 1	1/135 (0.74%)	0/132 (0.00%)
Escherichia bacteraemia ^† 1	1/135 (0.74%)	0/132 (0.00%)
Escherichia infection ^† 1	1/135 (0.74%)	0/132 (0.00%)
Gastroenteritis ^† 1	1/135 (0.74%)	1/132 (0.76%)
Gastroenteritis viral ^† 1	1/135 (0.74%)	0/132 (0.00%)
Klebsiella infection ^† 1	1/135 (0.74%)	0/132 (0.00%)
Lobar pneumonia ^† 1	1/135 (0.74%)	0/132 (0.00%)
Lung infection pseudomonal ^† 1	1/135 (0.74%)	0/132 (0.00%)
Neutropenic sepsis ^† 1	1/135 (0.74%)	1/132 (0.76%)
Pneumonia bacterial ^† 1	1/135 (0.74%)	1/132 (0.76%)
Pneumonia legionella ^† 1	1/135 (0.74%)	0/132 (0.00%)
Pneumonia viral ^† 1	1/135 (0.74%)	0/132 (0.00%)
Subcutaneous abscess ^† 1	1/135 (0.74%)	0/132 (0.00%)
Upper respiratory tract infection ^† 1	1/135 (0.74%)	0/132 (0.00%)
Viral infection ^† 1	1/135 (0.74%)	0/132 (0.00%)
Acute hepatitis B ^† 1	0/135 (0.00%)	1/132 (0.76%)
Pneumonia fungal ^† 1	0/135 (0.00%)	1/132 (0.76%)
Injury, poisoning and procedural complications
Fall ^† 1	1/135 (0.74%)	0/132 (0.00%)
Laceration ^† 1	1/135 (0.74%)	0/132 (0.00%)
Limb traumatic amputation ^† 1	1/135 (0.74%)	0/132 (0.00%)
Lumbar vertebral fracture ^† 1	1/135 (0.74%)	0/132 (0.00%)
Muscle strain ^† 1	1/135 (0.74%)	0/132 (0.00%)
Post procedural haemorrhage ^† 1	1/135 (0.74%)	0/132 (0.00%)
Postoperative wound complication ^† 1	1/135 (0.74%)	0/132 (0.00%)
Radius fracture ^† 1	1/135 (0.74%)	0/132 (0.00%)
Subdural haematoma ^† 1	1/135 (0.74%)	0/132 (0.00%)
Toxicity to various agents ^† 1	1/135 (0.74%)	0/132 (0.00%)
Traumatic haematoma ^† 1	1/135 (0.74%)	0/132 (0.00%)
Ulna fracture ^† 1	1/135 (0.74%)	0/132 (0.00%)
Femur fracture ^† 1	0/135 (0.00%)	1/132 (0.76%)
Overdose ^† 1	0/135 (0.00%)	1/132 (0.76%)
Upper limb fracture ^† 1	0/135 (0.00%)	1/132 (0.76%)
Investigations
Heart rate irregular ^† 1	1/135 (0.74%)	0/132 (0.00%)
Fibrin D dimer increased ^† 1	0/135 (0.00%)	1/132 (0.76%)
Hepatic enzyme increased ^† 1	0/135 (0.00%)	1/132 (0.76%)
Metabolism and nutrition disorders
Hyponatraemia ^† 1	3/135 (2.22%)	0/132 (0.00%)
Dehydration ^† 1	1/135 (0.74%)	1/132 (0.76%)
Musculoskeletal and connective tissue disorders
Back pain ^† 1	1/135 (0.74%)	0/132 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma ^† 1	5/135 (3.70%)	0/132 (0.00%)
Prostate cancer ^† 1	2/135 (1.48%)	0/132 (0.00%)
Squamous cell carcinoma ^† 1	2/135 (1.48%)	1/132 (0.76%)
Adenocarcinoma ^† 1	1/135 (0.74%)	0/132 (0.00%)
Basosquamous carcinoma of skin ^† 1	1/135 (0.74%)	0/132 (0.00%)
Colon adenoma ^† 1	1/135 (0.74%)	0/132 (0.00%)
Lung adenocarcinoma ^† 1	1/135 (0.74%)	0/132 (0.00%)
Non-small cell lung cancer ^† 1	1/135 (0.74%)	0/132 (0.00%)
Squamous cell carcinoma of skin ^† 1	1/135 (0.74%)	0/132 (0.00%)
Chronic lymphocytic leukaemia ^† 1	0/135 (0.00%)	1/132 (0.76%)
Nervous system disorders
Cauda equina syndrome ^† 1	1/135 (0.74%)	0/132 (0.00%)
Cerebral haemorrhage ^† 1	1/135 (0.74%)	0/132 (0.00%)
Headache ^† 1	1/135 (0.74%)	0/132 (0.00%)
Subarachnoid haemorrhage ^† 1	1/135 (0.74%)	0/132 (0.00%)
Transient ischaemic attack ^† 1	1/135 (0.74%)	1/132 (0.76%)
Cognitive disorder ^† 1	0/135 (0.00%)	1/132 (0.76%)
Epilepsy ^† 1	0/135 (0.00%)	1/132 (0.76%)
Ischaemic stroke ^† 1	0/135 (0.00%)	1/132 (0.76%)
Post herpetic neuralgia ^† 1	0/135 (0.00%)	1/132 (0.76%)
Presyncope ^† 1	0/135 (0.00%)	1/132 (0.76%)
Syncope ^† 1	0/135 (0.00%)	2/132 (1.52%)
Psychiatric disorders
Confusional state ^† 1	1/135 (0.74%)	0/132 (0.00%)
Somatoform disorder cardiovascular ^† 1	0/135 (0.00%)	1/132 (0.76%)
Renal and urinary disorders
Calculus ureteric ^† 1	1/135 (0.74%)	0/132 (0.00%)
Hydronephrosis ^† 1	1/135 (0.74%)	0/132 (0.00%)
Renal failure ^† 1	1/135 (0.74%)	0/132 (0.00%)
Renal failure acute ^† 1	1/135 (0.74%)	0/132 (0.00%)
Renal failure chronic ^† 1	1/135 (0.74%)	0/132 (0.00%)
Renal impairment ^† 1	1/135 (0.74%)	0/132 (0.00%)
Renal haemorrhage ^† 1	0/135 (0.00%)	1/132 (0.76%)
Urinary retention ^† 1	0/135 (0.00%)	1/132 (0.76%)
Reproductive system and breast disorders
Benign prostatic hyperplasia ^† 1	0/135 (0.00%)	1/132 (0.76%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion ^† 1	2/135 (1.48%)	2/132 (1.52%)
Acute respiratory failure ^† 1	1/135 (0.74%)	0/132 (0.00%)
Cough ^† 1	1/135 (0.74%)	0/132 (0.00%)
Hypercapnia ^† 1	1/135 (0.74%)	0/132 (0.00%)
Hypoxia ^† 1	1/135 (0.74%)	0/132 (0.00%)
Pneumomediastinum ^† 1	1/135 (0.74%)	0/132 (0.00%)
Wheezing ^† 1	1/135 (0.74%)	0/132 (0.00%)
Lung infiltration ^† 1	0/135 (0.00%)	1/132 (0.76%)
Skin and subcutaneous tissue disorders
Dermatitis allergic ^† 1	1/135 (0.74%)	0/132 (0.00%)
Rash macular ^† 1	1/135 (0.74%)	0/132 (0.00%)
Rash maculo-papular ^† 1	1/135 (0.74%)	0/132 (0.00%)
Subcutaneous emphysema ^† 1	1/135 (0.74%)	0/132 (0.00%)
Vascular disorders
Hypertension ^† 1	2/135 (1.48%)	0/132 (0.00%)
Aortic stenosis ^† 1	0/135 (0.00%)	1/132 (0.76%)
Peripheral artery aneurysm ^† 1	0/135 (0.00%)	1/132 (0.76%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA (17.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	PCI-32765	Chlorambucil
	Affected / at Risk (%)	Affected / at Risk (%)
Total	133/135 (98.52%)	123/132 (93.18%)
Blood and lymphatic system disorders
Anaemia ^† 1	24/135 (17.78%)	27/132 (20.45%)
Neutropenia ^† 1	20/135 (14.81%)	29/132 (21.97%)
Thrombocytopenia ^† 1	11/135 (8.15%)	17/132 (12.88%)
Increased tendency to bruise ^† 1	8/135 (5.93%)	4/132 (3.03%)
Cardiac disorders
Atrial fibrillation ^† 1	7/135 (5.19%)	0/132 (0.00%)
Eye disorders
Dry eye ^† 1	23/135 (17.04%)	6/132 (4.55%)
Lacrimation increased ^† 1	18/135 (13.33%)	8/132 (6.06%)
Vision blurred ^† 1	18/135 (13.33%)	10/132 (7.58%)
Visual acuity reduced ^† 1	15/135 (11.11%)	3/132 (2.27%)
Eye pain ^† 1	8/135 (5.93%)	2/132 (1.52%)
Vitreous floaters ^† 1	8/135 (5.93%)	6/132 (4.55%)
Cataract ^† 1	7/135 (5.19%)	2/132 (1.52%)
Gastrointestinal disorders
Diarrhoea ^† 1	57/135 (42.22%)	22/132 (16.67%)
Nausea ^† 1	30/135 (22.22%)	52/132 (39.39%)
Constipation ^† 1	20/135 (14.81%)	21/132 (15.91%)
Vomiting ^† 1	18/135 (13.33%)	27/132 (20.45%)
Abdominal pain ^† 1	17/135 (12.59%)	14/132 (10.61%)
Dyspepsia ^† 1	15/135 (11.11%)	3/132 (2.27%)
Stomatitis ^† 1	11/135 (8.15%)	5/132 (3.79%)
Gastrooesophageal reflux disease ^† 1	9/135 (6.67%)	1/132 (0.76%)
General disorders
Fatigue ^† 1	41/135 (30.37%)	50/132 (37.88%)
Oedema peripheral ^† 1	25/135 (18.52%)	12/132 (9.09%)
Pyrexia ^† 1	22/135 (16.30%)	17/132 (12.88%)
Asthenia ^† 1	10/135 (7.41%)	5/132 (3.79%)
Infections and infestations
Upper respiratory tract infection ^† 1	22/135 (16.30%)	23/132 (17.42%)
Urinary tract infection ^† 1	13/135 (9.63%)	10/132 (7.58%)
Conjunctivitis ^† 1	11/135 (8.15%)	3/132 (2.27%)
Nasopharyngitis ^† 1	10/135 (7.41%)	6/132 (4.55%)
Cellulitis ^† 1	8/135 (5.93%)	1/132 (0.76%)
Sinusitis ^† 1	7/135 (5.19%)	1/132 (0.76%)
Skin infection ^† 1	7/135 (5.19%)	3/132 (2.27%)
Herpes zoster ^† 1	0/135 (0.00%)	7/132 (5.30%)
Injury, poisoning and procedural complications
Contusion ^† 1	11/135 (8.15%)	2/132 (1.52%)
Investigations
Weight decreased ^† 1	14/135 (10.37%)	16/132 (12.12%)
Platelet count decreased ^† 1	7/135 (5.19%)	6/132 (4.55%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	13/135 (9.63%)	19/132 (14.39%)
Hyperuricaemia ^† 1	8/135 (5.93%)	1/132 (0.76%)
Hypokalaemia ^† 1	8/135 (5.93%)	2/132 (1.52%)
Hyponatraemia ^† 1	7/135 (5.19%)	1/132 (0.76%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	22/135 (16.30%)	9/132 (6.82%)
Back pain ^† 1	16/135 (11.85%)	9/132 (6.82%)
Muscle spasms ^† 1	15/135 (11.11%)	7/132 (5.30%)
Pain in extremity ^† 1	13/135 (9.63%)	7/132 (5.30%)
Musculoskeletal pain ^† 1	11/135 (8.15%)	3/132 (2.27%)
Myalgia ^† 1	8/135 (5.93%)	4/132 (3.03%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma ^† 1	7/135 (5.19%)	2/132 (1.52%)
Nervous system disorders
Headache ^† 1	16/135 (11.85%)	13/132 (9.85%)
Dizziness ^† 1	15/135 (11.11%)	16/132 (12.12%)
Psychiatric disorders
Insomnia ^† 1	11/135 (8.15%)	9/132 (6.82%)
Anxiety ^† 1	7/135 (5.19%)	2/132 (1.52%)
Renal and urinary disorders
Haematuria ^† 1	8/135 (5.93%)	3/132 (2.27%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	30/135 (22.22%)	20/132 (15.15%)
Dyspnoea ^† 1	14/135 (10.37%)	13/132 (9.85%)
Pleural effusion ^† 1	9/135 (6.67%)	1/132 (0.76%)
Epistaxis ^† 1	8/135 (5.93%)	5/132 (3.79%)
Oropharyngeal pain ^† 1	8/135 (5.93%)	5/132 (3.79%)
Skin and subcutaneous tissue disorders
Rash erythematous ^† 1	13/135 (9.63%)	5/132 (3.79%)
Night sweats ^† 1	9/135 (6.67%)	10/132 (7.58%)
Pruritus ^† 1	8/135 (5.93%)	7/132 (5.30%)
Rash maculo-papular ^† 1	8/135 (5.93%)	5/132 (3.79%)
Dry skin ^† 1	7/135 (5.19%)	3/132 (2.27%)
Vascular disorders
Hypertension ^† 1	18/135 (13.33%)	0/132 (0.00%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA (17.1)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.

Results Point of Contact

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Name/Title:	Dr. Lori Styles, Medical Monitor
Organization:	Pharmacyclics LLC
Phone:	+1 (408) 215-3770
EMail:	lstyles@pcyc.com

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

Barr PM, Owen C, Robak T, Tedeschi A, Bairey O, Burger JA, Hillmen P, Coutre SE, Dearden C, Grosicki S, McCarthy H, Li JY, Offner F, Moreno C, Zhou C, Hsu E, Szoke A, Kipps TJ, Ghia P. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022 Jun 14;6(11):3440-3450. doi: 10.1182/bloodadvances.2021006434.

Burger JA, Robak T, Demirkan F, Bairey O, Moreno C, Simpson D, Munir T, Stevens DA, Dai S, Cheung LWK, Kwei K, Lal I, Hsu E, Kipps TJ, Tedeschi A. Up to 6.5 years (median 4 years) of follow-up of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and high-risk genomic features: integrated analysis of two phase 3 studies. Leuk Lymphoma. 2022 Jun;63(6):1375-1386. doi: 10.1080/10428194.2021.2020779. Epub 2022 Jan 11.

Allan JN, Shanafelt T, Wiestner A, Moreno C, O'Brien SM, Li J, Krigsfeld G, Dean JP, Ahn IE. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022 Feb;196(4):947-953. doi: 10.1111/bjh.17984. Epub 2021 Dec 5.

Coutre SE, Byrd JC, Hillmen P, Barrientos JC, Barr PM, Devereux S, Robak T, Kipps TJ, Schuh A, Moreno C, Furman RR, Burger JA, O'Dwyer M, Ghia P, Valentino R, Chang S, Dean JP, James DF, O'Brien SM. Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood Adv. 2019 Jun 25;3(12):1799-1807. doi: 10.1182/bloodadvances.2018028761.

Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, Burger JA, Hillmen P, Coutre S, Devereux S, Grosicki S, McCarthy H, Li J, Simpson D, Offner F, Moreno C, Zhou C, Styles L, James D, Kipps TJ, Ghia P. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018 Sep;103(9):1502-1510. doi: 10.3324/haematol.2018.192328. Epub 2018 Jun 7.

Brown JR, Moslehi J, O'Brien S, Ghia P, Hillmen P, Cymbalista F, Shanafelt TD, Fraser G, Rule S, Kipps TJ, Coutre S, Dilhuydy MS, Cramer P, Tedeschi A, Jaeger U, Dreyling M, Byrd JC, Howes A, Todd M, Vermeulen J, James DF, Clow F, Styles L, Valentino R, Wildgust M, Mahler M, Burger JA. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017 Oct;102(10):1796-1805. doi: 10.3324/haematol.2017.171041. Epub 2017 Jul 27.

Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ; RESONATE-2 Investigators. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015 Dec 17;373(25):2425-37. doi: 10.1056/NEJMoa1509388. Epub 2015 Dec 6.

Layout table for additonal information

Responsible Party:	Pharmacyclics LLC.
ClinicalTrials.gov Identifier:	NCT01722487
Other Study ID Numbers:	PCYC-1115-CA 2012-003967-23 ( EudraCT Number )
First Submitted:	October 29, 2012
First Posted:	November 6, 2012
Results First Submitted:	March 31, 2016
Results First Posted:	May 4, 2016
Last Update Posted:	November 30, 2017

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