Everolimus in Combination With Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Who Are Refractory to Letrozole or Anastrozole (BOLERO-2)

• ClinicalTrials.gov Identifier: NCT00863655
• Recruitment Status: Completed
• First Posted: March 18, 2009
• Results First Posted: August 31, 2012
• Last Update Posted: May 2, 2017
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Drug: Everolimus; Drug: Exemestane; Drug: Everolimus Placebo
• Enrollment: 724

Participant Flow

Recruitment Details
Pre-assignment Details	Although 724 patients were randomized, 4 never received any study treatment and thus were excluded form the safety set.

Arm/Group Title	Everolimus + Exemestane	Placebo + Exemestane
Arm/Group Description	Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily
Period Title: Overall Study
Started	485	239
Completed	0 [1]	0 [1]
Not Completed	485	239
Reason Not Completed
Protocol Violation	4	0
Adverse Event	52	8
Withdrawal by Subject	47	7
Administrative problems	1	0
Death	7	1
New cancer therapy	5	1
Disease progression	364	221
Treatment completed as per protocol	5	1
[1] Completed means discontinued the treatment period.

Baseline Characteristics

Arm/Group Title		Everolimus + Exemestane	Placebo + Exemestane	Total
Arm/Group Description		Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily	Total of all reporting groups
Overall Number of Baseline Participants		485	239	724
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	485 participants	239 participants	724 participants
		62.5 (10.31)	61.2 (9.75)	62.1 (10.14)
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	485 participants	239 participants	724 participants
< 65 years		290	159	449
>= 65 years		195	80	275
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	485 participants	239 participants	724 participants
	Female	485 100.0%	239 100.0%	724 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) Based on Local Radiology Review of Tumor Assessments.
Description	Progression-free survival, the primary endpoint in this study, is defined as the time from the date of randomization to the date of first documented radiological progression or death due to any cause. Disease progression was based on the tumor assessment by the local radiologist or investigator using RECIST 1.0 criteria. If a patient did not progress or known to have died at the date of the analysis cut-off or start of another antineoplastic therapy, the PFS date was censored to the date of last adequate tumor assessment prior to cut-off date or start of antineoplastic therapy. For patients with lytic or mixed (lytic+sclerotic) bone lesions, the following is considered progression: appearance of ≥1 new lytic lesions in bone; the appearance of ≥ new lesions outside of bone and unequivocal progression of existing bone lesions.
Time Frame	date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to about 19 months

Outcome Measure Data

Analysis Population Description

All randomized patients were included in the Full Analysis Set.

Arm/Group Title	Everolimus + Exemestane	Placebo + Exemestane
Arm/Group Description:	Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily
Overall Number of Participants Analyzed	485	239
Median (95% Confidence Interval); Unit of Measure: months
	6.93; (6.44 to 8.05)	2.83; (2.76 to 4.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Everolimus + Exemestane, Placebo + Exemestane
	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	0.43
	Confidence Interval	(2-Sided) 95%; 0.35 to 0.54
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Overall Survival (OS) by Number of Deaths
Description	Overall survival, the key secondary endpoint in this study, is defined as the time from date of randomization to the date of death due to any cause. If a patient is not known to have died, survival was censored at the date of last contact.
Time Frame	up to 53 months

Outcome Measure Data

Analysis Population Description

All randomized patients were included in the Full Analysis Set.

Arm/Group Title	Everolimus + Exemestane	Placebo + Exemestane
Arm/Group Description:	Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily
Overall Number of Participants Analyzed	485	239
Measure Type: Number; Unit of Measure: Participants
	267	143

3. Secondary Outcome

Title	Overall Survival (OS) by Median
Description	Overall survival, the key secondary endpoint in this study, is defined as the time from date of randomization to the date of death due to any cause.
Time Frame	up to 53 months

Outcome Measure Data

Analysis Population Description

All randomized patients were included in the Full Analysis Set.

Arm/Group Title	Everolimus + Exemestane	Placebo + Exemestane
Arm/Group Description:	Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily
Overall Number of Participants Analyzed	485	239
Median (95% Confidence Interval); Unit of Measure: Months
	30.98; (27.96 to 34.56)	26.55; (22.57 to 33.08)

4. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	Overall response rate (ORR) is the percentage of patients with a best overall response of complete response (CR) or partial response (PR) according to RECIST 1.0. Per RECIST criteria 1.0, CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.
Time Frame	up to 21 months

Outcome Measure Data

Analysis Population Description

All randomized patients were included in the Full Analysis Set.

Arm/Group Title	Everolimus + Exemestane	Placebo + Exemestane
Arm/Group Description:	Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily
Overall Number of Participants Analyzed	485	239
Measure Type: Number; Unit of Measure: Percentage of participants
	9.5	0.4

5. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	CBR is defined as the percentage of patients with best overall response of either complete response (CR), a partial response (PR) or stable disease (SD) >= 24 weeks, according to RECIST 1.0. Per RECIST criteria 1.0, CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.
Time Frame	up to 21 months

Outcome Measure Data

Analysis Population Description

All randomized patients were included in the Full Analysis Set.

Arm/Group Title	Everolimus + Exemestane	Placebo + Exemestane
Arm/Group Description:	Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily
Overall Number of Participants Analyzed	485	239
Measure Type: Number; Unit of Measure: Percentage of participants
	33.4	18.0

6. Secondary Outcome

Title	Proportion of Patients With no Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) Using Kaplan-Meier
Description	The ECOG PS (Eastern Cooperative Oncology Group Performance Scale) is a standard criteria for measuring how treatment of cancer impacts level of functioning in terms of the ability to care for oneself, daily activity, & physical ability (walking, working, etc.). Scale score ranges:0 to 5, 5 being the worst. Scale index: 0: Fully active, able to carry on all pre-disease performance without restriction. 1: Restricted in physically strenuous activity but ambulatory & able to carry out work of a light or sedentary nature. 2: Ambulatory & capable of all self-care but unable to carry out any work activities. Up & about more than 50% of waking hours. 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 - Dead. A deterioration of ECOG is an increase of 1 of the ECOG PS without improvement back to initial level at a subsequent time of measurement.
Time Frame	2, 4, 6, 9 months

Outcome Measure Data

Analysis Population Description

All randomized patients were included in the Full Analysis Set.

Arm/Group Title	Everolimus + Exemestane	Placebo + Exemestane
Arm/Group Description:	Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily
Overall Number of Participants Analyzed	485	239
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Proportion of patients
2 Months	0.84; (0.80 to 0.87)	0.87; (0.82 to 0.91)
4 Months	0.74; (0.70 to 0.78)	0.80; (0.73 to 0.85)
6 Months	0.64; (0.58 to 0.69)	0.67; (0.57 to 0.75)
9 Months	0.57; (0.50 to 0.63)	0.47; (0.32 to 0.61)

7. Secondary Outcome

Title	Patient-reported Outcomes (PROs): Time to Deterioration of PRO Scores Using Kaplan Meier - EORTC QLQ-C30
Description	The QLQ-C30 is composed of both multi-item scales and single-item measures. These include 5 functional scales, 3 symptom scales, a global health status - QoL scale, and 6 single items. Each of the multi-item scales includes a different set of items - no item occurs in more than 1 scale. All of the scales measures range in score from 0 to 100. A high scale score = higher response level. Thus a high score for a functional scale represents a healthy level of function, a high score for the global health status / QoL represents a high quality of life but a high score for a symptom scale / item represents a high level of symptomatology / problems. The principle for scoring these scales: 1.) Estimate the average of the items that contribute to the scale = raw score. 2.) Linear transformation to standardize the raw score, so that scores range from 0 to 100; a higher score represents a higher ("better") level of functioning, or a higher ("worse") level of symptoms.
Time Frame	Up to 21 months

Outcome Measure Data

Analysis Population Description

All randomized patients were included in the Full Analysis Set.

Arm/Group Title	Everolimus + Exemestane	Placebo + Exemestane
Arm/Group Description:	Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily
Overall Number of Participants Analyzed	485	239
Median (95% Confidence Interval); Unit of Measure: Months
Deterioration global health status score ≥ 5%	4.53; (4.17 to 5.68)	4.40; (3.58 to 5.85)
Deterioration in PF domain score of ≥ 5%	4.83; (4.17 to 6.97)	4.37; (2.83 to 7.00)
Deterioration in EF domain score of ≥ 5%	6.93; (5.55 to 8.41)	6.93; (4.17 to 7.36)
Deterioration in SF domain score of ≥ 5%	8.34; (6.93 to 10.87)	7.03 [1]; (5.62 to NA)

[1]

NA: Median time to definitive deterioration computed using Kaplan-Meier method.95% CIs calculated using Brookmeyer & Crowley (1982) method. Therefore, upper boundary of 95% CI may not be estimable when median is close to the longest patient follow-up

8. Secondary Outcome

Title	Proportion of Patients With Having no Overall Response Based on Investigator Assessment
Description	overall response = complete response (CR) + partial response (PR) per RECIST 1.0 Time to overall response (CR or PR) based on investigator is the time between date of randomization/start of treatment until first documented response (CR or PR). This analysis included all patients/responders. Patients who did not achieve a confirmed PR or CR were censored at last adequate tumor assessment date when they did not progress. Per RECIST criteria 1.0, CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.
Time Frame	2, 4, 6, 9 months

Outcome Measure Data

Analysis Population Description

All randomized patients were included in the Full Analysis Set.

Arm/Group Title	Everolimus + Exemestane	Placebo + Exemestane
Arm/Group Description:	Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily
Overall Number of Participants Analyzed	485	239
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Proportion of patients
2 months	0.96; (0.94 to 0.98)	1.00; (0.97 to 1.00)
4 months	0.93; (0.91 to 0.95)	1.00; (0.97 to 1.00)
6 months	0.92; (0.89 to 0.94)	1.00; (0.97 to 1.00)
9 months	0.90; (0.88 to 0.93)	1.00; (0.97 to 1.00)

9. Secondary Outcome

Title	Duration of Response (Among Participants With Best Overall Response of CR or PR) Estimated Per Kaplan-Meier
Description	Duration of response of CR or PR based on investigator applies only to patients whose best overall response was CR or PR (RECIST 1.0). The start date was the date of first documented response (CR or PR) and the end date and censoring is defined the same as that for time to progression. Per RECIST criteria 1.0, CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.
Time Frame	21 months

Outcome Measure Data

Analysis Population Description

Randomized patients with best overall response of CR or PR.

Arm/Group Title	Everolimus + Exemestane	Placebo + Exemestane
Arm/Group Description:	Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily
Overall Number of Participants Analyzed	46	1
Median (95% Confidence Interval); Unit of Measure: Months
	8.21 [1]; (5.55 to NA)	NA [2]; (NA to NA)

[1]

NA - upper limit was not estimable

[2]

NA - median, lower and upper limit of the 95 % CI were not estimable

10. Secondary Outcome

Title	Everolimus Concentrations at Week 4
Description	Characterize the pharmacokinetics (PK) of everolimus in combination with exemestane using Cmin (pre-dose) and C2h (post-dose) at week 4 in a small group of patients.
Time Frame	pre-dose, 2 hours post-dose

Outcome Measure Data

Analysis Population Description

Safety Set population consisted of all patients who received at least one dose of study treatment and who had at least one valid post-baseline safety assessment. Although the safety set was considered for the analysis (N), only participants (n) who had pre-dose & 2 hours post-dose values for the given time points were analyzed for that time point.

Arm/Group Title	Everolimus + Exemestane
Arm/Group Description:	Everolimus 10 mg daily in combination with exemestane 25 mg daily
Overall Number of Participants Analyzed	24
Mean (Standard Deviation); Unit of Measure: ng/mL
Pre-dose (Cmin) (n:22)	16.04 (9.356)
2 hours post-dose (C2h) (n:24)	46.50 (17.954)

11. Secondary Outcome

Title	Exemestane Concentrations at Week 4
Description	Characterize the PK of exemestane in combination with or without everolimus using Cmin and C2h at week 4 in a small group of patients.
Time Frame	predose, 2 hours post-dose

Outcome Measure Data

Analysis Population Description

Safety Set population consisted of all patients who received at least one dose of study treatment and who had at least one valid post-baseline safety assessment. Although the safety set was considered for the analysis (N), only participants (n) who had pre-dose & 2 hours post-dose values for the given time points were analyzed for that time point.

Arm/Group Title	Everolimus + Exemestane	Placebo + Exemestane
Arm/Group Description:	Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily
Overall Number of Participants Analyzed	39	22
Mean (Standard Deviation); Unit of Measure: ng/mL
Pre-dose (Cmin) (n: 34, n: 22)	0.63 (0.474)	0.43 (0.376)
2 hours post-dose (C2h) (n: 39, n: 22)	23.16 (19.805)	13.30 (11.889)

12. Secondary Outcome

Title	Estradiol Plasma Concentrations
Description	Compare estradiol concentrations from baseline to week 4 in both treatment arms.
Time Frame	Baseline, Week 4

Outcome Measure Data

Analysis Population Description

Safety Set population consisted of all patients who received at least one dose of study treatment and who had at least one valid post-baseline safety assessment. Although the safety set was considered for the analysis (N), only participants (n) who had pre-dose & 2 hours post-dose values for the given time points were analyzed for that time point.

Arm/Group Title	Everolimus + Exemestane	Placebo + Exemestane
Arm/Group Description:	Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily
Overall Number of Participants Analyzed	41	15
Mean (Standard Deviation); Unit of Measure: pg/mL
Baseline (n: = 41, 14)	5.62 (3.342)	4.09 (1.792)
Week 4 (n: 38, 15)	3.50 (2.551)	5.17 (6.919)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	4 patients were excluded from the Safety Set; all 4 of these patients (3 in the everolimus plus exemestane arm and 1 in the placebo plus exemestane group) were randomized but subsequently didn't receive study treatment and didn't have an AE reported.
Arm/Group Title	Everolimus + Exemestane	Placebo + Exemestane
Arm/Group Description	Everolimus 10 mg daily in combination with exemestane 25 mg daily	Placebo of everolimus in combination with exemestane 25 mg daily
All-Cause Mortality
	Everolimus + Exemestane	Placebo + Exemestane
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Everolimus + Exemestane	Placebo + Exemestane
	Affected / at Risk (%)	Affected / at Risk (%)
Total	158/482 (32.78%)	37/238 (15.55%)
Blood and lymphatic system disorders
Anaemia † 1	7/482 (1.45%)	2/238 (0.84%)
Disseminated intravascular coagulation † 1	1/482 (0.21%)	0/238 (0.00%)
Lymphadenopathy † 1	0/482 (0.00%)	1/238 (0.42%)
Neutropenia † 1	0/482 (0.00%)	1/238 (0.42%)
Thrombocytopenia † 1	2/482 (0.41%)	0/238 (0.00%)
Anaemia † 2	8/482 (1.66%)	2/238 (0.84%)
Disseminated intravascular coagulation † 2	1/482 (0.21%)	0/238 (0.00%)
Febrile neutropenia † 2	1/482 (0.21%)	1/238 (0.42%)
Lymphadenopathy † 2	0/482 (0.00%)	1/238 (0.42%)
Neutropenia † 2	0/482 (0.00%)	1/238 (0.42%)
Thrombocytopenia † 2	3/482 (0.62%)	0/238 (0.00%)
Cardiac disorders
Arrhythmia † 1	1/482 (0.21%)	0/238 (0.00%)
Atrial fibrillation † 1	1/482 (0.21%)	0/238 (0.00%)
Cardiac arrest † 1	1/482 (0.21%)	0/238 (0.00%)
Cardiac disorder † 1	1/482 (0.21%)	0/238 (0.00%)
Cardiac failure † 1	0/482 (0.00%)	1/238 (0.42%)
Cardiomyopathy † 1	1/482 (0.21%)	0/238 (0.00%)
Cardiopulmonary failure † 1	1/482 (0.21%)	0/238 (0.00%)
Sinus tachycardia † 1	1/482 (0.21%)	0/238 (0.00%)
Tachyarrhythmia † 1	1/482 (0.21%)	0/238 (0.00%)
Tachycardia † 1	1/482 (0.21%)	0/238 (0.00%)
Angina pectoris † 2	1/482 (0.21%)	0/238 (0.00%)
Arrhythmia † 2	1/482 (0.21%)	0/238 (0.00%)
Atrial fibrillation † 2	1/482 (0.21%)	0/238 (0.00%)
Cardiac arrest † 2	1/482 (0.21%)	0/238 (0.00%)
Cardiac disorder † 2	1/482 (0.21%)	0/238 (0.00%)
Cardiac failure † 2	0/482 (0.00%)	1/238 (0.42%)
Cardiac failure congestive † 2	1/482 (0.21%)	0/238 (0.00%)
Cardiomyopathy † 2	1/482 (0.21%)	0/238 (0.00%)
Cardiopulmonary failure † 2	1/482 (0.21%)	0/238 (0.00%)
Left ventricular failure † 2	1/482 (0.21%)	0/238 (0.00%)
Sinus tachycardia † 2	1/482 (0.21%)	0/238 (0.00%)
Tachyarrhythmia † 2	1/482 (0.21%)	0/238 (0.00%)
Tachycardia † 2	1/482 (0.21%)	0/238 (0.00%)
Eye disorders
Diplopia † 2	1/482 (0.21%)	0/238 (0.00%)
Retinal artery thrombosis † 2	1/482 (0.21%)	0/238 (0.00%)
Gastrointestinal disorders
Abdominal distension † 1	1/482 (0.21%)	0/238 (0.00%)
Abdominal pain † 1	4/482 (0.83%)	0/238 (0.00%)
Abdominal pain upper † 1	3/482 (0.62%)	0/238 (0.00%)
Ascites † 1	1/482 (0.21%)	0/238 (0.00%)
Colitis † 1	1/482 (0.21%)	0/238 (0.00%)
Constipation † 1	0/482 (0.00%)	1/238 (0.42%)
Diarrhoea † 1	3/482 (0.62%)	0/238 (0.00%)
Duodenal obstruction † 1	1/482 (0.21%)	0/238 (0.00%)
Dysphagia † 1	1/482 (0.21%)	0/238 (0.00%)
Enterocolitis † 1	1/482 (0.21%)	0/238 (0.00%)
Gastric haemorrhage † 1	1/482 (0.21%)	0/238 (0.00%)
Gastritis † 1	1/482 (0.21%)	0/238 (0.00%)
Gastritis erosive † 1	1/482 (0.21%)	0/238 (0.00%)
Gastrointestinal disorder † 1	1/482 (0.21%)	0/238 (0.00%)
Gastrointestinal haemorrhage † 1	1/482 (0.21%)	0/238 (0.00%)
Haemorrhoidal haemorrhage † 1	1/482 (0.21%)	0/238 (0.00%)
Intestinal perforation † 1	1/482 (0.21%)	0/238 (0.00%)
Intestinal ulcer † 1	1/482 (0.21%)	0/238 (0.00%)
Large intestinal haemorrhage † 1	0/482 (0.00%)	1/238 (0.42%)
Nausea † 1	3/482 (0.62%)	2/238 (0.84%)
Periodontitis † 1	1/482 (0.21%)	0/238 (0.00%)
Rectal haemorrhage † 1	1/482 (0.21%)	0/238 (0.00%)
Small intestinal obstruction † 1	1/482 (0.21%)	0/238 (0.00%)
Stomatitis † 1	3/482 (0.62%)	0/238 (0.00%)
Vomiting † 1	6/482 (1.24%)	2/238 (0.84%)
Abdominal distension † 2	1/482 (0.21%)	0/238 (0.00%)
Abdominal pain † 2	6/482 (1.24%)	0/238 (0.00%)
Abdominal pain upper † 2	3/482 (0.62%)	0/238 (0.00%)
Ascites † 2	2/482 (0.41%)	0/238 (0.00%)
Colitis † 2	1/482 (0.21%)	0/238 (0.00%)
Constipation † 2	2/482 (0.41%)	1/238 (0.42%)
Diarrhoea † 2	4/482 (0.83%)	0/238 (0.00%)
Duodenal obstruction † 2	1/482 (0.21%)	0/238 (0.00%)
Dyspepsia † 2	1/482 (0.21%)	1/238 (0.42%)
Dysphagia † 2	1/482 (0.21%)	0/238 (0.00%)
Enterocolitis † 2	1/482 (0.21%)	0/238 (0.00%)
Faecaloma † 2	1/482 (0.21%)	0/238 (0.00%)
Gastric haemorrhage † 2	1/482 (0.21%)	0/238 (0.00%)
Gastritis † 2	1/482 (0.21%)	0/238 (0.00%)
Gastritis erosive † 2	1/482 (0.21%)	0/238 (0.00%)
Gastrointestinal disorder † 2	2/482 (0.41%)	0/238 (0.00%)
Gastrointestinal haemorrhage † 2	1/482 (0.21%)	0/238 (0.00%)
Haemorrhoidal haemorrhage † 2	1/482 (0.21%)	0/238 (0.00%)
Hernial eventration † 2	1/482 (0.21%)	0/238 (0.00%)
Intestinal obstruction † 2	1/482 (0.21%)	0/238 (0.00%)
Intestinal perforation † 2	1/482 (0.21%)	0/238 (0.00%)
Large intestinal haemorrhage † 2	0/482 (0.00%)	1/238 (0.42%)
Nausea † 2	5/482 (1.04%)	2/238 (0.84%)
Rectal haemorrhage † 2	1/482 (0.21%)	0/238 (0.00%)
Small intestinal obstruction † 2	1/482 (0.21%)	0/238 (0.00%)
Small intestine ulcer † 2	1/482 (0.21%)	0/238 (0.00%)
Stomatitis † 2	3/482 (0.62%)	0/238 (0.00%)
Vomiting † 2	6/482 (1.24%)	3/238 (1.26%)
General disorders
Asthenia † 1	5/482 (1.04%)	0/238 (0.00%)
Chest discomfort † 1	1/482 (0.21%)	0/238 (0.00%)
Chest pain † 1	1/482 (0.21%)	0/238 (0.00%)
Drug withdrawal syndrome † 1	1/482 (0.21%)	0/238 (0.00%)
Fatigue † 1	3/482 (0.62%)	1/238 (0.42%)
General physical health deterioration † 1	4/482 (0.83%)	0/238 (0.00%)
Hyperpyrexia † 1	1/482 (0.21%)	0/238 (0.00%)
Malaise † 1	1/482 (0.21%)	1/238 (0.42%)
Non-cardiac chest pain † 1	2/482 (0.41%)	1/238 (0.42%)
Pain † 1	2/482 (0.41%)	0/238 (0.00%)
Pyrexia † 1	6/482 (1.24%)	4/238 (1.68%)
Asthenia † 2	6/482 (1.24%)	0/238 (0.00%)
Chest discomfort † 2	1/482 (0.21%)	0/238 (0.00%)
Chest pain † 2	1/482 (0.21%)	0/238 (0.00%)
Drug withdrawal syndrome † 2	1/482 (0.21%)	0/238 (0.00%)
Fatigue † 2	3/482 (0.62%)	1/238 (0.42%)
General physical health deterioration † 2	6/482 (1.24%)	0/238 (0.00%)
Hyperpyrexia † 2	1/482 (0.21%)	0/238 (0.00%)
Malaise † 2	1/482 (0.21%)	1/238 (0.42%)
Non-cardiac chest pain † 2	2/482 (0.41%)	1/238 (0.42%)
Pain † 2	3/482 (0.62%)	0/238 (0.00%)
Pyrexia † 2	7/482 (1.45%)	4/238 (1.68%)
Hepatobiliary disorders
Acute hepatic failure † 1	0/482 (0.00%)	1/238 (0.42%)
Bile duct stone † 1	1/482 (0.21%)	0/238 (0.00%)
Cholecystitis † 1	1/482 (0.21%)	0/238 (0.00%)
Cholelithiasis † 1	1/482 (0.21%)	0/238 (0.00%)
Hepatic failure † 1	1/482 (0.21%)	0/238 (0.00%)
Acute hepatic failure † 2	0/482 (0.00%)	1/238 (0.42%)
Bile duct stone † 2	1/482 (0.21%)	0/238 (0.00%)
Cholecystitis † 2	1/482 (0.21%)	0/238 (0.00%)
Cholecystitis acute † 2	2/482 (0.41%)	0/238 (0.00%)
Cholelithiasis † 2	2/482 (0.41%)	0/238 (0.00%)
Hepatic failure † 2	2/482 (0.41%)	0/238 (0.00%)
Hyperbilirubinaemia † 2	1/482 (0.21%)	0/238 (0.00%)
Infections and infestations
Abdominal abscess † 1	1/482 (0.21%)	0/238 (0.00%)
Bronchitis † 1	2/482 (0.41%)	0/238 (0.00%)
Bronchopneumonia † 1	1/482 (0.21%)	0/238 (0.00%)
Cellulitis † 1	1/482 (0.21%)	1/238 (0.42%)
Enterocolitis infectious † 1	1/482 (0.21%)	0/238 (0.00%)
Erysipelas † 1	3/482 (0.62%)	0/238 (0.00%)
Gastroenteritis † 1	3/482 (0.62%)	0/238 (0.00%)
Hepatitis C † 1	1/482 (0.21%)	0/238 (0.00%)
Herpes zoster † 1	0/482 (0.00%)	1/238 (0.42%)
Klebsiella sepsis † 1	1/482 (0.21%)	0/238 (0.00%)
Lung infection † 1	1/482 (0.21%)	1/238 (0.42%)
Neutropenic sepsis † 1	0/482 (0.00%)	1/238 (0.42%)
Pneumonia † 1	8/482 (1.66%)	2/238 (0.84%)
Pneumonia primary atypical † 1	1/482 (0.21%)	0/238 (0.00%)
Pyelonephritis † 1	2/482 (0.41%)	0/238 (0.00%)
Sepsis † 1	2/482 (0.41%)	0/238 (0.00%)
Staphylococcal sepsis † 1	1/482 (0.21%)	0/238 (0.00%)
Upper respiratory tract infection † 1	1/482 (0.21%)	0/238 (0.00%)
Urinary tract infection † 1	1/482 (0.21%)	0/238 (0.00%)
Urinary tract infection bacterial † 1	1/482 (0.21%)	0/238 (0.00%)
Abdominal abscess † 2	2/482 (0.41%)	0/238 (0.00%)
Atypical pneumonia † 2	1/482 (0.21%)	0/238 (0.00%)
Bronchitis † 2	2/482 (0.41%)	0/238 (0.00%)
Bronchopneumonia † 2	1/482 (0.21%)	0/238 (0.00%)
Cellulitis † 2	1/482 (0.21%)	1/238 (0.42%)
Clostridium colitis † 2	1/482 (0.21%)	0/238 (0.00%)
Erysipelas † 2	3/482 (0.62%)	0/238 (0.00%)
Escherichia urinary tract infection † 2	1/482 (0.21%)	0/238 (0.00%)
Gastroenteritis † 2	3/482 (0.62%)	0/238 (0.00%)
Groin abscess † 2	1/482 (0.21%)	0/238 (0.00%)
Hepatitis C † 2	1/482 (0.21%)	0/238 (0.00%)
Herpes zoster † 2	0/482 (0.00%)	1/238 (0.42%)
Histoplasmosis † 2	1/482 (0.21%)	0/238 (0.00%)
Infectious colitis † 2	1/482 (0.21%)	0/238 (0.00%)
Klebsiella sepsis † 2	1/482 (0.21%)	0/238 (0.00%)
Lung infection † 2	2/482 (0.41%)	1/238 (0.42%)
Neutropenic sepsis † 2	0/482 (0.00%)	1/238 (0.42%)
Periodontitis † 2	1/482 (0.21%)	0/238 (0.00%)
Pneumonia † 2	11/482 (2.28%)	1/238 (0.42%)
Pneumonia bacterial † 2	0/482 (0.00%)	1/238 (0.42%)
Pyelonephritis † 2	3/482 (0.62%)	0/238 (0.00%)
Pyometra † 2	1/482 (0.21%)	0/238 (0.00%)
Respiratory tract infection † 2	2/482 (0.41%)	0/238 (0.00%)
Sepsis † 2	2/482 (0.41%)	0/238 (0.00%)
Staphylococcal infection † 2	1/482 (0.21%)	0/238 (0.00%)
Staphylococcal sepsis † 2	1/482 (0.21%)	0/238 (0.00%)
Urinary tract infection † 2	3/482 (0.62%)	0/238 (0.00%)
Urinary tract infection bacterial † 2	1/482 (0.21%)	0/238 (0.00%)
Injury, poisoning and procedural complications
Femur fracture † 1	0/482 (0.00%)	2/238 (0.84%)
Fracture † 1	0/482 (0.00%)	1/238 (0.42%)
Overdose † 1	2/482 (0.41%)	0/238 (0.00%)
Pulmonary radiation injury † 1	1/482 (0.21%)	0/238 (0.00%)
Spinal compression fracture † 1	1/482 (0.21%)	0/238 (0.00%)
Spinal fracture † 1	1/482 (0.21%)	0/238 (0.00%)
Wound dehiscence † 1	1/482 (0.21%)	0/238 (0.00%)
Femur fracture † 2	0/482 (0.00%)	3/238 (1.26%)
Fractured sacrum † 2	1/482 (0.21%)	0/238 (0.00%)
Hip fracture † 2	1/482 (0.21%)	0/238 (0.00%)
Joint dislocation † 2	1/482 (0.21%)	0/238 (0.00%)
Lower limb fracture † 2	0/482 (0.00%)	1/238 (0.42%)
Overdose † 2	1/482 (0.21%)	0/238 (0.00%)
Pulmonary radiation injury † 2	1/482 (0.21%)	0/238 (0.00%)
Spinal compression fracture † 2	1/482 (0.21%)	0/238 (0.00%)
Subdural haematoma † 2	1/482 (0.21%)	0/238 (0.00%)
Wound dehiscence † 2	1/482 (0.21%)	0/238 (0.00%)
Wrist fracture † 2	0/482 (0.00%)	1/238 (0.42%)
Investigations
Alanine aminotransferase increased † 1	1/482 (0.21%)	0/238 (0.00%)
Aspartate aminotransferase increased † 1	1/482 (0.21%)	0/238 (0.00%)
Blood creatinine increased † 1	2/482 (0.41%)	0/238 (0.00%)
Blood potassium decreased † 1	1/482 (0.21%)	0/238 (0.00%)
Computerised tomogram abnormal † 1	1/482 (0.21%)	0/238 (0.00%)
General physical condition abnormal † 1	1/482 (0.21%)	0/238 (0.00%)
Hepatic enzyme increased † 1	0/482 (0.00%)	1/238 (0.42%)
International normalised ratio increased † 1	1/482 (0.21%)	0/238 (0.00%)
Alanine aminotransferase increased † 2	1/482 (0.21%)	0/238 (0.00%)
Aspartate aminotransferase increased † 2	1/482 (0.21%)	0/238 (0.00%)
Blood creatinine increased † 2	2/482 (0.41%)	0/238 (0.00%)
Blood potassium decreased † 2	1/482 (0.21%)	0/238 (0.00%)
Hepatic enzyme increased † 2	0/482 (0.00%)	1/238 (0.42%)
International normalised ratio increased † 2	1/482 (0.21%)	0/238 (0.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	3/482 (0.62%)	0/238 (0.00%)
Dehydration † 1	3/482 (0.62%)	1/238 (0.42%)
Hypercholesterolaemia † 1	1/482 (0.21%)	0/238 (0.00%)
Hyperglycaemia † 1	5/482 (1.04%)	0/238 (0.00%)
Hyperkalaemia † 1	1/482 (0.21%)	0/238 (0.00%)
Hypertriglyceridaemia † 1	1/482 (0.21%)	0/238 (0.00%)
Hypokalaemia † 1	2/482 (0.41%)	0/238 (0.00%)
Hypophagia † 1	1/482 (0.21%)	0/238 (0.00%)
Decreased appetite † 2	3/482 (0.62%)	0/238 (0.00%)
Dehydration † 2	4/482 (0.83%)	1/238 (0.42%)
Hypercholesterolaemia † 2	1/482 (0.21%)	0/238 (0.00%)
Hyperglycaemia † 2	5/482 (1.04%)	0/238 (0.00%)
Hyperkalaemia † 2	1/482 (0.21%)	0/238 (0.00%)
Hypertriglyceridaemia † 2	1/482 (0.21%)	0/238 (0.00%)
Hypokalaemia † 2	2/482 (0.41%)	0/238 (0.00%)
Hyponatraemia † 2	1/482 (0.21%)	0/238 (0.00%)
Hypophagia † 2	1/482 (0.21%)	0/238 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	2/482 (0.41%)	0/238 (0.00%)
Back pain † 1	2/482 (0.41%)	0/238 (0.00%)
Bone pain † 1	3/482 (0.62%)	2/238 (0.84%)
Muscle haemorrhage † 1	2/482 (0.41%)	0/238 (0.00%)
Muscular weakness † 1	1/482 (0.21%)	0/238 (0.00%)
Musculoskeletal chest pain † 1	0/482 (0.00%)	1/238 (0.42%)
Osteonecrosis of jaw † 1	1/482 (0.21%)	0/238 (0.00%)
Pain in extremity † 1	0/482 (0.00%)	2/238 (0.84%)
Pathological fracture † 1	0/482 (0.00%)	1/238 (0.42%)
Arthralgia † 2	3/482 (0.62%)	0/238 (0.00%)
Back pain † 2	2/482 (0.41%)	0/238 (0.00%)
Bone pain † 2	1/482 (0.21%)	2/238 (0.84%)
Mobility decreased † 2	1/482 (0.21%)	0/238 (0.00%)
Muscle haemorrhage † 2	2/482 (0.41%)	0/238 (0.00%)
Muscular weakness † 2	1/482 (0.21%)	0/238 (0.00%)
Musculoskeletal chest pain † 2	0/482 (0.00%)	1/238 (0.42%)
Osteonecrosis of jaw † 2	2/482 (0.41%)	0/238 (0.00%)
Pain in extremity † 2	0/482 (0.00%)	2/238 (0.84%)
Pain in jaw † 2	1/482 (0.21%)	0/238 (0.00%)
Pathological fracture † 2	0/482 (0.00%)	2/238 (0.84%)
Spinal pain † 2	1/482 (0.21%)	0/238 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer † 1	1/482 (0.21%)	0/238 (0.00%)
Cancer pain † 1	0/482 (0.00%)	1/238 (0.42%)
Malignant pleural effusion † 1	2/482 (0.41%)	0/238 (0.00%)
Metastases to central nervous system † 1	1/482 (0.21%)	1/238 (0.42%)
Oesophageal carcinoma † 1	1/482 (0.21%)	0/238 (0.00%)
Pituitary tumour benign † 1	0/482 (0.00%)	1/238 (0.42%)
Thyroid cancer † 1	0/482 (0.00%)	1/238 (0.42%)
Tumour haemorrhage † 1	1/482 (0.21%)	0/238 (0.00%)
Tumour pain † 1	1/482 (0.21%)	1/238 (0.42%)
Cancer pain † 2	0/482 (0.00%)	1/238 (0.42%)
Invasive ductal breast carcinoma † 2	1/482 (0.21%)	0/238 (0.00%)
Malignant pleural effusion † 2	2/482 (0.41%)	0/238 (0.00%)
Metastases to central nervous system † 2	1/482 (0.21%)	0/238 (0.00%)
Metastases to eye † 2	1/482 (0.21%)	0/238 (0.00%)
Metastatic pain † 2	0/482 (0.00%)	1/238 (0.42%)
Oesophageal carcinoma † 2	1/482 (0.21%)	0/238 (0.00%)
Pituitary tumour benign † 2	0/482 (0.00%)	1/238 (0.42%)
Thyroid cancer † 2	0/482 (0.00%)	1/238 (0.42%)
Tumour haemorrhage † 2	1/482 (0.21%)	0/238 (0.00%)
Tumour pain † 2	1/482 (0.21%)	1/238 (0.42%)
Nervous system disorders
Cerebral infarction † 1	1/482 (0.21%)	0/238 (0.00%)
Convulsion † 1	1/482 (0.21%)	0/238 (0.00%)
Epilepsy † 1	1/482 (0.21%)	0/238 (0.00%)
Headache † 1	1/482 (0.21%)	0/238 (0.00%)
Hypersomnia † 1	1/482 (0.21%)	0/238 (0.00%)
Hypoaesthesia † 1	0/482 (0.00%)	1/238 (0.42%)
Intracranial pressure increased † 1	1/482 (0.21%)	0/238 (0.00%)
Lethargy † 1	1/482 (0.21%)	0/238 (0.00%)
Paraparesis † 1	1/482 (0.21%)	0/238 (0.00%)
Peripheral motor neuropathy † 1	0/482 (0.00%)	1/238 (0.42%)
Sciatica † 1	1/482 (0.21%)	0/238 (0.00%)
Spinal cord compression † 1	0/482 (0.00%)	1/238 (0.42%)
Syncope † 1	2/482 (0.41%)	0/238 (0.00%)
Transient ischaemic attack † 1	2/482 (0.41%)	0/238 (0.00%)
Tremor † 1	1/482 (0.21%)	0/238 (0.00%)
Carpal tunnel syndrome † 2	1/482 (0.21%)	0/238 (0.00%)
Cerebral infarction † 2	1/482 (0.21%)	0/238 (0.00%)
Convulsion † 2	1/482 (0.21%)	0/238 (0.00%)
Dizziness † 2	0/482 (0.00%)	1/238 (0.42%)
Epilepsy † 2	1/482 (0.21%)	0/238 (0.00%)
Headache † 2	2/482 (0.41%)	0/238 (0.00%)
Hypersomnia † 2	1/482 (0.21%)	0/238 (0.00%)
Hypoaesthesia † 2	0/482 (0.00%)	1/238 (0.42%)
Intracranial pressure increased † 2	1/482 (0.21%)	0/238 (0.00%)
Lethargy † 2	1/482 (0.21%)	0/238 (0.00%)
Paraparesis † 2	1/482 (0.21%)	0/238 (0.00%)
Peripheral motor neuropathy † 2	0/482 (0.00%)	1/238 (0.42%)
Sciatica † 2	1/482 (0.21%)	0/238 (0.00%)
Sensory disturbance † 2	1/482 (0.21%)	0/238 (0.00%)
Spinal cord compression † 2	0/482 (0.00%)	1/238 (0.42%)
Syncope † 2	2/482 (0.41%)	0/238 (0.00%)
Transient ischaemic attack † 2	2/482 (0.41%)	0/238 (0.00%)
Tremor † 2	1/482 (0.21%)	0/238 (0.00%)
Psychiatric disorders
Completed suicide † 1	1/482 (0.21%)	0/238 (0.00%)
Confusional state † 1	1/482 (0.21%)	0/238 (0.00%)
Delirium † 1	0/482 (0.00%)	1/238 (0.42%)
Mental status changes † 1	2/482 (0.41%)	1/238 (0.42%)
Bipolar disorder † 2	0/482 (0.00%)	1/238 (0.42%)
Completed suicide † 2	1/482 (0.21%)	0/238 (0.00%)
Confusional state † 2	2/482 (0.41%)	0/238 (0.00%)
Delirium † 2	1/482 (0.21%)	1/238 (0.42%)
Major depression † 2	0/482 (0.00%)	1/238 (0.42%)
Mania † 2	0/482 (0.00%)	1/238 (0.42%)
Mental status changes † 2	2/482 (0.41%)	1/238 (0.42%)
Substance-induced psychotic disorder † 2	0/482 (0.00%)	1/238 (0.42%)
Renal and urinary disorders
Azotaemia † 1	1/482 (0.21%)	0/238 (0.00%)
Hydronephrosis † 1	1/482 (0.21%)	0/238 (0.00%)
Renal disorder † 1	1/482 (0.21%)	0/238 (0.00%)
Renal failure † 1	5/482 (1.04%)	0/238 (0.00%)
Renal failure acute † 1	2/482 (0.41%)	0/238 (0.00%)
Renal impairment † 1	3/482 (0.62%)	0/238 (0.00%)
Azotaemia † 2	1/482 (0.21%)	0/238 (0.00%)
Bladder disorder † 2	1/482 (0.21%)	0/238 (0.00%)
Hydronephrosis † 2	1/482 (0.21%)	0/238 (0.00%)
Renal disorder † 2	1/482 (0.21%)	0/238 (0.00%)
Renal failure † 2	5/482 (1.04%)	0/238 (0.00%)
Renal failure acute † 2	4/482 (0.83%)	0/238 (0.00%)
Renal impairment † 2	3/482 (0.62%)	0/238 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome † 1	1/482 (0.21%)	0/238 (0.00%)
Cough † 1	2/482 (0.41%)	1/238 (0.42%)
Dyspnoea † 1	9/482 (1.87%)	2/238 (0.84%)
Dyspnoea exertional † 1	1/482 (0.21%)	1/238 (0.42%)
Haemoptysis † 1	2/482 (0.41%)	0/238 (0.00%)
Hypoxia † 1	1/482 (0.21%)	0/238 (0.00%)
Interstitial lung disease † 1	2/482 (0.41%)	0/238 (0.00%)
Lung disorder † 1	1/482 (0.21%)	0/238 (0.00%)
Pharyngeal inflammation † 1	1/482 (0.21%)	0/238 (0.00%)
Pleural effusion † 1	6/482 (1.24%)	1/238 (0.42%)
Pneumonitis † 1	12/482 (2.49%)	0/238 (0.00%)
Productive cough † 1	1/482 (0.21%)	0/238 (0.00%)
Pulmonary embolism † 1	7/482 (1.45%)	1/238 (0.42%)
Respiratory distress † 1	1/482 (0.21%)	0/238 (0.00%)
Acute respiratory distress syndrome † 2	1/482 (0.21%)	0/238 (0.00%)
Cough † 2	3/482 (0.62%)	1/238 (0.42%)
Dyspnoea † 2	12/482 (2.49%)	2/238 (0.84%)
Dyspnoea exertional † 2	2/482 (0.41%)	1/238 (0.42%)
Haemoptysis † 2	2/482 (0.41%)	0/238 (0.00%)
Hypoxia † 2	1/482 (0.21%)	0/238 (0.00%)
Interstitial lung disease † 2	5/482 (1.04%)	0/238 (0.00%)
Pharyngeal inflammation † 2	1/482 (0.21%)	0/238 (0.00%)
Pleural effusion † 2	6/482 (1.24%)	1/238 (0.42%)
Pneumonitis † 2	13/482 (2.70%)	0/238 (0.00%)
Productive cough † 2	1/482 (0.21%)	0/238 (0.00%)
Pulmonary embolism † 2	8/482 (1.66%)	1/238 (0.42%)
Respiratory distress † 2	1/482 (0.21%)	0/238 (0.00%)
Skin and subcutaneous tissue disorders
Angioedema † 1	1/482 (0.21%)	0/238 (0.00%)
Blister † 1	1/482 (0.21%)	0/238 (0.00%)
Dermatitis † 1	2/482 (0.41%)	0/238 (0.00%)
Erythema † 1	1/482 (0.21%)	0/238 (0.00%)
Pruritus † 1	1/482 (0.21%)	0/238 (0.00%)
Angioedema † 2	1/482 (0.21%)	0/238 (0.00%)
Blister † 2	1/482 (0.21%)	0/238 (0.00%)
Dermatitis † 2	2/482 (0.41%)	0/238 (0.00%)
Erythema † 2	1/482 (0.21%)	0/238 (0.00%)
Pruritus † 2	1/482 (0.21%)	0/238 (0.00%)
Skin necrosis † 2	1/482 (0.21%)	0/238 (0.00%)
Surgical and medical procedures
Preventive surgery † 1	0/482 (0.00%)	1/238 (0.42%)
Preventive surgery † 2	0/482 (0.00%)	1/238 (0.42%)
Vascular disorders
Deep vein thrombosis † 1	1/482 (0.21%)	0/238 (0.00%)
Embolism arterial † 1	0/482 (0.00%)	1/238 (0.42%)
Intra-abdominal haematoma † 1	1/482 (0.21%)	0/238 (0.00%)
Ischaemia † 1	1/482 (0.21%)	0/238 (0.00%)
Lymphoedema † 1	3/482 (0.62%)	0/238 (0.00%)
Thrombophlebitis † 1	1/482 (0.21%)	0/238 (0.00%)
Venous thrombosis limb † 1	1/482 (0.21%)	0/238 (0.00%)
Accelerated hypertension † 2	1/482 (0.21%)	0/238 (0.00%)
Deep vein thrombosis † 2	1/482 (0.21%)	0/238 (0.00%)
Embolism arterial † 2	0/482 (0.00%)	1/238 (0.42%)
Intra-abdominal haematoma † 2	1/482 (0.21%)	0/238 (0.00%)
Ischaemia † 2	1/482 (0.21%)	0/238 (0.00%)
Lymphoedema † 2	4/482 (0.83%)	0/238 (0.00%)
Thrombophlebitis † 2	1/482 (0.21%)	0/238 (0.00%)
Venous thrombosis limb † 2	1/482 (0.21%)	0/238 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA; 2 Term from vocabulary, MedDRA V16.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Everolimus + Exemestane	Placebo + Exemestane
	Affected / at Risk (%)	Affected / at Risk (%)
Total	479/482 (99.38%)	209/238 (87.82%)
Blood and lymphatic system disorders
Anaemia † 1	93/482 (19.29%)	9/238 (3.78%)
Leukopenia † 1	27/482 (5.60%)	3/238 (1.26%)
Neutropenia † 1	39/482 (8.09%)	3/238 (1.26%)
Thrombocytopenia † 1	61/482 (12.66%)	1/238 (0.42%)
Anaemia † 2	101/482 (20.95%)	11/238 (4.62%)
Leukopenia † 2	29/482 (6.02%)	4/238 (1.68%)
Neutropenia † 2	40/482 (8.30%)	4/238 (1.68%)
Thrombocytopenia † 2	63/482 (13.07%)	1/238 (0.42%)
Gastrointestinal disorders
Abdominal pain upper † 1	34/482 (7.05%)	7/238 (2.94%)
Constipation † 1	67/482 (13.90%)	31/238 (13.03%)
Diarrhoea † 1	157/482 (32.57%)	44/238 (18.49%)
Dry mouth † 1	51/482 (10.58%)	16/238 (6.72%)
Nausea † 1	138/482 (28.63%)	65/238 (27.31%)
Stomatitis † 1	281/482 (58.30%)	26/238 (10.92%)
Vomiting † 1	75/482 (15.56%)	27/238 (11.34%)
Abdominal pain † 2	25/482 (5.19%)	11/238 (4.62%)
Abdominal pain upper † 2	39/482 (8.09%)	7/238 (2.94%)
Constipation † 2	74/482 (15.35%)	31/238 (13.03%)
Diarrhoea † 2	172/482 (35.68%)	44/238 (18.49%)
Dry mouth † 2	55/482 (11.41%)	17/238 (7.14%)
Dyspepsia † 2	29/482 (6.02%)	12/238 (5.04%)
Nausea † 2	157/482 (32.57%)	69/238 (28.99%)
Stomatitis † 2	286/482 (59.34%)	28/238 (11.76%)
Vomiting † 2	88/482 (18.26%)	30/238 (12.61%)
General disorders
Asthenia † 1	63/482 (13.07%)	9/238 (3.78%)
Fatigue † 1	170/482 (35.27%)	65/238 (27.31%)
Oedema peripheral † 1	92/482 (19.09%)	15/238 (6.30%)
Pyrexia † 1	70/482 (14.52%)	12/238 (5.04%)
Asthenia † 2	70/482 (14.52%)	11/238 (4.62%)
Fatigue † 2	180/482 (37.34%)	65/238 (27.31%)
Oedema peripheral † 2	103/482 (21.37%)	15/238 (6.30%)
Pyrexia † 2	82/482 (17.01%)	13/238 (5.46%)
Infections and infestations
Nasopharyngitis † 1	46/482 (9.54%)	21/238 (8.82%)
Urinary tract infection † 1	45/482 (9.34%)	5/238 (2.10%)
Nasopharyngitis † 2	53/482 (11.00%)	21/238 (8.82%)
Upper respiratory tract infection † 2	32/482 (6.64%)	6/238 (2.52%)
Urinary tract infection † 2	49/482 (10.17%)	5/238 (2.10%)
Investigations
Alanine aminotransferase increased † 1	57/482 (11.83%)	10/238 (4.20%)
Aspartate aminotransferase increased † 1	64/482 (13.28%)	13/238 (5.46%)
Blood alkaline phosphatase increased † 1	12/482 (2.49%)	12/238 (5.04%)
Blood creatinine increased † 1	36/482 (7.47%)	2/238 (0.84%)
Blood lactate dehydrogenase increased † 1	27/482 (5.60%)	4/238 (1.68%)
Gamma-glutamyltransferase increased † 1	43/482 (8.92%)	20/238 (8.40%)
Weight decreased † 1	119/482 (24.69%)	15/238 (6.30%)
Alanine aminotransferase increased † 2	66/482 (13.69%)	11/238 (4.62%)
Aspartate aminotransferase increased † 2	75/482 (15.56%)	13/238 (5.46%)
Blood alkaline phosphatase increased † 2	18/482 (3.73%)	12/238 (5.04%)
Blood creatinine increased † 2	41/482 (8.51%)	3/238 (1.26%)
Blood lactate dehydrogenase increased † 2	30/482 (6.22%)	4/238 (1.68%)
Gamma-glutamyltransferase increased † 2	53/482 (11.00%)	20/238 (8.40%)
Weight decreased † 2	136/482 (28.22%)	17/238 (7.14%)
Metabolism and nutrition disorders
Decreased appetite † 1	142/482 (29.46%)	28/238 (11.76%)
Hypercholesterolaemia † 1	44/482 (9.13%)	2/238 (0.84%)
Hyperglycaemia † 1	63/482 (13.07%)	5/238 (2.10%)
Hypertriglyceridaemia † 1	26/482 (5.39%)	3/238 (1.26%)
Hypokalaemia † 1	34/482 (7.05%)	3/238 (1.26%)
Decreased appetite † 2	148/482 (30.71%)	31/238 (13.03%)
Hypercholesterolaemia † 2	50/482 (10.37%)	2/238 (0.84%)
Hyperglycaemia † 2	69/482 (14.32%)	5/238 (2.10%)
Hypertriglyceridaemia † 2	29/482 (6.02%)	3/238 (1.26%)
Hypokalaemia † 2	39/482 (8.09%)	4/238 (1.68%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	93/482 (19.29%)	40/238 (16.81%)
Back pain † 1	64/482 (13.28%)	23/238 (9.66%)
Bone pain † 1	31/482 (6.43%)	20/238 (8.40%)
Musculoskeletal chest pain † 1	29/482 (6.02%)	9/238 (3.78%)
Musculoskeletal pain † 1	24/482 (4.98%)	16/238 (6.72%)
Myalgia † 1	30/482 (6.22%)	15/238 (6.30%)
Pain in extremity † 1	41/482 (8.51%)	25/238 (10.50%)
Arthralgia † 2	107/482 (22.20%)	41/238 (17.23%)
Back pain † 2	81/482 (16.80%)	25/238 (10.50%)
Bone pain † 2	31/482 (6.43%)	15/238 (6.30%)
Musculoskeletal chest pain † 2	38/482 (7.88%)	10/238 (4.20%)
Musculoskeletal pain † 2	30/482 (6.22%)	17/238 (7.14%)
Myalgia † 2	35/482 (7.26%)	16/238 (6.72%)
Pain in extremity † 2	52/482 (10.79%)	26/238 (10.92%)
Nervous system disorders
Dizziness † 1	32/482 (6.64%)	15/238 (6.30%)
Dysgeusia † 1	104/482 (21.58%)	14/238 (5.88%)
Headache † 1	103/482 (21.37%)	34/238 (14.29%)
Dizziness † 2	38/482 (7.88%)	16/238 (6.72%)
Dysgeusia † 2	106/482 (21.99%)	14/238 (5.88%)
Headache † 2	112/482 (23.24%)	35/238 (14.71%)
Psychiatric disorders
Insomnia † 1	65/482 (13.49%)	19/238 (7.98%)
Anxiety † 2	25/482 (5.19%)	6/238 (2.52%)
Depression † 2	28/482 (5.81%)	11/238 (4.62%)
Insomnia † 2	68/482 (14.11%)	21/238 (8.82%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	116/482 (24.07%)	27/238 (11.34%)
Dyspnoea † 1	93/482 (19.29%)	24/238 (10.08%)
Epistaxis † 1	83/482 (17.22%)	3/238 (1.26%)
Oropharyngeal pain † 1	26/482 (5.39%)	7/238 (2.94%)
Pneumonitis † 1	66/482 (13.69%)	0/238 (0.00%)
Cough † 2	129/482 (26.76%)	27/238 (11.34%)
Dyspnoea † 2	105/482 (21.78%)	25/238 (10.50%)
Epistaxis † 2	86/482 (17.84%)	3/238 (1.26%)
Oropharyngeal pain † 2	29/482 (6.02%)	7/238 (2.94%)
Pneumonitis † 2	73/482 (15.15%)	0/238 (0.00%)
Skin and subcutaneous tissue disorders
Alopecia † 1	49/482 (10.17%)	11/238 (4.62%)
Dry skin † 1	35/482 (7.26%)	2/238 (0.84%)
Nail disorder † 1	38/482 (7.88%)	1/238 (0.42%)
Pruritus † 1	63/482 (13.07%)	11/238 (4.62%)
Rash † 1	186/482 (38.59%)	15/238 (6.30%)
Alopecia † 2	51/482 (10.58%)	12/238 (5.04%)
Dry skin † 2	39/482 (8.09%)	3/238 (1.26%)
Nail disorder † 2	40/482 (8.30%)	1/238 (0.42%)
Pruritus † 2	64/482 (13.28%)	11/238 (4.62%)
Rash † 2	190/482 (39.42%)	16/238 (6.72%)
Vascular disorders
Hot flush † 1	27/482 (5.60%)	34/238 (14.29%)
Hypertension † 1	39/482 (8.09%)	8/238 (3.36%)
Lymphoedema † 1	25/482 (5.19%)	4/238 (1.68%)
Hot flush † 2	31/482 (6.43%)	34/238 (14.29%)
Hypertension † 2	49/482 (10.17%)	9/238 (3.78%)
Lymphoedema † 2	30/482 (6.22%)	3/238 (1.26%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA; 2 Term from vocabulary, MedDRA V16.0

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.

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 the pooled data in the clinical trial.

Results Point of Contact

• Name/Title: Study Director
• Organization: Novartis Pharmaceuticals
• Phone: 862-778-8300

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

Wedam SB, Beaver JA, Amiri-Kordestani L, Bloomquist E, Tang S, Goldberg KB, Sridhara R, Ibrahim A, Kim G, Kluetz P, McKee A, Pazdur R. US Food and Drug Administration Pooled Analysis to Assess the Impact of Bone-Only Metastatic Breast Cancer on Clinical Trial Outcomes and Radiographic Assessments. J Clin Oncol. 2018 Apr 20;36(12):1225-1231. doi: 10.1200/JCO.2017.74.6917. Epub 2018 Mar 9.

Chandarlapaty S, Chen D, He W, Sung P, Samoila A, You D, Bhatt T, Patel P, Voi M, Gnant M, Hortobagyi G, Baselga J, Moynahan ME. Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial. JAMA Oncol. 2016 Oct 1;2(10):1310-1315. doi: 10.1001/jamaoncol.2016.1279. Erratum In: JAMA Oncol. 2019 Jan 1;5(1):122.

Hortobagyi GN, Chen D, Piccart M, Rugo HS, Burris HA 3rd, Pritchard KI, Campone M, Noguchi S, Perez AT, Deleu I, Shtivelband M, Masuda N, Dakhil S, Anderson I, Robinson DM, He W, Garg A, McDonald ER 3rd, Bitter H, Huang A, Taran T, Bachelot T, Lebrun F, Lebwohl D, Baselga J. Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2. J Clin Oncol. 2016 Feb 10;34(5):419-26. doi: 10.1200/JCO.2014.60.1971. Epub 2015 Oct 26. Erratum In: J Clin Oncol. 2019 Feb 1;37(4):354. J Clin Oncol. 2019 Feb 1;37(4):355.

Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, Noguchi S, Perez A, Rugo HS, Deleu I, Burris HA 3rd, Provencher L, Neven P, Gnant M, Shtivelband M, Wu C, Fan J, Feng W, Taran T, Baselga J. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2dagger. Ann Oncol. 2014 Dec;25(12):2357-2362. doi: 10.1093/annonc/mdu456. Epub 2014 Sep 17.

Rugo HS, Pritchard KI, Gnant M, Noguchi S, Piccart M, Hortobagyi G, Baselga J, Perez A, Geberth M, Csoszi T, Chouinard E, Srimuninnimit V, Puttawibul P, Eakle J, Feng W, Bauly H, El-Hashimy M, Taran T, Burris HA 3rd. Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2. Ann Oncol. 2014 Apr;25(4):808-815. doi: 10.1093/annonc/mdu009. Epub 2014 Mar 10.

Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M, Melichar B, Petrakova K, Arena FP, Erdkamp F, Harb WA, Feng W, Cahana A, Taran T, Lebwohl D, Rugo HS. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013 Oct;30(10):870-84. doi: 10.1007/s12325-013-0060-1. Epub 2013 Oct 25. Erratum In: Adv Ther. 2014 Sep;31(9):1008-9.

Campone M, Beck JT, Gnant M, Neven P, Pritchard KI, Bachelot T, Provencher L, Rugo HS, Piccart M, Hortobagyi GN, Nunzi M, Heng DY, Baselga J, Komorowski A, Noguchi S, Horiguchi J, Bennett L, Ziemiecki R, Zhang J, Cahana A, Taran T, Sahmoud T, Burris HA 3rd. Health-related quality of life and disease symptoms in postmenopausal women with HR(+), HER2(-) advanced breast cancer treated with everolimus plus exemestane versus exemestane monotherapy. Curr Med Res Opin. 2013 Nov;29(11):1463-73. doi: 10.1185/03007995.2013.836078. Epub 2013 Sep 4.

Noguchi S, Masuda N, Iwata H, Mukai H, Horiguchi J, Puttawibul P, Srimuninnimit V, Tokuda Y, Kuroi K, Iwase H, Inaji H, Ohsumi S, Noh WC, Nakayama T, Ohno S, Rai Y, Park BW, Panneerselvam A, El-Hashimy M, Taran T, Sahmoud T, Ito Y. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2. Breast Cancer. 2014 Nov;21(6):703-14. doi: 10.1007/s12282-013-0444-8. Epub 2013 Feb 13.

Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520-9. doi: 10.1056/NEJMoa1109653. Epub 2011 Dec 7.

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• ClinicalTrials.gov Identifier: NCT00863655
• Other Study ID Numbers: CRAD001Y2301; 2008-008698-69 ( EudraCT Number )
• First Submitted: March 16, 2009
• First Posted: March 18, 2009
• Results First Submitted: July 31, 2012
• Results First Posted: August 31, 2012
• Last Update Posted: May 2, 2017