Trial Outcomes & Findings for Eribulin Mesylate or Paclitaxel as First- or Second-Line Therapy in Treating Patients With Recurrent Stage IIIC-IV Breast Cancer (NCT NCT02037529)

NCT ID: NCT02037529

Last Updated: 2024-08-20

Results Overview

To demonstrate that patient-reported PRO-CTCAE data will be able to detect differences in symptoms between participants treated with eribulin and standard weekly paclitaxel at 12 weeks we will compare the mean change of overall Pro-CTCAE score by treatment arm. The overall Pro-CTCAE score is a normalized score scaled from 20 questions, each with a possible 1-5 patient selection, creating an overall score (0-100) where 0 represents the best outcome and 100 represents the worst possible outcome. The mean change from baseline to week 12 is reported.

Recruitment status

SUSPENDED

Study phase

PHASE3

Target enrollment

201 participants

Primary outcome timeframe

12 weeks

Results posted on

2024-08-20

Participant Flow

Participant milestones

Participant milestones
Measure	Arm A (Eribulin) Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Study STARTED	101	100
Overall Study COMPLETED	100	96
Overall Study NOT COMPLETED	1	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A (Eribulin) Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Study Withdrawal by Subject	1	3
Overall Study Adverse Event	0	1

Baseline Characteristics

Eribulin Mesylate or Paclitaxel as First- or Second-Line Therapy in Treating Patients With Recurrent Stage IIIC-IV Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A (Eribulin) n=101 Participants Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) n=100 Participants Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Total n=201 Participants Total of all reporting groups
Age, Continuous	62 years n=5 Participants	62 years n=7 Participants	62 years n=5 Participants
Sex: Female, Male Female	99 Participants n=5 Participants	100 Participants n=7 Participants	199 Participants n=5 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	95 Participants n=5 Participants	95 Participants n=7 Participants	190 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	12 Participants n=5 Participants	20 Participants n=7 Participants	32 Participants n=5 Participants
Race (NIH/OMB) White	85 Participants n=5 Participants	76 Participants n=7 Participants	161 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: 6 months

Population: All treated patients

To validate rs7349683 in EPHA5 as a predictor of peripheral neuropathy from treatment with a microtubule targeting agent (i.e., eribulin or paclitaxel) over the first 6 months of treatment we will compare the median cumulative dose level triggering a grade 2 or higher neuropathy event.

Outcome measures

Outcome measures
Measure	Arm A (Eribulin) n=100 Participants Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) n=98 Participants Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Cumulative Dose Level Triggering a Grade 2 or Higher Neuropathy Event.	39.25 mg/m^2 Interval 33.2 to 75.6	3950 mg/m^2 Interval 2442.0 to 6186.0

PRIMARY outcome

Timeframe: 12 weeks

Population: Treated patients that completed baseline and week 12 patient reported PRO-CTCAE packets.

Outcome measures

Outcome measures
Measure	Arm A (Eribulin) n=98 Participants Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) n=92 Participants Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Mean Change in Patient Reported PRO-CTCAE	3.72 score on a scale Standard Deviation 0.57	3.77 score on a scale Standard Deviation 0.61

SECONDARY outcome

Timeframe: 81 months

Population: All enrolled patients

The primary analysis will use the stratified log-rank tests, as described for overall survival. As a secondary analysis we will use a multivariable Cox proportional hazard model to estimate adjusted hazard ratios for eribulin mesylate over standard weekly paclitaxel, study stratification factors, and covariates for known prognostic factors, including disease free interval and visceral versus non-visceral metastases. Survival functions will be summarized using the Kaplan-Meier method according to treatment group.

Outcome measures

Outcome measures
Measure	Arm A (Eribulin) n=101 Participants Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) n=100 Participants Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Survival (OS)	18.1 months Interval 15.4 to 22.1	16.4 months Interval 14.5 to 23.3

SECONDARY outcome

Timeframe: 64 months

Population: All treated patients

Objective tumor response rate is assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

Outcome measures

Outcome measures
Measure	Arm A (Eribulin) n=100 Participants Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) n=98 Participants Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Objective Tumor Response Rate	0.14 proportion of participants	0.21 proportion of participants

SECONDARY outcome

Timeframe: 75 months

Population: All patients that achieved a response.

Will be summarized using the Kaplan-Meier method. Will use a two-sided type I alpha of 0.05, and point estimates will be reported with 95% confidence intervals. Duration of response is the time between a tumor response and progression.

Outcome measures

Outcome measures
Measure	Arm A (Eribulin) n=29 Participants Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) n=32 Participants Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Duration of Response	13.7 Months Interval 9.0 to 19.6	14.1 Months Interval 8.4 to 19.8

SECONDARY outcome

Timeframe: 64 months

Will use a two-sided type I alpha of 0.05, and point estimates will be reported with 95% confidence intervals.

Outcome measures

Outcome measures
Measure	Arm A (Eribulin) n=101 Participants Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) n=100 Participants Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Time to Treatment Failure	5.3 Months Interval 3.7 to 5.6	4.9 Months Interval 3.2 to 5.5

SECONDARY outcome

Timeframe: 64 months

Population: All enrolled patients

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. Each CTCAE term in the current version is a unique representation of a specific event used for medical documentation and scientific analysis and is a single MedDRA Lowest Level Term (LLT). Events determined to be possibly or probably attributed to a medical treatment suggest there is evidence to indicate a causal relationship between the drug and the adverse event. The number of patients that experienced an AE, of any grade, determined to be possibly or probably attributed to a medical treatment will be reported by arm.

Outcome measures

Outcome measures
Measure	Arm A (Eribulin) n=101 Participants Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) n=100 Participants Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Incidence of Treatment Related Adverse Events	94 Participants	90 Participants

SECONDARY outcome

Timeframe: 81 months

Will be summarized using the Kaplan-Meier method. Will use a two-sided type I alpha of 0.05, and point estimates will be reported with 95% confidence intervals.

Outcome measures

Outcome measures
Measure	Arm A (Eribulin) n=101 Participants Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) n=100 Participants Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Time to New Metastasis	8.2 Months Interval 5.7 to 16.9	8.7 Months Interval 6.0 to 11.3

SECONDARY outcome

Timeframe: 80 months

Will be summarized using the Kaplan-Meier method. Will use a two-sided type I alpha of 0.05, and point estimates will be reported with 95% confidence intervals. Progression free survival time is the time from date of randomization to the date of first progression or death.

Outcome measures

Outcome measures
Measure	Arm A (Eribulin) n=101 Participants Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) n=100 Participants Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Progression Free Survival Assessed by RECIST 1.1 Criteria	5.7 Months Interval 5.4 to 7.1	5.9 Months Interval 5.3 to 8.3

SECONDARY outcome

Timeframe: 24 weeks

Additional analyses will include the previously described analysis conducted over the first 24 weeks; a comparison of the incidence of patient-reported maximum score \>= 3 between arms through 12 and 24 weeks using chi-squared testing for each item; and a comparison of the time to patient-reported score \>= 3 between arms using Kaplan-Meier and log-rank analyses. Further, these three endpoints will be compared between patient- and clinician-report overall and within arms using appropriate paired analyses.

Outcome measures

Outcome measures
Measure	Arm A (Eribulin) n=101 Participants Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) n=100 Participants Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients With Reported Neurotoxicity	26 Participants	31 Participants

SECONDARY outcome

Timeframe: At baseline, 12, and 24 weeks

Population: This analysis was pre-specified in the Statistical Analysis Plan to be conducted overall and not separately for each of the arms. Only patients that fully filled out and submitted their PRO-CTCAE and EORTC QLQ-CIPN20 packets are included in this analysis.

The PRO-CTCAE sensory neuropathy items will be further validated by computing Pearson correlations between each item, severity and interference, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-Chemotherapy-Induced Peripheral Neuropathy 20 (CIPN20 )sensory scale score at baseline, 12 and 24 weeks.

Outcome measures

Outcome measures
Measure	Arm A (Eribulin) n=154 Participants Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Validation of PRO-CTCAE Sensory Neuropathy Item Week 12 - severity	0.71 Pearson correlation	—
Validation of PRO-CTCAE Sensory Neuropathy Item Week 24 - severity	0.79 Pearson correlation	—
Validation of PRO-CTCAE Sensory Neuropathy Item Week 12 - interference	0.51 Pearson correlation	—
Validation of PRO-CTCAE Sensory Neuropathy Item Week 24 - interference	0.85 Pearson correlation	—
Validation of PRO-CTCAE Sensory Neuropathy Item Baseline - Severity	0.72 Pearson correlation	—
Validation of PRO-CTCAE Sensory Neuropathy Item Baseline - interference	0.67 Pearson correlation	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 5 years

Will be summarized using the Kaplan-Meier method according to treatment group.

Outcome measures

Outcome data not reported

Adverse Events

Arm A (Eribulin)

Serious events: 30 serious events

Other events: 99 other events

Deaths: 80 deaths

Arm B (Paclitaxel)

Serious events: 30 serious events

Other events: 95 other events

Deaths: 79 deaths

Serious adverse events

Other adverse events

Additional Information

Minetta Liu

Mayo Clinic

Phone: 5072930526

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Arm A (Eribulin) n=101 participants at risk Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Arm B (Paclitaxel) n=100 participants at risk Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Blood and lymphatic system disorders Anemia	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Blood and lymphatic system disorders Febrile neutropenia	2.0% 2/101 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Cardiac disorders Atrial fibrillation	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Cardiac disorders Cardiac arrest	2.0% 2/101 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Cardiac disorders Chest pain - cardiac	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Cardiac disorders Heart failure	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Cardiac disorders Pericardial effusion	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	2.0% 2/100 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Cardiac disorders Restrictive cardiomyopathy	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Cardiac disorders Sinus tachycardia	2.0% 2/101 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Gastrointestinal disorders Abdominal pain	2.0% 2/101 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Gastrointestinal disorders Colitis	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Gastrointestinal disorders Constipation	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	2.0% 2/100 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Gastrointestinal disorders Diarrhea	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Gastrointestinal disorders Gastric ulcer	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Gastrointestinal disorders Mucositis oral	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Gastrointestinal disorders Nausea	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Gastrointestinal disorders Small intestinal obstruction	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Gastrointestinal disorders Vomiting	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
General disorders Death NOS	3.0% 3/101 • Number of events 3 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
General disorders Edema limbs	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
General disorders Flu like symptoms	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
General disorders Gait disturbance	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
General disorders Non-cardiac chest pain	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
General disorders Pain	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Immune system disorders Allergic reaction	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Infections and infestations Catheter related infection	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	2.0% 2/100 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Infections and infestations Infections and infestations - Oth spec	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Infections and infestations Lung infection	2.0% 2/101 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.	3.0% 3/100 • Number of events 3 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Infections and infestations Sepsis	2.0% 2/101 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Infections and infestations Skin infection	2.0% 2/101 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Infections and infestations Urinary tract infection	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Injury, poisoning and procedural complications Fall	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Injury, poisoning and procedural complications Fracture	3.0% 3/101 • Number of events 3 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Injury, poisoning and procedural complications Infusion related reaction	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Injury, poisoning and procedural complications Vascular access complication	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Investigations Aspartate aminotransferase increased	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Investigations Cardiac troponin I increased	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Investigations Investigations - Other, specify	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	2.0% 2/100 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Investigations Neutrophil count decreased	2.0% 2/101 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Metabolism and nutrition disorders Dehydration	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Metabolism and nutrition disorders Hyponatremia	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	2.0% 2/100 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Musculoskeletal and connective tissue disorders Bone pain	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Musculoskeletal and connective tissue disorders Muscle weakness lower limb	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, mal, uncpec - Oth spec	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	2.0% 2/100 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Nervous system disorders Encephalopathy	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Nervous system disorders Nervous system disorders - Oth spec	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Nervous system disorders Peripheral sensory neuropathy	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	2.0% 2/100 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Nervous system disorders Seizure	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Psychiatric disorders Confusion	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Renal and urinary disorders Acute kidney injury	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Renal and urinary disorders Renal and urinary disorders - Oth spec	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Respiratory, thoracic and mediastinal disorders Aspiration	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Respiratory, thoracic and mediastinal disorders Dyspnea	4.0% 4/101 • Number of events 4 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Respiratory, thoracic and mediastinal disorders Hypoxia	4.0% 4/101 • Number of events 4 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Respiratory, thoracic and mediastinal disorders Pleural effusion	2.0% 2/101 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	2.0% 2/100 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Vascular disorders Hypertension	0.99% 1/101 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.	0.00% 0/100 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Vascular disorders Lymphedema	0.00% 0/101 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.
Vascular disorders Thromboembolic event	2.0% 2/101 • Number of events 2 • Adverse events were followed for 64 months and mortality was followed for 81 months.	1.0% 1/100 • Number of events 1 • Adverse events were followed for 64 months and mortality was followed for 81 months.