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A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer (CLEOPATRA) (CLEOPATRA)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT00567190
First received: December 3, 2007
Last updated: April 6, 2016
Last verified: April 2016
Results First Received: August 14, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Metastatic Breast Cancer
Interventions: Drug: Pertuzumab
Drug: Placebo
Drug: Trastuzumab
Drug: Docetaxel

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Pertuzumab + Trastuzumab + Docetaxel Patients received pertuzumab 420 mg intravenously (IV) every 3 weeks (q3w) plus trastuzumab 6 mg/kg IV q3w plus docetaxel 75 mg/m^2 IV q3w for at least 6 cycles.
Placebo + Trastuzumab + Docetaxel Patients received placebo IV q3w plus trastuzumab 6 mg/kg IV q3w plus docetaxel 75 mg/m^2 IV q3w for at least 6 cycles.

Participant Flow:   Overall Study
    Pertuzumab + Trastuzumab + Docetaxel     Placebo + Trastuzumab + Docetaxel  
STARTED     402 [1]   406 [1]
COMPLETED     192 [2]   142 [3]
NOT COMPLETED     210     264  
Death                 168                 221  
Withdrew Consent or Lost to Follow-up                 42                 43  
[1] All randomized patients (Intent-to-Treat [ITT]) population
[2] On 11 February 2014, 67 were alive and on study treatment; 125 were alive and in survival follow-up
[3] On 11 February 2014, 37 were alive and on study treatment; 105 were alive and in survival follow-up



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population

Reporting Groups
  Description
Pertuzumab + Trastuzumab + Docetaxel Patients received pertuzumab 420 mg intravenously (IV) every 3 weeks (q3w) plus trastuzumab 6 mg/kg IV q3w plus docetaxel 75 mg/m^2 IV q3w for at least 6 cycles.
Placebo + Trastuzumab + Docetaxel Patients received placebo IV q3w plus trastuzumab 6 mg/kg IV q3w plus docetaxel 75 mg/m^2 IV q3w for at least 6 cycles.
Total Total of all reporting groups

Baseline Measures
    Pertuzumab + Trastuzumab + Docetaxel     Placebo + Trastuzumab + Docetaxel     Total  
Number of Participants  
[units: participants]
  402     406     808  
Age  
[units: years]
Mean (Standard Deviation)
  53.4  (10.94)     53.5  (11.35)     53.5  (11.14)  
Gender  
[units: Patients]
     
Female     402     404     806  
Male     0     2     2  



  Outcome Measures
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1.  Primary:   Progression-free Survival (PFS) Determined by an Independent Review Facility   [ Time Frame: Baseline to primary data cut-off on 13 May 2011 (up to 3 years, 3 months) ]

2.  Secondary:   Overall Survival   [ Time Frame: Baseline to the third data cut-off (11 February 2014) at 389 deaths (approximately 43 months after enrollment of the last patient, up to 6 years overall) ]

3.  Secondary:   Progression-free Survival (PFS) Determined by the Investigator   [ Time Frame: Baseline to the third data cut-off (11 February 2014) at 389 deaths (approximately 43 months after enrollment of the last patient, up to 6 years overall) ]

4.  Secondary:   Objective Response Determined by an Independent Review Facility   [ Time Frame: Baseline to primary data cut-off on 13 May 2011 (up to 3 years, 3 months) ]

5.  Secondary:   Duration of Objective Response Determined by an Independent Review Facility   [ Time Frame: Baseline to primary data cut-off on 13 May 2011 (up to 3 years, 3 months) ]

6.  Secondary:   Time to Symptom Progression   [ Time Frame: Baseline to primary data cut-off on 13 May 2011 (up to 3 years, 3 months) ]


  Serious Adverse Events
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Time Frame First treatment dose (12 February 2008) through final data analysis cut-off (11 February 2014) for a total safety analysis time frame of 6 years. The AE data derived from a snapshot taken on 24 March 2014 of the final analysis dataset (11 February 2014).
Additional Description Of those who started the study (pertuzumab [Ptz]=402, placebo[Pla]=406), 2 patients in each group received no treatment (total of 4), 9 Pla patients received at least 1 dose of Ptz, 1 Ptz patient received Pla at every cycle; resulting in Ptz=408 (402-2+9-1) and Pla=396 (406-2-9+1)

Reporting Groups
  Description
Placebo + Trastuzumab + Docetaxel Patients received placebo IV q3w plus trastuzumab 6 mg/kg IV q3w plus docetaxel 75 mg/m^2 IV q3w for at least 6 cycles. For the 48 patients that crossed over to the pertuzumab treatment group, AEs were analyzed from the day of their first placebo dose (Day 1) through the day just prior to their first pertuzumab dose. Any AEs occurring on, or after, the day of their first dose of pertuzumab were included in the Crossover treatment group analysis.
Pertuzumab + Trastuzumab + Docetaxel Patients received pertuzumab 420 mg intravenously (IV) every 3 weeks (q3w) plus trastuzumab 6 mg/kg IV q3w plus docetaxel 75 mg/m^2 IV q3w for at least 6 cycles.
Crossover From Placebo to Pertuzumab Forty-eight of 406 patients (11.8%) randomized to the placebo treatment group whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2012. Patients received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w until investigator-assessed radiographic or clinical evidence of PD, unacceptable toxicity, or withdrawal of consent. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol.

Serious Adverse Events
    Placebo + Trastuzumab + Docetaxel     Pertuzumab + Trastuzumab + Docetaxel     Crossover From Placebo to Pertuzumab  
Total, serious adverse events        
# participants affected / at risk     116/396 (29.29%)     149/408 (36.52%)     6/48 (12.50%)  
Blood and lymphatic system disorders        
Anaemia † 1      
# participants affected / at risk     3/396 (0.76%)     3/408 (0.74%)     1/48 (2.08%)  
Febrile neutropenia † 1      
# participants affected / at risk     20/396 (5.05%)     46/408 (11.27%)     0/48 (0.00%)  
Granulocytopenia † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Leukopenia † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Neutropenia † 1      
# participants affected / at risk     19/396 (4.80%)     18/408 (4.41%)     0/48 (0.00%)  
Cardiac disorders        
Atrial fibrillation † 1      
# participants affected / at risk     3/396 (0.76%)     0/408 (0.00%)     0/48 (0.00%)  
Cardiac failure congestive † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Coronary artery disease † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Left ventricular dysfunction † 1      
# participants affected / at risk     7/396 (1.77%)     6/408 (1.47%)     0/48 (0.00%)  
Myocardial infarction † 1      
# participants affected / at risk     3/396 (0.76%)     0/408 (0.00%)     0/48 (0.00%)  
Myocardial ischaemia † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Ventricular fibrillation † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Ear and labyrinth disorders        
Vertigo † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Eye disorders        
Cataract † 1      
# participants affected / at risk     0/396 (0.00%)     2/408 (0.49%)     0/48 (0.00%)  
Gastrointestinal disorders        
Abdominal pain † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Colitis † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Constipation † 1      
# participants affected / at risk     2/396 (0.51%)     0/408 (0.00%)     0/48 (0.00%)  
Diarrhoea † 1      
# participants affected / at risk     5/396 (1.26%)     13/408 (3.19%)     1/48 (2.08%)  
Duodenal ulcer † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Duodenal ulcer haemorrhage † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Enteritis † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Gastrointestinal haemorrhage † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Haemorrhoidal haemorrhage † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Haemorrhoids † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Intestinal ischaemia † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Intestinal obstruction † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Intestinal perforation † 1      
# participants affected / at risk     2/396 (0.51%)     0/408 (0.00%)     0/48 (0.00%)  
Lower gastrointestinal haemorrhage † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Nausea † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Oesophagitis † 1      
# participants affected / at risk     0/396 (0.00%)     2/408 (0.49%)     0/48 (0.00%)  
Rectal haemorrhage † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Upper gastrointestinal haemorrhage † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Vomiting † 1      
# participants affected / at risk     1/396 (0.25%)     2/408 (0.49%)     0/48 (0.00%)  
General disorders        
Drowning † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Asthenia † 1      
# participants affected / at risk     0/396 (0.00%)     2/408 (0.49%)     0/48 (0.00%)  
Chest pain † 1      
# participants affected / at risk     2/396 (0.51%)     1/408 (0.25%)     0/48 (0.00%)  
Death † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     1/48 (2.08%)  
Fatigue † 1      
# participants affected / at risk     1/396 (0.25%)     2/408 (0.49%)     0/48 (0.00%)  
General physical health deterioration † 1      
# participants affected / at risk     2/396 (0.51%)     0/408 (0.00%)     0/48 (0.00%)  
Influenza like illness † 1      
# participants affected / at risk     0/396 (0.00%)     2/408 (0.49%)     0/48 (0.00%)  
Mucosal inflammation † 1      
# participants affected / at risk     1/396 (0.25%)     1/408 (0.25%)     0/48 (0.00%)  
Pyrexia † 1      
# participants affected / at risk     3/396 (0.76%)     6/408 (1.47%)     1/48 (2.08%)  
Hepatobiliary disorders        
Cholecystitis acute † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Cholelithiasis † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Hepatic failure † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Immune system disorders        
Anaphylactic reaction † 1      
# participants affected / at risk     1/396 (0.25%)     1/408 (0.25%)     0/48 (0.00%)  
Drug hypersensitivity † 1      
# participants affected / at risk     3/396 (0.76%)     3/408 (0.74%)     0/48 (0.00%)  
Hypersensitivity † 1      
# participants affected / at risk     0/396 (0.00%)     3/408 (0.74%)     0/48 (0.00%)  
Infections and infestations        
Acute sinusitis † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Anal abscess † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Appendicitis † 1      
# participants affected / at risk     0/396 (0.00%)     2/408 (0.49%)     0/48 (0.00%)  
Breast abscess † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Breast cellulitis † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Bronchopneumonia † 1      
# participants affected / at risk     2/396 (0.51%)     0/408 (0.00%)     0/48 (0.00%)  
Campylobacter gastroenteritis † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Catheter site infection † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Cellulitis † 1      
# participants affected / at risk     2/396 (0.51%)     10/408 (2.45%)     0/48 (0.00%)  
Cellulitis gangrenous † 1      
# participants affected / at risk     0/396 (0.00%)     0/408 (0.00%)     1/48 (2.08%)  
Clostridium difficile colitis † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Coccidioidomycosis † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Device related infection † 1      
# participants affected / at risk     1/396 (0.25%)     2/408 (0.49%)     0/48 (0.00%)  
Diarrhoea infectious † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Erysipelas † 1      
# participants affected / at risk     0/396 (0.00%)     2/408 (0.49%)     0/48 (0.00%)  
Gastroenteritis † 1      
# participants affected / at risk     2/396 (0.51%)     2/408 (0.49%)     0/48 (0.00%)  
Gastrointestinal infection † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
H1N1 influenza † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Herpes zoster † 1      
# participants affected / at risk     3/396 (0.76%)     1/408 (0.25%)     0/48 (0.00%)  
Infection † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Lower respiratory tract infection † 1      
# participants affected / at risk     0/396 (0.00%)     4/408 (0.98%)     0/48 (0.00%)  
Lymph node tuberculosis † 1      
# participants affected / at risk     0/396 (0.00%)     0/408 (0.00%)     1/48 (2.08%)  
Neutropenic infection † 1      
# participants affected / at risk     1/396 (0.25%)     4/408 (0.98%)     0/48 (0.00%)  
Neutropenic sepsis † 1      
# participants affected / at risk     2/396 (0.51%)     0/408 (0.00%)     0/48 (0.00%)  
Onychomycosis † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Oral candidiasis † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Osteomyelitis † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Osteomyelitis chronic † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Pharyngitis † 1      
# participants affected / at risk     0/396 (0.00%)     2/408 (0.49%)     0/48 (0.00%)  
Pneumonia † 1      
# participants affected / at risk     9/396 (2.27%)     5/408 (1.23%)     1/48 (2.08%)  
Pneumonia staphylococcal † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Postoperative wound infection † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Pyelonephritis acute † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Rash pustular † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Respiratory tract infection † 1      
# participants affected / at risk     1/396 (0.25%)     1/408 (0.25%)     0/48 (0.00%)  
Respiratory tract infection viral † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Sepsis † 1      
# participants affected / at risk     3/396 (0.76%)     1/408 (0.25%)     0/48 (0.00%)  
Sepsis syndrome † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Septic shock † 1      
# participants affected / at risk     1/396 (0.25%)     1/408 (0.25%)     0/48 (0.00%)  
Skin infection † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Soft tissue infection † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Upper respiratory tract infection † 1      
# participants affected / at risk     0/396 (0.00%)     2/408 (0.49%)     0/48 (0.00%)  
Urinary tract infection † 1      
# participants affected / at risk     1/396 (0.25%)     3/408 (0.74%)     0/48 (0.00%)  
Urosepsis † 1      
# participants affected / at risk     0/396 (0.00%)     2/408 (0.49%)     0/48 (0.00%)  
Viral infection † 1      
# participants affected / at risk     2/396 (0.51%)     0/408 (0.00%)     0/48 (0.00%)  
Wound infection † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Wound infection staphylococcal † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Injury, poisoning and procedural complications        
Compression fracture † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Contusion † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Femur fracture † 1      
# participants affected / at risk     1/396 (0.25%)     3/408 (0.74%)     0/48 (0.00%)  
Fracture † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Post procedural discomfort † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Scapula fracture † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Tendon injury † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Thermal burn † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Tibia fracture † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Investigations        
Blood electrolytes abnormal † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Blood glucose increased † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Ejection fracture decreased † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Metabolism and nutrition disorders        
Decreased appetite † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Dehydration † 1      
# participants affected / at risk     2/396 (0.51%)     1/408 (0.25%)     1/48 (2.08%)  
Diabetes mellitus † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Fluid retention † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Hyperglycaemia † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Hypoglycaemia † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Musculoskeletal and connective tissue disorders        
Back pain † 1      
# participants affected / at risk     1/396 (0.25%)     2/408 (0.49%)     0/48 (0.00%)  
Mobility decreased † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Muscular weakness † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Myalgia † 1      
# participants affected / at risk     1/396 (0.25%)     1/408 (0.25%)     0/48 (0.00%)  
Neck pain † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Osteonecrosis of jaw † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)        
Breast cancer † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Colon cancer † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Endometrial cancer † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Glioblastoma multiforme † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Ocular neoplasm † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Pituitary tumour benign † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Tumour haemorrhage † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Uterine leiomyoma † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Nervous system disorders        
Cerebrovascular accident † 1      
# participants affected / at risk     1/396 (0.25%)     1/408 (0.25%)     0/48 (0.00%)  
Convulsion † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Monoparesis † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Peripheral sensorimotor neuropathy † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Somnolence † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Spinal cord compression † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Syncope † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
VIIth nerve paralysis † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Pregnancy, puerperium and perinatal conditions        
Abortion spontaneous † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Psychiatric disorders        
Suicide attempt † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Renal and urinary disorders        
Acute prerenal failure † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Haematuria † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Nephrolithiasis † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Renal failure † 1      
# participants affected / at risk     1/396 (0.25%)     1/408 (0.25%)     0/48 (0.00%)  
Renal failure acute † 1      
# participants affected / at risk     2/396 (0.51%)     0/408 (0.00%)     0/48 (0.00%)  
Renal failure chronic † 1      
# participants affected / at risk     0/396 (0.00%)     0/408 (0.00%)     1/48 (2.08%)  
Reproductive system and breast disorders        
Breast haemorrhage † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Metrorrhagia † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Vaginal haemorrhage † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Respiratory, thoracic and mediastinal disorders        
Asthma † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Dyspnoea † 1      
# participants affected / at risk     2/396 (0.51%)     2/408 (0.49%)     0/48 (0.00%)  
Haemoptysis † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Interstitial lung disease † 1      
# participants affected / at risk     0/396 (0.00%)     2/408 (0.49%)     0/48 (0.00%)  
Pleural effusion † 1      
# participants affected / at risk     4/396 (1.01%)     2/408 (0.49%)     0/48 (0.00%)  
Pneumonia aspiration † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Pneumonitis † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Pneumothorax † 1      
# participants affected / at risk     1/396 (0.25%)     1/408 (0.25%)     0/48 (0.00%)  
Pulmonary embolism † 1      
# participants affected / at risk     0/396 (0.00%)     5/408 (1.23%)     0/48 (0.00%)  
Respiratory failure † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Skin and subcutaneous tissue disorders        
Dermatitis allergic † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Drug eruption † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Rash maculo-papular † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Surgical and medical procedures        
Abortion induced † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Vascular disorders        
Aortic stenosis † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Deep vein thrombosis † 1      
# participants affected / at risk     0/396 (0.00%)     3/408 (0.74%)     0/48 (0.00%)  
Haematoma † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Hypertension † 1      
# participants affected / at risk     1/396 (0.25%)     1/408 (0.25%)     0/48 (0.00%)  
Hypertensive crisis † 1      
# participants affected / at risk     1/396 (0.25%)     0/408 (0.00%)     0/48 (0.00%)  
Hypotension † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Venous thrombosis limb † 1      
# participants affected / at risk     0/396 (0.00%)     1/408 (0.25%)     0/48 (0.00%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 16.1




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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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