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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
Genentech
ClinicalTrials.gov Identifier:
NCT00567190
First received: December 3, 2007
Last updated: January 22, 2014
Last verified: January 2014
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     406  
COMPLETED     315     287  
NOT COMPLETED     87     119  
Death                 69                 96  
Withdrew Consent                 12                 18  
Lost to Follow-up                 6                 5  



  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.
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.
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: participants]
     
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 data cut-off (up to 3 years, 3 months) ]

Measure Type Primary
Measure Title Progression-free Survival (PFS) Determined by an Independent Review Facility
Measure Description PFS was defined as the time from randomization to first documented disease progression (PD) using Response Evaluation Criteria in Solid Tumors (RECIST) or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions were selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, were identified as target lesions.
Time Frame Baseline to data cut-off (up to 3 years, 3 months)  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients.

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.

Measured Values
    Pertuzumab + Trastuzumab + Docetaxel     Placebo + Trastuzumab + Docetaxel  
Number of Participants Analyzed  
[units: participants]
  402     406  
Progression-free Survival (PFS) Determined by an Independent Review Facility  
[units: Months]
Median ( 95% Confidence Interval )
  18.5  
  ( 15.0 to 23.0 )  
  12.4  
  ( 10.0 to 13.0 )  

No statistical analysis provided for Progression-free Survival (PFS) Determined by an Independent Review Facility



2.  Secondary:   Overall Survival   [ Time Frame: Baseline to data cut-off (up to 3 years, 3 months) ]

Measure Type Secondary
Measure Title Overall Survival
Measure Description Overall survival was defined as the time from randomization to death from any cause.
Time Frame Baseline to data cut-off (up to 3 years, 3 months)  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients.

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.

Measured Values
    Pertuzumab + Trastuzumab + Docetaxel     Placebo + Trastuzumab + Docetaxel  
Number of Participants Analyzed  
[units: participants]
  402     406  
Overall Survival  
[units: Months]
Median ( 95% Confidence Interval )
  NA  
  ( 30 to NA ) [1]
  NA  
  ( NA to NA ) [1]
[1] An insufficient number of patients had died to calculate the outcome measure.

No statistical analysis provided for Overall Survival



3.  Secondary:   Progression-free Survival (PFS) Determined by the Investigator   [ Time Frame: Baseline to data cut-off (up to 3 years, 3 months) ]

Measure Type Secondary
Measure Title Progression-free Survival (PFS) Determined by the Investigator
Measure Description PFS was defined as the time from randomization to first documented disease progression (PD) using Response Evaluation Criteria in Solid Tumors (RECIST) or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions were selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, were identified as target lesions.
Time Frame Baseline to data cut-off (up to 3 years, 3 months)  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients.

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.

Measured Values
    Pertuzumab + Trastuzumab + Docetaxel     Placebo + Trastuzumab + Docetaxel  
Number of Participants Analyzed  
[units: participants]
  402     406  
Progression-free Survival (PFS) Determined by the Investigator  
[units: Months]
Median ( 95% Confidence Interval )
  18.5  
  ( 16.0 to 21.0 )  
  12.4  
  ( 10.0 to 13.0 )  

No statistical analysis provided for Progression-free Survival (PFS) Determined by the Investigator



4.  Secondary:   Objective Response   [ Time Frame: Baseline to data cut-off (up to 3 years, 3 months) ]

Measure Type Secondary
Measure Title Objective Response
Measure Description A patient had an objective response if they had a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart as determined by the investigator using RECIST. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions; a partial response was defined as the persistence of 1 or more non-target lesions.
Time Frame Baseline to data cut-off (up to 3 years, 3 months)  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients. Only patients with measurable disease at baseline were included in the analysis.

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.

Measured Values
    Pertuzumab + Trastuzumab + Docetaxel     Placebo + Trastuzumab + Docetaxel  
Number of Participants Analyzed  
[units: participants]
  343     336  
Objective Response  
[units: Percentage¬†of¬†patients]
Number ( 95% Confidence Interval )
  80.2  
  ( 75.6 to 84.3 )  
  69.3  
  ( 64.1 to 74.2 )  

No statistical analysis provided for Objective Response



5.  Secondary:   Duration of Objective Response   [ Time Frame: Baseline to data cut-off (up to 3 years, 3 months) ]

Measure Type Secondary
Measure Title Duration of Objective Response
Measure Description Duration of objective response was defined as the time from the initial response to documented disease progression or death from any cause, whichever occurred first.
Time Frame Baseline to data cut-off (up to 3 years, 3 months)  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients. Only patients with an objective response were included in the analysis.

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.

Measured Values
    Pertuzumab + Trastuzumab + Docetaxel     Placebo + Trastuzumab + Docetaxel  
Number of Participants Analyzed  
[units: participants]
  275     233  
Duration of Objective Response  
[units: Weeks]
Median ( 95% Confidence Interval )
  87.6  
  ( 71.0 to 106.0 )  
  54.1  
  ( 46.0 to 64.0 )  

No statistical analysis provided for Duration of Objective Response



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

Measure Type Secondary
Measure Title Time to Symptom Progression
Measure Description Time to symptom progression was defined as the time from randomization to the first symptom progression as measured by the Functional Assessment of Cancer Therapy-for patients with Breast Cancer (FACT-B) questionnaire with the Trial Outcomes Index-Physical/Functional/Breast (TOI-PFB) subscale. The FACT-B TOI-PFB subscale contains 24 items from 3 subsections of the FACT-B questionnaire: Physical well-being, functional well-being, and additional concerns for breast cancer patients (breast cancer subscale [BCS]). All items in the questionnaire were rated by the patient on a 5-point scale ranging from 0 (“not at all”) to 4 (“very much”). The total score ranged from 0 to 96. A higher score indicates better perceived quality of life. A positive change score from baseline indicates improvement. Symptom progression was defined as a decrease from baseline of 5 points or more.
Time Frame Baseline to data cut-off (up to 3 years, 3 months)  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients. Only female patients were included in the analysis.

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.

Measured Values
    Pertuzumab + Trastuzumab + Docetaxel     Placebo + Trastuzumab + Docetaxel  
Number of Participants Analyzed  
[units: participants]
  402     404  
Time to Symptom Progression  
[units: Weeks]
Median ( 95% Confidence Interval )
  18.4  
  ( 18.0 to 27.0 )  
  18.3  
  ( 18.0 to 27.0 )  

No statistical analysis provided for Time to Symptom Progression




  Serious Adverse Events
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Time Frame Baseline to data cut-off (up to 3 years, 3 months)
Additional Description Safety analysis population: All patients (Pt) who received any study treatment. Of the Pt who started the study (pertuzumab [Per]=402, placebo[Pla]=406) group, 2 Pt in each group received no treatment, 8 Pla Pt received at least 1 dose of Per, and 1 Per Pt received Pla at every cycle, resulting in Per=407 (402-2+8-1) and Pla=397 (406-2-8+1).

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.

Serious Adverse Events
    Pertuzumab + Trastuzumab + Docetaxel     Placebo + Trastuzumab + Docetaxel  
Total, serious adverse events      
# participants affected / at risk     140/407 (34.40%)     104/397 (26.20%)  
Blood and lymphatic system disorders      
Febrile neutropenia † 1    
# participants affected / at risk     46/407 (11.30%)     20/397 (5.04%)  
Neutropenia † 1    
# participants affected / at risk     18/407 (4.42%)     19/397 (4.79%)  
Anaemia † 1    
# participants affected / at risk     3/407 (0.74%)     3/397 (0.76%)  
Granulocytopenia † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Leukopenia † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Cardiac disorders      
Left ventricular dysfunction † 1    
# participants affected / at risk     4/407 (0.98%)     7/397 (1.76%)  
Atrial fibrillation † 1    
# participants affected / at risk     0/407 (0.00%)     2/397 (0.50%)  
Myocardial infarction † 1    
# participants affected / at risk     0/407 (0.00%)     2/397 (0.50%)  
Myocardial ischaemia † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Tachyarrhythmia † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Ventricular fibrillation † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Gastrointestinal disorders      
Diarrhoea † 1    
# participants affected / at risk     11/407 (2.70%)     5/397 (1.26%)  
Vomiting † 1    
# participants affected / at risk     2/407 (0.49%)     1/397 (0.25%)  
Constipation † 1    
# participants affected / at risk     0/407 (0.00%)     2/397 (0.50%)  
Intestinal perforation † 1    
# participants affected / at risk     0/407 (0.00%)     2/397 (0.50%)  
Oesophagitis † 1    
# participants affected / at risk     2/407 (0.49%)     0/397 (0.00%)  
Abdominal pain † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Duodenal ulcer † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Duodenal ulcer haemorrhage † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Gastrointestinal haemorrhage † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Haemorrhoidal haemorrhage † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Haemorrhoids † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Intestinal ischaemia † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Intestinal obstruction † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Nausea † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Rectal haemorrhage † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Upper gastrointestinal haemorrhage † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
General disorders      
Pyrexia † 1    
# participants affected / at risk     6/407 (1.47%)     3/397 (0.76%)  
Chest pain † 1    
# participants affected / at risk     1/407 (0.25%)     2/397 (0.50%)  
Fatigue † 1    
# participants affected / at risk     2/407 (0.49%)     1/397 (0.25%)  
Asthenia † 1    
# participants affected / at risk     2/407 (0.49%)     0/397 (0.00%)  
General physical health deterioration † 1    
# participants affected / at risk     0/407 (0.00%)     2/397 (0.50%)  
Influenza like illness † 1    
# participants affected / at risk     2/407 (0.49%)     0/397 (0.00%)  
Mucosal inflammation † 1    
# participants affected / at risk     1/407 (0.25%)     1/397 (0.25%)  
Death † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Hepatobiliary disorders      
Cholecystitis acute † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Cholelithiasis † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Hepatic failure † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Immune system disorders      
Drug hypersensitivity † 1    
# participants affected / at risk     3/407 (0.74%)     3/397 (0.76%)  
Hypersensitivity † 1    
# participants affected / at risk     3/407 (0.74%)     0/397 (0.00%)  
Anaphylactic reaction † 1    
# participants affected / at risk     1/407 (0.25%)     1/397 (0.25%)  
Infections and infestations      
Pneumonia † 1    
# participants affected / at risk     5/407 (1.23%)     7/397 (1.76%)  
Cellulitis † 1    
# participants affected / at risk     7/407 (1.72%)     2/397 (0.50%)  
Neutropenic infection † 1    
# participants affected / at risk     4/407 (0.98%)     1/397 (0.25%)  
Herpes zoster † 1    
# participants affected / at risk     1/407 (0.25%)     3/397 (0.76%)  
Sepsis † 1    
# participants affected / at risk     1/407 (0.25%)     3/397 (0.76%)  
Urinary tract infection † 1    
# participants affected / at risk     3/407 (0.74%)     1/397 (0.25%)  
Gastroenteritis † 1    
# participants affected / at risk     2/407 (0.49%)     1/397 (0.25%)  
Lower respiratory tract infection † 1    
# participants affected / at risk     3/407 (0.74%)     0/397 (0.00%)  
Device related infection † 1    
# participants affected / at risk     1/407 (0.25%)     1/397 (0.25%)  
Neutropenic sepsis † 1    
# participants affected / at risk     0/407 (0.00%)     2/397 (0.50%)  
Pharyngitis † 1    
# participants affected / at risk     2/407 (0.49%)     0/397 (0.00%)  
Respiratory tract infection † 1    
# participants affected / at risk     1/407 (0.25%)     1/397 (0.25%)  
Septic shock † 1    
# participants affected / at risk     1/407 (0.25%)     1/397 (0.25%)  
Upper respiratory tract infection † 1    
# participants affected / at risk     2/407 (0.49%)     0/397 (0.00%)  
Urosepsis † 1    
# participants affected / at risk     2/407 (0.49%)     0/397 (0.00%)  
Viral infection † 1    
# participants affected / at risk     0/407 (0.00%)     2/397 (0.50%)  
Anal abscess † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Appendicitis † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Breast abscess † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Bronchopneumonia † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Campylobacter intestinal infection † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Catheter site infection † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Clostridium difficile colitis † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Coccidioidomycosis † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Diarrhoea infectious † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Erysipelas † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Gastrointestinal infection † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
H1N1 influenza † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Oral candidiasis † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Osteomyelitis † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Osteomyelitis chronic † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Pneumonia staphylococcal † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Postoperative wound infection † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Pyelonephritis acute † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Rash pustular † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Respiratory tract infection viral † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Sepsis syndrome † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Skin infection † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Wound infection † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Infection † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Injury, poisoning and procedural complications      
Femur fracture † 1    
# participants affected / at risk     2/407 (0.49%)     1/397 (0.25%)  
Fracture † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Post procedural discomfort † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Scapula fracture † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Tendon injury † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Tibia fracture † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Investigations      
Blood electrolytes abnormal † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Blood glucose increased † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Metabolism and nutrition disorders      
Dehydration † 1    
# participants affected / at risk     1/407 (0.25%)     2/397 (0.50%)  
Decreased appetite † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Diabetes mellitus † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Fluid retention † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Hypoglycaemia † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Musculoskeletal and connective tissue disorders      
Back pain † 1    
# participants affected / at risk     2/407 (0.49%)     1/397 (0.25%)  
Myalgia † 1    
# participants affected / at risk     1/407 (0.25%)     1/397 (0.25%)  
Muscular weakness † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Neck pain † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Osteonecrosis of jaw † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Breast cancer † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Colon cancer † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Endometrial cancer † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Ocular neoplasm † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Tumour haemorrhage † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Uterine leiomyoma † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Nervous system disorders      
Cerebrovascular accident † 1    
# participants affected / at risk     1/407 (0.25%)     1/397 (0.25%)  
Convulsion † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Monoparesis † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Peripheral sensorimotor neuropathy † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Somnolence † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Spinal cord compression † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Syncope † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Pregnancy, puerperium and perinatal conditions      
Abortion spontaneous † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Psychiatric disorders      
Suicide attempt † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Renal and urinary disorders      
Renal failure † 1    
# participants affected / at risk     1/407 (0.25%)     1/397 (0.25%)  
Renal failure acute † 1    
# participants affected / at risk     0/407 (0.00%)     2/397 (0.50%)  
Acute prerenal failure † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Haematuria † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Reproductive system and breast disorders      
Breast haemorrhage † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Metrorrhagia † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Respiratory, thoracic and mediastinal disorders      
Pleural effusion † 1    
# participants affected / at risk     2/407 (0.49%)     4/397 (1.01%)  
Dyspnoea † 1    
# participants affected / at risk     2/407 (0.49%)     2/397 (0.50%)  
Pulmonary embolism † 1    
# participants affected / at risk     4/407 (0.98%)     0/397 (0.00%)  
Interstitial lung disease † 1    
# participants affected / at risk     2/407 (0.49%)     0/397 (0.00%)  
Asthma † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Haemoptysis † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Pneumonia aspiration † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Pneumonitis † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Pneumothorax † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Respiratory failure † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Skin and subcutaneous tissue disorders      
Dermatitis allergic † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Drug eruption † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Rash maculo-papular † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Surgical and medical procedures      
Abortion induced † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Vascular disorders      
Deep vein thrombosis † 1    
# participants affected / at risk     3/407 (0.74%)     0/397 (0.00%)  
Haematoma † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Hypertension † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Hypertensive crisis † 1    
# participants affected / at risk     0/407 (0.00%)     1/397 (0.25%)  
Hypotension † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Venous thrombosis limb † 1    
# participants affected / at risk     1/407 (0.25%)     0/397 (0.00%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA (14.0)




  Other Adverse Events


  Limitations and Caveats
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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
The survival data at the time of the data cut-off were not mature.


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