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A Study of Trastuzumab Emtansine Versus Capecitabine + Lapatinib in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer (EMILIA)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00829166
First received: January 22, 2009
Last updated: September 10, 2016
Last verified: September 2016
Results First Received: February 22, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Breast Cancer
Interventions: Drug: Trastuzumab emtansine
Drug: Lapatinib
Drug: Capecitabine

  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
Participants of "Lapatinib + Capecitabine" arm were allowed to cross over to receive trastuzumab emtansine based on statistically significant Overall Survival (OS) benefit in favor of trastuzumab emtansine demonstrated in second interim analysis (cut-off date 31 July 2012). The safety analysis of the arm was then reported.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) intravenous (IV) infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until disease progression (PD) (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 milligrams per square meter (mg/m^2) orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Participant Flow:   Overall Study
    Trastuzumab Emtansine   Lapatinib + Capecitabine
STARTED   495   496 
Treated   490   488 
COMPLETED   0   0 
NOT COMPLETED   495   496 
Death                305                333 
Lost to Follow-up                5                4 
Physician's Decision                4                3 
Subject's Decision                41                55 
Sponsor’s Decision                137                98 
Reason Not Specified                3                3 



  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.
Intent-to-treat (ITT) population included all randomized participants on the basis of the treatment assigned at randomization.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.
Total Total of all reporting groups

Baseline Measures
   Trastuzumab Emtansine   Lapatinib + Capecitabine   Total 
Overall Participants Analyzed 
[Units: Participants]
 495   496   991 
Age 
[Units: Years]
Mean (Standard Deviation)
 52.2  (11.0)   53.2  (10.8)   52.7  (10.9) 
Gender 
[Units: Participants]
     
Female   494   492   986 
Male   1   4   5 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Percentage of Participants With PD or Death as Assessed by an Independent Review Committee (IRC)   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

2.  Primary:   Progression-free Survival (PFS) as Assessed by an IRC (Co-primary Endpoint)   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

3.  Primary:   Percentage of Participants Who Died: Second Interim Analysis   [ Time Frame: From the date of randomization through the data cut-off date of 31 Jul 2012 (up to 3 years, 5 months) ]

4.  Primary:   Overall Survival: Second Interim Analysis (Co-primary Endpoint)   [ Time Frame: From the date of randomization through the data cut-off date of 31 Jul 2012 (up to 3 years, 5 months) ]

5.  Primary:   Percentage of Participants Who Died: Final Analysis   [ Time Frame: From the date of randomization through the data cut-off date of 31 Dec 2014 (up to 5 years, 11 months) ]

6.  Primary:   Overall Survival: Final Analysis   [ Time Frame: From the date of randomization through the data cut-off date of 31 Dec 2014 (up to 5 years, 11 months) ]

7.  Primary:   Percentage of Participants Who Were Alive at Year 1   [ Time Frame: Year 1 ]

8.  Primary:   Percentage of Participants Who Were Alive at Year 2   [ Time Frame: Year 2 ]

9.  Secondary:   Percentage of Participants With PD or Death as Assessed by the Investigator   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

10.  Secondary:   PFS as Assessed by the Investigator   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

11.  Secondary:   Percentage of Participants With Objective Response (OR) as Assessed by an IRC   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

12.  Secondary:   Duration of Objective Response (DOR) as Assessed by an IRC   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

13.  Secondary:   Percentage of Participants With Clinical Benefit as Assessed by an IRC   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

14.  Secondary:   Percentage of Participants With Treatment Failure   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

15.  Secondary:   Time to Treatment Failure   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

16.  Secondary:   Percentage of Participants With Symptom Progression   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]

17.  Secondary:   Time to Symptom Progression   [ Time Frame: From the date of randomization through the data cut-off date of 14 Jan 2012 (up to 2 years, 11 months) ]


  Serious Adverse Events
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Time Frame Only study-related serious adverse events (SAEs) were reported from randomization to first treatment; all SAEs and non-SAEs were reported from start of treatment until 30 days after treatment; and thereafter only treatment related SAEs were reported until data cut-off date of 21-Sep-2015 (up to 6 years and 7 months). For participants who crossed over from lapatinib + capecitabine to trastuzumab emtansine, data is reported from time of cross-over until 21-Sep-2015 (up to 3 years and 2 months).
Additional Description Safety population included participants who received at least 1 dose of study medication. Safety analyses were based on the actual treatment received.

Reporting Groups
  Description
Trastuzumab Emtansine Participants received trastuzumab emtansine 3.6 mg/kg IV infusion over 30-90 minutes on Day 1 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.
Lapatinib + Capecitabine Participants received lapatinib 1250 mg (five 250 mg tablets) orally once daily during each 21-day cycle + capecitabine 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination. Participants of this group were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.
Lapatinib + Capecitabine/ Trastuzumab Emtansine Participants of "Lapatinib + Capecitabine" arm were allowed to cross over to receive trastuzumab emtansine based on statistically significant OS benefit in favor of trastuzumab emtansine demonstrated in second interim analysis.

Serious Adverse Events
    Trastuzumab Emtansine   Lapatinib + Capecitabine   Lapatinib + Capecitabine/ Trastuzumab Emtansine
Total, serious adverse events       
# participants affected / at risk   92/490 (18.78%)   99/488 (20.29%)   19/136 (13.97%) 
Blood and lymphatic system disorders       
Anaemia * 1       
# participants affected / at risk   1/490 (0.20%)   1/488 (0.20%)   0/136 (0.00%) 
Anaemia of malignant disease * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Febrile neutropenia * 1       
# participants affected / at risk   0/490 (0.00%)   2/488 (0.41%)   0/136 (0.00%) 
Neutropenia * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Thrombocytopenia * 1       
# participants affected / at risk   4/490 (0.82%)   1/488 (0.20%)   1/136 (0.74%) 
Cardiac disorders       
Angina pectoris * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Atrial fibrillation * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Cardiomyopathy * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Coronary artery disease * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Pericardial effusion * 1       
# participants affected / at risk   0/490 (0.00%)   2/488 (0.41%)   0/136 (0.00%) 
Pericarditis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Supraventricular tachycardia * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Tachycardia * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Ear and labyrinth disorders       
Vertigo * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Eye disorders       
Macular hole * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   1/136 (0.74%) 
Gastrointestinal disorders       
Abdominal pain * 1       
# participants affected / at risk   4/490 (0.82%)   3/488 (0.61%)   0/136 (0.00%) 
Ascites * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   1/136 (0.74%) 
Colitis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Constipation * 1       
# participants affected / at risk   1/490 (0.20%)   1/488 (0.20%)   0/136 (0.00%) 
Diarrhoea * 1       
# participants affected / at risk   3/490 (0.61%)   17/488 (3.48%)   0/136 (0.00%) 
Enteritis * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Fistula of small intestine * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Gastric haemorrhage * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   1/136 (0.74%) 
Gastric ulcer * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Gastritis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Gastrointestinal haemorrhage * 1       
# participants affected / at risk   2/490 (0.41%)   0/488 (0.00%)   0/136 (0.00%) 
Gastrointestinal obstruction * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Ileus * 1       
# participants affected / at risk   0/490 (0.00%)   2/488 (0.41%)   0/136 (0.00%) 
Intestinal haemorrhage * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Intestinal obstruction * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Nausea * 1       
# participants affected / at risk   2/490 (0.41%)   3/488 (0.61%)   0/136 (0.00%) 
Peptic ulcer haemorrhage * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Upper gastrointestinal haemorrhage * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Vomiting * 1       
# participants affected / at risk   7/490 (1.43%)   10/488 (2.05%)   0/136 (0.00%) 
General disorders       
Malaise * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Asthenia * 1       
# participants affected / at risk   1/490 (0.20%)   2/488 (0.41%)   1/136 (0.74%) 
Chest pain * 1       
# participants affected / at risk   2/490 (0.41%)   0/488 (0.00%)   0/136 (0.00%) 
Fatigue * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Mucosal inflammation * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Multi-organ failure * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Oedema peripheral * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Pain * 1       
# participants affected / at risk   2/490 (0.41%)   1/488 (0.20%)   0/136 (0.00%) 
Pyrexia * 1       
# participants affected / at risk   8/490 (1.63%)   3/488 (0.61%)   2/136 (1.47%) 
Hepatobiliary disorders       
Cholangitis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Cholangitis acute * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   1/136 (0.74%) 
Cholestasis * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Hepatitis toxic * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Hepatotoxicity * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Hyperbilirubinaemia * 1       
# participants affected / at risk   0/490 (0.00%)   2/488 (0.41%)   0/136 (0.00%) 
Nodular regenerative hyperplasia * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   1/136 (0.74%) 
Portal hypertension * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Immune system disorders       
Hypersensitivity * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Infections and infestations       
Unmapped (Bacteremia due to infected port) * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Appendicitis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Bacteraemia * 1       
# participants affected / at risk   1/490 (0.20%)   1/488 (0.20%)   0/136 (0.00%) 
Bronchitis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Catheter site infection * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Cellulitis * 1       
# participants affected / at risk   2/490 (0.41%)   3/488 (0.61%)   1/136 (0.74%) 
Clostridium difficile colitis * 1       
# participants affected / at risk   1/490 (0.20%)   1/488 (0.20%)   0/136 (0.00%) 
Device related infection * 1       
# participants affected / at risk   2/490 (0.41%)   0/488 (0.00%)   0/136 (0.00%) 
Enterococcal infection * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   1/136 (0.74%) 
Erysipelas * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Gastroenteritis norovirus * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
H1N1 influenza * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Herpes zoster * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Infection * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Listeriosis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Lower respiratory tract infection * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Nasopharyngitis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Neutropenic sepsis * 1       
# participants affected / at risk   2/490 (0.41%)   0/488 (0.00%)   0/136 (0.00%) 
Parotitis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Pneumocystis jirovecii pneumonia * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   1/136 (0.74%) 
Pneumonia * 1       
# participants affected / at risk   4/490 (0.82%)   1/488 (0.20%)   1/136 (0.74%) 
Pneumonia bacterial * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Post procedural infection * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Pyelonephritis acute * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Respiratory tract infection * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   2/136 (1.47%) 
Salmonellosis * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Sepsis * 1       
# participants affected / at risk   1/490 (0.20%)   1/488 (0.20%)   0/136 (0.00%) 
Staphylococcal sepsis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Tooth infection * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Upper respiratory tract infection * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Urinary tract infection * 1       
# participants affected / at risk   3/490 (0.61%)   0/488 (0.00%)   1/136 (0.74%) 
Urosepsis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Injury, poisoning and procedural complications       
Ankle fracture * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Delayed haemolytic transfusion reaction * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Extradural haematoma * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Fall * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Femoral neck fracture * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Femur fracture * 1       
# participants affected / at risk   3/490 (0.61%)   2/488 (0.41%)   0/136 (0.00%) 
Fibula fracture * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Hip fracture * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Infusion related reaction * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   1/136 (0.74%) 
Subdural haemorrhage * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Synovial rupture * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   1/136 (0.74%) 
Wound * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Wound secretion * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   1/136 (0.74%) 
Wrist fracture * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Investigations       
Alanine aminotransferase increased * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Blood bilirubin increased * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Gamma-glutamyltransferase increased * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Haemoglobin decreased * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   1/136 (0.74%) 
Metabolism and nutrition disorders       
Dehydration * 1       
# participants affected / at risk   0/490 (0.00%)   2/488 (0.41%)   0/136 (0.00%) 
Failure to thrive * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Hypercalcaemia * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Hypokalaemia * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Hyponatraemia * 1       
# participants affected / at risk   2/490 (0.41%)   1/488 (0.20%)   0/136 (0.00%) 
Musculoskeletal and connective tissue disorders       
Back pain * 1       
# participants affected / at risk   3/490 (0.61%)   0/488 (0.00%)   0/136 (0.00%) 
Bone pain * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Muscular weakness * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Osteonecrosis of jaw * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Pain in extremity * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Pathological fracture * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Spinal column stenosis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Spondylitis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Acute myeloid leukaemia * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Breast cancer * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   1/136 (0.74%) 
Infected neoplasm * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Lentigo maligna * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   1/136 (0.74%) 
Myelodysplastic syndrome * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Second primary malignancy * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Squamous cell carcinoma * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   1/136 (0.74%) 
Uterine cancer * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Nervous system disorders       
Cerebrovascular accident * 1       
# participants affected / at risk   1/490 (0.20%)   1/488 (0.20%)   0/136 (0.00%) 
Coma * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Dizziness * 1       
# participants affected / at risk   2/490 (0.41%)   2/488 (0.41%)   0/136 (0.00%) 
Epilepsy * 1       
# participants affected / at risk   1/490 (0.20%)   1/488 (0.20%)   0/136 (0.00%) 
Headache * 1       
# participants affected / at risk   1/490 (0.20%)   2/488 (0.41%)   0/136 (0.00%) 
Hemiplegia * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Hydrocephalus * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Metabolic encephalopathy * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Parkinson's disease * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Status epilepticus * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Syncope * 1       
# participants affected / at risk   0/490 (0.00%)   2/488 (0.41%)   0/136 (0.00%) 
Psychiatric disorders       
Agitation * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Confusional state * 1       
# participants affected / at risk   1/490 (0.20%)   1/488 (0.20%)   0/136 (0.00%) 
Depression * 1       
# participants affected / at risk   0/490 (0.00%)   2/488 (0.41%)   0/136 (0.00%) 
Substance-induced psychotic disorder * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Renal and urinary disorders       
Dysuria * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Renal failure * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Ureteric obstruction * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Urinary tract obstruction * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Reproductive system and breast disorders       
Menometrorrhagia * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Metrorrhagia * 1       
# participants affected / at risk   2/490 (0.41%)   1/488 (0.20%)   0/136 (0.00%) 
Ovarian cyst * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Uterine haemorrhage * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Acute respiratory distress syndrome * 1       
# participants affected / at risk   1/490 (0.20%)   2/488 (0.41%)   0/136 (0.00%) 
Alveolitis allergic * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Asthma * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Dyspnoea * 1       
# participants affected / at risk   2/490 (0.41%)   0/488 (0.00%)   0/136 (0.00%) 
Epistaxis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   1/136 (0.74%) 
Haemoptysis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Hypoxia * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   1/136 (0.74%) 
Pleural effusion * 1       
# participants affected / at risk   1/490 (0.20%)   1/488 (0.20%)   0/136 (0.00%) 
Pleuritic pain * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Pneumonitis * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Pneumothorax * 1       
# participants affected / at risk   0/490 (0.00%)   0/488 (0.00%)   1/136 (0.74%) 
Pulmonary embolism * 1       
# participants affected / at risk   0/490 (0.00%)   9/488 (1.84%)   0/136 (0.00%) 
Pulmonary oedema * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Respiratory failure * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Skin and subcutaneous tissue disorders       
Dermatitis contact * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Rash * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Skin haemorrhage * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Urticaria * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
Surgical and medical procedures       
Abortion induced * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Vascular disorders       
Deep vein thrombosis * 1       
# participants affected / at risk   0/490 (0.00%)   2/488 (0.41%)   0/136 (0.00%) 
Labile blood pressure * 1       
# participants affected / at risk   1/490 (0.20%)   0/488 (0.00%)   0/136 (0.00%) 
Thrombosis * 1       
# participants affected / at risk   0/490 (0.00%)   2/488 (0.41%)   0/136 (0.00%) 
Venous thrombosis * 1       
# participants affected / at risk   0/490 (0.00%)   1/488 (0.20%)   0/136 (0.00%) 
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA 18.1




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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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