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LUME-Ovar 1: Nintedanib (BIBF 1120) or Placebo in Combination With Paclitaxel and Carboplatin in First Line Treatment of Ovarian Cancer

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ClinicalTrials.gov Identifier: NCT01015118
Recruitment Status : Completed
First Posted : November 18, 2009
Results First Posted : January 15, 2015
Last Update Posted : December 7, 2017
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double;   Primary Purpose: Treatment
Conditions Ovarian Neoplasms
Peritoneal Neoplasms
Interventions Drug: Placebo
Drug: Paclitaxel
Drug: BIBF 1120
Drug: Carboplatin
Enrollment 1366
Recruitment Details  
Pre-assignment Details 1366 patients were randomised for this study.
Arm/Group Title Nintedanib Placebo
Hide Arm/Group Description Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses. Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Period Title: Overall Study
Started 911 455
Completed 242 [1] 128 [1]
Not Completed 669 327
Reason Not Completed
Protocol Violation             5             6
Withdrawal by Subject             103             27
Other Adverse Event (AE)             141             33
Worsening or AE of underlying disease             5             4
Progressive disease             364             229
Not treated             9             5
Other than stated above             42             23
[1]
Patients who completed max trial therapy duration.
Arm/Group Title Nintedanib Placebo Total
Hide Arm/Group Description Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses. Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses. Total of all reporting groups
Overall Number of Baseline Participants 911 455 1366
Hide Baseline Analysis Population Description
Randomised Set (RS): included all randomised patients, regardless of whether or not they had received treatment. Patients were assigned to nintedanib or placebo as randomised.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 911 participants 455 participants 1366 participants
57.5  (11.0) 56.9  (11.1) 57.3  (11.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 911 participants 455 participants 1366 participants
Female
911
 100.0%
455
 100.0%
1366
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title PFS Based on Investigator Assessment According to Modified Response Evaluation Criteria in Solid Tumors, Version 1.1 (mRECIST), and Additional Clinical Criteria.
Hide Description

Progression free survival (PFS) is calculated as the time from randomisation to the date of disease progression, or to the date of death, whichever occurs first according to the Investigator assessment.

The primary PFS analysis of this trial was performed when approximately 753 patients had experienced a PFS event

Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.

Time Frame First drug administration to date of disease progression or death whichever occurs first , upto 29 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised Set (RS)
Arm/Group Title Nintedanib Placebo
Hide Arm/Group Description:
Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed 911 455
Median (Inter-Quartile Range)
Unit of Measure: Months
17.2
(11.1 to 32.5)
16.6
(10.8 to 30.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib, Placebo
Comments Hazard ratio (HR), Confidence Interval (CI) and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level Area under curve 5 (AUC5) vs. Area under curve 6 (AUC6).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0239
Comments [Not Specified]
Method Log Rank
Comments Breslow method was used for handling ties.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.72 to 0.98
Estimation Comments If hazard ratio is below 1 then favours nintedanib.
2.Primary Outcome
Title PFS Based on Investigator Assessment According to Modified Response Evaluation Criteria in Solid Tumors, Version 1.1 (mRECIST), and Additional Clinical Criteria (Follow up Analysis).
Hide Description

Follow-up analysis was conducted at the time of overall survival analysis. Progression free survival (PFS) is calculated as the time from randomisation to the date of disease progression, or to the date of death, whichever occurs first according to the Investigator assessment.

Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.

Time Frame First drug administration to date of disease progression or death whichever occurs first until final Data Base Lock (DBL) 26September16, upto 62 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised Set (RS)
Arm/Group Title Nintedanib Placebo
Hide Arm/Group Description:
Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed 911 455
Median (Inter-Quartile Range)
Unit of Measure: Months
17.6
(11.1 to 38.0)
16.6
(10.8 to 37.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib, Placebo
Comments Hazard ratio (HR), Confidence Interval (CI) and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0286
Comments [Not Specified]
Method Log Rank
Comments Breslow method was used for handling ties.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.75 to 0.98
Estimation Comments If hazard ratio is below 1 then favours nintedanib.
3.Secondary Outcome
Title PFS Based on Investigator Assessment According to mRECIST Version 1.1 (Key Secondary Endpoint).
Hide Description

Progression free survival is calculated as the time from randomisation to the date of disease progression, or to the date of death, whichever occurs first based on the Investigator assessment according to Modified Response Evaluation Criteria (mRECIST), version 1.1.

The primary PFS analysis of this trial was performed when approximately 753 patients had experienced a PFS event.

Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.

Time Frame First drug administration to date of disease progression or death whichever occurs first , upto 29 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised Set (RS)
Arm/Group Title Nintedanib Placebo
Hide Arm/Group Description:
Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed 911 455
Median (Inter-Quartile Range)
Unit of Measure: Months
18.3
(11.1 to 32.5)
16.6
(10.8 to 30.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib, Placebo
Comments HR, CI and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0186
Comments [Not Specified]
Method Log Rank
Comments Breslow method was used for handling ties.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.72 to 0.97
Estimation Comments If hazard ratio is below 1 then favours nintedanib.
4.Secondary Outcome
Title PFS Based on Investigator Assessment According to mRECIST Version 1.1 (Key Secondary Endpoint - Follow up Analysis).
Hide Description Follow-up analysis was conducted at the time of overall survival analysis. Progression free survival is calculated as the time from randomisation to the date of disease progression, or to the date of death, whichever occurs first based on the Investigator assessment according to Modified Response Evaluation Criteria (mRECIST), version 1.1. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.
Time Frame First drug administration to date of disease progression or death whichever occurs first until final Data Base Lock (DBL) 26September16, upto 62 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised Set (RS)
Arm/Group Title Nintedanib Placebo
Hide Arm/Group Description:
Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed 911 455
Median (Inter-Quartile Range)
Unit of Measure: Months
18.4
(11.1 to 38.5)
16.6
(10.8 to 37.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib, Placebo
Comments HR, CI and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0256
Comments [Not Specified]
Method Log Rank
Comments Breslow method was used for handling ties.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.74 to 0.98
Estimation Comments If hazard ratio is below 1 then favours nintedanib.
5.Secondary Outcome
Title Overall Survival
Hide Description

Overall survival is defined as time from randomization to date of death (irrespective of reason).

Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.

Time Frame First drug administration to date of death until final DBL 26September16, upto 62 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised Set (RS)
Arm/Group Title Nintedanib Placebo
Hide Arm/Group Description:
Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed 911 455
Median (Inter-Quartile Range)
Unit of Measure: Months
62.0 [1] 
(30.0 to NA)
62.8 [1] 
(30.6 to NA)
[1]
Not calculable because of insufficient number of participants with events
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib, Placebo
Comments HR, CI and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8653
Comments [Not Specified]
Method Log Rank
Comments Breslow method was used for handling ties.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.83 to 1.17
Estimation Comments If hazard ratio is below 1 then favours nintedanib.
6.Secondary Outcome
Title Time to CA-125 Tumour Marker Progression
Hide Description Time to tumour-marker progression was defined as the time from randomisation until the date when Carbohydrate (cancer) antigen (CA-125) values increased to higher than twice the nadir value. CA-125 >=2 x nadir in case nadir value > Upper limit of normal (ULN) or CA-125 >=2 x ULN in case nadir value <= ULN.
Time Frame First drug administration until final DBL 26September16, upto 62 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised set (RS)
Arm/Group Title Nintedanib Placebo
Hide Arm/Group Description:
Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed 911 455
Median (Inter-Quartile Range)
Unit of Measure: Months
16.6
(10.6 to 47.0)
14.1
(8.6 to 42.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib, Placebo
Comments HR, CI and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0749
Comments [Not Specified]
Method Log Rank
Comments Breslow method was used for handling ties.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.77 to 1.01
Estimation Comments If hazard ratio is below 1 then favours nintedanib.
7.Secondary Outcome
Title Objective Response Based on Investigator Assessment
Hide Description Objective tumour response defined as either complete response [CR] or partial response [PR] in patients with at least 1 target lesion reported at baseline
Time Frame First drug administration until final DBL 26September16, upto 62 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised Set (RS) for patients with at least 1 target lesion reported at baseline
Arm/Group Title Nintedanib Placebo
Hide Arm/Group Description:
Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed 911 455
Measure Type: Number
Unit of Measure: percentage of participants
74.3 70.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib, Placebo
Comments Odds ratio and p-value are obtained from logistic regression model adjusting for, macroscopic residual postoperative tumour (yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3490
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.22
Confidence Interval (2-Sided) 95%
0.81 to 1.82
Estimation Comments An odds ratio >1 favours nintedanib.
8.Secondary Outcome
Title Change in Abdominal/Gastro-intestinal Symptoms Over Time
Hide Description

Change in abdominal/gastro-intestinal over time was calculated on symptoms (scale composite of items 31 to 37 of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Module for Ovarian Cancer 28 (EORTC QLQ OV-28).

As specified in the EORTC scoring manual, for each scale or item, a linear transformation was applied to standardize the raw score to a range from 0 to 100 (high scores represent a high/severe level of symptomatology).

Mean presented is Adjusted mean. Adjusted for the stratification factors macroscopic residual postoperative tumour at baseline (yes vs. no), FIGO stage (IIB-III vs IV), and Carboplatin level (AUC5 vs. AUC6).

Time Frame First drug administration until final DBL 26September16, upto 62 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised Set (RS) for patients with abdominal/gastro-intestinal symptoms
Arm/Group Title Nintedanib Placebo
Hide Arm/Group Description:
Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed 911 455
Mean (Standard Error)
Unit of Measure: units on a scale
24.63  (0.49) 19.34  (0.64)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib, Placebo
Comments Adjusted for the stratification factors macroscopic residual postoperative tumour at baseline (yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) stage (IIB-III vs IV), and carboplatin level (AUC5 vs. AUC6).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed effect growth curve model
Comments Mixed-effects growth curve models (longitudinal models) with the average profile over time for each endpoint described by a piecewise linear model.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 5.29
Confidence Interval (2-Sided) 95%
3.88 to 6.69
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.72
Estimation Comments Mean difference presented is the Adjusted mean difference. Difference calculated as nintedanib minus placebo. High values represent a worse level of symptoms.
9.Secondary Outcome
Title Change in Global Health Status/ Quality of Life (QoL) Scale Over Time.
Hide Description

Change in Global Health Status/ Quality of life (QoL) over time was calculated on Global Health Status/QoL scale (composite of items 29 and 30 of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-30 (EORTC QLQ-C30) as a general measure.

As specified in the EORTC scoring manual, for each scale or item, a linear transformation was applied to standardize the raw score to a range from 0 to 100 (high scores represent a high/healthy level of functioning).

Mean presented is Adjusted mean. Adjusted for the stratification factors macroscopic residual postoperative tumour at baseline (yes vs. no), FIGO stage (IIB-III vs IV), and Carboplatin level (AUC5 vs. AUC6).

Time Frame First drug administration until final DBL 26September16, upto 62 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised Set (RS) for patients with global health status/QoL
Arm/Group Title Nintedanib Placebo
Hide Arm/Group Description:
Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed 911 455
Mean (Standard Error)
Unit of Measure: units on a scale
68.79  (0.48) 70.67  (0.65)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib, Placebo
Comments Adjusted for the stratification factors macroscopic residual postoperative tumour at baseline (yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) stage (IIB-III vs IV), and carboplatin level (AUC5 vs. AUC6).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0124
Comments [Not Specified]
Method Mixed effect growth curve model
Comments Mixed-effects growth curve models (longitudinal models) with the average profile over time for each endpoint described by a piecewise linear model.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -1.88
Confidence Interval (2-Sided) 95%
-3.35 to -0.41
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.75
Estimation Comments Mean difference calculated is the Adjusted mean. High values represent a better level of functioning. Difference calculated as nintedanib minus placebo.
Time Frame First drug administration until data cut-off 26September16, up to 62 months
Adverse Event Reporting Description Adverse Events were reported for the treated patients.
 
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses. Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
All-Cause Mortality
Placebo Nintedanib
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Placebo Nintedanib
Affected / at Risk (%) Affected / at Risk (%)
Total   157/450 (34.89%)   379/902 (42.02%) 
Blood and lymphatic system disorders     
Anaemia  1  9/450 (2.00%)  36/902 (3.99%) 
Febrile bone marrow aplasia  1  0/450 (0.00%)  1/902 (0.11%) 
Febrile neutropenia  1  6/450 (1.33%)  20/902 (2.22%) 
Haemolytic uraemic syndrome  1  0/450 (0.00%)  1/902 (0.11%) 
Haemorrhagic anaemia  1  0/450 (0.00%)  1/902 (0.11%) 
Leukopenia  1  1/450 (0.22%)  8/902 (0.89%) 
Lymphadenopathy  1  2/450 (0.44%)  1/902 (0.11%) 
Microangiopathic haemolytic anaemia  1  0/450 (0.00%)  1/902 (0.11%) 
Neutropenia  1  6/450 (1.33%)  24/902 (2.66%) 
Pancytopenia  1  1/450 (0.22%)  8/902 (0.89%) 
Splenic infarction  1  1/450 (0.22%)  0/902 (0.00%) 
Splenic vein thrombosis  1  1/450 (0.22%)  0/902 (0.00%) 
Thrombocytopenia  1  6/450 (1.33%)  21/902 (2.33%) 
Thrombotic thrombocytopenic purpura  1  0/450 (0.00%)  1/902 (0.11%) 
Cardiac disorders     
Acute coronary syndrome  1  1/450 (0.22%)  1/902 (0.11%) 
Acute myocardial infarction  1  0/450 (0.00%)  1/902 (0.11%) 
Angina pectoris  1  0/450 (0.00%)  3/902 (0.33%) 
Atrial fibrillation  1  2/450 (0.44%)  1/902 (0.11%) 
Atrioventricular block  1  0/450 (0.00%)  1/902 (0.11%) 
Bundle branch block left  1  0/450 (0.00%)  1/902 (0.11%) 
Cardiac arrest  1  0/450 (0.00%)  1/902 (0.11%) 
Cardio-respiratory arrest  1  0/450 (0.00%)  1/902 (0.11%) 
Cardiogenic shock  1  0/450 (0.00%)  2/902 (0.22%) 
Cardiovascular disorder  1  1/450 (0.22%)  0/902 (0.00%) 
Mitral valve incompetence  1  1/450 (0.22%)  0/902 (0.00%) 
Myocardial infarction  1  1/450 (0.22%)  3/902 (0.33%) 
Myocardial ischaemia  1  0/450 (0.00%)  1/902 (0.11%) 
Palpitations  1  1/450 (0.22%)  0/902 (0.00%) 
Sinus tachycardia  1  0/450 (0.00%)  2/902 (0.22%) 
Supraventricular tachyarrhythmia  1  1/450 (0.22%)  0/902 (0.00%) 
Tachycardia  1  0/450 (0.00%)  1/902 (0.11%) 
Ventricular tachycardia  1  0/450 (0.00%)  1/902 (0.11%) 
Congenital, familial and genetic disorders     
Cancer gene carrier  1  0/450 (0.00%)  1/902 (0.11%) 
Ear and labyrinth disorders     
Deafness  1  0/450 (0.00%)  1/902 (0.11%) 
Tinnitus  1  0/450 (0.00%)  1/902 (0.11%) 
Vertigo  1  2/450 (0.44%)  0/902 (0.00%) 
Endocrine disorders     
Goitre  1  0/450 (0.00%)  1/902 (0.11%) 
Toxic nodular goitre  1  0/450 (0.00%)  1/902 (0.11%) 
Eye disorders     
Vision blurred  1  1/450 (0.22%)  0/902 (0.00%) 
Gastrointestinal disorders     
Abdominal adhesions  1  1/450 (0.22%)  0/902 (0.00%) 
Abdominal discomfort  1  1/450 (0.22%)  1/902 (0.11%) 
Abdominal distension  1  1/450 (0.22%)  1/902 (0.11%) 
Abdominal hernia  1  2/450 (0.44%)  2/902 (0.22%) 
Abdominal pain  1  6/450 (1.33%)  30/902 (3.33%) 
Abdominal pain upper  1  0/450 (0.00%)  8/902 (0.89%) 
Abdominal wall haematoma  1  1/450 (0.22%)  0/902 (0.00%) 
Acute abdomen  1  0/450 (0.00%)  1/902 (0.11%) 
Anal fissure  1  0/450 (0.00%)  1/902 (0.11%) 
Anal fistula  1  0/450 (0.00%)  1/902 (0.11%) 
Anal haemorrhage  1  0/450 (0.00%)  1/902 (0.11%) 
Aphthous ulcer  1  0/450 (0.00%)  1/902 (0.11%) 
Ascites  1  8/450 (1.78%)  14/902 (1.55%) 
Colitis  1  2/450 (0.44%)  0/902 (0.00%) 
Colonic fistula  1  0/450 (0.00%)  2/902 (0.22%) 
Constipation  1  10/450 (2.22%)  13/902 (1.44%) 
Diaphragmatic hernia  1  0/450 (0.00%)  1/902 (0.11%) 
Diarrhoea  1  8/450 (1.78%)  41/902 (4.55%) 
Diverticulum intestinal  1  1/450 (0.22%)  0/902 (0.00%) 
Dysphagia  1  1/450 (0.22%)  0/902 (0.00%) 
Enteritis  1  1/450 (0.22%)  1/902 (0.11%) 
Enterocutaneous fistula  1  0/450 (0.00%)  2/902 (0.22%) 
Faecaloma  1  1/450 (0.22%)  1/902 (0.11%) 
Femoral hernia  1  0/450 (0.00%)  1/902 (0.11%) 
Fistula of small intestine  1  0/450 (0.00%)  2/902 (0.22%) 
Functional gastrointestinal disorder  1  0/450 (0.00%)  1/902 (0.11%) 
Gastritis  1  2/450 (0.44%)  2/902 (0.22%) 
Gastrointestinal haemorrhage  1  0/450 (0.00%)  1/902 (0.11%) 
Gastrointestinal inflammation  1  0/450 (0.00%)  2/902 (0.22%) 
Gastrointestinal pain  1  1/450 (0.22%)  0/902 (0.00%) 
Haematemesis  1  0/450 (0.00%)  1/902 (0.11%) 
Haemorrhoidal haemorrhage  1  0/450 (0.00%)  1/902 (0.11%) 
Ileus  1  8/450 (1.78%)  17/902 (1.88%) 
Impaired gastric emptying  1  0/450 (0.00%)  1/902 (0.11%) 
Intestinal obstruction  1  4/450 (0.89%)  7/902 (0.78%) 
Intestinal perforation  1  1/450 (0.22%)  5/902 (0.55%) 
Intussusception  1  0/450 (0.00%)  1/902 (0.11%) 
Large intestinal obstruction  1  0/450 (0.00%)  1/902 (0.11%) 
Mallory-Weiss syndrome  1  1/450 (0.22%)  0/902 (0.00%) 
Mechanical ileus  1  0/450 (0.00%)  1/902 (0.11%) 
Nausea  1  10/450 (2.22%)  24/902 (2.66%) 
Pancreatitis  1  0/450 (0.00%)  1/902 (0.11%) 
Pancreatitis acute  1  1/450 (0.22%)  0/902 (0.00%) 
Rectal haemorrhage  1  0/450 (0.00%)  1/902 (0.11%) 
Small intestinal obstruction  1  4/450 (0.89%)  12/902 (1.33%) 
Small intestinal perforation  1  1/450 (0.22%)  1/902 (0.11%) 
Stomatitis  1  0/450 (0.00%)  2/902 (0.22%) 
Subileus  1  2/450 (0.44%)  8/902 (0.89%) 
Umbilical hernia  1  0/450 (0.00%)  1/902 (0.11%) 
Vomiting  1  12/450 (2.67%)  33/902 (3.66%) 
General disorders     
Asthenia  1  2/450 (0.44%)  13/902 (1.44%) 
Catheter site haematoma  1  1/450 (0.22%)  0/902 (0.00%) 
Chest pain  1  4/450 (0.89%)  4/902 (0.44%) 
Chills  1  0/450 (0.00%)  1/902 (0.11%) 
Cyst  1  1/450 (0.22%)  0/902 (0.00%) 
Death  1  0/450 (0.00%)  2/902 (0.22%) 
Fatigue  1  2/450 (0.44%)  10/902 (1.11%) 
General physical health deterioration  1  5/450 (1.11%)  17/902 (1.88%) 
Hernia  1  0/450 (0.00%)  1/902 (0.11%) 
Impaired healing  1  0/450 (0.00%)  1/902 (0.11%) 
Implant site erythema  1  1/450 (0.22%)  0/902 (0.00%) 
Influenza like illness  1  1/450 (0.22%)  2/902 (0.22%) 
Infusion site extravasation  1  0/450 (0.00%)  1/902 (0.11%) 
Mucosal inflammation  1  0/450 (0.00%)  1/902 (0.11%) 
Nodule  1  1/450 (0.22%)  0/902 (0.00%) 
Oedema  1  1/450 (0.22%)  0/902 (0.00%) 
Oedema peripheral  1  1/450 (0.22%)  1/902 (0.11%) 
Pain  1  2/450 (0.44%)  1/902 (0.11%) 
Performance status decreased  1  1/450 (0.22%)  1/902 (0.11%) 
Pyrexia  1  8/450 (1.78%)  23/902 (2.55%) 
Sudden death  1  2/450 (0.44%)  0/902 (0.00%) 
Surgical failure  1  0/450 (0.00%)  1/902 (0.11%) 
Hepatobiliary disorders     
Cholecystitis  1  0/450 (0.00%)  4/902 (0.44%) 
Cholelithiasis  1  1/450 (0.22%)  2/902 (0.22%) 
Hyperbilirubinaemia  1  0/450 (0.00%)  1/902 (0.11%) 
Immune system disorders     
Allergy to arthropod bite  1  0/450 (0.00%)  1/902 (0.11%) 
Anaphylactic reaction  1  0/450 (0.00%)  2/902 (0.22%) 
Anaphylactoid reaction  1  1/450 (0.22%)  0/902 (0.00%) 
Contrast media allergy  1  1/450 (0.22%)  0/902 (0.00%) 
Drug hypersensitivity  1  3/450 (0.67%)  9/902 (1.00%) 
Hypersensitivity  1  1/450 (0.22%)  1/902 (0.11%) 
Infections and infestations     
Abdominal abscess  1  0/450 (0.00%)  1/902 (0.11%) 
Abdominal wall abscess  1  0/450 (0.00%)  2/902 (0.22%) 
Abscess  1  0/450 (0.00%)  1/902 (0.11%) 
Appendicitis  1  1/450 (0.22%)  0/902 (0.00%) 
Bacteraemia  1  0/450 (0.00%)  1/902 (0.11%) 
Beta haemolytic streptococcal infection  1  0/450 (0.00%)  1/902 (0.11%) 
Cellulitis  1  0/450 (0.00%)  3/902 (0.33%) 
Clostridial infection  1  1/450 (0.22%)  0/902 (0.00%) 
Clostridium difficile colitis  1  0/450 (0.00%)  2/902 (0.22%) 
Clostridium difficile infection  1  1/450 (0.22%)  1/902 (0.11%) 
Cystitis  1  0/450 (0.00%)  6/902 (0.67%) 
Device related infection  1  3/450 (0.67%)  4/902 (0.44%) 
Diverticulitis  1  0/450 (0.00%)  1/902 (0.11%) 
Endocarditis bacterial  1  1/450 (0.22%)  0/902 (0.00%) 
Enteritis infectious  1  1/450 (0.22%)  0/902 (0.00%) 
Enterobacter infection  1  0/450 (0.00%)  1/902 (0.11%) 
Enterocolitis bacterial  1  0/450 (0.00%)  1/902 (0.11%) 
Erysipelas  1  0/450 (0.00%)  2/902 (0.22%) 
Escherichia urinary tract infection  1  0/450 (0.00%)  1/902 (0.11%) 
Febrile infection  1  0/450 (0.00%)  1/902 (0.11%) 
Gastroenteritis  1  3/450 (0.67%)  4/902 (0.44%) 
Gastrointestinal infection  1  0/450 (0.00%)  2/902 (0.22%) 
Infected lymphocele  1  0/450 (0.00%)  1/902 (0.11%) 
Infection  1  1/450 (0.22%)  3/902 (0.33%) 
Infectious pleural effusion  1  0/450 (0.00%)  1/902 (0.11%) 
Joint abscess  1  0/450 (0.00%)  1/902 (0.11%) 
Klebsiella infection  1  1/450 (0.22%)  0/902 (0.00%) 
Liver abscess  1  1/450 (0.22%)  1/902 (0.11%) 
Lung infection  1  0/450 (0.00%)  2/902 (0.22%) 
Mesenteric abscess  1  0/450 (0.00%)  1/902 (0.11%) 
Nasopharyngitis  1  1/450 (0.22%)  0/902 (0.00%) 
Neutropenic sepsis  1  0/450 (0.00%)  2/902 (0.22%) 
Pelvic abscess  1  0/450 (0.00%)  1/902 (0.11%) 
Peritonitis  1  1/450 (0.22%)  2/902 (0.22%) 
Pharyngeal abscess  1  1/450 (0.22%)  0/902 (0.00%) 
Pneumonia  1  3/450 (0.67%)  6/902 (0.67%) 
Postoperative abscess  1  0/450 (0.00%)  1/902 (0.11%) 
Postoperative wound infection  1  0/450 (0.00%)  1/902 (0.11%) 
Pseudomonal sepsis  1  0/450 (0.00%)  1/902 (0.11%) 
Pulpitis dental  1  1/450 (0.22%)  0/902 (0.00%) 
Pyelonephritis  1  2/450 (0.44%)  2/902 (0.22%) 
Pyelonephritis acute  1  0/450 (0.00%)  2/902 (0.22%) 
Rectal abscess  1  0/450 (0.00%)  1/902 (0.11%) 
Respiratory tract infection  1  2/450 (0.44%)  0/902 (0.00%) 
Sepsis  1  1/450 (0.22%)  4/902 (0.44%) 
Septic shock  1  0/450 (0.00%)  2/902 (0.22%) 
Sinusitis  1  1/450 (0.22%)  0/902 (0.00%) 
Subdiaphragmatic abscess  1  1/450 (0.22%)  0/902 (0.00%) 
Tooth abscess  1  0/450 (0.00%)  1/902 (0.11%) 
Upper respiratory tract infection  1  1/450 (0.22%)  2/902 (0.22%) 
Urinary tract infection  1  3/450 (0.67%)  17/902 (1.88%) 
Urinary tract infection bacterial  1  1/450 (0.22%)  0/902 (0.00%) 
Urinary tract infection enterococcal  1  1/450 (0.22%)  0/902 (0.00%) 
Urosepsis  1  2/450 (0.44%)  2/902 (0.22%) 
Injury, poisoning and procedural complications     
Abdominal wound dehiscence  1  0/450 (0.00%)  1/902 (0.11%) 
Ankle fracture  1  0/450 (0.00%)  1/902 (0.11%) 
Facial bones fracture  1  1/450 (0.22%)  0/902 (0.00%) 
Fall  1  2/450 (0.44%)  1/902 (0.11%) 
Femoral neck fracture  1  1/450 (0.22%)  0/902 (0.00%) 
Femur fracture  1  1/450 (0.22%)  1/902 (0.11%) 
Fibula fracture  1  0/450 (0.00%)  1/902 (0.11%) 
Fractured coccyx  1  0/450 (0.00%)  1/902 (0.11%) 
Gastrointestinal anastomotic leak  1  0/450 (0.00%)  2/902 (0.22%) 
Gastrointestinal stoma complication  1  1/450 (0.22%)  1/902 (0.11%) 
Head injury  1  1/450 (0.22%)  0/902 (0.00%) 
Humerus fracture  1  1/450 (0.22%)  2/902 (0.22%) 
Iatrogenic injury  1  1/450 (0.22%)  0/902 (0.00%) 
Incisional hernia  1  4/450 (0.89%)  8/902 (0.89%) 
Inflammation of wound  1  0/450 (0.00%)  1/902 (0.11%) 
Infusion related reaction  1  0/450 (0.00%)  1/902 (0.11%) 
Ligament sprain  1  1/450 (0.22%)  0/902 (0.00%) 
Meniscus injury  1  1/450 (0.22%)  1/902 (0.11%) 
Post procedural diarrhoea  1  0/450 (0.00%)  1/902 (0.11%) 
Postoperative fever  1  0/450 (0.00%)  1/902 (0.11%) 
Procedural haemorrhage  1  0/450 (0.00%)  1/902 (0.11%) 
Scar  1  1/450 (0.22%)  0/902 (0.00%) 
Stoma site haemorrhage  1  1/450 (0.22%)  0/902 (0.00%) 
Tibia fracture  1  1/450 (0.22%)  1/902 (0.11%) 
Vulvovaginal injury  1  0/450 (0.00%)  1/902 (0.11%) 
Wound dehiscence  1  2/450 (0.44%)  1/902 (0.11%) 
Investigations     
Alanine aminotransferase increased  1  0/450 (0.00%)  1/902 (0.11%) 
Aspartate aminotransferase increased  1  0/450 (0.00%)  1/902 (0.11%) 
Biopsy vulva  1  0/450 (0.00%)  1/902 (0.11%) 
Blood creatinine increased  1  0/450 (0.00%)  1/902 (0.11%) 
Blood glucose increased  1  1/450 (0.22%)  0/902 (0.00%) 
Body temperature increased  1  0/450 (0.00%)  2/902 (0.22%) 
C-reactive protein increased  1  0/450 (0.00%)  1/902 (0.11%) 
Creatinine renal clearance decreased  1  0/450 (0.00%)  1/902 (0.11%) 
Eastern Cooperative Oncology Group performance status worsened  1  0/450 (0.00%)  3/902 (0.33%) 
Electrocardiogram abnormal  1  1/450 (0.22%)  0/902 (0.00%) 
Fibrin D dimer increased  1  0/450 (0.00%)  1/902 (0.11%) 
Gamma-glutamyltransferase increased  1  0/450 (0.00%)  2/902 (0.22%) 
Glomerular filtration rate decreased  1  1/450 (0.22%)  0/902 (0.00%) 
Haemoglobin decreased  1  0/450 (0.00%)  3/902 (0.33%) 
Lipase increased  1  0/450 (0.00%)  1/902 (0.11%) 
Neutrophil count decreased  1  2/450 (0.44%)  1/902 (0.11%) 
Platelet count decreased  1  0/450 (0.00%)  5/902 (0.55%) 
Troponin increased  1  0/450 (0.00%)  1/902 (0.11%) 
Weight decreased  1  0/450 (0.00%)  3/902 (0.33%) 
White blood cell count decreased  1  1/450 (0.22%)  3/902 (0.33%) 
Metabolism and nutrition disorders     
Decreased appetite  1  0/450 (0.00%)  4/902 (0.44%) 
Dehydration  1  6/450 (1.33%)  21/902 (2.33%) 
Electrolyte imbalance  1  0/450 (0.00%)  2/902 (0.22%) 
Failure to thrive  1  0/450 (0.00%)  1/902 (0.11%) 
Hypercalcaemia  1  0/450 (0.00%)  1/902 (0.11%) 
Hypoalbuminaemia  1  1/450 (0.22%)  0/902 (0.00%) 
Hypocalcaemia  1  0/450 (0.00%)  1/902 (0.11%) 
Hypoglycaemia  1  0/450 (0.00%)  1/902 (0.11%) 
Hypokalaemia  1  2/450 (0.44%)  6/902 (0.67%) 
Hypomagnesaemia  1  0/450 (0.00%)  3/902 (0.33%) 
Hyponatraemia  1  0/450 (0.00%)  3/902 (0.33%) 
Hypovolaemia  1  0/450 (0.00%)  1/902 (0.11%) 
Malnutrition  1  0/450 (0.00%)  1/902 (0.11%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/450 (0.22%)  0/902 (0.00%) 
Arthritis  1  2/450 (0.44%)  0/902 (0.00%) 
Back pain  1  1/450 (0.22%)  1/902 (0.11%) 
Bone pain  1  2/450 (0.44%)  0/902 (0.00%) 
Intervertebral disc protrusion  1  0/450 (0.00%)  3/902 (0.33%) 
Lumbar spinal stenosis  1  0/450 (0.00%)  1/902 (0.11%) 
Muscle haemorrhage  1  0/450 (0.00%)  1/902 (0.11%) 
Musculoskeletal chest pain  1  0/450 (0.00%)  1/902 (0.11%) 
Musculoskeletal pain  1  0/450 (0.00%)  1/902 (0.11%) 
Myalgia  1  2/450 (0.44%)  1/902 (0.11%) 
Osteoarthritis  1  2/450 (0.44%)  1/902 (0.11%) 
Pain in extremity  1  1/450 (0.22%)  0/902 (0.00%) 
Rhabdomyolysis  1  0/450 (0.00%)  1/902 (0.11%) 
Spinal column stenosis  1  1/450 (0.22%)  0/902 (0.00%) 
Spinal osteoarthritis  1  1/450 (0.22%)  0/902 (0.00%) 
Synovial cyst  1  1/450 (0.22%)  0/902 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Abdominal wall neoplasm  1  1/450 (0.22%)  0/902 (0.00%) 
Basal cell carcinoma  1  1/450 (0.22%)  0/902 (0.00%) 
Benign neoplasm of thyroid gland  1  0/450 (0.00%)  1/902 (0.11%) 
Bladder cancer  1  0/450 (0.00%)  1/902 (0.11%) 
Brain cancer metastatic  1  0/450 (0.00%)  1/902 (0.11%) 
Breast cancer  1  1/450 (0.22%)  2/902 (0.22%) 
Breast cancer recurrent  1  0/450 (0.00%)  1/902 (0.11%) 
Bronchioloalveolar carcinoma  1  0/450 (0.00%)  1/902 (0.11%) 
Cerebellar tumour  1  1/450 (0.22%)  0/902 (0.00%) 
Clear cell renal cell carcinoma  1  1/450 (0.22%)  0/902 (0.00%) 
Invasive ductal breast carcinoma  1  0/450 (0.00%)  1/902 (0.11%) 
Malignant melanoma  1  0/450 (0.00%)  1/902 (0.11%) 
Malignant neoplasm progression  1  7/450 (1.56%)  15/902 (1.66%) 
Metastases to central nervous system  1  2/450 (0.44%)  1/902 (0.11%) 
Metastases to large intestine  1  1/450 (0.22%)  0/902 (0.00%) 
Metastases to reproductive organ  1  1/450 (0.22%)  0/902 (0.00%) 
Metastases to small intestine  1  1/450 (0.22%)  1/902 (0.11%) 
Neoplasm  1  0/450 (0.00%)  2/902 (0.22%) 
Neoplasm progression  1  0/450 (0.00%)  1/902 (0.11%) 
Ovarian cancer  1  2/450 (0.44%)  0/902 (0.00%) 
Ovarian epithelial cancer  1  0/450 (0.00%)  1/902 (0.11%) 
Papillary thyroid cancer  1  0/450 (0.00%)  1/902 (0.11%) 
Paraneoplastic syndrome  1  0/450 (0.00%)  1/902 (0.11%) 
Pelvic neoplasm  1  0/450 (0.00%)  1/902 (0.11%) 
Peritoneal neoplasm  1  0/450 (0.00%)  1/902 (0.11%) 
Renal cell carcinoma  1  1/450 (0.22%)  0/902 (0.00%) 
Thyroid cancer  1  1/450 (0.22%)  0/902 (0.00%) 
Tumour associated fever  1  1/450 (0.22%)  0/902 (0.00%) 
Nervous system disorders     
Amnesia  1  1/450 (0.22%)  0/902 (0.00%) 
Asterixis  1  0/450 (0.00%)  1/902 (0.11%) 
Carpal tunnel syndrome  1  0/450 (0.00%)  1/902 (0.11%) 
Cerebral infarction  1  0/450 (0.00%)  2/902 (0.22%) 
Cerebrovascular accident  1  1/450 (0.22%)  1/902 (0.11%) 
Coma  1  0/450 (0.00%)  1/902 (0.11%) 
Dizziness  1  1/450 (0.22%)  5/902 (0.55%) 
Guillain-Barre syndrome  1  0/450 (0.00%)  1/902 (0.11%) 
Headache  1  0/450 (0.00%)  5/902 (0.55%) 
Hemianopia homonymous  1  0/450 (0.00%)  1/902 (0.11%) 
Intracranial aneurysm  1  0/450 (0.00%)  1/902 (0.11%) 
Ischaemic stroke  1  0/450 (0.00%)  1/902 (0.11%) 
Myoclonus  1  1/450 (0.22%)  0/902 (0.00%) 
Neuralgia  1  0/450 (0.00%)  1/902 (0.11%) 
Neuropathy peripheral  1  1/450 (0.22%)  1/902 (0.11%) 
Paraesthesia  1  1/450 (0.22%)  1/902 (0.11%) 
Peripheral sensorimotor neuropathy  1  0/450 (0.00%)  1/902 (0.11%) 
Sciatica  1  0/450 (0.00%)  1/902 (0.11%) 
Syncope  1  1/450 (0.22%)  6/902 (0.67%) 
Transient ischaemic attack  1  1/450 (0.22%)  1/902 (0.11%) 
Trigeminal neuralgia  1  0/450 (0.00%)  1/902 (0.11%) 
Product Issues     
Device dislocation  1  0/450 (0.00%)  1/902 (0.11%) 
Thrombosis in device  1  0/450 (0.00%)  1/902 (0.11%) 
Psychiatric disorders     
Anxiety  1  2/450 (0.44%)  0/902 (0.00%) 
Conversion disorder  1  0/450 (0.00%)  1/902 (0.11%) 
Depression  1  1/450 (0.22%)  3/902 (0.33%) 
Hallucination  1  0/450 (0.00%)  1/902 (0.11%) 
Mental disorder  1  1/450 (0.22%)  0/902 (0.00%) 
Personality change  1  1/450 (0.22%)  0/902 (0.00%) 
Renal and urinary disorders     
Acute kidney injury  1  3/450 (0.67%)  4/902 (0.44%) 
Bladder tamponade  1  0/450 (0.00%)  1/902 (0.11%) 
Haematuria  1  1/450 (0.22%)  1/902 (0.11%) 
Hydronephrosis  1  2/450 (0.44%)  7/902 (0.78%) 
Incontinence  1  0/450 (0.00%)  1/902 (0.11%) 
Proteinuria  1  0/450 (0.00%)  1/902 (0.11%) 
Renal failure  1  1/450 (0.22%)  4/902 (0.44%) 
Ureteric obstruction  1  0/450 (0.00%)  4/902 (0.44%) 
Ureteric stenosis  1  1/450 (0.22%)  1/902 (0.11%) 
Urinary bladder haemorrhage  1  1/450 (0.22%)  0/902 (0.00%) 
Urinary retention  1  0/450 (0.00%)  3/902 (0.33%) 
Urinary tract obstruction  1  0/450 (0.00%)  2/902 (0.22%) 
Urogenital fistula  1  0/450 (0.00%)  1/902 (0.11%) 
Vesicocutaneous fistula  1  1/450 (0.22%)  0/902 (0.00%) 
Reproductive system and breast disorders     
Cervical polyp  1  1/450 (0.22%)  0/902 (0.00%) 
Metrorrhagia  1  0/450 (0.00%)  1/902 (0.11%) 
Pelvic pain  1  0/450 (0.00%)  2/902 (0.22%) 
Uterine fistula  1  0/450 (0.00%)  1/902 (0.11%) 
Vaginal fistula  1  0/450 (0.00%)  1/902 (0.11%) 
Vaginal haemorrhage  1  2/450 (0.44%)  1/902 (0.11%) 
Vaginal prolapse  1  0/450 (0.00%)  1/902 (0.11%) 
Vaginal ulceration  1  0/450 (0.00%)  1/902 (0.11%) 
Respiratory, thoracic and mediastinal disorders     
Asthma  1  1/450 (0.22%)  0/902 (0.00%) 
Cough  1  1/450 (0.22%)  1/902 (0.11%) 
Dyspnoea  1  4/450 (0.89%)  10/902 (1.11%) 
Dyspnoea at rest  1  0/450 (0.00%)  1/902 (0.11%) 
Hydrothorax  1  1/450 (0.22%)  2/902 (0.22%) 
Pleural effusion  1  1/450 (0.22%)  6/902 (0.67%) 
Pneumonitis  1  0/450 (0.00%)  1/902 (0.11%) 
Pneumothorax  1  0/450 (0.00%)  3/902 (0.33%) 
Pulmonary embolism  1  5/450 (1.11%)  11/902 (1.22%) 
Pulmonary haemorrhage  1  1/450 (0.22%)  0/902 (0.00%) 
Respiratory failure  1  1/450 (0.22%)  1/902 (0.11%) 
Skin and subcutaneous tissue disorders     
Dermatomyositis  1  0/450 (0.00%)  1/902 (0.11%) 
Drug eruption  1  0/450 (0.00%)  1/902 (0.11%) 
Psoriasis  1  0/450 (0.00%)  1/902 (0.11%) 
Rash  1  0/450 (0.00%)  1/902 (0.11%) 
Skin erosion  1  1/450 (0.22%)  0/902 (0.00%) 
Urticarial vasculitis  1  0/450 (0.00%)  1/902 (0.11%) 
Surgical and medical procedures     
Catheter placement  1  1/450 (0.22%)  0/902 (0.00%) 
Central venous catheter removal  1  1/450 (0.22%)  0/902 (0.00%) 
Chemotherapy  1  1/450 (0.22%)  1/902 (0.11%) 
Cholecystectomy  1  0/450 (0.00%)  1/902 (0.11%) 
Cytoreductive surgery  1  2/450 (0.44%)  0/902 (0.00%) 
Ileostomy  1  0/450 (0.00%)  1/902 (0.11%) 
Intestinal resection  1  0/450 (0.00%)  1/902 (0.11%) 
Laparotomy  1  0/450 (0.00%)  2/902 (0.22%) 
Large intestine anastomosis  1  0/450 (0.00%)  1/902 (0.11%) 
Vaginal operation  1  1/450 (0.22%)  0/902 (0.00%) 
Vascular disorders     
Accelerated hypertension  1  0/450 (0.00%)  1/902 (0.11%) 
Aortic aneurysm  1  1/450 (0.22%)  0/902 (0.00%) 
Axillary vein thrombosis  1  0/450 (0.00%)  1/902 (0.11%) 
Circulatory collapse  1  0/450 (0.00%)  1/902 (0.11%) 
Deep vein thrombosis  1  5/450 (1.11%)  4/902 (0.44%) 
Haematoma  1  0/450 (0.00%)  1/902 (0.11%) 
Hypertension  1  0/450 (0.00%)  5/902 (0.55%) 
Hypertensive crisis  1  0/450 (0.00%)  2/902 (0.22%) 
Hypotension  1  1/450 (0.22%)  4/902 (0.44%) 
Lymphocele  1  2/450 (0.44%)  6/902 (0.67%) 
Lymphoedema  1  0/450 (0.00%)  1/902 (0.11%) 
Malignant hypertension  1  0/450 (0.00%)  1/902 (0.11%) 
Orthostatic hypotension  1  0/450 (0.00%)  1/902 (0.11%) 
Pelvic venous thrombosis  1  0/450 (0.00%)  1/902 (0.11%) 
Thrombophlebitis  1  0/450 (0.00%)  1/902 (0.11%) 
Thrombosis  1  1/450 (0.22%)  6/902 (0.67%) 
Varicose vein  1  0/450 (0.00%)  1/902 (0.11%) 
Vasculitis  1  1/450 (0.22%)  0/902 (0.00%) 
Vena cava thrombosis  1  0/450 (0.00%)  1/902 (0.11%) 
Venous occlusion  1  1/450 (0.22%)  0/902 (0.00%) 
Venous thrombosis limb  1  0/450 (0.00%)  2/902 (0.22%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Nintedanib
Affected / at Risk (%) Affected / at Risk (%)
Total   442/450 (98.22%)   891/902 (98.78%) 
Blood and lymphatic system disorders     
Anaemia  1  129/450 (28.67%)  317/902 (35.14%) 
Leukopenia  1  78/450 (17.33%)  165/902 (18.29%) 
Neutropenia  1  203/450 (45.11%)  419/902 (46.45%) 
Thrombocytopenia  1  87/450 (19.33%)  301/902 (33.37%) 
Gastrointestinal disorders     
Abdominal distension  1  20/450 (4.44%)  55/902 (6.10%) 
Abdominal pain  1  111/450 (24.67%)  281/902 (31.15%) 
Abdominal pain upper  1  58/450 (12.89%)  125/902 (13.86%) 
Constipation  1  151/450 (33.56%)  254/902 (28.16%) 
Diarrhoea  1  114/450 (25.33%)  692/902 (76.72%) 
Dyspepsia  1  24/450 (5.33%)  77/902 (8.54%) 
Flatulence  1  9/450 (2.00%)  53/902 (5.88%) 
Nausea  1  231/450 (51.33%)  583/902 (64.63%) 
Stomatitis  1  24/450 (5.33%)  51/902 (5.65%) 
Vomiting  1  119/450 (26.44%)  391/902 (43.35%) 
General disorders     
Asthenia  1  65/450 (14.44%)  163/902 (18.07%) 
Fatigue  1  201/450 (44.67%)  388/902 (43.02%) 
Mucosal inflammation  1  30/450 (6.67%)  62/902 (6.87%) 
Oedema peripheral  1  47/450 (10.44%)  48/902 (5.32%) 
Pain  1  27/450 (6.00%)  35/902 (3.88%) 
Pyrexia  1  46/450 (10.22%)  64/902 (7.10%) 
Immune system disorders     
Drug hypersensitivity  1  21/450 (4.67%)  58/902 (6.43%) 
Hypersensitivity  1  32/450 (7.11%)  53/902 (5.88%) 
Infections and infestations     
Cystitis  1  17/450 (3.78%)  66/902 (7.32%) 
Nasopharyngitis  1  36/450 (8.00%)  73/902 (8.09%) 
Urinary tract infection  1  50/450 (11.11%)  131/902 (14.52%) 
Investigations     
Alanine aminotransferase increased  1  49/450 (10.89%)  259/902 (28.71%) 
Aspartate aminotransferase increased  1  41/450 (9.11%)  219/902 (24.28%) 
Blood alkaline phosphatase increased  1  16/450 (3.56%)  74/902 (8.20%) 
Haemoglobin decreased  1  24/450 (5.33%)  56/902 (6.21%) 
Neutrophil count decreased  1  23/450 (5.11%)  74/902 (8.20%) 
Platelet count decreased  1  17/450 (3.78%)  63/902 (6.98%) 
Metabolism and nutrition disorders     
Decreased appetite  1  63/450 (14.00%)  168/902 (18.63%) 
Hypokalaemia  1  25/450 (5.56%)  85/902 (9.42%) 
Hypomagnesaemia  1  25/450 (5.56%)  92/902 (10.20%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  137/450 (30.44%)  242/902 (26.83%) 
Back pain  1  54/450 (12.00%)  83/902 (9.20%) 
Bone pain  1  39/450 (8.67%)  62/902 (6.87%) 
Musculoskeletal pain  1  29/450 (6.44%)  56/902 (6.21%) 
Myalgia  1  107/450 (23.78%)  201/902 (22.28%) 
Pain in extremity  1  56/450 (12.44%)  95/902 (10.53%) 
Nervous system disorders     
Dizziness  1  36/450 (8.00%)  77/902 (8.54%) 
Dysgeusia  1  37/450 (8.22%)  126/902 (13.97%) 
Headache  1  53/450 (11.78%)  140/902 (15.52%) 
Neuropathy peripheral  1  85/450 (18.89%)  172/902 (19.07%) 
Paraesthesia  1  64/450 (14.22%)  100/902 (11.09%) 
Peripheral sensory neuropathy  1  114/450 (25.33%)  214/902 (23.73%) 
Polyneuropathy  1  25/450 (5.56%)  50/902 (5.54%) 
Psychiatric disorders     
Anxiety  1  27/450 (6.00%)  36/902 (3.99%) 
Depression  1  32/450 (7.11%)  51/902 (5.65%) 
Insomnia  1  57/450 (12.67%)  105/902 (11.64%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  34/450 (7.56%)  57/902 (6.32%) 
Dyspnoea  1  55/450 (12.22%)  109/902 (12.08%) 
Epistaxis  1  17/450 (3.78%)  72/902 (7.98%) 
Skin and subcutaneous tissue disorders     
Alopecia  1  278/450 (61.78%)  519/902 (57.54%) 
Pruritus  1  32/450 (7.11%)  44/902 (4.88%) 
Rash  1  50/450 (11.11%)  95/902 (10.53%) 
Vascular disorders     
Hot flush  1  45/450 (10.00%)  73/902 (8.09%) 
Hypertension  1  23/450 (5.11%)  119/902 (13.19%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01015118    
Other Study ID Numbers: 1199.15
AGO-OVAR12 ( Other Identifier: OTHER )
2008-006831-10 ( EudraCT Number: EudraCT )
First Submitted: November 9, 2009
First Posted: November 18, 2009
Results First Submitted: November 14, 2014
Results First Posted: January 15, 2015
Last Update Posted: December 7, 2017