Trial Outcomes & Findings for A Trial to Compare Nintedanib With Placebo for Patients With Scleroderma Related Lung Fibrosis (NCT NCT02597933)

NCT ID: NCT02597933

Last Updated: 2019-12-13

Results Overview

Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test. For this endpoint reported means represent the adjusted rate.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 580 participants
• Primary outcome timeframe: up to week (wk) 52 after the start of administration
• Results posted on: 2019-12-13

Participant Flow

This was a randomised, placebo-controlled, double-blind, parallel design trial. Abbreviation used: treatment (trt) baseline (bl.) categorical (cat.) continuous (cont.) number (no.) patient (pt) Placebo (pl.) discontinued (disc.) primary analysis (PA) Antitopoisomerase Antibody (ATA)

All subjects were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they (the subjects) met all implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial drug if any of the specific entry criteria was violated

Participant milestones

Measure	Placebo Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Overall Study STARTED	290	290
Overall Study Treated Patients	288	288
Overall Study COMPLETED	252	239
Overall Study NOT COMPLETED	38	51

Reasons for withdrawal

Measure	Placebo Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Overall Study Withdrawal by Subject	7	5
Overall Study Protocol Violation	2	2
Overall Study Adverse Event	20	28
Overall Study Not treated	2	2
Overall Study Other than stated above	7	14

Baseline Characteristics

A Trial to Compare Nintedanib With Placebo for Patients With Scleroderma Related Lung Fibrosis

Baseline characteristics by cohort

Measure	Placebo n=288 Participants Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 Participants Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Total n=576 Participants Total of all reporting groups
Age, Continuous	53.4 Years STANDARD_DEVIATION 12.6 • n=5 Participants	54.6 Years STANDARD_DEVIATION 11.8 • n=7 Participants	54.0 Years STANDARD_DEVIATION 12.2 • n=5 Participants
Sex: Female, Male Female	212 Participants n=5 Participants	221 Participants n=7 Participants	433 Participants n=5 Participants
Sex: Female, Male Male	76 Participants n=5 Participants	67 Participants n=7 Participants	143 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	18 Participants n=5 Participants	22 Participants n=7 Participants	40 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	270 Participants n=5 Participants	266 Participants n=7 Participants	536 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) Asian	81 Participants n=5 Participants	62 Participants n=7 Participants	143 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	16 Participants n=5 Participants	20 Participants n=7 Participants	36 Participants n=5 Participants
Race (NIH/OMB) White	186 Participants n=5 Participants	201 Participants n=7 Participants	387 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Baseline pulmonary efficacy variables - Forced Vital Capacity (FVC)	2541.0 mL STANDARD_DEVIATION 815.5 • n=5 Participants	2458.5 mL STANDARD_DEVIATION 735.9 • n=7 Participants	2499.7 mL STANDARD_DEVIATION 777.2 • n=5 Participants

PRIMARY outcome

Timeframe: up to week (wk) 52 after the start of administration

Population: Treated Set

Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test.

For this endpoint reported means represent the adjusted rate.

Outcome measures

Measure	Placebo n=288 Participants Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 Participants Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Annual Rate of Decline in Forced Vital Capacity (FVC) Over 52 Weeks	-93.3 millilitre (mL)/year (yr) Standard Error 13.5	-52.4 millilitre (mL)/year (yr) Standard Error 13.8

SECONDARY outcome

Timeframe: Baseline and up to 52 weeks after the start of administration

Population: Treated Set

This is the first key secondary endpoint.

The modified Rodnan Skin Score (mRSS) is an evaluation of the patient's skin thickness rated by clinical palpation using a 0 to 3 scale. The scale differentiates between 0 = normal skin, 1 = mild thickness, 2 = moderate thickness, and 3 = severe thickness with inability to pinch the skin into a fold.

The palpation is done for each of the 17 surface anatomic areas of the body: face, anterior chest, abdomen, fingers (right and left separately), forearms, upper arms, thighs, lower legs, dorsum of hands and feet. The sum of these individual values is defined as the total skin score. The mRSS has a range from 0 (no thickening) to 51 (severe thickening in all 17 areas). A high score corresponds to worse skin thickness.

Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).

Outcome measures

Measure	Placebo n=288 Participants Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 Participants Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Absolute Change From Baseline in the Modified Rodnan Skin Score (mRSS) at Week 52	-1.96 unit on scale Standard Error 0.26	-2.17 unit on scale Standard Error 0.27

SECONDARY outcome

Timeframe: Baseline and up to 52 weeks after the start of administration

Population: Treated set

This is the second key secondary endpoint.

The Saint George's Respiratory Questionnaire measures the health status in patients with chronic airflow limitation. It consists of 2 parts that cover 3 domains: symptoms, activities, and impacts. The symptom domain relates to the effect, frequency and severity of respiratory symptoms. The activity domain relates to activities that cause or are limited by breathlessness. The impact domain evaluates a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. The scores of these domains range from 0 (no impairment) to 100 (worst possible). The calculated total score summarises the impact of the disease on overall health status. A high score corresponds to worse health.

Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).

Outcome measures

Measure	Placebo n=288 Participants Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 Participants Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Absolute Change From Baseline in Saint George's Respiratory Questionnaire (SGRQ) Total Score at Week 52.	-0.88 unit on scale Standard Error 0.87	0.81 unit on scale Standard Error 0.88

SECONDARY outcome

Timeframe: up to 52 weeks after the start of administration

Population: Treated set

Annual rate of decline in FVC in percentage (%) predicted over 52 weeks.

For this endpoint reported means represent the adjusted rate.

Outcome measures

Measure	Placebo n=288 Participants Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 Participants Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Annual Rate of Decline in FVC in Percentage (%) Predicted Over 52 Weeks	-2.6 % predicted/yr Standard Error 0.4	-1.4 % predicted/yr Standard Error 0.4

SECONDARY outcome

Timeframe: Baseline and up to 52 weeks after the start of administration

Population: Treated Set

Absolute change from baseline in FVC in mL at Week 52. Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).

Outcome measures

Measure	Placebo n=288 Participants Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 Participants Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Absolute Change From Baseline in FVC in mL at Week 52	-101.03 mL Standard Error 13.62	-54.63 mL Standard Error 13.94

SECONDARY outcome

Timeframe: Baseline and up to 52 weeks after the start of administration

Population: Treated set

Relative change from baseline [%] of mRSS at Week 52.

The modified Rodnan Skin Score (mRSS) is an evaluation of the patient's skin thickness rated by clinical palpation using a 0 to 3 scale. The scale differentiates between 0 = normal skin, 1 = mild thickness, 2 = moderate thickness, and 3 = severe thickness with inability to pinch the skin into a fold.

The palpation is done for each of the 17 surface anatomic areas of the body: face, anterior chest, abdomen, fingers (right and left separately), forearms, upper arms, thighs, lower legs, dorsum of hands and feet. The sum of these individual values is defined as the total skin score. The mRSS has a range from 0 (no thickening) to 51 (severe thickening in all 17 areas). A high score corresponds to worse skin thickness.

Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).

Outcome measures

Measure	Placebo n=288 Participants Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 Participants Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Relative Change From Baseline [%] of mRSS at Week 52	-3.92 percent change Standard Error 5.89	-10.20 percent change Standard Error 5.98

SECONDARY outcome

Timeframe: From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)

Population: Treated set

Time to event analysis of patients with death. The number of observed patients with death are reported.

Outcome measures

Measure	Placebo n=288 Participants Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 Participants Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Time to Death	9 Participants	10 Participants

SECONDARY outcome

Timeframe: Week 52

Population: Treated set

The percentage (%) of responder based on Combined Response Index in Systemic Sclerosis (CRISS) at Week 52.

This is a composite endpoint, based on the mRSS, FVC percent predicted, HAQ-DI, patient's global impression of overall health Visual Analogue Scale (VAS) and physician's global impression of patient's overall health VAS, as well as the absence of significant worsening of interstitial lung disease, a new scleroderma renal crisis, left ventricular failure or pulmonary arterial hypertension.

The CRISS index score represents a probability of improvement and ranges between 0 and 1.

This is a 2 stage process to predict probability of improvement:

Step 1 - absence of major organ progression (SRC etc.) - score "0" Step 2 - predicted probability of improvement - (score "0 - 1")

Outcome measures

Measure	Placebo n=288 Participants Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 Participants Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
The Percentage (%) of Responder Based on Combined Response Index in Systemic Sclerosis (CRISS) at Week 52	11.8 (%) of responder based on CRISS	12.2 (%) of responder based on CRISS

SECONDARY outcome

Timeframe: Baseline and up to 52 weeks after the start of administration

Population: Treated set

Absolute change from baseline in Carbon Monoxide Diffusion Capacity (DLco) in % predicted at Week 52.

Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).

Outcome measures

Measure	Placebo n=288 Participants Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 Participants Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Absolute Change From Baseline in Carbon Monoxide Diffusion Capacity (DLco) in % Predicted at Week 52	-2.77 % predicted DLco Standard Error 0.54	-3.21 % predicted DLco Standard Error 0.54

SECONDARY outcome

Timeframe: Baseline and up to 52 weeks after the start of administration

Population: Treated set

Absolute change from baseline in digital ulcer net burden (defined as the number of new digital ulcers (DUs) plus the number of DUs that have been verified at any earlier assessment during the trial) at Week 52.

It is calculated at a visit by counting the total number of fingertips with ulcers (i.e. number of fingers with presence of digital ulcer ticked "Yes") at the corresponding visit

Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).

Outcome measures

Measure	Placebo n=288 Participants Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 Participants Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Absolute Change From Baseline in Digital Ulcer Net Burden at Week 52	0.06 fingers Standard Error 0.04	0.03 fingers Standard Error 0.05

SECONDARY outcome

Timeframe: Baseline and up to 52 weeks after the start of administration

Population: Treated set

Absolute change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 52.

The HAQ-DI score is calculated as follows:

Each question is scored 0-3 (where 0= "without difficulty" & 3= "unable to do"). There are 8 categories (Dressing & Grooming, Arising, Eating, Walking, Hygiene, Reach, Grip, Activities), each including 2 or 3 questions. The score for each category corresponds to maximum question score within each category.

Finally, HAQ-DI score corresponds to sum of the sub-scores of all 8 categories divided by number of categories completed. Please note that if there are fewer than 6 categories with responses, then a score cannot be calculated.

The HAQ-DI score scale has 25 possible values (i.e., 0, 0.125, 0.250, 0.375 … 3). A high score corresponds to worse impairment.

Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).

Outcome measures

Measure	Placebo n=288 Participants Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 Participants Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Absolute Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52	0.022 unit on a scale Standard Error 0.024	0.054 unit on a scale Standard Error 0.024

SECONDARY outcome

Timeframe: Baseline and up to 52 weeks after the start of administration

Population: Treated set

Absolute change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) dyspnoea score at Week 52.

FACIT-Dyspnoea (Dyspnoea) 10 Item Short Form include a 4-point rating scale (no shortness of breath=0; mildly short of breath=1; moderately short of breath = 2; severely short of breath =3; or I did not do this in the past 7 days =4).

A raw score is calculated as: Sum individual item scores * 10 / number of items answered. Raw scores are then converted to scale scores using the table included in the FACIT Dyspnoea Scale Short Form Scoring Guideline. FACIT dyspnea scale score ranges between 0 and 75.9.

The FACIT-Dyspnea short forms are scored such that a high score represents high levels of dyspnea.

Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).

Outcome measures

Measure	Placebo n=288 Participants Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 Participants Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Absolute Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnoea Score at Week 52	0.34 Unit on a scale Standard Error 0.41	0.99 Unit on a scale Standard Error 0.42

Adverse Events

Placebo

Serious events: 79 serious events

Other events: 239 other events

Deaths: 9 deaths

Nintedanib

Serious events: 88 serious events

Other events: 270 other events

Deaths: 10 deaths

Serious adverse events

Measure	Placebo n=288 participants at risk Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 participants at risk Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Immune system disorders Anti-neutrophil cytoplasmic antibody positive vasculitis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Adenovirus infection	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Appendicitis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Bronchitis	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Campylobacter gastroenteritis	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Cellulitis	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Device related infection	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Diverticulitis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Gangrene	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Gastroenteritis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Herpes zoster	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Influenza	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Lower respiratory tract infection	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Lung infection	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Osteomyelitis	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Pneumonia	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	3.5% 10/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Pneumonia bacterial	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Pyelonephritis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Pyelonephritis acute	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Respiratory tract infection	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	1.0% 3/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Sepsis	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Septic shock	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Skin infection	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Systemic candida	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Tuberculosis	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Upper respiratory tract infection	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Urinary tract infection	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Urosepsis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Injury, poisoning and procedural complications Ankle fracture	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Injury, poisoning and procedural complications Femur fracture	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Injury, poisoning and procedural complications Joint dislocation	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Injury, poisoning and procedural complications Postoperative ileus	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Investigations Cell marker increased	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Investigations Forced vital capacity decreased	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Investigations Haemoglobin decreased	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Investigations Neutrophil count decreased	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Investigations White blood cell count decreased	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Metabolism and nutrition disorders Dehydration	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Metabolism and nutrition disorders Fluid overload	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Arthritis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Bursitis	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Drooping shoulder syndrome	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Fistula	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	1.0% 3/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Osteonecrosis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Polymyalgia rheumatica	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Scleroderma	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Systemic scleroderma	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign mesothelioma	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric cancer	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Mesothelioma malignant	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Nasopharyngeal cancer	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal cancer	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Sweat gland tumour	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Nervous system disorders Carotid artery aneurysm	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Nervous system disorders Carotid artery stenosis	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Nervous system disorders Cerebral amyloid angiopathy	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Nervous system disorders Cerebral infarction	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Nervous system disorders Cerebral microhaemorrhage	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Nervous system disorders Cerebrovascular disorder	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Nervous system disorders Depressed level of consciousness	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Nervous system disorders Seizure	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Nervous system disorders Subarachnoid haemorrhage	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Nervous system disorders Syncope	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Psychiatric disorders Delirium	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Psychiatric disorders Major depression	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Renal and urinary disorders Acute kidney injury	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	1.0% 3/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Renal and urinary disorders Bladder perforation	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Renal and urinary disorders Renal failure	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Renal and urinary disorders Scleroderma renal crisis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Renal and urinary disorders Urinary incontinence	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Renal and urinary disorders Urinary tract obstruction	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Reproductive system and breast disorders Benign prostatic hyperplasia	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Reproductive system and breast disorders Ovarian cyst	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	1.0% 3/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Reproductive system and breast disorders Vulvovaginal swelling	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Acute lung injury	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Aspiration	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Cough	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.8% 8/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	1.7% 5/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Haemothorax	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	2.1% 6/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	3.5% 10/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Painful respiration	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Pneumothorax spontaneous	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Pulmonary arterial hypertension	1.4% 4/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	1.4% 4/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Pulmonary fibrosis	1.4% 4/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	1.4% 4/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	1.4% 4/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	1.7% 5/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Systemic sclerosis pulmonary	1.7% 5/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	1.0% 3/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Skin and subcutaneous tissue disorders Actinic keratosis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Skin and subcutaneous tissue disorders Digital pitting scar	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Skin and subcutaneous tissue disorders Petechiae	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Skin and subcutaneous tissue disorders Sclerema	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Skin and subcutaneous tissue disorders Skin ulcer	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Vascular disorders Deep vein thrombosis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Vascular disorders Extremity necrosis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Vascular disorders Hypertension	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Vascular disorders Hypertensive crisis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Vascular disorders Hypotension	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Vascular disorders Peripheral arterial occlusive disease	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Vascular disorders Peripheral artery occlusion	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Vascular disorders Raynaud's phenomenon	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Vascular disorders Thrombophlebitis superficial	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Vascular disorders Vena cava thrombosis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Blood and lymphatic system disorders Immune thrombocytopenic purpura	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Blood and lymphatic system disorders Iron deficiency anaemia	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Blood and lymphatic system disorders Leukopenia	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Blood and lymphatic system disorders Thrombotic microangiopathy	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Acute myocardial infarction	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Arrhythmia	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Atrial fibrillation	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Atrial flutter	1.0% 3/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Atrioventricular block complete	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Cardiac arrest	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Cardiac failure	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Cardiac failure congestive	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Coronary artery disease	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Myocardial infarction	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Myocarditis	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Palpitations	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Pericardial effusion	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Pericarditis	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Pleuropericarditis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Restrictive cardiomyopathy	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Right ventricular failure	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Cardiac disorders Ventricular fibrillation	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Congenital, familial and genetic disorders Hypertrophic cardiomyopathy	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Ear and labyrinth disorders Vertigo	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Endocrine disorders Adrenal insufficiency	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Eye disorders Glaucoma	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Eye disorders Macular oedema	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Eye disorders Retinal detachment	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Eye disorders Retinal vein occlusion	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Eye disorders Rhegmatogenous retinal detachment	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Colitis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Colitis ischaemic	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Diarrhoea	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Gastritis	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Gastrointestinal disorder	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Haematemesis	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Haematochezia	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Ileus	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Ileus paralytic	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Intestinal mass	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Intestinal pseudo-obstruction	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Large intestine polyp	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Pancreatitis acute	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Vomiting	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
General disorders Brain death	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
General disorders General physical health deterioration	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
General disorders Multiple organ dysfunction syndrome	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
General disorders Polyp	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
General disorders Pyrexia	0.69% 2/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
General disorders Systemic inflammatory response syndrome	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Hepatobiliary disorders Bile duct stone	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Hepatobiliary disorders Cholecystitis	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Hepatobiliary disorders Drug-induced liver injury	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Hepatobiliary disorders Hepatocellular injury	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Hepatobiliary disorders Liver disorder	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Hepatobiliary disorders Liver injury	0.00% 0/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)

Other adverse events

Measure	Placebo n=288 participants at risk Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.	Nintedanib n=288 participants at risk Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.
Gastrointestinal disorders Abdominal pain	7.3% 21/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	12.5% 36/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Abdominal pain upper	5.2% 15/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	7.3% 21/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Constipation	6.6% 19/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	5.2% 15/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Diarrhoea	31.9% 92/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	75.7% 218/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Gastrooesophageal reflux disease	9.0% 26/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	6.9% 20/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Nausea	14.2% 41/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	33.3% 96/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Gastrointestinal disorders Vomiting	10.8% 31/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	27.1% 78/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
General disorders Fatigue	7.3% 21/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	11.5% 33/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
General disorders Pyrexia	4.5% 13/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	6.9% 20/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Bronchitis	9.4% 27/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	7.6% 22/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Influenza	5.2% 15/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	5.6% 16/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Nasopharyngitis	19.4% 56/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	14.9% 43/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Respiratory tract infection	5.6% 16/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	3.5% 10/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Upper respiratory tract infection	14.9% 43/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	13.5% 39/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Infections and infestations Urinary tract infection	9.7% 28/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	9.7% 28/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Investigations Alanine aminotransferase increased	1.4% 4/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	7.6% 22/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Investigations Aspartate aminotransferase increased	0.35% 1/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	5.6% 16/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Investigations Gamma-glutamyltransferase increased	1.4% 4/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	6.6% 19/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Investigations Weight decreased	5.2% 15/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	13.5% 39/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Metabolism and nutrition disorders Decreased appetite	4.9% 14/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	9.7% 28/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Arthralgia	8.0% 23/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	8.0% 23/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Back pain	5.2% 15/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	6.9% 20/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Myalgia	3.8% 11/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	5.6% 16/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Musculoskeletal and connective tissue disorders Pain in extremity	4.9% 14/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	5.2% 15/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Nervous system disorders Dizziness	5.2% 15/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	6.6% 19/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Nervous system disorders Headache	9.7% 28/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	11.8% 34/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Cough	21.5% 62/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	14.2% 41/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Dyspnoea	9.4% 27/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	8.0% 23/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Respiratory, thoracic and mediastinal disorders Epistaxis	5.6% 16/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	2.8% 8/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Skin and subcutaneous tissue disorders Skin ulcer	18.8% 54/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)	19.4% 56/288 • From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)

Additional Information

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