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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02597933
Recruitment Status : Completed
First Posted : November 5, 2015
Results First Posted : December 13, 2019
Last Update Posted : December 13, 2019
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Scleroderma, Systemic
Interventions Drug: Nintedanib
Drug: Placebo
Enrollment 580
Recruitment Details

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)

Pre-assignment Details 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
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 290 [1] 290 [1]
Treated Patients 288 288
Completed 252 239
Not Completed 38 51
Reason Not Completed
Withdrawal by Subject             7             5
Protocol Violation             2             2
Adverse Event             20             28
Not treated             2             2
Other than stated above             7             14
[1]
Started are randomised
Arm/Group Title Placebo Nintedanib Total
Hide Arm/Group Description 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. 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 of all reporting groups
Overall Number of Baseline Participants 288 288 576
Hide Baseline Analysis Population Description
Treated set (TS): The treated set consisted of patients who were randomised to a treatment group and received at least 1 dose of trial medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 288 participants 288 participants 576 participants
53.4  (12.6) 54.6  (11.8) 54.0  (12.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 288 participants 288 participants 576 participants
Female
212
  73.6%
221
  76.7%
433
  75.2%
Male
76
  26.4%
67
  23.3%
143
  24.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 288 participants 288 participants 576 participants
Hispanic or Latino
18
   6.3%
22
   7.6%
40
   6.9%
Not Hispanic or Latino
270
  93.8%
266
  92.4%
536
  93.1%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 288 participants 288 participants 576 participants
American Indian or Alaska Native
3
   1.0%
2
   0.7%
5
   0.9%
Asian
81
  28.1%
62
  21.5%
143
  24.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
1
   0.3%
1
   0.2%
Black or African American
16
   5.6%
20
   6.9%
36
   6.3%
White
186
  64.6%
201
  69.8%
387
  67.2%
More than one race
2
   0.7%
2
   0.7%
4
   0.7%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Baseline pulmonary efficacy variables - Forced Vital Capacity (FVC)  
Mean (Standard Deviation)
Unit of measure:  mL
Number Analyzed 288 participants 288 participants 576 participants
2541.0  (815.5) 2458.5  (735.9) 2499.7  (777.2)
1.Primary Outcome
Title Annual Rate of Decline in Forced Vital Capacity (FVC) Over 52 Weeks
Hide Description

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.

Time Frame up to week (wk) 52 after the start of administration
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 288 288
Mean (Standard Error)
Unit of Measure: millilitre (mL)/year (yr)
-93.3  (13.5) -52.4  (13.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments The primary analysis is a restricted maximum likelihood (REML) based approach using a random slope & intercept model. The analysis included the fixed, categorical effects of treatment, ATA status & gender, fixed continuous effects of time & baseline FVC (mL), age and height as well as the treatment-by time & baseline-by-time interactions. Random effects was included for patient response for both time & intercept.Within-patient errors are modelled by an unstructured variance-covariance matrix
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0350
Comments [Not Specified]
Method random coefficient regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 40.95
Confidence Interval (2-Sided) 95%
2.88 to 79.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 19.38
Estimation Comments The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments

This is a sensitivity analysis (SA) on primary endpoint including only on-trt measurements of FVC [mL]. The random coefficient model was used. The analysis included fixed, categorical effects of trt, ATA status & gender, fixed continuous effects of time & bl. FVC (mL), age, height, trt -by time & bl.-by-time interactions. Random effects included for patient response for both time & intercept.

Within−patient errors were modelled by an Unstructured variance−covariance matrix.

Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0378
Comments [Not Specified]
Method random coefficient regression
Comments The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 43.13
Confidence Interval (2-Sided) 95%
2.44 to 83.83
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments In multiple imputation SA 1, missing FVC values at wk 52 in pts who were alive at wk 52 were imputed assuming similar rate of FVC decline as in pts from corresponding trt group who prematurely disc. trial drug but had wk 52 FVC value. Missing FVC values at wk 52 in pts who died before wk 52 were imputed assuming similar rate of FVC decline as in pl. pts with wk 52 FVC value who prematurely disc. trial drug with most severe declines.The imputation model was similar to statistical model of PA.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1046
Comments [Not Specified]
Method random coefficient regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 30.00
Confidence Interval (2-Sided) 95%
-6.22 to 66.22
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments In multiple imputation SA 2, missing FVC values at wk 52 in pts who were alive at wk 52 were imputed assuming similar rate of FVC decline as in pts from pl. group who prematurely disc. trial drug but had a wk 52 FVC value. Missing FVC values at wk 52 in pts who died before wk 52 were imputed assuming similar rate of FVC decline as in pl. pts with a wk 52 FVC value who prematurely disc. trial drug with most severe declines. The imputation model was similar to the statistical model of the PA
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0740
Comments [Not Specified]
Method random coefficient regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 32.93
Confidence Interval (2-Sided) 95%
-3.19 to 69.06
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments In multiple imputation SA 3, missing FVC values at wk 52 in pts who were alive at wk 52 were imputed assuming a similar rate of FVC decline as in all pts in the pl. group who were included in the PA. Missing FVC values at wk 52 in pts who died before wk 52 were imputed assuming a similar rate of FVC decline as in all placebo patients included in the primary analysis with the most severe declines. The imputation model was similar to the statistical model of the PA.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0644
Comments [Not Specified]
Method random coefficient regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 33.86
Confidence Interval (2-Sided) 95%
-2.03 to 69.75
Estimation Comments [Not Specified]
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments This is sensitivity analysis using the model similar to the primary analysis but including a different set of covariates: the fixed, categorical effects of treatment, ATA status, the fixed continuous effects of time, baseline FVC (mL), and the treatment-by-time and baseline-by-time interactions.Random effects was included for patient response for both time and intercept.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0351
Comments [Not Specified]
Method random coefficient regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 40.95
Confidence Interval (2-Sided) 95%
2.88 to 79.01
Estimation Comments [Not Specified]
Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments This is sensitivity analysis using the model similar to the primary analysis but including a different set of covariates: the fixed, categorical effects of treatment, ATA status (Positive / Negative), gender and mycophenolate mofetil /sodium background therapy use (Yes / No), fixed continuous effects of time, age , height and baseline FVC (mL), the treatment-by-time and baseline-by-time interactions. Random effects was included for patient response for both time and intercept
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0349
Comments [Not Specified]
Method random coefficient regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 40.98
Confidence Interval (2-Sided) 95%
2.92 to 79.04
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Absolute Change From Baseline in the Modified Rodnan Skin Score (mRSS) at Week 52
Hide Description

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).

Time Frame Baseline and up to 52 weeks after the start of administration
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 288 288
Least Squares Mean (Standard Error)
Unit of Measure: unit on scale
-1.96  (0.26) -2.17  (0.27)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments The mixed model repeated measures (MMRM) approach was used. The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5785
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.21
Confidence Interval (2-Sided) 95%
-0.94 to 0.53
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.37
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Absolute Change From Baseline in Saint George's Respiratory Questionnaire (SGRQ) Total Score at Week 52.
Hide Description

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).

Time Frame Baseline and up to 52 weeks after the start of administration
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 288 288
Least Squares Mean (Standard Error)
Unit of Measure: unit on scale
-0.88  (0.87) 0.81  (0.88)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments Based on mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-by visit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1711
Comments [Not Specified]
Method MMRM
Comments The MMRM model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.69
Confidence Interval (2-Sided) 95%
-0.73 to 4.12
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.24
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Annual Rate of Decline in FVC in Percentage (%) Predicted Over 52 Weeks
Hide Description

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

For this endpoint reported means represent the adjusted rate.

Time Frame up to 52 weeks after the start of administration
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 288 288
Mean (Standard Error)
Unit of Measure: % predicted/yr
-2.6  (0.4) -1.4  (0.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments

Based on a random coefficient regression with fixed categorical effects of treatment, ATA status, fixed continuous effects of time, baseline FVC [% pred], & including treatment−by−time and baseline−by−time interactions. Random effect was included for patient specific intercept & time.

Within−patient errors are modelled by an Unstructured variance−covariance matrix.

Inter−individual variability is modelled by a Variance−Components variance−covariance matrix.

Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0331
Comments [Not Specified]
Method MMRM
Comments The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.15
Confidence Interval (2-Sided) 1.15%
0.09 to 2.21
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.54
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Absolute Change From Baseline in FVC in mL at Week 52
Hide Description 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).
Time Frame Baseline and up to 52 weeks after the start of administration
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 288 288
Least Squares Mean (Standard Error)
Unit of Measure: mL
-101.03  (13.62) -54.63  (13.94)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments Based on mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-by-visit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0177
Comments [Not Specified]
Method MMRM
Comments The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 46.41
Confidence Interval (2-Sided) 95%
8.09 to 84.73
Parameter Dispersion
Type: Standard Error of the Mean
Value: 19.51
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Relative Change From Baseline [%] of mRSS at Week 52
Hide Description

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).

Time Frame Baseline and up to 52 weeks after the start of administration
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 288 288
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-3.92  (5.89) -10.20  (5.98)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments Based on mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-by-visit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4547
Comments [Not Specified]
Method MMRM
Comments The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -6.28
Confidence Interval (2-Sided) 95%
-22.77 to 10.21
Parameter Dispersion
Type: Standard Error of the Mean
Value: 8.39
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Time to Death
Hide Description Time to event analysis of patients with death. The number of observed patients with death are reported.
Time Frame From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 288 288
Measure Type: Count of Participants
Unit of Measure: Participants
9
   3.1%
10
   3.5%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7535
Comments [Not Specified]
Method Regression, Cox
Comments Based on Cox’s regression model (Wald test), stratified by ATA status.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.16
Confidence Interval (2-Sided) 95%
0.47 to 2.84
Estimation Comments [Not Specified]
8.Secondary Outcome
Title The Percentage (%) of Responder Based on Combined Response Index in Systemic Sclerosis (CRISS) at Week 52
Hide Description

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")

Time Frame Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 288 288
Measure Type: Number
Unit of Measure: (%) of responder based on CRISS
11.8 12.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments The comparison between both treatment groups was performed using a Cochran-Mantel-Haenszel test. CRISS score at Week 52 was transformed into 100 binary responder endpoints using multiple imputation. These were analyzed using a Cochran-Mantel-Haenszel test, stratified by ATA status OR and the 95% confidence interval (CI) as obtained from all 100 imputations were combined using Rubin´s rule.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9115
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.03
Confidence Interval (2-Sided) 95%
0.57 to 1.88
Estimation Comments [Not Specified]
Other Statistical Analysis Missing values were imputed using worst case, i.e. considered having disease progression.
9.Secondary Outcome
Title Absolute Change From Baseline in Carbon Monoxide Diffusion Capacity (DLco) in % Predicted at Week 52
Hide Description

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).

Time Frame Baseline and up to 52 weeks after the start of administration
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 288 288
Least Squares Mean (Standard Error)
Unit of Measure: % predicted DLco
-2.77  (0.54) -3.21  (0.54)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments Based on mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-by-visit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5668
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.44
Confidence Interval (2-Sided) 95%
-1.94 to 1.06
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.76
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Absolute Change From Baseline in Digital Ulcer Net Burden at Week 52
Hide Description

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).

Time Frame Baseline and up to 52 weeks after the start of administration
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Treated set
Arm/Group Title Placebo Nintedanib
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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.
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 Number of Participants Analyzed 288 288
Least Squares Mean (Standard Error)
Unit of Measure: fingers
0.06  (0.04) 0.03  (0.05)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments Based on mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-by-visit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5914
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.03
Confidence Interval (2-Sided) 95%
-0.16 to 0.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.06
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Absolute Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52
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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).

Time Frame Baseline and up to 52 weeks after the start of administration
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 288 288
Least Squares Mean (Standard Error)
Unit of Measure: unit on a scale
0.022  (0.024) 0.054  (0.024)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments Based on mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-by-visit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3447
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.032
Confidence Interval (2-Sided) 95%
-0.035 to 0.099
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.034
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Absolute Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnoea Score at Week 52
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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).

Time Frame Baseline and up to 52 weeks after the start of administration
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
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.
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 Number of Participants Analyzed 288 288
Least Squares Mean (Standard Error)
Unit of Measure: Unit on a scale
0.34  (0.41) 0.99  (0.42)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments Based on mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-by-visit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2727
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.64
Confidence Interval (2-Sided) 95%
-0.51 to 1.79
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.58
Estimation Comments [Not Specified]
Time Frame From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Placebo Nintedanib
Affected / at Risk (%) Affected / at Risk (%)
Total   9/288 (3.13%)   10/288 (3.47%) 
Hide Serious Adverse Events
Placebo Nintedanib
Affected / at Risk (%) Affected / at Risk (%)
Total   79/288 (27.43%)   88/288 (30.56%) 
Blood and lymphatic system disorders     
Immune thrombocytopenic purpura  1  1/288 (0.35%)  0/288 (0.00%) 
Iron deficiency anaemia  1  1/288 (0.35%)  0/288 (0.00%) 
Leukopenia  1  0/288 (0.00%)  1/288 (0.35%) 
Thrombotic microangiopathy  1  0/288 (0.00%)  1/288 (0.35%) 
Cardiac disorders     
Acute myocardial infarction  1  1/288 (0.35%)  0/288 (0.00%) 
Arrhythmia  1  0/288 (0.00%)  1/288 (0.35%) 
Atrial fibrillation  1  2/288 (0.69%)  1/288 (0.35%) 
Atrial flutter  1  3/288 (1.04%)  0/288 (0.00%) 
Atrioventricular block complete  1  0/288 (0.00%)  1/288 (0.35%) 
Cardiac arrest  1  1/288 (0.35%)  0/288 (0.00%) 
Cardiac failure  1  0/288 (0.00%)  1/288 (0.35%) 
Cardiac failure congestive  1  0/288 (0.00%)  1/288 (0.35%) 
Coronary artery disease  1  2/288 (0.69%)  0/288 (0.00%) 
Myocardial infarction  1  1/288 (0.35%)  0/288 (0.00%) 
Myocarditis  1  1/288 (0.35%)  1/288 (0.35%) 
Palpitations  1  0/288 (0.00%)  1/288 (0.35%) 
Pericardial effusion  1  0/288 (0.00%)  1/288 (0.35%) 
Pericarditis  1  1/288 (0.35%)  1/288 (0.35%) 
Pleuropericarditis  1  0/288 (0.00%)  1/288 (0.35%) 
Restrictive cardiomyopathy  1  1/288 (0.35%)  0/288 (0.00%) 
Right ventricular failure  1  1/288 (0.35%)  1/288 (0.35%) 
Ventricular fibrillation  1  0/288 (0.00%)  1/288 (0.35%) 
Congenital, familial and genetic disorders     
Hypertrophic cardiomyopathy  1  1/288 (0.35%)  0/288 (0.00%) 
Ear and labyrinth disorders     
Vertigo  1  0/288 (0.00%)  1/288 (0.35%) 
Endocrine disorders     
Adrenal insufficiency  1  1/288 (0.35%)  0/288 (0.00%) 
Eye disorders     
Glaucoma  1  0/288 (0.00%)  1/288 (0.35%) 
Macular oedema  1  1/288 (0.35%)  0/288 (0.00%) 
Retinal detachment  1  0/288 (0.00%)  1/288 (0.35%) 
Retinal vein occlusion  1  1/288 (0.35%)  0/288 (0.00%) 
Rhegmatogenous retinal detachment  1  1/288 (0.35%)  0/288 (0.00%) 
Gastrointestinal disorders     
Colitis  1  0/288 (0.00%)  1/288 (0.35%) 
Colitis ischaemic  1  1/288 (0.35%)  0/288 (0.00%) 
Diarrhoea  1  2/288 (0.69%)  2/288 (0.69%) 
Gastritis  1  1/288 (0.35%)  0/288 (0.00%) 
Gastrointestinal disorder  1  0/288 (0.00%)  1/288 (0.35%) 
Haematemesis  1  1/288 (0.35%)  0/288 (0.00%) 
Haematochezia  1  0/288 (0.00%)  1/288 (0.35%) 
Ileus  1  0/288 (0.00%)  1/288 (0.35%) 
Ileus paralytic  1  0/288 (0.00%)  1/288 (0.35%) 
Intestinal mass  1  1/288 (0.35%)  0/288 (0.00%) 
Intestinal pseudo-obstruction  1  0/288 (0.00%)  1/288 (0.35%) 
Large intestine polyp  1  1/288 (0.35%)  0/288 (0.00%) 
Lower gastrointestinal haemorrhage  1  0/288 (0.00%)  1/288 (0.35%) 
Pancreatitis acute  1  0/288 (0.00%)  1/288 (0.35%) 
Rectal haemorrhage  1  0/288 (0.00%)  1/288 (0.35%) 
Upper gastrointestinal haemorrhage  1  0/288 (0.00%)  1/288 (0.35%) 
Vomiting  1  2/288 (0.69%)  0/288 (0.00%) 
General disorders     
Brain death  1  1/288 (0.35%)  0/288 (0.00%) 
General physical health deterioration  1  1/288 (0.35%)  0/288 (0.00%) 
Multiple organ dysfunction syndrome  1  0/288 (0.00%)  1/288 (0.35%) 
Polyp  1  1/288 (0.35%)  0/288 (0.00%) 
Pyrexia  1  2/288 (0.69%)  0/288 (0.00%) 
Systemic inflammatory response syndrome  1  0/288 (0.00%)  1/288 (0.35%) 
Hepatobiliary disorders     
Bile duct stone  1  0/288 (0.00%)  1/288 (0.35%) 
Cholecystitis  1  0/288 (0.00%)  1/288 (0.35%) 
Drug-induced liver injury  1  1/288 (0.35%)  1/288 (0.35%) 
Hepatocellular injury  1  0/288 (0.00%)  1/288 (0.35%) 
Liver disorder  1  0/288 (0.00%)  1/288 (0.35%) 
Liver injury  1  0/288 (0.00%)  1/288 (0.35%) 
Immune system disorders     
Anti-neutrophil cytoplasmic antibody positive vasculitis  1  0/288 (0.00%)  2/288 (0.69%) 
Infections and infestations     
Adenovirus infection  1  0/288 (0.00%)  1/288 (0.35%) 
Appendicitis  1  0/288 (0.00%)  1/288 (0.35%) 
Bronchitis  1  1/288 (0.35%)  0/288 (0.00%) 
Campylobacter gastroenteritis  1  1/288 (0.35%)  0/288 (0.00%) 
Cellulitis  1  1/288 (0.35%)  1/288 (0.35%) 
Device related infection  1  0/288 (0.00%)  1/288 (0.35%) 
Diverticulitis  1  0/288 (0.00%)  2/288 (0.69%) 
Gangrene  1  0/288 (0.00%)  2/288 (0.69%) 
Gastroenteritis  1  0/288 (0.00%)  1/288 (0.35%) 
Herpes zoster  1  1/288 (0.35%)  0/288 (0.00%) 
Influenza  1  0/288 (0.00%)  1/288 (0.35%) 
Lower respiratory tract infection  1  1/288 (0.35%)  2/288 (0.69%) 
Lung infection  1  2/288 (0.69%)  0/288 (0.00%) 
Osteomyelitis  1  1/288 (0.35%)  0/288 (0.00%) 
Pneumonia  1  2/288 (0.69%)  10/288 (3.47%) 
Pneumonia bacterial  1  0/288 (0.00%)  1/288 (0.35%) 
Pyelonephritis  1  0/288 (0.00%)  1/288 (0.35%) 
Pyelonephritis acute  1  1/288 (0.35%)  0/288 (0.00%) 
Respiratory tract infection  1  0/288 (0.00%)  3/288 (1.04%) 
Sepsis  1  1/288 (0.35%)  2/288 (0.69%) 
Septic shock  1  0/288 (0.00%)  1/288 (0.35%) 
Skin infection  1  0/288 (0.00%)  1/288 (0.35%) 
Systemic candida  1  0/288 (0.00%)  1/288 (0.35%) 
Tuberculosis  1  1/288 (0.35%)  0/288 (0.00%) 
Upper respiratory tract infection  1  1/288 (0.35%)  0/288 (0.00%) 
Urinary tract infection  1  0/288 (0.00%)  1/288 (0.35%) 
Urosepsis  1  0/288 (0.00%)  1/288 (0.35%) 
Injury, poisoning and procedural complications     
Ankle fracture  1  1/288 (0.35%)  0/288 (0.00%) 
Femur fracture  1  0/288 (0.00%)  1/288 (0.35%) 
Joint dislocation  1  0/288 (0.00%)  1/288 (0.35%) 
Postoperative ileus  1  0/288 (0.00%)  1/288 (0.35%) 
Investigations     
Cell marker increased  1  1/288 (0.35%)  0/288 (0.00%) 
Forced vital capacity decreased  1  0/288 (0.00%)  1/288 (0.35%) 
Haemoglobin decreased  1  0/288 (0.00%)  1/288 (0.35%) 
Neutrophil count decreased  1  0/288 (0.00%)  1/288 (0.35%) 
White blood cell count decreased  1  0/288 (0.00%)  1/288 (0.35%) 
Metabolism and nutrition disorders     
Dehydration  1  1/288 (0.35%)  0/288 (0.00%) 
Fluid overload  1  1/288 (0.35%)  0/288 (0.00%) 
Hypokalaemia  1  0/288 (0.00%)  1/288 (0.35%) 
Musculoskeletal and connective tissue disorders     
Arthritis  1  0/288 (0.00%)  1/288 (0.35%) 
Bursitis  1  1/288 (0.35%)  0/288 (0.00%) 
Drooping shoulder syndrome  1  1/288 (0.35%)  0/288 (0.00%) 
Fistula  1  1/288 (0.35%)  0/288 (0.00%) 
Intervertebral disc protrusion  1  3/288 (1.04%)  1/288 (0.35%) 
Musculoskeletal chest pain  1  1/288 (0.35%)  0/288 (0.00%) 
Musculoskeletal pain  1  0/288 (0.00%)  1/288 (0.35%) 
Osteonecrosis  1  0/288 (0.00%)  1/288 (0.35%) 
Polymyalgia rheumatica  1  0/288 (0.00%)  1/288 (0.35%) 
Scleroderma  1  0/288 (0.00%)  1/288 (0.35%) 
Systemic scleroderma  1  2/288 (0.69%)  1/288 (0.35%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Basal cell carcinoma  1  0/288 (0.00%)  1/288 (0.35%) 
Benign mesothelioma  1  0/288 (0.00%)  1/288 (0.35%) 
Colon cancer  1  1/288 (0.35%)  0/288 (0.00%) 
Gastric cancer  1  1/288 (0.35%)  0/288 (0.00%) 
Lung adenocarcinoma  1  0/288 (0.00%)  1/288 (0.35%) 
Malignant melanoma  1  0/288 (0.00%)  1/288 (0.35%) 
Mesothelioma malignant  1  0/288 (0.00%)  1/288 (0.35%) 
Nasopharyngeal cancer  1  1/288 (0.35%)  0/288 (0.00%) 
Non-small cell lung cancer  1  1/288 (0.35%)  0/288 (0.00%) 
Rectal cancer  1  1/288 (0.35%)  0/288 (0.00%) 
Squamous cell carcinoma of skin  1  1/288 (0.35%)  2/288 (0.69%) 
Sweat gland tumour  1  0/288 (0.00%)  1/288 (0.35%) 
Nervous system disorders     
Carotid artery aneurysm  1  1/288 (0.35%)  0/288 (0.00%) 
Carotid artery stenosis  1  1/288 (0.35%)  0/288 (0.00%) 
Cerebral amyloid angiopathy  1  0/288 (0.00%)  1/288 (0.35%) 
Cerebral infarction  1  1/288 (0.35%)  0/288 (0.00%) 
Cerebral microhaemorrhage  1  0/288 (0.00%)  1/288 (0.35%) 
Cerebrovascular disorder  1  0/288 (0.00%)  1/288 (0.35%) 
Depressed level of consciousness  1  0/288 (0.00%)  1/288 (0.35%) 
Seizure  1  0/288 (0.00%)  1/288 (0.35%) 
Subarachnoid haemorrhage  1  0/288 (0.00%)  1/288 (0.35%) 
Syncope  1  0/288 (0.00%)  1/288 (0.35%) 
Psychiatric disorders     
Delirium  1  0/288 (0.00%)  1/288 (0.35%) 
Major depression  1  0/288 (0.00%)  1/288 (0.35%) 
Renal and urinary disorders     
Acute kidney injury  1  1/288 (0.35%)  3/288 (1.04%) 
Bladder perforation  1  1/288 (0.35%)  0/288 (0.00%) 
Renal failure  1  1/288 (0.35%)  0/288 (0.00%) 
Scleroderma renal crisis  1  0/288 (0.00%)  1/288 (0.35%) 
Urinary incontinence  1  1/288 (0.35%)  0/288 (0.00%) 
Urinary tract obstruction  1  1/288 (0.35%)  0/288 (0.00%) 
Reproductive system and breast disorders     
Benign prostatic hyperplasia  1  0/288 (0.00%)  1/288 (0.35%) 
Ovarian cyst  1  0/288 (0.00%)  3/288 (1.04%) 
Vulvovaginal swelling  1  1/288 (0.35%)  0/288 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute lung injury  1  0/288 (0.00%)  1/288 (0.35%) 
Acute respiratory failure  1  1/288 (0.35%)  0/288 (0.00%) 
Aspiration  1  1/288 (0.35%)  0/288 (0.00%) 
Cough  1  1/288 (0.35%)  0/288 (0.00%) 
Dyspnoea  1  8/288 (2.78%)  5/288 (1.74%) 
Haemothorax  1  1/288 (0.35%)  0/288 (0.00%) 
Hypoxia  1  0/288 (0.00%)  1/288 (0.35%) 
Interstitial lung disease  1  6/288 (2.08%)  10/288 (3.47%) 
Painful respiration  1  0/288 (0.00%)  1/288 (0.35%) 
Pleural effusion  1  1/288 (0.35%)  2/288 (0.69%) 
Pneumonia aspiration  1  0/288 (0.00%)  2/288 (0.69%) 
Pneumothorax  1  1/288 (0.35%)  1/288 (0.35%) 
Pneumothorax spontaneous  1  0/288 (0.00%)  1/288 (0.35%) 
Pulmonary arterial hypertension  1  4/288 (1.39%)  4/288 (1.39%) 
Pulmonary embolism  1  2/288 (0.69%)  0/288 (0.00%) 
Pulmonary fibrosis  1  4/288 (1.39%)  4/288 (1.39%) 
Pulmonary hypertension  1  4/288 (1.39%)  5/288 (1.74%) 
Respiratory failure  1  1/288 (0.35%)  1/288 (0.35%) 
Systemic sclerosis pulmonary  1  5/288 (1.74%)  3/288 (1.04%) 
Skin and subcutaneous tissue disorders     
Actinic keratosis  1  0/288 (0.00%)  1/288 (0.35%) 
Digital pitting scar  1  0/288 (0.00%)  1/288 (0.35%) 
Petechiae  1  1/288 (0.35%)  0/288 (0.00%) 
Sclerema  1  1/288 (0.35%)  0/288 (0.00%) 
Skin ulcer  1  2/288 (0.69%)  2/288 (0.69%) 
Vascular disorders     
Deep vein thrombosis  1  0/288 (0.00%)  1/288 (0.35%) 
Extremity necrosis  1  0/288 (0.00%)  2/288 (0.69%) 
Hypertension  1  1/288 (0.35%)  0/288 (0.00%) 
Hypertensive crisis  1  0/288 (0.00%)  1/288 (0.35%) 
Hypotension  1  1/288 (0.35%)  0/288 (0.00%) 
Peripheral arterial occlusive disease  1  0/288 (0.00%)  1/288 (0.35%) 
Peripheral artery occlusion  1  0/288 (0.00%)  1/288 (0.35%) 
Raynaud's phenomenon  1  1/288 (0.35%)  0/288 (0.00%) 
Thrombophlebitis superficial  1  1/288 (0.35%)  0/288 (0.00%) 
Vena cava thrombosis  1  0/288 (0.00%)  1/288 (0.35%) 
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Nintedanib
Affected / at Risk (%) Affected / at Risk (%)
Total   239/288 (82.99%)   270/288 (93.75%) 
Gastrointestinal disorders     
Abdominal pain  1  21/288 (7.29%)  36/288 (12.50%) 
Abdominal pain upper  1  15/288 (5.21%)  21/288 (7.29%) 
Constipation  1  19/288 (6.60%)  15/288 (5.21%) 
Diarrhoea  1  92/288 (31.94%)  218/288 (75.69%) 
Gastrooesophageal reflux disease  1  26/288 (9.03%)  20/288 (6.94%) 
Nausea  1  41/288 (14.24%)  96/288 (33.33%) 
Vomiting  1  31/288 (10.76%)  78/288 (27.08%) 
General disorders     
Fatigue  1  21/288 (7.29%)  33/288 (11.46%) 
Pyrexia  1  13/288 (4.51%)  20/288 (6.94%) 
Infections and infestations     
Bronchitis  1  27/288 (9.38%)  22/288 (7.64%) 
Influenza  1  15/288 (5.21%)  16/288 (5.56%) 
Nasopharyngitis  1  56/288 (19.44%)  43/288 (14.93%) 
Respiratory tract infection  1  16/288 (5.56%)  10/288 (3.47%) 
Upper respiratory tract infection  1  43/288 (14.93%)  39/288 (13.54%) 
Urinary tract infection  1  28/288 (9.72%)  28/288 (9.72%) 
Investigations     
Alanine aminotransferase increased  1  4/288 (1.39%)  22/288 (7.64%) 
Aspartate aminotransferase increased  1  1/288 (0.35%)  16/288 (5.56%) 
Gamma-glutamyltransferase increased  1  4/288 (1.39%)  19/288 (6.60%) 
Weight decreased  1  15/288 (5.21%)  39/288 (13.54%) 
Metabolism and nutrition disorders     
Decreased appetite  1  14/288 (4.86%)  28/288 (9.72%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  23/288 (7.99%)  23/288 (7.99%) 
Back pain  1  15/288 (5.21%)  20/288 (6.94%) 
Myalgia  1  11/288 (3.82%)  16/288 (5.56%) 
Pain in extremity  1  14/288 (4.86%)  15/288 (5.21%) 
Nervous system disorders     
Dizziness  1  15/288 (5.21%)  19/288 (6.60%) 
Headache  1  28/288 (9.72%)  34/288 (11.81%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  62/288 (21.53%)  41/288 (14.24%) 
Dyspnoea  1  27/288 (9.38%)  23/288 (7.99%) 
Epistaxis  1  16/288 (5.56%)  8/288 (2.78%) 
Skin and subcutaneous tissue disorders     
Skin ulcer  1  54/288 (18.75%)  56/288 (19.44%) 
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
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: NCT02597933    
Other Study ID Numbers: 1199.214
2015-000392-28 ( EudraCT Number )
First Submitted: October 8, 2015
First Posted: November 5, 2015
Results First Submitted: October 28, 2019
Results First Posted: December 13, 2019
Last Update Posted: December 13, 2019