Clinical Trial Results:
SENSCIS®: A double-blind, randomised, placebo-controlled trial evaluating efficacy and safety of oral nintedanib treatment for at least 52 weeks in patients with ‘Systemic Sclerosisassociated
Interstitial Lung Disease’ (SSc-ILD)
Summary
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EudraCT number |
2015-000392-28 |
Trial protocol |
NL DE GB PT DK BE ES GR FR PL IE FI NO SE AT HU CZ IT |
Global end of trial date |
28 Nov 2018
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Results information
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Results version number |
v2(current) |
This version publication date |
14 Nov 2021
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First version publication date |
13 Nov 2019
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Other versions |
v1 |
Version creation reason |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
1199.214
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02597933 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Boehringer Ingelheim
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Sponsor organisation address |
173 Binger Strasse, Ingelheim am Rhein, Germany, 55216
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Public contact |
QRPE Processes and Systems Coordination
Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
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Scientific contact |
QRPE Processes and Systems Coordination
Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
19 Dec 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Oct 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Nov 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To investigate the efficacy and safety of nintedanib 150 mg twice daily (bid) in patients with SSc-ILD
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Protection of trial subjects |
Only subjects that met all the study inclusion and none of the exclusion criteria were entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Nov 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Argentina: 7
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Country: Number of subjects enrolled |
Australia: 13
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Country: Number of subjects enrolled |
Austria: 2
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Country: Number of subjects enrolled |
Belgium: 23
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Country: Number of subjects enrolled |
Brazil: 7
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Country: Number of subjects enrolled |
Canada: 6
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Country: Number of subjects enrolled |
Chile: 8
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Country: Number of subjects enrolled |
China: 39
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Country: Number of subjects enrolled |
Czechia: 5
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Country: Number of subjects enrolled |
Denmark: 15
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Country: Number of subjects enrolled |
Finland: 5
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Country: Number of subjects enrolled |
France: 73
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Country: Number of subjects enrolled |
Germany: 63
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Country: Number of subjects enrolled |
Greece: 18
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Country: Number of subjects enrolled |
Hungary: 2
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Country: Number of subjects enrolled |
India: 54
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Country: Number of subjects enrolled |
Ireland: 2
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Country: Number of subjects enrolled |
Israel: 15
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Country: Number of subjects enrolled |
Italy: 41
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Country: Number of subjects enrolled |
Japan: 92
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Country: Number of subjects enrolled |
Malaysia: 8
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Country: Number of subjects enrolled |
Mexico: 2
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Country: Number of subjects enrolled |
Netherlands: 22
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Country: Number of subjects enrolled |
Norway: 5
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Country: Number of subjects enrolled |
Poland: 33
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Country: Number of subjects enrolled |
Portugal: 17
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Country: Number of subjects enrolled |
Spain: 27
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Country: Number of subjects enrolled |
Sweden: 2
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Country: Number of subjects enrolled |
Switzerland: 5
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Country: Number of subjects enrolled |
Thailand: 9
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Country: Number of subjects enrolled |
United Kingdom: 18
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Country: Number of subjects enrolled |
United States: 181
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Worldwide total number of subjects |
819
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EEA total number of subjects |
355
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
641
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From 65 to 84 years |
178
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85 years and over |
0
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Recruitment
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Recruitment details |
This was a randomised, placebo-controlled, double-blind, parallel design trial. Abbreviaton used: treatment (trt) baseline (bl.) categorical (cat.) continuous (cont.) number (no.) patient (pt) Placebo (pl.) discontinued (disc.) primary analysis (PA) | ||||||||||||||||||||||||
Pre-assignment
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Screening 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 | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst | ||||||||||||||||||||||||
Blinding implementation details |
This was a randomised, placebo-controlled, double-blind, parallel design trial.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm 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. Two subjects randomised to matching placebo were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started. | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, soft
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Routes of administration |
Oral use
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Dosage and administration details |
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.
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Arm title
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Nintedanib | ||||||||||||||||||||||||
Arm description |
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. Two subjects randomised to Nintedanib were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Nintedanib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, soft
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Routes of administration |
Oral use
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Dosage and administration details |
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.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication. |
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting 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. Two subjects randomised to matching placebo were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Nintedanib
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Reporting group description |
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. Two subjects randomised to Nintedanib were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting 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. Two subjects randomised to matching placebo were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started. | ||
Reporting group title |
Nintedanib
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Reporting group description |
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. Two subjects randomised to Nintedanib were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started. |
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End point title |
Annual rate of decline in Forced Vital Capacity (FVC) over 52 weeks | ||||||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
up to week (wk) 52 after the start of administration
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Notes [1] - Treated Set [2] - Treated Set |
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Statistical analysis title |
Statistical Analysis I | ||||||||||||
Statistical analysis description |
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
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Comparison groups |
Placebo v Nintedanib
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Number of subjects included in analysis |
576
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | ||||||||||||
P-value |
= 0.035 | ||||||||||||
Method |
random coefficient regression | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
40.95
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
2.88 | ||||||||||||
upper limit |
79.01 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
19.38
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Notes [3] - The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial. |
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Statistical analysis title |
Statistical Analysis II | ||||||||||||
Statistical analysis description |
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.
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Comparison groups |
Placebo v Nintedanib
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Number of subjects included in analysis |
576
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Analysis specification |
Pre-specified
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Analysis type |
other [4] | ||||||||||||
P-value |
= 0.0378 | ||||||||||||
Method |
random coefficient regression | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
43.13
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
2.44 | ||||||||||||
upper limit |
83.83 | ||||||||||||
Notes [4] - The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial. |
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Statistical analysis title |
Statistical Analysis III | ||||||||||||
Statistical analysis description |
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.
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Comparison groups |
Placebo v Nintedanib
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Number of subjects included in analysis |
576
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.1046 | ||||||||||||
Method |
random coefficient regression | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
30
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-6.22 | ||||||||||||
upper limit |
66.22 | ||||||||||||
Statistical analysis title |
Statistical Analysis IV | ||||||||||||
Statistical analysis description |
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
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Comparison groups |
Placebo v Nintedanib
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Number of subjects included in analysis |
576
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.074 | ||||||||||||
Method |
random coefficient regression | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
32.93
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-3.19 | ||||||||||||
upper limit |
69.06 | ||||||||||||
Statistical analysis title |
Statistical Analysis V | ||||||||||||
Statistical analysis description |
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.
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Comparison groups |
Placebo v Nintedanib
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Number of subjects included in analysis |
576
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.0644 | ||||||||||||
Method |
random coefficient regression | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
33.86
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-2.03 | ||||||||||||
upper limit |
69.75 | ||||||||||||
Statistical analysis title |
Statistical Analysis VI | ||||||||||||
Statistical analysis description |
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.
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Comparison groups |
Placebo v Nintedanib
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Number of subjects included in analysis |
576
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.0351 | ||||||||||||
Method |
random coefficient regression | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
40.95
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
2.88 | ||||||||||||
upper limit |
79.01 | ||||||||||||
Statistical analysis title |
Statistical Analysis VII | ||||||||||||
Statistical analysis description |
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
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Comparison groups |
Placebo v Nintedanib
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Number of subjects included in analysis |
576
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.0349 | ||||||||||||
Method |
random coefficient regression | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
40.98
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
2.92 | ||||||||||||
upper limit |
79.04 |
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End point title |
Absolute change from baseline in the Modified Rodnan Skin Score (mRSS) at Week 52 | ||||||||||||
End point 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).
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End point type |
Secondary
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End point timeframe |
Baseline and up to 52 weeks after the start of administration
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Notes [5] - Treated Set [6] - Treated Set |
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Statistical analysis title |
Statistical Analysis I | ||||||||||||
Statistical analysis description |
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.
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Comparison groups |
Placebo v Nintedanib
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Number of subjects included in analysis |
576
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.5785 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.21
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.94 | ||||||||||||
upper limit |
0.53 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.37
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End point title |
Absolute change from baseline in Saint George’s Respiratory Questionnaire (SGRQ) total score at Week 52. | ||||||||||||
End point description |
This is the second key secondary endoint. 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).
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End point type |
Secondary
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End point timeframe |
Baseline and up to 52 weeks after the start of administration
|
||||||||||||
|
|||||||||||||
Notes [7] - Treated Set [8] - Treated Set |
|||||||||||||
Statistical analysis title |
Statistical Analysis I | ||||||||||||
Statistical analysis description |
The 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.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib
|
||||||||||||
Number of subjects included in analysis |
576
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [9] | ||||||||||||
P-value |
= 0.1711 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.69
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.73 | ||||||||||||
upper limit |
4.12 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.24
|
||||||||||||
Notes [9] - 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. |
|
|||||||||||||
End point title |
Annual rate of decline in FVC in percentage (%) predicted over 52 weeks | ||||||||||||
End point description |
Annual rate of decline in FVC in percentage (%) predicted over 52 weeks. For this endpoint reported means represent the adjusted rate.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
up to 52 weeks after the start of administration
|
||||||||||||
|
|||||||||||||
Notes [10] - Treated set [11] - Treated set |
|||||||||||||
Statistical analysis title |
Statistical Analysis I | ||||||||||||
Statistical analysis description |
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.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib
|
||||||||||||
Number of subjects included in analysis |
576
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [12] | ||||||||||||
P-value |
= 0.0331 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.15
|
||||||||||||
Confidence interval |
|||||||||||||
level |
1.15% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.09 | ||||||||||||
upper limit |
2.21 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.54
|
||||||||||||
Notes [12] - The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial. |
|
|||||||||||||
End point title |
Absolute change from baseline in FVC in mL at Week 52 | ||||||||||||
End point 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).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and up to 52 weeks after the start of administration
|
||||||||||||
|
|||||||||||||
Notes [13] - Treated set [14] - Treated set |
|||||||||||||
Statistical analysis title |
Statistical Analysis I | ||||||||||||
Statistical analysis description |
The mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-byvisit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib
|
||||||||||||
Number of subjects included in analysis |
576
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [15] | ||||||||||||
P-value |
= 0.0177 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
46.41
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
8.09 | ||||||||||||
upper limit |
84.73 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
19.51
|
||||||||||||
Notes [15] - The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial. |
|
|||||||||||||
End point title |
Relative change from baseline [%] of mRSS at Week 52 | ||||||||||||
End point description |
Relative change from baseline [%] of mRSS 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).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and up to 52 weeks after the start of administration
|
||||||||||||
|
|||||||||||||
Notes [16] - Treated set [17] - Treated set |
|||||||||||||
Statistical analysis title |
Statistical Analysis I | ||||||||||||
Statistical analysis description |
The 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.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib
|
||||||||||||
Number of subjects included in analysis |
576
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [18] | ||||||||||||
P-value |
= 0.4547 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-6.28
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-22.77 | ||||||||||||
upper limit |
10.21 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
8.39
|
||||||||||||
Notes [18] - The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial. |
|
|||||||||||||
End point title |
Time to death | ||||||||||||
End point description |
Length of survival of patients treated with a placebo or Nintedanib 150 mg bid over the whole trial. The number of patients who observed an event are summarized below.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
|
||||||||||||
|
|||||||||||||
Notes [19] - Treated set [20] - Treated set |
|||||||||||||
Statistical analysis title |
Statistical Analysis I | ||||||||||||
Statistical analysis description |
Based on Cox’s regression model (Wald test), stratified by ATA status.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib
|
||||||||||||
Number of subjects included in analysis |
576
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.7535 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.16
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.47 | ||||||||||||
upper limit |
2.84 |
|
|||||||||||||
End point title |
The percentage (%) of responder based on Combined Response Index in Systemic Sclerosis (CRISS) at Week 52 | ||||||||||||
End point 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 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”).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 52
|
||||||||||||
|
|||||||||||||
Notes [21] - Treated set [22] - Treated set |
|||||||||||||
Statistical analysis title |
Statistical Analysis I | ||||||||||||
Statistical analysis description |
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% CI as obtained from all 100 imputations were combined using Rubin´s rule.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib
|
||||||||||||
Number of subjects included in analysis |
576
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.9115 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.03
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.57 | ||||||||||||
upper limit |
1.88 |
|
|||||||||||||
End point title |
Absolute change from baseline in Carbon Monoxide Diffusion Capacity (DLco) in % predicted at Week 52 | ||||||||||||
End point 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).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and up to 52 weeks after the start of administration
|
||||||||||||
|
|||||||||||||
Notes [23] - Treated set [24] - Treated set |
|||||||||||||
Statistical analysis title |
Statistical Analysis I | ||||||||||||
Statistical analysis description |
The 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.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib
|
||||||||||||
Number of subjects included in analysis |
576
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.5668 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.44
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.94 | ||||||||||||
upper limit |
1.06 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.76
|
|
|||||||||||||
End point title |
Absolute change from baseline in digital ulcer net burden at Week 52 | ||||||||||||
End point 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).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and up to 52 weeks after the start of administration
|
||||||||||||
|
|||||||||||||
Notes [25] - Treated set [26] - Treated set |
|||||||||||||
Statistical analysis title |
Statistical Analysis I | ||||||||||||
Statistical analysis description |
The 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.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib
|
||||||||||||
Number of subjects included in analysis |
576
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.5914 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.03
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.16 | ||||||||||||
upper limit |
0.09 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.06
|
|
|||||||||||||
End point title |
Absolute change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 52 | ||||||||||||
End point description |
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).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and up to 52 weeks after the start of administration
|
||||||||||||
|
|||||||||||||
Notes [27] - Treated set [28] - Treated set |
|||||||||||||
Statistical analysis title |
Statistical Analysis I | ||||||||||||
Statistical analysis description |
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.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib
|
||||||||||||
Number of subjects included in analysis |
576
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.3447 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.032
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.035 | ||||||||||||
upper limit |
0.099 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.034
|
|
|||||||||||||
End point title |
Absolute change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) dyspnoea score at Week 52 | ||||||||||||
End point description |
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). Next, using the same 10 items, respondents are asked to rate the amount of difficulty they experienced when doing these tasks on a 4-point Likert scale (no difficulty=0; a little difficulty=1; some difficulty =2; much difficulty = 3). 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).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and up to 52 weeks after the start of administration
|
||||||||||||
|
|||||||||||||
Notes [29] - Treated set [30] - Treated set |
|||||||||||||
Statistical analysis title |
Statistical Analysis I | ||||||||||||
Statistical analysis description |
The 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.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib
|
||||||||||||
Number of subjects included in analysis |
576
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.2727 | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.64
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.51 | ||||||||||||
upper limit |
1.79 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.58
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks).
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
Placebo
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Reporting 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. Two subjects randomised to matching placebo were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Nintedanib
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Reporting group description |
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. Two subjects randomised to Nintedanib were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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02 Mar 2016 |
The following main changes in the conduct of the trial were introduced by the amendment:
1) To ensure regular pregnancy testing as requested by health authorities, information was added that women of childbearing potential had to perform a pregnancy test every 4 to 6 weeks. Once intervals between site visits were >6 weeks, home urine dipstick pregnancy tests were centrally provided and had to be performed at home.
2)For Inclusion Criterion No. 5, the reference time point for the historical HRCT, which had to be performed within 12 months, was changed from Visit 2 to Visit 1, as Visit 1
represented the better predictable time point
3) Exclusion Criterion No. 8 was updated to clarify that not only digital ulcers but also severe other ulcers could have led to the exclusion of a patient at the discretion of the investigator
4) Exclusion Criterion No. 12 was updated to clarify that also severe gastrointestinal symptoms due to SSc could have led to the exclusion of a patient
5) Exclusion Criterion No. 25 was added based on advice from regulatory agencies: patients with underlying chronic liver disease (Child Pugh A, B, C hepatic impairment)
6) The restrictions regarding concomitant treatment with corticosteroids were modified.
7) Patients on low dose corticosteroid therapy were eligible for the trial even if the dose of the corticosteroid medication was not stable
8) The description of the method of measuring DLco was harmonised within the CTP, by removal of the adjustments for altitude and carboxyhaemoglobin incorrectly mentioned in
one section of the CTP
9) Addition of mycophenolate sodium to clarify that for ‘mycophenolate’ 2 possible salt forms are available. |
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26 Jan 2017 |
1)For selection of trial population, it was added that recruitment of pts who were on stable dose of mycophenolate or methotrexate background medications could have been restricted, although enrolment was generally competitive 2)Numbers of sites & countries contributing pts worldwide were updated from approximately 170sites to about 230sites & from about 20 to 33 countries 3)Inclusion Criterion No. 4 was revised &requested SSc disease onset (defined by first non-Raynaud symptom) had to occur within 7 years instead of 5 years of Visit 1.This change was introduced to facilitate recruitment into trial, without compromising characterisation of trial population.4)For Exclusion Criterion No.4, reference time point to assess eligibility regarding airway obstruction (pre-bronchodilator FEV1/FVC <0.7) was changed from Visit1 to Visit2 to ensure consistency with all other lung function criteria 5)To Exclusion Criterion No. 18 & restrictions of concomitant trt required washout period of at least 8 weeks before Visit 2 was added for mycophenolate mofetil/sodium or methotrexate 6)In Exclusion Criterion No. 22 tubal occlusion was removed as an example for method of permanent sterilization, since according to Clinical Trial Facilitation Group recommendations (2014),woman who underwent tubal ligation is still to be considered ‘of childbearing potential’ 7)Exclusion Criterion No.26 was added: pts with history of SSc renal crisis 8)For AE collection & reporting it was clarified that independent adjudication committee reviewed all fatal cases for primary causes of death.Data protection measures for committee & adjudication process were clarified too. 9)Absolute change from bl. at wk 52 in CRISS index score was added as secondary endpoint & removed from list of further endpoints; however, TSAP defined to analyse proportion of responders instead of absolute change from bl.10)ATA status & bl. FVC% predicted were included as covariates in analysis of rate of decline in FVC in % predicted. |
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15 Feb 2018 |
The following main changes in the conduct of the trial were introduced by the amendment:
1) The end of trial for patients on-treatment as well as for patients who prematurely discontinued trial medication and attended visits as planned was clarified. Details regarding the time point of the EOT Visit and requirements for Follow-up Visits were added.
2) The restrictions regarding concomitant treatment were modified. The definition of clinically significant deterioration was extended to other clinical parameters than mRSS
and FVC
3) Clarification that based on the half-life of the trial drug, a safety analysis restricted to AEs that occurred between the start of treatment and up to 7 days after the date of the last dose of trial medication were analysed in addition |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |