Clinical Trial Results:
A 52 weeks, double blind, randomized, placebo-controlled trial evaluating the effect of oral BIBF 1120, 150 mg twice daily, on Forced Vital Capacity decline , in patients with Idiopathic Pulmonary Fibrosis (IPF)
Summary
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EudraCT number |
2010-024252-29 |
Trial protocol |
FI DE PT GR NL ES |
Global end of trial date |
15 Oct 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Jun 2016
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First version publication date |
01 Aug 2015
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Other versions |
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 |
1199.34
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01335477 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Boehringer Ingelheim
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Sponsor organisation address |
Binger Strasse 173 , Ingelheim am Rhein , Germany,
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Public contact |
QRPE Processes and Systems Coordination , Boehringer Ingelheim Pharma GmbH & Co. KG , +1 800243 0127, clintriage.rdg@boehringer-ingelheim.com
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Scientific contact |
QRPE Processes and Systems Coordination, Boehringer Ingelheim Pharma GmbH & Co. KG , +1 800243 0127, 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 |
18 Nov 2013
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
18 Sep 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
15 Oct 2013
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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 demonstrate a reduction of lung function decline, as measured by a change of the yearly rate of decline of forced vital capacity (FVC).
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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. Rescue medication was allowed for all patients as required.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 May 2011
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
7 Years | ||
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 |
Canada: 20
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Country: Number of subjects enrolled |
Chile: 11
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Country: Number of subjects enrolled |
China: 84
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Country: Number of subjects enrolled |
Finland: 21
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Country: Number of subjects enrolled |
France: 76
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Country: Number of subjects enrolled |
Germany: 52
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Country: Number of subjects enrolled |
Greece: 28
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Country: Number of subjects enrolled |
India: 35
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Country: Number of subjects enrolled |
Japan: 83
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Country: Number of subjects enrolled |
Korea, Democratic People's Republic of: 97
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Country: Number of subjects enrolled |
Mexico: 7
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Country: Number of subjects enrolled |
Netherlands: 23
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Country: Number of subjects enrolled |
Portugal: 28
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Country: Number of subjects enrolled |
Russian Federation: 4
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Country: Number of subjects enrolled |
Spain: 28
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Country: Number of subjects enrolled |
Turkey: 55
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Country: Number of subjects enrolled |
United States: 142
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Worldwide total number of subjects |
794
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EEA total number of subjects |
256
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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) |
314
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From 65 to 84 years |
475
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85 years and over |
5
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
All subjects were screened for eligibility to participate in the trial. Subjects attended one specialist site which would then ensure that they (the subjects) met all inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated. | ||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Treatment period (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 | ||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||||
Arm description |
Oral administration of placebo matching nintedanib soft gelatine capsules. One patient was randomised to the placebo arm, however this patient was not treated. Consequently, number of subject that started is 220 but only 219 reported to ensure consistent reporting with baseline characteristics that includes only treated patients. | ||||||||||||||||||||||||||||||
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 |
Oral administration of placebo matching nintedanib soft gelatine capsules.
twice daily (bid)
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Arm title
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Nintedanib 150mg | ||||||||||||||||||||||||||||||
Arm description |
Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events. Two patients were randomised to the placebo arm, however those two patients were not treated. Consequently, number of subject that started is 331 but only 329 reported to ensure consistent reporting with baseline characteristics that includes only treated patients. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Nintedanib 150mg
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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 |
twice daily (bid)
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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 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 |
Oral administration of placebo matching nintedanib soft gelatine capsules. One patient was randomised to the placebo arm, however this patient was not treated. Consequently, number of subject that started is 220 but only 219 reported to ensure consistent reporting with baseline characteristics that includes only treated patients. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Nintedanib 150mg
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Reporting group description |
Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events. Two patients were randomised to the placebo arm, however those two patients were not treated. Consequently, number of subject that started is 331 but only 329 reported to ensure consistent reporting with baseline characteristics that includes only treated patients. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Oral administration of placebo matching nintedanib soft gelatine capsules. One patient was randomised to the placebo arm, however this patient was not treated. Consequently, number of subject that started is 220 but only 219 reported to ensure consistent reporting with baseline characteristics that includes only treated patients. | ||
Reporting group title |
Nintedanib 150mg
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Reporting group description |
Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events. Two patients were randomised to the placebo arm, however those two patients were not treated. Consequently, number of subject that started is 331 but only 329 reported to ensure consistent reporting with baseline characteristics that includes only treated patients. |
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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 |
52 weeks
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Notes [1] - Treated Set (Only patients with observed cases (OC) values were analysed) [2] - Treated Set (Only patients with observed cases (OC) values were analysed) |
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Random coefficient regression with fixed effects for treatment, gender, age, height and random effect of patient specific intercept and time.
A hierarchical procedure was used in order to demonstrate the superiority of nintedanib over placebo for the primary and two key secondary endpoints.
The consecutive steps of the hierarchy were only considered if the previous step was significant at the one-sided 2.5% level and the results were in favour of nintedanib.
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Comparison groups |
Placebo v Nintedanib 150mg
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Number of subjects included in analysis |
548
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
= 0.0002 | ||||||||||||
Method |
Random coefficient regression | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
93.73
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
44.78 | ||||||||||||
upper limit |
142.68 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
24.907
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Notes [3] - The Roger-Kenward approximation was used to estimate denominators degrees of freedom. Within-patient errors are modelled by an Unstructured variance-covariance matrix. Inter-individual variability is modelled by a Variance-components variance-covariance matrix. Nintedanib 150 mg bid versus Placebo. |
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End point title |
Change From Baseline in Saint George’s Respiratory Questionnaire (SGRQ) Total Score at 52 Weeks | ||||||||||||
End point description |
This is a key secondary endpoint.
SGRQ is a health-related quality of life questionnaire divided into 3 components : symptoms, activity
and impact.
The total score (summed weights) can range from 0 to 100 with a lower score denoting a better health
status.
Means provided are the adjusted means based on all analyzed 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 52 weeks
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Notes [4] - TS (Only patients with observed cases (OC) values were analysed) [5] - TS (Only patients with observed cases (OC) values were analysed) |
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SGRQ Total score, baseline SGRQ Total score-by-visit and random effect for patient.
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Comparison groups |
Placebo v Nintedanib 150mg
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Number of subjects included in analysis |
533
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Analysis specification |
Pre-specified
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Analysis type |
superiority [6] | ||||||||||||
P-value |
= 0.0197 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-2.69
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-4.95 | ||||||||||||
upper limit |
-0.43 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1.151
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Notes [6] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix. |
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End point title |
Time to First Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation | ||||||||||||||||||
End point description |
Due to rare events, the median of time to event is not calculable, thus the percentages of patients with (IPF) exacerbation are reported and
represented as a key secondary endpoint.
An acute exacerbation (reported as an AE by the investigator) was defined as follows:
Otherwise unexplained clinical features including all of the following:
- Unexplained worsening or development of dyspnoea within 30 days
- New diffuse pulmonary infiltrates on chest X-ray, and/or new HRCT parenchymal abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) since the last visit
- Exclusion of infection as per routine clinical practice and microbiological studies
- Exclusion of alternative causes as per routine clinical practice including left heart failure, pulmonary embolism and identifiable cause of acute lung injury.
Failure is the proportion of patients with at least one acute IPF exacerbation over 52 weeks (up to randomisation + 372 days), based on all investigator-
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End point type |
Secondary
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End point timeframe |
52 weeks
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Notes [7] - Treated Set (Only patients with observed cases (OC) values were analysed) [8] - Treated Set (Only patients with observed cases (OC) values were analysed) |
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||
Statistical analysis description |
Hazard Ratio is based on a Cox's regression model with terms for treatment, gender,
age and height.
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Comparison groups |
Placebo v Nintedanib 150mg
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Number of subjects included in analysis |
548
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Analysis specification |
Pre-specified
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Analysis type |
superiority [9] | ||||||||||||||||||
P-value |
= 0.005 | ||||||||||||||||||
Method |
Logrank | ||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||
Point estimate |
0.38
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.19 | ||||||||||||||||||
upper limit |
0.77 | ||||||||||||||||||
Notes [9] - Nintedanib 150 mg bid versus Placebo. |
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End point title |
Absolute Change From Baseline in Forced Vital Capacity (FVC) Over 52 weeks | ||||||||||||
End point description |
Means provided are the adjusted means. Adjusted mean is based on all analysed patients in the model (not only patients with a change from baseline to week 52).
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End point type |
Secondary
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End point timeframe |
Baseline and 52 weeks
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Notes [10] - TS (Only patients with observed cases (OC) values were analysed) [11] - TS (Only patients with observed cases (OC) values were analysed) |
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Based on Mixed Model for Repeated Measures (MMRM), with fixed effects for
treatment, visit, gender, age, height, treatment-by-visit, baseline FVC, baseline FVC
-by-visit and random effect for patient.
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Comparison groups |
Placebo v Nintedanib 150mg
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Number of subjects included in analysis |
544
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Analysis specification |
Pre-specified
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Analysis type |
superiority [12] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
109.77
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
70.92 | ||||||||||||
upper limit |
148.62 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
19.808
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Notes [12] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix. |
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End point title |
Absolute Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks | ||||||||||||
End point description |
Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).
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End point type |
Secondary
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End point timeframe |
Baseline and 52 weeks
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Notes [13] - TS (Only patients with observed cases (OC) values were analysed) [14] - TS (Only patients with observed cases (OC) values were analysed) |
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Based on Mixed Model for Repeated Measures (MMRM), with fixed effects for
treatment, visit, gender, age, height, treatment-by-visit, baseline FVC [%predicted],
baseline FVC [%predicted]-by-visit and random effect for patient.
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Comparison groups |
Placebo v Nintedanib 150mg
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Number of subjects included in analysis |
544
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Analysis specification |
Pre-specified
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Analysis type |
superiority [15] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
3.06
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1.87 | ||||||||||||
upper limit |
4.25 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.607
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Notes [15] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix. |
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End point title |
Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 5% Threshold | |||||||||||||||||||||
End point description |
Absolute categorical change of FVC (% predicted) by categories at 52 weeks - 5% threshold (decrease by >5%, increase by >5%, and change within ≤5%).
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End point type |
Secondary
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End point timeframe |
Baseline and 52 weeks
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No statistical analyses for this end point |
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End point title |
Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 10% Threshold | |||||||||||||||||||||
End point description |
Absolute categorical change of FVC (% predicted) by categories at 52 weeks - 10% threshold (decrease by > 10%, increase by >10%, and change within ≤10%)
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End point type |
Secondary
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End point timeframe |
Baseline and 52 weeks
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No statistical analyses for this end point |
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End point title |
FVC Responders Using 10% Threshold at 52 Weeks | ||||||||||||
End point description |
FVC responders using 10% threshold at 52 weeks, defined as patients with absolute decline in FVC% predicted no greater than 10% and with an FVC
evaluation at 52 weeks.
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End point type |
Secondary
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End point timeframe |
52 weeks
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Notes [16] - TS (Only patients with observed cases (OC) values were analysed) [17] - TS (Only patients with observed cases (OC) values were analysed) |
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Logistic regression with terms treatment, age, gender, height and baseline FVC %
predicted
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Comparison groups |
Placebo v Nintedanib 150mg
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Number of subjects included in analysis |
548
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Analysis specification |
Pre-specified
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Analysis type |
superiority [18] | ||||||||||||
P-value |
= 0.1833 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.286
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.89 | ||||||||||||
upper limit |
1.86 | ||||||||||||
Notes [18] - Nintedanib 150 mg bid versus Placebo |
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End point title |
Proportion of FVC Responders Using 5% Threshold at 52 Weeks | ||||||||||||
End point description |
Proportion of FVC responders using 5% threshold at 52 weeks, defined as patients with absolute decline in FVC% predicted no greater than 5% and with an FVC evaluation at 52 weeks.
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End point type |
Secondary
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End point timeframe |
52 weeks
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Notes [19] - TS (Only patients with observed cases (OC) values were analysed) [20] - TS (Only patients with observed cases (OC) values were analysed) |
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Logistic regression with terms treatment, age, gender, height and baseline FVC %
predicted
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Comparison groups |
Placebo v Nintedanib 150mg
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Number of subjects included in analysis |
548
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Analysis specification |
Pre-specified
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Analysis type |
superiority [21] | ||||||||||||
P-value |
= 0.0011 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.794
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||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
1.26 | ||||||||||||
upper limit |
2.55 | ||||||||||||
Notes [21] - Nintedanib 150 mg bid versus Placebo |
|
|||||||||||||
End point title |
Proportion of SGRQ Responders at 52 Weeks: Patient Reported Outcomes (PROs) | ||||||||||||
End point description |
Proportion of SGRQ Responders at 52 Weeks. Responders defined as <= -4 points change in change from baseline in SGRQ total score at 52 weeks.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and 52 weeks
|
||||||||||||
|
|||||||||||||
Notes [22] - TS (Only patients with observed cases (OC) values were analysed) [23] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Logistic regression with terms treatment, baseline SGRQ total score
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
548
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [24] | ||||||||||||
P-value |
= 0.0218 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.664
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
1.08 | ||||||||||||
upper limit |
2.57 | ||||||||||||
Notes [24] - Nintedanib 150 mg bid versus Placebo |
|
|||||||||||||
End point title |
Change From Baseline in SGRQ Symptom Score at 52 Weeks (Points): Patient Reported Outcomes (PROs) | ||||||||||||
End point description |
SGRQ Symptom score is a sub-component of SGRQ total score and is concerned with the effect of respiratory symptoms, their frequency and
severity. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better symptom-related quality of life.
Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
baseline and 52 weeks
|
||||||||||||
|
|||||||||||||
Notes [25] - TS (Only patients with observed cases (OC) values were analysed) [26] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment,
visit, treatment-by-visit, baseline SGRQ Symptoms component, baseline SGRQ
Symptoms component-by-visit and random effect for patient.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
537
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [27] | ||||||||||||
P-value |
= 0.4019 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-1.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-4.69 | ||||||||||||
upper limit |
1.88 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.675
|
||||||||||||
Notes [27] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix. |
|
|||||||||||||
End point title |
Change From Baseline in SGRQ Activity Score at 52 Weeks (Points): Patient Reported Outcomes (PROs) | ||||||||||||
End point description |
SGRQ Activity score is a sub-component of SGRQ total score and concerned with activities that cause or are limited by breathlessness. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better activity-related quality of life.
Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
baseline and 52 weeks
|
||||||||||||
|
|||||||||||||
Notes [28] - TS (Only patients with observed cases (OC) values were analysed) [29] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment,
visit, treatment-by-visit, baseline SGRQ Activities component, baseline SGRQ
Activities component-by-visit and random effect for patient
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
536
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [30] | ||||||||||||
P-value |
= 0.0152 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-3.31
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-5.97 | ||||||||||||
upper limit |
-0.64 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.36
|
||||||||||||
Notes [30] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix. |
|
|||||||||||||
End point title |
Change From Baseline in SGRQ Impact Score at 52 Weeks (Points): Patient Reported Outcomes (PROs) | ||||||||||||
End point description |
SGRQ Impact score is a sub-component of SGRQ total score and covers a range of aspects concerned with social functioning and psychological
disturbances resulting from airway disease. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better
impact-related quality of life.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
baseline and 52 weeks
|
||||||||||||
|
|||||||||||||
Notes [31] - TS (Only patients with observed cases (OC) values were analysed) [32] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment,
visit, treatment-by-visit, baseline SGRQ impact component, baseline SGRQ impact
component-by-visit and random effect for patient
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
535
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [33] | ||||||||||||
P-value |
= 0.022 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-3.08
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-5.71 | ||||||||||||
upper limit |
-0.45 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.342
|
||||||||||||
Notes [33] - Nintedanib 150 mg bid versus Placebo. Within-patient error are modelled by compound symmetry covariance matrix. |
|
|||||||||||||
End point title |
Change From Baseline in Idiopathic Pulmonary Fibrosis (IPF) Specific Version of SGRQ (SGRQ-I) Total Score at 52 Weeks (Points): Patient Reported Outcomes (PROs) | ||||||||||||
End point description |
SGRQ-I is the IPF specific version of SGRQ comprises of selected items from the SGRQ divided into three components, Symptoms, Activity and
Impact. Each component is scored separately. The weights for all items with a positive responses are summed and the weights from missed items are deducted from the maximum possible weight for the total score.
The total score is calculated by dividing the summed weights from positive items in the questionnaire by maximum possible weight for all items in the questionnaire. The total score can range from 0 to 100 with a lower score denoting a better health-related quality of life. Change from baseline is calculated as the difference between total score at week 52 and total score at baseline as measured by the scale.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
baseline and 52 weeks
|
||||||||||||
|
|||||||||||||
Notes [34] - TS (Only patients with observed cases (OC) values were analysed) [35] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SGRQ-I Total score, baseline SGRQ-I Total score-by-visit and random effect for patient.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
533
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [36] | ||||||||||||
P-value |
= 0.0089 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-3.12
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-5.46 | ||||||||||||
upper limit |
-0.79 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.192
|
||||||||||||
Notes [36] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix. |
|
|||||||||||||
End point title |
Change From Baseline in Shortness of Breath Questionnaire (SOBQ) at 52 Weeks: Patient Reported Outcomes (PROs) | ||||||||||||
End point description |
Shortness of Breath Questionnaire measures the shortness of breath. It comprises of 24 items. Each item is scored on a scale between 0-5 where 5 represents maximal breathlessness. The responses to all items are summed up to provide the overall score that can range from 0 (best outcome) to 120 (worst outcome).
Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
baseline and 52 weeks
|
||||||||||||
|
|||||||||||||
Notes [37] - TS (Only patients with observed cases (OC) values were analysed) [38] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SOBQ score, baseline SOBQ score-by-visit and random effect for patient.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
506
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [39] | ||||||||||||
P-value |
= 0.1587 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-2.38
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-5.68 | ||||||||||||
upper limit |
0.93 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.685
|
||||||||||||
Notes [39] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix. |
|
|||||||||||||
End point title |
Change From Baseline in Cough Symptom Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks: Patient Reported Outcomes (PROs) | ||||||||||||
End point description |
The cough domains of the Cough and Sputum Assessment Questionnaire (CASAQ(CD)) assess the frequency and severity of cough and sputum and
their impact on everyday life. It contains 4 domains cough/sputum symptom and impact with each scale ranging from 0 to 100 with lower scores
indicating higher symptoms/impact levels (worst outcome).
Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
baseline and 52 weeks
|
||||||||||||
|
|||||||||||||
Notes [40] - TS (Only patients with observed cases (OC) values were analysed) [41] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment,
visit, treatment-by-visit, baseline CASA-Q Cough symptoms score, baseline CASAQ
Cough symptoms score-by-visit and random effect for patient.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
538
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [42] | ||||||||||||
P-value |
= 0.2326 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
2.05
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.31 | ||||||||||||
upper limit |
5.41 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.713
|
||||||||||||
Notes [42] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix. |
|
|||||||||||||
End point title |
Change From Baseline in Cough Impact Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks: Patient Reported Outcomes (PROs) | ||||||||||||
End point description |
The cough domains of the Cough and Sputum Assessment Questionnaire (CASA-Q) assess the frequency and severity of cough and sputum and their impact on everyday life. It contains 4 domains cough/sputum symptom and impact with each scale ranging from 0 to 100 with lower scores indicating higher symptoms/impact levels (worst outcome).
Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
baseline and 52 weeks
|
||||||||||||
|
|||||||||||||
Notes [43] - Treated set [44] - Treated set |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment,
visit, treatment-by-visit, baseline CASA-Q Cough impact score, baseline CASA-Q
Cough impact score-by-visit and random effect for patient.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
537
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [45] | ||||||||||||
P-value |
= 0.2475 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.81
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.26 | ||||||||||||
upper limit |
4.88 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.564
|
||||||||||||
Notes [45] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix. |
|
|||||||||||||
End point title |
Proportion of Patient’s Global Impression of Change (PGI-C) Responders at 52 Weeks: Patient Reported Outcomes (PROs) | ||||||||||||
End point description |
Proportion of Patient's Global Impression of Change (PGI-C) responders at 52 weeks. Responders are defined as 'Very much better'/ 'Much better'/ 'A little better'/ 'No change'.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
52 weeks
|
||||||||||||
|
|||||||||||||
Notes [46] - TS (Only patients with observed cases (OC) values were analysed) [47] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Logistic regression with term treatment
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
548
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [48] | ||||||||||||
P-value |
= 0.069 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.379
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.98 | ||||||||||||
upper limit |
1.95 | ||||||||||||
Notes [48] - Nintedanib 150 mg bid versus Placebo |
|
||||||||||||||||||||||
End point title |
Change From Baseline in EuroQol 5-Dimensional Quality of Life Questionnaire (EQ-5D) Health State up to 52 Weeks: Patient Reported Outcomes (PROs) | |||||||||||||||||||||
End point description |
The EuroQol 5-dimensional Health State is based on a visual analog scale (EQ-VAS) representing the general patient's health state labelled from 100 (best imaginable health state) to 0 (worst imaginable health state). A higher score indicating a better health state. Change from baseline is calculated as the difference between health state at week 12, 24 and 52 respectively and health state at baseline as measured by the scale.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
baseline, 12 weeks, 24 weeks and 52 weeks
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Notes [49] - TS (Only patients with observed cases (OC) values were analysed) [50] - TS (Only patients with observed cases (OC) values were analysed) |
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Time to Death Over 52 Weeks | ||||||||||||||||||
End point description |
Due to rare events, the median of time to event is not calculable, thus the percentages of patients who did or did not experienced death before or at 372 days after randomisation or last contact date (whichever occurs first) are reported.
Failure is the proportion of patients who died over 52 weeks (up to 372 days after randomisation).
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
52 weeks
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [51] - TS (Only patients with observed cases (OC) values were analysed) [52] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||
Statistical analysis description |
Hazard ratio is based on a Cox´s regression model with terms for treatment, gender,
age and height.
|
||||||||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||||||||
Number of subjects included in analysis |
548
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority [53] | ||||||||||||||||||
P-value |
= 0.2995 | ||||||||||||||||||
Method |
Logrank | ||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||
Point estimate |
0.74
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
95% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.4 | ||||||||||||||||||
upper limit |
1.35 | ||||||||||||||||||
Notes [53] - Nintedanib 150 mg bid versus Placebo |
|
|||||||||||||||||||
End point title |
Time to Death Due to Respiratory Cause Over 52 Weeks (Adjudicated) | ||||||||||||||||||
End point description |
Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experienced death due to
respiratory causes before or at 372 days after randomisation or last contact date (whichever occurs first) are reported.
Failure is the the proportion of patients who died due to respiratory causes over 52 weeks (up to 372 days after randomisation).
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
52 weeks
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [54] - TS (Only patients with observed cases (OC) values were analysed) [55] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||
Statistical analysis description |
Hazard ratio is based on Cox´s regression model with terms for treatment, gender,
age and height.
|
||||||||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||||||||
Number of subjects included in analysis |
548
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority [56] | ||||||||||||||||||
P-value |
= 0.6654 | ||||||||||||||||||
Method |
Logrank | ||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||
Point estimate |
0.86
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
95% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.39 | ||||||||||||||||||
upper limit |
1.9 | ||||||||||||||||||
Notes [56] - Nintedanib 150 mg bid versus Placebo |
|
|||||||||||||||||||
End point title |
Time to On-treatment Death | ||||||||||||||||||
End point description |
Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not die before or at last trial
medication intake + 28 days were censored at last trial medication intake + 28 days and reported.
Failure is the the proportion of patients who died on-treatment (up to 28 days after last treatment intake).
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
52 weeks
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [57] - TS (Only patients with observed cases (OC) values were analysed) [58] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||
Statistical analysis description |
Hazard ratio is based on a Cox´s regression model with terms for treatment, gender,
age and height.
|
||||||||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||||||||
Number of subjects included in analysis |
548
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority [59] | ||||||||||||||||||
P-value |
= 0.2209 | ||||||||||||||||||
Method |
Logrank | ||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||
Point estimate |
0.68
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
95% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.34 | ||||||||||||||||||
upper limit |
1.35 | ||||||||||||||||||
Notes [59] - Nintedanib 150 mg bid versus Placebo |
|
|||||||||||||||||||
End point title |
Time to Death or Lung Transplant Over 52 Weeks | ||||||||||||||||||
End point description |
Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experience event (death or lung transplant) before or at 372 days after randomisation or last contact date (whichever occurs first) are reported.
Failure is the proportion of patients who died or had lung transplant over 52 weeks (up to 372 days after randomisation).
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
52 weeks
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [60] - TS (Only patients with observed cases (OC) values were analysed) [61] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||
Statistical analysis description |
Hazard ratio is based on Cox´s regression model with terms for treatment, gender,
age and height.
|
||||||||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||||||||
Number of subjects included in analysis |
548
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority [62] | ||||||||||||||||||
P-value |
= 0.1664 | ||||||||||||||||||
Method |
Logrank | ||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||
Point estimate |
0.67
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
95% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.37 | ||||||||||||||||||
upper limit |
1.21 | ||||||||||||||||||
Notes [62] - Nintedanib 150 mg bid versus Placebo |
|
|||||||||||||||||||
End point title |
Time to Death or Lung Transplant or Qualifying for Lung Transplant Over 52 Weeks. | ||||||||||||||||||
End point description |
Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experienced death or lung transplant or qualifying for lung transplant over 52 weeks are reported. A patient was considered qualifying for lung transplant by the investigator if he or she fulfilled the following criteria:
FVC <45% predicted or Carbon monoxide diffusion capacity (DL(CO)) <30% pred or Oxygen saturation on pulse oximetry (SpO2) <88% at rest, at sea level (to be adapted for other heights).
These criteria were evaluated by investigators judgement. Failure is the proportion of patients who died or had lung transplant or qualified for lung transplant over 52 weeks (up to 372 days after randomisation).
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
52 weeks
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [63] - TS (Only patients with observed cases (OC) values were analysed) [64] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||
Statistical analysis description |
Hazard ratio is based on Cox´s regression model with terms for treatment, gender,
age and height.
|
||||||||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||||||||
Number of subjects included in analysis |
548
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority [65] | ||||||||||||||||||
P-value |
= 0.2123 | ||||||||||||||||||
Method |
Logrank | ||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||
Point estimate |
0.8
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
95% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.55 | ||||||||||||||||||
upper limit |
1.16 | ||||||||||||||||||
Notes [65] - Nintedanib 150 mg bid versus Placebo |
|
|||||||||||||
End point title |
Change From Baseline in SpO2 (Oxygen Saturation, Expressed in Percent) at Rest up Over 52 Weeks | ||||||||||||
End point description |
Means presented are the adjusted means. Adjusted mean is based on
all analyzed patients in the model (not only patients with a change
from baseline to week 52)
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
baseline and 52 weeks
|
||||||||||||
|
|||||||||||||
Notes [66] - TS (Only patients with observed cases (OC) values were analysed) [67] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment,
visit, gender, age, height, treatment-by-visit, baseline SpO2, baseline SpO2-by-visit
and random effect for patient
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
532
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [68] | ||||||||||||
P-value |
= 0.2032 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.27
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.15 | ||||||||||||
upper limit |
0.69 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.213
|
||||||||||||
Notes [68] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix. |
|
|||||||||||||
End point title |
Change From Baseline in Carbon Monoxide Diffusion Capacity (DLCO) at Rest Over 52 Weeks | ||||||||||||
End point description |
Means provided are the adjusted means and are based on all analysed
patients in the model (not only patients with a change from baseline
to week 52).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
baseline and 52 weeks
|
||||||||||||
|
|||||||||||||
Notes [69] - TS (Only patients with observed cases (OC) values were analysed) [70] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Mixed Model for Repeated Measures with fixed effects for treatment, visit, gender,
age, height, treatment-by-visit, baseline DLCO (HGB Corrected) [mmol/min/kPa],
baseline DLCO (HGB Corrected) [mmol/min/kPa]-by-visit and random effect for
patient.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
504
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [71] | ||||||||||||
P-value |
= 0.26 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.113
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.084 | ||||||||||||
upper limit |
0.31 | ||||||||||||
Notes [71] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix. |
|
|||||||||||||
End point title |
Relative Change From Baseline in Forced Vital Capacity (FVC) Over 52 Weeks | ||||||||||||
End point description |
Percentage change from baseline in FVC over 52 weeks. Means provided
are the adjusted means and are based on all analysed patients in the model
(not only patients with a change from baseline to week 52).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and 52 weeks
|
||||||||||||
|
|||||||||||||
Notes [72] - Treated Set (Only patients with observed cases (OC) values were analysed) [73] - Treated Set (Only patients with observed cases (OC) values were analysed) |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Based on Mixed Model for Repeated Measures (MMRM), with fixed effects for
treatment, visit, gender, age, height, treatment-by-visit, baseline FVC, baseline FVC-by visit
and random effect for patient.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
544
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [74] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
4.24
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
2.78 | ||||||||||||
upper limit |
5.69 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.742
|
||||||||||||
Notes [74] - Within-patient errors are modelled by compound symmetry covariance matrix. Nintedanib 150 mg bid versus Placebo. |
|
|||||||||||||
End point title |
Relative Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks | ||||||||||||
End point description |
Percentage change from baseline in FVC (% predicted) at 52 weeks. Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and 52 weeks
|
||||||||||||
|
|||||||||||||
Notes [75] - TS (Only patients with observed cases (OC) values were analysed) [76] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Based on Mixed Model for Repeated Measures (MMRM), with fixed effects for
treatment, visit, gender, age, height, treatment-by-visit, baseline FVC [%predicted],
baseline FVC [%predicted]-by-visit and random effect for patient.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
544
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [77] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
4.21
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
2.76 | ||||||||||||
upper limit |
5.67 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.743
|
||||||||||||
Notes [77] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix. Clinical |
|
|||||||||||||
End point title |
Risk of an Acute IPF Exacerbation Over 52 Weeks | ||||||||||||
End point description |
Incidence rate of exacerbations (calculated as the number of patients with at least 1 acute IPF exacerbation divided by the total number of years at risk *100)
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
52 weeks
|
||||||||||||
|
|||||||||||||
Notes [78] - TS (Only patients with observed cases (OC) values were analysed) [79] - TS (Only patients with observed cases (OC) values were analysed) |
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Risk ratio was calculated as the ratio of risk of exacerbation in both treatment groups. The log of the risk ratio was assumed to follow a normal distribution with mean 0 and variance equal to the sum of the reciprocals of the number of patients with at least one exacerbation in each treatment arm.
|
||||||||||||
Comparison groups |
Placebo v Nintedanib 150mg
|
||||||||||||
Number of subjects included in analysis |
548
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [80] | ||||||||||||
P-value |
= 0.007 | ||||||||||||
Method |
Normal distribution | ||||||||||||
Parameter type |
Risk ratio (RR) | ||||||||||||
Point estimate |
0.38
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.19 | ||||||||||||
upper limit |
0.77 | ||||||||||||
Notes [80] - Nintedanib 150 mg bid versus Placebo. |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From the first drug administration until 28 days after the last drug administration, up to 428 days.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Oral administration of Placebo matching nintedanib soft gelatine capsules | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Nintedanib 150mg bid
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Reporting group description |
Oral administration of soft gelatine capsules of Nintedanib 150 mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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17 Nov 2011 |
- ‘Acute IPF exacerbation’ was clarified each time ‘exacerbation’ was mentioned
- Procedures and appropriate measures in case of suspicion of a ‘drug induced liver injury’ event were implemented
- A re-test was allowed in case a laboratory parameter was found to be abnormal at Visit 1. This was to be conducted if laboratory tests were thought to be a measurement error and not related to the patient’s condition
- Patients were to be excluded from the trial if they were not able to follow trial procedures including completion of self administered questionnaires without help
- Instructions were included for Investigators on the reporting of DLCO in the eCRF
- Addition of the ‘always serious AEs’ according to new BI standards to ensure proper reporting of these events
- Inclusion criterion 4 was changed to: ‘Chest HRCT performed within 12 months of Visit 1’, instead of ‘Chest HRCT performed within 12 months of Visit 2’ |
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04 Sep 2012 |
- Addition of exploratory biomarker analyses in order to explore the effect of nintedanib on biomarkers related to IPF pathology and prognostic markers of the disease. Exploratory analyses of samples from patients who gave specific informed
consent were performed. Pharmacogenomic analysis was also added
- The criterion for poor compliance was defined as a protocol violation |
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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 |