Clinical Trial Results:
Multicenter, International, Double-blind, Two-Arm, Randomized, Placebo-controlled Phase II Trial of Pirfenidone in Patients with Unclassifiable Progressive Fibrosing ILD
Summary
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EudraCT number |
2016-002744-17 |
Trial protocol |
ES DK CZ DE PL PT GR BE GB IT |
Global end of trial date |
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Results information
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Results version number |
v1 |
This version publication date |
03 Dec 2019
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First version publication date |
03 Dec 2019
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Other versions |
v2 |
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 |
MA39189
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03099187 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
F. Hoffmann-La Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124., Basel, Switzerland, CH-4070
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Public contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
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Scientific contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.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 |
Interim
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Date of interim/final analysis |
21 Nov 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Nov 2018
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Global end of trial reached? |
No
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General information about the trial
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Main objective of the trial |
The main objective of the trial was to evaluate the effect of pirfenidone versus (vs.) placebo on lung function parameters.
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Protection of trial subjects |
All study subjects were required to read and sign an Informed Consent Form
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
15 May 2017
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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 |
12 Months | ||
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 |
Australia: 38
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Country: Number of subjects enrolled |
Belgium: 13
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Country: Number of subjects enrolled |
Canada: 6
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Country: Number of subjects enrolled |
Czech Republic: 8
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Country: Number of subjects enrolled |
Denmark: 11
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Country: Number of subjects enrolled |
Germany: 19
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Country: Number of subjects enrolled |
Greece: 13
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Country: Number of subjects enrolled |
Ireland: 5
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Country: Number of subjects enrolled |
Israel: 30
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Country: Number of subjects enrolled |
Italy: 21
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Country: Number of subjects enrolled |
Poland: 16
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Country: Number of subjects enrolled |
Portugal: 18
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Country: Number of subjects enrolled |
Spain: 15
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Country: Number of subjects enrolled |
United Kingdom: 40
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Worldwide total number of subjects |
253
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EEA total number of subjects |
179
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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) |
85
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From 65 to 84 years |
165
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85 years and over |
3
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Recruitment
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Recruitment details |
A total of 253 subjects were randomized at 65 study centers) in Australia, Europe, the Middle East, and North America. Subjects who were withdrawn from the trial were not replaced. | |||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Subjects were requested to taper and/or discontinue all prohibited medications in the 28 days prior to the start of screening during the washout period. | |||||||||||||||||||||||||||||||||||||||||||||
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 | |||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Pirfenidone | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received pirfenidone 267 mg capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Pirfenidone
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Investigational medicinal product code |
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Other name |
Esbriet
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Pirfenidone was administered at a daily dose of 2403 mg orally in the form of three 267 mg capsules (801 mg) three times daily with food.
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Arm title
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Placebo | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received matching placebo capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Pirfenidone matching placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Pirfenisone matching placebo was administered orally in the form of hard capsules three times daily.
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Baseline characteristics reporting groups
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Reporting group title |
Pirfenidone
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Reporting group description |
Subjects received pirfenidone 267 mg capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects received matching placebo capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Pirfenidone
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Reporting group description |
Subjects received pirfenidone 267 mg capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24. | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects received matching placebo capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24. | ||
Subject analysis set title |
Intent-toTreat Population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses.
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Subject analysis set title |
Safety Population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The safety population was defined as all subjects with at least one intake of pirfenidone or placebo, i.e., at least one record in the drug-log of the double-blind period with a non-zero dose. Subjects in the safety population were assigned to a treatment arm according to the actual treatment they received.
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End point title |
Rate of Decline in Forced Vital Capacity (FVC) Over the 24-week Double-blind Treatment Period | ||||||||||||
End point description |
Rate of decline in FVC was measured in mL by daily handheld spirometer. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. Only subjects for whom data were collected are included in the analysis.
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End point type |
Primary
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End point timeframe |
Up to Week 24
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Statistical analysis title |
Superiority | ||||||||||||
Statistical analysis description |
Mean FVC decline comparison between treatment groups using a Student's t-test with a two-sided significance level of 0.05
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Comparison groups |
Placebo v Pirfenidone
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Number of subjects included in analysis |
247
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.6777 [1] | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Difference in Group Means | ||||||||||||
Point estimate |
-134.6
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-772.4 | ||||||||||||
upper limit |
503.3 | ||||||||||||
Notes [1] - p-value is not adjusted for multiplicity and is provided for descriptive purpose only |
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End point title |
Change in Percent Predicted FVC | |||||||||||||||||||||||||||||||||
End point description |
FVC was measured in liter (L) by spirometry. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. Only subjects for whom data were collected are included in the analysis.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to Week 24
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Notes [2] - Number of subjects analysed was different at each time point; only collected data were analysed. [3] - Number of subjects analysed was different at each time point; only collected data were analysed. |
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Statistical analysis title |
Superiority | |||||||||||||||||||||||||||||||||
Comparison groups |
Pirfenidone v Placebo
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Number of subjects included in analysis |
253
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||||||||||||||
P-value |
= 0.0383 | |||||||||||||||||||||||||||||||||
Method |
rank ANCOVA | |||||||||||||||||||||||||||||||||
Confidence interval |
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End point title |
Change in FVC | |||||||||||||||||||||||||||||||||
End point description |
FVC was measured in liter (L) by spirometry. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. Only subjects for whom data were collected are included in the analysis.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to Week 24
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Notes [4] - Number of subjects analysed was different at each time point; only collected data were analysed. [5] - Number of subjects analysed was different at each time point; only collected data were analysed. |
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Statistical analysis title |
Superiority | |||||||||||||||||||||||||||||||||
Comparison groups |
Pirfenidone v Placebo
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Number of subjects included in analysis |
253
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||||||||||||||
P-value |
= 0.0018 [6] | |||||||||||||||||||||||||||||||||
Method |
Student's t-test | |||||||||||||||||||||||||||||||||
Parameter type |
Overall Mean Difference | |||||||||||||||||||||||||||||||||
Point estimate |
95.3
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Confidence interval |
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level |
95% | |||||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
35.9 | |||||||||||||||||||||||||||||||||
upper limit |
154.6 | |||||||||||||||||||||||||||||||||
Notes [6] - p-value is not adjusted for multiplicity and is provided for descriptive purpose only. |
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End point title |
Categorical Change in FVC of >5% | |||||||||
End point description |
Categorical change in FVC was measured both by daily spirometry as well as by spirometry during clinical visits. Only the site spirometry data were used as the daily spirometry data were not normally distributed. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to Week 24
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Statistical analysis title |
Superiority | |||||||||
Comparison groups |
Pirfenidone v Placebo
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Number of subjects included in analysis |
253
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.0006 [7] | |||||||||
Method |
Cochran-Mantel-Haenszel | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
0.42
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.25 | |||||||||
upper limit |
0.69 | |||||||||
Notes [7] - p-values was not adjusted for multiplicity and was provided for descriptive purpose only |
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End point title |
Categorical Change in FVC of >10% | |||||||||
End point description |
Categorical change in FVC was measured both by daily spirometry as well as by spirometry during clinical visits. Only the site spirometry data were used as the daily spirometry data were not normally distributed. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to Week 24
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Statistical analysis title |
Superiority | |||||||||
Comparison groups |
Pirfenidone v Placebo
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Number of subjects included in analysis |
253
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.0114 [8] | |||||||||
Method |
Cochran-Mantel-Haenszel | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
0.44
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.23 | |||||||||
upper limit |
0.84 | |||||||||
Notes [8] - p-values was not adjusted for multiplicity and was provided for descriptive purpose only |
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End point title |
Change in Percent Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) | |||||||||||||||||||||
End point description |
The DLco is a pulmonary function test that measures the capacity for the lung to carry out gas exchange between the inhaled breath and the pulmonary capillary blood vessels and the DLco %-predicted represents the DLco expressed as a percentage of the expected normal valued based on the participant's age, height, gender and ethnicity. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. Only subjects for whom data were collected are included in the analysis.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to Week 24
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Notes [9] - Number of subjects analysed was different at each time point; only collected data were analysed. [10] - Number of subjects analysed was different at each time point; only collected data were analysed. |
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Statistical analysis title |
Superiority | |||||||||||||||||||||
Comparison groups |
Pirfenidone v Placebo
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Number of subjects included in analysis |
252
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.0385 [11] | |||||||||||||||||||||
Method |
rank ANCOVA | |||||||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||||||||
Point estimate |
0.25
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
0.07 | |||||||||||||||||||||
upper limit |
0.93 | |||||||||||||||||||||
Notes [11] - p-value was not adjusted for multiplicity and was provided for descriptive purpose only |
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End point title |
Change in 6-minute Walk Distance (6MWD) | |||||||||||||||||||||
End point description |
Comparison of 6-minute walk distance before beginning and after completing study therapy. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. Only subjects for whom data were collected are included in the analysis.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to Week 24
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Notes [12] - Number of subjects analysed was different at each time point; only collected data were analysed. [13] - Number of subjects analysed was different at each time point; only collected data were analysed. |
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Statistical analysis title |
Superiority | |||||||||||||||||||||
Comparison groups |
Pirfenidone v Placebo
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Number of subjects included in analysis |
253
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.9198 [14] | |||||||||||||||||||||
Method |
Regression, Logistic | |||||||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||||||||
Point estimate |
1.03
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
0.59 | |||||||||||||||||||||
upper limit |
1.78 | |||||||||||||||||||||
Notes [14] - p-value was not adjusted for multiplicity and was provided for descriptive purpose only |
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End point title |
Change in University of California, San Diego-Shortness of Breath Questionnaire Score | |||||||||||||||||||||
End point description |
University of California, San Diego Shortness of Breath Questionnaire (SOBQ) consists of 24-item on a scale of 0 to 5 with 0=not at all and 5=maximal or unable to do because of breathlessness. The total scores were calculated by summation of the 24 items scores and transformed into 0-100, with 0= poor quality of life , and 100= excellent quality of life. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. Only subjects for whom data were collected are included in the analysis.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to Week 24
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Notes [15] - Number of subjects analysed was different at each time point; only collected data were analysed. [16] - Number of subjects analysed was different at each time point; only collected data were analysed. |
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Statistical analysis title |
Superiority | |||||||||||||||||||||
Comparison groups |
Pirfenidone v Placebo
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Number of subjects included in analysis |
227
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.7788 | |||||||||||||||||||||
Method |
rank ANCOVA | |||||||||||||||||||||
Parameter type |
Hodges-Lehmann Median Difference | |||||||||||||||||||||
Point estimate |
0
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Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-5 | |||||||||||||||||||||
upper limit |
5 |
|
||||||||||||||||||||||
End point title |
Change in Score in Leicester Cough Questionnaire Score | |||||||||||||||||||||
End point description |
The Leicester Cough Questionnaire is a subject-reported questionnaire evaluating the impact of cough on quality of life. The questionnaire comprises 19 items. Each item assesses symptoms, or the impact of symptoms, over the last 2 weeks on a seven-point Likert scale. Scores in three domains (physical, psychological and social) were calculated as a mean for each domain (range 1 to 7). A total score (range 3 to 21) was also calculated by adding the domain scores together. Higher scores indicate better quality of life. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. Only subjects for whom data were collected are included in the analysis.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline (Day 1) to Week 24
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Notes [17] - Number of subjects analysed was different at each time point; only collected data were analysed. [18] - Number of subjects analysed was different at each time point; only collected data were analysed. |
||||||||||||||||||||||
Statistical analysis title |
Superiority | |||||||||||||||||||||
Comparison groups |
Pirfenidone v Placebo
|
|||||||||||||||||||||
Number of subjects included in analysis |
252
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.1872 [19] | |||||||||||||||||||||
Method |
rank ANCOVA | |||||||||||||||||||||
Parameter type |
Hodges-Lehmann Median difference | |||||||||||||||||||||
Point estimate |
0.29
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.45 | |||||||||||||||||||||
upper limit |
1.04 | |||||||||||||||||||||
Notes [19] - p-value was not adjusted for multiplicity and was provided for descriptive purpose only |
|
||||||||||||||||||||||
End point title |
Change in Cough Visual Analog Scale (VAS) Score | |||||||||||||||||||||
End point description |
Cough VAS are 100-mm linear scales on which subjects indicate the severity of their cough; 0 mm represents no cough and 100 mm the worst cough ever. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. Only subjects for whom data were collected are included in the analysis.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline (Day 1) to Week 24
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Notes [20] - Number of subjects analysed was different at each time point; only collected data were analysed. [21] - Number of subjects analysed was different at each time point; only collected data were analysed. |
||||||||||||||||||||||
Statistical analysis title |
Superiority | |||||||||||||||||||||
Comparison groups |
Pirfenidone v Placebo
|
|||||||||||||||||||||
Number of subjects included in analysis |
252
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.2995 | |||||||||||||||||||||
Method |
rank ANCOVA | |||||||||||||||||||||
Parameter type |
Hodges-Lehmann Median Difference | |||||||||||||||||||||
Point estimate |
-2
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-10 | |||||||||||||||||||||
upper limit |
4 |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change in Total and Sub-scores of the Saint George's Respiratory Questionnaire (SGRQ) | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
SGRQ is a health related quality of life questionnaire consisting of 40 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. Only subjects for whom data were collected are included in the analysis.
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline (Day 1) to Week 24
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
Notes [22] - Number of subjects analysed was different at each time point; only collected data were analysed. [23] - Number of subjects analysed was different at each time point; only collected data were analysed. |
|||||||||||||||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Superiority | ||||||||||||||||||||||||||||||||||||||||||||||||
Comparison groups |
Pirfenidone v Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
253
|
||||||||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||||||||||||||
Analysis type |
|||||||||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.163 | ||||||||||||||||||||||||||||||||||||||||||||||||
Method |
rank ANCOVA | ||||||||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Hodges-Lehmann Median Difference | ||||||||||||||||||||||||||||||||||||||||||||||||
Point estimate |
-1.86
|
||||||||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||||||||||||||
lower limit |
-5.06 | ||||||||||||||||||||||||||||||||||||||||||||||||
upper limit |
1.38 |
|
||||||||||||||||
End point title |
Number of Subjects with Non-elective Hospitalization, Both Respiratory and all Cause | |||||||||||||||
End point description |
Subjects with non-elective hospitalization are reported. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Baseline (Day 1) to Week 24
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
Superiority | |||||||||||||||
Comparison groups |
Pirfenidone v Placebo
|
|||||||||||||||
Number of subjects included in analysis |
253
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
||||||||||||||||
P-value |
= 0.5922 | |||||||||||||||
Method |
Logrank | |||||||||||||||
Parameter type |
Hazard ratio (HR) | |||||||||||||||
Point estimate |
1.22
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
0.59 | |||||||||||||||
upper limit |
2.49 |
|
|||||||||||||
End point title |
Percentage of Subjects with Investigator-reported Acute Exacerbations | ||||||||||||
End point description |
Percentage of subjects with acute exacerbation are reported. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Day 1) to Week 24
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Time to First Investigator-reported Acute Exacerbations | ||||||||||||
End point description |
Time to first investigator reported acute exacerbations from start of treatment are reported. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. 9999=not estimable; The end point could not be analysed due to the limited number of events.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Day 1) to Week 24
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Progression-free Survival (PFS) | ||||||||||||
End point description |
PFS is defined as the time to the first occurrence of a >10% absolute decline in percent predicted FVC, a >50 m decline of 6MWD, or death. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. 9999=not estimable
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Day 1) to Week 24
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority | ||||||||||||
Comparison groups |
Pirfenidone v Placebo
|
||||||||||||
Number of subjects included in analysis |
253
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
= 0.366 | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Cox proportional hazard | ||||||||||||
Point estimate |
0.84
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.56 | ||||||||||||
upper limit |
1.24 |
|
|||||||||||||
End point title |
Progression-free Survival (PFS) | ||||||||||||
End point description |
PFS is defined as the time to the first occurrence of a >10% absolute decline in percent predicted FVC, non-elective respiratory hospitalization, or death. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. 9999=not estimable
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Day 1) to Week 24
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Superiority | ||||||||||||
Comparison groups |
Pirfenidone v Placebo
|
||||||||||||
Number of subjects included in analysis |
253
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
= 0.2726 | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Cox proportional hazard | ||||||||||||
Point estimate |
0.79
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.52 | ||||||||||||
upper limit |
1.2 |
|
|||||||||||||
End point title |
Time to Death From any Cause | ||||||||||||
End point description |
Time to first documented death from start of treatment is reported. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. 9999=not estimable
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Day 1) to Week 24
|
||||||||||||
|
|||||||||||||
Notes [24] - The end point could not be analysed due to the limited number of events. [25] - The end point could not be analysed due to the limited number of events |
|||||||||||||
Statistical analysis title |
Superiority | ||||||||||||
Comparison groups |
Pirfenidone v Placebo
|
||||||||||||
Number of subjects included in analysis |
253
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
= 0.9969 | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Cox proportional hazard | ||||||||||||
Point estimate |
1.01
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.06 | ||||||||||||
upper limit |
16.08 |
|
|||||||||||||
End point title |
Time to Death from Respiratory Diseases | ||||||||||||
End point description |
Time to first documented death due to respiratory diseases from start of treatment will be reported. The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses. 9999=not estimable
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Day 1) to Week 24
|
||||||||||||
|
|||||||||||||
Notes [26] - The end point could not be analysed due to the limited number of events [27] - The end point could not be analysed due to the limited number of events |
|||||||||||||
Statistical analysis title |
Superiority | ||||||||||||
Comparison groups |
Pirfenidone v Placebo
|
||||||||||||
Number of subjects included in analysis |
253
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
= 0.3231 | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Cox proportional hazard | ||||||||||||
Point estimate |
0
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0 | ||||||||||||
upper limit |
0 |
|
||||||||||
End point title |
Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | |||||||||
End point description |
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. The safety population was defined as all subjects with at least one intake of pirfenidone or placebo, i.e., at least one record in the drug-log of the double-blind period with a non-zero dose. Subjects in the safety population were assigned to a treatment arm according to the actual treatment they received.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Baseline (Day 1) to Week 28
|
|||||||||
|
||||||||||
Notes [28] - Two subjects did not receive treatment. |
||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of Subjects With Dose Reductions and Treatment Interruptions | |||||||||||||||
End point description |
Number of subjects with dose reduction and treatment interruptions are reported. The safety population was defined as all subjects with at least one intake of pirfenidone or placebo, i.e., at least one record in the drug-log of the double-blind period with a non-zero dose. Subjects in the safety population were assigned to a treatment arm according to the actual treatment they received.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From administration of the first dose of study drug to Week 24
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of Subjects Withdrawn from Trial Treatment or Trial Discontinuations | |||||||||
End point description |
Number of subjects withdrawn from trial treatment or trial discontinuations are reported. The safety population was defined as all subjects with at least one intake of pirfenidone or placebo, i.e., at least one record in the drug-log of the double-blind period with a non-zero dose. Subjects in the safety population were assigned to a treatment arm according to the actual treatment they received.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Baseline (Day 1) to Week 24
|
|||||||||
|
||||||||||
Notes [29] - Two subjects did not receive treatment. |
||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Baseline (Day 1) to Week 28
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The safety population was defined as all subjects with at least one intake of pirfenidone or placebo, i.e., at least one record in the drug-log of the double-blind period with a non-zero dose. Subjects in the safety population were assigned to a treatment arm according to the actual treatment they received.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
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Reporting group title |
Pirfenidone
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Reporting group description |
Participants received pirfenidone 267 mg capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received matching placebo capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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03 Mar 2017 |
1) Version included additional safety monitoring during the 12-month safety follow-up period, in accordance with the pirfenidone Investigator’s Brochure (RO0220912) and the Summary of Product Characteristics (Esbriet). Increased safety monitoring included additional liver function and pregnancy tests initially at monthly visits during the first 6 months and approximately every 3 months, thereafter. Urine pregnancy tests would continue to be performed on a monthly basis. Relevant sections of the protocol including the Schedule of Assessments have been amended. 2) Guidance text for sections on inclusion and exclusion criteria was amended in order to provide more clear guidance as to when subjects must fulfil the eligibility criteria in order to participate in the trial since results for screening assessments may not all be available at the time of screening. 3) Inclusion criterion no. 11 was amended in order to correct the error in the classification of the acceptable methods of contraception. 4) Section on ‘Trial Rationale and Benefit-Risk Assessment’ was amended to provide further clarification that trial subjects are allowed to be treated with mycophenolate (MMF) regardless of which treatment arm they were randomized onto during the 24-week double-blind period and throughout the study. |
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03 Mar 2017 |
5) Section on ‘Pirfenidone and Placebo’ was amended in order to correct that no markings were made on the capsules. The list of printing ink ingredients was deleted. 6) Section on ‘Method of Treatment Assignment and Unblinding’ was amended in order to delete the sentence providing Investigators with the option of unblinding subjects for any other reason but safety. Unblinding could only occur for safety reasons. 6) Section on ‘Electrocardiograms’ was amended in order to revise the template text requiring for ECGs to be obtained prior to other trial procedures and not prior to treatment administration. This template text did not apply to this trial as there were no cardiac safety concerns with pirfenidone treatment or any justification for requiring ECGs to be obtained prior to any other study procedures. 7) The ‘Cough Visual Analogue Scale’ was amended in order to replace the previous scale with the actual scale and guidance text that would be provided to the subjects. |
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28 Jun 2018 |
Protocol was amended mainly in order to provide additional guidance on trial specific procedures. Changes to the protocol including the rationale for each change: 1) Synopsis (Target Population) and Protocol Section 4.1 (Patients) of the protocol were amended in order to provide guidance on conditions for allowing the rescreening of subjects. 2) Section 4.5.5 (FVC) was amended to provide guidance on when to use a short-acting bronchodilator prior to on-site spirometry for subjects who are routinely treated with such medication. 3) Sections 4.5.9 (Electrocardiograms) and 5.1.1.8 (Management of Increases in QT Interval) were amended to provide more clear guidance for ECGs and the management of increases in QT interval. 4) Section 4.5.10 (Patient-Reported Outcomes) was amended as the timing for the completion of the Patient-Reported Outcomes was independent of the administration time of the trial treatment. 5) Section 4.6.1 (Patient Discontinuation) was amended to include lung transplantation during the trial as a reason for subject discontinuation. 6) Schedule of Assessments was amended to reflect the changes made to the body of the protocol and also to provide further trial-specific guidance. |
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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 |