Clinical Trial Results:
A Phase 2 Study of PTC124 as an Oral Treatment for Nonsense-Mutation-Mediated Cystic Fibrosis
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Summary
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EudraCT number |
2007-000724-40 |
Trial protocol |
BE |
Global end of trial date |
29 Feb 2008
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Mar 2020
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First version publication date |
21 Mar 2020
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Other versions |
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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 |
PTC124-GD-006-CF
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00458341 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
PTC Therapeutics, Inc.
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Sponsor organisation address |
100 Corporate Court, South Plainfield, United States, NJ 07080
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Public contact |
Medical Information, PTC Therapeutics, Inc., +011 44 1-866-562-4620, medinfo@ptcbio.com
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Scientific contact |
Medical Information, PTC Therapeutics International Limited, +353 19068700, medinfo@ptcbio.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000115-PIP02-09 | ||
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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
21 Dec 2009
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
29 Feb 2008
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Global end of trial reached? |
Yes
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Global end of trial date |
29 Feb 2008
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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 |
The primary objective of this study was to determine whether PTC124 safely provides pharmacologic activity as evaluated by transepithelial potential difference (TEPD) assessment of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride transport.
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Protection of trial subjects |
The trial was conducted in accordance with Declaration of Helsinki (revised version of Edinburgh, Scotland, 2000) and the International Conference on Harmonisation (ICH) GCP guidance documents.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Mar 2007
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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 |
5 Years | ||
Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Belgium: 8
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Country: Number of subjects enrolled |
France: 22
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Worldwide total number of subjects |
30
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EEA total number of subjects |
30
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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) |
11
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Adolescents (12-17 years) |
18
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Adults (18-64 years) |
1
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||
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Pre-assignment
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Screening details |
Participants were randomized so that half received the lower-dose level in Cycle 1 and then the higher-dose level in Cycle 2 (low-to-high dose sequence) and half received the higher-dose level in Cycle 1 and then the lower-dose level in Cycle 2 (high-to-low dose sequence). | ||||||||||||||||||
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Period 1
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Period 1 title |
Cycle 1
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Ataluren 4, 4, and 8 mg/kg, then ataluren 10, 10, and 20 mg/kg | ||||||||||||||||||
Arm description |
During Cycle 1, participants received ataluren at 4 milligrams (mg/kg) in the morning, 4 mg/kg at midday, and 8 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants crossed over to the other ataluren dose regimen (ataluren 10, 10, and 20 mg/kg) for Cycle 2. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Ataluren
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Investigational medicinal product code |
PTC124
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Other name |
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Pharmaceutical forms |
Powder for oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Ataluren was administered as per the dose and schedule specified in the respective arms.
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Arm title
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Ataluren 10, 10, and 20 mg/kg, then ataluren 4, 4, and 8 mg/kg | ||||||||||||||||||
Arm description |
During Cycle 1, participants received ataluren at 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants crossed over to the other ataluren dose regimen (ataluren 4, 4, and 8 mg/kg) for Cycle 2. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Ataluren
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Investigational medicinal product code |
PTC124
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Other name |
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Pharmaceutical forms |
Powder for oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Ataluren was administered as per the dose and schedule specified in the respective arms.
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Period 2
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Period 2 title |
Cycle 2
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Is this the baseline period? |
No | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Ataluren 4, 4, and 8 mg/kg, then ataluren 10, 10, and 20 mg/kg | ||||||||||||||||||
Arm description |
During Cycle 1, participants received ataluren at 4 milligrams (mg/kg) in the morning, 4 mg/kg at midday, and 8 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants crossed over to the other ataluren dose regimen (ataluren 10, 10, and 20 mg/kg) for Cycle 2. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Ataluren
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Investigational medicinal product code |
PTC124
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Other name |
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Pharmaceutical forms |
Powder for oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Ataluren was administered as per the dose and schedule specified in the respective arms.
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Arm title
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Ataluren 10, 10, and 20 mg/kg, then ataluren 4, 4, and 8 mg/kg | ||||||||||||||||||
Arm description |
During Cycle 1, participants received ataluren at 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants crossed over to the other ataluren dose regimen (ataluren 4, 4, and 8 mg/kg) for Cycle 2. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Ataluren
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Investigational medicinal product code |
PTC124
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Other name |
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Pharmaceutical forms |
Powder for oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Ataluren was administered as per the dose and schedule specified in the respective arms.
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Baseline characteristics reporting groups
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Reporting group title |
Cycle 1
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Ataluren 4, 4, and 8 mg/kg, then ataluren 10, 10, and 20 mg/kg
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
During Cycle 1, participants received ataluren at 4 milligrams (mg/kg) in the morning, 4 mg/kg at midday, and 8 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants crossed over to the other ataluren dose regimen (ataluren 10, 10, and 20 mg/kg) for Cycle 2.
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Subject analysis set title |
Ataluren 10, 10, and 20 mg/kg, then ataluren 4, 4, and 8 mg/kg
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
During Cycle 1, participants received ataluren at 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants crossed over to the other ataluren dose regimen (ataluren 4, 4, and 8 mg/kg) for Cycle 2.
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End points reporting groups
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Reporting group title |
Ataluren 4, 4, and 8 mg/kg, then ataluren 10, 10, and 20 mg/kg
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Reporting group description |
During Cycle 1, participants received ataluren at 4 milligrams (mg/kg) in the morning, 4 mg/kg at midday, and 8 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants crossed over to the other ataluren dose regimen (ataluren 10, 10, and 20 mg/kg) for Cycle 2. | ||
Reporting group title |
Ataluren 10, 10, and 20 mg/kg, then ataluren 4, 4, and 8 mg/kg
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Reporting group description |
During Cycle 1, participants received ataluren at 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants crossed over to the other ataluren dose regimen (ataluren 4, 4, and 8 mg/kg) for Cycle 2. | ||
Reporting group title |
Ataluren 4, 4, and 8 mg/kg, then ataluren 10, 10, and 20 mg/kg
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Reporting group description |
During Cycle 1, participants received ataluren at 4 milligrams (mg/kg) in the morning, 4 mg/kg at midday, and 8 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants crossed over to the other ataluren dose regimen (ataluren 10, 10, and 20 mg/kg) for Cycle 2. | ||
Reporting group title |
Ataluren 10, 10, and 20 mg/kg, then ataluren 4, 4, and 8 mg/kg
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Reporting group description |
During Cycle 1, participants received ataluren at 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants crossed over to the other ataluren dose regimen (ataluren 4, 4, and 8 mg/kg) for Cycle 2. | ||
Subject analysis set title |
Ataluren 4, 4, and 8 mg/kg, then ataluren 10, 10, and 20 mg/kg
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
During Cycle 1, participants received ataluren at 4 milligrams (mg/kg) in the morning, 4 mg/kg at midday, and 8 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants crossed over to the other ataluren dose regimen (ataluren 10, 10, and 20 mg/kg) for Cycle 2.
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Subject analysis set title |
Ataluren 10, 10, and 20 mg/kg, then ataluren 4, 4, and 8 mg/kg
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
During Cycle 1, participants received ataluren at 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants crossed over to the other ataluren dose regimen (ataluren 4, 4, and 8 mg/kg) for Cycle 2.
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End point title |
Change From Baseline in Total Chloride Transport at Day 14 of Cycles 1 and 2 [1] | ||||||||||||||||||||||||
End point description |
TEPD assessed in each participant. Warmed solutions of Ringer’s solution, amiloride, chloride-free gluconate, isoproterenol, and adenosine triphosphate (ATP) were perfused through a nasal catheter while a voltage tracing was recorded. Total chloride transport computed for each nostril. The total chloride transport values calculated by subtracting the voltages at the end of a perfusion from the voltage at the end of an earlier perfusion (isoproterenol-amiloride). Population included randomized participants receiving ≥1 dose of study drug with evaluable chloride transport data. Baseline data for Cycles 1 and 2 and change from Baseline data at Day 14 of Cycles 1 and 2 are presented. Via a 2-sided t-test, the Baseline of Cycle 1 vs Day 14 of Cycle 1 at Ataluren 4, 4, and 8 mg/kg p-value=0.133 and at Ataluren 10, 10, and 20 mg/kg p-value=0.190 and the Baseline of Cycle 2 vs Day 14 of Cycle 2 at Ataluren 4, 4, and 8 mg/kg p-value=0.123 and at Ataluren 10, 10, and 20 mg/kg p-value=0.592.
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End point type |
Primary
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End point timeframe |
Baseline of Cycle 1 and Cycle 2, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to database restrictions, statistical analysis data are presented in the Endpoint Description. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Number of Participants With a Chloride Transport Response at Day 14 of Cycles 1 and 2 [2] | |||||||||||||||
End point description |
Nasal TEPD assessed in each participant. Warmed solutions of Ringer’s solution, amiloride, chloride-free gluconate, isoproterenol, and ATP perfused through a nasal catheter while a voltage tracing was recorded. Total chloride transport computed for each nostril. Total chloride transport values calculated by subtracting the voltages at the end of a perfusion from the voltage at the end of an earlier perfusion (isoproterenol-amiloride). Response to study treatment defined as an increase in total chloride transport as indicated by a change of at least -5 mV in nasal TEPD. Population included randomized participants receiving ≥1 dose of study drug with evaluable chloride transport data. Via a chi-squared test, the observed rate with the null hypothesis response rate of 10% for Cycle 1 at Ataluren 4, 4, and 8 mg/kg p-value=0.021 and at Ataluren 10, 10, and 20 mg/kg p-value=0.021 and for Cycle 2 at Ataluren 4, 4, and 8 mg/kg p-value=0.021 and at Ataluren 10, 10, and 20 mg/kg p-value=0.518.
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End point type |
Primary
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End point timeframe |
Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days)
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to database restrictions, statistical analysis data are presented in the Endpoint Description. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Number of Participants With Normalization of Chloride Transport Between Baseline and Day 14 of Cycles 1 and 2 [3] | |||||||||||||||||||||||||||
End point description |
Nasal TEPD was assessed in each participant using standardized techniques. Warmed solutions of Ringer’s solution, amiloride, chloride-free gluconate, isoproterenol, and ATP were perfused for ≥3-minute sequentially through a nasal catheter while a voltage tracing was recorded. Total chloride transport was computed for each nostril. The total chloride transport values were calculated by subtracting the voltages at the end of a perfusion from the voltage at the end of an earlier perfusion (isoproterenol - amiloride). The average of the values for each nostril was computed. If the assessment was available in only 1 nostril, this value was used as if it were the average of both nostrils. Normalization of chloride transport (normal range [NR]) was defined as nasal TEPD that was at least as electrically negative as -5 mV. Population included all randomized participants who received at least 1 dose of study drug and had evaluable normalization of chloride transport data.
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End point type |
Primary
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End point timeframe |
Overall Baseline and Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days)
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to database restrictions, statistical analysis data are presented in the Endpoint Description. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Parameters of Transepithelial Difference at Day 14 of Cycles 1 and 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
To assess TEPD, warmed solutions of Ringer’s solution, amiloride, chloride-free gluconate, isoproterenol and ATP were perfused for ≥3-minutes sequentially through a nasal catheter while a voltage tracing was recorded. Total chloride transport was computed per nostril. Totals were calculated by subtracting voltages at end of perfusion from voltage at end of earlier perfusion for: sodium transport (amiloride–Ringer’s solution), intrinsic chloride transport (CL trans) (chloride-free gluconate–amiloride), stimulated CL trans (isoproterenol–chloride-free gluconate), total potential difference (dif) (isoproterenol–Ringer’s solution), and ATP-mediated CL trans (ATP–isoproterenol). Basal potential dif voltage was obtained at end of Ringer’s solution perfusion. Population included all randomized participants who received at least 1 dose of study drug and had evaluable transepithelial difference data.
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End point type |
Secondary
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End point timeframe |
Baseline of Cycle 1 and Cycle 2, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Change From Baseline in CFTR Protein in Nasal Mucosa as Determined by Immunofluorescence at Overall Day 56 | ||||||||||||||||||
End point description |
The immunofluorescence staining of normal epithelial cells (for example, from nasal mucosal curettage) reveals the presence of cystic fibrosis transmembrane regulator (CFTR) protein at the apical surface. Cells were stained with antibodies that recognized an epitope in the C-terminal portion of the CFTR protein, and the cells were imaged microscopically. The percentage of epithelial cells that showed apical CFTR staining was determined by 2 expert readers who were blinded to the timepoint at which the samples were obtained. The scores of the reviewers were averaged to determine the final percentage of cells with apical CFTR. Population included all randomized participants who received at least 1 dose of study drug and had evaluable apical cell data. Overall Baseline data for the study and change from overall Baseline data at overall Day 56 are presented.
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End point type |
Secondary
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End point timeframe |
Overall Baseline, Overall Day 56
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline in Nonsense Mutation CFTR mRNA in Nasal Mucosa as Determined by Quantitative Real-Time Polymerase Chain Reaction (RT-PCR) Assay at Overall Day 42 | ||||||||||||
End point description |
The collection and processing of the nasal mucosal curettage from each nostril of each participant for measurement of CFTR protein by immunofluorescence and for quantification of CFTR messenger ribonucleic acid (mRNA) was performed using standardized techniques. The slides were processed and immunostained for detection of CFTR protein. Microscopic images were to be captured photographically for analysis. Because the nasal brushing used to collect nasal mucosal epithelial cells did not result in collection of sufficient cells for RT-PCR to be performed, an insufficient number of paired baseline and follow-up samples were available for analysis. As a result, no data were available to evaluate the effects of ataluren on CFTR mRNA. Population included all randomized participants who received at least 1 dose of study drug and had evaluable CFTR mRNA data.
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End point type |
Secondary
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End point timeframe |
Overall Baseline, Overall Day 42
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| Notes [4] - No data are available to evaluate the effects of ataluren on CFTR mRNA. [5] - No data are available to evaluate the effects of ataluren on CFTR mRNA. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Pulmonary Function as Measured by Spirometry at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Pulmonary function tests, including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and forced expiratory flow25-75 (FEF25-75), were measured using standard spirometry techniques. Overall Baseline data for the study and change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented. Population included all randomized participants who received at least 1 dose of study drug and had evaluable pulmonary function data.
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End point type |
Secondary
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End point timeframe |
Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Sputum Markers of Inflammation (Free Elastase) at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | ||||||||||||||||||||||||
End point description |
The inflammatory marker free elastase was measured in induced sputum from each participant. Hypertonic saline (3%) inhalation was used to induce the sputum (with efforts made to avoid oropharyngeal contamination). The sputum sample was divided into 4 aliquots (1 aliquot each for determination of cell count, IL-8 level, and elastase activity and 1 aliquot for potential future viscosity measurements). Population included all randomized participants who received at least 1 dose of study drug and had evaluable sputum markers of inflammation data. Change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented.
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||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in Sputum Markers of Inflammation (Matrix Metalloproteinase 9 [MMP-9] active) at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | ||||||||||||||||||||||||
End point description |
The inflammatory marker MMP-9 active was measured in induced sputum from each participant. Hypertonic saline (3%) inhalation was used to induce the sputum (with efforts made to avoid oropharyngeal contamination). The sputum sample was divided into 4 aliquots (1 aliquot each for determination of cell count, IL-8 level, and elastase activity and 1 aliquot for potential future viscosity measurements). Population included all randomized participants who received at least 1 dose of study drug and had evaluable sputum markers of inflammation data. Change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change From Baseline in Sputum Markers of Inflammation (Tumor Necrosis Factor-Alpha [TNF-α], Interleukin-8 [IL-8], Transforming Growth Factor Beta 1 [TGF-β1]) at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The inflammatory markers TNF-α, IL-8, and TGF-β1 were measured in induced sputum from each participant. Hypertonic saline (3%) inhalation was used to induce the sputum (with efforts made to avoid oropharyngeal contamination). The sputum sample was divided into 4 aliquots (1 aliquot each for determination of cell count, IL-8 level, and elastase activity and 1 aliquot for potential future viscosity measurements). Change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented.
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in Sputum Markers of Inflammation (Uridine-5'-triphosphate [UTP]) at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | ||||||||||||||||||||||||
End point description |
The inflammatory marker UTP was measured in induced sputum from each participant. Hypertonic saline (3%) inhalation was used to induce the sputum (with efforts made to avoid oropharyngeal contamination). The sputum sample was divided into 4 aliquots (1 aliquot each for determination of cell count, IL-8 level, and elastase activity and 1 aliquot for potential future viscosity measurements). Population included all randomized participants who received at least 1 dose of study drug and had evaluable sputum markers of inflammation data. Change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in Clinically Significant Neutrophil Levels in Blood at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | ||||||||||||||||||||||||
End point description |
To assess inflammatory markers in the blood, neutrophil levels in the blood were measured. Higher levels of neutrophils are indicative of more inflammation. Population included all randomized participants who received at least 1 dose of study drug and had evaluable data of neutrophil levels in blood. Change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in Clinically Significant Serum Levels of C-Reactive Protein at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | ||||||||||||||||||||||||
End point description |
To assess inflammatory markers in the blood, serum levels of C-reactive protein were measured. Higher levels of C-reactive protein are indicative of more inflammation. Population included all randomized participants who received at least 1 dose of study drug and had evaluable serum levels of C-reactive data. Change from overall Baseline data at Day 14 or 15 of Cycles 1 and 2 and at overall Day 56 are presented.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in Body Weight at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56 | ||||||||||||||||||||||||
End point description |
Body weight were measured for each participant in kilograms (kg). Population included all randomized participants who received at least 1 dose of study drug and had evaluable body weight data. Overall Baseline data for the study and change from overall Baseline data at Day 14 of Cycles 1 and 2 and at overall Day 56 are presented.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Overall Baseline, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in the CF-Related Symptom Scores, as Assessed Using a Participant-Reported Questionnaire at Day 14 of Cycles 1 and 2 and Overall Day 56 | ||||||||||||||||||||||||
End point description |
The CF symptom self-reported (or their guardians) questionnaire includes questions related to daytime cough, nighttime cough, sputum volume, sputum clearance, physical fatigue, and shortness of breath. For each symptom, the participants were asked to choose the response that best matched their experience during the 3 days before the questionnaire was completed. The scale of the 4 possible responses for each question was 0 (best response) to 4 (worse response). The sum of the scores for all of the questions was calculated. The scale for the sum of the scores was 0 (best response) to 24 (worse response). Population included all randomized participants who received at least 1 dose of study drug and had evaluable CF-related symptom scores. Overall Baseline data for the study and change from overall Baseline data at Day 14 of Cycles 1 and 2 and at overall Day 56 are presented.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Overall Baseline, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||
End point title |
PK: Area Under the Concentration Time Curve from Time 0 (Dosing) to 24 hours (AUC0-24) of Ataluren | ||||||||||||
End point description |
All PK parameters were calculated using the actual postdose blood sampling times in relationship to the time of the first dose (morning dose) on Day 14 of each treatment cycle. AUC0-24 values were calculated by WinNonlin by extrapolation to 24 hours if the last sampling timepoint was before 24 hours and by interpolation if the last sampling timepoint was after 24 hours. Extrapolation of AUC to 24 hours was performed only if the last sampling timepoint did not deviate from the nominal collection time by more than approximately 10%. Population included all randomized participants who received at least 1 dose of study drug and had evaluable AUC0-24 data. The data for each dose level represents pooled data for participants in the low-to-high dose sequence and the high-to-low dose sequence.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
0 (predose), 2 and 3 hours postdose of the morning dose; 0 (predose), 2 and 3 hours postdose of the midday dose; and 0 hours (predose), 2, 3, and 12 hours postdose of the evening dose on Day 14 of Cycle 1 and Cycle 2
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||
End point title |
Compliance with Study Treatment | ||||||||||||||||||||||||
End point description |
For each participant, compliance was described in terms of the percentage of drug actually taken relative to the amount that was prescribed (taking into account physician-prescribed reductions and interruptions). The number of doses described as “taken less than planned” includes cases in which the participants took less than the prescribed dose and/or cases in which the Investigator reduced the dose. Population included all randomized participants who received at least 1 dose of study drug and had evaluable compliance data. The data for each dose level represents pooled data for participants in the low-to-high dose sequence and the high-to-low dose sequence.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline up to Day 14 in Cycle 1 and Cycle 2
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
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Timeframe for reporting adverse events |
Overall Baseline up to Overall Day 56
|
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Adverse event reporting additional description |
The data for each dose level represents pooled data for participants in the low-to-high dose sequence and the high-to-low dose sequence.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
11.1
|
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Reporting groups
|
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Reporting group title |
Ataluren Cohort 1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants in Cohort 1 received ataluren at 4 mg/kg in the morning, 4 mg/kg at midday, and 8 mg/kg in the evening for 14 days during Cycle 1 and received ataluren at 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days during Cycle 2. There was a 14-day follow up period without treatment in between Cycle 1 and Cycle 2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Ataluren Cohort 2
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants in Cohort 2 received ataluren at 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days during Cycle 1 and received ataluren at 4 mg/kg in the morning, 4 mg/kg at midday, and 8 mg/kg in the evening for 14 days during Cycle 2. There was a 14-day follow up period without treatment in between Cycle 1 and Cycle 2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
