Clinical Trial Results:
A Phase 2a Study of Ataluren (PTC124) as an Oral Treatment for Nonsense-Mutation-Mediated Hemophilia A and B
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Summary
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EudraCT number |
2010-020224-22 |
Trial protocol |
FR |
Global end of trial date |
30 Aug 2011
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Jun 2020
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First version publication date |
13 Jun 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-011-HEM
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00947193 | ||
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) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
29 Aug 2012
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Aug 2011
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Aug 2011
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective of the study was to determine whether ataluren provides pharmacological
effect in hemophilia type A (HA)/type B (HB) as measured by plasma factor 8 (FVIII)/factor 9 (FIX) activity.
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Protection of trial subjects |
The trial was conducted in accordance with Declaration of Helsinki (revised version of Edinburgh, Scotland, 2000), FDA GCP regulations (CFR 21 parts 50, 56, and 312), and the International Conference on Harmonisation (ICH) GCP guidance documents.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Oct 2009
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Long term follow-up planned |
No
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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 |
Italy: 2
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Country: Number of subjects enrolled |
France: 3
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Country: Number of subjects enrolled |
United States: 7
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Country: Number of subjects enrolled |
Canada: 1
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Worldwide total number of subjects |
13
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EEA total number of subjects |
5
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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) |
12
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
In this study, participants with HA or HB due to a nonsense mutation were recruited for the study. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Participants requiring treatment with FVIII/FIX concentrate during 14-day ataluren treatment could continue ataluren treatment for at least 14 days following discontinuing FVIII concentrate treatment for HA and for at least 18 days following discontinuing FIX concentrate treatment for HB. | ||||||||||||||||||||||||
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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 |
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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5 mg/kg, 5 mg/kg, and 10 mg/kg Ataluren | ||||||||||||||||||||||||
Arm description |
Ataluren was provided as a vanilla-flavored powder to be mixed with water or milk. Ataluren was taken 3 times per day, with dosing based on the participant's body weight. The dose level for ataluren was 5 milligrams/kilograms (mg/kg) in the morning, 5 mg/kg at midday, and 10 mg/kg in the evening for 14 days, followed by an interval of 14 days without treatment. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Ataluren
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Investigational medicinal product code |
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Other name |
PTC124®
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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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10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | ||||||||||||||||||||||||
Arm description |
Ataluren was provided as a vanilla-flavored powder to be mixed with water or milk. Ataluren was taken 3 times per day, with dosing based on the participant's body weight. The dose level for ataluren was 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by an interval of 14 days without treatment. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Ataluren
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Investigational medicinal product code |
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Other name |
PTC124®
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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 |
Overall Study
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Ataluren Overall Study
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Ataluren was provided as a vanilla-flavored powder to be mixed with water or milk. Ataluren was taken 3 times per day, with dosing based on the participant's body weight. The dose level for ataluren was 5 mg/kg in the morning, 5 mg/kg at midday, and 10 mg/kg in the evening or 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by an interval of 14 days without treatment.
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Subject analysis set title |
10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Ataluren was provided as a vanilla-flavored powder to be mixed with water or milk. Ataluren was taken 3 times per day, with dosing based on the participant's body weight. The dose level for ataluren was 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by an interval of 14 days without treatment.
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End points reporting groups
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Reporting group title |
5 mg/kg, 5 mg/kg, and 10 mg/kg Ataluren
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Reporting group description |
Ataluren was provided as a vanilla-flavored powder to be mixed with water or milk. Ataluren was taken 3 times per day, with dosing based on the participant's body weight. The dose level for ataluren was 5 milligrams/kilograms (mg/kg) in the morning, 5 mg/kg at midday, and 10 mg/kg in the evening for 14 days, followed by an interval of 14 days without treatment. | ||
Reporting group title |
10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren
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Reporting group description |
Ataluren was provided as a vanilla-flavored powder to be mixed with water or milk. Ataluren was taken 3 times per day, with dosing based on the participant's body weight. The dose level for ataluren was 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by an interval of 14 days without treatment. | ||
Subject analysis set title |
Ataluren Overall Study
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Ataluren was provided as a vanilla-flavored powder to be mixed with water or milk. Ataluren was taken 3 times per day, with dosing based on the participant's body weight. The dose level for ataluren was 5 mg/kg in the morning, 5 mg/kg at midday, and 10 mg/kg in the evening or 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by an interval of 14 days without treatment.
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Subject analysis set title |
10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Ataluren was provided as a vanilla-flavored powder to be mixed with water or milk. Ataluren was taken 3 times per day, with dosing based on the participant's body weight. The dose level for ataluren was 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by an interval of 14 days without treatment.
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End point title |
Number of Participants With a Plasma FVIII/FIX Activity Response at Day 14 [1] | ||||||
End point description |
A plasma FVIII/FIX activity response was defined as an end-of-treatment (Day 14) activity of ≥1%. Population included all enrolled participants who received at least 1 dose of study drug and completed the study.
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End point type |
Primary
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End point timeframe |
Baseline up to Day 14
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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: This type of statistical analysis is not applicable for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants With a Change From Baseline in Plasma Anti-FVIII/FIX Inhibitor Titers at Day 14 | ||||||
End point description |
To assess the change from Baseline in plasma anti-FVIII/FIX inhibitor titers, it was determined if any potential antibodies were neutralizing using the Bethesda assay. The Bethesda assay demonstrates antibodies that are neutralizing by quantifying residual FVIII/FIX activity in normal plasma after serial dilutions with participant plasma. For this assay, the neutralizing antibody threshold value was 0.6 Bethesda units (BU). Population included all enrolled participants who received at least 1 dose of study drug and completed the study.
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End point type |
Secondary
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End point timeframe |
Baseline and Day 14
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) by Severity and Relationship to Study Drug | ||||||||||||||
End point description |
The relationship of TEAEs and SAEs to the study drugs was assessed as: probable related, possible related, unlikely related, and unrelated. The severity of TEAEs were graded using the Common Terminology Criteria for Adverse Events, Version 3.0, as: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal). A summary of other non-serious adverse events (AEs) and all serious AEs, regardless of causality is located in Reported AE section. Population included all enrolled participants who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to Day 28
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Number of Participants With a Clinically Meaningful Abnormal Adrenal assays, Biochemistry, and Urinalysis Parameters | ||||||||||||
End point description |
The Investigator used his/her judgment in determining whether an abnormality was clinically significant, diagnostic evaluation was warranted, and potential interruption of ataluren was appropriate. Life-threatening (Grade 4) or severe (Grade 3) laboratory abnormalities were considered dose-limiting, although recurrent or persistent moderate (Grade 2) events were also considered dose-limiting in certain circumstances. Values considered abnormal included -Adrenal: Plasma adrenocorticotropic hormone >ULN (and cortisol within normal limits); and -Renal: serum creatinine Grade 1 (>ULN–1.5*ULN) and Serum blood urea nitrogen ≥1.5–3.0*ULN. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Population included all enrolled participants who received at least 1 dose of study drug and had evaluable parameter data.
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End point type |
Secondary
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End point timeframe |
Baseline up to Day 28
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Participants With a Clinically Meaningful Hematology Parameters | ||||||
End point description |
The Investigator used his/her judgment in determining whether an abnormality was clinically significant, diagnostic evaluation was warranted, and potential interruption of ataluren was appropriate. Life-threatening (Grade 4) or severe (Grade 3) laboratory abnormalities were considered dose-limiting, although recurrent or persistent moderate (Grade 2) events were also considered dose-limiting in certain circumstances. Values considered abnormal included Serum total bilirubin Grade 2 (>1.5-3.0*upper limit of normal [ULN]) and Serum alanine aminotransferase, Serum aspartate aminotransferase, and Serum gamma glutamyl transferase Grade 2 (>2.5-3.0*ULN). A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Population included all enrolled participants who received at least 1 dose of study drug and had evaluable hematology data.
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End point type |
Secondary
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End point timeframe |
Baseline up to Day 28
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| No statistical analyses for this end point | |||||||
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End point title |
Compliance With Ataluren Administration | ||||||
End point description |
Ataluren compliance as assessed by quantification of used and unused drug. Data were not collected or analyzed for this measure because participants were terminated early from the study. Population included all enrolled participants who received at least 1 dose of study drug, completed the study, and had evaluable compliance with ataluren administration data.
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End point type |
Secondary
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End point timeframe |
Baseline up to Day 28
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| Notes [2] - Data were not collected/analyzed because participants were terminated early from study. |
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| No statistical analyses for this end point | |||||||
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End point title |
Ataluren Plasma Exposure | ||||||||||||
End point description |
The ataluren plasma concentrations before and 2 hours after the first morning dose at end of treatment was measured. Population included all enrolled participants who received at least 1 dose of study drug, completed the study, and had evaluable plasma data.
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End point type |
Secondary
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End point timeframe |
Day 10 (pre-dose) and Day 14 (post-dose)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Occurrence of Bleeding Episodes | ||||||
End point description |
Frequency, timing, anatomic location, and severity of any bleeding episodes were recorded. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module. Population included all enrolled participants who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to Day 28
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| No statistical analyses for this end point | |||||||
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Adverse events information
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Timeframe for reporting adverse events |
Baseline up to Day 28
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Adverse event reporting additional description |
Adverse event data were collected from all enrolled participants who received at least 1 dose of study drug.
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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 |
11.0
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Reporting groups
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Reporting group title |
Ataluren Overall Study
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Reporting group description |
Ataluren was provided as a vanilla-flavored powder to be mixed with water or milk. Ataluren was taken 3 times per day, with dosing based on the participant's body weight. The dose level for ataluren was 5 mg/kg in the morning, 5 mg/kg at midday, and 10 mg/kg in the evening or 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by an interval of 14 days without treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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13 Jul 2009 |
-Clarification that the study would only be enrolling adults who were able to provide
consent.
-Clarification that participants would be provided a stipend for participation in the study.
-Clarification that only the participants would be given instruction on study drug preparation.
-Clarification that the screening period would be extended to -14 to -1 days.
-Addition of vital signs measurements.
-Addition of height and weight measurements.
-Clarification that participants’ FVIII/FIX activity level should be checked approximately 5 to
7 days after the last FVIII/FIX concentrate infusion during the pretreatment and treatment
periods.
-Clarification that bleeding episodes would be recorded in a patient diary.
-Clarification that FVIII/FIX activity assessment would be performed using a clotting
assay. In addition, a chromogenic assay and a thrombin generation assay would be
performed. -Clarification that ataluren plasma samples would be collected at Visit 9 (Day 14 of Cycle 2). |
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09 Apr 2010 |
-The amendment reduced the number of clinic visits by reducing the number of cycles of ataluren administration from 2 to 1. In addition, the amendment specified that the dose
level of ataluren for the single cycle would be 10 mg/kg (in the morning), 10 mg/kg (at midday), and 20 mg/kg (in the evening).
The rationale for eliminating 1 cycle of ataluren administration is to simplify the study and thus enhance the ability to accumulate sufficient data to address the primary
objective of determining the pharmacologic effect of ataluren on plasma FVIII/FIX activity.
The rationale for changing to a single dose level from those previously proposed is to accommodate the amended 1-cycle study design and to reconsider dosing in the context
of data from other nonsense mutation genetic disorders. Previously, this hemophilia study was to assess 2 dose levels: a low dose level of 5, 5, 10 mg/kg in the first cycle and a high
dose level of 20, 20, 40 mg/kg in the second cycle. For the revised protocol, a single intermediate dose level of 10, 10, 20 mg/kg will be assessed. The change of dose level is
supported by knowledge that this dose level has shown pharmacodynamic activity and safety in participants with nonsense mutation cystic fibrosis (nmCF) receiving ataluren over periods of 2 weeks to 12 weeks and
that the 10-, 10-, 20-mg/kg dose level is being studied in a Phase 3 study evaluating 48 weeks of ataluren treatment in nmCF. |
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09 Apr 2010 |
Amendment Dated April 09, 2010 Continued: The change in dose level is also supported by results from a recently completed Phase 2b study involving 48 weeks of study drug therapy in 174 participants (age range 5 to 20 years) with nonsense mutation Duchenne muscular
dystrophy (nmDMD). Participants in this study were randomized to ataluren at the 20-, 20-, 40-mg/kg dose level (n=60), to ataluren at the 10-, 10-, 20-mg/kg dose level (n=57), or to placebo (n=57). The study indicated that ataluren was well tolerated at both the 20-, 20-, 40-mg/kg and 10-, 10-, 20-mg/kg dose levels. Preliminary analyses indicate that participants receiving the 10-, 10-, 20-mg/kg dose level of ataluren experienced better outcomes on measures of efficacy than participants receiving the 20-, 20-, 40-mg/kg/day dose level of ataluren or than participants receiving placebo. -The amendment allowed participants who needed treatment of a bleeding episode with FVIII/FIX concentrates to continue with ataluren administration. This was allowed through 2 bleeding episodes. This increases the likelihood that participants who have enrolled in the study will be able to complete the study and provide further activity and safety data with ataluren. |
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28 Jul 2010 |
-Inclusion criteria were updated to indicate that gene sequencing blood sample for reconfirmation was not needed if the participant's initial gene sequencing was performed at the reference lab being used for this study. -This version provided updated information on concomitant study medication use involving nephrotoxic intravenous antibiotics and importance for the participant to remain hydrated during the course of the study. This update was based on recent information from the Phase 3 cystic fibrosis clinical trial. |
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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 | |||
