Clinical Trial Results:
A Phase 2 Study of Ataluren (PTC124®) as an Oral Treatment for Nonsense Mutation Methylmalonic Acidemia
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Summary
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EudraCT number |
2009-016654-41 |
Trial protocol |
FR GB IT BE |
Global end of trial date |
03 Nov 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-012-MMA
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01141075 | ||
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, Inc., +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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Aug 2012
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
03 Nov 2011
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Global end of trial reached? |
Yes
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Global end of trial date |
03 Nov 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 treatment with ataluren reduces plasma methylmalonic acid (MMacid) levels.
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles of Good Clinical Practice,
according to the International Conference on Harmonisation (ICH) Harmonized Tripartite Guideline.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
19 Jul 2010
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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 |
Belgium: 2
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Country: Number of subjects enrolled |
France: 4
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Country: Number of subjects enrolled |
Germany: 1
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Country: Number of subjects enrolled |
Italy: 1
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Country: Number of subjects enrolled |
Switzerland: 2
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Country: Number of subjects enrolled |
United Kingdom: 1
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Worldwide total number of subjects |
11
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EEA total number of subjects |
9
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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) |
5
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Adolescents (12-17 years) |
6
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Adults (18-64 years) |
0
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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 |
Participants must have been ≥2 years of age with MMacid of the mitochondrial enzyme methylmalonyl-CoA mutase gene, cobalamin A (cblA), or cobalamin B (cblB) type due to a nonsense mutation in the relevant gene as documented by genotyping. | ||||||||
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Pre-assignment
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Screening details |
This study was suspended on 27 September 2011 and was terminated on 22 April 2014 due to low enrollment and unclear pharmacologic effect in available pharmacodynamic data (not due to any safety concerns). | ||||||||
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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 |
Not applicable
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Blinding used |
Not blinded | ||||||||
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Arms
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Arm title
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Ataluren | ||||||||
Arm description |
Cycle 1: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 5 milligrams/kilograms (mg/kg) (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there was then an interval of 21 up to 42 days without treatment. Cycle 2: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there was then an interval of 14 days without treatment. | ||||||||
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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Arm title
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Ataluren | ||||||||
Arm description |
Cycle 1: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 5 mg/kg (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there was then an interval of 21 up to 42 days without treatment. Cycle 2: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there was then an interval of 14 days without treatment. | ||||||||
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 |
Ataluren
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Reporting group description |
Cycle 1: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 5 milligrams/kilograms (mg/kg) (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there was then an interval of 21 up to 42 days without treatment. Cycle 2: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there was then an interval of 14 days without treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Ataluren
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Reporting group description |
Cycle 1: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 5 milligrams/kilograms (mg/kg) (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there was then an interval of 21 up to 42 days without treatment. Cycle 2: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there was then an interval of 14 days without treatment. | ||
Reporting group title |
Ataluren
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Reporting group description |
Cycle 1: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 5 mg/kg (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there was then an interval of 21 up to 42 days without treatment. Cycle 2: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there was then an interval of 14 days without treatment. | ||
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End point title |
Plasma Methylmalonic Acid (MMacid) Levels [1] | ||||||||||||||||||||
End point description |
Normal plasma MMacid level is <0.27 micromole/liters (umol/L). Plasma samples for MMacid levels were collected after a 2- to 4-hour fast. Plasma MMacid levels were measured by a standard gas chromatography/mass spectroscopy (GC/MS) stable-isotope dilution method. Individual participant values in plasma MMacid levels at Baseline and end-to-treatment (Day 28 and Day 29 [last day of dosing]) in each cycle were recorded. Population included all randomized participants who received at least 1 dose of study drug.
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End point type |
Primary
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End point timeframe |
Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
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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 |
Urinary MMacid Levels | ||||||||||||||||||||
End point description |
The normal urinary MMacid level is <4 millimole/mole (mmol/mol) creatinine. Urinary samples for MMacid levels were collected after a 2- to 4-hour fast. Urinary MMacid levels were measured by a standard GC/MS stable-isotope dilution method. Population included all randomized 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 and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Plasma Propionylcarnitine Levels | ||||||||||||||||||||
End point description |
Plasma samples for propionylcarnitine levels were evaluated to detect disease activity. The level of propionylcarnitine was measured using gas chromatography and liquid chromatography with tandem mass spectroscopy (LC-MS-MS). An increase in propionylcarnitine values indicates greater disease activity. Population included all randomized 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 and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Urine Methylcitric Acid Levels | ||||||||||||||||||||
End point description |
Urine methylcitric acid levels were evaluated to detect disease activity. An increase in methylcitric acid values indicates greater disease activity. Population included all randomized 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 and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Number of Participants with Adverse Events (AEs) | ||||||||||||||||
End point description |
An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the Investigator on a scale of mild, moderate and severe, with severe as an AE that prevents usual activities. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Population included all randomized 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 112 (end of study follow-up)
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Number of Participants with Potentially Clinically Significant Laboratory (Hematology and Biochemistry) Abnormal Results | ||||||||||
End point description |
Results graded according to Common Terminology Criteria for Adverse Events (CTCAE) severity grade (Grade [G]1 [mild], G2 [moderate], G3 [severe], G4 [life-threatening], or G5 [fatal]). Life-threatening (G4) or severe (G3) laboratory abnormalities were considered clinically significant. Recurrent/persistent moderate (G2) abnormalities were also considered clinically significant in certain circumstances. Hematology: white blood cell count with differential, hemoglobin, hematocrit, other red cell parameters, and platelet count. Biochemistry: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, bilirubin (direct and indirect), aspartate aminotransferase, alanine aminotransferase, glutamyl transferase, creatine kinase, lactate dehydrogenase, alkaline phosphatase, total cholesterol, and triglycerides. Population: randomized 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 112 (end of study follow-up)
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Participants with a Metabolic Decompensation Episode | ||||||
End point description |
A metabolic decompensation episode is characterized by vomiting, hypotonia, and alteration of consciousness associated with metabolic acidosis and hyperammonemia. Population included all randomized 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 112 (end of study follow-up)
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants Compliant with Study Treatment | ||||||||||
End point description |
For each participant, compliance was described in terms of the proportion of drug actually taken relative to the amount that should have been taken during the time the participant was on study (both Cycle 1 and Cycle 2). Population included all randomized 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 29 of Cycles 1 and 2
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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 on Days 1 and 28 of Cycles 1 and 2 were measured. Validated quantitative methods employing HPLC-MS-MS were used to determine plasma concentrations of unchanged ataluren. Population included all randomized 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 |
0 (predose), 1, 2, 3, and 4 hours postdose of the morning dose and 0 (predose) of the midday dose on Day 0 of Cycles 1 and 2; 0 (predose), 1, 2, 3, and 4 hours postdose of the morning dose, the midday dose, and the evening dose on Day 28 of Cycles 1 and 2
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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 112 (end of study follow-up)
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Adverse event reporting additional description |
All randomized 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 |
11.1
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Reporting groups
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Reporting group title |
Ataluren
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Reporting group description |
Cycle 1: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 5 mg/kg (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there was then an interval of 21 up to 42 days without treatment. Cycle 2: Ataluren treatment was taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there was then 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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03 Aug 2010 |
This amendment was to incorporate the following changes to the protocol: • Updated information on concomitant medication use involving nephrotoxic IV antibiotics and the importance of staying hydrated during the course of the study was provided, based on newly available data from Phase 3 study ataluren in cystic fibrosis. • Baseline ages for the Bayley Scale of Infant Development, the Wechsler Preschool and Primary Scale of Intelligence, and Wechsler Intelligence Scale for Children were changed for the purpose of internal consistency within the protocol. • Cognitive testing frequency was modified to only be performed at Screening. • Inclusion criteria for the gene sequencing sample drawn during screening were modified to not require the sample to be collected if there was written documentation that gene sequencing had been performed previously in the reference laboratory being used in this study. • The study drug administration was modified to include mixing with milk. • A stable regimen of antibiotics for participants normally receiving antibiotic therapy was defined. • Instruction to encourage study participants to maintain adequate hydration during the study was added. • Vital sign assessment visits were modified to reflect the Schedule of Events. • Biochemistry and urinalysis laboratory assessments were added to Day 28 of both cycles. • Urinalysis sample shipment was modified to require urine samples to be shipped at ambient conditions. • Glomerular filtration rate measurement was modified to include age-appropriate formulas based on serum creatinine and serum cystatin C. • The maximum and total blood volumes to be drawn for this study and the National Institutes of Health blood drawing guidelines were updated. • Guidelines for reporting the pregnancy of any participant at any time after the first administration of study drug and within 60 days of receipt of last administration of study drug were provided. |
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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. | |||
| Study terminated due to low enrollment and unclear pharmacologic effect in available pharmacodynamic data (not due to any safety concerns). | |||
