Back to resultsAtaluren for Nonsense Mutation Methylmalonic Acidemia
Primary Purpose
Amino Acid Metabolism, Inborn Errors
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Ataluren
Sponsored by
About this trial
This is an interventional treatment trial for Amino Acid Metabolism, Inborn Errors
Eligibility Criteria
Major Inclusion Criteria:
- Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if applicable)
- Age ≥2 years
- Phenotypic evidence of methylmalonic acidemia (MMA) based on the presence of characteristic clinical symptoms or signs and an elevated plasma MMacid level (>0.27 micromole/liter (umol/L)
- Presence of a nonsense mutation in at least 1 allele of the mutase (mut), Cobalamin A (cblA), or Cobalamin B (cblB) gene
- Glomerular filtration rate ≥30 milliliters (mL)/minutes/1.73 meters squared (m^2), serum aminotransferase values ≤2.5*the upper limit of normal, serum bilirubin ≤1.5*the upper limit of normal, plasma adrenocorticotropic (ACTH) within normal limits
- Willingness and ability to comply with scheduled visits, drug administration plan, study restrictions, and study procedures
Major Exclusion Criteria:
- Known hypersensitivity to any of the ingredients or excipients of the study drug
- Any change in chronic treatment for MMA within 2 months prior to start of screening laboratory assessments
- Episode of metabolic decompensation within 1 month prior to start of Screening laboratory assessments
- History of organ transplantation
- Ongoing dialysis for renal dysfunction
Sites / Locations
- ZNA Queen Paola Child Hospital and Provincial Centre for Metabolic Disorders
- Hôpital Edouard Herriot
- Necker-Enfants Malades Hospital
- University Children's Hospital
- Istituti Clinici di Perfezionamento, Milano
- Federico II University
- University Hospital, Department of Pediatrics
- University Children's Hospital
- Great Ormand Street Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Ataluren
Arm Description
Cycle 1: Ataluren treatment will be 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 will then be an interval of 21 up to 42 days without treatment. Cycle 2: Ataluren treatment will be 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 will then be an interval of 14 days without treatment.
Outcomes
Primary Outcome Measures
Plasma Methylmalonic Acid (MMacid) Levels
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.
Secondary Outcome Measures
Urinary MMacid Levels
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.
Plasma Propionylcarnitine Levels
Plasma samples for propionylcarnitine levels were evaluated to detect disease activity. The level of propionylcarnitine was measured using gas chromatography and LC/MS-MS. An increase in propionylcarnitine values indicates greater disease activity.
Urine Methylcitric Acid Levels
Urine methylcitric acid levels were evaluated to detect disease activity. An increase in methylcitric acid values indicates greater disease activity.
Number of Participants With Adverse Events (AEs)
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.
Number of Participants With Potentially Clinically Significant Laboratory (Hematology and Biochemistry) Abnormal Results
Hematological and biochemistry data graded according to Common Terminology Criteria for Adverse Events (CTCAE) severity grade (Grade 1 [mild], Grade 2 [moderate], Grade 3 [severe], Grade 4 [life-threatening], or Grade 5 [fatal]). Life-threatening (Grade 4) or severe (Grade 3) laboratory abnormalities were considered clinically significant. Recurrent or persistent moderate (Grade 2) abnormalities were also considered clinically significant in certain circumstances. Hematology assessments: white blood cell count with differential, hemoglobin, hematocrit, other red cell parameters, and platelet count. Biochemistry assessments: 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.
Number of Participants With a Metabolic Decompensation Episode
A metabolic decompensation episode is characterized by vomiting, hypotonia, and alteration of consciousness associated with metabolic acidosis and hyperammonemia.
Number of Participants Compliant With Study Treatment
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).
Ataluren Plasma Exposure
Validated quantitative methods employing high performance liquid chromatography with tandem mass spectroscopy (HPLC-MS-MS) were used to determine plasma concentrations of unchanged ataluren. The median and full range of the total of all of the ataluren plasma concentrations collected at Baseline and at Day 28 are reported.
Full Information
NCT ID
NCT01141075
First Posted
June 7, 2010
Last Updated
June 22, 2020
Sponsor
PTC Therapeutics
Collaborators
Genzyme, a Sanofi Company
1. Study Identification
Unique Protocol Identification Number
NCT01141075
Brief Title
Ataluren for Nonsense Mutation Methylmalonic Acidemia
Official Title
A Phase 2 Study of Ataluren (PTC124®) as an Oral Treatment for Nonsense Mutation Methylmalonic Acidemia
Study Type
Interventional
2. Study Status
Record Verification Date
June 2020
Overall Recruitment Status
Terminated
Why Stopped
Terminated due to low enrollment and unclear pharmacologic effect in available pharmacodynamic data (not due to any safety concerns).
Study Start Date
July 19, 2010 (Actual)
Primary Completion Date
November 3, 2011 (Actual)
Study Completion Date
November 3, 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
PTC Therapeutics
Collaborators
Genzyme, a Sanofi Company
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Methylmalonic acidemia (MMA) is a rare genetic disorder caused by mutations in the gene for mitochondrial enzyme methylmalonyl-CoA mutase (MCM) or in one of the genes for adenosylcobalamin (AdoCbl). Lack of these proteins causes toxic elevations of methylmalonic acid (MMacid) in blood, urine, and other tissues. A specific type of mutation, called a nonsense (premature stop codon) mutation, is the cause of the disease in approximately 5% to 20% of participants with mutations in the MCM gene, and approximately 20% to >50% of participants with mutations in one of the AdoCbl genes. Ataluren is an orally delivered, investigational drug that acts to overcome the effects of the premature stop codon, potentially enabling the production of functional MCM/AdoCbl. This study is a Phase 2a trial evaluating the safety and activity of ataluren in participants with MMA due to a nonsense mutation. The main purpose of this study is to understand whether ataluren can safely decrease MMacid levels.
Detailed Description
In this study, participants with MMA due to a nonsense mutation will be administered an investigational drug called ataluren. Evaluation procedures to determine if a participant qualifies for the study will be performed within 14 days prior to the start of drug administration. Eligible participants who elect to enroll in the study will then participate in 2 drug administration and follow-up periods. Within the first period, ataluren will be 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 will then be an interval of approximately 21 days without ataluren. Within the second period, ataluren will be 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 will then be an interval of approximately 14 days without ataluren. During the study, ataluren activity, safety, and pharmacokinetics will be evaluated, and MMacid levels in blood and urine will be measured periodically.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amino Acid Metabolism, Inborn Errors
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
11 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Ataluren
Arm Type
Experimental
Arm Description
Cycle 1: Ataluren treatment will be 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 will then be an interval of 21 up to 42 days without treatment.
Cycle 2: Ataluren treatment will be 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 will then be an interval of 14 days without treatment.
Intervention Type
Drug
Intervention Name(s)
Ataluren
Other Intervention Name(s)
PTC124
Intervention Description
Ataluren will be provided as a vanilla-flavored powder to be mixed with water.
Primary Outcome Measure Information:
Title
Plasma Methylmalonic Acid (MMacid) Levels
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.
Time Frame
Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
Secondary Outcome Measure Information:
Title
Urinary MMacid Levels
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.
Time Frame
Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
Title
Plasma Propionylcarnitine Levels
Description
Plasma samples for propionylcarnitine levels were evaluated to detect disease activity. The level of propionylcarnitine was measured using gas chromatography and LC/MS-MS. An increase in propionylcarnitine values indicates greater disease activity.
Time Frame
Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
Title
Urine Methylcitric Acid Levels
Description
Urine methylcitric acid levels were evaluated to detect disease activity. An increase in methylcitric acid values indicates greater disease activity.
Time Frame
Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
Title
Number of Participants With Adverse Events (AEs)
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.
Time Frame
Baseline up to Day 112 (end of study follow-up)
Title
Number of Participants With Potentially Clinically Significant Laboratory (Hematology and Biochemistry) Abnormal Results
Description
Hematological and biochemistry data graded according to Common Terminology Criteria for Adverse Events (CTCAE) severity grade (Grade 1 [mild], Grade 2 [moderate], Grade 3 [severe], Grade 4 [life-threatening], or Grade 5 [fatal]). Life-threatening (Grade 4) or severe (Grade 3) laboratory abnormalities were considered clinically significant. Recurrent or persistent moderate (Grade 2) abnormalities were also considered clinically significant in certain circumstances. Hematology assessments: white blood cell count with differential, hemoglobin, hematocrit, other red cell parameters, and platelet count. Biochemistry assessments: 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.
Time Frame
Baseline up to Day 112 (end of study follow-up)
Title
Number of Participants With a Metabolic Decompensation Episode
Description
A metabolic decompensation episode is characterized by vomiting, hypotonia, and alteration of consciousness associated with metabolic acidosis and hyperammonemia.
Time Frame
Baseline up to Day 112 (end of study follow-up)
Title
Number of Participants Compliant With Study Treatment
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).
Time Frame
Baseline up to Day 29 of Cycles 1 and 2
Title
Ataluren Plasma Exposure
Description
Validated quantitative methods employing high performance liquid chromatography with tandem mass spectroscopy (HPLC-MS-MS) were used to determine plasma concentrations of unchanged ataluren. The median and full range of the total of all of the ataluren plasma concentrations collected at Baseline and at Day 28 are reported.
Time Frame
Baseline on Day 0 of Cycles 1 and 2 [0 (predose), 1, 2, 3, and 4 hours postdose of the morning dose and 0 (predose) of the midday dose]; Day 28 of Cycles 1 and 2 [0 (predose), 1, 2, 3, and 4 hours postdose of the morning, midday, and evening doses]
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Major Inclusion Criteria:
Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if applicable)
Age ≥2 years
Phenotypic evidence of methylmalonic acidemia (MMA) based on the presence of characteristic clinical symptoms or signs and an elevated plasma MMacid level (>0.27 micromole/liter (umol/L)
Presence of a nonsense mutation in at least 1 allele of the mutase (mut), Cobalamin A (cblA), or Cobalamin B (cblB) gene
Glomerular filtration rate ≥30 milliliters (mL)/minutes/1.73 meters squared (m^2), serum aminotransferase values ≤2.5*the upper limit of normal, serum bilirubin ≤1.5*the upper limit of normal, plasma adrenocorticotropic (ACTH) within normal limits
Willingness and ability to comply with scheduled visits, drug administration plan, study restrictions, and study procedures
Major Exclusion Criteria:
Known hypersensitivity to any of the ingredients or excipients of the study drug
Any change in chronic treatment for MMA within 2 months prior to start of screening laboratory assessments
Episode of metabolic decompensation within 1 month prior to start of Screening laboratory assessments
History of organ transplantation
Ongoing dialysis for renal dysfunction
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jay Barth, MD
Organizational Affiliation
PTC Therapeutics
Official's Role
Study Director
Facility Information:
Facility Name
ZNA Queen Paola Child Hospital and Provincial Centre for Metabolic Disorders
City
Antwerp
Country
Belgium
Facility Name
Hôpital Edouard Herriot
City
Lyon
Country
France
Facility Name
Necker-Enfants Malades Hospital
City
Paris
Country
France
Facility Name
University Children's Hospital
City
Duesseldorf
Country
Germany
Facility Name
Istituti Clinici di Perfezionamento, Milano
City
Milan
Country
Italy
Facility Name
Federico II University
City
Naples
Country
Italy
Facility Name
University Hospital, Department of Pediatrics
City
Padova
Country
Italy
Facility Name
University Children's Hospital
City
Zürich
Country
Switzerland
Facility Name
Great Ormand Street Hospital
City
London
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
17450125
Citation
Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007 May 3;447(7140):87-91. doi: 10.1038/nature05756. Epub 2007 Apr 22.
Results Reference
background
PubMed Identifier
17389552
Citation
Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol. 2007 Apr;47(4):430-44. doi: 10.1177/0091270006297140.
Results Reference
background
Links:
URL
http://www.ptcbio.com
Description
PTC Therapeutics' website
Learn more about this trial
Ataluren for Nonsense Mutation Methylmalonic Acidemia
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