Amino Acid Metabolism, Inborn ErrorsPhase 2NCT01141075
Ataluren for Nonsense Mutation Methylmalonic Acidemia
A Phase 2 study testing Ataluren in people with Amino Acid Metabolism, Inborn Errors, run by PTC Therapeutics at 9 sites in 6 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 years and older
- Conditions the study is for
- Amino Acid Metabolism, Inborn Errors
- What is being tested?
- Ataluren
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11 participants
- Where
- 9 sitesin 6 countries
- Study dates
- 19 Jul 2010to 3 Nov 2011
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
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
Trial locations and contacts
9 sites in 6 countries.
9 sites in 6 countries
Italy3 sites
Istituti Clinici di Perfezionamento, Milano
Milan
Federico II University
Naples
University Hospital, Department of Pediatrics
Padova
France2 sites
Hôpital Edouard Herriot
Lyon
Necker-Enfants Malades Hospital
Paris
Belgium1 site
ZNA Queen Paola Child Hospital and Provincial Centre for Metabolic Disorders
Antwerp
About this study
Official title: A Phase 2 Study of Ataluren (PTC124®) as an Oral Treatment for Nonsense Mutation Methylmalonic Acidemia
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.
Read the 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.
- Conditions
- Amino Acid Metabolism, Inborn Errors
- Being tested
- Ataluren
- Medical subject headings
- Amino Acid Metabolism, Inborn Errors
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AtalurenDrug
Also called PTC124
Ataluren will be provided as a vanilla-flavored powder to be mixed with water.
| Study group | Role | What they receive |
|---|---|---|
| Ataluren | Experimental | 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. Receives: Drug: Ataluren |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
Secondary outcomes (8)
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.
Measured: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
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.
Measured: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
Urine Methylcitric Acid Levels
Urine methylcitric acid levels were evaluated to detect disease activity. An increase in methylcitric acid values indicates greater disease activity.
Measured: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
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.
Measured: Baseline up to Day 112 (end of study follow-up)
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.
Measured: Baseline up to Day 112 (end of study follow-up)
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.
Measured: Baseline up to Day 112 (end of study follow-up)
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).
Measured: Baseline up to Day 29 of Cycles 1 and 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.
Measured: 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]
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jun 2010 (estimated)
- Study start19 Jul 2010
- Primary completion3 Nov 2011
- Study completion3 Nov 2011
Why it stopped: Terminated due to low enrollment and unclear pharmacologic effect in available pharmacodynamic data (not due to any safety concerns).
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Amino Acid Metabolism, Inborn ErrorsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- PTC Therapeutics
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Genzyme, a Sanofi Company
- Responsible party
- Sponsor
- Investigators
- Jay Barth, MD, Study director, PTC Therapeutics
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01141075
- Sponsor's protocol ID
- PTC124-GD-012-MMA
- Status last verified
- Jun 2020
- First submitted
- 7 Jun 2010
- Last updated
- 7 Jul 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
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.
PubMed 17450125Hirawat 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.
PubMed 17389552
Study at a glance
From the registry record, last updated by the sponsor on 7 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2 Study of Ataluren (PTC124®) as an Oral Treatment for Nonsense Mutation Methylmalonic Acidemia
- ClinicalTrials.gov ID
- NCT01141075
- Acronym / sponsor ID
- PTC124-GD-012-MMA
- Conditions
- Amino Acid Metabolism, Inborn Errors
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Terminated due to low enrollment and unclear pharmacologic effect in available pharmacodynamic data (not due to any safety concerns).
- Enrolment
- 11 participants (actual)
- Lead sponsor
- PTC TherapeuticsIndustry (pharma, biotech, devices)
- Collaborators
- Genzyme, a Sanofi Company
- Study start
- 19 Jul 2010 (actual)
- Primary completion
- 3 Nov 2011 (actual)
- Study completion
- 3 Nov 2011 (actual)
- First posted
- 10 Jun 2010 (estimated)
- Results
- Posted 7 Jul 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Ataluren | Experimental | Drug: AtalurenCycle 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. |
Who may qualify
- Ages
- 2 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AtalurenAlso: PTC124Ataluren will be provided as a vanilla-flavored powder to be mixed with water. | Drug | Ataluren |
Primary outcome
Plasma Methylmalonic Acid (MMacid) Levels
Time frame: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
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.
8 secondary outcomes
Urinary MMacid Levels
Time frame: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
Plasma Propionylcarnitine Levels
Time frame: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
Urine Methylcitric Acid Levels
Time frame: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
Number of Participants With Adverse Events (AEs)
Time frame: Baseline up to Day 112 (end of study follow-up)
Number of Participants With Potentially Clinically Significant Laboratory (Hematology and Biochemistry) Abnormal Results
Time frame: Baseline up to Day 112 (end of study follow-up)
Number of Participants With a Metabolic Decompensation Episode
Time frame: Baseline up to Day 112 (end of study follow-up)
Number of Participants Compliant With Study Treatment
Time frame: Baseline up to Day 29 of Cycles 1 and 2
Ataluren Plasma Exposure
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]
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Jul 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 17450125Welch 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.
- Background: PubMed 17389552Hirawat 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.
- PTC Therapeutics' websiteLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jay Barth, MD study director
PTC Therapeutics
9 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ataluren in people with Amino Acid Metabolism, Inborn Errors, run by PTC Therapeutics at 9 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 7 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in Italy, France, Belgium, Germany, Switzerland and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 7 Jul 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Plasma Methylmalonic Acid (MMacid) Levels (time frame: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01141075, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Jul 2020; AzTrials last refreshed its copy on 30 Oct 2026.