Trial Outcomes & Findings for Ataluren for Nonsense Mutation Methylmalonic Acidemia (NCT NCT01141075)

NCT ID: NCT01141075

Last Updated: 2020-07-07

Results Overview

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.

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 11 participants
• Primary outcome timeframe: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
• Results posted on: 2020-07-07

Participant Flow

Participant milestones

Measure	Ataluren 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.
Cycle 1 STARTED	11
Cycle 1 Received at Least 1 Dose of Study Drug	11
Cycle 1 COMPLETED	11
Cycle 1 NOT COMPLETED	0
Cycle 2 STARTED	11
Cycle 2 Received at Least 1 Dose of Study Drug	11
Cycle 2 COMPLETED	11
Cycle 2 NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Ataluren for Nonsense Mutation Methylmalonic Acidemia

Baseline characteristics by cohort

Measure	Ataluren n=11 Participants 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.
Age, Continuous	12 years STANDARD_DEVIATION 7.8 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2

Population: All randomized participants who received at least 1 dose of study drug.

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.

Outcome measures

Measure	Ataluren n=11 Participants 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.
Plasma Methylmalonic Acid (MMacid) Levels Baseline of Cycle 1	153.7 umol/L Interval 15.5 to 971.5
Plasma Methylmalonic Acid (MMacid) Levels Day 28 of Cycle 1	160.3 umol/L Interval 20.5 to 1163.3
Plasma Methylmalonic Acid (MMacid) Levels Day 29 of Cycle 1	175.9 umol/L Interval 20.4 to 1432.9
Plasma Methylmalonic Acid (MMacid) Levels Baseline of Cycle 2	196.5 umol/L Interval 29.3 to 933.1
Plasma Methylmalonic Acid (MMacid) Levels Day 28 of Cycle 2	280.9 umol/L Interval 22.8 to 1083.3
Plasma Methylmalonic Acid (MMacid) Levels Day 29 of Cycle 2	188.1 umol/L Interval 20.7 to 1390.4

SECONDARY outcome

Timeframe: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2

Population: All randomized participants who received at least 1 dose of study drug.

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.

Outcome measures

Measure	Ataluren n=11 Participants 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.
Urinary MMacid Levels Baseline of Cycle 1	1870.8 mmol/mol creatinine Interval 84.9 to 10875.7
Urinary MMacid Levels Day 28 of Cycle 1	1953.0 mmol/mol creatinine Interval 100.9 to 12768.5
Urinary MMacid Levels Day 29 of Cycle 1	1364.6 mmol/mol creatinine Interval 173.2 to 31412.4
Urinary MMacid Levels Baseline of Cycle 2	1577.7 mmol/mol creatinine Interval 241.8 to 16603.9
Urinary MMacid Levels Day 28 of Cycle 2	1479.1 mmol/mol creatinine Interval 162.6 to 8914.4
Urinary MMacid Levels Day 29 of Cycle 2	1588.3 mmol/mol creatinine Interval 150.1 to 14063.2

SECONDARY outcome

Timeframe: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2

Population: All randomized participants who received at least 1 dose of study drug.

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.

Outcome measures

Measure	Ataluren n=11 Participants 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.
Plasma Propionylcarnitine Levels Baseline of Cycle 1	7.5 umol/L Interval 1.8 to 39.1
Plasma Propionylcarnitine Levels Day 28 of Cycle 1	6.9 umol/L Interval 2.2 to 17.6
Plasma Propionylcarnitine Levels Day 29 of Cycle 1	4.3 umol/L Interval 1.9 to 16.8
Plasma Propionylcarnitine Levels Baseline of Cycle 2	6.6 umol/L Interval 1.0 to 33.9
Plasma Propionylcarnitine Levels Day 28 of Cycle 2	5.5 umol/L Interval 0.9 to 19.6
Plasma Propionylcarnitine Levels Day 29 of Cycle 2	4.5 umol/L Interval 0.4 to 17.6

SECONDARY outcome

Timeframe: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2

Population: All randomized participants who received at least 1 dose of study drug.

Urine methylcitric acid levels were evaluated to detect disease activity. An increase in methylcitric acid values indicates greater disease activity.

Outcome measures

Measure	Ataluren n=11 Participants 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.
Urine Methylcitric Acid Levels Baseline of Cycle 1	48.1 mmol/mol creatinine Interval 10.2 to 309.5
Urine Methylcitric Acid Levels Day 28 of Cycle 1	124.2 mmol/mol creatinine Interval 12.0 to 380.3
Urine Methylcitric Acid Levels Day 29 of Cycle 1	83.2 mmol/mol creatinine Interval 17.3 to 498.4
Urine Methylcitric Acid Levels Baseline of Cycle 2	84.9 mmol/mol creatinine Interval 14.2 to 211.0
Urine Methylcitric Acid Levels Day 28 of Cycle 2	72.3 mmol/mol creatinine Interval 35.7 to 243.5
Urine Methylcitric Acid Levels Day 29 of Cycle 2	65.1 mmol/mol creatinine Interval 30.3 to 201.3

SECONDARY outcome

Timeframe: Baseline up to Day 112 (end of study follow-up)

Population: All randomized participants who received at least 1 dose of study drug.

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.

Outcome measures

Measure	Ataluren n=11 Participants 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.
Number of Participants With Adverse Events (AEs) Any AE	10 Participants
Number of Participants With Adverse Events (AEs) Severe AE	0 Participants
Number of Participants With Adverse Events (AEs) Treatment-related AE	3 Participants
Number of Participants With Adverse Events (AEs) Serious AE	0 Participants
Number of Participants With Adverse Events (AEs) AE leading to discontinuation	0 Participants

SECONDARY outcome

Timeframe: Baseline up to Day 112 (end of study follow-up)

Population: All randomized participants who received at least 1 dose of study drug.

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.

Outcome measures

Measure	Ataluren n=11 Participants 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.
Number of Participants With Potentially Clinically Significant Laboratory (Hematology and Biochemistry) Abnormal Results With at least 1 hematology abnormality	0 Participants
Number of Participants With Potentially Clinically Significant Laboratory (Hematology and Biochemistry) Abnormal Results With at least 1 biochemistry abnormality	2 Participants

SECONDARY outcome

Timeframe: Baseline up to Day 112 (end of study follow-up)

Population: All randomized participants who received at least 1 dose of study drug.

A metabolic decompensation episode is characterized by vomiting, hypotonia, and alteration of consciousness associated with metabolic acidosis and hyperammonemia.

Outcome measures

Measure

Ataluren n=11 Participants 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.

Number of Participants With a Metabolic Decompensation Episode

0 Participants

SECONDARY outcome

Timeframe: Baseline up to Day 29 of Cycles 1 and 2

Population: All randomized participants who received at least 1 dose of study drug.

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).

Outcome measures

Measure	Ataluren n=11 Participants 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.
Number of Participants Compliant With Study Treatment Received at least 1 different dose than planned	4 Participants
Number of Participants Compliant With Study Treatment Received all doses of study drug	11 Participants

SECONDARY outcome

Timeframe: 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]

Population: All randomized participants who received at least 1 dose of study drug and had evaluable ataluren plasma exposure data.

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.

Outcome measures

Measure	Ataluren n=11 Participants 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.
Ataluren Plasma Exposure Baseline of Cycle 1	6.1 microgram/milliliters (μg/mL) Interval 1.3 to 16.3
Ataluren Plasma Exposure Day 28 of Cycle 1	6.6 microgram/milliliters (μg/mL) Interval 0.6 to 29.9
Ataluren Plasma Exposure Baseline of Cycle 2	14.5 microgram/milliliters (μg/mL) Interval 3.2 to 29.2
Ataluren Plasma Exposure Day 28 of Cycle 2	13.2 microgram/milliliters (μg/mL) Interval 1.8 to 44.8

Adverse Events

Ataluren

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Ataluren n=11 participants at risk 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.
Renal and urinary disorders Glomerular vascular disorder	18.2% 2/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Renal and urinary disorders Hypercreatininaemia	18.2% 2/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Hepatobiliary disorders Hypertransaminasaemia	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hypercalcaemia	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hypercholesterolaemia	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Infections and infestations Gastroenteritis	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal pain	18.2% 2/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hypertriglyceridaemia	18.2% 2/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Vascular disorders Haematoma	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Vomiting	36.4% 4/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Diarrhoea	18.2% 2/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Muscle strain	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Skin discolouration	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Nervous system disorders Convulsion	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Infections and infestations Nasopharyngitis	36.4% 4/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
General disorders Pyrexia	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Flatulence	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Rash	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Nervous system disorders Headache	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Scoliosis	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hypoglycaemia	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hypernatraemia	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hyperuricaemia	9.1% 1/11 • Baseline up to Day 112 (end of study follow-up) All randomized participants who received at least 1 dose of study drug.

Additional Information

Patient Advocacy

PTC Therapeutics, Inc.

Phone: 1-866-562-4620

Email: medinfo@ptcbio.com

Results disclosure agreements

• Principal investigator is a sponsor employee The Sponsor can review results and/or communications prior to public release and can embargo communications regarding trial results for a period that is up to 180 days from the time submitted to the sponsor for review. The sponsor may consult with the PI to require changes to the communication or extend the embargo.
• Publication restrictions are in place

Restriction type: OTHER