Study of Ataluren in ≥2 to <5 Year-Old Male Participants With Duchenne Muscular Dystrophy

A Phase 2 Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Ataluren (PTC124®) in Patients Aged ≥2 to <5 Years Old With Nonsense Mutation Dystrophinopathy

This is a Phase 2, multiple-dose, open-label study evaluating the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ataluren in participants aged ≥2 to <5 years old with Duchenne muscular dystrophy (DMD) caused by a nonsense mutation in the dystrophin gene.

Study Overview

• Status: Completed
• Conditions: Duchenne Muscular Dystrophy
• Intervention / Treatment: Drug: Ataluren

Detailed Description

In nonsense mutation DMD (nmDMD), early start of treatment is important and necessary and, therefore, it is relevant to understand the correct and tolerable dose in this age group, particularly since ataluren is dosed by weight. This study included a 4-week screening period, a 52-week treatment period (the first 4 weeks of which included PK parameters), and a 4-week follow-up period for participants who completed the treatment period (60 weeks total duration). The objective of the extension period (treatment period after PK parameters have been completed) was to assess the long-term safety of chronic administration of ataluren in this participant population.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gulf Breeze, Florida, United States, 32561
      • Child Neuro NWF
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Texas
    • Dallas, Texas, United States, 75390-8843
      • Children's Medical Center Dallas
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Males ≥2 to <5 years of age
• Body weight ≥12 kg
• Diagnosis of DMD
• Nonsense mutation in at least 1 allele of the dystrophin gene

Exclusion Criteria:

• Participation in any other drug or device clinical investigation
• Ongoing use of prohibited concomitant medications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ataluren; Participants will be administered ataluren orally at a dose of 10 milligrams/kilograms (mg/kg) in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening (for a total of 40 mg/kg/day) for up to 52 weeks. Dose will be provided based upon the weight of each participant, which will be assessed every 12 weeks.	Drug: Ataluren; White to off-white powder for oral suspension.; Other Names: PTC124; Translarna

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs), TEAEs Leading to Discontinuation, and Serious Adverse Events (SAEs)	A TEAE was any untoward medical occurrence or undesirable event that begins or worsens following administration of study drug, whether or not considered related to study drug by Investigator. An SAE was an adverse event (AE) resulting in any of the following outcomes or deemed significant for any other reason, death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying) or persistent or significant disability/incapacity not related to dystrophinopathy. An event was not reported as an SAE, if event was exclusively a relapse or expected change or progression of baseline dystrophinopathy. AEs included both SAEs and nonserious AEs. AEs classified according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and coded using Medical Dictionary for Regulatory Activities. A summary of SAEs and all non-serious AEs, regardless of causality, is located in the Reported Adverse Events section.	Baseline up to Week 56
Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Biochemistry, Hematology, and Urinalysis) Parameter	Clinical laboratory results that were considered clinically meaningful were to be determined by the Investigator and Sponsor. Biochemistry parameters included sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, bilirubin (total, direct, and indirect), aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, creatine kinase, lactate dehydrogenase, alkaline phosphatase, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, and cystatin C. Hematology parameters included white blood cell count with differential, hemoglobin, hematocrit, other red cell parameters, and platelet count. Urinalysis parameters included pH, specific gravity, glucose, ketones, blood, protein, urobilinogen, bilirubin, nitrite, and leukocyte esterase. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.	Baseline up to Week 56
Number of Participants With a Clinically Meaningful Abnormal Electrocardiogram (ECG) Test Results	ECG results that were considered clinically meaningful were to be determined by the Investigator. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.	Baseline up to Week 56
Number of Participants With a Dose-Limiting Toxicity as Measured by Hepatic and Renal Toxicity	Dose-limiting toxicity was measured through clinical evaluations for potential hepatic and renal toxicities. The clinical evaluations included the following: Hepatic: The participant's medical history, hepatitis screening results, all clinical blood values (particularly serum bilirubin, gamma-glutamyl transferase [GGT], aspartate aminotransferase [AST], and alanine aminotransferase [ALT] values), and all concomitant medications were reviewed.; Renal: The participant's medical history, all clinical blood and urine renal values, serum electrolytes, medications, and potential pre- or post-renal conditions were reviewed.	Baseline up to Week 56

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics: Maximum Observed Plasma Concentration From Time Zero up to 6 Hours After the Morning Dose (Cmax0-6hr)	Ataluren concentrations in plasma were analyzed using a validated high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method.	0 (predose), 1, 2, 4, and 6 (postdose) hours on Days 1 and 28
Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration From Time Zero up to 6 Hours After the Morning Dose (Tmax0-6hr)	Ataluren concentrations in plasma were analyzed using a validated HPLC-MS/MS method.	0 (predose), 1, 2, 4, and 6 (postdose) hours on Days 1 and 28
Area Under the Plasma Concentration Time Curve From Time Zero up to 10 Hours After the Morning Dose (AUC0-10hr)	Ataluren concentrations in plasma were analyzed using a validated HPLC-MS/MS method. AUC0-10hr was measured using the linear trapezoidal rule during the ascending portion of the curve and the log-trapezoidal rule during the descending portion of the curve.	0 (predose), 1, 2, 4, 6, 8, and 10 (postdose) hours on Days 1 and 28
Pharmacokinetics: Concentration at the End of the First (Morning) Dose Interval (Ctrough6hr)	Ataluren concentrations in plasma were analyzed using a validated HPLC-MS/MS method.	0 (predose), 1, 2, 4, and 6 (postdose) hours on Days 1 and 28
Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs	TFTs included time to stand from supine position (rise to standing), time to run/walk 10 meters (m), and time to ascend/descend 4 stairs. A decrease from baseline reflects faster completion of the functional task and, thus, better muscle function. If the time taken to perform a test exceeded 30 seconds or if a participant could not perform the test due to disease progression (PD), a value of 30 seconds was used.	Baseline, Week 28 and Week 52
Change From Baseline in Physical Function as Measured by the NSAA	NSAA consists of 17 activities, including items assessing abilities necessary to remain functionally ambulant (that is, ability to rise from floor, to get from lying to sitting/sitting to standing, and that are known to progressively deteriorate); items that can be partly present in DMD early stages (that is, assessing head raise and standing on heels); and a number of activities such as hopping, jumping, and running. Since the boys were <5 years old, revised 16 point, 8-point, and 3-point scales were used over the 17 point scale. Scores for evaluations=0 (Unable to achieve independently), 1 (Modified method but achieved goal independent of physical assistance), or 2 (Normal, no obvious modification of activity). Maximum total score for the 16-point scale=32, 8-point scale=16, and 3-point scale=6. If an activity couldn't be performed due to PD/loss of ambulation, a score of 0 was assigned. Change from Baseline calculated by subtracting Baseline value from value at Week 28 and Week 52.	Baseline, Week 28 and Week 52
Change From Baseline in Height of Participants at Weeks 4, 16, 28, 40, 52, and 56		Baseline, Weeks 4, 16, 28, 40, 52, and 56
Change From Baseline in Weight of Participants at Weeks 4, 16, 28, 40, 52, and 56		Baseline, Weeks 4, 16, 28, 40, 52, and 56
Change From Baseline in Body Mass Index of Participants at Weeks 4, 16, 28, 40, 52, and 56	Body mass index is an estimate of body fat based on body weight divided by height squared.	Baseline, Weeks 4, 16, 28, 40, 52, and 56
Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire	To assess palatability characteristics, participants/parents or guardians were asked to provide a response of "Strongly disagree", "Disagree", "Neither agree or disagree", "Agree", or "Strongly Agree" to the following 3 questions: Question 1. "Is the medicine palatable?" Question 2. "On the basis of reaction / facial expression of your child, do you think that the medication is pleasant?" Question 3."You sometimes have problems in giving the medication to your child because he/she refuses to take it or throws it up?"	Baseline up to Week 28

Collaborators and Investigators

• Sponsor: PTC Therapeutics
• Investigators: Study Director: Francesco Bibbiani, MD, PTC Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): June 9, 2016
• Primary Completion (Actual): February 9, 2018
• Study Completion (Actual): February 9, 2018

Study Registration Dates

• First Submitted: June 16, 2016
• First Submitted That Met QC Criteria: June 27, 2016
• First Posted (Estimate): June 30, 2016

Study Record Updates

• Last Update Posted (Actual): August 28, 2020
• Last Update Submitted That Met QC Criteria: August 12, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophy, Duchenne
• Other Study ID Numbers: PTC124-GD-030-DMD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided