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

• ClinicalTrials.gov Identifier: NCT02819557
• Recruitment Status: Completed
• First Posted: June 30, 2016
• Results First Posted: August 28, 2020
• Last Update Posted: August 28, 2020
• Sponsor: PTC Therapeutics
• Information provided by (Responsible Party): PTC Therapeutics

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Duchenne Muscular Dystrophy	Drug: Ataluren	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: June 9, 2016
• Actual Primary Completion Date: February 9, 2018
• Actual Study Completion Date: February 9, 2018

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment Emergent Adverse Events (TEAEs), TEAEs Leading to Discontinuation, and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Week 56 ]
   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.
2. Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Biochemistry, Hematology, and Urinalysis) Parameter [ Time Frame: Baseline up to Week 56 ]
   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.
3. Number of Participants With a Clinically Meaningful Abnormal Electrocardiogram (ECG) Test Results [ Time Frame: Baseline up to Week 56 ]
   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.
4. Number of Participants With a Dose-Limiting Toxicity as Measured by Hepatic and Renal Toxicity [ Time Frame: Baseline up to Week 56 ]

   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.

Secondary Outcome Measures :

1. Pharmacokinetics: Maximum Observed Plasma Concentration From Time Zero up to 6 Hours After the Morning Dose (Cmax0-6hr) [ Time Frame: 0 (predose), 1, 2, 4, and 6 (postdose) hours on Days 1 and 28 ]
   Ataluren concentrations in plasma were analyzed using a validated high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method.
2. Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration From Time Zero up to 6 Hours After the Morning Dose (Tmax0-6hr) [ Time Frame: 0 (predose), 1, 2, 4, and 6 (postdose) hours on Days 1 and 28 ]
   Ataluren concentrations in plasma were analyzed using a validated HPLC-MS/MS method.
3. Area Under the Plasma Concentration Time Curve From Time Zero up to 10 Hours After the Morning Dose (AUC0-10hr) [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, and 10 (postdose) hours on Days 1 and 28 ]
   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.
4. Pharmacokinetics: Concentration at the End of the First (Morning) Dose Interval (Ctrough6hr) [ Time Frame: 0 (predose), 1, 2, 4, and 6 (postdose) hours on Days 1 and 28 ]
   Ataluren concentrations in plasma were analyzed using a validated HPLC-MS/MS method.
5. Change From Baseline in Proximal Muscle Function as Assessed by Speed During TFTs [ Time Frame: Baseline, Week 28 and Week 52 ]
   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.
6. Change From Baseline in Physical Function as Measured by the NSAA [ Time Frame: Baseline, Week 28 and Week 52 ]
   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.
7. Change From Baseline in Height of Participants at Weeks 4, 16, 28, 40, 52, and 56 [ Time Frame: Baseline, Weeks 4, 16, 28, 40, 52, and 56 ]
8. Change From Baseline in Weight of Participants at Weeks 4, 16, 28, 40, 52, and 56 [ Time Frame: Baseline, Weeks 4, 16, 28, 40, 52, and 56 ]
9. Change From Baseline in Body Mass Index of Participants at Weeks 4, 16, 28, 40, 52, and 56 [ Time Frame: Baseline, 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.
10. Ataluren Palatability Characteristics as Determined by a Parent/Caregiver Questionnaire [ Time Frame: Baseline up to Week 28 ]

    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?"

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Florida

Child Neuro NWF

Gulf Breeze, Florida, United States, 32561

United States, Illinois

Rush University Medical Center

Chicago, Illinois, United States, 60612

United States, Massachusetts

Children's Hospital Boston

Boston, Massachusetts, United States, 02115

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

United States, Texas

Children's Medical Center Dallas

Dallas, Texas, United States, 75390-8843

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84112

Sponsors and Collaborators

PTC Therapeutics

Investigators

• Study Director: Francesco Bibbiani, MD; PTC Therapeutics

  Study Documents (Full-Text)

Documents provided by PTC Therapeutics:

Study Protocol  [PDF] January 28, 2016

Statistical Analysis Plan  [PDF] March 19, 2018

More Information

• Responsible Party: PTC Therapeutics
• ClinicalTrials.gov Identifier: NCT02819557
• Other Study ID Numbers: PTC124-GD-030-DMD
• First Posted: June 30, 2016
• Results First Posted: August 28, 2020
• Last Update Posted: August 28, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Additional relevant MeSH terms:

Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked