A Study of Ataluren in Pediatric Participants With Cystic Fibrosis

PTC Therapeutics

Status and phase: Completed; Phase 2

Conditions: Cystic Fibrosis

Treatments: Drug: Ataluren

Study type: Interventional

Funder types: Industry

Identifiers

NCT00458341

PTC124-GD-006-CF

Details and patient eligibility

About

In some participants with cystic fibrosis (CF), the disease is caused by a nonsense mutation (premature stop codon) in the gene that makes the cystic fibrosis transmembrane regulator (CFTR) protein. Ataluren has been shown to partially restore CFTR production in animals with CF due to a nonsense mutation. The main purpose of this study is to understand whether ataluren can safely increase functional CFTR protein in the cells of participants with CF due to a nonsense mutation.

Full description

In this study, participants with CF due to a nonsense mutation will be treated with a new investigational drug called ataluren. Evaluation procedures (history, physical examination, blood and urine tests to assess organ function, electrocardiogram [ECG], chest x-ray, and CF-specific tests) to determine if a participant qualifies for the study will be performed within 21 days prior to the start of treatment. Eligible participants with nonsense-mutation-mediated CF will receive 2 repeated 28-day cycles, each comprising of 14 days on therapy and 14 days off therapy. In a crossover design, participants will be randomized to receive ataluren treatment in Cycle 1 by either of the following regimens:

• Ataluren, given 3 times per day (TID) with a regimen of 4 milligrams/kilograms (mg/kg) at breakfast, 4 mg/kg at lunch, and 8 mg/kg at dinner, or
• Ataluren, given 3 TID with a regimen of 10 mg/kg at breakfast, 10 mg/kg at lunch and 20 mg/kg at dinner.

In Cycle 2, participants will then receive the drug according to the regimen opposite from that given in Cycle 1.

There will be a 2-night stay at the clinical research center at the beginning and at the end of each 14 days of ataluren treatment, which means that there will be four 2-night stays at the clinical research center during the study. During the study, ataluren efficacy, safety, and pharmacokinetics (PK) will be evaluated periodically with measurements of transepithelial potential difference (TEPD), nasal mucosal brushing to assess for cellular CFTR messenger ribonucleic acid (mRNA) and protein, medical history, physical examinations, blood tests, sputum test, urinalysis, ECGs, chest x-ray, and pulmonary function tests.

The measurement of TEPD, also known as nasal potential difference, provides a sensitive evaluation of sodium and chloride transport directly in secretory epithelial cells. TEPD assessments are made on the nasal epithelium cells lining the inferior turbinate because these cells are easier to access than the respiratory epithelial cells lining the lower airways and have been shown to have the same ion transport characteristics. As an endpoint, TEPD has the advantage that it can detect chloride transport changes that are a quantitative integration of the presence, functional activity, and apical location of the CFTR in airway cells. Furthermore, it is a direct measure of CFTR activity that is not likely to be affected by supportive or palliative treatments for CF (with the possible exception of systemically administered aminoglycoside antibiotics).

Enrollment: 30 patients

Sex: All

Ages: 6 to 18 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria: Participants must meet all of the following conditions to be eligible for enrollment into the study:

1. Diagnosis of CF based on conclusively abnormal sweat test (sweat chloride >35 milliequivalents [mEq]/liter).
2. Abnormal nasal epithelial TEPD total chloride conductance (a more electrically negative value than 5 mV for Δchloride-free+isoproterenol).
3. Presence of a mutation in both alleles.
4. Documentation that a blood sample has been drawn for reconfirmation of the presence of a nonsense mutation in the CFTR gene.
5. Age ≥6 years.
6. Body weight ≥25 kg.
7. FEV1 ≥40% of predicted for age, gender, and height.
8. Oxygen saturation ≥92% on room air.
9. Willingness of male and female participants, if not surgically sterile, to abstain from sexual intercourse or employ a barrier or medical method of contraception during the study drug administration and follow-up periods.
10. Negative pregnancy test (for females of childbearing potential).
11. Willingness and ability to comply with scheduled visits, drug administration plan, study procedures (including TEPD measurements, clinical laboratory tests, pulmonary function tests, and PK sampling), and study restrictions.
12. Ability to provide written informed consent and/or assent.
13. Evidence of signed and dated informed consent document (by the participant or a legal guardian) indicating that the participant and/or the legal guardian has been informed of all pertinent aspects of the trial.

Exclusion Criteria: The presence of any of the following conditions will exclude a participant from enrollment in the study:

1. Prior exposure to ataluren.
2. Prior or ongoing medical condition (for example, concomitant illness, alcoholism, drug abuse, psychiatric condition), medical history, physical findings, ECG findings, or laboratory abnormality that, in the Investigator's opinion, could adversely affect the safety of the participant, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.
3. Ongoing acute illness including acute upper or lower respiratory infections within 2 weeks before start of study treatment.
4. History of major complications of lung disease (including recent massive hemoptysis or pneumothorax) within 2 months prior to start of study treatment.
5. Abnormalities on screening chest x-ray suggesting clinically significant active pulmonary disease other than CF, or new, significant abnormalities such as atelectasis or pleural effusion which may be indicative of clinically significant active pulmonary involvement secondary to CF.
6. Positive hepatitis B surface antigen, hepatitis C antibody test, or human immunodeficiency virus (HIV) test.
7. Hemoglobin <10 grams/deciliter (g/dL).
8. Serum albumin <2.5 g/dL.
9. Abnormal liver function (serum total bilirubin > the upper limit of normal, or serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or gamma-glutamyl transferase (GGT) >2.0 times the upper limit of normal).
10. Abnormal renal function (serum creatinine >1.5 times upper limit of normal).
11. Pregnancy or breast-feeding.
12. History of solid organ or hematological transplantation.
13. Exposure to another investigational drug within 14 days prior to start of study treatment.
14. Ongoing participation in any other therapeutic clinical trial.
15. Ongoing use of thiazolidinedione peroxisome proliferator-activated receptor gamma (PPAR γ) agonists, for example, rosiglitazone (Avandia® or equivalent) or pioglitazone (Actos® or equivalent).
16. Change in intranasal medications (including use of corticosteroids, cromolyn, ipratropium bromide, phenylephrine, or oxymetazoline) within 14 days prior to start of study treatment.
17. Change in treatment with systemic or inhaled corticosteroids within 14 days prior to start of study treatment.
18. Use of or requirement for inhaled gentamicin or amikacin within 14 days prior to start of study treatment or during study treatment.
19. Requirement for systemic aminoglycoside antibiotics within 14 days prior to start of study treatment.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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30 participants in 2 patient groups

Ataluren 4, 4, and 8 mg/kg, then ataluren 10, 10, and 20 mg/kg

Experimental group

Description:

During Cycle 1, participants will receive ataluren at 4 mg/kg in the morning, 4 mg/kg at midday, and 8 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants will crossover to the other ataluren dose regimen (ataluren 10, 10, and 20 mg/kg) for Cycle 2.

Treatment:

Drug: Ataluren

Ataluren 10, 10, and 20 mg/kg, then ataluren 4, 4, and 8 mg/kg

Experimental group

Description:

During Cycle 1, participants will receive ataluren at 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by a 14-day follow-up period without treatment. Then, the participants will crossover to the other ataluren dose regimen (ataluren 4, 4, and 8 mg/kg) for Cycle 2.

Treatment:

Drug: Ataluren