Clinical trial NCT00458341: A Study of Ataluren in Pediatric Participants With Cystic Fibrosis
Official title: A Phase 2 Study of PTC124 as an Oral Treatment for Nonsense-Mutation-Mediated Cystic Fibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cystic Fibrosis
Keywords: Cystic fibrosis
Nonsense mutation
Premature stop codon
Lead sponsor: PTC Therapeutics
Sponsor class: INDUSTRY
First posted: 2007-04-10
Enrollment: 30
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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).

Eligibility 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.

Primary outcomes:
measure: Change From Baseline in Total Chloride Transport at Day 14 of Cycles 1 and 2
timeFrame: Baseline of Cycle 1 and Cycle 2, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days)
measure: Number of Participants With a Chloride Transport Response at Day 14 of Cycles 1 and 2
timeFrame: Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days)
measure: Number of Participants With Normalization of Chloride Transport Between Baseline and Day 14 of Cycles 1 and 2
timeFrame: Overall Baseline and Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days)
Secondary outcomes:
measure: Change From Baseline in Parameters of Transepithelial Difference at Day 14 of Cycles 1 and 2
timeFrame: Baseline of Cycle 1 and Cycle 2, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days)
measure: Change From Baseline in CFTR Protein in Nasal Mucosa as Determined by Immunofluorescence at Overall Day 56
timeFrame: Overall Baseline, Overall Day 56
measure: Change From Baseline in Nonsense Mutation CFTR mRNA in Nasal Mucosa as Determined by Quantitative Real-Time Polymerase Chain Reaction (RT-PCR) Assay at Overall Day 42
timeFrame: Overall Baseline, Overall Day 42
measure: Change From Baseline in Pulmonary Function as Measured by Spirometry at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56
timeFrame: Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
measure: Change From Baseline in Sputum Markers of Inflammation (Free Elastase) at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56
timeFrame: Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
measure: Change From Baseline in Sputum Markers of Inflammation (Matrix Metalloproteinase 9 [MMP-9] Active) at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56
timeFrame: Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
measure: Change From Baseline in Sputum Markers of Inflammation (Tumor Necrosis Factor-Alpha [TNF-α], Interleukin-8 [IL-8], Transforming Growth Factor Beta 1 [TGF-β1]) at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56
timeFrame: Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
measure: Change From Baseline in Sputum Markers of Inflammation (Uridine-5'-Triphosphate [UTP]) at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56
timeFrame: Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
measure: Change From Baseline in Clinically Significant Neutrophil Levels in Blood at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56
timeFrame: Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
measure: Change From Baseline in Clinically Significant Serum Levels of C-Reactive Protein at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56
timeFrame: Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
measure: Change From Baseline in Body Weight at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56
timeFrame: Overall Baseline, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
measure: Change From Baseline in the CF-Related Symptom Scores, as Assessed Using a Participant-Reported Questionnaire at Day 14 of Cycles 1 and 2 and Overall Day 56
timeFrame: Overall Baseline, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56
measure: PK: Area Under the Concentration Time Curve From Time 0 (Dosing) to 24 Hours (AUC0-24) of Ataluren
timeFrame: 0 (predose), 2 and 3 hours postdose of the morning dose; 0 (predose), 2 and 3 hours postdose of the midday dose; and 0 hours (predose), 2, 3, and 12 hours postdose of the evening dose on Day 14 of Cycle 1 and Cycle 2
measure: Compliance With Study Treatment
timeFrame: Baseline up to Day 14 in Cycle 1 and Cycle 2
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Reine Fabiola Hospital
city: Leuven
country: Belgium
facility: UZ Gasthuisberg Leuven
city: Paris
country: France
facility: Hopital Necker Enfants Malades
Study officials:
affiliation: Hopital Necker
name: Isabelle Sermet-Gaudelus, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sermet-Gaudelus I, Boeck KD, Casimir GJ, Vermeulen F, Leal T, Mogenet A, Roussel D, Fritsch J, Hanssens L, Hirawat S, Miller NL, Constantine S, Reha A, Ajayi T, Elfring GL, Miller LL. Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis. Am J Respir Crit Care Med. 2010 Nov 15;182(10):1262-72. doi: 10.1164/rccm.201001-0137OC. Epub 2010 Jul 9.