A Study of Ataluren in Pediatric Participants With Cystic Fibrosis

NCT00458341 | Completed Phase 2 Results

• 1 other identifier: PTC124-GD-006-CF
• Study Type: interventional
• Target: 30
• Locations: 2 countries
• Sites: 3

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.

Conditions

Cystic Fibrosis

Keywords

Cystic fibrosis; Nonsense mutation; Premature stop codon

Outcome Measures

Primary Outcomes (3)

• Change From Baseline in Total Chloride Transport at Day 14 of Cycles 1 and 2

  Nasal transepithelial potential difference (TEPD) was assessed in each participant using standardized techniques. Warmed solutions of Ringer's solution, amiloride, chloride-free gluconate, isoproterenol, and adenosine triphosphate (ATP) were perfused for ≥3-minute sequentially through a nasal catheter while a voltage tracing was recorded. Total chloride transport was computed for each nostril. The total chloride transport values were calculated by subtracting the voltages at the end of a perfusion from the voltage at the end of an earlier perfusion (isoproterenol - amiloride). The average of the values for each nostril was computed. If the assessment was available in only 1 nostril, this value was used as if it were the average of both nostrils. Baseline data for Cycle 1 and Cycle 2 and change from Baseline data at Day 14 of Cycles 1 and 2 are presented.

  Baseline of Cycle 1 and Cycle 2, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days)

• Number of Participants With a Chloride Transport Response at Day 14 of Cycles 1 and 2

  Nasal TEPD was assessed in each participant using standardized techniques. Warmed solutions of Ringer's solution, amiloride, chloride-free gluconate, isoproterenol, and ATP were perfused for ≥3-minute sequentially through a nasal catheter while a voltage tracing was recorded. Total chloride transport was computed for each nostril. The total chloride transport values were calculated by subtracting the voltages at the end of a perfusion from the voltage at the end of an earlier perfusion (isoproterenol - amiloride). The average of the values for each nostril was computed. If the assessment was available in only 1 nostril, this value was used as if it were the average of both nostrils. Response to study treatment defined as an increase in total chloride transport as indicated by a change of at least -5 mV in nasal TEPD.

  Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days)

• Number of Participants With Normalization of Chloride Transport Between Baseline and Day 14 of Cycles 1 and 2

  Nasal TEPD was assessed in each participant using standardized techniques. Warmed solutions of Ringer's solution, amiloride, chloride-free gluconate, isoproterenol, and ATP were perfused for ≥3-minute sequentially through a nasal catheter while a voltage tracing was recorded. Total chloride transport was computed for each nostril. The total chloride transport values were calculated by subtracting the voltages at the end of a perfusion from the voltage at the end of an earlier perfusion (isoproterenol - amiloride). The average of the values for each nostril was computed. If the assessment was available in only 1 nostril, this value was used as if it were the average of both nostrils. Normalization of chloride transport (normal range \[NR\]) was defined as nasal TEPD that was at least as electrically negative as -5 mV. Normalization in chloride transport can also be referred to as hyperpolarization.

  Overall Baseline and Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days)

Secondary Outcomes (14)

• Change From Baseline in Parameters of Transepithelial Difference at Day 14 of Cycles 1 and 2

  Baseline of Cycle 1 and Cycle 2, Day 14 of Cycle 1 and Cycle 2 (1 cycle=28 days)

• Change From Baseline in CFTR Protein in Nasal Mucosa as Determined by Immunofluorescence at Overall Day 56

  Overall Baseline, Overall Day 56

• 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

  Overall Baseline, Overall Day 42

• Change From Baseline in Pulmonary Function as Measured by Spirometry at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56

  Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56

• Change From Baseline in Sputum Markers of Inflammation (Free Elastase) at Day 14 or 15 of Cycles 1 and 2 and Overall Day 56

  Overall Baseline, Day 14 or 15 of Cycle 1 and Cycle 2 (1 cycle=28 days), and Overall Day 56

Study Arms (2)

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

EXPERIMENTAL

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.

Drug: Ataluren

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

EXPERIMENTAL

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.

Drug: Ataluren

Interventions

Ataluren DRUG

Ataluren will be provided as a vanilla-flavored powder to be mixed with water, milk, or apple juice. Participants are to receive a total of 42 doses of ataluren during each cycle, for a total of 84 doses of ataluren in both cycles.

Also known as: PTC124

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

Eligibility Criteria

• Age: 6 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Diagnosis of CF based on conclusively abnormal sweat test (sweat chloride \>35 milliequivalents \[mEq\]/liter).
• Abnormal nasal epithelial TEPD total chloride conductance (a more electrically negative value than 5 mV for Δchloride-free+isoproterenol).
• Presence of a mutation in both alleles.
• Documentation that a blood sample has been drawn for reconfirmation of the presence of a nonsense mutation in the CFTR gene.
• Age ≥6 years.
• Body weight ≥25 kg.
• FEV1 ≥40% of predicted for age, gender, and height.
• Oxygen saturation ≥92% on room air.
• 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.
• Negative pregnancy test (for females of childbearing potential).
• 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.
• Ability to provide written informed consent and/or assent.
• 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.

You may not qualify if:

• Prior exposure to ataluren.
• 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.
• Ongoing acute illness including acute upper or lower respiratory infections within 2 weeks before start of study treatment.
• History of major complications of lung disease (including recent massive hemoptysis or pneumothorax) within 2 months prior to start of study treatment.
• 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.
• Positive hepatitis B surface antigen, hepatitis C antibody test, or human immunodeficiency virus (HIV) test.
• Hemoglobin \<10 grams/deciliter (g/dL).
• Serum albumin \<2.5 g/dL.
• 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).
• Abnormal renal function (serum creatinine \>1.5 times upper limit of normal).
• Pregnancy or breast-feeding.
• History of solid organ or hematological transplantation.
• Exposure to another investigational drug within 14 days prior to start of study treatment.
• Ongoing participation in any other therapeutic clinical trial.
• Ongoing use of thiazolidinedione peroxisome proliferator-activated receptor gamma (PPAR γ) agonists, for example, rosiglitazone (Avandia® or equivalent) or pioglitazone (Actos® or equivalent).

Sponsors & Collaborators

• PTC Therapeutics: lead

Study Sites (3)

Reine Fabiola Hospital

Brussels, 1020, Belgium

Location

UZ Gasthuisberg Leuven

Leuven, 3000, Belgium

Location

Hopital Necker Enfants Malades

Paris, 75015, France

Location

Related Publications (1)

• 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.

  PMID: 20622033 DERIVED

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

ataluren

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Results Point of Contact

• Title: Patient Advocacy
• Organization: PTC Therapeutics, Inc.

medinfo@ptcbio.com

1-866-562-4620

Study Officials

• Isabelle Sermet-Gaudelus, MD

  Hopital Necker

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 6, 2007
• First Posted: April 10, 2007
• Study Start: March 23, 2007
• Primary Completion: February 29, 2008
• Study Completion: February 29, 2008
• Last Updated: March 6, 2020
• Results First Posted: March 6, 2020

Record last verified: 2020-02

Locations

FR (1); BE (2)