Clinical trial NCT00803205: Study of Ataluren (PTC124™) in Cystic Fibrosis
Official title: A Phase 3 Efficacy and Safety Study of PTC124 as an Oral Treatment for Nonsense-Mutation-Mediated Cystic Fibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cystic Fibrosis
Keywords: Cystic fibrosis
Nonsense mutation
Premature stop codon
PTC124
Ataluren
PTC Therapeutics
Lead sponsor: PTC Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Cystic Fibrosis Foundation
First posted: 2008-12-05
Enrollment: 238
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Cystic fibrosis (CF) is a genetic disorder caused by a mutation in the gene that makes the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A specific type of mutation called a nonsense (premature stop codon) mutation is the cause of CF in approximately 10% of patients with the disease. Ataluren is an orally delivered investigational drug that has the potential to overcome the effects of the nonsense mutation. This study is a Phase 3 trial that will evaluate the clinical benefit of ataluren in adult and pediatric participants with CF due to a nonsense mutation. The main goals of the study are to understand whether ataluren can improve pulmonary function and whether the drug can safely be given for a long period of time. The study will also assess the effects of ataluren on CF pulmonary exacerbation frequency, cough frequency, health-related quality of life, antibiotic use for CF-related infections, CF-related disruptions to daily living, body weight, and CF pathophysiology.

Detailed description: This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, efficacy and safety study, designed to document the clinical benefit of ataluren when administered as therapy of participants with CF due to a nonsense mutation (premature stop codon) in the CFTR gene. It is planned that \~208 participants who are ≥6 years of age and have a forced expiratory volume in 1 second (FEV1) ≥40% and ≤90% of predicted will be enrolled. Study participants will be enrolled at sites in North America, Europe, and Israel. They will be randomized in a 1:1 ratio to either ataluren or placebo. Participants will receive study drug 3 times per day (at morning, midday, and evening) for 48 weeks. Participants will be evaluated at clinic visits every 8 weeks. Additional safety laboratory testing, which may be performed at the investigational site or at an accredited local laboratory or clinic, is required every 4 weeks for the first 6 months of study participation. At the completion of blinded treatment, all compliant participants will be eligible to receive open-label ataluren in a separate extension study.

Eligibility criteria: Inclusion Criteria:

* Ability to provide written informed consent (parental/guardian consent and participant assent if \<18 years of age)
* Age ≥6 years
* Body weight ≥16 kg
* Abnormal nasal transepithelial potential difference (TEPD) total chloride conductance (a less electrically negative value than -5 millivolts (mV) for total chloride conductance \[Δchloride-free+isoproterenol\])
* Sweat chloride \>40 milliequivalents/liter (mEq/L)
* Documentation of the simultaneous presence of a nonsense mutation in at least 1 allele of the CFTR gene and a CF-causing mutation in the other CFTR allele, as determined by gene sequencing from a laboratory certified by the College of American Pathologists (CAP), under the Clinical Laboratory Improvement Act/Amendment (CLIA), or by an equivalent organization
* Verification that a blood sample has been drawn for confirmation of the presence of a nonsense mutation in the CFTR gene
* Ability to perform a valid, reproducible spirometry test using the study-specific spirometer with demonstration of an FEV1 ≥40% and ≤90% of predicted for age, gender, and height
* Resting oxygen saturation (as measured by pulse oximetry) ≥92% on room air
* Documentation by VivoMetrics that the participant has satisfactorily completed a 24-hour LifeShirt® cough frequency assessment
* Confirmed screening laboratory values within the central laboratory ranges (hepatic, adrenal, renal, serum electrolytes, and reproduction \[women only\] parameters)
* In participants who are sexually active, willingness to abstain from sexual intercourse or employ a barrier or medical method of contraception during the study drug administration and 4-week follow-up period
* Willingness and ability to comply with scheduled visits, drug administration plan, study restrictions, and study procedures

Exclusion Criteria:

* Known hypersensitivity to any of the ingredients or excipients of the study drug
* Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or reinitiation) in a chronic treatment/prophylaxis regimen for CF or for CF-related conditions within 4 weeks prior to start of study treatment
* Exposure to another investigational drug within 4 weeks prior to start of study treatment
* Treatment with systemic aminoglycoside antibiotics at the time of the Baseline TEPD assessment
* Treatment with intravenous antibiotics within 3 weeks prior to start of study treatment
* History of solid organ or hematological transplantation
* Ongoing immunosuppressive therapy (other than corticosteroids)
* Ongoing warfarin, phenytoin, or tolbutamide therapy
* Ongoing participation in any other therapeutic clinical trial
* Major complications of lung disease (including massive hemoptysis, pneumothorax, or pleural effusion) within 8 weeks prior to start of study treatment
* Evidence of pulmonary exacerbation or acute upper or lower respiratory tract infection (including viral illnesses) within 3 weeks prior to randomization
* Known portal hypertension
* Positive hepatitis B surface antigen, hepatitis C antibody test, or human immunodeficiency virus (HIV) test
* Pregnancy or breast-feeding
* Current smoker or a smoking history of ≥10 pack-years (number of cigarette packs/day \* number of years smoked)
* Prior or ongoing medical condition (for example, concomitant illness, alcoholism, drug abuse, psychiatric condition), medical history, physical findings, electrocardiography 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.

Primary outcomes:
measure: Percentage of Predicted Function (Percent-Predicted) of Forced Expiratory Volume in One Second (FEV1) at Baseline
timeFrame: Baseline (Week 1)
measure: Percentage Change From Baseline in Percent-Predicted of FEV1 at Week 48
timeFrame: End of Treatment (EOT) (Week 48)
Secondary outcomes:
measure: Rate of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria Over 48 Weeks
timeFrame: Baseline to EOT (Week 48)
measure: Change From Baseline in Awake Cough Hourly Rate at Week 48
timeFrame: Baseline, EOT (Week 48)
measure: Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48
timeFrame: Baseline, EOT (Week 48)
measure: Percent-Predicted of Forced Vital Capacity (FVC) at Baseline
timeFrame: Baseline (Week 1)
measure: Percentage Change From Baseline in Percent-Predicted of FVC at Week 48
timeFrame: EOT (Week 48)
Other outcomes:
measure: Percentage of Participants With Treatment-Emergent Adverse Events (TEAE)
timeFrame: Baseline up to 4 Weeks Post-Treatment (Week 52) or Premature Discontinuation (PD)
measure: Rate of Study Drug Compliance by Drug Accountability
timeFrame: Baseline up to EOT (Week 48)
measure: Rate of Study Drug Compliance by Patient-Reported Data
timeFrame: Baseline up to EOT (Week 48)
measure: Concentration of Ataluren
timeFrame: Predose and 2 Hours Postdose at Week 1, Week 16, Week 32, EOT (Week 48)
measure: Rate of Interventions for Respiratory Symptoms
timeFrame: Baseline up to EOT (Week 48)
measure: Rate of Disruptions in Activities of Daily Living Because of Pulmonary Symptoms
timeFrame: Baseline up to EOT (Week 48)
measure: Change From Baseline in Body Weight at Week 48
timeFrame: Baseline, EOT (Week 48)
measure: Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48
timeFrame: Baseline, EOT (Week 48)
measure: Change From Baseline in the Concentration of Neutrophil Elastase in Sputum at Week 48
timeFrame: Baseline, EOT (Week 48)
measure: Change From Baseline in the Concentration of C-Reactive Protein (CRP) in Serum at Week 48
timeFrame: Baseline, EOT (Week 48)
measure: Change From Baseline in the Total Lung Score as Assessed by Computed Tomography (CT) at Week 48
timeFrame: Baseline, EOT (Week 48)
measure: Change From Baseline in Total Nasal Chloride Transport as Assessed by Transepithelial Potential Difference (TEPD) at Week 48
timeFrame: Baseline, EOT (Week 48)
measure: Change From Baseline in Sweat Chloride Concentration at Week 48
timeFrame: Baseline, EOT (Week 48)
Locations:
city: Birmingham
country: United States
facility: University of Alabama-Birmingham
state: Alabama
city: Long Beach
country: United States
facility: Miller Children's Hospital Long Beach
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital
state: California
city: Palo Alto
country: United States
facility: Stanford
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital - San Diego
state: California
city: Aurora
country: United States
facility: The Children's Hospital
state: Colorado
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Miami
country: United States
facility: Miami Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Emory University Cystic Fibrosis Center
state: Georgia
city: Chicago
country: United States
facility: Children's Memorial Hospital
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins Children's Center
state: Maryland
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Cleveland
country: United States
facility: Rainbow Babies & Children's Hospital
state: Ohio
city: Pittsburgh
country: United States
facility: Childrens Hospital of Pittsburgh
state: Pennsylvania
city: Tyler
country: United States
facility: University of Texas
state: Texas
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Brussels
country: Belgium
facility: Hôpital Erasme
city: Brussels
country: Belgium
facility: Hôpital Universitaire des Enfants Reine Fabiola
city: Brussels
country: Belgium
facility: University Hospital Brussels
city: Leuven
country: Belgium
facility: University Hospital Leuven
city: Toronto
country: Canada
facility: University of Toronto
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Hôpital Necker - Enfants Malades
city: Toulouse
country: France
facility: Hôpital des Enfants
city: Köln
country: Germany
facility: Klinikum der Universität Köln
city: Jerusalem
country: Israel
facility: Hadassah University Hospital - Mount Scopus
city: Rome
country: Italy
facility: Università La Sapienza
city: Verona
country: Italy
facility: Azienda Ospedaliera di Verona
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Huddinge
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's Hospital
Study officials:
affiliation: PTC Therapeutics
name: Temitayo Ajayi, MD
role: STUDY_DIRECTOR
References:
citation: Kerem E, Konstan MW, De Boeck K, Accurso FJ, Sermet-Gaudelus I, Wilschanski M, Elborn JS, Melotti P, Bronsveld I, Fajac I, Malfroot A, Rosenbluth DB, Walker PA, McColley SA, Knoop C, Quattrucci S, Rietschel E, Zeitlin PL, Barth J, Elfring GL, Welch EM, Branstrom A, Spiegel RJ, Peltz SW, Ajayi T, Rowe SM; Cystic Fibrosis Ataluren Study Group. Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med. 2014 Jul;2(7):539-47. doi: 10.1016/S2213-2600(14)70100-6. Epub 2014 May 15.