Study of Ataluren (PTC124™) in Cystic Fibrosis

NCT ID: NCT00803205

Last Updated: 2020-05-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 238 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-09-08
• Study Completion Date: 2011-11-12

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.

Conditions

Cystic Fibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Ataluren

Participants will receive ataluren 3 times per day (TID): 10 milligrams (mg)/kilogram (kg) of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment will continue for 48 weeks, after which participants will be followed for 4 weeks.

Group Type: EXPERIMENTAL

Ataluren

Intervention Type: DRUG

Ataluren will be provided as a vanilla-flavored powder to be mixed with water.

Placebo

Participants will receive placebo TID: 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment will continue for 48 weeks, after which participants will be followed for 4 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo matching to ataluren will be provided.

Interventions

Ataluren

Ataluren will be provided as a vanilla-flavored powder to be mixed with water.

Intervention Type: DRUG

Placebo

Placebo matching to ataluren will be provided.

Intervention Type: DRUG

Other Intervention Names

PTC124

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.

• Minimum Eligible Age: 6 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cystic Fibrosis Foundation

OTHER

Sponsor Role: collaborator

PTC Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Temitayo Ajayi, MD

Role: STUDY_DIRECTOR

PTC Therapeutics

Locations

University of Alabama-Birmingham

Birmingham, Alabama, United States

Miller Children's Hospital Long Beach

Long Beach, California, United States

Lucile Packard Children's Hospital

Palo Alto, California, United States

Stanford

Palo Alto, California, United States

Rady Children's Hospital - San Diego

San Diego, California, United States

The Children's Hospital

Aurora, Colorado, United States

University of Miami

Miami, Florida, United States

Miami Children's Hospital

Miami, Florida, United States

Emory University Cystic Fibrosis Center

Atlanta, Georgia, United States

Children's Memorial Hospital

Chicago, Illinois, United States

University of Iowa

Iowa City, Iowa, United States

Johns Hopkins Children's Center

Baltimore, Maryland, United States

Children's Hospital Boston

Boston, Massachusetts, United States

Washington University

St Louis, Missouri, United States

Beth Israel Medical Center

New York, New York, United States

New York Medical College

Valhalla, New York, United States

University of North Carolina

Chapel Hill, North Carolina, United States

Rainbow Babies & Children's Hospital

Cleveland, Ohio, United States

Childrens Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

University of Texas

Tyler, Texas, United States

University of Washington

Seattle, Washington, United States

Hôpital Erasme

Brussels, , Belgium

Hôpital Universitaire des Enfants Reine Fabiola

Brussels, , Belgium

University Hospital Brussels

Brussels, , Belgium

University Hospital Leuven

Leuven, , Belgium

University of Toronto

Toronto, , Canada

Hôpital Cochin

Paris, , France

Hôpital Necker - Enfants Malades

Paris, , France

Hôpital des Enfants

Toulouse, , France

Klinikum der Universität Köln

Cologne, , Germany

Hadassah University Hospital - Mount Scopus

Jerusalem, , Israel

Università La Sapienza

Rome, , Italy

Azienda Ospedaliera di Verona

Verona, , Italy

Universitair Medisch Centrum Utrecht

Utrecht, , Netherlands

Hospital Universitario La Paz

Madrid, , Spain

Karolinska University Hospital, Huddinge

Stockholm, , Sweden

Belfast City Hospital

Belfast, , United Kingdom

Alder Hey Children's Hospital

Liverpool, , United Kingdom

Countries

United States; Belgium; Canada; France; Germany; Israel; Italy; Netherlands; Spain; Sweden; United Kingdom

References

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.

Reference Type: RESULT

PMID: 24836205 (View on PubMed)

Aslam AA, Sinha IP, Southern KW. Ataluren and similar compounds (specific therapies for premature termination codon class I mutations) for cystic fibrosis. Cochrane Database Syst Rev. 2023 Mar 3;3(3):CD012040. doi: 10.1002/14651858.CD012040.pub3.

Reference Type: DERIVED

PMID: 36866921 (View on PubMed)

Other Identifiers

Orphan Product Grant #FD003715

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

2008-003924-52

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PTC124-GD-009-CF

Identifier Type: -

Identifier Source: org_study_id