Study of Ataluren (PTC124™) in Cystic Fibrosis

NCT00803205 | Completed Phase 3 Results DMC

• 3 other identifiers: PTC124-GD-009-CFOrphan Product Grant #FD0037152008-003924-52
• Study Type: interventional
• Target: 238
• Locations: 11 countries
• Sites: 38

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.

Conditions

Cystic Fibrosis

Keywords

Cystic fibrosis; Nonsense mutation; Premature stop codon; PTC124; Ataluren; PTC Therapeutics

Outcome Measures

Primary Outcomes (2)

• Percentage of Predicted Function (Percent-Predicted) of Forced Expiratory Volume in One Second (FEV1) at Baseline

  Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FEV1 (the amount of air that can be exhaled in 1 second). Spirometry was assessed by using current guidelines of the American Thoracic Society (ATS) and European Respiratory Society (ERS). Baseline was the average of percent-predicted FEV1 at screening and randomization.

  Baseline (Week 1)

• Percentage Change From Baseline in Percent-Predicted of FEV1 at Week 48

  Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FEV1 (the amount of air that can be exhaled in 1 second). Spirometry was assessed by using current guidelines of the American Thoracic Society (ATS) and European Respiratory Society (ERS). The percentage of change in percent-predicted of FEV1 was calculated as follows: (\[percent-predicted FEV1-Baseline percent-predicted FEV1\]/Baseline percent-predicted FEV1)\*100. Baseline was the average of percent-predicted FEV1 at screening and randomization. A negative change from Baseline indicates that percent-predicted of FEV1 decreased.

  End of Treatment (EOT) (Week 48)

Secondary Outcomes (5)

• Rate of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria Over 48 Weeks

  Baseline to EOT (Week 48)

• Change From Baseline in Awake Cough Hourly Rate at Week 48

  Baseline, EOT (Week 48)

• Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48

  Baseline, EOT (Week 48)

• Percent-Predicted of Forced Vital Capacity (FVC) at Baseline

  Baseline (Week 1)

• Percentage Change From Baseline in Percent-Predicted of FVC at Week 48

  EOT (Week 48)

Other Outcomes (13)

• Percentage of Participants With Treatment-Emergent Adverse Events (TEAE)

  Baseline up to 4 Weeks Post-Treatment (Week 52) or Premature Discontinuation (PD)

• Rate of Study Drug Compliance by Drug Accountability

  Baseline up to EOT (Week 48)

• Rate of Study Drug Compliance by Patient-Reported Data

  Baseline up to EOT (Week 48)

Study Arms (2)

Ataluren

EXPERIMENTAL

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.

Drug: Ataluren

Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo

Interventions

Ataluren DRUG

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

Also known as: PTC124

Ataluren

Placebo DRUG

Placebo matching to ataluren will be provided.

Placebo

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• PTC Therapeutics: lead
• Cystic Fibrosis Foundation: collaborator

Study Sites (38)

University of Alabama-Birmingham

Birmingham, Alabama, 35233, United States

Location

Miller Children's Hospital Long Beach

Long Beach, California, 90806, United States

Location

Lucile Packard Children's Hospital

Palo Alto, California, 94304, United States

Location

Stanford

Palo Alto, California, 94304, United States

Location

Rady Children's Hospital - San Diego

San Diego, California, 92123, United States

Location

The Children's Hospital

Aurora, Colorado, 80045, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

Miami Children's Hospital

Miami, Florida, 33155, United States

Location

Emory University Cystic Fibrosis Center

Atlanta, Georgia, 30322, United States

Location

Children's Memorial Hospital

Chicago, Illinois, 60614, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Johns Hopkins Children's Center

Baltimore, Maryland, 21287, United States

Location

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Beth Israel Medical Center

New York, New York, 10011, United States

Location

New York Medical College

Valhalla, New York, 10595, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Rainbow Babies & Children's Hospital

Cleveland, Ohio, 44106, United States

Location

Childrens Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

University of Texas

Tyler, Texas, 75708, United States

Location

University of Washington

Seattle, Washington, 98195, United States

Location

Hôpital Erasme

Brussels, Belgium

Location

Hôpital Universitaire des Enfants Reine Fabiola

Brussels, Belgium

Location

University Hospital Brussels

Brussels, Belgium

Location

University Hospital Leuven

Leuven, Belgium

Location

University of Toronto

Toronto, Canada

Location

Hôpital Cochin

Paris, France

Location

Hôpital Necker - Enfants Malades

Paris, France

Location

Hôpital des Enfants

Toulouse, 31059, France

Location

Klinikum der Universität Köln

Cologne, Germany

Location

Hadassah University Hospital - Mount Scopus

Jerusalem, 91240, Israel

Location

Università La Sapienza

Rome, Italy

Location

Azienda Ospedaliera di Verona

Verona, Italy

Location

Universitair Medisch Centrum Utrecht

Utrecht, Netherlands

Location

Hospital Universitario La Paz

Madrid, Spain

Location

Karolinska University Hospital, Huddinge

Stockholm, Sweden

Location

Belfast City Hospital

Belfast, United Kingdom

Location

Alder Hey Children's Hospital

Liverpool, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 24836205 RESULT

• 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.

  PMID: 36866921 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

• Temitayo Ajayi, MD

  PTC Therapeutics

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 4, 2008
• First Posted: December 5, 2008
• Study Start: September 8, 2009
• Primary Completion: November 12, 2011
• Study Completion: November 12, 2011
• Last Updated: May 14, 2020
• Results First Posted: May 14, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will not share

Locations

BE (4); FR (3); DE (1); IT (2); ES (1); SE (1); GB (2); IL (1); CA (1); US (21); NL (1)