Study of Ataluren in Nonsense Mutation Cystic Fibrosis (ACT CF)

NCT ID: NCT02139306

Last Updated: 2020-05-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 279 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-08-31
• Study Completion Date: 2016-11-30

Brief Summary

This is a Phase 3, international, multicenter, randomized, double-blind, placebo-controlled, efficacy and safety study of ataluren in patients with nonsense mutation cystic fibrosis (nmCF) not receiving chronic inhaled aminoglycosides.

Detailed Description

This study is to enroll 208 subjects (184 fully evaluable) with nonsense-mutation-mediated CF who are at least 6 years of age and have an forced expiratory volume in 1 second (FEV1) >= 40% and <= 90% of predicted. Subjects will be stratified based on age, inhaled antibiotic use, and baseline FEV1, and will be randomized in a 1:1 ratio to receive oral ataluren administered 3 times per day (TID) at respective morning, midday, and evening doses of 10-, 10-, and 20-mg/kg or placebo. Based on the results of a previously conducted study, patients treated with chronic inhaled aminoglycosides (including TOBI) will not be eligible for participation. Spirometry measurement at the screening visit will establish patient eligibility for inclusion based on lung function. FEV1 stability will be assessed during the approximately 4-week screening period, at the conclusion of which patients will be required to demonstrate a relative change in %-predicted FEV1 of less than 15% when compared to the screening value. Assessments will be performed every 8 weeks, depending upon the outcome measure.

Conditions

Cystic Fibrosis

Study Design

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

Study Groups

Ataluren (PTC124®)

Participants received ataluren as oral powder for suspension at the dosages of 10, 10, and 20-mg/kg at morning, midday and evening, respectively for 48 weeks of treatment duration or until treatment discontinuation.

Group Type: EXPERIMENTAL

Ataluren (PTC124®)

Intervention Type: DRUG

Oral Ataluren TID

Placebo

Participants received matching placebo orally at morning, midday and evening for 48 weeks of treatment duration or until treatment discontinuation.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Oral Placebo TID

Interventions

Ataluren (PTC124®)

Oral Ataluren TID

Intervention Type: DRUG

Placebo

Oral Placebo TID

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Evidence of signed and dated informed consent/assent document(s) indicating that the subject (and/or his parent/legal guardian) has been informed of all pertinent aspects of the trial
• Age >=6 years.
• Body weight >=16 kg.
• Sweat chloride >60 milliequivalent per liter (mEq/L)
• Documentation of the presence of a nonsense mutation in at least 1 allele of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, as determined by genotyping performed at a laboratory certified by the College of American Pathologists (CAP), or under the Clinical Laboratory Improvement Act/Amendment (CLIA), or by an equivalent organization
• Verification that a blood sample has been drawn for sequencing of 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
• Demonstration at Visit 2 of a valid %-predicted FEV1 within 15% of the Screening % predicted FEV1 value
• Resting oxygen saturation (as measured by pulse oximetry) >=92% on room air.
• Confirmed screening laboratory values within pre-specified ranges
• In subjects 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 60-day follow-up period
• Willingness and ability to comply with all study procedures and assessments, including scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions

Exclusion Criteria

• Known hypersensitivity to any of the ingredients or excipients of the study drug
• Previous participation in the Phase 3 trial of ataluren (PTC124-GD-009-CF).
• Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or re-initiation) in a chronic treatment/prophylaxis regimen for Cystic Fibrosis (CF) or for CF-related conditions within 4 weeks prior to screening
• Chronic use of inhaled aminoglycosides (eg, tobramycin) or use of inhaled aminoglycosides within 4 weeks prior to screening.
• Exposure to another investigational drug within 4 weeks prior to screening
• Ongoing participation in any other therapeutic clinical trial
• Evidence of pulmonary exacerbation or acute upper or lower respiratory tract infection (including viral illnesses) within 3 weeks prior to screening
• Treatment with intravenous antibiotics within 3 weeks prior to screening
• Ongoing immunosuppressive therapy (other than corticosteroids)
• Ongoing warfarin, phenytoin, or tolbutamide therapy
• History of solid organ or hematological transplantation
• Major complications of lung disease (including massive hemoptysis, pneumothorax, or pleural effusion) within 8 weeks prior to screening
• 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 x number of years smoked).
• Prior or ongoing medical condition (eg, concomitant illness, alcoholism, drug abuse, psychiatric condition), medical history, physical findings, electrocardiogram (ECG) findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the subject, 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

ECFS-Clinical Trial Network (ECFS-CTN)

UNKNOWN

Sponsor Role: collaborator

PTC Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Joseph McIntosh, MD

Role: STUDY_DIRECTOR

PTC Therapeutics

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Pulmonary Associates of Mobile PC

Mobile, Alabama, United States

Miller Children's Hospital Long Beach

Long Beach, California, United States

Children's Hospital Los Angeles

Los Angeles, California, United States

Children's Hospital and Research Center at Oakland

Oakland, California, United States

Stanford University-Children's Hospital

Palo Alto, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Nemours Children's Clinic

Jacksonville, Florida, United States

University of Miami

Miami, Florida, United States

Miami Children's Hospital

Miami, Florida, United States

All Children's Hospital

St. Petersburg, Florida, United States

Ann and Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

Indiana University

Indianapolis, Indiana, United States

Children's Hospital Boston

Boston, Massachusetts, United States

Washington University

St Louis, Missouri, United States

Monmouth Medical Center

Long Branch, New Jersey, United States

Morristown Medical Center

Morristown, New Jersey, United States

Beth Israel Medical Center

New York, New York, United States

New York University Langone Medical Center

New York, New York, United States

Columbia University Medical Center

New York, New York, United States

SUNY Upstate Medical University

Syracuse, New York, United States

University of Cincinnati

Cincinnati, Ohio, United States

Rainbow Babies & Children's Hospital

Cleveland, Ohio, United States

Santiago Reyes, MD

Oklahoma City, Oklahoma, United States

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Drexel University College of Medicine

Philadelphia, Pennsylvania, United States

Texas Children's Hospital

Houston, Texas, United States

University of Texas Health Science Center

Tyler, Texas, United States

Childrens Hospital of Wisconsin

Milwaukee, Wisconsin, United States

Hospital Universitario Austral

Buenos Aires, , Argentina

Hospital de Niños Dr. Ricardo Gutiérrez

Buenos Aires, , Argentina

Hospital de Niños Superiora Sor Maria Ludovica

La Plata, , Argentina

Royal Adelaide Hospital

Adelaide, , Australia

Prince Charles Hospital

Chermside, , Australia

Princess Margaret Hospital

Perth, , Australia

Hôpital Universitaire des Enfants Reine Fabiola

Brussels, , Belgium

University Hospital Brussels

Brussels, , Belgium

University Hospital Leuven

Leuven, , Belgium

Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul

Porto Alegre, , Brazil

Instituto da Criança - Hospital das Clínicas

São Paulo, , Brazil

University Mulitiprofile Hospital for Active Treatment Sveti Georgi EAD

Plovdiv, , Bulgaria

University Multiprofile Hospital for Active Treatment Aleksandrovska EAD

Sofia, , Bulgaria

Clinical Research Institute of Montreal

Montreal, , Canada

CHU de Quebec - Hopital CHUL

Québec, , Canada

University of Toronto Hospital for Sick Children

Toronto, , Canada

British Columbia Children's Hospital

Vancouver, , Canada

Hôpital Femme-Mère-Enfant

Bron, , France

Hôpital Arnaud de Villeneuve

Montpellier, , France

Hôpital Necker-Enfants Malades

Paris, , France

Centre de Perharidy

Roscoff, , France

Centre Hospitalier Regional Sud Reunion

Saint-Pierre, , France

Charité Universitätsmedizin Berlin

Berlin, , Germany

St. Josef Hospital GmbH

Bochum, , Germany

Universitätsklinikum Köln

Cologne, , Germany

Christiane Herzog CF-Zentrum

Frankfurt am Main, , Germany

Universitätsklinikum Jena

Jena, , Germany

LMU Klinikum der Universität München

München, , Germany

Dr. Von Haunersches Kinderspital

München, , Germany

General Hospital of Thessaloniki Ippokration

Thessaloniki, , Greece

Meyer Children's Hospital

Haifa, , Israel

Hadassah University Hospital

Jerusalem, , Israel

Ospedali Riuniti di Ancona

Ancona, , Italy

Azienda Ospedaliera A Meyer

Florence, , Italy

Lombardia Cystic Fibrosis Center

Milan, , Italy

Ospedale Pediatrico Bambino Gesù IRCCS

Roma, , Italy

Azienda Policlinico Umberto I

Rome, , Italy

University of Verona

Verona, , Italy

Radboud University

Nijmegen, , Netherlands

Erasmus MC

Rotterdam, , Netherlands

Hagaziekenhuis

The Hague, , Netherlands

Szpital Dzieciecy Polanki im Macieja Plazynskiego w Gdansku

Gdansk, , Poland

NZOZ Sanatorium Cassia-Villa Medica

Rabka-Zdrój, , Poland

NZOZ Podkarpacki Osrodek Pulmonologii i Alergologii

Rzeszów, , Poland

Instytut Matki I Dziecka

Warsaw, , Poland

Hospital Universitario Vall d'Hebron

Barcelona, , Spain

Hospital University

Barcelona, , Spain

Hospital Sant Joan de Deu

Esplugues de Llobregat, , Spain

Hospital Regional Universitario de Malaga

Málaga, , Spain

Hospital de Sabadell, Consorci Sanitari Parc Tauli

Sabadell, , Spain

Hospital Universitario Virgen del Rocio

Seville, , Spain

Birmingham Children's Hospital NHS Foundation Trust

Birmingham, , United Kingdom

Heart of England NHS Foundation Trust

Birmingham, , United Kingdom

Southern General Hospital

Glasgow, , United Kingdom

St James's University Hospital

Leeds, , United Kingdom

Royal Brompton Hospital

London, , United Kingdom

Llandough Hospital

Penarth, , United Kingdom

Southampton University Hospitals NHS Trust

Southampton, , United Kingdom

Countries

United States; Argentina; Australia; Belgium; Brazil; Bulgaria; Canada; France; Germany; Greece; Israel; Italy; Netherlands; Poland; Spain; United Kingdom

References

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)

VanDevanter DR, Hamblett NM, Simon N, McIntosh J, Konstan MW. Evaluating assumptions of definition-based pulmonary exacerbation endpoints in cystic fibrosis clinical trials. J Cyst Fibros. 2021 Jan;20(1):39-45. doi: 10.1016/j.jcf.2020.07.008. Epub 2020 Jul 15.

Reference Type: DERIVED

PMID: 32682670 (View on PubMed)

Konstan MW, VanDevanter DR, Rowe SM, Wilschanski M, Kerem E, Sermet-Gaudelus I, DiMango E, Melotti P, McIntosh J, De Boeck K; ACT CF Study Group. Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: The international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF). J Cyst Fibros. 2020 Jul;19(4):595-601. doi: 10.1016/j.jcf.2020.01.007. Epub 2020 Jan 23.

Reference Type: DERIVED

PMID: 31983658 (View on PubMed)

Related Links

http://www.ptcbio.com

Related Info

Other Identifiers

2013-004581-34

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PTC124-GD-021-CF

Identifier Type: -

Identifier Source: org_study_id