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

A Phase 3 Efficacy and Safety Study of Ataluren (PTC124®) in Patients With Nonsense Mutation Cystic Fibrosis

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Ataluren (PTC124®); Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 279
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, B1629ODT
    • Hospital Universitario Austral
  • Buenos Aires, Argentina, C1425EFD
    • Hospital de Niños Dr. Ricardo Gutiérrez
  • La Plata, Argentina, 1900
    • Hospital de Niños Superiora Sor María Ludovica
• Australia
  • Adelaide, Australia, 5000
    • Royal Adelaide Hospital
  • Chermside, Australia, 4032
    • Prince Charles Hospital
  • Perth, Australia, 6840
    • Princess Margaret Hospital
• Belgium
  • Brussels, Belgium, 1090
    • University Hospital Brussels
  • Bruxelles, Belgium, 1020
    • Hôpital Universitaire des Enfants Reine Fabiola
  • Leuven, Belgium, 3000
    • University Hospital Leuven
• Brazil
  • Porto Alegre, Brazil
    • Hospital Sao Lucas da Pontificia Universidade Catolica do Rio Grande do Sul
  • São Paulo, Brazil, 05403-000
    • Instituto da Criança - Hospital das Clínicas
• Bulgaria
  • Plovdiv, Bulgaria
    • University Mulitiprofile Hospital for Active Treatment Sveti Georgi EAD
  • Sofia, Bulgaria
    • University Multiprofile Hospital for Active Treatment Aleksandrovska EAD
• Canada
  • Montreal, Canada, H2W 1R7
    • Clinical Research Institute of Montreal
  • Québec City, Canada, G1V 4G2
    • CHU de Quebec - Hopital CHUL
  • Toronto, Canada, M5G 1X8
    • University of Toronto Hospital for Sick Children
  • Vancouver, Canada, V6H 3V4
    • British Columbia Children's Hospital
• France
  • Bron, France, 69677
    • Hôpital Femme-Mère-Enfant
  • Montpellier, France, 34295
    • Hôpital Arnaud de Villeneuve
  • Paris, France, 75015
    • Hôpital Necker-Enfants Malades
  • Roscoff, France, 29684
    • Centre de Perharidy
  • Saint-Pierre, France, 97448
    • Centre Hospitalier Regional Sud Reunion
• Germany
  • Berlin, Germany, 13353
    • Charite Universitatsmedizin Berlin
  • Bochum, Germany, 44791
    • St. Josef Hospital GmbH
  • Cologne, Germany, 50937
    • Universitätsklinikum Köln
  • Frankfurt am Main, Germany, 60590
    • Christiane Herzog CF-Zentrum
  • Jena, Germany, 07745
    • Universitätsklinikum Jena
  • München, Germany, 80337
    • Dr. von Haunersches Kinderspital
  • München, Germany, 80336
    • LMU Klinikum der Universität München
• Greece
  • Thessaloniki, Greece
    • General Hospital of Thessaloniki Ippokration
• Israel
  • Haifa, Israel, 31096
    • Meyer Children's Hospital
  • Jerusalem, Israel, 91240
    • Hadassah University Hospital
• Italy
  • Ancona, Italy, 60123
    • Ospedali Riuniti Di Ancona
  • Firenze, Italy, 50139
    • Azienda Ospedaliera A Meyer
  • Milan, Italy, 20122
    • Lombardia Cystic Fibrosis Center
  • Roma, Italy
    • Ospedale Pediatrico Bambino Gesù IRCCS
  • Rome, Italy, 00161
    • Azienda Policlinico Umberto I
  • Verona, Italy, 37126
    • University of Verona
• Netherlands
  • Den Haag, Netherlands, 2491
    • HagaZiekenhuis
  • Nijmegen, Netherlands, 6525 GA
    • Radboud University
  • Rotterdam, Netherlands
    • Erasmus MC
• Poland
  • Gdansk, Poland
    • Szpital Dzieciecy Polanki im Macieja Plazynskiego w Gdansku
  • Rabka-Zdrój, Poland, 34-700
    • NZOZ Sanatorium Cassia-Villa Medica
  • Rzeszow, Poland, 35-612
    • NZOZ Podkarpacki Osrodek Pulmonologii i Alergologii
  • Warsaw, Poland, 01-211
    • Instytut Matki i Dziecka
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain, 08035
    • Hospital University
  • Esplugues De Llobregat, Spain, 08950
    • Hospital Sant Joan de Déu
  • Málaga, Spain
    • Hospital Regional Universitario de Malaga
  • Sabadell, Spain, 08208
    • Hospital de Sabadell, Consorci Sanitari Parc Tauli
  • Sevilla, Spain
    • Hospital Universitario Virgen del Rocío
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Children's Hospital NHS Foundation Trust
  • Birmingham, United Kingdom
    • Heart of England NHS Foundation Trust
  • Glasgow, United Kingdom, G120YN
    • Southern General Hospital
  • Leeds, United Kingdom
    • St James's University Hospital
  • London, United Kingdom
    • Royal Brompton Hospital
  • Penarth, United Kingdom, CF64 2XX
    • LLandough Hospital
  • Southampton, United Kingdom
    • Southampton University Hospitals NHS Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
    • Mobile, Alabama, United States, 36608
      • Pulmonary Associates of Mobile PC
  • California
    • Long Beach, California, United States, 90806
      • Miller Children's Hospital Long Beach
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Oakland, California, United States, 94609
      • Children's Hospital and Research Center at Oakland
    • Palo Alto, California, United States, 94304
      • Stanford University-Children's Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Miami, Florida, United States, 33136
      • University of Miami
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H. Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New Jersey
    • Long Branch, New Jersey, United States, 07740
      • Monmouth Medical Center
    • Morristown, New Jersey, United States, 07960
      • Morristown Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10003
      • Beth Israel Medical Center
    • New York, New York, United States, 10016
      • New York University Langone Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • Ohio
    • Cincinnati, Ohio, United States, 45221
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies & Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Santiago Reyes, MD
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19129
      • Drexel University College of Medicine
  • Texas
    • Houston, Texas, United States, 77094
      • Texas Children's Hospital
    • Tyler, Texas, United States, 75708
      • University of Texas Health Science Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Childrens Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Ataluren (PTC124®); Oral Ataluren TID
Placebo Comparator: Placebo; Participants received matching placebo orally at morning, midday and evening for 48 weeks of treatment duration or until treatment discontinuation.	Drug: Placebo; Oral Placebo TID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline in Percent-predicted Forced Expiratory Volume in One Second (ppFEV1) at Week 48	The FEV1 is the volume of air forcibly exhaled in one second and is measured using forced expiratory air spirometry. Change in ppFEV1 at Week 48 was defined as the average between the change from baseline at Week 40 and that at Week 48. Baseline for ppFEV1 was defined as an average of ppFEV1 at Screening (Weeks -4 to -1) and Baseline (Day 1) visits.	From Baseline to Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
48-week Rate of Pulmonary Exacerbations	Pulmonary exacerbations were assessed using expanded Fuchs criteria. The expanded Fuchs exacerbation is defined as the presence of at least 4 of 12 Fuchs' signs and symptoms requiring treatment with any form of antibiotic treatment (inhaled, oral, or intravenous). Fuchs' signs and symptoms included increased cough; change in sputum volume, color, or consistency; new or increased hemoptysis; increased dyspnea during moderate or mild exertion, or at rest; sinus pain or tenderness; change in sinus discharge; malaise, fatigue, or lethargy; anorexia or weight loss; temperature above 38 degrees Celsius; change in findings on chest examination; relative 10% decrease in ppFEV1, and chest radiography results consistent with pulmonary infection. The 48-week rate was calculated as: 48-week rate = total number of events /treatment duration by week*48.	Week 48
Change From Baseline in the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain at Week 48	The teen/adult CFQ-R was used for this study. It was developed specifically for participants with cystic fibrosis. It is a disease-specific instrument designed to measure impact on overall health, daily life, perceived well-being, and symptoms. The respiratory domain assessed respiratory symptoms like coughing, congestion, wheezing etc. Scaling of each item is done via 4-point Likert scales. Scores for each item are summed up to generate a domain score. Scores ranges from 0 to 100, with higher scores indicating better health and lower scores indicating worse health.	Baseline (Day 1) and Week 48
Change From Baseline in Body Mass Index (BMI) at Week 48	Malnutrition is common in participants with cystic fibrosis. The BMI is an important clinical measure of nutritional status.	Baseline (Day 1) and Week 48
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)	An adverse event (AE) is any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A TEAE is defined as an AE that occurs or worsens in the period extending from first dose of study drug to 4 weeks after last dose of study drug. An SAE is an untoward medical occurrence or effect associated with the use of a study drug at any dose, regardless of whether it is considered to be related to the study drug, which results in one of the following: death; inpatient hospitalization or prolongation of existing hospitalization; life threatening adverse event; persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions; any other medically important event; or a pregnancy resulting in spontaneous abortion, stillbirth, neonatal death, or congenital anomaly.	From study drug administration to 4-week post treatment follow-up visit (approximately 52 weeks)
Number of Participants With TEAEs by Severity and Relationship to Study Drugs	The relationship of TEAEs to the study drugs were assessed as: probable related, possibly related, unlikely related, and unrelated. The severity of TEAEs were graded using the Common Terminology Criteria for Adverse Events, Version 3.0 as: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal).	From study drug administration to 4-week post treatment follow-up visit (approximately 52 weeks)
Number of Participants With SAEs by Severity and Relationship to Study Drugs	The relationship of SAEs to the study drugs were assessed as: probable related, possibly related, unlikely related, and unrelated. The severity of SAEs were graded using the Common Terminology Criteria for Adverse Events, Version 3.0 as: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal).	From study drug administration to 4-week post treatment follow-up visit (approximately 52 weeks)
Number of Participants With Abnormal Vital Signs Reported as TEAEs	Vital signs included systolic and diastolic blood pressure, pulse rate, pulse oximetry, and body temperature. Participants with abnormal vital signs who required clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test) unless they are associated with an already reported clinical event are reported.	From study drug administration to 4-week post treatment follow-up visit (approximately 52 weeks)
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs	Clinical laboratory tests included haematology, biochemistry, and urinalysis. Participants with abnormal laboratory parameters who required clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test) unless they are associated with an already reported clinical event are reported.	From study drug administration to 4-week post treatment follow-up visit (approximately 52 weeks)
Number of Participants With Abnormal Electrocardiogram Reported as TEAEs	Participants with abnormal electrocardiogram who required clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test) unless they are associated with an already reported clinical event are reported.	From study drug administration to 4-week post treatment follow-up visit (approximately 52 weeks)

Collaborators and Investigators

• Sponsor: PTC Therapeutics
• Collaborators: Cystic Fibrosis Foundation; ECFS-Clinical Trial Network (ECFS-CTN)
• Investigators: Study Director: Joseph McIntosh, MD, PTC Therapeutics

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2014
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: May 13, 2014
• First Submitted That Met QC Criteria: May 14, 2014
• First Posted (Estimate): May 15, 2014

Study Record Updates

• Last Update Posted (Actual): May 14, 2020
• Last Update Submitted That Met QC Criteria: May 4, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: PTC124-GD-021-CF; 2013-004581-34 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No