Study of Ataluren in Nonsense Mutation Cystic Fibrosis (ACT CF)
- Registration Number
- NCT02139306
- Lead Sponsor
- PTC Therapeutics
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 279
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Ataluren (PTC124®) 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. Placebo Placebo Participants received matching placebo orally at morning, midday and evening for 48 weeks of treatment duration or until treatment discontinuation.
- Primary Outcome Measures
Name Time Method Absolute Change From Baseline in Percent-predicted Forced Expiratory Volume in One Second (ppFEV1) at Week 48 From Baseline to 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.
- Secondary Outcome Measures
Name Time Method Change From Baseline in the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain at Week 48 Baseline (Day 1) and 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.
48-week Rate of Pulmonary Exacerbations Week 48 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.
Number of Participants With TEAEs by Severity and Relationship to Study Drugs From study drug administration to 4-week post treatment follow-up visit (approximately 52 weeks) 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).
Change From Baseline in Body Mass Index (BMI) at Week 48 Baseline (Day 1) and Week 48 Malnutrition is common in participants with cystic fibrosis. The BMI is an important clinical measure of nutritional status.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) From study drug administration to 4-week post treatment follow-up visit (approximately 52 weeks) 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.
Number of Participants With SAEs by Severity and Relationship to Study Drugs From study drug administration to 4-week post treatment follow-up visit (approximately 52 weeks) 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).
Number of Participants With Abnormal Vital Signs Reported as TEAEs From study drug administration to 4-week post treatment follow-up visit (approximately 52 weeks) 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.
Number of Participants With Abnormal Electrocardiogram Reported as TEAEs From study drug administration to 4-week post treatment follow-up visit (approximately 52 weeks) 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.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs From study drug administration to 4-week post treatment follow-up visit (approximately 52 weeks) 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.
Trial Locations
- Locations (88)
Rainbow Babies & Children's Hospital
🇺🇸Cleveland, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Drexel University College of Medicine
🇺🇸Philadelphia, Pennsylvania, United States
Instituto da Criança - Hospital das Clínicas
🇧🇷São Paulo, Brazil
New York University Langone Medical Center
🇺🇸New York, New York, United States
Princess Margaret Hospital
🇦🇺Perth, Australia
Penn State Milton S. Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
SUNY Upstate Medical University
🇺🇸Syracuse, New York, United States
University Hospital Brussels
🇧🇪Brussels, Belgium
Royal Adelaide Hospital
🇦🇺Adelaide, Australia
Hospital de Niños Dr. Ricardo Gutiérrez
🇦🇷Buenos Aires, Argentina
Beth Israel Medical Center
🇺🇸New York, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Heart of England NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
Southampton University Hospitals NHS Trust
🇬🇧Southampton, United Kingdom
Hospital de Sabadell, Consorci Sanitari Parc Tauli
🇪🇸Sabadell, Spain
General Hospital of Thessaloniki Ippokration
🇬🇷Thessaloniki, Greece
Lombardia Cystic Fibrosis Center
🇮🇹Milan, Italy
Hospital University
🇪🇸Barcelona, Spain
Hadassah University Hospital
🇮🇱Jerusalem, Israel
Birmingham Children's Hospital NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
Llandough Hospital
🇬🇧Penarth, United Kingdom
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Regional Universitario de Malaga
🇪🇸Málaga, Spain
Southern General Hospital
🇬🇧Glasgow, United Kingdom
St James's University Hospital
🇬🇧Leeds, United Kingdom
Washington University
🇺🇸Saint Louis, Missouri, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Morristown Medical Center
🇺🇸Morristown, New Jersey, 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 and Research Center at Oakland
🇺🇸Oakland, California, United States
Stanford University-Children's Hospital
🇺🇸Palo Alto, California, United States
University of Miami
🇺🇸Miami, Florida, United States
All Children's Hospital
🇺🇸Saint Petersburg, Florida, United States
Ann and Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States
Indiana University
🇺🇸Indianapolis, Indiana, United States
University of Texas Health Science Center
🇺🇸Tyler, Texas, United States
Prince Charles Hospital
🇦🇺Chermside, Australia
British Columbia Children's Hospital
🇨🇦Vancouver, Canada
Hôpital Arnaud de Villeneuve
🇫🇷Montpellier, France
Hôpital Necker-Enfants Malades
🇫🇷Paris, France
Hôpital Femme-Mère-Enfant
🇫🇷Bron, France
Meyer Children's Hospital
🇮🇱Haifa, Israel
Monmouth Medical Center
🇺🇸Long Branch, New Jersey, United States
Nemours Children's Clinic
🇺🇸Jacksonville, Florida, United States
Miami Children's Hospital
🇺🇸Miami, Florida, United States
University Hospital Leuven
🇧🇪Leuven, Belgium
Hôpital Universitaire des Enfants Reine Fabiola
🇧🇪Bruxelles, Belgium
University Multiprofile Hospital for Active Treatment Aleksandrovska EAD
🇧🇬Sofia, Bulgaria
Clinical Research Institute of Montreal
🇨🇦Montreal, Canada
CHU de Quebec - Hopital CHUL
🇨🇦Québec City, Canada
Children's Hospital Boston
🇺🇸Boston, Massachusetts, United States
Hospital Universitario Austral
🇦🇷Buenos Aires, Argentina
Dr. Von Haunersches Kinderspital
🇩🇪München, Germany
Ospedali Riuniti di Ancona
🇮🇹Ancona, Italy
Hagaziekenhuis
🇳🇱Den Haag, Netherlands
Hospital de Niños Superiora Sor Maria Ludovica
🇦🇷La Plata, Argentina
Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul
🇧🇷Porto Alegre, Brazil
University Mulitiprofile Hospital for Active Treatment Sveti Georgi EAD
🇧🇬Plovdiv, Bulgaria
Charité Universitätsmedizin Berlin
🇩🇪Berlin, Germany
Erasmus MC
🇳🇱Rotterdam, Netherlands
Ospedale Pediatrico Bambino Gesù IRCCS
🇮🇹Roma, Italy
University of Toronto Hospital for Sick Children
🇨🇦Toronto, Canada
Universitätsklinikum Köln
🇩🇪Cologne, Germany
Universitätsklinikum Jena
🇩🇪Jena, Germany
LMU Klinikum der Universität München
🇩🇪München, Germany
Centre de Perharidy
🇫🇷Roscoff, France
Centre Hospitalier Regional Sud Reunion
🇫🇷Saint-Pierre, France
St. Josef Hospital GmbH
🇩🇪Bochum, Germany
Christiane Herzog CF-Zentrum
🇩🇪Frankfurt am Main, Germany
Azienda Policlinico Umberto I
🇮🇹Rome, Italy
Azienda Ospedaliera A Meyer
🇮🇹Firenze, Italy
Radboud University
🇳🇱Nijmegen, Netherlands
Instytut Matki I Dziecka
🇵🇱Warsaw, Poland
University of Verona
🇮🇹Verona, Italy
Szpital Dzieciecy Polanki im Macieja Plazynskiego w Gdansku
🇵🇱Gdansk, Poland
NZOZ Podkarpacki Osrodek Pulmonologii i Alergologii
🇵🇱Rzeszow, Poland
NZOZ Sanatorium Cassia-Villa Medica
🇵🇱Rabka-Zdrój, Poland
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Santiago Reyes, MD
🇺🇸Oklahoma City, Oklahoma, United States
Childrens Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Hospital Sant Joan de Deu
🇪🇸Esplugues De Llobregat, Spain
Hospital Universitario Virgen del Rocio
🇪🇸Sevilla, Spain
Royal Brompton Hospital
🇬🇧London, United Kingdom