Clinical trial NCT02139306: Study of Ataluren in Nonsense Mutation Cystic Fibrosis (ACT CF)
Official title: A Phase 3 Efficacy and Safety Study of Ataluren (PTC124®) in Patients With Nonsense Mutation Cystic Fibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cystic Fibrosis
Lead sponsor: PTC Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Cystic Fibrosis Foundation
name: ECFS-Clinical Trial Network (ECFS-CTN)
First posted: 2014-05-15
Enrollment: 279
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

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