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

Cystic Fibrosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02139306
• Other study ID #: PTC124-GD-021-CF
• Secondary ID: 2013-004581-34
• Status: Completed
• Phase: Phase 3
• Start date: August 2014
• Est. completion date: November 2016

Study information

• Verified date: May 2020
• Source: PTC Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 279
• Est. completion date: November 2016
• Est. primary completion date: November 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• Ataluren (PTC124®)
Oral Ataluren TID
• Placebo
Oral Placebo TID

Locations

Country	Name	City	State
Argentina	Hospital de Niños Dr. Ricardo Gutiérrez	Buenos Aires
Argentina	Hospital Universitario Austral	Buenos Aires
Argentina	Hospital de Niños Superiora Sor Maria Ludovica	La Plata
Australia	Royal Adelaide Hospital	Adelaide
Australia	Prince Charles Hospital	Chermside
Australia	Princess Margaret Hospital	Perth
Belgium	University Hospital Brussels	Brussels
Belgium	Hôpital Universitaire des Enfants Reine Fabiola	Bruxelles
Belgium	University Hospital Leuven	Leuven
Brazil	Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul	Porto Alegre
Brazil	Instituto da Criança - Hospital das Clínicas	São Paulo
Bulgaria	University Mulitiprofile Hospital for Active Treatment Sveti Georgi EAD	Plovdiv
Bulgaria	University Multiprofile Hospital for Active Treatment Aleksandrovska EAD	Sofia
Canada	Clinical Research Institute of Montreal	Montreal
Canada	CHU de Quebec - Hopital CHUL	Québec City
Canada	University of Toronto Hospital for Sick Children	Toronto
Canada	British Columbia Children's Hospital	Vancouver
France	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
Germany	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	Dr. Von Haunersches Kinderspital	München
Germany	LMU Klinikum der Universität München	München
Greece	General Hospital of Thessaloniki Ippokration	Thessaloniki
Israel	Meyer Children's Hospital	Haifa
Israel	Hadassah University Hospital	Jerusalem
Italy	Ospedali Riuniti di Ancona	Ancona
Italy	Azienda Ospedaliera A Meyer	Firenze
Italy	Lombardia Cystic Fibrosis Center	Milan
Italy	Ospedale Pediatrico Bambino Gesù IRCCS	Roma
Italy	Azienda Policlinico Umberto I	Rome
Italy	University of Verona	Verona
Netherlands	Hagaziekenhuis	Den Haag
Netherlands	Radboud University	Nijmegen
Netherlands	Erasmus MC	Rotterdam
Poland	Szpital Dzieciecy Polanki im Macieja Plazynskiego w Gdansku	Gdansk
Poland	NZOZ Sanatorium Cassia-Villa Medica	Rabka-Zdrój
Poland	NZOZ Podkarpacki Osrodek Pulmonologii i Alergologii	Rzeszow
Poland	Instytut Matki I Dziecka	Warsaw
Spain	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	Sevilla
United Kingdom	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 States	Children's Hospital Colorado	Aurora	Colorado
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Ann and Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	Rainbow Babies & Children's Hospital	Cleveland	Ohio
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Texas Children's Hospital	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	Miller Children's Hospital Long Beach	Long Beach	California
United States	Monmouth Medical Center	Long Branch	New Jersey
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Miami Children's Hospital	Miami	Florida
United States	University of Miami	Miami	Florida
United States	Childrens Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Pulmonary Associates of Mobile PC	Mobile	Alabama
United States	Morristown Medical Center	Morristown	New Jersey
United States	Beth Israel Medical Center	New York	New York
United States	Columbia University Medical Center	New York	New York
United States	New York University Langone Medical Center	New York	New York
United States	Children's Hospital and Research Center at Oakland	Oakland	California
United States	Santiago Reyes, MD	Oklahoma City	Oklahoma
United States	Stanford University-Children's Hospital	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Drexel University College of Medicine	Philadelphia	Pennsylvania
United States	Washington University	Saint Louis	Missouri
United States	All Children's Hospital	Saint Petersburg	Florida
United States	SUNY Upstate Medical University	Syracuse	New York
United States	University of Texas Health Science Center	Tyler	Texas

Sponsors (3)

Lead Sponsor	Collaborator
PTC Therapeutics	Cystic Fibrosis Foundation, ECFS-Clinical Trial Network (ECFS-CTN)

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)

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