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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02139306
Recruitment Status : Completed
First Posted : May 15, 2014
Results First Posted : May 14, 2020
Last Update Posted : May 14, 2020
Sponsor:
Collaborators:
Cystic Fibrosis Foundation
ECFS-Clinical Trial Network (ECFS-CTN)
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Cystic Fibrosis Drug: Ataluren (PTC124®) Drug: Placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 279 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3 Efficacy and Safety Study of Ataluren (PTC124®) in Patients With Nonsense Mutation Cystic Fibrosis
Actual Study Start Date : August 2014
Actual Primary Completion Date : November 2016
Actual Study Completion Date : November 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cystic Fibrosis

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




Primary Outcome Measures :
  1. Absolute Change From Baseline in Percent-predicted Forced Expiratory Volume in One Second (ppFEV1) at Week 48 [ Time Frame: 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 :
  1. 48-week Rate of Pulmonary Exacerbations [ Time Frame: 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.

  2. Change From Baseline in the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain at Week 48 [ Time Frame: 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.

  3. Change From Baseline in Body Mass Index (BMI) at Week 48 [ Time Frame: Baseline (Day 1) and Week 48 ]
    Malnutrition is common in participants with cystic fibrosis. The BMI is an important clinical measure of nutritional status.

  4. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) [ Time Frame: 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.

  5. Number of Participants With TEAEs by Severity and Relationship to Study Drugs [ Time Frame: 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).

  6. Number of Participants With SAEs by Severity and Relationship to Study Drugs [ Time Frame: 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).

  7. Number of Participants With Abnormal Vital Signs Reported as TEAEs [ Time Frame: 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.

  8. Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs [ Time Frame: 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.

  9. Number of Participants With Abnormal Electrocardiogram Reported as TEAEs [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02139306


Locations
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United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
Pulmonary Associates of Mobile PC
Mobile, Alabama, United States, 36608
United States, California
Miller Children's Hospital Long Beach
Long Beach, California, United States, 90806
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
Children's Hospital and Research Center at Oakland
Oakland, California, United States, 94609
Stanford University-Children's Hospital
Palo Alto, California, United States, 94304
United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
United States, Florida
Nemours Children's Clinic
Jacksonville, Florida, United States, 32207
University of Miami
Miami, Florida, United States, 33136
Miami Children's Hospital
Miami, Florida, United States, 33155
All Children's Hospital
Saint Petersburg, Florida, United States, 33701
United States, Illinois
Ann and Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States, 60611
United States, Indiana
Indiana University
Indianapolis, Indiana, United States, 46202
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington University
Saint Louis, Missouri, United States, 63110
United States, New Jersey
Monmouth Medical Center
Long Branch, New Jersey, United States, 07740
Morristown Medical Center
Morristown, New Jersey, United States, 07960
United States, New York
Beth Israel Medical Center
New York, New York, United States, 10003
New York University Langone Medical Center
New York, New York, United States, 10016
Columbia University Medical Center
New York, New York, United States, 10032
SUNY Upstate Medical University
Syracuse, New York, United States, 13210
United States, Ohio
University of Cincinnati
Cincinnati, Ohio, United States, 45221
Rainbow Babies & Children's Hospital
Cleveland, Ohio, United States, 44106
United States, Oklahoma
Santiago Reyes, MD
Oklahoma City, Oklahoma, United States, 73112
United States, Pennsylvania
Penn State Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Drexel University College of Medicine
Philadelphia, Pennsylvania, United States, 19129
United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77094
University of Texas Health Science Center
Tyler, Texas, United States, 75708
United States, Wisconsin
Childrens Hospital of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Argentina
Hospital Universitario Austral
Buenos Aires, Argentina, B1629ODT
Hospital de Niños Dr. Ricardo Gutiérrez
Buenos Aires, Argentina, C1425EFD
Hospital de Niños Superiora Sor Maria Ludovica
La Plata, Argentina, 1900
Australia
Royal Adelaide Hospital
Adelaide, Australia, 5000
Prince Charles Hospital
Chermside, Australia, 4032
Princess Margaret Hospital
Perth, Australia, 6840
Belgium
University Hospital Brussels
Brussels, Belgium, 1090
Hôpital Universitaire des Enfants Reine Fabiola
Bruxelles, Belgium, 1020
University Hospital Leuven
Leuven, Belgium, 3000
Brazil
Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul
Porto Alegre, Brazil
Instituto da Criança - Hospital das Clínicas
São Paulo, Brazil, 05403-000
Bulgaria
University Mulitiprofile Hospital for Active Treatment Sveti Georgi EAD
Plovdiv, Bulgaria
University Multiprofile Hospital for Active Treatment Aleksandrovska EAD
Sofia, Bulgaria
Canada
Clinical Research Institute of Montreal
Montreal, Canada, H2W 1R7
CHU de Quebec - Hopital CHUL
Québec City, Canada, G1V 4G2
University of Toronto Hospital for Sick Children
Toronto, Canada, M5G 1X8
British Columbia Children's Hospital
Vancouver, Canada, V6H 3V4
France
Hôpital Femme-Mère-Enfant
Bron, France, 69677
Hôpital Arnaud de Villeneuve
Montpellier, France, 34295
Hôpital Necker-Enfants Malades
Paris, France, 75015
Centre de Perharidy
Roscoff, France, 29684
Centre Hospitalier Regional Sud Reunion
Saint-Pierre, France, 97448
Germany
Charité Universitätsmedizin Berlin
Berlin, Germany, 13353
St. Josef Hospital GmbH
Bochum, Germany, 44791
Universitätsklinikum Köln
Cologne, Germany, 50937
Christiane Herzog CF-Zentrum
Frankfurt am Main, Germany, 60590
Universitätsklinikum Jena
Jena, Germany, 07745
LMU Klinikum der Universität München
München, Germany, 80336
Dr. Von Haunersches Kinderspital
München, Germany, 80337
Greece
General Hospital of Thessaloniki Ippokration
Thessaloniki, Greece
Israel
Meyer Children's Hospital
Haifa, Israel, 31096
Hadassah University Hospital
Jerusalem, Israel, 91240
Italy
Ospedali Riuniti di Ancona
Ancona, Italy, 60123
Azienda Ospedaliera A Meyer
Firenze, Italy, 50139
Lombardia Cystic Fibrosis Center
Milan, Italy, 20122
Ospedale Pediatrico Bambino Gesù IRCCS
Roma, Italy
Azienda Policlinico Umberto I
Rome, Italy, 00161
University of Verona
Verona, Italy, 37126
Netherlands
Hagaziekenhuis
Den Haag, Netherlands, 2491
Radboud University
Nijmegen, Netherlands, 6525 GA
Erasmus MC
Rotterdam, Netherlands
Poland
Szpital Dzieciecy Polanki im Macieja Plazynskiego w Gdansku
Gdansk, Poland
NZOZ Sanatorium Cassia-Villa Medica
Rabka-Zdrój, Poland, 34-700
NZOZ Podkarpacki Osrodek Pulmonologii i Alergologii
Rzeszow, Poland, 35-612
Instytut Matki I Dziecka
Warsaw, Poland, 01-211
Spain
Hospital Universitario Vall d'Hebron
Barcelona, Spain, 08035
Hospital University
Barcelona, Spain, 08035
Hospital Sant Joan de Deu
Esplugues De Llobregat, Spain, 08950
Hospital Regional Universitario de Malaga
Málaga, Spain
Hospital de Sabadell, Consorci Sanitari Parc Tauli
Sabadell, Spain, 08208
Hospital Universitario Virgen del Rocio
Sevilla, Spain
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, G120YN
St James's University Hospital
Leeds, United Kingdom
Royal Brompton Hospital
London, United Kingdom
Llandough Hospital
Penarth, United Kingdom, CF64 2XX
Southampton University Hospitals NHS Trust
Southampton, United Kingdom
Sponsors and Collaborators
PTC Therapeutics
Cystic Fibrosis Foundation
ECFS-Clinical Trial Network (ECFS-CTN)
Investigators
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Study Director: Joseph McIntosh, MD PTC Therapeutics
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: PTC Therapeutics
ClinicalTrials.gov Identifier: NCT02139306    
Other Study ID Numbers: PTC124-GD-021-CF
2013-004581-34 ( EudraCT Number )
First Posted: May 15, 2014    Key Record Dates
Results First Posted: May 14, 2020
Last Update Posted: May 14, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Cystic Fibrosis
Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases