A Phase 3 Study of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)

Cystic Fibrosis Clinical Trial

Official title:

A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03525444
• Other study ID #: VX17-445-102
• Secondary ID: 2018-000183-28
• Status: Completed
• Phase: Phase 3
• Start date: June 15, 2018
• Est. completion date: April 24, 2019

Study information

• Verified date: May 2020
• Source: Vertex Pharmaceuticals Incorporated
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the efficacy of VX-445 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are heterozygous for F508del and a minimal function mutation (F/MF subjects).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 405
• Est. completion date: April 24, 2019
• Est. primary completion date: April 24, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Key Inclusion Criteria:

• Heterozygous for the F508del mutation (F/MF)

• Forced expiratory volume in 1 second (FEV1) value =40% and =90% of predicted mean for age, sex, and height

Key Exclusion Criteria:

• Clinically significant cirrhosis with or without portal hypertension

• Lung infection with organisms associated with a more rapid decline in pulmonary status

• Solid organ or hematological transplantation

Other protocol defined Inclusion/Exclusion criteria may apply

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• VX-445/TEZ/IVA
Participants received VX-445/TEZ/IVA orally once daily in the morning.
• IVA
Participants received IVA orally once daily in the evening
• Placebo
Participants received placebo matched VX-445/TEZ/IVA orally once daily in the morning and placebo matched to IVA orally once daily in the evening.

Locations

Country	Name	City	State
Australia	Women & Children's Hospital	North Adelaide
Australia	The Royal Children's Hospital	Parkville
Australia	Mater Adult Hospital	South Brisbane
Australia	The Children's Hospital at Westmead	Westmead
Australia	Westmead Hospital	Westmead
Austria	University of Graz	Graz
Austria	Medizinische Universitat Innsbruck	Innsbruck
Austria	LKH - Universitätsklinikum der PMU Salzburg	Salzburg
Austria	Medizinische Universitat Wien	Vienna
Belgium	Cliniques Universitaires de Bruxelles Hopital Erasme	Brussels
Belgium	Universitair Ziekenhuis Brussel - Campus Jette	Brussels
Belgium	UZ Antwerpen	Edegem
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	Universitaire Ziekenhuizen Leuven - Campus Gathuisberg	Leuven
Canada	University of Calgary Medical Clinic of the Foothills Medical Centre	Calgary
Canada	McGill University Health Centre, Glen Site, Montreal Children's Hospital	Montréal	Quebec
Canada	Centre Hospitalier De L'Universite Laval	Qubec
Canada	Saint John Regional Hospital	Saint John
Canada	The Hospital for Sick Children	Toronto
Canada	British Columbia's Children's Hospital	Vancouver	British Columbia
Canada	St. Paul's Hospital	Vancouver	British Columbia
Canada	Vancouver Island Health Authority	Victoria
Czechia	Fakultni Nemocnice Brno	Brno
Czechia	Fakultni nemocnice v Motole	Praha 5
France	Centre Hospitalier Lyon Sud	Benite Cedex
France	Groupe Hospitaler Pellegrin, CHU De Bordeaux	Bordeaux Cedex
France	CHU Marseille - Hopital Nord	Marseille
France	CHU de Nice - Hopital Pasteur	Nice
France	Hopital Cochin	Paris
France	CHU de Rouen - Hopital Charles Nicolle	Rouen Cedex, Seine Maritime
France	Hopital Foch (Suresnes), Hopital Foch, Adultes	Suresnes
Germany	Friedrich-Alexander University of Erlangen-Nuremberg, University Children's Hospital	Erlangen
Germany	Justus-Leibig-Universitat Zentrum fur Kinderheilkunde und Jugendmedizin	Giessen
Germany	Hannover Medical School	Hannover
Germany	Heidelberg Cystic Fibrosis Center	Heidelberg
Germany	Johannes Gutenberg-Universitaet	Mainz
Germany	Dr. von Haunersches Kinderspital	München
Germany	Universitaetsklinikum Tuebingen Klinik fuer Kinder- und Jugendmedizin	Tuebingen
Germany	University Hospital Wuerzburg	Wuerzburg
Greece	General Hospital of Attika "Sismanoglio"(Adult CF center, NHS)	Maroúsi
Italy	Azienda Ospedaliero Universitaria Ospedale Riuniti	Ancona
Italy	Azienda Ospedaliero Universitaria Ospedale Pediatrico Meyer	Firenze
Italy	IRCCS Istituto Giannina Gaslini-Ospedale Pediatrico	Genova
Italy	Azienda Ospedaliera Universitaria Policlinico G. Martino	Messina
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano
Italy	Centro Regionale Fibrosi Cistica, A.O. Ospedale San Carlo	Potenza
Italy	Azienda Ospedaliera di Verona-Ospedale Civile Maggiore	Verona
Netherlands	Academic Medical Center	Amsterdam
Netherlands	HagaZiekenhuis van den Haag	Den Haag
Netherlands	University Medical Center, Utrecht, Department of Pulmonology and Tuberculosis	Heidelberglaan
Netherlands	UMC St. Radboud	Nijmegen
Netherlands	Erasmus Medical Center	Rotterdam
Sweden	Karolinska Univeritetssjukhuset, Huddinge	Stockholm
United Kingdom	The Royal Belfast Hospital for Sick Children	Belfast
United Kingdom	Heart of England NHS Foundation Trust, Birmingham Heartlands Hospital	Brimingham
United Kingdom	Royal Hospital for Sick Children	Edinburgh
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Royal Devon and Exeter NHS Foundation Trust, Royal Devon and Exeter Hospital	Exeter
United Kingdom	Leeds General Infirmary	Leeds
United Kingdom	King's College Hospital	London
United Kingdom	Royal Manchester Children's Hospital	Manchester
United Kingdom	Southampton General Hospital	Southampton
United States	Akron Children's Hospital	Akron	Ohio
United States	University of New Mexico Clinical & Translational Science Center	Albuquerque	New Mexico
United States	Children's Speciality Services at North Druid Hills	Atlanta	Georgia
United States	Augusta University	Augusta	Georgia
United States	Austin Children's Chest Associates	Austin	Texas
United States	Billings Clinic	Billings	Montana
United States	Massachusetts General Hospital Cystic Fibrosis Center	Boston	Massachusetts
United States	UNC Marsico Clinical Research Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia Primary Care Center	Charlottesville	Virginia
United States	Ann & Robert Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	UC Health Holmes	Cincinnati	Ohio
United States	University Hospitals Cleveland Medical Center/ Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Vermont Lung Center	Colchester	Vermont
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	The University of Texas Southwestern Medical Center	Dallas	Texas
United States	Dayton Children's Hospital	Dayton	Ohio
United States	National Jewish Health	Denver	Colorado
United States	Harper University Hospital	Detroit	Michigan
United States	University of Florida, Shands Hospital	Gainesville	Florida
United States	Joe DiMaggio Cystic Fibrosis & Pulmonary Center/ Joe DiMaggio Children's Hospital/ Memorial Regional Hospital	Hollywood	Florida
United States	Nemours Children's Specialty Care	Jacksonville	Florida
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Miller Children's Hospital/ Long Beach Memorial	Long Beach	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Valley Children's Hospital/ Children's Hospital of Central California	Madera	California
United States	University of Wisconsin Hospitals and Clinics	Madison	Wisconsin
United States	CTSI Adult Translational Research Unit/Medical College of Wisconsin/Froedtert Hospital	Milwaukee	Wisconsin
United States	Children's Respiratory and Critical Care Specialists, P.A., Children's Hospitals and Clinics of Minnesota	Minneapolis	Minnesota
United States	West Virginia University	Morgantown	West Virginia
United States	Morristown Medical Center	Morristown	New Jersey
United States	Tulane Medical Center	New Orleans	Louisiana
United States	Mount Sinai Beth Israel	New York	New York
United States	Children's Hospital of the King's Daughters	Norfolk	Virginia
United States	Kaiser Permanente	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nebraska Medical Center	Omaha	Nebraska
United States	Central Florida Pulmonary Group	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Saint Francis Medical Center/ Children's Hospital of Illinois/OSF	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Maine Medical Partners	Portland	Maine
United States	Children's Hospital of Richmond at VCU, Children's Pavilion	Richmond	Virginia
United States	University of California Davis Medical Center	Sacramento	California
United States	UCSF Gateway Medical Center	San Francisco	California
United States	University of Washington Medical Center	Seattle	Washington
United States	Tampa General Hospital Cardiac and Lung Transplant Clinic	Tampa	Florida
United States	ProMedica Toledo Hospital/ Toledo Children's Hospital/ Pediatric Pulmonary & Cystic Fibrosis Center	Toledo	Ohio
United States	Banner University of Arizona Medical Center	Tucson	Arizona
United States	The University of Texas Health Science Center at Tyler	Tyler	Texas
United States	New York Medical College	Valhalla	New York

Sponsors (1)

Lead Sponsor	Collaborator
Vertex Pharmaceuticals Incorporated

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czechia,  France,  Germany,  Greece,  Italy,  Netherlands,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.	From Baseline at Week 4
Secondary	Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.	From Baseline through Week 24
Secondary	Number of Pulmonary Exacerbations (PEx)	Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms.	From Baseline through Week 24
Secondary	Absolute Change in Sweat Chloride (SwCl)	Sweat samples were collected using an approved collection device.	From Baseline through Week 24
Secondary	Absolute Change in Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain Score	The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.	From Baseline through Week 24
Secondary	Absolute Change in Body Mass Index (BMI)	BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2).	From Baseline at Week 24
Secondary	Absolute Change in Sweat Chloride	Sweat samples were collected using an approved collection device.	From Baseline at Week 4
Secondary	Absolute Change in Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain Score	The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.	From Baseline at Week 4
Secondary	Time-to-first Pulmonary Exacerbation (PEx)	Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms.	From Baseline through Week 24
Secondary	Absolute Change in BMI Z-score for Participants <=20 Years of Age at Baseline	BMI was defined as weight in kg divided by height in m^2. Z-score is a statistical measure to describe whether a mean was above or below the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher BMI.	From Baseline at Week 24
Secondary	Absolute Change in Body Weight		From Baseline at Week 24
Secondary	Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)		From first dose of study drug in TC treatment period up to 28 days after last dose of study drug or to the completion of study participation date, whichever occurs first (up to 28 weeks)
Secondary	Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA		Pre-dose on Week 4, 8, 12, and 16