A Study to Evaluate Safety, Efficacy, and Tolerability of TEZ/IVA in Orkambi® (Lumacaftor/Ivacaftor) -Experienced Subjects With Cystic Fibrosis (CF)

Phase 3b, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Safety, Efficacy, and Tolerability of Tezacaftor/Ivacaftor (TEZ/IVA) in an Orkambi-experienced Population Who Are Homozygous for the F508del CFTR Mutation

Study VX16-661-114 (Study 114) is a Phase 3b, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in subjects aged 12 years and older with CF who are homozygous for the F508del mutation on the cystic fibrosis transmembrane conductance regulator gene (CFTR) gene and who discontinued treatment with Orkambi due to respiratory symptoms considered related to treatment. This study is designed to evaluate the safety and efficacy of Tezacaftor/Ivacaftor (TEZ/IVA).

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Tezacaftor/Ivacaftor; Drug: Ivacaftor; Drug: Placebo; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 3

Expanded Access

Approved for sale to the public. See expanded access record.

Contacts and Locations

Study Locations

• France
  • Créteil, France
    • Centre Hospitalier Intercommunal de Créteil
  • Grenoble, France
    • Centre Hospitalier Universitaire de Grenoble - Hôpital Michallon
  • Montpellier Cedex 5, France
    • CHU de Montpellier - Hôpital Arnaud de Villeneuve
  • Nantes, France
    • Centre Hospitalier Universitaire de Nantes
  • Nice, France
    • Centre hospitalier universitaire de Nice, Pulmonology
  • Paris Cedex 14, France
    • Hôpital Cochin
  • Rouen, France
    • Centre Hospitalier Universitaire - Hopitaux de Rouen
• Germany
  • Berlin, Germany
    • Charite Paediatric Pulmonology Department
  • Essen, Germany
    • Ruhrlandklinik Westdeutsches Lungenzentrum am Klinikum Essen
  • Muenchen, Germany
    • Pneumologische Praxis Pasing
  • Muenchen, Germany
    • Klinikum Innenstadt, University of Munich
  • Tuebingen, Germany
    • Universitaetsklinikum Tuebingen Klinik fuer Kinder- und Jugendmedizin
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Fresno, California, United States, 93701
      • UCSF - Fresno, Community Regional Medical Center
    • Long Beach, California, United States, 90806
      • Miller Children's Hospital / Long Beach Memorial
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • San Diego, California, United States, 92123
      • Rady Children's Hospital
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale New Haven Hospital
  • Florida
    • Orlando, Florida, United States, 32803
      • Central Florida Pulmonary Group
    • Orlando, Florida, United States, 32806
      • Arnold Palmer Hospital
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital Cardiac and Lung Transplant Clinic
  • Georgia
    • Atlanta, Georgia, United States, 30324
      • Children's Speciality Services at North Druid Hills
  • Idaho
    • Boise, Idaho, United States, 83702
      • St. Luke's CF Center of Idaho
  • Illinois
    • Niles, Illinois, United States, 60714
      • Advocate Children's Hospital - Park Ridge / North Suburban Pulmonary and Critical Care Consultants
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children at Indiana University Health
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • The University of Iowa Hospitals and Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Kentucky Clinic
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cystic Fibrosis Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • Montana
    • Billings, Montana, United States, 59101
      • Billings Clinic
  • New York
    • New York, New York, United States, 10003
      • Mount Sinai Beth Israel
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Baptist Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
    • Oklahoma City, Oklahoma, United States, 73112
      • Santiago Reyes, M.D.
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Drexel University College of Medicine/ Drexel Adult Cystic Fibrosis Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37920
      • The University of Tennessee Medical Center
  • Texas
    • Austin, Texas, United States, 78723
      • Dell Children's Medical Center of Central Texas
    • San Antonio, Texas, United States, 78207
      • The University of Texas Health Science Center at San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah / Primary Children's Medical Center
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
    • Richmond, Virginia, United States, 23298
      • Children's Hospital of Richmond at VCU, Children's Pavilion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
• Prior discontinuation of Orkambi, with at least 1 respiratory sign or symptom considered related to therapy.
• Resolution or stabilization of qualifying event(s) >28 days prior to Screening.
• Discontinuation of Orkambi therapy must have occurred within approximately 12 weeks from the first dose of Orkambi.
• Homozygous for F508del mutation in the CFTR gene as documented in the subject's medical record. If genotype documentation is not available in the medical record, genotyping will be performed during screening.
• FEV1 ≥25% and ≤90% of predicted normal for age, sex, and height.
• Stable CF disease as judged by the investigator.
• Other protocol defined inclusion criteria could apply.

Exclusion Criteria:

• History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject.
• Recent rapid or progressive deterioration in respiratory status.
• Receiving continuous oxygen at >2L/min or on face-mask ventilation.
• Any protocol-defined exclusionary laboratory values at Screening.
• Child-Pugh Class B or C hepatic impairment.
• An acute upper or lower respiratory infection, pulmonary exacerbation, or change in therapy for pulmonary disease within 28 days before Day 1.
• Documentation of colonization with organisms associated with a more rapid decline in pulmonary status.
• History of lung transplantation since most recent initiation of Orkambi.
• History of alcohol or drug abuse in the past year as deemed by the investigator.
• Participation in an investigational drug study or use of a CFTR modulator within 28 days or 5 terminal half-lives of the investigational drug or modulator (whichever is longer).
• Use of restricted medications or foods within the specified window before the first dose of study drug, or an anticipated need or use of restricted medication or foods after the first dose of study drug.
• Pregnant or nursing females: Females of child-bearing potential must have a negative pregnancy test at Screening and Day 1.
• Other protocol defined exclusion criteria could apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants received placebo matched to TEZ/IVA fixed-dose combination tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 56 days.	Drug: Placebo; Placebo matched to TEZ/IVA fixed-dose combination tablet.; Drug: Placebo; Placebo matched to IVA tablet.
Experimental: TEZ/IVA; Participants received TEZ 100 milligram (mg)/IVA 150 mg fixed-dose combination tablet orally once daily in the morning and IVA 150 mg tablet orally once daily in the evening for 56 days.	Drug: Tezacaftor/Ivacaftor; TEZ 100 mg/IVA 150 mg fixed-dose combination tablet.; Other Names: TEZ/IVA; VX-661/VX-770; Drug: Ivacaftor; IVA 150 mg tablet.; Other Names: VX-770; IVA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Respiratory Adverse Events of Special Interest (RAESIs)	RAESIs included chest discomfort, dyspnea (shortness of breath), respiration abnormal (chest tightness), asthma, bronchial hyperreactivity, bronchospasm, and wheezing.	Day 1 up to Day 84

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Day 28 and Day 56 Measurements	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.	Baseline, Day 28 and Day 56
Relative Change From Baseline in ppFEV1 at Average of Day 28 and Day 56 Measurements	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.	Baseline, Day 28 and Day 56
Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Day 28 and Day 56 Measurements	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.	Baseline, Day 28 and Day 56
Tolerability as Assessed by Number of Participants Who Discontinued Treatment		Day 1 through Day 56
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)		Day 1 up to Day 84

Collaborators and Investigators

• Sponsor: Vertex Pharmaceuticals Incorporated

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2017
• Primary Completion (Actual): August 9, 2018
• Study Completion (Actual): August 9, 2018

Study Registration Dates

• First Submitted: May 3, 2017
• First Submitted That Met QC Criteria: May 9, 2017
• First Posted (Actual): May 12, 2017

Study Record Updates

• Last Update Posted (Actual): September 12, 2019
• Last Update Submitted That Met QC Criteria: September 11, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Chloride Channel Agonists; Ivacaftor
• Other Study ID Numbers: VX16-661-114; 2017-000540-18 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No