Study of VX-661 Alone and in Combination With Ivacaftor in Subjects Homozygous or Heterozygous to the F508del-Cystic Fibrosis Transmembrane Conductance Regulator(CFTR) Mutation

• ClinicalTrials.gov Identifier: NCT01531673
• Recruitment Status: Completed
• First Posted: February 13, 2012
• Results First Posted: April 13, 2018
• Last Update Posted: April 13, 2018
• Sponsor: Vertex Pharmaceuticals Incorporated
• Information provided by (Responsible Party): Vertex Pharmaceuticals Incorporated

Study Description

Brief Summary:

The purpose of this study is to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) effects of VX-661 alone and when coadministered with ivacaftor in participants with cystic fibrosis (CF) who are homozygous or heterozygous for the F508del-CFTR mutation.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis	Drug: VX-661; Drug: Ivacaftor; Drug: Placebo matched to VX-661; Drug: Placebo matched to ivacaftor	Phase 2

Detailed Description:

This is a Phase 2, randomized, multicenter, double-blinded, placebo-controlled, study of VX-661 monotherapy, and VX-661/ivacaftor co-therapy in participants with CF who are homozygous or heterozygous for the F508del CFTR mutation.

This study is separated into seven groups: Group 1-7, respectively. Approximately 180 participants were randomized in a ratio of 4:1; active drug to matching placebo in each group.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 194 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Double-Blinded, Placebo Controlled Study to Evaluate Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of VX-661 Monotherapy and VX-661/Ivacaftor Cotherapy in Subjects With Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation
• Study Start Date: February 2012
• Actual Primary Completion Date: March 2014
• Actual Study Completion Date: March 2014

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Group 1-6d Combined: Placebo; All participants in group 1, 2a, 2b, 3a, 3b, 4, 5a, 5b, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.	Drug: Placebo matched to VX-661; Drug: Placebo matched to ivacaftor
Experimental: Group 1: VX-661 10 mg qd; All participants in group 1 who received VX-661 10 milligram (mg) tablet orally once daily (qd) for up to 28 days.	Drug: VX-661
Experimental: Group 2a: VX-661 30 mg qd; All participants in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet every 12 hours (q12h) for up to 28 days.	Drug: VX-661; Drug: Placebo matched to ivacaftor
Experimental: Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h; All participants in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	Drug: VX-661; Drug: Ivacaftor
Experimental: Group 3a: VX-661 100 mg qd; All participants in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	Drug: VX-661; Drug: Placebo matched to ivacaftor
Experimental: Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h; All participants in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	Drug: VX-661; Drug: Ivacaftor
Experimental: Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h; All participants in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	Drug: VX-661; Drug: Ivacaftor
Experimental: Group 5a: VX-661 150 mg qd; All participants in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.	Drug: VX-661
Experimental: Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h; All participants in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	Drug: VX-661; Drug: Ivacaftor
Experimental: Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h; All participants in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.	Drug: VX-661; Drug: Ivacaftor
Experimental: Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h; All participants in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	Drug: VX-661; Drug: Ivacaftor
Placebo Comparator: Group 7: Placebo; All participants in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco (Ivacaftor) for up to 28 days.	Drug: Ivacaftor; Drug: Placebo matched to VX-661
Experimental: Group 7: VX-661 100 mg qd; All participants in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco (Ivacaftor) for up to 28 days.	Drug: VX-661; Drug: Ivacaftor

Outcome Measures

Primary Outcome Measures :

1. Safety as Determined by Adverse Events (AEs) [ Time Frame: Start of study drug through the Follow-up Visit (Up to Day 56) ]
   An AE is defined as any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the Informed Consent Form is signed. AE includes serious as well as non-serious AEs. Serious Adverse Event (SAE) is any AE that results in any of the following: death; life-threatening condition; inpatient hospitalization or prolongation of hospitalization; persistent or significant disability or incapacity; congenital anomaly or birth defect; or other important medical event. Treatment-emergent adverse events are defined as adverse events that were reported or worsened on or after start of study drug through the Follow-up Visit (28 days after last dose of study drug) or premature discontinuation.
2. Change in Sweat Chloride From Baseline Through Study Day 28 for Group 1-5b [ Time Frame: Baseline through Day 28 ]
   Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.
3. Change in Sweat Chloride From Baseline Through Study Day 28 for Group 6 [ Time Frame: Baseline through Day 28 ]
   Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
4. Change in Sweat Chloride From Baseline Through Study Day 28 for Group 7 [ Time Frame: Baseline through Day 28 ]
   Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.

Secondary Outcome Measures :

1. Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 1-5b [ Time Frame: Baseline, Day 7, Day 14, Day 21, Day 28 ]
   Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.
2. Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 6 [ Time Frame: Baseline, Day 7, Day 14, Day 21, Day 28 ]
   Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
3. Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 7 [ Time Frame: Baseline, Day 7, Day 14, Day 21, Day 28 ]
   Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.
4. Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b [ Time Frame: Baseline, Day 7, Day 14, Day 21, Day 28 ]
   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
5. Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6 [ Time Frame: Baseline, Day 7, Day 14, Day 21, Day 28 ]
   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
6. Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7 [ Time Frame: Baseline, Day 7, Day 14, Day 21, Day 28 ]
   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
7. Change in FEV1 (Liter [L]) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b [ Time Frame: Baseline, Day 7, Day 14, Day 21, Day 28 ]
   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
8. Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6 [ Time Frame: Baseline, Day 7, Day 14, Day 21, Day 28 ]
   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
9. Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7 [ Time Frame: Baseline, Day 7, Day 14, Day 21, Day 28 ]
   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
10. Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b [ Time Frame: Baseline, Day 14, Day 28 ]
    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 (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
11. Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6 [ Time Frame: Baseline, Day 14, Day 28 ]
    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 (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
12. Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7 [ Time Frame: Baseline, Day 14, Day 28 ]
    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 (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
13. Area Under the Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24h) of VX-661 After Administration of VX-661 Monotherapy [ Time Frame: Day 28 ]
    Participants who received VX-661 monotherapy (Group 1, 2a, 3a and 5a) were analyzed for this outcome measure. PK analysis (AUC0-24h) was not planned for placebo reporting arms.
14. AUC0-24h of VX-661 and AUC0-12h of Ivacaftor After Administration of VX-661 in Combination With Ivacaftor [ Time Frame: Day 28 ]
    Participants who received VX-661 in combination with Ivacaftor (Group 2b, 3b, 4, 5b, 6a, 6d and 7) were analyzed for this outcome measure. PK analysis was not planned for placebo reporting arms.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Male or female with confirmed diagnosis of CF
• Must have the F508del-CFTR gene mutation in both alleles (Groups 1, 2, 3, 4, 5, 6). Group 7 participants must have the F508del-CFTR mutation on 1 allele, and gating mutation G551D on the second allele and have been on their physician prescribed 150 mg KalydecoTM q12h (commercially available ivacaftor) for at least 28 days at the Screening Visit.
• Forced expiratory volume in 1 second(FEV1) 40% to 90% (inclusive) of predicted normal for age, gender, and height (Knudson standards) at screening
• Weight >40 kg and BMI >18.5
• Participants of child-bearing potential and who are sexually active must meet the contraception requirements.

Exclusion Criteria:

• History of any illness 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 participant.
• An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Study Day 1.
• History of solid organ or hematological transplantation
• Participation in a clinical study involving administration of either an investigational or a marketed drug within 30 days or 5 terminal half-lives (whichever is longer) before screening
• History of alcohol, medication, or illicit drug abuse within 1 year prior to screening
• Pregnant, breast-feeding, or not willing to follow contraception requirements

Contacts and Locations

Locations

United States, Alabama

Vertex Investigational Site

Birmingham, Alabama, United States

United States, California

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Oakland, California, United States

United States, Idaho

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Boise, Idaho, United States

United States, Illinois

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Chicago, Illinois, United States

United States, Massachusetts

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Boston, Massachusetts, United States

United States, Michigan

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Grand Rapids, Michigan, United States

United States, Missouri

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Kansas City, Missouri, United States

United States, New Jersey

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Long Branch, New Jersey, United States

United States, New York

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New Hyde Park, New York, United States

United States, North Carolina

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Chapel Hill, North Carolina, United States

United States, Ohio

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Cincinnati, Ohio, United States

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Columbus, Ohio, United States

United States, Oklahoma

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Oklahoma City, Oklahoma, United States

United States, Pennsylvania

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Hershey, Pennsylvania, United States

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Pittsburgh, Pennsylvania, United States

United States, South Carolina

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Charleston, South Carolina, United States

United States, Utah

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Salt Lake City, Utah, United States

United States, Vermont

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Burlington, Vermont, United States

United States, Washington

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Seattle, Washington, United States

Canada, Alberta

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Calgary, Alberta, Canada

Canada, British Columbia

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Vancouver, British Columbia, Canada

Canada, Nova Scotia

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Halifax, Nova Scotia, Canada

Canada, Ontario

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Toronto, Ontario, Canada

Germany

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Erlangen, Bayern, Germany

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Frankfurt, Hessen, Germany

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Hannover, Niedersachsen, Germany

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Koeln, Nordrhein Westfalen, Germany

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Berlin, Germany

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Bochum, Germany

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Jena, Germany

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Munich, Germany

United Kingdom

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Cambridge, Cambridgeshire, United Kingdom

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London, Greater London, United Kingdom

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Manchester, Greater Manchester, United Kingdom

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Southhampton, Hampshire, United Kingdom

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Cardiff, Vale Of Glamorgen, United Kingdom

Sponsors and Collaborators

Vertex Pharmaceuticals Incorporated

Investigators

• Principal Investigator: Scott Donaldson, MD; University of North Carolina

More Information

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT01531673
• Other Study ID Numbers: VX11-661-101; 2011-003821-93 ( EudraCT Number )
• First Posted: February 13, 2012
• Results First Posted: April 13, 2018
• Last Update Posted: April 13, 2018
• Last Verified: March 2018

Additional relevant MeSH terms:

Cystic Fibrosis; Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Ivacaftor; Chloride Channel Agonists; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action