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A Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis

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ClinicalTrials.gov Identifier: NCT03227471
Recruitment Status : Completed
First Posted : July 24, 2017
Last Update Posted : November 19, 2019
Sponsor:
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated

Tracking Information
First Submitted Date  ICMJE July 18, 2017
First Posted Date  ICMJE July 24, 2017
Last Update Posted Date November 19, 2019
Actual Study Start Date  ICMJE January 23, 2017
Actual Primary Completion Date March 27, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 22, 2017)
  • Safety and tolerability as assessed by number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: from baseline through safety follow-up (up to 10 days after last dose for Part A, B, and C) ]
    Number of subjects with AEs and SAEs will be reported.
  • Safety and tolerability as assessed by number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: from baseline through safety follow-up (up to 35 days after last dose for Parts D, E, and F). ]
    Number of subjects with AEs and SAEs will be reported.
  • Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) [Parts D, E, and F only] [ Time Frame: from baseline through Day 29 ]
    Absolute change in ppFEV1 will be reported.
Original Primary Outcome Measures  ICMJE
 (submitted: July 21, 2017)
  • Safety and tolerability as assessed by number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: from baseline through safety follow-up (up to 10 days after last dose for Part A, B, and C) ]
    Number of subjects with AEs and SAEs will be reported.
  • Safety and tolerability as assessed by number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: from baseline through safety follow-up (up to 35 days after last dose for Parts D and E). ]
    Number of subjects with AEs and SAEs will be reported.
  • Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) [Parts D and E only] [ Time Frame: from baseline through Day 29 ]
    Absolute change in ppFEV1 will be reported.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 22, 2017)
  • Absolute change in sweat chloride concentrations [Parts C, D, E, and F only] [ Time Frame: from baseline through Day 29 ]
    Absolute change in sweat chloride concentrations will be reported.
  • Relative change in ppFEV1 [Parts D, E, and F only] [ Time Frame: from baseline through Day 29 ]
    Relative change in ppFEV1 will be reported.
  • Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score [Parts D, E, and F only] [ Time Frame: from baseline through Day 29 ]
    The absolute change in CFQ-R respiratory domain score will be reported.
  • Maximum observed concentration (Cmax) of VX-445,TEZ and metabolites (M1-TEZ and M2-TEZ), IVA and metabolites (M1-IVA and M6-IVA) and VX-561 [ Time Frame: from Day 1 through Day 43 ]
    Maximum plasma concentration [Cmax] will be reported.
  • Area under the concentration versus time curve during a dosing interval (AUCtau) of VX-445, TEZ and metabolites (M1-TEZ and M2-TEZ), IVA and metabolites (M1-IVA and M6-IVA) and VX-561 [ Time Frame: from Day 1 through Day 43 ]
    Area under the concentration versus time curve during a dosing interval (AUCtau) will be reported.
  • Observed pre-dose concentration (Ctrough) of VX-445, TEZ and metabolites (M1-TEZ and M2-TEZ), IVA and metabolites (M1-IVA and M6-IVA) and VX-561 [ Time Frame: from Day 1 through Day 43 ]
    Trough plasma concentration [Ctrough] will be reported.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 21, 2017)
  • Absolute change in sweat chloride concentrations [Parts C, D and E only] [ Time Frame: from baseline through Day 29 ]
    Absolute change in sweat chloride concentrations will be reported.
  • Relative change in ppFEV1 [Parts D and E only] [ Time Frame: from baseline through Day 29 ]
    Relative change in ppFEV1 will be reported.
  • Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score [Parts D and E only] [ Time Frame: from baseline through Day 29 ]
    The absolute change in CFQ-R respiratory domain score will be reported.
  • Maximum observed concentration (Cmax) of VX-445,TEZ and metabolites (M1-TEZ and M2-TEZ), and IVA and metabolites (M1-IVA and M6-IVA) [ Time Frame: from Day 1 through Day 43 ]
    Maximum plasma concentration [Cmax] will be reported.
  • Area under the concentration versus time curve during a dosing interval (AUCtau) of VX-445, TEZ and metabolites (M1-TEZ and M2-TEZ), and IVA and metabolites (M1-IVA and M6-IVA) [ Time Frame: from Day 1 through Day 43 ]
    Area under the concentration versus time curve during a dosing interval (AUCtau) will be reported.
  • Observed pre-dose concentration (Ctrough) of VX-445, TEZ and metabolites (M1-TEZ and M2-TEZ), and IVA and metabolites (M1-IVA and M6-IVA) [ Time Frame: from Day 1 through Day 43 ]
    Trough plasma concentration [Ctrough] will be reported.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis
Official Title  ICMJE A Phase 1/2 Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis
Brief Summary This is a first-in-human and proof-of-concept study of VX-445. The study includes 6 parts. Parts A, B, and C will be conducted in healthy subjects. Parts D, E, and F will be conducted in subjects with Cystic Fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F/F genotype), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ, IVA, or TEZ/IVA (F/MF genotypes).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Cystic Fibrosis
Intervention  ICMJE
  • Drug: IVA
    150-mg IVA film-coated tablet for oral administration
    Other Name: VX-770
  • Drug: TEZ/IVA
    100-mg TEZ / 150-mg IVA fixed dose combination (FDC) tablet for oral administration.
    Other Name: VX-661/VX-770
  • Drug: VX-445
    VX-445 tablet for oral administration.
  • Drug: Matched Placebo
    Matched placebo.
  • Drug: TEZ
    50-mg tablet for oral administration.
  • Drug: VX-561
    50-mg tablet for oral administration.
    Other Name: CTP-656
Study Arms  ICMJE
  • Experimental: Part A: VX-445 in Healthy Subjects (HS)
    Part A includes single dose escalation.
    Intervention: Drug: VX-445
  • Placebo Comparator: Part A: Placebo
    Intervention: Drug: Matched Placebo
  • Experimental: Part B: VX-445 in HS
    Part B includes multiple-dose escalation.
    Intervention: Drug: VX-445
  • Placebo Comparator: Part B: Placebo
    Intervention: Drug: Matched Placebo
  • Experimental: Part C: VX-445 in Triple Combination (TC) with TEZ/IVA in HS
    Multiple-dose escalation of VX-445 in TC with TEZ/IVA
    Interventions:
    • Drug: IVA
    • Drug: TEZ/IVA
    • Drug: VX-445
  • Placebo Comparator: Part C: Placebo
    Intervention: Drug: Matched Placebo
  • Experimental: Part D1: F/MF genotypes TC
    Subjects will receive 100 mg VX-445 qd in TC with TEZ and IVA for 4 weeks.
    Interventions:
    • Drug: IVA
    • Drug: TEZ/IVA
    • Drug: VX-445
  • Placebo Comparator: Part D1: Placebo
    Subjects will receive placebo for 4 weeks.
    Intervention: Drug: Matched Placebo
  • Experimental: Part D2: F/MF genotypes TC-High
    Subjects will receive VX-445 in TC with TEZ and IVA for 4 weeks.
    Interventions:
    • Drug: IVA
    • Drug: TEZ/IVA
    • Drug: VX-445
  • Experimental: Part D2: F/MF genotypes TC-Mid
    Subjects will receive VX-445 in TC with TEZ and IVA for 4 weeks.
    Interventions:
    • Drug: IVA
    • Drug: TEZ/IVA
    • Drug: VX-445
  • Experimental: Part D2: F/MF genotypes TC-Low
    Subjects will receive VX-445 in TC with TEZ and IVA for 4 weeks.
    Interventions:
    • Drug: IVA
    • Drug: TEZ/IVA
    • Drug: VX-445
    • Drug: Matched Placebo
  • Placebo Comparator: Part D2: Placebo
    Intervention: Drug: Matched Placebo
  • Experimental: Part E: F/F genotype - TC
    Subjects will receive VX-445 in TC with TEZ and IVA for 4 weeks
    Interventions:
    • Drug: IVA
    • Drug: TEZ/IVA
    • Drug: VX-445
  • Active Comparator: Part E: TEZ/IVA
    Subjects will receive TEZ and IVA for 4 weeks.
    Interventions:
    • Drug: IVA
    • Drug: TEZ/IVA
    • Drug: Matched Placebo
  • Experimental: Part F: F/MF genotypes - TC
    Subjects will receive VX-445 in TC with TEZ and VX-561 for 4 weeks.
    Interventions:
    • Drug: VX-445
    • Drug: TEZ
    • Drug: VX-561
  • Experimental: Part F: Placebo
    Intervention: Drug: Matched Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 26, 2018)
230
Original Estimated Enrollment  ICMJE
 (submitted: July 21, 2017)
200
Actual Study Completion Date  ICMJE March 27, 2018
Actual Primary Completion Date March 27, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

Parts A, B, and C:

  • Female subjects must be of non-childbearing potential.
  • Between the ages of 18 and 55 years, inclusive.
  • Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, and a total body weight >50 kg

Parts D, E, and F:

  • Body weight ≥35 kg.
  • Subjects must have an eligible CFTR genotype:

    • Parts D and F: Heterozygous for F508del and an MF mutation (F/MF)
    • Part E: Homozygous for F508del (F/F)
  • FEV1 value ≥40% and ≤90% of predicted mean for age, sex, and height.

Key Exclusion Criteria:

Parts A, B, and C:

  • Any condition possibly affecting drug absorption.
  • History of febrile illness within 14 days before the first study drug dose.
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Parts D, E, and F:

  • History of clinically significant cirrhosis with or without portal hypertension.
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
  • Lung infection with organisms associated with a more rapid decline in pulmonary status.
  • History of solid organ or hematological transplantation.

Other protocol defined Inclusion/Exclusion criteria may apply.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Netherlands,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03227471
Other Study ID Numbers  ICMJE VX16-445-001
2017-000797-11 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Vertex Pharmaceuticals Incorporated
Study Sponsor  ICMJE Vertex Pharmaceuticals Incorporated
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Vertex Pharmaceuticals Incorporated
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP