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A Study Evaluating the Safety and Efficacy of VX-440 Combination Therapy in Subjects With Cystic Fibrosis

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ClinicalTrials.gov Identifier: NCT02951182
Recruitment Status : Completed
First Posted : November 1, 2016
Results First Posted : August 28, 2020
Last Update Posted : August 28, 2020
Sponsor:
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated

Tracking Information
First Submitted Date  ICMJE October 26, 2016
First Posted Date  ICMJE November 1, 2016
Results First Submitted Date  ICMJE August 11, 2020
Results First Posted Date  ICMJE August 28, 2020
Last Update Posted Date August 28, 2020
Actual Study Start Date  ICMJE October 2016
Actual Primary Completion Date August 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 27, 2020)
  • Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From first dose of Study Drug in the Treatment Period through Safety Follow-up Visit (Up to Day 57 for Part 1 and Day 85 for Part 2) ]
  • Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) [ Time Frame: From Baseline through Day 29 ]
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Original Primary Outcome Measures  ICMJE
 (submitted: October 28, 2016)
  • Safety and tolerability as assessed by number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: from baseline up to 16 weeks ]
  • Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) [ Time Frame: from baseline up to 12 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 27, 2020)
  • Absolute Change in Sweat Chloride Concentrations [ Time Frame: From Baseline through Day 29 ]
    Sweat samples were collected using an approved collection device.
  • Relative Change in ppFEV1 [ Time Frame: From Baseline through Day 29 ]
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
  • Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score [ Time Frame: From Baseline at Day 29 ]
    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.
  • Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA [ Time Frame: Predose at Day 8, Day 15 and Day 29 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 28, 2016)
  • Absolute Change in Sweat Chloride Concentrations [ Time Frame: from baseline up to 12 weeks ]
  • Relative Change in ppFEV1 [ Time Frame: from baseline up to 12 weeks ]
  • Number of pulmonary exacerbations [ Time Frame: through Week 12 (12-week cohort only) ]
  • Time to first pulmonary exacerbation [ Time Frame: through Week 12 (12-week cohort only) ]
  • Absolute change in body mass index (BMI) [ Time Frame: from baseline at Week 12 (12-week cohort only) ]
  • Absolute change in BMI z-score [ Time Frame: from baseline at Week 12 (12-week cohort only) ]
  • Absolute change in weight [ Time Frame: from baseline at Week 12 (12-week cohort only) ]
  • Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score [ Time Frame: from baseline up to 12 weeks ]
  • Maximum observed concentration (Cmax) of VX-152, TEZ, M1-TEZ, IVA, and M1-IVA (μg/mL) [ Time Frame: from Day 1 through Day 43 (4-week cohorts), and through Week 12 (12-week cohort) ]
  • Area under the concentration versus time curve during a dosing interval (AUCtau) of VX-152, TEZ, M1-TEZ, IVA, and M1-IVA (μg.h/mL) [ Time Frame: from Day 1 through Day 43 (4-week cohorts), and through Week 12 (12-week cohort) ]
  • Observed pre-dose concentration (Ctrough) of VX-152, TEZ, M1-TEZ, IVA, and M1-IVA (μg/mL) [ Time Frame: from Day 1 through Day 43 (4-week cohorts), and through Week 12 (12-week cohort) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study Evaluating the Safety and Efficacy of VX-440 Combination Therapy in Subjects With Cystic Fibrosis
Official Title  ICMJE A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-440 Combination Therapy in Subjects Aged 12 Years and Older With Cystic Fibrosis
Brief Summary This is a Phase 2, randomized, double-blind, placebo- and active-controlled, parallel group, multicenter study to evaluate the safety, tolerability, and efficacy of VX-440 in dual and triple combination with tezacaftor (TEZ; VX-661) and ivacaftor (IVA; VX-770) in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F508del/F508del), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ and/or IVA therapy (F508del/MF).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE 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: TEZ
    Other Names:
    • tezacaftor
    • VX-661
  • Drug: IVA
    Other Names:
    • ivacaftor
    • VX-770
  • Drug: VX-440
  • Drug: Matched Placebo
Study Arms  ICMJE
  • Placebo Comparator: Part 1: Placebo - Cohort 1A and 1B Combined
    Participants received placebo matched to VX-440/TEZ/IVA as triple combination for 4 weeks.
    Intervention: Drug: Matched Placebo
  • Experimental: Part 1 Cohort 1A: Triple Combination (TC)
    Participants received VX-440 200 milligram (mg) every 12 hours (q12h)/TEZ 100 mg once daily (qd)/IVA 150 mg q12h as triple combination for 4 weeks.
    Interventions:
    • Drug: TEZ
    • Drug: IVA
    • Drug: VX-440
  • Experimental: Part 1 Cohort 1B: TC Low Dose
    Participants received VX-440 200 mg q12h/TEZ 50 mg q12h/IVA 150 mg q12h as triple combination for 4 weeks.
    Interventions:
    • Drug: TEZ
    • Drug: IVA
    • Drug: VX-440
  • Experimental: Part 1 Cohort 1B: TC High Dose
    Participants received VX-440 600 mg q12h/TEZ 50 mg q12h/IVA 300 mg q12h as triple combination for 4 weeks.
    Interventions:
    • Drug: TEZ
    • Drug: IVA
    • Drug: VX-440
  • Active Comparator: Part 2: TEZ/IVA
    Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received placebo matched to VX-440 and TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period.
    Interventions:
    • Drug: TEZ
    • Drug: IVA
    • Drug: Matched Placebo
  • Experimental: Part 2: TC-2
    Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received VX-440 600 mg q12h/ TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period.
    Interventions:
    • Drug: TEZ
    • Drug: IVA
    • Drug: VX-440
Publications * Not Provided

*   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: September 28, 2017)
74
Original Estimated Enrollment  ICMJE
 (submitted: October 28, 2016)
200
Actual Study Completion Date  ICMJE August 2017
Actual Primary Completion Date August 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
  • To prevent pregnancy, female participants of childbearing potential and their male partners will be required to use pre-specified, highly effective methods of non-hormonal contraception. Male participants with female partners of childbearing potential will be required to use a condom.
  • Body weight ≥35 kg.
  • Sweat chloride value ≥60 mmol/L from test results obtained during screening.
  • Subjects must have an eligible CFTR genotype:

    • Heterozygous for F508del and a minimal function (MF) mutation known or predicted not to be responsive to TEZ and/or IVA.
    • Homozygous for F508del
  • Subjects must have an FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height at the Screening Visit
  • Stable CF disease as judged by the investigator.
  • Willing to remain on a stable CF medication regimen through the planned end of treatment or, if applicable, the Safety Follow up Visit.

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.
  • History of cirrhosis with portal hypertension.
  • Risk factors for Torsade de Pointes
  • History of hemolysis.
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency assessed at Screening.
  • Clinically significant abnormal laboratory values at screening
  • An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 28 days before the first dose of study drug.
  • Lung infection with organisms associated with a more rapid decline in pulmonary status
  • An acute illness not related to CF within 14 days before the first dose of study drug
  • A standard digital ECG demonstrating QTc >450 msec at screening.
  • History of solid organ or hematological transplantation.
  • History or evidence of cataract or lens opacity determined to be clinically significant by the ophthalmologist or optometrist based on the ophthalmologic examination during the Screening Period.
  • History of alcohol or drug abuse in the past year, including but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator.
  • Ongoing or prior participation in an investigational drug study, with certain exceptions. (e.g., ongoing participation in NCT02565914)
  • Use of commercially available CFTR modulator (e.g., Kalydeco, Orkambi) within 14 days before screening (applies only to the Heterozygous F508del/MF cohorts; does not apply to the Homozygous F508del/F508del Cohort).
  • Pregnant or nursing females: Females of childbearing potential must have a negative pregnancy test at screening and Day 1.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Canada,   Denmark,   Germany,   Italy,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02951182
Other Study ID Numbers  ICMJE VX15-440-101
2016-000454-36 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
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 August 2020

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