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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
Last Update Posted : October 2, 2017
Sponsor:
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated

Study Description
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
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).

Condition or disease Intervention/treatment Phase
Cystic Fibrosis Drug: Tezacaftor Drug: Ivacaftor Drug: VX-440 Drug: Matched Placebos Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 74 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : October 2016
Actual Primary Completion Date : August 2017
Actual Study Completion Date : August 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cystic Fibrosis
Drug Information available for: Ivacaftor
U.S. FDA Resources

Arms and Interventions
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Arm Intervention/treatment
Experimental: Heterozygous F508del/MF 4-week Cohort A:Triple Combination(TC)

VX-440 200 milligram (mg) administered every 12 hours (q12h). TEZ 100 mg administered once daily (qd). IVA 150 mg q12h.

Morning Dose: VX-440 + TEZ/IVA

Evening Dose: VX-440 + IVA

 Drug: Tezacaftor
Other Names:
  • TEZ
  • VX-661
Drug: Ivacaftor
Other Names:
  • IVA
  • VX-770
  • Kalydeco
Drug: VX-440
Placebo Comparator: Heterozygous F508del/MF 4-week Cohort A: Triple Placebo
Placebos matched to VX-440, TEZ/IVA, and IVA.
 Drug: Matched Placebos
Experimental: Heterozygous F508del/MF 4-week Cohort B TC-High

To be initiated after blinded review of Cohort A, if supported by safety and PK Data.

The dosage of VX-440 may be adjusted based on data from Cohort A.

Morning Dose: VX-440 + TEZ + IVA

Evening Dose: VX-440 + TEZ + IVA

 Drug: Tezacaftor
Other Names:
  • TEZ
  • VX-661
Drug: Ivacaftor
Other Names:
  • IVA
  • VX-770
  • Kalydeco
Drug: VX-440
Experimental: Heterozygous F508del/MF 4-week Cohort B:TC-Low

To be initiated after blinded review of Cohort A, if supported by safety and PK Data.

Placebo matched to VX-440

Morning Dose: VX-440 + TEZ + IVA

Evening Dose: VX-440 + TEZ + IVA

 Drug: Tezacaftor
Other Names:
  • TEZ
  • VX-661
Drug: Ivacaftor
Other Names:
  • IVA
  • VX-770
  • Kalydeco
Drug: VX-440 Drug: Matched Placebos
Placebo Comparator: Heterozygous F508del/MF 4- week Cohort B: Triple Placebo

To be initiated after blinded review of Cohort A, if supported by safety and PK Data.

Placebos matched to VX-440, TEZ, and IVA.

 Drug: Matched Placebos
Experimental: Homozygous F508del/F508del 4-week Cohort: TC- High

To be initiated after the Cohort A blinded review, if supported by safety and PK data.

The dosage of VX-440 may be adjusted based on data from Cohort A.

Placebo matched to morning TEZ/IVA.

Morning Dose: VX-440 + TEZ + IVA

Evening Dose: VX-440 + TEZ + IVA

The treatment period will be preceded by a 4-week run-in period and followed by a 4-week washout period, during both of which subjects will receive:

TEZ 100 mg administered once daily (qd). IVA 150 mg q12h.

 Drug: Tezacaftor
Other Names:
  • TEZ
  • VX-661
Drug: Ivacaftor
Other Names:
  • IVA
  • VX-770
  • Kalydeco
Drug: VX-440 Drug: Matched Placebos
Active Comparator: Homozygous F508del/F508del 4-week Cohort: TEZ/IVA

To be initiated after blinded review of Cohort A, if supported by safety and PK Data.

Placebos matched to VX-440, evening TEZ, and morning IVA.

TEZ 100 mg administered once daily (qd). IVA 150 mg q12h.

Morning Dose: TEZ/IVA

Evening Dose: IVA

The treatment period will be preceded by a 4-week run-in period and followed by a 4-week washout period, during both of which subjects will receive:

TEZ 100 mg administered once daily (qd). IVA 150 mg q12h.

 Drug: Tezacaftor
Other Names:
  • TEZ
  • VX-661
Drug: Ivacaftor
Other Names:
  • IVA
  • VX-770
  • Kalydeco
Drug: Matched Placebos
Experimental: Heterozygous F508del/MF 12-week Cohort: TC-High

To be initiated after blinded review of Cohorts A and B, if supported by safety, PK, and efficacy data.

The dosage of VX-440 will be determined based on data from Heterozygous F508del/MF 4-week Cohorts A and B.

Morning Dose: VX-440 + TEZ + IVA

Evening Dose: VX-440 + TEZ + IVA

 Drug: Tezacaftor
Other Names:
  • TEZ
  • VX-661
Drug: Ivacaftor
Other Names:
  • IVA
  • VX-770
  • Kalydeco
Drug: VX-440
Experimental: Heterozygous F508del/MF 12-week Cohort: TC-Low

To be initiated after blinded review of Cohorts A and B, if supported by safety, PK, and efficacy data.

The dosage of VX-440 will be determined based on data from Heterozygous F508del/MF 4-week Cohorts A and B.

Placebo matched to VX-440

Morning Dose: VX-440 + TEZ + IVA

Evening Dose: VX-440 + TEZ + IVA

 Drug: Tezacaftor
Other Names:
  • TEZ
  • VX-661
Drug: Ivacaftor
Other Names:
  • IVA
  • VX-770
  • Kalydeco
Drug: VX-440 Drug: Matched Placebos
Experimental: Heterozygous F508del/MF 12-week Cohort: Dual IVA

To be initiated after blinded review of Cohorts A and B, if supported by safety, PK, and efficacy data.

The dosage of VX-440 will be determined based on data from Heterozygous F508del/MF 4-week Cohorts A and B.

Placebo matched to TEZ.

Morning Dose: VX-440 + IVA

Evening Dose: VX-440 + IVA

 Drug: Ivacaftor
Other Names:
  • IVA
  • VX-770
  • Kalydeco
Drug: VX-440 Drug: Matched Placebos
Experimental: Heterozygous F508del/MF 12-week Cohort: Dual TEZ

To be initiated after blinded review of Cohorts A and B, if supported by safety, PK, and efficacy data.

The dosage of VX-440 will be determined based on data from Heterozygous F508del/MF 4-week Cohorts A and B.

Placebo matched to IVA

Morning Dose: VX-440 + TEZ

Evening Dose: VX-440 + TEZ

VX-440 administered in combination with TEZ q12h and placebo matched IVA.

 Drug: Tezacaftor
Other Names:
  • TEZ
  • VX-661
Drug: VX-440 Drug: Matched Placebos
Placebo Comparator: Heterozygous F508del/MF 12-week Cohort: Triple Placebo

To be initiated after blinded review of Cohorts A and B, if supported by safety, PK, and efficacy data.

Placebos matched to VX-440, TEZ, and IVA.

 Drug: Matched Placebos


Outcome Measures
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Primary Outcome Measures :
  1. 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 ]
  2. Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) [ Time Frame: from baseline up to 12 weeks ]

Secondary Outcome Measures :
  1. Absolute change in sweat chloride concentrations [ Time Frame: from baseline up to 12 weeks ]
  2. Relative change in ppFEV1 [ Time Frame: from baseline up to 12 weeks ]
  3. Number of pulmonary exacerbations [ Time Frame: through Week 12 (12-week cohort only) ]
  4. Time to first pulmonary exacerbation [ Time Frame: through Week 12 (12-week cohort only) ]
  5. Absolute change in body mass index (BMI) [ Time Frame: from baseline at Week 12 (12-week cohort only) ]
  6. Absolute change in BMI z-score [ Time Frame: from baseline at Week 12 (12-week cohort only) ]
  7. Absolute change in weight [ Time Frame: from baseline at Week 12 (12-week cohort only) ]
  8. Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score [ Time Frame: from baseline up to 12 weeks ]
  9. Maximum observed concentration (Cmax) of VX-440, 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) ]
  10. Area under the concentration versus time curve during a dosing interval (AUCtau) of VX-440, 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) ]
  11. Observed pre-dose concentration (Ctrough) of VX-440, 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) ]

Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

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.
Contacts and Locations
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02951182


  Show 40 Study Locations
Sponsors and Collaborators
Vertex Pharmaceuticals Incorporated
More Information
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party: Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier: NCT02951182     History of Changes
Other Study ID Numbers: VX15-440-101
2016-000454-36 ( EudraCT Number )
First Posted: November 1, 2016    Key Record Dates
Last Update Posted: October 2, 2017
Last Verified: September 2017

Additional relevant MeSH terms:
Fibrosis
Cystic 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