A Study Evaluating the Safety and Efficacy of VX-440 Combination Therapy in Subjects With Cystic Fibrosis
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Purpose
| Condition | Intervention | Phase |
|---|---|---|
| Cystic Fibrosis | Drug: Tezacaftor Drug: Ivacaftor Drug: VX-440 Drug: Matched Placebos | Phase 2 |
| Study Type: | Interventional |
| Study Design: | 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 |
- 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 ]
- 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-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) ]
- 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) ]
- 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) ]
| Enrollment: | 74 |
| Study Start Date: | October 2016 |
| Study Completion Date: | August 2017 |
| Primary Completion Date: | August 2017 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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:
Drug: Ivacaftor
Other Names:
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:
Drug: Ivacaftor
Other Names:
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:
Drug: Ivacaftor
Other Names:
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:
Drug: Ivacaftor
Other Names:
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:
Drug: Ivacaftor
Other Names:
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:
Drug: Ivacaftor
Other Names:
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:
Drug: Ivacaftor
Other Names:
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:
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:
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 |
Eligibility
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| Ages Eligible for Study: | 12 Years and older (Child, Adult, Senior) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
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
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 Submitted: | October 26, 2016 |
| First Posted: | November 1, 2016 |
| 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 |