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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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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: 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) ]
| Estimated Enrollment: | 200 |
| Study Start Date: | October 2016 |
| Estimated Study Completion Date: | May 2018 |
| Estimated Primary Completion Date: | May 2018 (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| 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 LocationsPlease refer to this study by its ClinicalTrials.gov identifier: NCT02951182
| Contact: Medical Information | 617-341-6777 | medicalinfo@vrtx.com |
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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 ) |
| Study First Received: | October 26, 2016 |
| Last Updated: | March 22, 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 |
ClinicalTrials.gov processed this record on June 26, 2017