E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Part A: To evaluate the Pharmacokinetics (PK) of VX-661 and ivacaftor after administration of multiple doses of VX-661 in combination with ivacaftor. Part B: To evaluate the safety and tolerability of VX-661 in combination with ivacaftor through Week 24. |
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E.2.2 | Secondary objectives of the trial |
Part A • To evaluate the PK of VX-661 metabolites, M1-661 and M2-661, and ivacaftor metabolites, M1-ivacaftor and M6-ivacaftor, after administration of multiple doses of VX-661 in combination with ivacaftor • To evaluate the safety and tolerability of multiple doses of VX-661 in combination with ivacaftor Part B • To evaluate the PK of VX-661, M1-661, M2-661, ivacaftor, M1-ivacaftor, and M6-ivacaftor after administration of multiple doses of VX-661 in combination with ivacaftor • To evaluate the efficacy of VX-661 in combination with ivacaftor through Week 24 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Subjects who weigh ≥15 kg without shoes at the Screening Visit. • All genotypes as specified by the study protocol are eligible in Part A. • The following genotypes are eligible in Part B: - homozygous for the F508del CFTR mutation - heterozygous for the F508del CFTR mutation and with a second allele with a CFTR mutation predicted to have residual function. - heterozygous for the F508del CFTR mutation and with a second CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive • Subjects with a confirmed diagnosis of CF defined as a sweat chloride value >= 60 mmol/L or chronic sinopulmonary and/or gastrointestinal disease consistent with a diagnosis of CF. Subjects who are homozygous for the F508del-CFTR mutation must have a sweat chloride value ≥60 mmol/L. • Subjects with ppFEV1 of >= 40 percentage points at the Screening Visit • Subjects with stable CF disease as deemed by the investigator at the Screening Visit. • Subjects who are willing to remain on their stable CF medication regimen through Day 14 (Part A) or through Week 24 (Part B) or, if applicable, through the Safety Follow up Visit. • Subjects who are able to swallow tablets. • Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Day 1 Visit before receiving the first dose of study drug. • Subjects of childbearing potential who are sexually active must meet the contraception requirements |
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E.4 | Principal exclusion criteria |
• History of any comorbidity reviewed at the Screening Visit 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. • Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject. • An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 28 days before Day 1 • Colonization with organisms associated with a more rapid decline in pulmonary status. • A standard 12 lead ECG demonstrating QTc >450 msec at the Screening Visit. • History of solid organ or hematological transplantation at the Screening Visit. • Ongoing or prior participation in an investigational drug study or use of commercially available CFTR modulator (except physician-prescribed Kalydeco for approved indications) within 30 days of screening. • Use of restricted medication or food within a specified duration before the Screening Visit or first dose of study drug and/or unwillingness to maintain the restrictions. • History or evidence of cataract, lens opacity, Y-suture, or lamellar rings determined to be clinically significant by the ophthalmologist during the ophthalmologic examination at the Screening Visit. • Pregnant and nursing females. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1) Part A: Maximum Observed Concentration (Cmax) of VX-661 and Ivacaftor 2) Part A: Area Under the Concentration Versus Time Curve During a Dosing Interval (AUCτ) of VX-661 and Ivacaftor 3) Part B: Safety and tolerability of VX-661 in combination with ivacaftor as determined by adverse events (AEs) and serious adverse events (SAEs) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1 and 2: Day 1 and Day 14 3: From baseline through 29 weeks
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E.5.2 | Secondary end point(s) |
1) Part A: Cmax of selected metabolites for VX-661 and Ivacaftor 2) Part A: AUCτ of selected metabolites for VX-661 and Ivacaftor 3) Part A: Safety and tolerability of VX-661 in combination with ivacaftor as determined by adverse events (AEs) and serious adverse events (SAEs) 4) Part B: Cmax of VX-661, M1-661, M2-661, ivacaftor, M1-ivacaftor, and M6-ivacaftor 5) Part B: AUCτ of VX-661, M1-661, M2-661, ivacaftor, M1-ivacaftor, and M6-ivacaftor 6) Part B: Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) 7) Part B: Relative change in ppFEV1 8) Part B: Absolute change in weight 9) Part B: Absolute change in weight for age z-score 10) Part B: Absolute change in height 11) Part B: Absolute change in height for age z-score 12) Part B: Absolute change in body mass index (BMI) 13) Part B: Absolute change in BMI for age z-score 14) Part B: Absolute change in sweat chloride 15) Part B: Absolute change in sweat chloride 16) Part B: Absolute change in Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain score |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 and 2: Day 1 and Day 14 3: From Baseline through Day 31 4 and 5: Day 1 through Week 16 6 to 16: From Baseline through Week 24 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 19 |