A Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis

NCT03227471 — Phase 1 / Phase 2, Completed, 225 participants, Vertex Pharmaceuticals Incorporated

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A Phase 1/2 Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis

Registry	NCT03227471
Status	Completed
Phase	Phase 1 / Phase 2
Study type	Interventional; randomized, parallel, masking: quadruple, treatment
Enrollment	225 (Actual)
Sponsor	Vertex Pharmaceuticals Incorporated (Industry)
Conditions	Cystic Fibrosis
Interventions	IVA, TEZ/IVA, VX-445, Matched Placebo, TEZ, VX-561 (Drug)
Dates	start 2017-01-23, primary completion 2018-03-27, completion 2018-03-27, first posted 2017-07-24, last updated 2022-01-18
Locations	38 sites in United States, Australia, Belgium, Netherlands

-Summary

This is a first-in-human and proof-of-concept study of VX-445. The study includes 6 parts. Parts A, B, and C were conducted in healthy subjects. Parts D, E, and F were conducted in subjects with Cystic Fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F/F genotype), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ, IVA, or TEZ/IVA (F/MF genotypes).

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+Arms and interventions

Arm	Type	Interventions	Description
Part A: Pooled Placebo (Except Cohort A7)	Placebo comparator	Drug: Matched Placebo	Participants without CF who received single dose of placebo matched to VX-445 in Cohort A1 to A5.
Part A: VX-445 (Except Cohort A7)	Experimental	Drug: VX-445	Participants without CF who received single ascending dose of VX-445 tablet starting from 20 milligrams (mg) to 360 mg in Cohort A1 to A5.
Part A: VX-445 (Cohort A7)	Experimental	Drug: VX-445	Participants without CF who received single dose of VX-445 100 mg tablet on Day 1 in fasted state and on Day 7 in fed state, followed by VX-445 20 mg intravenous (IV) injection on Day 13 in fed state in Cohort A7.
Part B: Pooled Placebo (Cohort B1 to B4)	Placebo comparator	Drug: Matched Placebo	Participants without CF who received multiple doses of placebo matched to VX-445 once daily (qd) for 10 days in Cohort B1 to B4.
Part B: VX-445 (Cohort B1 to B4)	Experimental	Drug: VX-445	Participants without CF who received VX-445 tablet qd for 10 days in Cohort B1 (60 mg), B2 (120 mg), B3 (240 mg) and B4 (340 mg).
Part C: Pooled Placebo (Cohort C1 to C3)	Placebo comparator	Drug: Matched Placebo	Participants without CF who received placebo matched to VX-445/TEZ/IVA triple combination (TC) qd in the morning and placebo matched to IVA in the evening for 14 days.
Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3)	Experimental	Drug: IVA; Drug: TEZ/IVA; Drug: VX-445	Participants without CF who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C1; VX-445 280 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C2 and VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C3 for 14 days.
Part D: Placebo	Placebo comparator	Drug: Matched Placebo	Participants with CF, F/MF genotype who received placebo matched to VX-445/TEZ/IVA TC qd in the morning and placebo matched to IVA qd in the evening for 4 weeks in the TC treatment period.
Part D: VX-445/TEZ/IVA TC - Low Dose	Experimental	Drug: IVA; Drug: TEZ/IVA; Drug: VX-445	Participants with CF, F/MF genotype who received VX-445 50 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period.
Part D: VX-445/TEZ/IVA TC - Medium Dose	Experimental	Drug: IVA; Drug: TEZ/IVA; Drug: VX-445	Participants with CF, F/MF genotype who received VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period.
Part D: VX-445/TEZ/IVA TC - High Dose	Experimental	Drug: IVA; Drug: TEZ/IVA; Drug: VX-445	Participants with CF, F/MF genotype who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period.
Part E: TEZ/IVA	Active comparator	Drug: TEZ/IVA	Following run-in period of 4 weeks with TEZ/IVA, participants with CF, F/F genotype who received TEZ 100 mg qd/IVA 150 mg q12h and placebo matched to VX-445 for 4 weeks in the TC treatment period.
Part E: VX-445/TEZ/IVA TC	Experimental	Drug: IVA; Drug: TEZ/IVA; Drug: VX-445	Following run-in period of 4 weeks with TEZ/IVA, participants with CF, F/F genotype who received VX-445 200 mg qd/TEZ 100 mg qd /IVA 150 mg q12h for 4 weeks in the TC treatment period.
Part F: Placebo	Placebo comparator	Drug: Matched Placebo	Participants with CF, F/MF genotype who received placebo matched to VX-445/TEZ/VX-561 for 4 weeks in the TC treatment period.
Part F: VX-445/TEZ/VX-561 TC	Experimental	Drug: VX-445; Drug: TEZ; Drug: VX-561	Participants with CF, F/MF genotype who received VX-445 200 mg qd/TEZ 100 mg qd/VX-561 150 mg qd for 4 weeks in the TC treatment period.

IVA (Drug), also known as VX-770, ivacaftor: IVA tablet for oral administration
TEZ/IVA (Drug), also known as VX-661/VX-770, tezacaftor/ivacaftor: TEZ/IVA fixed-dose combination for oral administration.
VX-445 (Drug), also known as ELX, elexacaftor: VX-445 tablet for oral administration.
Matched Placebo (Drug): Matched placebo.
TEZ (Drug), also known as VX-661, tezacaftor: Tablet for oral administration.
VX-561 (Drug), also known as CTP-656: Tablet for oral administration.
VX-445 (Drug), also known as ELX, elexacaftor: VX-445 IV injection

+Outcome measures

Primary outcomes

Parts A, B and C: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [From first dose of study drug in treatment period up to safety follow-up (up to 28 days)]
Parts D, E and F: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [From first dose of study drug in TC treatment period up to 28 days after last dose of study drug (up to 5 weeks)]
Part D: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) [From Baseline through Day 29]: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Part E: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) [From Baseline through Day 29]: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Part F: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) [From Baseline through Day 29]: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Secondary outcomes

Part A: Maximum Observed Concentration (Cmax) of VX-445 [Cohort A1-A5: Pre-dose to 96 hours post-dose; Cohort A7: Pre-dose to 120 hours post-dose]
Part A: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445 [Cohort A1-5: Pre-dose to 96 hours post-dose; Cohort A7: Pre-dose to 120 hours post-dose]
Part B: Maximum Observed Concentration (Cmax) of VX-445 [Pre-dose to 96 hours post-dose on Day 1 and Day 10]
Part B: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445 [Pre-dose to 96 hours post-dose on Day 1 and Day 10]
Part B: Observed Pre-dose Plasma Concentration (Ctrough) of VX-445 [Pre-dose on Day 10]
Part C: Maximum Observed Concentration (Cmax) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) [Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14]
Part C: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) [Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14]
Part C: Maximum Observed Concentration (Cmax) of IVA and Its Metabolites (M1-IVA and M6-IVA) [Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14]
Part C: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of IVA and Its Metabolites (M1-IVA and M6-IVA) [Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14]
Part C: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) [Pre-dose on Day 7 and Day 14]
Part C: Observed Pre-dose Concentration (Ctrough) of IVA and Its Metabolites (M1-IVA and M6-IVA) [Pre-dose on Day 7 and Day 14]
Part D: Observed Pre-dose Plasma Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ), IVA and Its Metabolite (M1-IVA) [Pre-dose on Day 15 and Day 29]
Part E: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ) and IVA and Its Metabolite (M1-IVA) [Pre-dose on Day 15 and Day 29]
Part F: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ) and VX-561 [Pre-dose on Day 15 and Day 29]
Part D: Absolute Change in Sweat Chloride Concentration [From Baseline through Day 29]: Sweat samples were collected using an approved collection device.
Part E: Absolute Change in Sweat Chloride Concentration [From Baseline through Day 29]: Sweat samples were collected using an approved collection device.
Part F: Absolute Change in Sweat Chloride Concentration [From Baseline through Day 29]: Sweat samples were collected using an approved collection device.
Part D: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) [From Baseline through Day 29]: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Part E: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) [From Baseline through Day 29]: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Part F: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) [From Baseline through Day 29]: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Part D: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score [From Baseline through 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.
Part E: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score [From Baseline through 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.
Part F: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score [From Baseline through 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.

+Eligibility

Sex: All, ages: 18 Years to any, accepts healthy volunteers

Key Inclusion Criteria:

Parts A, B, and C:

* Female subjects must be of non-childbearing potential.
* Between the ages of 18 and 55 years, inclusive.
* Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, and a total body weight >50 kg

Parts D, E, and F:

* Body weight ≥35 kg.
* Subjects must have an eligible CFTR genotype:

  * Parts D and F: Heterozygous for F508del and an MF mutation (F/MF)
  * Part E: Homozygous for F508del (F/F)
* FEV1 value ≥40% and ≤90% of predicted mean for age, sex, and height.

Key Exclusion Criteria:

Parts A, B, and C:

* Any condition possibly affecting drug absorption.
* History of febrile illness within 14 days before the first study drug dose.
* Glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Parts D, E, and F:

* History of clinically significant cirrhosis with or without portal hypertension.
* Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
* Lung infection with organisms associated with a more rapid decline in pulmonary status.
* History of solid organ or hematological transplantation.

Other protocol defined Inclusion/Exclusion criteria may apply.

+Posted results

Participant flow

Milestone	Part A: Pooled Placebo (Except Cohort A7)	Part A: VX-445 (Except Cohort A7)	Part A: VX-445 (Cohort A7)	Part B: Pooled Placebo (Cohort B1 to B4)	Part B: VX-445 (Cohort B1 to B4)	Part C: Pooled Placebo (Cohort C1 to C3)	Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3)	Part D: Placebo	Part D: VX-445/TEZ/IVA TC - Low Dose	Part D: VX-445/TEZ/IVA TC - Medium Dose	Part D: VX-445/TEZ/IVA TC - High Dose	Part E: TEZ/IVA	Part E: VX-445/TEZ/IVA TC	Part F: Placebo	Part F: VX-445/TEZ/VX-561 TC
Started	9	30	8	7	25	6	17	12	10	22	21	7	21	8	22
Safety set	9	30	8	7	25	6	17	12	10	22	21	7	21	8	21
Completed	9	30	8	7	24	6	17	12	10	22	21	7	20	8	21
Not completed	0	0	0	0	1	0	0	0	0	0	0	0	1	0	1

Outcome results

Parts A, B and C: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) (Primary), Count of participants, Participants: Part A: Pooled Placebo (Except Cohort A7) 0; Part A: VX-445 (Except Cohort A7) 3; Part A: VX-445 (Cohort A7) 1; Part B: Pooled Placebo (Cohort B1 to B4) 2; Part B: VX-445 (Cohort B1 to B4) 2; Part C: Pooled Placebo (Cohort C1 to C3) 2; Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3) 5
Parts D, E and F: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) (Primary), Count of participants, Participants: Part D: Placebo 12; Part D: VX-445/TEZ/IVA TC 49; Part E: TEZ/IVA 5; Part E: VX-445/TEZ/IVA TC 19; Part F: Placebo 7; Part F: VX-445/TEZ/VX-561 TC 19
Part D: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) (Primary), Least squares mean, percentage points: Part D: Placebo 0.0 +/- 2.0; Part D: VX-445/TEZ/IVA TC - Low Dose 11.1 +/- 2.1; Part D: VX-445/TEZ/IVA TC - Medium Dose 7.9 +/- 1.4; Part D: VX-445/TEZ/IVA TC - High Dose 13.8 +/- 1.4 (p 0.9943)
Part E: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) (Primary), Least squares mean, percentage points: Part E: TEZ/IVA 0.4 +/- 2.8; Part E: VX-445/TEZ/IVA TC 11.0 +/- 1.5 (p 0.8869)
Part F: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) (Primary), Least squares mean, percentage points: Part F: Placebo 1.2 +/- 2.6; Part F: VX-445/TEZ/VX-561 TC 11.7 +/- 1.6 (p 0.6407)
Part A: Maximum Observed Concentration (Cmax) of VX-445 (Secondary), Geometric mean, microgram per milliliter: Part A: VX-445 (Cohort A1) 0.398 +/- 23.0; Part A: VX-445 (Cohort A2) 0.989 +/- 35.1; Part A: VX-445 (Cohort A3) 2.52 +/- 13.0; Part A: VX-445 (Cohort A4) 4.56 +/- 28.2; Part A: VX-445 (Cohort A5) 7.07 +/- 19.1; Part A: VX-445 (Cohort A7-Fasted) 0.486 +/- 27.4; Part A: VX-445 (Cohort A7-Fed) 1.76 +/- 14.6; Part A: VX-445 (Cohort A7-IV) 0.740 +/- 27.1
Part A: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445 (Secondary), Geometric mean, microgram*hour per milliliter: Part A: VX-445 (Cohort A1) 11.4 +/- 34.2; Part A: VX-445 (Cohort A2) 30.8 +/- 21.2; Part A: VX-445 (Cohort A3) 87.1 +/- 39.9; Part A: VX-445 (Cohort A4) 125 +/- 34.2; Part A: VX-445 (Cohort A5) 286 +/- 9.30; Part A: VX-445 (Cohort A7-Fasted) 21.8 +/- 31.5; Part A: VX-445 (Cohort A7-Fed) 55.1 +/- 14.9; Part A: VX-445 (Cohort A7-IV) 13.6 +/- 19.7
Part B: Maximum Observed Concentration (Cmax) of VX-445 (Secondary), Geometric mean, microgram per milliliter: Part B: VX-445 (Cohort B1) 1.18 +/- 19.9; Part B: VX-445 (Cohort B2) 2.82 +/- 25.5; Part B: VX-445 (Cohort B3) 3.47 +/- 52.9; Part B: VX-445 (Cohort B4) 9.56 +/- 65.6
Part B: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445 (Secondary), Geometric mean, microgram*hour per milliliter: Part B: VX-445 (Cohort B1) 17.9 +/- 20.0; Part B: VX-445 (Cohort B2) 42.2 +/- 19.5; Part B: VX-445 (Cohort B3) 57.9 +/- 42.8; Part B: VX-445 (Cohort B4) 119 +/- 27.5
Part B: Observed Pre-dose Plasma Concentration (Ctrough) of VX-445 (Secondary), Geometric mean, microgram per milliliter: Part B: VX-445 (Cohort B1) 1.05 +/- 24.5; Part B: VX-445 (Cohort B2) 2.81 +/- 33.2; Part B: VX-445 (Cohort B3) 7.10 +/- 30.1; Part B: VX-445 (Cohort B4) 11.5 +/- 32.0
Part C: Maximum Observed Concentration (Cmax) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) (Secondary), Geometric mean, microgram per milliliter: Part C: VX-445/TEZ/IVA TC (Cohort C1) 3.04 +/- 23.2; Part C: VX-445/TEZ/IVA TC (Cohort C2) 4.86 +/- 25.4; Part C: VX-445/TEZ/IVA TC (Cohort C3) 1.72 +/- 16.5
Part C: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) (Secondary), Geometric mean, microgram*hour per milliliter: Part C: VX-445/TEZ/IVA TC (Cohort C1) 48.6 +/- 22.7; Part C: VX-445/TEZ/IVA TC (Cohort C2) 72.5 +/- 20.7; Part C: VX-445/TEZ/IVA TC (Cohort C3) 26.4 +/- 13.8
Part C: Maximum Observed Concentration (Cmax) of IVA and Its Metabolites (M1-IVA and M6-IVA) (Secondary), Geometric mean, nanogram per milliliter: Part C: VX-445/TEZ/IVA TC (Cohort C1) 425 +/- 29.8; Part C: VX-445/TEZ/IVA TC (Cohort C2) 461 +/- 49.3; Part C: VX-445/TEZ/IVA TC (Cohort C3) 437 +/- 9.63
Part C: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of IVA and Its Metabolites (M1-IVA and M6-IVA) (Secondary), Geometric mean, nanogram*hour per milliliter: Part C: VX-445/TEZ/IVA TC (Cohort C1) 6350 +/- 40.9; Part C: VX-445/TEZ/IVA TC (Cohort C2) 6210 +/- 45.5; Part C: VX-445/TEZ/IVA TC (Cohort C3) 5480 +/- 28.5
Part C: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) (Secondary), Geometric mean, microgram per milliliter: Part C: VX-445/TEZ/IVA TC (Cohort C1) 4.63 +/- 46.8; Part C: VX-445/TEZ/IVA TC (Cohort C2) 5.91 +/- 35.5; Part C: VX-445/TEZ/IVA TC (Cohort C3) 2.09 +/- 14.9
Part C: Observed Pre-dose Concentration (Ctrough) of IVA and Its Metabolites (M1-IVA and M6-IVA) (Secondary), Geometric mean, nanogram per milliliter: Part C: VX-445/TEZ/IVA TC (Cohort C1) 753 +/- 75; Part C: VX-445/TEZ/IVA TC (Cohort C2) 759 +/- 45.7; Part C: VX-445/TEZ/IVA TC (Cohort C3) 604 +/- 32.8
Part D: Observed Pre-dose Plasma Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ), IVA and Its Metabolite (M1-IVA) (Secondary), Mean, microgram per milliliter: Part D: VX-445/TEZ/IVA TC - Low Dose 1.04 +/- 0.612; Part D: VX-445/TEZ/IVA TC - Medium Dose 2.15 +/- 0.977; Part D: VX-445/TEZ/IVA TC - High Dose 5.77 +/- 4.14
Part E: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ) and IVA and Its Metabolite (M1-IVA) (Secondary), Mean, microgram per milliliter: Part E: TEZ/IVA ; Part E: VX-445/TEZ/IVA TC 5.07 +/- 2.47
Part F: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ) and VX-561 (Secondary), Mean, microgram per milliliter: Part F: VX-445/TEZ/VX-561 TC 4.40 +/- 1.54
Part D: Absolute Change in Sweat Chloride Concentration (Secondary), Least squares mean, millimole per liter (mmol/L): Part D: Placebo -2.2 +/- 3.9; Part D: VX-445/TEZ/IVA TC - Low Dose -38.2 +/- 4.2; Part D: VX-445/TEZ/IVA TC - Medium Dose -33.2 +/- 2.8; Part D: VX-445/TEZ/IVA TC - High Dose -39.1 +/- 2.9 (p 0.5802)
8 more outcome measures not shown.

Adverse events

Time frame: Parts A, B and C: From first dose of study drug in treatment period up to safety follow-up (up to 28 days); Parts D, E and F: From first dose of study drug in TC treatment period up to 28 days after last dose of study drug (up to 5 weeks)

Arm	Deaths	Serious adverse events	Other adverse events
Part A: Pooled Placebo (Except Cohort A7)	0/9 (0.0%)	0/9 (0.0%)	0/9 (0.0%)
Part A: VX-445 (Except Cohort A7)	0/30 (0.0%)	0/30 (0.0%)	3/30 (10.0%)
Part A: VX-445 (Cohort A7)	0/8 (0.0%)	0/8 (0.0%)	1/8 (12.5%)
Part B: Pooled Placebo (Cohort B1 to B4)	0/7 (0.0%)	0/7 (0.0%)	2/7 (28.6%)
Part B: VX-445 (Cohort B1 to B4)	0/25 (0.0%)	0/25 (0.0%)	2/25 (8.0%)
Part C: Pooled Placebo (Cohort C1 to C3)	0/6 (0.0%)	0/6 (0.0%)	2/6 (33.3%)
Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3)	0/17 (0.0%)	0/17 (0.0%)	5/17 (29.4%)
Part D: Placebo	0/12 (0.0%)	2/12 (16.7%)	12/12 (100.0%)
Part D: VX-445/TEZ/IVA TC - Low Dose	0/10 (0.0%)	1/10 (10.0%)	10/10 (100.0%)
Part D: VX-445/TEZ/IVA TC - Medium Dose	0/22 (0.0%)	2/22 (9.1%)	19/22 (86.4%)
Part D: VX-445/TEZ/IVA TC - High Dose	0/21 (0.0%)	0/21 (0.0%)	17/21 (81.0%)
Part E: TEZ/IVA	0/7 (0.0%)	1/7 (14.3%)	5/7 (71.4%)
Part E: VX-445/TEZ/IVA TC	0/21 (0.0%)	0/21 (0.0%)	18/21 (85.7%)
Part F: Placebo	0/8 (0.0%)	1/8 (12.5%)	7/8 (87.5%)
Part F: VX-445/TEZ/VX-561 TC	0/21 (0.0%)	0/21 (0.0%)	17/21 (81.0%)

Serious adverse events by term

Term	Organ system	Part A: Pooled Placebo (Except Cohort A7)	Part A: VX-445 (Except Cohort A7)	Part A: VX-445 (Cohort A7)	Part B: Pooled Placebo (Cohort B1 to B4)	Part B: VX-445 (Cohort B1 to B4)	Part C: Pooled Placebo (Cohort C1 to C3)	Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3)	Part D: Placebo	Part D: VX-445/TEZ/IVA TC - Low Dose	Part D: VX-445/TEZ/IVA TC - Medium Dose	Part D: VX-445/TEZ/IVA TC - High Dose	Part E: TEZ/IVA	Part E: VX-445/TEZ/IVA TC	Part F: Placebo	Part F: VX-445/TEZ/VX-561 TC
Infective pulmonary exacerbation of cystic fibrosis	Infections and infestations	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	1/10	2/22	0/21	1/7	0/21	1/8	0/21
Distal intestinal obstruction syndrome	Gastrointestinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	1/10	0/22	0/21	0/7	0/21	0/8	0/21
Influenza A virus test positive	Investigations	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	1/22	0/21	0/7	0/21	0/8	0/21
Haemoptysis	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Jugular vein thrombosis	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	1/10	0/22	0/21	0/7	0/21	0/8	0/21

Other adverse events by term

Term	Organ system	Part A: Pooled Placebo (Except Cohort A7)	Part A: VX-445 (Except Cohort A7)	Part A: VX-445 (Cohort A7)	Part B: Pooled Placebo (Cohort B1 to B4)	Part B: VX-445 (Cohort B1 to B4)	Part C: Pooled Placebo (Cohort C1 to C3)	Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3)	Part D: Placebo	Part D: VX-445/TEZ/IVA TC - Low Dose	Part D: VX-445/TEZ/IVA TC - Medium Dose	Part D: VX-445/TEZ/IVA TC - High Dose	Part E: TEZ/IVA	Part E: VX-445/TEZ/IVA TC	Part F: Placebo	Part F: VX-445/TEZ/VX-561 TC
Diarrhoea	Gastrointestinal disorders	0/9	1/30	0/8	0/7	0/25	1/6	1/17	1/12	1/10	3/22	0/21	0/7	0/21	1/8	1/21
Nausea	Gastrointestinal disorders	0/9	1/30	0/8	0/7	0/25	1/6	0/17	2/12	2/10	3/22	1/21	1/7	1/21	3/8	2/21
Constipation	Gastrointestinal disorders	0/9	0/30	0/8	1/7	1/25	0/6	0/17	0/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Abdominal pain	Gastrointestinal disorders	0/9	0/30	0/8	0/7	1/25	0/6	0/17	1/12	0/10	1/22	0/21	0/7	2/21	1/8	0/21
Dysphagia	Gastrointestinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	1/17	0/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Salivary hypersecretion	Gastrointestinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	1/17	0/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Vomiting	Gastrointestinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	1/17	0/12	0/10	1/22	1/21	1/7	0/21	2/8	0/21
Abdominal pain upper	Gastrointestinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	1/10	1/22	1/21	1/7	0/21	0/8	1/21
Abdominal discomfort	Gastrointestinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Gastrooesophageal reflux disease	Gastrointestinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Myalgia	Musculoskeletal and connective tissue disorders	0/9	1/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	1/22	0/21	1/7	0/21	0/8	0/21
Neck pain	Musculoskeletal and connective tissue disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	0/22	1/21	1/7	1/21	0/8	0/21
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	1/10	0/22	0/21	0/7	0/21	1/8	0/21
Catheter site pain	General disorders	0/9	0/30	1/8	0/7	0/25	0/6	0/17	0/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Infusion site pain	General disorders	0/9	0/30	0/8	0/7	0/25	0/6	1/17	0/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Fatigue	General disorders	0/9	0/30	0/8	0/7	0/25	0/6	1/17	4/12	1/10	0/22	0/21	0/7	4/21	0/8	0/21
Headache	Nervous system disorders	0/9	0/30	0/8	0/7	1/25	0/6	2/17	2/12	2/10	2/22	2/21	1/7	0/21	1/8	1/21
Dizziness	Nervous system disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	1/22	1/21	0/7	0/21	1/8	0/21
Dysgeusia	Nervous system disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Arthralgia	Musculoskeletal and connective tissue disorders	0/9	0/30	0/8	1/7	0/25	0/6	0/17	0/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Dermatitis	Skin and subcutaneous tissue disorders	0/9	0/30	0/8	0/7	0/25	1/6	2/17	0/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Pruritus	Skin and subcutaneous tissue disorders	0/9	0/30	0/8	0/7	0/25	1/6	1/17	0/12	0/10	0/22	0/21	0/7	0/21	1/8	0/21
Acne	Skin and subcutaneous tissue disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	2/10	0/22	1/21	0/7	0/21	0/8	1/21
Pruritus generalised	Skin and subcutaneous tissue disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Eczema	Skin and subcutaneous tissue disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	0/22	0/21	0/7	0/21	1/8	0/21
Conjunctivitis	Infections and infestations	0/9	0/30	0/8	0/7	0/25	0/6	1/17	0/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Abnormal dreams	Psychiatric disorders	0/9	0/30	0/8	0/7	0/25	0/6	1/17	0/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Anxiety	Psychiatric disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	0/22	0/21	1/7	0/21	0/8	0/21
Cough	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	1/17	1/12	4/10	5/22	7/21	1/7	7/21	2/8	5/21
Sputum increased	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	3/12	3/10	4/22	5/21	0/7	8/21	1/8	3/21
Haemoptysis	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	2/12	0/10	5/22	2/21	0/7	3/21	1/8	1/21
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	2/12	2/10	2/22	2/21	1/7	1/21	2/8	5/21
Nasal congestion	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	2/12	2/10	2/22	2/21	0/7	0/21	1/8	3/21
Dyspnoea	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	1/22	0/21	0/7	1/21	1/8	0/21
Sinus congestion	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	1/22	1/21	1/7	1/21	0/8	2/21
Paranasal sinus hypersecretion	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	1/10	1/22	0/21	0/7	1/21	0/8	1/21
Productive cough	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	0/22	0/21	0/7	0/21	1/8	2/21
Respiration abnormal	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	1/22	1/21	0/7	2/21	1/8	0/21
Sputum discoloured	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	1/22	0/21	0/7	2/21	1/8	1/21
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	3/22	0/21	0/7	1/21	0/8	0/21
Epistaxis	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	1/22	0/21	0/7	1/21	1/8	0/21
Wheezing	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	0/22	1/21	0/7	1/21	0/8	0/21
Lower respiratory tract congestion	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	0/22	0/21	1/7	0/21	0/8	0/21
Pleuritic pain	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	0/22	1/21	0/7	0/21	0/8	0/21
Bronchiectasis	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	0/22	0/21	0/7	0/21	1/8	0/21
Pulmonary mass	Respiratory, thoracic and mediastinal disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Nasopharyngitis	Infections and infestations	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	1/10	0/22	4/21	1/7	1/21	1/8	0/21
Sinusitis	Infections and infestations	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	1/22	0/21	0/7	0/21	1/8	1/21
Upper respiratory tract infection	Infections and infestations	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	0/22	1/21	0/7	0/21	0/8	2/21
Oral candidiasis	Infections and infestations	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	0/22	0/21	0/7	1/21	1/8	0/21
Viral upper respiratory tract infection	Infections and infestations	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	1/10	0/22	0/21	0/7	1/21	0/8	0/21
Gastroenteritis viral	Infections and infestations	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	0/22	0/21	1/7	0/21	0/8	0/21
Otitis media	Infections and infestations	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	0/22	0/21	0/7	0/21	0/8	0/21
Tonsillitis	Infections and infestations	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	0/22	0/21	1/7	0/21	0/8	0/21
Viral infection	Infections and infestations	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	0/22	0/21	1/7	0/21	0/8	0/21
Pyrexia	General disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	5/22	1/21	1/7	3/21	0/8	0/21
Malaise	General disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	1/22	0/21	0/7	1/21	0/8	1/21
Pain	General disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	1/12	0/10	0/22	1/21	1/7	1/21	0/8	0/21
Chest pain	General disorders	0/9	0/30	0/8	0/7	0/25	0/6	0/17	0/12	0/10	0/22	0/21	0/7	1/21	0/8	2/21

20 more terms not shown.

+Locations (38)

Facility	City	Country
Banner University of Arizona Medical Center	Tucson, Arizona	United States
University of Arkansas for Medical Sciences	Little Rock, Arkansas	United States
Valley Children's Healthcare	Madera, California	United States
(Kaiser Permanente) Oakland Medical Center	Oakland, California	United States
National Jewish Health	Denver, Colorado	United States
Central Florida Pulmonary Group	Orlando, Florida	United States
Tampa General Hospital Cardiac and Lung Transplant Clinic	Tampa, Florida	United States
Children's Specialty Services at North Druid Hills	Atlanta, Georgia	United States
Northwestern Memorial Hospital	Chicago, Illinois	United States
Covance Clinical Research Unit Inc., Evansville Clinic [Parts A, B, C only]	Evansville, Indiana	United States
University of Kansas Medical Center	Kansas City, Kansas	United States
Tulane Medical Center	New Orleans, Louisiana	United States
Harper University Hospital	Detroit, Michigan	United States
Children's Respiratory and Critical Care Specialists, P.A., Children's Hospitals and Clinics of Minn	Minneapolis, Minnesota	United States
Morristown Medical Center	Morristown, New Jersey	United States
University of New Mexico School of Medicine	Albuquerque, New Mexico	United States
UC Health Office of Clinical Research	Cincinnati, Ohio	United States
University Hospitals Cleveland Medical Center/Rainbow Babies and Children's Hospital	Cleveland, Ohio	United States
Nationwide Children's Hospital	Columbus, Ohio	United States
Austin Children's Chest Associates	Austin, Texas	United States
The University of Vermont	Burlington, Vermont	United States
University of Virginia Health System	Charlottesville, Virginia	United States
West Virginia University Hospitals	Morgantown, Virginia	United States
Children's Hospital of the King's Daughters	Norfolk, Virginia	United States
Virginia Commonwealth University	Richmond, Virginia	United States
Medical College of Wisconsin	Milwaukee, Wisconsin	United States
Monash Medical Center	Clayton, Victoria	Australia
The Alfred Hospital	Melbourne, Victoria	Australia
The Royal Children's Hospital Melbourne	Parkville, Victoria	Australia
Mater Adult Hospital	Brisbane	Australia
Royal Prince Alfred Hospital	Sydney	Australia
Westmead Hospital	Sydney	Australia
Antwerp University Hospital	Edegem	Belgium
Universitair Ziekenhuis Gent	Ghent	Belgium
Academic Medical Centre	Amsterdam	Netherlands
Radboud UMC	Nijmegen	Netherlands
Erasmus Medical Center	Rotterdam	Netherlands
HagaZiekenhuis van den Haag	The Hague	Netherlands

+Publications

Results publication: Heneghan M, Southern KW, Murphy J, Sinha IP, Nevitt SJ. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). Cochrane Database Syst Rev. 2023 Nov 20;11(11):CD010966. doi: 10.1002/14651858.CD010966.pub4. PMID 37983082
Results publication: Southern KW, Murphy J, Sinha IP, Nevitt SJ. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). Cochrane Database Syst Rev. 2020 Dec 17;12(12):CD010966. doi: 10.1002/14651858.CD010966.pub3. PMID 33331662
Results publication: Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, Ramsey BW, Rowe SM, Sass LA, Tullis E, McKee CM, Moskowitz SM, Robertson S, Savage J, Simard C, Van Goor F, Waltz D, Xuan F, Young T, Taylor-Cousar JL; VX16-445-001 Study Group. VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med. 2018 Oct 25;379(17):1612-1620. doi: 10.1056/NEJMoa1807120. Epub 2018 Oct 18. PMID 30334692

+Study documents

Study Protocol (PDF, 2017-08-08)
Statistical Analysis Plan (PDF, 2017-10-06)

+Funding

NIH grants: 2017

My Notes

Public

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