Clinical Trial Results:
A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del Mutation (F/F)
Summary
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EudraCT number |
2018-000184-89 |
Trial protocol |
GB BE NL |
Global end of trial date |
28 Dec 2018
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Results information
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Results version number |
v2(current) |
This version publication date |
29 Apr 2020
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First version publication date |
17 Jul 2019
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
VX17-445-103
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03525548 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Vertex Pharmaceuticals Incorporated
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Sponsor organisation address |
50 Northern Avenue, Boston, Massachusetts, United States,
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Public contact |
Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617 341 6777, medicalinfo@vrtx.com
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Scientific contact |
Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617 341 6777, medicalinfo@vrtx.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-002324-PIP01-17 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
07 Feb 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
28 Dec 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Dec 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the efficacy of VX-445 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation (F/F).
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Protection of trial subjects |
The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Council on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Aug 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Belgium: 14
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Country: Number of subjects enrolled |
Netherlands: 12
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Country: Number of subjects enrolled |
United Kingdom: 14
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Country: Number of subjects enrolled |
United States: 73
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Worldwide total number of subjects |
113
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EEA total number of subjects |
40
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
33
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Adults (18-64 years) |
80
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||
Pre-assignment
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Screening details |
This study was conducted in subjects with cystic fibrosis (CF) aged 12 years or older. | |||||||||
Period 1
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Period 1 title |
Triple Combination Treatment Period (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | |||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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TEZ/IVA | |||||||||
Arm description |
Following a run-in period of 4 weeks with TEZ/IVA, subjects received TEZ/IVA for 4 weeks in the TC treatment period. | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Placebo (matched to VX-445/TEZ/IVA)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received placebo matched to VX-445/TEZ/IVA once daily in the morning.
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Investigational medicinal product name |
TEZ/IVA
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Investigational medicinal product code |
VX-661/VX-770
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Other name |
Tezacaftor/Ivacaftor fixed dose combination
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received TEZ/IVA once daily in the morning.
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Investigational medicinal product name |
IVA
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Investigational medicinal product code |
VX-770
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Other name |
Ivacaftor
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received IVA once daily in the evening.
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Arm title
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VX-445/TEZ/IVA TC | |||||||||
Arm description |
Following a run-in period of 4 weeks with TEZ/IVA, subjects received VX-445/TEZ/IVA for 4 weeks in the TC treatment period. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
VX-445/TEZ/IVA
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Investigational medicinal product code |
VX-445/VX-661/VX-770
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Other name |
VX-445/Tezacaftor/Ivacaftor fixed dose combination
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received VX-445/TEZ/IVA once daily in the morning.
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Investigational medicinal product name |
Placebo (matched to TEZ/IVA)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received placebo matched to TEZ/IVA once daily in the morning.
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Investigational medicinal product name |
IVA
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Investigational medicinal product code |
VX-770
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Other name |
Ivacaftor
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received IVA once daily in the evening.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: In the above disposition summary, data is presented for 107 subjects dosed in the TC treatment period. 6 subjects were included in the run-in period but were not dosed in TC treatment period. Therefore, the total enrolled subjects are 113 whereas the subjects reported in disposition and baseline are 107. |
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Baseline characteristics reporting groups
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Reporting group title |
TEZ/IVA
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Reporting group description |
Following a run-in period of 4 weeks with TEZ/IVA, subjects received TEZ/IVA for 4 weeks in the TC treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
VX-445/TEZ/IVA TC
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Reporting group description |
Following a run-in period of 4 weeks with TEZ/IVA, subjects received VX-445/TEZ/IVA for 4 weeks in the TC treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
TEZ/IVA
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Reporting group description |
Following a run-in period of 4 weeks with TEZ/IVA, subjects received TEZ/IVA for 4 weeks in the TC treatment period. | ||
Reporting group title |
VX-445/TEZ/IVA TC
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Reporting group description |
Following a run-in period of 4 weeks with TEZ/IVA, subjects received VX-445/TEZ/IVA for 4 weeks in the TC treatment period. |
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End point title |
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | ||||||||||||
End point description |
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. FAS.
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End point type |
Primary
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End point timeframe |
At Week 4
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Statistical analysis title |
Statistical Analysis | ||||||||||||
Comparison groups |
TEZ/IVA v VX-445/TEZ/IVA TC
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Number of subjects included in analysis |
107
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mixed-effects model for repeated measure | ||||||||||||
Parameter type |
Least Square (LS) mean difference | ||||||||||||
Point estimate |
10
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
7.4 | ||||||||||||
upper limit |
12.6 |
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End point title |
Absolute Change in Sweat Chloride (SwCl) | ||||||||||||
End point description |
Sweat samples were collected using an approved collection device. FAS.
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End point type |
Secondary
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End point timeframe |
From Baseline at Week 4
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Statistical analysis title |
TEZ/IVA vs VX-445/TEZ/IVA TC | ||||||||||||
Comparison groups |
VX-445/TEZ/IVA TC v TEZ/IVA
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Number of subjects included in analysis |
107
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mixed-effects model for repeated measure | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
-45.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-50.1 | ||||||||||||
upper limit |
-40.1 |
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End point title |
Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | ||||||||||||
End point description |
The CFQ-R is a validated subject-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicate fewer symptoms and better health-related quality of life. FAS.
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End point type |
Secondary
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End point timeframe |
From Baseline at Week 4
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Statistical analysis title |
TEZ/IVA vs VX-445/TEZ/IVA TC | ||||||||||||
Comparison groups |
TEZ/IVA v VX-445/TEZ/IVA TC
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Number of subjects included in analysis |
107
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mixed-effects model for repeated measure | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
17.4
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
11.8 | ||||||||||||
upper limit |
23 |
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End point title |
Safety and Tolerability as Assessed by Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | |||||||||||||||
End point description |
Safety set included all subjects who received at least 1 dose of study drug in the TC treatment period.
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End point type |
Secondary
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End point timeframe |
From first dose of study drug in TC treatment period up to 28 days after last dose of study drug or to the completion of study participation date, whichever occurs first (up to Week 8)
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No statistical analyses for this end point |
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End point title |
Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | ||||||||||||||||||||||||||||||||||||
End point description |
Pharmacokinetic analysis set included all subjects who received at least 1 dose of study drug in the TC treatment period. Here “n” signifies those subjects who were evaluable for this endpoint at specified time points and "99999" represents "Not Applicable" as data could not be calculated for the category with n=0 subject for 'TEZ/IVA' and indicates that data was not reported at the specified time point as all the observations were below the limit of quantitation for 'VX-445/TEZ/IVA TC' arm.
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End point type |
Secondary
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End point timeframe |
Day 1 and Week 4
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From first dose of study drug in TC treatment period up to 28 days after last dose of study drug or to the completion of study participation date, whichever occurs first (up to Week 8)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
TEZ/IVA
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Reporting group description |
Following a run-in period of 4 weeks with TEZ/IVA, subjects received TEZ/IVA for 4 weeks in the TC treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
VX-445/TEZ/IVA TC
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Reporting group description |
Following a run-in period of 4 weeks with TEZ/IVA, subjects received VX-445/TEZ/IVA for 4 weeks in the TC treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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13 Apr 2018 |
Updated study drug regimen, dosing guidance, dose and population rationale. |
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19 Jul 2018 |
Revised exclusion criteria. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |