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 Heterozygous for the F508del Mutation and a Gating or Residual Function Mutation (F/G and F/RF Genotypes)

Trial information Top of page
Trial identification
Sponsor protocol code	VX18-445-104
Additional study identifiers
ISRCTN number	-
US NCT number	NCT04058353
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Vertex Pharmaceuticals Incorporated
Sponsor organisation address	50 Northern Avenue, Boston, Massachusetts, United States,
Public contact	Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617 341 6777, medicalinfo@vrtx.com
Scientific contact	Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617 341 6777, medicalinfo@vrtx.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	Yes
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	30 Jun 2020
Is this the analysis of the primary completion data?	Yes
Primary completion date	12 Jun 2020
Global end of trial reached?	Yes
Global end of trial date	12 Jun 2020
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To evaluate the efficacy of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) in cystic fibrosis (CF) subjects who are heterozygous for F508del and a gating or residual function mutation (F/G and F/RF genotypes).
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).
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	28 Aug 2019
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	United States: 92
Country: Number of subjects enrolled	Australia: 27
Country: Number of subjects enrolled	France: 27
Country: Number of subjects enrolled	United Kingdom: 25
Country: Number of subjects enrolled	Italy: 20
Country: Number of subjects enrolled	Germany: 16
Country: Number of subjects enrolled	Netherlands: 14
Country: Number of subjects enrolled	Belgium: 13
Country: Number of subjects enrolled	Canada: 12
Country: Number of subjects enrolled	Spain: 12
Country: Number of subjects enrolled	Ireland: 11
Country: Number of subjects enrolled	Denmark: 2
Worldwide total number of subjects	271
EEA total number of subjects	140
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	24
Adults (18-64 years)	242
From 65 to 84 years	5
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	-
Pre-assignment
Screening details	This study was conducted in cystic fibrosis (CF) subjects aged 12 years or older.
Period 1
Period 1 title	Triple Combination Treatment Period (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator, Carer, Assessor
Arms
Are arms mutually exclusive	Yes
Arm title	Control: IVA or TEZ/IVA
Arm description	Following an IVA or TEZ/IVA run-in period of 4 weeks, subjects either received IVA or TEZ/IVA in the treatment period for 8 weeks.
Arm type	Active comparator
Investigational medicinal product name	IVA
Investigational medicinal product code	VX-770
Other name	Ivacaftor
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Subjects received IVA every 12 hours.
Investigational medicinal product name	TEZ/IVA
Investigational medicinal product code	VX-661/VX-770
Other name	Tezacaftor/Ivacaftor
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Subjects received TEZ once daily and IVA every 12 hours.
Arm title	Triple Combination (TC): ELX/TEZ/IVA
Arm description	Following an IVA or TEZ/IVA run-in period of 4 weeks, subjects received ELX/TEZ/IVA TC in the treatment period for 8 weeks.
Arm type	Experimental
Investigational medicinal product name	ELX/TEZ/IVA
Investigational medicinal product code	VX-445/VX-661/VX-770
Other name	Elexacaftor/Tezacaftor/Ivacaftor
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Subjects received VX-445/TEZ/IVA fixed dose combination once daily in the morning.
Investigational medicinal product name	IVA
Investigational medicinal product code	VX-770
Other name	Ivacaftor
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Subjects received IVA once daily in the evening.
Number of subjects in period 1 [1] Control: IVA or TEZ/IVA Triple Combination (TC): ELX/TEZ/IVA Started 126 132 Completed 122 131 Not completed 4 1      Physician decision 1 -      Other 1 -      Adverse Events 2 1
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: A total of 271 subjects enrolled, 12 subjects discontinued in run-in period of the study. Of 259 subjects, 1 subject randomized but not dosed in the treatment period. Therefore, only 258 subjects are included in the subject disposition and baseline section.

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Control: IVA or TEZ/IVA
Reporting group description	Following an IVA or TEZ/IVA run-in period of 4 weeks, subjects either received IVA or TEZ/IVA in the treatment period for 8 weeks.
Reporting group title	Triple Combination (TC): ELX/TEZ/IVA
Reporting group description	Following an IVA or TEZ/IVA run-in period of 4 weeks, subjects received ELX/TEZ/IVA TC in the treatment period for 8 weeks.
Reporting group values Control: IVA or TEZ/IVA Triple Combination (TC): ELX/TEZ/IVA Total Number of subjects 126 132 258 Age categorical Units: Subjects Age continuous Units: years     arithmetic mean (standard deviation) 37.6 ( 14.3 ) 37.7 ( 14.7 ) - Gender categorical Units: Subjects     Female 61 67 128     Male 65 65 130

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Control: IVA or TEZ/IVA
Reporting group description	Following an IVA or TEZ/IVA run-in period of 4 weeks, subjects either received IVA or TEZ/IVA in the treatment period for 8 weeks.
Reporting group title	Triple Combination (TC): ELX/TEZ/IVA
Reporting group description	Following an IVA or TEZ/IVA run-in period of 4 weeks, subjects received ELX/TEZ/IVA TC in the treatment period for 8 weeks.

End points Top of page

Primary: Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) for the ELX/TEZ/IVA group Top of page
End point title	Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) for the ELX/TEZ/IVA group [1] [2]
End point description
End point type	Primary
End point timeframe	From Baseline Through Week 8
Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only within treatment group comparison was planned for this endpoint. Individual within-group comparison cannot be reported in the EudraCT database. Therefore, no statistical comparisons are reported. [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is applicable only for the triple combination arm.
End point values Triple Combination (TC): ELX/TEZ/IVA Number of subjects analysed 132 Units: percentage points     least squares mean (confidence interval 95%) 3.7 (2.8 to 4.6)
No statistical analyses for this end point

Primary: Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) for the ELX/TEZ/IVA group Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Day 1 up to Week 12
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	23.0
Reporting groups
Reporting group title	Control: IVA or TEZ/IVA
Reporting group description	Following an IVA or TEZ/IVA run-in period of 4 weeks, subjects either received IVA or TEZ/IVA in the treatment period for 8 weeks.
Reporting group title	Triple Combination (TC): ELX/TEZ/IVA
Reporting group description	Following an IVA or TEZ/IVA run-in period of 4 weeks, subjects received ELX/TEZ/IVA TC in the treatment period for 8 weeks.
Serious adverse events Control: IVA or TEZ/IVA Triple Combination (TC): ELX/TEZ/IVA Total subjects affected by serious adverse events      subjects affected / exposed 11 / 126 (8.73%) 5 / 132 (3.79%)      number of deaths (all causes) 0 0      number of deaths resulting from adverse events Ear and labyrinth disorders Tinnitus      subjects affected / exposed 0 / 126 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Hepatobiliary disorders Cholecystitis      subjects affected / exposed 0 / 126 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Respiratory, thoracic and mediastinal disorders Haemoptysis      subjects affected / exposed 1 / 126 (0.79%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 1 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Psychiatric disorders Anxiety      subjects affected / exposed 1 / 126 (0.79%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Depression      subjects affected / exposed 1 / 126 (0.79%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Endocrine disorders Hyperparathyroidism primary      subjects affected / exposed 1 / 126 (0.79%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Infections and infestations Cellulitis      subjects affected / exposed 0 / 126 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Infective pulmonary exacerbation of cystic fibrosis      subjects affected / exposed 7 / 126 (5.56%) 2 / 132 (1.52%)      occurrences causally related to treatment / all 0 / 7 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 Pneumonia      subjects affected / exposed 1 / 126 (0.79%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Control: IVA or TEZ/IVA Triple Combination (TC): ELX/TEZ/IVA Total subjects affected by non serious adverse events      subjects affected / exposed 47 / 126 (37.30%) 35 / 132 (26.52%) Investigations Alanine aminotransferase increased      subjects affected / exposed 0 / 126 (0.00%) 8 / 132 (6.06%)      occurrences all number 0 9 Aspartate aminotransferase increased      subjects affected / exposed 0 / 126 (0.00%) 8 / 132 (6.06%)      occurrences all number 0 8 Nervous system disorders Headache      subjects affected / exposed 19 / 126 (15.08%) 11 / 132 (8.33%)      occurrences all number 30 11 Gastrointestinal disorders Abdominal pain      subjects affected / exposed 2 / 126 (1.59%) 7 / 132 (5.30%)      occurrences all number 2 7 Diarrhoea      subjects affected / exposed 8 / 126 (6.35%) 5 / 132 (3.79%)      occurrences all number 13 5 Nausea      subjects affected / exposed 9 / 126 (7.14%) 2 / 132 (1.52%)      occurrences all number 16 2 Respiratory, thoracic and mediastinal disorders Cough      subjects affected / exposed 18 / 126 (14.29%) 3 / 132 (2.27%)      occurrences all number 21 3 Sputum increased      subjects affected / exposed 8 / 126 (6.35%) 6 / 132 (4.55%)      occurrences all number 8 6 Infections and infestations Infective pulmonary exacerbation of cystic fibrosis      subjects affected / exposed 10 / 126 (7.94%) 2 / 132 (1.52%)      occurrences all number 11 2

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
02 Dec 2019	Amended to add an exploratory endpoint.
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

More information Top of page