Clinical Trial Results:
A Phase 3b Open-label Study Evaluating the Effects of Elexacaftor/Tezacaftor/Ivacaftor on Cough and Physical Activity in Cystic Fibrosis Subjects 12 Years of Age and Older Who Are Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)

Trial information Top of page
Trial identification
Sponsor protocol code	VX20-445-126
Additional study identifiers
ISRCTN number	-
US NCT number	NCT04969224
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	14 Sep 2022
Is this the analysis of the primary completion data?	Yes
Primary completion date	26 Jul 2022
Global end of trial reached?	Yes
Global end of trial date	26 Jul 2022
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To evaluate the effects of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on cough and physical activity using wearable technology in Cystic Fibrosis(CF) subjects.
Protection of trial subjects	The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	12 Oct 2021
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Spain: 7
Country: Number of subjects enrolled	Belgium: 31
Country: Number of subjects enrolled	Canada: 7
Country: Number of subjects enrolled	Australia: 37
Worldwide total number of subjects	82
EEA total number of subjects	38
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)	58
From 65 to 84 years	0
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 subjects with cystic fibrosis, aged 12 years and older, who are heterozygous for the F508del mutation and the minimal function mutation (F/MF).
Period 1
Period 1 title	Overall Period
Is this the baseline period?	Yes
Allocation method	Not applicable
Blinding used	Not blinded
Arms
Arm title	ELX/TEZ/IVA
Arm description	Subjects received ELX/TEZ/IVA fixed-dose combination (FDC) in the morning and IVA in the evening.
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 ELX/TEZ/IVA FDC 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 dose once daily in the evening.
Number of subjects in period 1 [1] ELX/TEZ/IVA Started 81 Completed 80 Not completed 1      Adverse event 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 82 subjects were enrolled in the study. One subject was enrolled but not dosed in this study. Therefore, data for 81 subjects are reported in the subject disposition and baseline characteristics sections.

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Overall Period
Reporting group description	Subjects received ELX/TEZ/IVA fixed-dose combination (FDC) in the morning and IVA in the evening.
Reporting group values Overall Period Total Number of subjects 81 81 Age categorical Units: Subjects     Less than (<)18 years 24 24     More than or equal to (≥)18 years 57 57 Age continuous Units: years     arithmetic mean (standard deviation) 25.7 ( 9.6 ) - Gender categorical Units: Subjects     Female 37 37     Male 44 44

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	ELX/TEZ/IVA
Reporting group description	Subjects received ELX/TEZ/IVA fixed-dose combination (FDC) in the morning and IVA in the evening.

End points Top of page

Primary: Percent Reduction From Baseline in Cough Frequency (cough events per day) to the Average of Week 8 Through Week 12 Top of page
End point title	Percent Reduction From Baseline in Cough Frequency (cough events per day) to the Average of Week 8 Through Week 12 [1]
End point description
End point type	Primary
End point timeframe	Baseline, Week 8 through Week 12
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: Participants’ post-baseline values were compared to their baseline values with a mixed model for repeated measures with change from baseline at each post-baseline visit on the natural log scale as the dependent variable. The primary result obtained from the model was the estimated percent reduction in cough frequency from baseline to the average of Week 8 through Week 12, i.e. 100% × (1-(exp (LS mean)).
End point values ELX/TEZ/IVA Number of subjects analysed 80 Units: Percent     number (confidence interval 95%) 91.7 (89.2 to 93.6)
No statistical analyses for this end point

Primary: Percent Reduction From Baseline in Cough Frequency (cough events per day) to the Average of Week 8 Through Week 12 Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Day 1 up to Week 17
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	25.0
Reporting groups
Reporting group title	ELX/TEZ/IVA
Reporting group description	Subjects received ELX/TEZ/IVA FDC in the morning and IVA in the evening.
Serious adverse events ELX/TEZ/IVA Total subjects affected by serious adverse events      subjects affected / exposed 2 / 81 (2.47%)      number of deaths (all causes) 0      number of deaths resulting from adverse events Gastrointestinal disorders Pancreatitis      subjects affected / exposed 1 / 81 (1.23%)      occurrences causally related to treatment / all 1 / 1      deaths causally related to treatment / all 0 / 0 Psychiatric disorders Anxiety      subjects affected / exposed 1 / 81 (1.23%)      occurrences causally related to treatment / all 1 / 1      deaths causally related to treatment / all 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events ELX/TEZ/IVA Total subjects affected by non serious adverse events      subjects affected / exposed 56 / 81 (69.14%) Nervous system disorders Headache      subjects affected / exposed 14 / 81 (17.28%)      occurrences all number 19 Gastrointestinal disorders Abdominal pain      subjects affected / exposed 8 / 81 (9.88%)      occurrences all number 10 Abdominal pain upper      subjects affected / exposed 7 / 81 (8.64%)      occurrences all number 7 Diarrhoea      subjects affected / exposed 11 / 81 (13.58%)      occurrences all number 13 Respiratory, thoracic and mediastinal disorders Cough      subjects affected / exposed 6 / 81 (7.41%)      occurrences all number 6 Nasal congestion      subjects affected / exposed 5 / 81 (6.17%)      occurrences all number 5 Oropharyngeal pain      subjects affected / exposed 8 / 81 (9.88%)      occurrences all number 8 Skin and subcutaneous tissue disorders Rash      subjects affected / exposed 5 / 81 (6.17%)      occurrences all number 6 Infections and infestations Nasopharyngitis      subjects affected / exposed 13 / 81 (16.05%)      occurrences all number 15 COVID-19      subjects affected / exposed 13 / 81 (16.05%)      occurrences all number 15 Upper respiratory tract infection      subjects affected / exposed 7 / 81 (8.64%)      occurrences all number 7

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? No
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

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