Clinical Trial Results:
A Phase 3b Open label Study Evaluating the Long term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor Combination Therapy in Cystic Fibrosis Subjects Ages 6 Years 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	VX20-445-119
Additional study identifiers
ISRCTN number	-
US NCT number	NCT04545515
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, medicalinfo@vrtx.com
Scientific contact	Medical Monitor, Vertex Pharmaceuticals Incorporated, 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	20 Apr 2023
Is this the analysis of the primary completion data?	Yes
Primary completion date	24 Mar 2023
Global end of trial reached?	Yes
Global end of trial date	24 Mar 2023
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To evaluate the long term safety and tolerability of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) in subjects with Cystic Fibrosis (CF)
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	11 Jan 2021
Long term follow-up planned	Yes
Long term follow-up rationale	Safety, Efficacy
Long term follow-up duration	23 Months
Independent data monitoring committee (IDMC) involvement?	Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Netherlands: 7
Country: Number of subjects enrolled	Spain: 8
Country: Number of subjects enrolled	United Kingdom: 17
Country: Number of subjects enrolled	Denmark: 3
Country: Number of subjects enrolled	France: 13
Country: Number of subjects enrolled	Germany: 31
Country: Number of subjects enrolled	Australia: 11
Country: Number of subjects enrolled	Canada: 13
Country: Number of subjects enrolled	Switzerland: 12
Country: Number of subjects enrolled	Israel: 5
Worldwide total number of subjects	120
EEA total number of subjects	62
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)	120
Adolescents (12-17 years)	0
Adults (18-64 years)	0
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	Subjects from the parent study VX19-445-116 (NCT04353817) were enrolled in this study. A total of 120 subjects were enrolled in this study.
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 6 to less than <12 year of age and weighing <30 kilogram (kg) at Day 1 received ELX 100 milligram (mg) once daily (qd) /TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) and those weighing more than or equal to (≥) 30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 96 weeks. Doses were adjusted upward with subsequent changes in weight. Subjects ≥12 years age at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 96 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 ELX/TEZ/IVA fixed dose combination (FDC), 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 ELX/TEZ/IVA Started 120 Completed 110 Not completed 10      Adverse event 1      Withdrawal of consent (not due to AE) 2      Commercial drug is available for subject 7

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Overall Period
Reporting group description	Baseline data for the long-term safety analysis is based on the parent study baseline, which is defined as the most recent non-missing measurement collected before the first dose of study drug in the treatment period of parent study.
Reporting group values Overall Period Total Number of subjects 120 120 Age categorical Units: Subjects Age continuous Units: years     arithmetic mean (standard deviation) 9.1 ( 1.7 ) - Gender categorical Units: Subjects     Female 69 69     Male 51 51

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	ELX/TEZ/IVA
Reporting group description	Subjects 6 to less than <12 year of age and weighing <30 kilogram (kg) at Day 1 received ELX 100 milligram (mg) once daily (qd) /TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) and those weighing more than or equal to (≥) 30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 96 weeks. Doses were adjusted upward with subsequent changes in weight. Subjects ≥12 years age at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 96 weeks.

End points Top of page

Primary: Safety and Tolerability as Assessed by Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Top of page
End point title	Safety and Tolerability as Assessed by Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [1]
End point description	The Open-Label Safety Set (OL-SS) included all subjects who had received at least 1 dose of study drug in the OL study.
End point type	Primary
End point timeframe	From Day 1 up to Week 100
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 descriptive statistics were planned. No statistical comparisons were planned for the primary safety endpoint.
End point values ELX/TEZ/IVA Number of subjects analysed 120 Units: Subjects     Subjects With TEAEs 118     Subjects With SAEs 13
No statistical analyses for this end point

Primary: Safety and Tolerability as Assessed by Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Day 1 up to Week 100
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	25.1
Reporting groups
Reporting group title	ELX/TEZ/IVA
Reporting group description	Subjects 6 to <12 year of age and weighing <30 kg at Day 1 received ELX 100 mg qd /TEZ 50 mg qd/IVA 75 mg q12h and those weighing ≥30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 96 weeks. Doses were adjusted upward with subsequent changes in weight. Subjects ≥12 years age at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 96 weeks.
Serious adverse events ELX/TEZ/IVA Total subjects affected by serious adverse events      subjects affected / exposed 13 / 120 (10.83%)      number of deaths (all causes) 0      number of deaths resulting from adverse events Investigations Blood glucose increased      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Injury, poisoning and procedural complications Head injury      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 General disorders and administration site conditions General physical health deterioration      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Gastrointestinal disorders Constipation      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 0 / 2      deaths causally related to treatment / all 0 / 0 Enteritis      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Steatorrhoea      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 1 / 1      deaths causally related to treatment / all 0 / 0 Intestinal obstruction      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Ileus paralytic      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Renal and urinary disorders Haematuria      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Infections and infestations Pneumonia staphylococcal      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Pneumonia pseudomonal      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Bacterial disease carrier      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Infective pulmonary exacerbation of cystic fibrosis      subjects affected / exposed 2 / 120 (1.67%)      occurrences causally related to treatment / all 0 / 2      deaths causally related to treatment / all 0 / 0 Metabolism and nutrition disorders Diabetes mellitus inadequate control      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Weight gain poor      subjects affected / exposed 1 / 120 (0.83%)      occurrences causally related to treatment / all 0 / 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 118 / 120 (98.33%) Investigations SARS-CoV-2 test positive      subjects affected / exposed 12 / 120 (10.00%)      occurrences all number 13 Bacterial test positive      subjects affected / exposed 7 / 120 (5.83%)      occurrences all number 10 Aspartate aminotransferase increased      subjects affected / exposed 6 / 120 (5.00%)      occurrences all number 8 Alanine aminotransferase increased      subjects affected / exposed 11 / 120 (9.17%)      occurrences all number 15 Staphylococcus test positive      subjects affected / exposed 9 / 120 (7.50%)      occurrences all number 12 Nervous system disorders Headache      subjects affected / exposed 45 / 120 (37.50%)      occurrences all number 106 General disorders and administration site conditions Pyrexia      subjects affected / exposed 48 / 120 (40.00%)      occurrences all number 85 Fatigue      subjects affected / exposed 6 / 120 (5.00%)      occurrences all number 8 Ear and labyrinth disorders Ear pain      subjects affected / exposed 8 / 120 (6.67%)      occurrences all number 13 Immune system disorders Immunisation reaction      subjects affected / exposed 8 / 120 (6.67%)      occurrences all number 12 Eye disorders Conjunctivitis allergic      subjects affected / exposed 7 / 120 (5.83%)      occurrences all number 12 Gastrointestinal disorders Constipation      subjects affected / exposed 8 / 120 (6.67%)      occurrences all number 8 Abdominal pain upper      subjects affected / exposed 11 / 120 (9.17%)      occurrences all number 13 Abdominal pain      subjects affected / exposed 27 / 120 (22.50%)      occurrences all number 44 Diarrhoea      subjects affected / exposed 15 / 120 (12.50%)      occurrences all number 22 Nausea      subjects affected / exposed 9 / 120 (7.50%)      occurrences all number 13 Vomiting      subjects affected / exposed 24 / 120 (20.00%)      occurrences all number 42 Respiratory, thoracic and mediastinal disorders Productive cough      subjects affected / exposed 17 / 120 (14.17%)      occurrences all number 30 Cough      subjects affected / exposed 62 / 120 (51.67%)      occurrences all number 163 Nasal congestion      subjects affected / exposed 13 / 120 (10.83%)      occurrences all number 15 Oropharyngeal pain      subjects affected / exposed 32 / 120 (26.67%)      occurrences all number 51 Rhinorrhoea      subjects affected / exposed 22 / 120 (18.33%)      occurrences all number 50 Musculoskeletal and connective tissue disorders Pain in extremity      subjects affected / exposed 9 / 120 (7.50%)      occurrences all number 12 Infections and infestations Nasopharyngitis      subjects affected / exposed 54 / 120 (45.00%)      occurrences all number 115 Influenza      subjects affected / exposed 11 / 120 (9.17%)      occurrences all number 12 Infective pulmonary exacerbation of cystic fibrosis      subjects affected / exposed 19 / 120 (15.83%)      occurrences all number 27 Hordeolum      subjects affected / exposed 10 / 120 (8.33%)      occurrences all number 12 COVID-19      subjects affected / exposed 70 / 120 (58.33%)      occurrences all number 78 Bacterial disease carrier      subjects affected / exposed 8 / 120 (6.67%)      occurrences all number 11 Viral upper respiratory tract infection      subjects affected / exposed 13 / 120 (10.83%)      occurrences all number 17 Upper respiratory tract infection      subjects affected / exposed 37 / 120 (30.83%)      occurrences all number 65 Rhinitis      subjects affected / exposed 29 / 120 (24.17%)      occurrences all number 50 Metabolism and nutrition disorders Decreased appetite      subjects affected / exposed 6 / 120 (5.00%)      occurrences all number 9

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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