NCT04058353

A Phase 3 Study of VX-445 Combination Therapy in Cystic Fibrosis (CF) Subjects Heterozygous for F508del and a Gating or Residual Function Mutation (F/G and F/RF Genotypes)

Completed Phase 3 Results posted Last updated 2 July 2021

What this trial tests

Phase 3 trial testing ELX/TEZ/IVA in Cystic Fibrosis in 271 participants. Completed in 12 June 2020.

Timeline

28 August 2019

Primary endpoint
12 June 2020

12 June 2020

Quick facts

Lead sponsor	Vertex Pharmaceuticals Incorporated
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	271
Start date	28 August 2019
Primary completion	12 June 2020
Estimated completion	12 June 2020
Sites	93 locations across Denmark, France, Italy, Netherlands, Belgium, Ireland, United Kingdom, Germany

Drugs / interventions tested

• ELX/TEZ/IVA — full drug profile →
• IVA — full drug profile →
• TEZ/IVA — full drug profile →

Conditions studied

• Cystic Fibrosis — all drugs for Cystic Fibrosis →

Sponsor

Vertex Pharmaceuticals Incorporated — full company profile →

Who can join

12 and older, any sex, with Cystic Fibrosis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for ELX/TEZ/IVA Group Primary · From Baseline Through Week 8

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Group	Value	95% CI
TC: ELX/TEZ/IVA	3.7	2.8 – 4.6

Absolute Change in Sweat Chloride (SwCl) for ELX/TEZ/IVA Group Secondary · From Baseline Through Week 8

Sweat samples were collected using an approved collection device.

Group	Value	95% CI
TC: ELX/TEZ/IVA	-22.3	-24.5 – -20.2

Absolute Change in ppFEV1 for the ELX/TEZ/IVA Group Compared to the Control Group Secondary · From Baseline Through Week 8

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Group	Value	95% CI
Control: IVA or TEZ/IVA	0.2	-0.7 – 1.1
TC: ELX/TEZ/IVA	3.7	2.8 – 4.6

Absolute Change in SwCl for ELX/TEZ/IVA Group Compared to the Control Group Secondary · From Baseline Through Week 8

Sweat samples were collected using an approved collection device.

Group	Value	95% CI
Control: IVA or TEZ/IVA	0.7	-1.4 – 2.8
TC: ELX/TEZ/IVA	-22.3	-24.5 – -20.2

Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for ELX/TEZ/IVA Group Secondary · From Baseline Through Week 8

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.

Group	Value	95% CI
TC: ELX/TEZ/IVA	10.3	8.0 – 12.7

Absolute Change in CFQ-R Respiratory Domain Score for ELX/TEZ/IVA Group Compared to the Control Group Secondary · From Baseline Through Week 8

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.

Group	Value	95% CI
Control: IVA or TEZ/IVA	1.6	-0.8 – 4.1
TC: ELX/TEZ/IVA	10.3	8.0 – 12.7

Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Secondary · Day 1 up to Week 12

Participants With TEAEs

Group	Value	95% CI
Control: IVA or TEZ/IVA	83
TC: ELX/TEZ/IVA	88

Participants With SAEs

Group	Value	95% CI
Control: IVA or TEZ/IVA	11
TC: ELX/TEZ/IVA	5

Adverse events — posted to ClinicalTrials.gov

Time frame: Day 1 up to Week 12. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Control: IVA or TEZ/IVA

Serious: 11/126 (9%)

Deaths: 0/126

TC: ELX/TEZ/IVA

Serious: 5/132 (4%)

Deaths: 0/132

Serious adverse events (9 terms)

Reaction	System	Control: IVA or TEZ/IVA	TC: ELX/TEZ/IVA
Infective pulmonary exacerbation of cystic fibrosis	Infections and infestations	—	—
Tinnitus	Ear and labyrinth disorders	—	—
Hyperparathyroidism primary	Endocrine disorders	—	—
Cholecystitis	Hepatobiliary disorders	—	—
Cellulitis	Infections and infestations	—	—
Pneumonia	Infections and infestations	—	—
Anxiety	Psychiatric disorders	—	—
Depression	Psychiatric disorders	—	—
Haemoptysis	Respiratory, thoracic and mediastinal disorders	—	—

Other adverse events (9 terms — click to expand)

Reaction	System	Control: IVA or TEZ/IVA	TC: ELX/TEZ/IVA
Headache	Nervous system disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Infective pulmonary exacerbation of cystic fibrosis	Infections and infestations	—	—
Nausea	Gastrointestinal disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Alanine aminotransferase increased	Investigations	—	—
Aspartate aminotransferase increased	Investigations	—	—
Sputum increased	Respiratory, thoracic and mediastinal disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—

Most-reported serious reactions: Infective pulmonary exacerbation of cystic fibrosis, Tinnitus, Hyperparathyroidism primary, Cholecystitis, Cellulitis, Pneumonia, Anxiety, Depression.

Data from ClinicalTrials.gov NCT04058353 adverse events section.

Sponsor's own description

This study will evaluate the efficacy, safety and pharmacodynamics of elexacaftor (ELX, VX-445) in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are heterozygous for F508del and a gating or residual function mutation (F/G and F/RF genotypes).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine.
   Lopes-Pacheco M. · · 2019 · cited 349× · PMID 32153386 · DOI 10.3389/fphar.2019.01662
2. Triple Therapy for Cystic Fibrosis <i>Phe508del</i>-Gating and -Residual Function Genotypes.
   Barry PJ, Mall MA, Álvarez A, Colombo C, et al · · 2021 · cited 214× · PMID 34437784 · DOI 10.1056/nejmoa2100665
3. Elexacaftor-Tezacaftor-Ivacaftor: The First Triple-Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapy.
   Ridley K, Condren M. · · 2020 · cited 90× · PMID 32265602 · DOI 10.5863/1551-6776-25.3.192
4. From Ivacaftor to Triple Combination: A Systematic Review of Efficacy and Safety of CFTR Modulators in People with Cystic Fibrosis.
   Gramegna A, Contarini M, Aliberti S, Casciaro R, et al · · 2020 · cited 60× · PMID 32824306 · DOI 10.3390/ijms21165882
5. The impact of FDA and EMA regulatory decision-making process on the access to CFTR modulators for the treatment of cystic fibrosis.
   Costa E, Girotti S, Pauro F, Leufkens HGM, et al · · 2022 · cited 43× · PMID 35525974 · DOI 10.1186/s13023-022-02350-5
6. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del).
   Southern KW, Murphy J, Sinha IP, Nevitt SJ. · · 2020 · cited 32× · PMID 33331662 · DOI 10.1002/14651858.cd010966.pub3
7. Novel therapeutic approaches for the management of cystic fibrosis.
   Jaques R, Shakeel A, Hoyle C. · · 2020 · cited 13× · PMID 33282281 · DOI 10.4081/mrm.2020.690
8. Efficacy and Safety of Triple Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Patients With Cystic Fibrosis: A Meta-Analysis of Randomized Controlled Trials.
   Wang Y, Ma B, Li W, Li P. · · 2022 · cited 6× · PMID 35359862 · DOI 10.3389/fphar.2022.863280