A Study Evaluating the Efficacy and Safety of VX-445/Tezacaftor/Ivacaftor in Cystic Fibrosis Subjects, Homozygous for F508del
Sponsor
Vertex Pharmaceuticals Incorporated (Industry)
Overall Status
Completed
CT.gov ID
NCT04105972
Collaborator
(none)
176
35
2
9.7
5
0.5
Study Details
Study Description
Brief Summary
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 homozygous for F508del.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
176 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 3b, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-445/Tezacaftor/Ivacaftor in Cystic Fibrosis Subjects, Homozygous for F508del
Actual Study Start Date
:
Oct 3, 2019
Actual Primary Completion Date
:
Jul 24, 2020
Actual Study Completion Date
:
Jul 24, 2020
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: TEZ/IVA Following TEZ/IVA run-in period of 4 weeks, participants received TEZ 100 milligrams (mg) once daily (qd)/IVA 150 mg every 12 hours (q12h) in the treatment period for 24 weeks. |
Drug: TEZ/IVA
Fixed-dose combination (FDC) tablet for oral administration.
Other Names:
Drug: IVA
Mono tablet for oral administration.
Other Names:
|
| Experimental: ELX/TEZ/IVA Following TEZ/IVA run-in period of 4 weeks, participants received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. |
Drug: ELX/TEZ/IVA
FDC tablet for oral administration.
Other Names:
Drug: IVA
Mono tablet for oral administration.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Absolute Change in CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score [From Baseline Through Week 24]
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.
Secondary Outcome Measures
- Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) [From Baseline Through Week 24]
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
- Absolute Change in Sweat Chloride (SwCl) [From Baseline Through Week 24]
Sweat samples were collected using an approved collection device.
- Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [From Day 1 in the 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 28)]
Eligibility Criteria
Criteria
Ages Eligible for Study:
12 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Key Inclusion Criteria:
-
Homozygous for the F508del mutation (F/F)
-
Forced expiratory volume in 1 second (FEV1) value ≥40% and ≤90% of predicted mean for age, sex, and height
Key Exclusion Criteria:
-
Clinically significant cirrhosis with or without portal hypertension
-
Lung infection with organisms associated with a more rapid decline in pulmonary status
-
Solid organ or hematological transplantation
Other protocol defined Inclusion/Exclusion criteria may apply
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | The Prince Charles Hospital | Chermside | Australia | ||
| 2 | Institute for Respiratory Health | Nedlands | Australia | ||
| 3 | Perth Children's Hospital | Nedlands | Australia | ||
| 4 | John Hunter Hospital & Hunter Medical Research Institute and John Hunter Children's Hospital | New Lambton | Australia | ||
| 5 | The Royal Children's Hospital | Parkville, VIC | Australia | ||
| 6 | Queensland Children's Hospital | South Brisbane | Australia | ||
| 7 | Universitair Ziekenhuis Brussel - Campus Jette | Brussels | Belgium | ||
| 8 | UZ Antwerpen | Edegem | Belgium | ||
| 9 | Universitair Ziekenhuis Gent | Gent | Belgium | ||
| 10 | Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg | Leuven | Belgium | ||
| 11 | Charite Paediatric Pulmonology Department | Berlin | Germany | ||
| 12 | Ruhrlandklinik Westdeutsches Lungenzentrum am Klinikum Essen | Essen | Germany | ||
| 13 | Universitatsklinikum Essen (AoR), Kinderklinik III, Abt. fur Pneumologie | Essen | Germany | ||
| 14 | Johann Wolfgang Goethe University | Frankfurt | Germany | ||
| 15 | Mukeviszidose-Zentrum am Universitatsklinikum Jena, Klinik fuer Kinder- und Jugendmedizin | Jena | Germany | ||
| 16 | Universitaetsklinkum Koeln, CF-Studienzentrum | Koeln | Germany | ||
| 17 | Pneumologisches Studienzentrum Muenchen-West | Muenchen | Germany | ||
| 18 | Klinikum Innenstadt, University of Munich | München | Germany | ||
| 19 | Belfast City Hospital | Belfast | United Kingdom | ||
| 20 | University Hospitals Birmingham NHS Foundation Trust | Birmingham | United Kingdom | ||
| 21 | University Hospitals Bristol NHS Foundation Trust, Bristol Royal Hospital | Bristol | United Kingdom | ||
| 22 | Papworth Hospital NHS Foundation Trust, Papworth Everard | Cambridge | United Kingdom | ||
| 23 | Western General Hospital | Edinburgh | United Kingdom | ||
| 24 | Royal Devon and Exeter NHS Foundation Trust, Royal Devon and Exeter Hospital | Exeter | United Kingdom | ||
| 25 | Clinical Research Facility, Queen Elizabeth University Hospital | Glasgow | United Kingdom | ||
| 26 | Leeds General Infirmary | Leeds, West Yorkshire | United Kingdom | ||
| 27 | St. James University Hospital | Leeds | United Kingdom | ||
| 28 | Alder Hey Children's Alder Hey Children's NHS Foundation Trust | Liverpool | United Kingdom | ||
| 29 | Great Ormond Street Hospital for Sick Children | London | United Kingdom | ||
| 30 | London and St Bartholomew's Hospital | London | United Kingdom | ||
| 31 | The University Hospital of South Manchester | Manchester | United Kingdom | ||
| 32 | The Newcastle upon Tyne Hospitals NHS Foundation Trust, The Royal Victoria Infirmary | Newcastle Upon Tyne | United Kingdom | ||
| 33 | Nottingham University Hospitals NHS Trust, Queens Medical Center | Nottingham | United Kingdom | ||
| 34 | All Wales Adult Cystic Fibrosis Centre, University Hospital Llandough | Penarth | United Kingdom | ||
| 35 | Southampton General Hospital | Southampton | United Kingdom |
Sponsors and Collaborators
- Vertex Pharmaceuticals Incorporated
Investigators
None specified.Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier:
NCT04105972
Other Study ID Numbers:
- VX18-445-109
- 2019-001735-31
First Posted:
Sep 26, 2019
Last Update Posted:
Aug 18, 2021
Last Verified:
Jul 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | A total of 176 participants were enrolled in the study. Out of those 176 participants, 1 participant was randomized but not dosed in the treatment period. Therefore, results are presented for only 175 participants. |
|---|---|
| Pre-assignment Detail | This study was conducted in cystic fibrosis (CF) participants aged 12 years or older. |
| Arm/Group Title | TEZ/IVA | ELX/TEZ/IVA |
|---|---|---|
| Arm/Group Description | Following TEZ (tezacaftor)/IVA (ivacaftor) run-in period of 4 weeks, participants received TEZ 100 milligrams (mg) once daily (qd)/IVA 150 mg every 12 hours (q12h) in the treatment period for 24 weeks. | Following TEZ/IVA run-in period of 4 weeks, participants received ELX (elexacaftor) 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. |
| Period Title: Overall Study | ||
| STARTED | 88 | 87 |
| COMPLETED | 86 | 86 |
| NOT COMPLETED | 2 | 1 |
Baseline Characteristics
| Arm/Group Title | TEZ/IVA | ELX/TEZ/IVA | Total |
|---|---|---|---|
| Arm/Group Description | Following TEZ/IVA run-in period of 4 weeks, participants received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. | Following TEZ/IVA run-in period of 4 weeks, participants received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. | Total of all reporting groups |
| Overall Participants | 88 | 87 | 175 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
27.8
(11.0)
|
27.9
(11.8)
|
27.8
(11.4)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
45
51.1%
|
43
49.4%
|
88
50.3%
|
| Male |
43
48.9%
|
44
50.6%
|
87
49.7%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
2
2.3%
|
1
1.1%
|
3
1.7%
|
| Not Hispanic or Latino |
83
94.3%
|
85
97.7%
|
168
96%
|
| Unknown or Not Reported |
3
3.4%
|
1
1.1%
|
4
2.3%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| Asian |
0
0%
|
2
2.3%
|
2
1.1%
|
| White |
88
100%
|
84
96.6%
|
172
98.3%
|
| White, Asian |
0
0%
|
1
1.1%
|
1
0.6%
|
| CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score (units on a scale) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [units on a scale] |
73.1
(17.6)
|
71.2
(19.6)
|
72.2
(18.6)
|
Outcome Measures
| Title | Absolute Change in CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score |
|---|---|
| Description | 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. |
| Time Frame | From Baseline Through Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set (FAS) included all randomized participants who carried the intended CF transmembrane conductance regulator (CFTR) allele mutation and received at least 1 dose of study drug in treatment period. |
| Arm/Group Title | TEZ/IVA | ELX/TEZ/IVA |
|---|---|---|
| Arm/Group Description | Following TEZ/IVA run-in period of 4 weeks, participants received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. | Following TEZ/IVA run-in period of 4 weeks, participants received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. |
| Measure Participants | 88 | 87 |
| Least Squares Mean (Standard Error) [units on a scale] |
1.2
(1.5)
|
17.1
(1.5)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TEZ/IVA, ELX/TEZ/IVA |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | < 0.0001 |
| Comments | ||
| Method | Mixed-effects Model for Repeated Measure | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares (LS) Mean Difference |
| Estimated Value | 15.9 | |
| Confidence Interval |
(2-Sided) 95% 11.7 to 20.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) |
|---|---|
| Description | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
| Time Frame | From Baseline Through Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| FAS. |
| Arm/Group Title | TEZ/IVA | ELX/TEZ/IVA |
|---|---|---|
| Arm/Group Description | Following TEZ/IVA run-in period of 4 weeks, participants received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. | Following TEZ/IVA run-in period of 4 weeks, participants received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. |
| Measure Participants | 88 | 87 |
| Least Squares Mean (Standard Error) [percentage points] |
1.0
(0.7)
|
11.2
(0.7)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TEZ/IVA, ELX/TEZ/IVA |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | ||
| Method | Mixed-effects Model for Repeated Measure | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 10.2 | |
| Confidence Interval |
(2-Sided) 95% 8.2 to 12.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Absolute Change in Sweat Chloride (SwCl) |
|---|---|
| Description | Sweat samples were collected using an approved collection device. |
| Time Frame | From Baseline Through Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| FAS. |
| Arm/Group Title | TEZ/IVA | ELX/TEZ/IVA |
|---|---|---|
| Arm/Group Description | Following TEZ/IVA run-in period of 4 weeks, participants received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. | Following TEZ/IVA run-in period of 4 weeks, participants received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. |
| Measure Participants | 88 | 87 |
| Least Squares Mean (Standard Error) [millimole per liter (mmol/L)] |
-3.4
(1.2)
|
-46.2
(1.3)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TEZ/IVA, ELX/TEZ/IVA |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | -42.8 | |
| Confidence Interval |
(2-Sided) 95% -46.2 to -39.3 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |
|---|---|
| Description | |
| Time Frame | From Day 1 in the 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 28) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety set included all participants who received at least 1 dose of study drug in the treatment period. |
| Arm/Group Title | TEZ/IVA | ELX/TEZ/IVA |
|---|---|---|
| Arm/Group Description | Following TEZ/IVA run-in period of 4 weeks, participants received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. | Following TEZ/IVA run-in period of 4 weeks, participants received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. |
| Measure Participants | 88 | 87 |
| Participants With TEAEs |
81
92%
|
77
88.5%
|
| Participants With SAEs |
14
15.9%
|
5
5.7%
|
Adverse Events
| Time Frame | From Day 1 in the 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 28) | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | TEZ/IVA | ELX/TEZ/IVA | ||
| Arm/Group Description | Following TEZ/IVA run-in period of 4 weeks, participants received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. | Following TEZ/IVA run-in period of 4 weeks, participants received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. | ||
All Cause Mortality |
||||
| TEZ/IVA | ELX/TEZ/IVA | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/88 (0%) | 0/87 (0%) | ||
Serious Adverse Events |
||||
| TEZ/IVA | ELX/TEZ/IVA | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 14/88 (15.9%) | 5/87 (5.7%) | ||
| Blood and lymphatic system disorders | ||||
| Thrombocytopenia | 0/88 (0%) | 1/87 (1.1%) | ||
| Cardiac disorders | ||||
| Extrasystoles | 1/88 (1.1%) | 0/87 (0%) | ||
| Gastrointestinal disorders | ||||
| Distal intestinal obstruction syndrome | 1/88 (1.1%) | 0/87 (0%) | ||
| Infections and infestations | ||||
| Infective pulmonary exacerbation of cystic fibrosis | 9/88 (10.2%) | 1/87 (1.1%) | ||
| Lower respiratory tract infection | 1/88 (1.1%) | 0/87 (0%) | ||
| Investigations | ||||
| Alanine aminotransferase increased | 0/88 (0%) | 1/87 (1.1%) | ||
| Metabolism and nutrition disorders | ||||
| Type 3 diabetes mellitus | 0/88 (0%) | 1/87 (1.1%) | ||
| Psychiatric disorders | ||||
| Anxiety | 1/88 (1.1%) | 1/87 (1.1%) | ||
| Depression | 0/88 (0%) | 1/87 (1.1%) | ||
| Insomnia | 1/88 (1.1%) | 0/87 (0%) | ||
| Obsessive-compulsive disorder | 1/88 (1.1%) | 0/87 (0%) | ||
| Psychotic disorder | 1/88 (1.1%) | 0/87 (0%) | ||
| Renal and urinary disorders | ||||
| Nephrolithiasis | 0/88 (0%) | 1/87 (1.1%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Haemoptysis | 1/88 (1.1%) | 0/87 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| TEZ/IVA | ELX/TEZ/IVA | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 72/88 (81.8%) | 59/87 (67.8%) | ||
| Gastrointestinal disorders | ||||
| Abdominal pain | 7/88 (8%) | 4/87 (4.6%) | ||
| Diarrhoea | 7/88 (8%) | 8/87 (9.2%) | ||
| Infections and infestations | ||||
| Infective pulmonary exacerbation of cystic fibrosis | 32/88 (36.4%) | 10/87 (11.5%) | ||
| Nasopharyngitis | 13/88 (14.8%) | 17/87 (19.5%) | ||
| Upper respiratory tract infection | 5/88 (5.7%) | 9/87 (10.3%) | ||
| Investigations | ||||
| Alanine aminotransferase increased | 1/88 (1.1%) | 6/87 (6.9%) | ||
| Aspartate aminotransferase increased | 0/88 (0%) | 5/87 (5.7%) | ||
| Bacterial test positive | 5/88 (5.7%) | 1/87 (1.1%) | ||
| Nervous system disorders | ||||
| Headache | 18/88 (20.5%) | 25/87 (28.7%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 23/88 (26.1%) | 11/87 (12.6%) | ||
| Haemoptysis | 6/88 (6.8%) | 3/87 (3.4%) | ||
| Nasal congestion | 0/88 (0%) | 6/87 (6.9%) | ||
| Oropharyngeal pain | 7/88 (8%) | 11/87 (12.6%) | ||
| Productive cough | 3/88 (3.4%) | 8/87 (9.2%) | ||
| Sputum increased | 16/88 (18.2%) | 10/87 (11.5%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Rash | 0/88 (0%) | 7/87 (8%) | ||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Results Point of Contact
| Name/Title | Medical Monitor |
|---|---|
| Organization | Vertex Pharmaceuticals Incorporated |
| Phone | 617-341-6777 |
| medicalinfo@vrtx.com |
Responsible Party:
Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier:
NCT04105972
Other Study ID Numbers:
- VX18-445-109
- 2019-001735-31
First Posted:
Sep 26, 2019
Last Update Posted:
Aug 18, 2021
Last Verified:
Jul 1, 2021