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Trial record 1 of 1 for:    VX18-445-104-
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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04058353
Recruitment Status : Completed
First Posted : August 15, 2019
Results First Posted : July 2, 2021
Last Update Posted : July 2, 2021
Sponsor:
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Cystic Fibrosis
Interventions Drug: ELX/TEZ/IVA
Drug: IVA
Drug: TEZ/IVA
Enrollment 271
Recruitment Details A total of 271 participants were enrolled in this study out of which 12 participants discontinued in run-in period. Of 259 participants, 1 participant was randomized but not dosed in the treatment period. Therefore, results are presented for only 258 participants.
Pre-assignment Details This study was conducted in cystic fibrosis (CF) participants aged 12 years or older.
Arm/Group Title Control: IVA or TEZ/IVA Triple Combination (TC): ELX/TEZ/IVA
Hide Arm/Group Description Following an IVA (ivacaftor) or TEZ (tezacaftor)/IVA run-in period of 4 weeks, participants either received IVA 150 milligrams (mg) every 12 hours (q12h) or TEZ 100 mg once daily (qd)/IVA 150 mg q12h in the treatment period for 8 weeks. Following an IVA or 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 8 weeks.
Period Title: Overall Study
Started 126 132
Completed 122 131
Not Completed 4 1
Reason Not Completed
Adverse Event             2             1
Physician Decision             1             0
Other             1             0
Arm/Group Title Control: IVA or TEZ/IVA TC: ELX/TEZ/IVA Total
Hide Arm/Group Description Following an IVA or TEZ/IVA run-in period of 4 weeks, participants either received IVA 150 mg q12h or TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 8 weeks. Following an IVA or 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 8 weeks. Total of all reporting groups
Overall Number of Baseline Participants 126 132 258
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 126 participants 132 participants 258 participants
37.6  (14.3) 37.7  (14.7) 37.7  (14.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 126 participants 132 participants 258 participants
Female
61
  48.4%
67
  50.8%
128
  49.6%
Male
65
  51.6%
65
  49.2%
130
  50.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 126 participants 132 participants 258 participants
Hispanic or Latino
4
   3.2%
5
   3.8%
9
   3.5%
Not Hispanic or Latino
114
  90.5%
117
  88.6%
231
  89.5%
Unknown or Not Reported
8
   6.3%
10
   7.6%
18
   7.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 126 participants 132 participants 258 participants
Black or African American
2
   1.6%
0
   0.0%
2
   0.8%
Not Collected per Local Regulations
9
   7.1%
9
   6.8%
18
   7.0%
Aboriginal
2
   1.6%
1
   0.8%
3
   1.2%
Latin-American
1
   0.8%
0
   0.0%
1
   0.4%
Lebanese
1
   0.8%
0
   0.0%
1
   0.4%
White
110
  87.3%
122
  92.4%
232
  89.9%
White, American Indian or Alaska Native
1
   0.8%
0
   0.0%
1
   0.4%
Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)   [1] 
Mean (Standard Deviation)
Unit of measure:  Percentage points
Number Analyzed 126 participants 132 participants 258 participants
68.1  (16.4) 67.1  (15.7) 67.6  (16.0)
[1]
Measure Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
1.Primary Outcome
Title Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for ELX/TEZ/IVA Group
Hide 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 8
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants who have the intended CF transmembrane conductance regulator (CFTR) allele mutation and received at least 1 dose of study drug in the treatment period. This outcome measure was applicable only for the triple combination arm.
Arm/Group Title TC: ELX/TEZ/IVA
Hide Arm/Group Description:
Following an IVA or 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 8 weeks.
Overall Number of Participants Analyzed 132
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percentage points
3.7
(2.8 to 4.6)
2.Secondary Outcome
Title Absolute Change in Sweat Chloride (SwCl) for ELX/TEZ/IVA Group
Hide Description Sweat samples were collected using an approved collection device.
Time Frame From Baseline Through Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
FAS. This outcome measure was applicable only for the triple combination group.
Arm/Group Title TC: ELX/TEZ/IVA
Hide Arm/Group Description:
Following an IVA or 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 8 weeks.
Overall Number of Participants Analyzed 132
Least Squares Mean (95% Confidence Interval)
Unit of Measure: millimole per Liter (mmol/L)
-22.3
(-24.5 to -20.2)
3.Secondary Outcome
Title Absolute Change in ppFEV1 for the ELX/TEZ/IVA Group Compared to the Control Group
Hide 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 8
Hide Outcome Measure Data
Hide Analysis Population Description
FAS.
Arm/Group Title Control: IVA or TEZ/IVA TC: ELX/TEZ/IVA
Hide Arm/Group Description:
Following an IVA or TEZ/IVA run-in period of 4 weeks, participants either received IVA 150 mg q12h or TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 8 weeks.
Following an IVA or 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 8 weeks.
Overall Number of Participants Analyzed 126 132
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percentage points
0.2
(-0.7 to 1.1)
3.7
(2.8 to 4.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Control: IVA or TEZ/IVA, TC: ELX/TEZ/IVA
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed-effects model for repeated measure
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares (LS) Mean Difference
Estimated Value 3.5
Confidence Interval (2-Sided) 95%
2.2 to 4.7
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Absolute Change in SwCl for ELX/TEZ/IVA Group Compared to the Control Group
Hide Description Sweat samples were collected using an approved collection device.
Time Frame From Baseline Through Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
FAS.
Arm/Group Title Control: IVA or TEZ/IVA TC: ELX/TEZ/IVA
Hide Arm/Group Description:
Following an IVA or TEZ/IVA run-in period of 4 weeks, participants either received IVA 150 mg q12h or TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 8 weeks.
Following an IVA or 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 8 weeks.
Overall Number of Participants Analyzed 126 132
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mmol/L
0.7
(-1.4 to 2.8)
-22.3
(-24.5 to -20.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Control: IVA or TEZ/IVA, TC: ELX/TEZ/IVA
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed-effects model for repeated measure
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -23.1
Confidence Interval (2-Sided) 95%
-26.1 to -20.1
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for ELX/TEZ/IVA Group
Hide 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 8
Hide Outcome Measure Data
Hide Analysis Population Description
FAS. This outcome measure was applicable only for the triple combination arm.
Arm/Group Title TC: ELX/TEZ/IVA
Hide Arm/Group Description:
Following an IVA or 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 8 weeks.
Overall Number of Participants Analyzed 132
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
10.3
(8.0 to 12.7)
6.Secondary Outcome
Title Absolute Change in CFQ-R Respiratory Domain Score for ELX/TEZ/IVA Group Compared to the Control Group
Hide 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 8
Hide Outcome Measure Data
Hide Analysis Population Description
FAS.
Arm/Group Title Control: IVA or TEZ/IVA TC: ELX/TEZ/IVA
Hide Arm/Group Description:
Following an IVA or TEZ/IVA run-in period of 4 weeks, participants either received IVA 150 mg q12h or TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 8 weeks.
Following an IVA or 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 8 weeks.
Overall Number of Participants Analyzed 126 132
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
1.6
(-0.8 to 4.1)
10.3
(8.0 to 12.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Control: IVA or TEZ/IVA, TC: ELX/TEZ/IVA
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed-effects model for repeated measure
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 8.7
Confidence Interval (2-Sided) 95%
5.3 to 12.1
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Hide Description [Not Specified]
Time Frame Day 1 up to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Safety set included all participants who received at least 1 dose of study drug in the treatment period.
Arm/Group Title Control: IVA or TEZ/IVA TC: ELX/TEZ/IVA
Hide Arm/Group Description:
Following an IVA or TEZ/IVA run-in period of 4 weeks, participants either received IVA 150 mg q12h or TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 8 weeks.
Following an IVA or 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 8 weeks.
Overall Number of Participants Analyzed 126 132
Measure Type: Number
Unit of Measure: participants
Participants With TEAEs 83 88
Participants With SAEs 11 5
Time Frame Day 1 up to Week 12
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Control: IVA or TEZ/IVA TC: ELX/TEZ/IVA
Hide Arm/Group Description Following an IVA or TEZ/IVA run-in period of 4 weeks, participants either received IVA 150 mg q12h or TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 8 weeks. Following an IVA or 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 8 weeks.
All-Cause Mortality
Control: IVA or TEZ/IVA TC: ELX/TEZ/IVA
Affected / at Risk (%) Affected / at Risk (%)
Total   0/126 (0.00%)   0/132 (0.00%) 
Hide Serious Adverse Events
Control: IVA or TEZ/IVA TC: ELX/TEZ/IVA
Affected / at Risk (%) Affected / at Risk (%)
Total   11/126 (8.73%)   5/132 (3.79%) 
Ear and labyrinth disorders     
Tinnitus † 1  0/126 (0.00%)  1/132 (0.76%) 
Endocrine disorders     
Hyperparathyroidism primary † 1  1/126 (0.79%)  0/132 (0.00%) 
Hepatobiliary disorders     
Cholecystitis † 1  0/126 (0.00%)  1/132 (0.76%) 
Infections and infestations     
Cellulitis † 1  0/126 (0.00%)  1/132 (0.76%) 
Infective pulmonary exacerbation of cystic fibrosis † 1  7/126 (5.56%)  2/132 (1.52%) 
Pneumonia † 1  1/126 (0.79%)  0/132 (0.00%) 
Psychiatric disorders     
Anxiety † 1  1/126 (0.79%)  0/132 (0.00%) 
Depression † 1  1/126 (0.79%)  0/132 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Haemoptysis † 1  1/126 (0.79%)  1/132 (0.76%) 
1
Term from vocabulary, MedDRA 23.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Control: IVA or TEZ/IVA TC: ELX/TEZ/IVA
Affected / at Risk (%) Affected / at Risk (%)
Total   47/126 (37.30%)   35/132 (26.52%) 
Gastrointestinal disorders     
Abdominal pain † 1  2/126 (1.59%)  7/132 (5.30%) 
Diarrhoea † 1  8/126 (6.35%)  5/132 (3.79%) 
Nausea † 1  9/126 (7.14%)  2/132 (1.52%) 
Infections and infestations     
Infective pulmonary exacerbation of cystic fibrosis † 1  10/126 (7.94%)  2/132 (1.52%) 
Investigations     
Alanine aminotransferase increased † 1  0/126 (0.00%)  8/132 (6.06%) 
Aspartate aminotransferase increased † 1  0/126 (0.00%)  8/132 (6.06%) 
Nervous system disorders     
Headache † 1  19/126 (15.08%)  11/132 (8.33%) 
Respiratory, thoracic and mediastinal disorders     
Cough † 1  18/126 (14.29%)  3/132 (2.27%) 
Sputum increased † 1  8/126 (6.35%)  6/132 (4.55%) 
1
Term from vocabulary, MedDRA 23.0
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
 
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Monitor
Organization: Vertex Pharmaceuticals Incorporated
Phone: 617-341-6777
EMail: medicalinfo@vrtx.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier: NCT04058353    
Other Study ID Numbers: VX18-445-104
2018-002835-76 ( EudraCT Number )
First Submitted: August 14, 2019
First Posted: August 15, 2019
Results First Submitted: June 11, 2021
Results First Posted: July 2, 2021
Last Update Posted: July 2, 2021