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A Study of VX-659 Combination Therapy in CF Subjects Homozygous for F508del (F/F)

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: NCT03460990
Recruitment Status : Completed
First Posted : March 9, 2018
Results First Posted : October 17, 2019
Last Update Posted : October 17, 2019
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: VX-659/TEZ/IVA
Drug: TEZ/IVA
Drug: IVA
Drug: Placebo
Enrollment 116
Recruitment Details A total of 116 participants were enrolled in the study, of which 5 participants were included in the run-in period but were not dosed in TC treatment period. Results are presented for 111 participants dosed in the TC treatment period.
Pre-assignment Details This study was conducted in participants with cystic fibrosis (CF) aged 12 years or older.
Arm/Group Title TEZ/IVA VX-659/TEZ/IVA TC
Hide Arm/Group Description Following a run-in period of 4 weeks with Tezacaftor (TEZ)/Ivacaftor (IVA), participants received TEZ 100 milligram (mg)/IVA 150 mg as fixed-dose combination (FDC) tablet in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the triple combination (TC) treatment period. Following a run-in period of 4 weeks with TEZ/IVA, participants received VX-659 240 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period.
Period Title: Overall Study
Started 57 54
Completed 57 54
Not Completed 0 0
Arm/Group Title TEZ/IVA VX-659/TEZ/IVA TC Total
Hide Arm/Group Description Following a run-in period of 4 weeks with TEZ/IVA, participants received TEZ 100 mg/IVA 150 mg as FDC tablet in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period. Following a run-in period of 4 weeks with TEZ/IVA, participants received VX-659 240 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period. Total of all reporting groups
Overall Number of Baseline Participants 57 54 111
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 57 participants 54 participants 111 participants
26.2  (9.1) 28.3  (9.6) 27.2  (9.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 57 participants 54 participants 111 participants
Female
33
  57.9%
26
  48.1%
59
  53.2%
Male
24
  42.1%
28
  51.9%
52
  46.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 57 participants 54 participants 111 participants
Hispanic or Latino
1
   1.8%
1
   1.9%
2
   1.8%
Not Hispanic or Latino
56
  98.2%
52
  96.3%
108
  97.3%
Unknown or Not Reported
0
   0.0%
1
   1.9%
1
   0.9%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 57 participants 54 participants 111 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
56
  98.2%
54
 100.0%
110
  99.1%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
1
   1.8%
0
   0.0%
1
   0.9%
Forced Expiratory Volume in 1 Second (ppFEV1)   [1] 
Mean (Standard Deviation)
Unit of measure:  Percentage points
Number Analyzed 57 participants 54 participants 111 participants
62.9  (14.9) 62.0  (14.8) 62.4  (14.8)
[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)
Hide Description FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame From Baseline at Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants who carried the intended CF transmembrane conductance regulator gene (CFTR) allele mutation and received at least 1 dose of study drug in the TC Treatment Period.
Arm/Group Title TEZ/IVA VX-659/TEZ/IVA TC
Hide Arm/Group Description:
Following a run-in period of 4 weeks with TEZ/IVA, participants received TEZ 100 mg/IVA 150 mg as FDC tablet in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period.
Following a run-in period of 4 weeks with TEZ/IVA, participants received VX-659 240 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period.
Overall Number of Participants Analyzed 57 54
Least Squares Mean (Standard Error)
Unit of Measure: percentage points
0.3  (0.9) 10.2  (0.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TEZ/IVA, VX-659/TEZ/IVA TC
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 10
Confidence Interval (2-Sided) 95%
7.4 to 12.5
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Absolute Change in Sweat Chloride (SwCl)
Hide Description Sweat samples were collected using an approved collection device.
Time Frame From Baseline at Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
FAS.
Arm/Group Title TEZ/IVA VX-659/TEZ/IVA TC
Hide Arm/Group Description:
Following a run-in period of 4 weeks with TEZ/IVA, participants received TEZ 100 mg/IVA 150 mg as FDC tablet in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period.
Following a run-in period of 4 weeks with TEZ/IVA, participants received VX-659 240 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period.
Overall Number of Participants Analyzed 57 54
Least Squares Mean (Standard Error)
Unit of Measure: millimole per liter (mmol/L)
1.5  (1.8) -47.2  (1.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TEZ/IVA, VX-659/TEZ/IVA TC
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 -48.7
Confidence Interval (2-Sided) 95%
-53.9 to -43.5
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score
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 at Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
FAS.
Arm/Group Title TEZ/IVA VX-659/TEZ/IVA TC
Hide Arm/Group Description:
Following a run-in period of 4 weeks with TEZ/IVA, participants received TEZ 100 mg/IVA 150 mg as FDC tablet in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period.
Following a run-in period of 4 weeks with TEZ/IVA, participants received VX-659 240 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period.
Overall Number of Participants Analyzed 57 54
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
3.0  (1.7) 16.5  (1.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TEZ/IVA, VX-659/TEZ/IVA TC
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 13.5
Confidence Interval (2-Sided) 95%
8.8 to 18.3
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Hide Description [Not Specified]
Time Frame From first dose of study drug in TC 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 8)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety set included all participants who received at least 1 dose of study drug in the TC treatment period.
Arm/Group Title TEZ/IVA VX-659/TEZ/IVA TC
Hide Arm/Group Description:
Following a run-in period of 4 weeks with TEZ/IVA, participants received TEZ 100 mg/IVA 150 mg as FDC tablet in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period.
Following a run-in period of 4 weeks with TEZ/IVA, participants received VX-659 240 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period.
Overall Number of Participants Analyzed 57 54
Measure Type: Number
Unit of Measure: participants
Participants with AEs 31 33
Participants with SAEs 0 2
5.Secondary Outcome
Title Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA
Hide Description [Not Specified]
Time Frame From Day 1 and Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all participants who received at least 1 dose of study drug in the TC treatment period. Here "Number analyzed" signifies those participants who were evaluable at specified time points.
Arm/Group Title TEZ/IVA VX-659/TEZ/IVA TC
Hide Arm/Group Description:
Following a run-in period of 4 weeks with TEZ/IVA, participants received TEZ 100 mg/IVA 150 mg as FDC tablet in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period.
Following a run-in period of 4 weeks with TEZ/IVA, participants received VX-659 240 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period.
Overall Number of Participants Analyzed 57 54
Mean (Standard Deviation)
Unit of Measure: nanogram per milliliter (ng/mL)
Day 1: VX-659 Number Analyzed 0 participants 0 participants
Week 4: VX-659 Number Analyzed 0 participants 52 participants
720  (589)
Day 1: TEZ Number Analyzed 57 participants 54 participants
1780  (832) 1590  (1020)
Week 4: TEZ Number Analyzed 56 participants 53 participants
1730  (885) 1280  (594)
Day 1: M1-TEZ Number Analyzed 57 participants 54 participants
5170  (1620) 4840  (1860)
Week 4: M1-TEZ Number Analyzed 56 participants 53 participants
5010  (1810) 4730  (1380)
Day 1: IVA Number Analyzed 57 participants 54 participants
717  (616) 563  (400)
Week 4: IVA Number Analyzed 56 participants 53 participants
722  (642) 401  (211)
Time Frame From first dose of study drug in TC 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 8)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title TEZ/IVA VX-659/TEZ/IVA TC
Hide Arm/Group Description Following a run-in period of 4 weeks with TEZ/IVA, participants received TEZ 100 mg/IVA 150 mg as FDC tablet in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period. Following a run-in period of 4 weeks with TEZ/IVA, participants received VX-659 240 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period.
All-Cause Mortality
TEZ/IVA VX-659/TEZ/IVA TC
Affected / at Risk (%) Affected / at Risk (%)
Total   0/57 (0.00%)   0/54 (0.00%) 
Hide Serious Adverse Events
TEZ/IVA VX-659/TEZ/IVA TC
Affected / at Risk (%) Affected / at Risk (%)
Total   0/57 (0.00%)   2/54 (3.70%) 
Gastrointestinal disorders     
Constipation † 1  0/57 (0.00%)  1/54 (1.85%) 
Psychiatric disorders     
Depression † 1  0/57 (0.00%)  1/54 (1.85%) 
Suicidal ideation † 1  0/57 (0.00%)  1/54 (1.85%) 
1
Term from vocabulary, MedDRA 21.1
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
TEZ/IVA VX-659/TEZ/IVA TC
Affected / at Risk (%) Affected / at Risk (%)
Total   19/57 (33.33%)   23/54 (42.59%) 
Gastrointestinal disorders     
Diarrhoea † 1  0/57 (0.00%)  4/54 (7.41%) 
Infections and infestations     
Infective pulmonary exacerbation of cystic fibrosis † 1  9/57 (15.79%)  2/54 (3.70%) 
Investigations     
Alanine aminotransferase increased † 1  2/57 (3.51%)  3/54 (5.56%) 
Aspartate aminotransferase increased † 1  1/57 (1.75%)  3/54 (5.56%) 
C-reactive protein increased † 1  0/57 (0.00%)  4/54 (7.41%) 
Nervous system disorders     
Headache † 1  5/57 (8.77%)  3/54 (5.56%) 
Respiratory, thoracic and mediastinal disorders     
Sputum increased † 1  0/57 (0.00%)  9/54 (16.67%) 
Cough † 1  3/57 (5.26%)  4/54 (7.41%) 
1
Term from vocabulary, MedDRA 21.1
†
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
Layout table for additonal information
Responsible Party: Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier: NCT03460990    
Other Study ID Numbers: VX17-659-103
2017-004133-82 ( EudraCT Number )
First Submitted: March 1, 2018
First Posted: March 9, 2018
Results First Submitted: September 26, 2019
Results First Posted: October 17, 2019
Last Update Posted: October 17, 2019