Page Title
Clinical Trial Finder
Restore CFTR Protein Completed with Results
Phase 1/2 study of VX-445 combination drug in healthy adults and then in people with cystic fibrosis (VX-445-001)
This study evaluated the safety, tolerability and effectiveness of the drug VX-445 in combination with tezacaftor/ivacaftor (Symdeko®) in people who either have two copies of the F508del CFTR mutation or have one copy of F508del and one copy of a minimal function CFTR mutation.
This study had three parts. In Part 1, participants who have one copy of F508del and one copy of a minimal function CFTR mutation were randomized to receive either 4 weeks of one of three doses of VX-445 (50mg, 100mg, or 200mg once per day) in triple combination with tezacaftor (100mg once per day) and ivacaftor (150 mg every 12 hours) or matching placebo. Following the 4-week treatment period, participants taking the VX-445 triple combination therapy received only tezacaftor/ivacaftor for 4 days in order to study the effects of eliminating VX-445. In Part 2, participants who have two copies of the F508del CFTR mutation were enrolled. Because dual combination CFTR modulators are available to people who have two copies of the F508del CFTR mutation, tezacaftor/ivacaftor was used as a part of the placebo control. All participants received 4 weeks or tezacaftor/ivacaftor before being randomized to either 4 weeks of VX-445 (200mg once per day) in triple combination with tezacaftor (100mg once per day) and ivacaftor (150 mg every 12 hours) or placebo plus tezacaftor and ivacaftor. Following the 4-week treatment period, all participants received only tezacaftor/ivacaftor for an additional 4 weeks in order to study the effects of eliminating VX-445. In Part 3, participants who have one copy of F508del and one copy of a minimal function CFTR mutation were randomized to either 4 weeks of VX-445 (200mg once per day) in combination with tezacaftor (100mg once per day) and VX-561 (deuterated ivacaftor, 150 mg once per day) or matching placebo.
Eligibility
See other primary eligibility criteria for more information.
-
Age:
18 Years and Older -
Mutation(s):
Two Copies F508del or One Copy F508del -
FEV1% Predicted:
40 to 90%
For more information about the results of this study and where it was conducted, visit ClinicalTrials.gov.
Other Primary Eligibility Criteria
There are over 195 minimal function mutations that are eligible for this study. Some of the most common eligible mutations include: G542X, N1303K, W1282X, R553X, 621+1G->T, 1717-1G->A, 3120+1G->A, I507del, R1162X, 3659delC, 1898+1G->A, G85E, R560T, R347P, 2184insA, 2184delA, Q493X This is not a complete list of eligible mutations. Please contact a research coordinator to find out if your particular mutation is eligible for this study.
Study Results
-
What We Learned:
This study found that VX-445 in combination with tezacaftor and ivacaftor as well as VX-445 in combination with tezacaftor and VX-561 resulted in a significant improvement in lung function (ppFEV1), sweat chloride and quality of life (CFQ-R) when compared with placebo.
Additionally, VX-445 in combination with tezacaftor and ivacaftor as well as VX-445 in combination with tezacaftor and VX-561 was generally well-tolerated when compared to placebo when taken by people who have two copies of the F508del CFTR mutation or who have one copy of F508del and one copy of a minimal function CFTR mutation. Elevated liver enzymes were seen in a subset of participants taking VX-445 triple combination.
-
Primary Findings:
Effectiveness:
This study was conducted between July 2017 and March 2018. In Part 1 (participants who have one copy of F508del and one copy of a minimal function CFTR mutation), 65 participants were enrolled (N= 12 to placebo, N=10 to VX-445 50mg, N=22 to VX-445 100mg, N=21 to VX-445 200mg). There were two discontinuations in Part 1 due to an adverse event.
In Part 2 (participants who have two copies of the F508del CFTR mutation), 28 participants were enrolled (N=7 to placebo and N=21 to VX-445 200mg). There were three discontinuations in Part 2. Two of those were due to an adverse event.
In Part 3 (participants who have two copies of the F508del CFTR mutation), 30 participants were enrolled (N=8 to placebo and N=22 to VX-445 200mg). There was one discontinuation due to an adverse event.
The primary efficacy measure was change in lung function from baseline as measured by absolute change in FEV1 percent predicted. This study met its primary endpoint as significant improvements in lung function from baseline were seen in participants who received the triple combination in all parts of the studies at all doses tested compared with placebo.
Notably, at the dose of the triple combination selected to move forward into phase 3 (VX-445 200 mg + tezacaftor/ivacaftor) FEV1 percent predicted increased by 14% (p<0.001) for participants with two copies of F508del and by 11% (p<0.001) for participants with one copy of F508del FEV1% predicted.
Significant improvements were also seen in sweat chloride when compared with placebo. At the 200mg dose that moved into phase 3 trials, sweat chloride significantly dropped in all genotypes (-39 mmol/L in participants who have one copy of F508del and one copy of a minimal function CFTR mutation and -40 mmol/L in participants who have two copies of the F508del CFTR mutation).
Additionally, improvements were seen in the respiratory domain of a quality of life questionnaire (CFQ-R) in both genotype groups.
Safety:
VX-445 in combination with tezacaftor/ivacaftor was generally well-tolerated. Adverse events leading to discontinuations in those receiving VX-445 triple combination included rash, elevated bilirubin levels, and chest pain. The most common adverse events in participants receiving the VX-445 triple combination (greater than 10%) were cough, increased sputum production, infective pulmonary exacerbation, coughing up blood, and fever.
Elevated liver enzymes ALT or AST greater than three times the upper limit of normal range occurred in 8% of participants receiving VX-445 in triple combination. Elevated bilirubin greater than two times the upper limit of normal range occurred in 3% of participants.
-
Citation:
N Eng J Med 2018;DOI 10.1056/NEJMoa1807120. Epub 2018 Oct 18 [Epub ahead of print]
For current information about the overall development status of this drug, please check the Drug Development Pipeline.
Study Design
-
Study Type: ?more info
Interventional -
Randomized Study: ?more info
Yes -
Placebo Controlled: ?more info
Yes -
Length of Participation:
12 weeks -
Number of Study Visits:
6
Additional Information
-
Phase: ?more info
Phase One -
Study Sponsor: ?more info
Vertex -
Study Drugs:
Eligibility
See other primary eligibility criteria for more information.
-
Age:
18 Years and Older -
Mutation(s):
Two Copies F508del or One Copy F508del -
FEV1% Predicted:
40 to 90%
For more information about the results of this study and where it was conducted, visit ClinicalTrials.gov.
Other Primary Eligibility Criteria
There are over 195 minimal function mutations that are eligible for this study. Some of the most common eligible mutations include: G542X, N1303K, W1282X, R553X, 621+1G->T, 1717-1G->A, 3120+1G->A, I507del, R1162X, 3659delC, 1898+1G->A, G85E, R560T, R347P, 2184insA, 2184delA, Q493X This is not a complete list of eligible mutations. Please contact a research coordinator to find out if your particular mutation is eligible for this study.

CONTACT THE CLINICAL TRIAL NAVIGATOR
Get personalized assistance and answers to your clinical trial questions.
Learn MoreSign up for clinical trial alerts
Get email updates about clinical trials that matter to you.
Check the Drug Development Pipeline
We’re attacking CF from every angle. Learn about the status of CF drugs in development.
Learn More