Main objective:Part ATo evaluate the long-term safety and tolerability of VX-661 in combination with ivacaftor in subjects with CF, homozygous or heterozygous for the F508del-CFTR mutation who are in the Treatment Cohort.Part B and Part CNot…
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Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part A
For the Treatment Cohort:
Safety and tolerability of long-term treatment of VX-661 in combination with
ivacaftor based on adverse events (AEs), ophthalmologic
examinations (subjects <18 years of age, clinical laboratory values (serum
chemistry, hematology, coagulation, lipids, vitamins, and
urinalysis), standard digital electrocardiograms (ECGs), vital signs, and pulse
oximetry
Secondary outcome
Part A
For the Treatment Cohort:
* Absolute change from baseline in percent predicted forced expiratory volume
in 1 second (ppFEV1)
* Relative change from baseline in ppFEV1
* Number of pulmonary exacerbations
* Absolute change from baseline in body mass index (BMI)
* Absolute change from baseline in BMI z score for subjects aged <20 years
* Absolute change from baseline in Cystic Fibrosis Questionnaire*Revised (CFQ
R) respiratory domain score
* Absolute change from baseline in body weight
* Absolute change from baseline in body weight z-score for subjects aged <20
years
* Absolute change from baseline in height z-score for subjects aged <20 years
* Time to first pulmonary exacerbation,
* Pharmacokinetic (PK) parameters of VX 661, a VX-661 metabolite (M1 661),
ivacaftor, and an ivacaftor metabolite (M1 ivacaftor)
For the Observational Cohort:
* Safety, as determined by related serious adverse events (SAEs)
Part B
* AEs
* Ophthalmologic exams (subjects < 18 years of age [age on the date of informed
consent/assent in the parent study])
* Serum liver function tests (LFTs)
* Absolute change from baseline in percent predicted forced expiratory volume
in 1 second (ppFEV1)
* Absolute change from baseline in body mass index (BMI)
* Absolute change from baseline in BMI z score for subjects aged <20 years
* Number of pulmonary exacerbations
Part C
* AEs
* Ophthalmologic examinations (for subjects <18 years of age [age on date of
informed consent/assent in the parent study])
* Serum liver function tests (LFTs)
Background summary
Cystic fibrosis is an autosomal recessive genetic disease caused by a defect in
the gene encoding the CF transmembrane conductance regulator (CFTR), an
epithelial chloride ion (Cl*) channel activated by cyclic adenosine
monophosphate-dependent protein kinase A that is responsible for aiding in the
regulation of salt and water absorption and secretion in various tissues. This
function is defective in patients with CF due to a loss of either cell surface
expression and/or function.
More than 1900 mutations in the CFTR gene have been identified. Mutations in
the CFTR gene have been classified based on the molecular and functional
consequence of the mutation on the CFTR protein and can be generally considered
to reduce the quantity of functional CFTR protein that reaches the epithelial
cell surface or reduce the function of CFTR protein located at the cell
surface. CFTR gene mutations that affect the quantity of functional cell
surface CFTR protein include defects that reduce CFTR protein synthesis and
defects that impede the cellular processing and delivery of CFTR proteins to
the cell surface. VX-661 is a compound developed by Vertex Pharmaceuticals
Incorporated (Vertex) that has
been shown to have CFTR corrector properties.
Study objective
Main objective:
Part A
To evaluate the long-term safety and tolerability of VX-661 in combination with
ivacaftor in subjects with CF, homozygous or heterozygous for the F508del-CFTR
mutation who are in the Treatment Cohort.
Part B and Part C
Not applicable
Secondary objectives:
Part A
Treatment Cohort
To evaluate the long-term efficacy of VX-661 in combination with ivacaftor for
subjects in the Treatment Cohort.
Observational Cohort
To evaluate the post-treatment safety of VX-661 in combination with ivacaftor
for subjects in the Observational Cohort.
Part B
To evaluate the long-term safety, tolerability, and efficacy of VX 661 in
combination with ivacaftor in subjects with CF, homozygous or
heterozygous for the F508del-CFTR mutation.
Part C
To evaluate the long-term safety and tolerability of VX-661 in combination with
ivacaftor in subjects with CF, homozygous or heterozygous for the F508del-CFTR
mutation.
Study design
This is a Phase 3, multicenter, open-label, rollover study in subjects with CF
who are homozygous or heterozygous for the F508del-CFTR mutation and who
participated in Studies 103, 106, 107, 108, 109, or 111. The study is designed
to evaluate the safety and efficacy of long-term treatment of VX-661 in
combination with ivacaftor.
This study consists of a Treatment Cohort and an Observational Cohort. The
Treatment Cohort and the Observational Cohort will be open to enrollment in
parallel.
Treatment Cohort:
Subjects who completed study drug treatment (i.e., VX-661/ivacaftor, ivacaftor
monotherapy, or placebo) during the Treatment Period in a parent study (Studies
103 [Placebo-Controlled Phase or Open-Label Extension Phase], 106, 107, 108, or
109) or study drug treatment and the Safety Follow-up Visit for subjects from
Study 111 who meet the eligibility criteria will be offered the opportunity to
enroll in Study 110. Subjects who permanently discontinue study drug treatment
or who withdrew consent during the parent study are not eligible for enrollment
in the Treatment Cohort.
The Treatment Cohort will be open-label, and all subjects will receive VX-661
100 mg/ ivacaftor 150-mg FDC tablet daily (qd) in the morning and
ivacaftor 150-mg tablet qd in the evening. The Treatment Period will be
approximately 96 weeks.
During the course of study conduct, if VX-661 in combination with ivacaftor is
approved and available for the treatment of CF in populations enrolled in Study
110, subjects with the approved CFTR genotypes may be discontinued from this
rollover study at the discretion of the sponsor. If a subject is continuing
onto commercially available VX-661/ivacaftor, the Early Treatment Termination
Visit will be completed before dosing with commercial drug begins, and the
Safety Follow-up Visit will not be required. Alternatively, if local health
authorities decline to approve, or if clinical benefit is not demonstrated for
the use of VX-661 in combination with ivacaftor for the treatment of CF in
populations enrolled in Study 110, subjects with the relevant CFTR genotypes
may be discontinued after communication to investigators and IRBs/IECs of the
risks/benefits related to the safety and efficacy observed for the subset of
subjects. If subjects are discontinued from the study, an Early Treatment
Termination Visit should occur within 7 days of the last dose of study drug and
a Safety Follow-up Visit should occur within 28 (± 7) days after the last dose
of study drug.
Observational Cohort
Subjects <18 years of age (age on the date of informed consent/assent in the
parent study) who received at least 4 weeks of study drug in the parent study,
who are not eligible for the Treatment Cohort or who elect not to enroll in the
Treatment Cohort, and meet eligibility criteria will be offered the opportunity
to enroll in the Observational Cohort.
Subjects in the Observational Cohort will not receive study drug and will have
regularly scheduled telephone calls for approximately 2 years after their last
dose of study drug in the parent study to assess post-treatment safety of
VX-661/ivacaftor combination therapy.
Intervention
Treatment Cohort:
For the Treatment Cohort, study drug will be administered for approximately 96
weeks with a Safety Follow-up Visit 28 days [± 7 days] after the last dose).
Observational Cohort:
For the Observational Cohort, maximum subject participation will be
approximately 2 years.
Study burden and risks
Cystic fibrosis (CF) affects an estimated 70,000 children and adults worldwide
and is the most common fatal genetic disease in persons of European descent.
Based on the size of the population, CF qualifies as an orphan disease. Despite
progress in the treatment of CF with
antibiotics and mucolytics, the predicted median age of survival for a person
with CF is in the mid-30s. Although the disease affects multiple organs, most
morbidity and mortality are caused by progressive loss of lung function.
Ivacaftor (also known as VX-770) is the first CFTR modulator to show an
improvement in CFTR function and clinical benefit in patients with CF. Results
from several Phase 3 studies showed that ivacaftor is effective in the
treatment of patients with CF who have mutations that result in gating defects
as evidenced by sustained improvements in CFTR channel function (measured by
reduction in sweat chloride concentration) and corresponding substantial,
durable improvements in lung function, respiratory symptoms, and weight gain.
Ivacaftor was also well tolerated, as evidenced by the rates and reasons for
premature discontinuation and results of safety assessments.
Common adverse events in studies of CF subjects, who took VX-661, ivacaftor, or
VX-661 in combination with ivacaftor are Infective pulmonary exacerbation of CF
(temporary worsening of lung function due to an infection or inflammation),
Cough, Headache, Nausea, Sputum increased
Fatigue, Upper respiratory tract infection (common cold), Oropharyngeal pain
(sore throat), Nasal congestion (stuffy nose), Nasopharyngitis (inflammation of
the nose and pharynx), Abdominal Pain, Diarrhea, Rash, Dizziness (feeling
faint).
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Age
Inclusion criteria
Part A
Subjects entering the Treatment Cohort must meet all of the following criteria:
*Elect to enroll in the Treatment Cohort.
*Completed study drug treatment during the Treatment Period in a parent study
(Studies 103, 106, 107, 108, or 109) or study drug treatment and the Safety
Follow up Visit for subjects from Study 111 or study drug treatment and
follow-up as specified in other Vertex studies investigating VX-661 in
combination with ivacaftor.
* Willing to remain on a stable CF medication (and supplement) regimen through
the Safety Follow-up Visit., Subjects re-enrolling in the treatment cohort must
meet all the following criteria:
* Previously received at least 4 weeks of study drug before discontinuing Study
110 to participate in another qualified Vertex study
* Completed the last required visit of another qualified Vertex study before or
during the returning visit in Part A in Study 110
* Willing to remain on a stable CF medication (and supplement) regimen through
the Safety Follow-up Visit of Part A.
* Subjects who discontinue Study 110 more than once to participate in another
qualified Vertex study may not re-enroll in Part A a second time., Subjects
entering the Part A Observational Cohort must meet the following criteria:
* <18 years of age (age on the date of informed consent/assent in the parent
study)
* Completed study drug treatment during the Treatment Period in a parent study
(Studies 103, 106, 107, 108, or 109) or study drug treatment and the Safety
Follow up Visit for subjects from Study 111 or study drug treatment and
follow-up as specified in other Vertex studies investigating VX-661 in
combination with ivacaftor, but do not elect to enroll in the Study 110
Treatment Cohort; or
* Received at least 4 weeks of study drug treatment in a parent study, but do
not meet eligibility criteria for enrollment into the Treatment Cohort.
Part B
*Completed study drug treatment during the Treatment Period in Part A of VX14
661 110, Studies VX15 661 112 or VX16 661 114 or other eligible Vertex studies.
*For subjects in the middle of an approved sutdy drug interruption at the end
of the Parent study or Part A, or who re-started study drug after an
interruption <4 weeks before the end of the Parent study or Part A, criteria
for study drug resumption or rechallenge must be performed.
*Willing to remain on a stable CF medication (and supplement) regimen through
the 96 weeks visit. Subjects re enrolling in Part B must meet all of the
following criteria
*Previously received at least 4 weeks of studydrug before discontinuing Study
VX661 110 to participate in another qualified Vertex study.
*Completed the last required visit of another qualified Vertex study before or
during the Returning Visite in Part B.
*Willing to remain on a stable CF medication (and supplement) regimen through
the 96 week visit in Part B.
Part C:
Subjects who meet all of the following inclusion criteria will be eligible for
Part C.
* Signed and dated an ICF, and where appropriate, signed and dated an assent
form.
* Did not withdraw consent from Part B of Study VX14-661-110.
* Able to understand and comply with protocol requirements, restrictions, and
instructions, and likely to complete the study as planned, as judged by the
investigator and Vertex, based in part on study compliance in the parent study
and Study VX14-661-110 (Part A and B).
* Completed study drug treatment during the Treatment Period in Part B of
VX14-661-110.
* For subjects in the middle of an approved study drug interruption at the end
of the Part B, or who re-started study drug after an interruption <4 weeks
before the end of Part B, criteria for study drug resumption must be met and
safety monitoring following resumption or rechallenge must be performed.
* Willing to remain on a stable CF medication (and supplement) regimen through
the 96 week visit of Study VX14-661-110 Part C.
Exclusion criteria
Part A Treatment Cohort only:
* History of any comorbidity that, in the opinion of the investigator, might
confound the results of the study or pose an additional risk in administering
study drug to the subject.
* Pregnant and nursing females. Females of childbearing potential must have a
negative urine pregnancy test at the Day 1 Visit (and at Returning Visit for
subjects who re-enroll) and before receiving the first dose of study drug.
* Sexually active subjects of reproductive potential who are not willing to
follow the contraception requirements.
* History of drug intolerance in the parent study or other qualified Vertex
study that would pose an additional risk to the subject.
* History of poor compliance with study drug and/or procedures in the parent
study or other qualified Vertex study as deemed by the investigator.
* Participation in an investigational drug trial other than Studies 103, 106,
107, 108, 109, and 111, other Vertex studies investigating VX-661 in
combination with ivacaftor, or other qualified study, or use of a commercially
available CFTR modulator (e.g., Kalydeco).
* Previous re-enrollment in the Part A Treatment Cohort of Study 110 after
participating in other qualified Vertex studie.
History of any comorbidity that, in the opinion of the investigator,
might confound the results of the study or pose an additional risk in
administering study drug to the subject.
* Pregnant and nursing females
* Sexually active subjects of reproductive potential who are not willing
to follow the contraception requirements
* Subjects who permanently discontinue study drug treatment during
the parent study or Part A
* History of drug intolerance in the parent study, Part A of study VX14-
661-110, or other qualified Vertex study that would pose an additional
risk to the subject in the opinion of investigator or Vertex
* History of poor compliance with study drug and/or procedures in the
parent study, Part A of Study VX14-661-110, or other qualified Vertex
study as deemed by the investigator
* Participation in an investigational drug trial (other than Studies VX13
661 103, VX14 661 106, VX14 661 107, VX14 661 108, VX14 661 109,
VX14 661 111, VX15 661 112, VX16 661 114, Part A of Study VX14-661-
110, or other eligible Vertex studies investigating VX 661 in combination
with ivacaftor) or use of a commercially available CFTR modulator (e.g.,
Kalydeco)
* Discontinued Study VX14 661 110 (either Part A or Part B) more than
once to participate in another qualified Vertex study.
Part C
Subjects who meet any of the following exclusion criteria will NOT be
eligible for this study.
* History of any comorbidity that, in the opinion of the investigator,
might confound the results of the study or pose an additional risk in
administering study drug to the subject. For example:
* History of cirrhosis with portal hypertension, and/or history of risk
factors for Torsade de Pointes (e.g., familial long QT syndrome,
hypokalemia, heart failure, left ventricular hypertrophy, bradycardia,
myocardial infarction, cardiomyopathy, history of arrhythmia
[ventricular and atrial fibrillation], obesity, acute neurologic events
[subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular
accident, and intracranial trauma], and autonomic neuropathy)
* Pregnant and nursing females. Females of childbearing potential must
have a negative urine pregnancy test at the Day 1 Visit of Part C and
before receiving the first dose of study drug in Part C.
* Sexually active subjects of reproductive potential who are not willing
to follow the contraception requirements.
* Subjects who permanently discontinue study drug treatment during
the parent study or Study VX14-661-110 (Part A or Part B), including at
the last visit of the Treatment Period.
* History of drug intolerance in the parent study or Study VX14-661-110
(Part A or Part B), that would pose an additional risk to the subject in
the opinion of investigator or Vertex. Examples of subjects who may not
be eligible for Part C include but are not limited to the following:
* Subjects with a history of allergy or hypersensitivity to the study drug
* Other severe or life-threatening reactions to the study drug in the
parent study or Study VX14-661-110 (Part A or Part B).
* History of poor compliance with study drug and/or procedures in the
parent study or Study VX14-661-110 (Part A or Part B) as deemed by the
investigator.
* Participation in an investigational drug trial or use of a commercially
available CFTR modulator (e.g., Kalydeco).
NOTE:
participation in a noninterventional study (including observational
studies, registry studies, and studies requiring blood collections without
administration of study drug), and screening for other qualified Vertex
studies is permitted.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-004827-29-NL |
| CCMO | NL54556.072.15 |