primary objective: To evaluate the long-term safety and tolerability of lumacaftor in combination with ivacaftor in subjects with cystic fibrosis (CF), homozygous or heterozygous for the F508del-cystic fibrosis transmembrane conductance regulator (…
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part A and Part B Treatment Cohorts:
Safety of long-term treatment of lumacaftor in combination with ivacaftor based
on adverse events (AEs), clinical laboratory values (serum chemistry,
hematology, coagulation studies, and urinalysis), standard digital
electrocardiograms (ECGs), vital signs, and pulse oximetry
Part A Observational Cohort:
Not applicable.
Secondary outcome
Part A and Part B Treatment Cohorts
The following efficacy endpoints will be analyzed using baseline values in the
previous study (i.e., Study VX12-809-103 [Study 103] or Study VX12-809-104
[Study 104] for Part A, and Cohort 4 of Study VX09-809-102 [Study 102] for Part
B):
* Absolute change from baseline in percent predicted forced expiratory volume
in 1 second (FEV1)
* Relative change from baseline in percent predicted FEV1
* Absolute change from baseline in body mass index (BMI)
* Number of pulmonary exacerbations starting from the previous study (Part A
only)
* Absolute change from baseline in Cystic Fibrosis Questionnaire * Revised
(CFQ-R) respiratory domain score
* Absolute change in BMI z-score (Part A only)
* Absolute change from baseline in body weight
* Time-to-first pulmonary exacerbation including pulmonary exacerbations in the
previous study (Part A only)
* Event of having at least 1 pulmonary exacerbation, including pulmonary
exacerbations in the previous study (Part A only)
The following efficacy endpoints will be analyzed using baseline values in the
current study (Study VX12-809-105 [Study 105]):
* Absolute change from baseline in percent predicted FEV1
* Relative change from baseline in percent predicted FEV1
* Absolute change from baseline in BMI
* Number of pulmonary exacerbations starting from the current study (Part A
only)
* Absolute change from baseline in CFQ-R respiratory domain score
* Absolute change in BMI z-score (Part A only)
* Absolute change from baseline in body weight
* Time-to-first pulmonary exacerbation in the current study (Part A only)
* Event of having at least 1 pulmonary exacerbation in the current study (Part
A only)
The following efficacy endpoint will also be analyzed:
Rate of change in percent predicted FEV1
Part A Observational Cohort
Safety, as determined by serious adverse events (SAEs)
Background summary
Cystic fibrosis (CF) affects an estimated 70,000 children and adults worldwide1
and is the most common fatal genetic disease in persons of European descent.2
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 is caused by progressive loss of lung function.Cystic
fibrosis is an autosomal recessive genetic disease caused by a defect in the
gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR).
Study objective
primary objective:
To evaluate the long-term safety and tolerability of lumacaftor in combination
with ivacaftor in subjects with cystic fibrosis (CF), homozygous or
heterozygous for the F508del-cystic fibrosis transmembrane conductance
regulator (CFTR) mutation, who are in the Part A and Part B Treatment Cohorts
secondary objectives:
Part A
- To evaluate the long-term efficacy and durability of lumacaftor in
combination with ivacaftor for subjects in the Part A Treatment Cohort
- To evaluate the post-treatment safety and tolerability of lumacaftor in
combination with ivacaftor for subjects in the Part A Observational Cohort
Part B (patients in the Netherlands will not participate in this part)
To evaluate the long-term efficacy and durability of lumacaftor in combination
with ivacaftor for subjects in the Part B Treatment Cohort
Study design
This is a Phase 3, parallel-group, multicenter, rollover study in subjects with
CF who are homozygous or heterozygous for the F508del-CFTR mutation and who
participated in Study 103, Study 104, or Cohort 4 of Study 102. Study 105 is
designed to evaluate the safety and efficacy of long-term treatment of
lumacaftor in combination with ivacaftor.
Study 105 consists of 2 parts (Part A and Part B), which will be enrolled in
parallel. Part A will enroll subjects from Study 103 and Study 104. Part B will
enroll subjects from Cohort 4 of Study 102.
Part A consists of a Part A Treatment Cohort and a Part A Observational Cohort,
which will enroll subjects from Study 103 and Study 104. The Part A Treatment
Cohort and the Part A Observational Cohort will be enrolled in parallel.
Part B (Subjects From Cohort 4 of Study 102) (patients in the Netherlands will
not participate in this part)
Part B will consist of a Part B Treatment Cohort that will enroll subjects from
Cohort 4 of Study 102.
Intervention
The Part A Treatment Cohort will be double-blind and will consist of 2 treatment
arms:
- Treatment Arm 1: 600 mg lumacaftor once daily (qd) + 250 mg ivacaftor every
12 hours (q12h)
- Treatment Arm 2: 400 mg lumacaftor q12h + 250 mg ivacaftor q12h
Subjects who received lumacaftor in combination with ivacaftor in Study 103 or
Study 104 will continue to receive the same dose and regimen of study drug in a
double-blind fashion in Study 105 for 96 weeks as follows:
- Subjects who were randomized to Treatment Arm A in Study 103 or Study 104 are
eligible for enrollment in Treatment Arm 1
- Subjects who were randomized to Treatment Arm B in Study 103 or Study 104 are
eligible for enrollment in Treatment Arm 2
- Subjects who received placebo in Study 103 or Study 104 (Treatment Arm C in
Study 103 or Study 104) will be randomized (1:1) to 1 of the
2 double-blind treatment arms (Treatment Arm 1 or Treatment Arm 2)
Part A Observational Cohort
Subjects in the Part A 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 Study 103 or Study 104 to assess
post-treatment safety of lumacaftor and ivacaftor combination therapy.
The Part B (not applicable in the Netherlands)Treatment Cohort will be
open-label and will consist of 1 treatment arm:
- Treatment Arm 3: 400 mg lumacaftor q12h + 250 mg ivacaftor q12h
Subjects who received lumacaftor in combination with ivacaftor in Cohort 4 of
Study 102 will be enrolled in Treatment Arm 3 and will continue to receive the
same dose and regimen of study drug in Study 105 for 96 weeks as follows:
- Subjects who received active study drug in Cohort 4 of Study 102 are eligible
for enrollment in Treatment Arm 3
- Subjects who received placebo in Cohort 4 of Study 102 are eligible for
enrollment in Treatment Arm 3
Study burden and risks
Based on in vitro and clinical data to date, it is hypothesized that the
combination of a CFTR corrector and potentiator, such as lumacaftor and
ivacaftor, respectively, will optimally enhance ion transport of chloride in
patients with CF, leading to meaningful improvements in lung function and other
clinical outcomes. Clinical proof-of-concept demonstrating the potential for
improvements in subjects with CF who are homozygous for the F508del CFTR
mutation was achieved in Study 102. In Study 102, during the 28 day period of
combination therapy, a significant increase in FEV1 was observed in the active
treatment cohorts (600 mg qd or 400 mg q12h lumacaftor in combination with 250
mg ivacaftor q12h), while a decrease in FEV1 was observed in the placebo group.
Study 105 will evaluate the long-term efficacy and safety of lumacaftor in
combination with ivacaftor in CF subjects homozygous and heterozygous for the
F508del-CFTR mutation.
Because lumacaftor in combination with the 250 mg q12h dose of ivacaftor is an
investigational drug, there may be risks and side effects that are not yet
known. The overall risk to subjects participating in this study will be
minimized as much as possible. Key safety eligibility criteria, close safety
monitoring of subjects, contraceptive requirements, and guidance for use of
concomitant medications are included in the study protocol. In addition, all
subjects will be required to complete safety follow-up visit(s) regardless of
whether they complete study drug dosing.
Subjects participating in Study 105 may directly benefit from this study,
although the potential benefits would not be expected to persist after the end
of the treatment period. The information gained from Study 105 will inform the
development of lumacaftor in combination with ivacaftor, and demonstrate
long-term efficacy and safety data to enable the submission of a marketing
authorization application, which could provide an additional treatment option
for patient with CF.
Based on data from nonclinical and clinical studies to date, and the potential
for benefit to patients with CF from the development of this treatment, the
overall risk-benefit balance for Study 105 is considered to be acceptable.
Northern Avenue 50
Boston, MA 02210
US
Northern Avenue 50
Boston, MA 02210
US
Listed location countries
Age
Inclusion criteria
Subjects who meet all of the following inclusion criteria will be eligible for this study.
1. Signed informed consent form (ICF), and where appropriate, signed assent form.
2. Subjects entering the Part A Treatment Cohort must meet both of the following
criteria:
* Completed 24 weeks of study drug treatment in Study 103 or Study 104
* Subjects who had study drug interruptions, but completed study visits up to
Week 24 of Study 103 or 104 are eligible. Subjects who are not taking study drug
at the Week 24 Visit, including subjects that require study drug interruption to be either continued or initiated at Day 1 in Study 105, must have received Vertex approval for enrollment/randomization in the Part A Treatment Cohort.
* Elect to enroll in the Part A Treatment Cohort
Subjects entering the Part A Observational Cohort must meet the following criteria:
* Completed 24 weeks of study drug treatment in Study 103 or Study 104, but do not
elect to enroll in the Part A Treatment Cohort
* Subjects who received at least 4 weeks of study drug and completed visits up to
Week 24 Visit of Study 103 or 104 but are not taking study drug at the Week 24
Visit because of a drug interruption and did not receive Vertex approval for
enrollment into the Part A Treatment Cohort (or elect not to enroll in the Part A
Treatment Cohort).
* Subjects who permanently discontinued study drug after receiving at least
4 weeks of study drug and remained in the study from the time of discontinuation
of study drug treatment through the Week 24 Visit in Study 103 or Study 104
Subjects entering the Part B Treatment Cohort must meet both of the following
criteria:
* Completed 56 days of study drug treatment in Cohort 4 of Study 102
* Subjects who had study drug interruptions but completed study visits up to
Day 56 are eligible. Subjects who are not taking study drug at the Day 56 Visit, including subjects that require study drug interruption to be either continued or initiated at Day 1 in Study 105,
must have received Vertex approval for enrollment/randomization in the Part B Treatment
Cohort.
* Elect to enroll in the Part B Treatment Cohort
3. Willing to remain on a stable CF medication regimen through the end of study (Part A
and Part B Treatment Cohorts only).
4. 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 Study 103, Study 104, and Cohort 4 of Study 102.
Exclusion criteria
Subjects who meet any of the following exclusion criteria will NOT be eligible for this study.
1. Any comorbidity or laboratory abnormality 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 (e.g., cirrhosis with portal hypertension).
2. Pregnant and nursing females. Females of childbearing potential must have a negative
urine pregnancy test at the Day 1 Visit (enrollment/randomization) and before recieving the first dose of study drug (Section 12.7.2).
3. Sexually active subjects of reproductive potential who are not willing to follow the
contraception requirements outlined in Section 12.7.7. of the protocol
4. History of drug intolerance in the prior study 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 any of the treatment arms include the following:
* Subjects with a history of allergy or hypersensitivity to the study drug
* Liver function test (LFT) abnormality during study drug treatment in the previous
study (Study 103, Study 104, or Cohort 4 of Study 102) for which a clear cause was not identified.
* Other severe or life-threatening reactions to the study drug in the previous study
5. History of poor compliance with study drug and/or procedures in the previous study as
deemed by the investigator.
6. Participation in an investigational drug trial (including studies investigating lumacaftor
and/or ivacaftor. NOTE: participation in a noninterventional study (including observational studies and studies requiring blood collections without administration of study drug 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 | EUCTR2013-000604-41-NL |
| ClinicalTrials.gov | NCT01931839 |
| CCMO | NL45864.018.13 |