Primary ObjectiveTo evaluate the efficacy of lumacaftor/ivacaftor combination therapy (LUM/IVA) in subjects with cystic fibrosis (CF) 12 years of age and older who have at least one A455E mutation.Other Objectives* To explore the association between…
ID
Source
Brief title
Condition
- Respiratory disorders congenital
- Autoimmune disorders
- Lower respiratory tract disorders (excl obstruction and infection)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Absolute change from baseline in percent predicted forced expiratory volume in
1 second (ppFEV1) through 8 weeks of treatment.
Secondary outcome
* Change from baseline in sweat chloride through 8 weeks of treatment.
* Change from baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) at
8 weeks of treatment.
* Organoid-based measurements of LUM/IVA-induced CFTR function in vitro versus
clinical outcomes.
* Change from baseline in glucose and insulin levels during the oral glucose
tolerance test (OGTT) after approximately 8 weeks of treatment.
Background summary
The A455E-CFTR mutation is reported to occur in less than 0.1% of patients with
CF worldwide, but large regional differences in prevalence exist. In The
Netherlands, it is the second most prevalent mutation, occurring in 3.6% of all
patients with CF. An especially high prevalence has been reported in the
Southeast and Southwest regions of The
Netherlands. Although it was initially reported that the A455E mutation is
associated with mild lung disease, current clinical experience in The
Netherlands shows marked differences
in clinical disease severity, ranging from relatively mild to severe loss of
lung function at
young adulthood.
The A455E mutation results in a severe reduction of mature CFTR protein at the
cell surface. In recent research, it was noted that when both F508del-CFTR and
264del-CFTR were transfected into the same cells, the expression of mature
F508del-CFTR protein was increased. Similarly, when both A455E-CFTR and
264del-CFTR were transfected into the same cells, the expression of mature
A455E-CFTR protein was increased. Furthermore, compounds known to be able to
rescue F508del-CFTR were also able to rescue
A455E-CFTR in vitro. This suggests that A455E-CFTR could be rescued by the same
strategies as F508del-CFTR. These findings suggested that A455E might be a
suitable candidate for LUM/IVA treatment.
A novel functional CFTR assay has been established using patient-derived
intestinal stem cell cultures termed organoids. Organoids have crypt-like
structures and an internal lumen lined by differentiated cells, recapitulating
the in vivo tissue architecture. Intestinal CFTR is expressed at the apical
membrane of the organoid. Activation of CFTR by forskolin (which increases cAMP
levels) drives CFTR-dependent chloride secretion, inducing rapid, measurable
swelling of organoids. In this in vitro model, organoids derived from patients
with the F508del/F508del CFTR genotype display less forskolin-induced swelling
than organoids derived from healthy controls. Incubation of these
F508del/F508del organoids with LUM/IVA enhances forskolin-induced swelling. A
similar improvement by LUM/IVA on forskolin-induced swelling is observed in
A455E/F508del organoids. Based on these findings in the organoid model, it is
hypothesized that LUM/IVA treatment can increase CFTR function and improve
disease parameters in patients with CF who have an A455E mutation.
In this study, the clinical response of subjects with the A455E mutation to
LUM/IVA will be investigated. The associations between the responses in the
organoid model and the clinical response will be explored. Thus, the study will
provide insights on the clinical utility of the organoid assay, potentially
informing future studies in patients with very rare CFTR mutations. Also, the
effect of CFTR modulation on subjects* pancreatic endocrine function,
as measured by glucose levels and insulin response in the oral glucose
tolerance test (OGTT),
will be explored.
Study objective
Primary Objective
To evaluate the efficacy of lumacaftor/ivacaftor combination therapy (LUM/IVA)
in subjects with cystic fibrosis (CF) 12 years of age and older who have at
least one A455E mutation.
Other Objectives
* To explore the association between LUM/IVA-induced cystic fibrosis
transmembrane conductance regulator (CFTR) function in in vitro organoid-based
measurements and clinical response to LUM/IVA in subjects with CF 12 years of
age and older who have at least one A455E mutation.
* To explore the effect of LUM/IVA on glucose tolerance and insulin secretion
in subjects with CF 12 years of age and older who have at least one A455E
mutation.
Study design
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter,
crossover study. The crossover design includes two 8-week treatment periods
separated by an 8-week (± 7 days) washout period. Subjects will be randomized
(1:1) to 1 of 2 treatment sequences: LUM/IVA followed by placebo or placebo
followed by LUM/IVA.
Intervention
Active substance: LUM/IVA fixed-dose combination
Activity: CFTR corrector and potentiator (chloride ion secretion)
Strength and route of administration: 200-mg lumacaftor/125-mg ivacaftor
(200/125 mg) film-coated tablets for oral administration
Dosage: LUM 400 mg/IVA 250 mg every 12 hours (q12h)
The subject will receive two tablets of study drug (whether it is the placebo
or the Lumacaftor/Ivacaftor Combination) in the morning and two tablets in the
evening (approximately every 12 hours) every day of each Treatment Period.
Study burden and risks
In CF subjects who received lumacaftor/ivacaftor combination treatment, some
subjects have had blood tests that showed liver abnormalities. These tests,
called ALT, AST, and bilirubin, led to stopping of study drug in some subjects
(<1%). In these subjects, liver tests got better after study drug was stopped.
Tests of patien's liver will be performed during the study.
Potential symptoms of liver injury are not specific and may include loss of
appetite, upset stomach, tiredness, pain in the right upper belly, vomiting,
dark urine, and/or yellowing of the eyes or skin. The patient should tell the
study doctor if he/she has any of these symptoms or anything else unusual.
In very bad cases, significant liver injury can potentially become permanent
and even be life-threatening.
In patients with existing severe liver disease (cirrhosis with portal
hypertension), there is a greater risk for worsening of liver function. The
worsening of liver function can cause encephalopathy (confusion) or death.
Some respiratory symptoms, such as shortness of breath and/or chest tightness
can occur with lumacaftor/ivacaftor combination treatment. The majority of
these events began during the first week of treatment. These respiratory
symptoms were more common in subjects with poor lung function. These
respiratory symptoms can be serious and may lead to stopping treatment,
especially in patients with poor lung function. The patient should tell the
study doctor if he/she has any of these symptoms.
In a study in children 6 to 11 years old, a drop in lung function was observed
during the start of lumacaftor/ivacaftor combination treatment. The biggest
drop in lung function was about 8%, and was seen 4 to 6 hours after first dose
on Day 1. This drop was much smaller on Day 15 and went away by Week 16 with
continued treatment.
Irregular or abnormal periods have been seen in female subjects treated with
lumacaftor/ivacaftor combination treatment, especially those taking hormonal
contraceptives (birth-control pills). If the patient is female, hormonal
contraceptives (birth control pills) will not work while she is on Study Drug.
Eye examinations performed in studies involving children receiving ivacaftor or
lumacaftor/ivacaftor combination treatment have identified several subjects
with cataracts (cloudiness of the lens of the eye). While the data do not
support a link between ivacaftor and cataracts, a possible link cannot be
excluded.
Increases in blood pressure have been observed in patients treated with
lumacaftor/ivacaftor. Patien's blood pressure will be monitored periodically
while he/she is in the study.
The Study Drug contains a very small amount of lactose, a sugar found in dairy
products. The amount of lactose in a single pill is roughly the same as 5 ml of
milk. This amount of lactose is unlikely to cause symptoms in people who have
lactose-intolerance.
Possible Risks Based on Animal Studies:
In a study in which ivacaftor was given to newborn rats, cataracts (cloudiness
of the lens of the eye) were seen. No cataracts were seen in studies of older
animals (rats and dogs) dosed with ivacaftor for longer periods of time. The
importance of this finding in humans is unknown.
Reproductive Risks:
De patient should not become pregnant or father a baby while on this study
because the drugs in this study can affect an unborn baby. Women should not
breastfeed a baby while in this study. Patient and his partner must use a
study-approved method of birth control (unless they are infertile, meaning not
able to get pregnant or make a female pregnant). De patient should check with
the Study Doctor about what kind of birth control methods to use and how long
to use them. Some methods might not be approved for use in this study. If you
are female, hormonal contraceptives (birth control pills) will not work while
you are on Study Drug.
If the patient or his female partner becomes pregnant during the study he
should notify the Study Doctor right away. If the patient or his female partner
becomes pregnant, he will need to stop Study Drug immediately and permanently.
The Study Doctor will ask to follow the pregnancy to its outcome and until the
infant is one year of age. If his female partner becomes pregnant, she will be
asked for permission to follow the pregnancy.
Drug Interaction Risks (medicines working with or against each other):
Almost all medicines can cause side effects. Many are mild, but some can
sometimes become life threatening if they are not treated. The combination of
the Study Drug and any other medications, dietary supplements, natural
remedies, and vitamins could be harmful to you. You should tell your study
doctor about every medicine, dietary supplement, natural remedy, and vitamin
(or change) while you are in the study.
Unknown Risks:
There may be side effects that are not yet known. De patient should call the
Study Doctor if he/she thinks he/she is having any of the problems listed above
or even if de patient is having problems that are not on this list. Please note
that the treatment that will follow may involve risks which are currently
unforeseeable to the patient and the fetus, embryo or unborn child.
Study Procedure Risks:
Blood sample collection: De patient may have a bruise (a black and blue mark)
or pain where we take the blood samples. Some people get dizzy or faint from a
blood draw. De patient could also get an infection (rare), or have bleeding,
redness, or bruising at the skin puncture.
Spirometry: De patient may feel the need to cough or may feel short of breath
during or after the test.
Eye Exam: The drops used to dilate your pupils can cause blurry vision for a
few hours. They can also make it uncomfortable to be around bright lights.
Patient's eye doctor will tell him/her about this.
Rectal Biopsy: De patient will feel some discomfort while the biopsy is being
taken. Also during and after the biopsy, he/she may experience bloating,
abdominal discomfort or passing gas for a few hours after the procedure. It is
not uncommon to find a small amount of blood in your first bowel movement after
your rectal biopsy.
However, the patient should contact the Study doctor if he/she experiences:
* extreme abdominal pain
* fever
* more than one bloody bowel movement, especially if bleeding is heavy or
clotted
* a feeling of faintness
Northern Avenue 50
Boston MA 02210-1862
US
Northern Avenue 50
Boston MA 02210-1862
US
Listed location countries
Age
Inclusion criteria
Subjects who meet all of the following inclusion criteria will be eligible:
1. Male or female with confirmed diagnosis of CF. The subject must have both of the
following:
o One or more characteristic phenotypic features, such as chronic cough and sputum
production, persistent chest radiograph abnormalities, or airway obstruction
manifested by wheezing and air trapping; or a history of CF in a sibling; or a
positive newborn screening test result;
o An increased sweat chloride concentration by pilocarpine iontophoresis on two or
more occasions; or identification of two CF mutations; or demonstration of
abnormal nasal epithelial ion transport.
2. Age 12 years or older on the date of informed consent.
3. All subjects must have an A455E mutation on at least 1 CFTR allele.
4. Forced expiratory volume in one second (FEV1) *30% of predicted and *90% of
predicted at the Screening Visit, based on the Global Lung Function Initiative (GLI)-
2012 multi-ethnic all-age reference equations.
5. Stable CF disease as judged by the investigator.
6. Willing to remain on a stable medication regimen for CF from 4 weeks before Day 1
through the Follow-up Visit.
7. Willing and able to comply with scheduled visits, treatment plan, study restrictions,
laboratory tests, contraceptive guidelines, and other study procedures.
8. Subject (or subject*s legally appointed and authorized representative) will sign and date
an informed consent form (ICF), and where appropriate, assent form.
Exclusion criteria
Subjects who meet any of the following exclusion criteria will not be eligible:
1. History of any comorbidity reviewed at the Screening Visit 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:
o A history of cirrhosis with portal hypertension.
o An acute upper or lower respiratory infection, pulmonary exacerbation, or
changes in therapy (including antibiotics) for pulmonary disease within 28 days
before Day 1 (the first dose of study drug).
2. A G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or
R117H mutation on at least one CFTR allele.
3. Ongoing or prior participation in an investigational drug study (including studies
investigating LUM/IVA or IVA) within 30 days before the Screening Visit.
o A washout period of 5 terminal half-lives of the previous investigational study
drug or 30 days, whichever is longer, must elapse before the Screening Visit. The
duration of the elapsed time may be longer if required by local regulations.
o Subjects who participated in Vertex Study VX14-661-108 may not be enrolled.
o Ongoing participation in a noninterventional study (including observational
studies) is permitted.
4. Pregnant or breastfeeding.
5. Any of the following abnormal laboratory values at the Screening Visit:
* Hemoglobin <10 g/dL
* Any 2 or more of the following:
o aspartate aminotransferase (AST) *3 × upper limit of normal (ULN)
o alanine aminotransferase (ALT) *3 × ULN
o gamma-glutamyl transpeptidase (GGT) *3 × ULN
o alkaline phosphatase *3 × ULN
* ALT or AST >5 × ULN
* Bilirubin >2 × ULN
* Glomerular filtration rate *45 mL/min/1.73 m2 (calculated by the Counahan-Barratt
equation).25
6. History of cataract/lens opacity, or evidence of cataract/lens opacity determined to be
clinically significant by the ophthalmologist or optometrist during the ophthalmologic
examination at the Screening Visit (if applicable).
7. Use of strong inhibitors or strong inducers of CYP3A, including consumption of certain
herbal medications (e.g., St. John*s Wort) and certain fruit and fruit juices, within 14 days
before Day 1 (the first dose of study drug).
8. Sexually active subjects of reproductive potential who are not willing to follow the
contraception requirements outlined in Section 11.6.5.
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 |
|---|---|
| Other | 2016-001585-29 |
| EudraCT | EUCTR2016-001585-29-NL |
| CCMO | NL57898.041.16 |