Primary objective: - To evaluate the efficacy of VX-445/TEZ/IVA in CF subjects who are heterozygous for F508del and a gating or residual function mutation (F/G and F/RF genotypes).Secondary objectives: - To evaluate the safety of VX-445/TEZ/IVA- To…
ID
Source
Brief title
Condition
- Other condition
- Chromosomal abnormalities, gene alterations and gene variants
Synonym
Health condition
Cystic fibrosis
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint
- Absolute change in percent predicted forced expiratory volume in 1 second
(ppFEV1) from baseline through Week 8 for the VX-445/TEZ/IVA group
Secondary outcome
Key Secondary Endpoints
- Absolute change in sweat chloride (SwCl) from baseline through Week 8 for the
VX-445/TEZ/IVA group
- Absolute change in ppFEV1 from baseline through Week 8 for the VX-445/TEZ/IVA
group compared to the control group
- Absolute change in SwCl from baseline through Week 8 for the VX-445/TEZ/IVA
group compared to the control group
Other Secondary Endpoints
- Absolute change in CF Questionnaire-Revised (CFQ-R) respiratory domain (RD)
score from baseline through Week 8 for the VX-445/TEZ/IVA group
- Absolute change in CFQ-R RD score from baseline through Week 8 for the
VX-445/TEZ/IVA group compared to the control group
- Safety and tolerability assessments based on adverse events (AEs), clinical
laboratory values, ECGs, vital signs, and pulse oximetry
Background summary
Cystic fibrosis (CF) is an autosomal recessive chronic disease with serious
morbidities and frequent premature mortality. CF affects more than 70,000
individuals worldwide (approximately 30,000 in the US and 45,000 in the EU).
Based on its prevalence, CF qualifies as an orphan disease.
CF is caused by decreased quantity and/or function of the CFTR protein due to
mutations in the CFTR gene.CFTR is an ion channel that regulates the flow of
chloride and other ions across epithelia in various tissues, including the
lungs, pancreas and other gastrointestinal organs, and sweat glands.Decreased
CFTR quantity or function results in the failure to regulate chloride transport
in these tissues leading to the multisystem pathology associated with CF. In
the lungs, obstruction of airways with thick mucus, establishment of a chronic
bacterial infection in the airways, and damaging inflammatory responses are all
thought to play a role in causing irreversible structural changes in the lungs,
leading to respiratory failure. Progressive loss of lung function is the
leading cause of mortality.
The most common disease-causing CFTR mutation is F508del, which accounts for
approximately 70% of the identified alleles in people with CF. Approximately
40% to 45% of people with CF are homozygous for F508del (F/F), and
approximately 85% have at least 1 F508del allele.
Based on the understanding of the molecular defects caused by CFTR mutations, 2
complementary approaches have been developed to address the decreased quantity
and/or function of CFTR in order to enhance chloride transport in patients with
CF. Correctors facilitate the cellular processing and trafficking to increase
the quantity of CFTR at the cell surface. Potentiators increase the channel
open probability (channel gating activity) of the CFTR protein delivered to the
cell surface to enhance ion transport. With differing mechanisms of action, a
combination of correctors and potentiators increases F508del CFTR-mediated
chloride transport more than either type of modulator alone.
The therapeutic activity of CFTR modulators has been established with products
developed by Vertex and approved for the treatment of CF: ivacaftor (IVA)
monotherapy (Kalydeco), lumacaftor (LUM)/IVA (Orkambi), and tezacaftor
(TEZ)/IVA (Symdeko/Symkevi). VX-445 is a next-generation CFTR corrector. In
vitro, the triple combination (TC) of VX-445, TEZ, and IVA (VX-445/TEZ/IVA)
increased CFTR chloride transport more than any of the dual combinations
(VX-445/TEZ, VX-445/IVA, and TEZ/IVA) or individual components (VX-445, TEZ,
and IVA) when added to human bronchial epithelial (HBE) cells derived from 2
groups of CF patients: those heterozygous for F508del with a second CFTR allele
carrying a minimal function (MF) mutation that is not responsive to TEZ, IVA,
and TEZ/IVA (F/MF genotypes); and those homozygous for F508del (F/F genotypes).
This study will evaluate the efficacy and safety of VX-445/TEZ/IVA in CF
subjects who are heterozygous for F508del and a second CFTR allele carrying
either a gating mutation or a residual function mutation (F/G and F/RF
genotypes). Results from the Phase 1/2 study showed that treatment with
VX-445/TEZ/IVA resulted in clinically meaningful improvements in percent
predicted forced expiratory volume in 1 second (ppFEV1) and sweat chloride
(SwCl) in CF subjects with 1 or 2 copies of the F508del mutation, namely those
with F/MF and F/F genotypes (for the latter, as compared to their TEZ/IVA
baseline). These results suggest that VX-445/TEZ/IVA treatment may result in
clinical benefit beyond currently approved standard of care CFTR modulators for
CF subjects who have F/G and F/RF genotypes.
Study objective
Primary objective:
- To evaluate the efficacy of VX-445/TEZ/IVA in CF subjects who are
heterozygous for F508del and a gating or residual function mutation (F/G and
F/RF genotypes).
Secondary objectives:
- To evaluate the safety of VX-445/TEZ/IVA
- To evaluate the pharmacodynamics (PD) of VX-445/TEZ/IVA
Study design
This is a Phase 3, randomized, double-blind, active-controlled, parallel-group,
multicenter study.
The study consists of 4 periods:
- Screening Period
- Run-In Period
- Treatment Period
- Safety Follow-Up Period
Screening Period
The Screening Period will last about 4 weeks.
Run-In period
The Run-In Period will last about 4 weeks. In the Run-in Period, subjects will
be assigned to the IVA or TEZ/IVA comparator group based on genotype. Subjects
assigned to the IVA comparator group will receive IVA 150 mg every 12 hours
(q12h) and subjects assigned to the TEZ/IVA comparator group will receive TEZ
100 mg once daily (qd)/IVA 150 mg q12h.
Treatment Period
The Treatment Period will last about 8 weeks. In the Treatment Period, subjects
will be randomized (1:1) to the VX-445/TEZ/IVA treatment arm or control arm
under a single randomization scheme. Subjects in the control arm who received
IVA in the Run-in Period will receive IVA in the Treatment Period; subjects in
the control arm who received TEZ/IVA in the Run-in Period will receive TEZ/IVA
in the Treatment Period.
Randomization will be stratified based on comparator group (IVA comparator
versus TEZ/IVA comparator), ppFEV1 as determined during the Run-in Period (Day
-14 assessment; <70 versus *70), and SwCl as determined during the Run-in
Period (Day -14 assessment; <30 mmol/L versus *30 mmol/L).
Safety Follow-Up Period
The Safety Follow-Up period may last up to 4 weeks after the last dose of study
drug.
If subjects stop taking the study drug early they will have an early treatment
termination visit. The Safety Follow-Up Visit may take place 4 week after the
last dose of study drug.
Intervention
During the Run-in Period, study drug refers to TEZ/IVA and IVA, as applicable.
During the Treatment Period, study drug refers to VX-445/TEZ/IVA and matching
placebo, TEZ/IVA and matching placebo, and IVA and matching placebo, as
applicable.
Active study drugs will be orally administered as fixed-dose combination (FDC)
film-coated tablets of VX-445/TEZ/IVA or TEZ/IVA and film-coated IVA tablets.
Active substance: VX-445/TEZ/IVA
Activity: VX-445 is a CFTR corrector, TEZ is a CFTR corrector, and IVA is a
CFTR potentiator
(increased Cl* secretion)
Strength: 100 mg/50 mg/75 mg FDC tablet
Active substance: TEZ/IVA
Activity: CFTR corrector and CFTR potentiator (increased Cl* secretion)
Strength: 100 mg/150 mg FDC tablet
Active substance: IVA
Activity: CFTR potentiator (increased Cl* secretion)
Strength: 150 mg tablet
Study burden and risks
Risks associated with VX-445 (elexacaftor; ELX)/Tezacaftor (TEZ)/Ivacaftor
(IVA) triple combination therapy (referred to as VX-445/TEZ/IVA):
To date, VX-445/TEZ/IVA has been administered to more than 500 clinical trial
participants with cystic fibrosis. In addition, VX-445 has been administered
alone or in combination with TEZ/IVA to approximately 200 healthy volunteers.
The side effects associated with VX-445/TEZ/IVA are listed or described in the
text below. For the listed side effects, the percentages of people with cystic
fibrosis in a large study who experienced these side effects are shown.
* Headache (17%)
* Diarrhea (13%)
* Upper respiratory tract infection (common cold) (12%)
* Increased liver enzymes in blood (may be a sign of a liver problem) (11%)
* Rash (11%)
* Stomach ache (10%)
* Nasal congestion (9%)
* Increased blood enzyme called creatine phosphokinase (may be a sign of a
muscle problem) (9%)
* Runny nose (8%)
Risks associated with TEZ/IVA dual combination therapy:
To date, approximately 2000 clinical trial participants have received at least
1 dose of TEZ/IVA.
The side effects associated with TEZ/IVA are listed or described in the text
below. For the listed side effects, the percentages of participants with cystic
fibrosis who experienced these side effects are shown.
* Headache (14%)
* Common cold (12%)
* Nausea (8%)
* Sinus congestion (3%)
* Dizziness (3%)
Risks associated with IVA monotherapy:
Up to now, more than 35 studies of IVA have been completed or are ongoing in
approximately 400 healthy adult subjects and 800 adult and pediatric subjects
with CF.
Adverse reactions identified in at least 5% of subjects with CF in the pooled
48-week placebo-controlled Phase 3 studies are:
* Headache (24%)
* Oropharyngeal pain (22%)
* Upper respiratory infection (22%)
* Nasal congestion (20%)
* Abdominal pain (16%)
* Diarrhea (13%)
* Nasopharyngitis (15%)
* Rash (13%)
* Dizziness (9%)
* Bacteria in sputum (7%)
* Sinus congestion (7%)
* Rhinitis (7%)
The study drug may also have side effects that are as yet unknown.
Risks from tests:
Blood draws can be painful or cause bruising.
ECG: The sticky strips used for this test may irritate the skin. Removing the
stickers causes the same discomfort as removing a plaster.
Spirometry: Subject may feel the need to cough during the test, or may get
short of breath.
Sweat chloride test: The sweat test may cause a tingling sensation on the skin
where the adhesive strips are placed. In some cases, blister-like bumps may
develop, which go away within 2-3 hours.
Van Swietenlaan 6
Groningen 9728NZ
NL
Van Swietenlaan 6
Groningen 9728NZ
NL
Listed location countries
Age
Inclusion criteria
1. Subject (or his or her legally appointed and authorized representative) will
sign and date an informed consent form (ICF), and, when appropriate, an assent
form.
2. Willing and able to comply with scheduled visits, treatment plan, study
restrictions, laboratory tests, contraceptive guidelines, and other study
procedures.
3. Age 12 years or older, at the date of informed consent.
4. Confirmed diagnosis of CF as determined by the investigator.
5. Subject is heterozygous for F508del and either a gating or residual function
mutation (F/G and F/RF genotypes) and is in a region where their genotype and
age group are approved indications for treatment with IVA and/or TEZ/IVA (see
Appendix A for qualifying mutations).
6. Forced expiratory volume in 1 second (FEV1) value *40% and *90% of predicted
mean for age, sex, race, and height (equations of the Global Lung Function
Initiative [GLI]) at the Screening Visit. Spirometry measurements must meet
American Thoracic Society/European Respiratory Society criteria for
acceptability and repeatability.
7. Subjects must be able to produce a valid (quantity-sufficient) sweat sample
at screening.
8. Stable CF disease as judged by the investigator.
9. Willing to remain on a stable CF treatment regimen through completion of
study participation.
Exclusion criteria
1. History of any illness or any clinical condition that, in the opinion of the
investigator, might confound the results of the study or pose an additional
risk in administering study drug(s) to the subject. This includes, but is not
limited to, the following
- Clinically significant cirrhosis with or without portal hypertension.
- Solid organ or hematological transplantation.
- Alcohol or drug abuse in the past year, including, but not limited to,
cannabis, cocaine, and opiates, as deemed by the investigator.
- Cancer, except for squamous cell skin cancer, basal cell skin cancer, and
Stage 0 cervical carcinoma in situ (each being disease-free for the last 5
years).
2. Any of the following abnormal laboratory values at screening.
- Hemoglobin <10 g/dL
- Total bilirubin *2 × upper limit of normal (ULN)
- Aspartate transaminase (AST), alanine transaminase (ALT), or gamma-glutamyl
transferase (GGT) *3 × ULN
- Abnormal renal function defined as estimated glomerular filtration rate *50
mL/min/1.73 m^2 (calculated by the Modification of Diet in Renal Disease Study
Equation) for subjects *18 years of age, or *45 mL/min/1.73 m^2 (calculated by
the Counahan-Barratt equation) for subjects 12 to 17 years of age (inclusive)
3. An acute upper or lower respiratory infection, pulmonary exacerbation (PEx),
or change in therapy (including antibiotics) for sinopulmonary disease within
28 days before the first dose of study drug in the Run-in Period (Day -28).
4. Lung infection with a microbial pathogen that is associated with a more
rapid decline in pulmonary status (including, but not limited to, Burkholderia
cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). For subjects
who have had a history of a positive culture, the investigator will apply the
following criteria to establish whether the subject is free of infection with
such organisms:
- The subject has not had respiratory tract culture positive for these
organisms within the 12 months before the date of informed consent.
- The subject has had at least 2 respiratory tract cultures negative for such
organisms within the 12 months before the date of informed consent, with the
first and last of these separated by at least 3 months, and the most recent one
within the 6 months before the date of informed consent.
5. An acute illness not related to CF (e.g., gastroenteritis) within 14 days
before the first dose of study drug in the Run-in Period (Day -28).
6. Ongoing or prior participation in a study of an investigational treatment
other than a Vertex CFTR modulator within 28 days or 5 terminal half-lives
(whichever is longer) before screening. The duration of the elapsed time may be
longer if required by local regulations.
7. Use of prohibited medications as defined in the protocol within the
specified window before the first dose of study drug in the Run-in Period (Day
-28).
8. Pregnant or breast-feeding females. All female subjects, regardless of
childbearing potential status, must have negative pregnancy tests at the
Screening Visit (Day -56) and at the Day -28 Visit, before the first dose of
study drug in the Run-in Period.
9. The subject or a close relative of the subject is the investigator or a
subinvestigator, research assistant, pharmacist, study coordinator, or other
staff directly involved with the conduct of the study at that site. However, an
adult (aged 18 years or older) who is a relative of a study staff member may be
enrolled in the study provided that
- the adult lives independently of and does not reside with the study staff
member, and
- the adult participates in the study at a site other than the site at which
the family member is employed.
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 | EUCTR2018-002835-76-NL |
| CCMO | NL70511.041.19 |
| Other | tbd |