Primary objective (Parts A and B):To evaluate the long-term safety and tolerability of VX-445/TEZ/IVA in subjects with CF who are heterozygous for the F508del mutation and a gating (F/G) or residual function (F/RF) mutation.Secondary objectives (…
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint (Parts A and B):
Safety and tolerability of long-term treatment with VX-445/TEZ/IVA based on
adverse events (AEs), clinical laboratory values, ECGs, vital signs, and pulse
oximetry.
Secondary outcome
Secondary Endpoints (Part A only):
- Absolute change in percent predicted forced expiratory volume in 1 second
(ppFEV1)
- Absolute change in sweat chloride (SwCl)
- Absolute change in body mass index (BMI)
- Absolute change in BMI z-score
- Absolute change in body weight
- Absolute change in CFQ-R respiratory domain (RD) score
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 provide data on the long-term safety, efficacy, and durability
of VX-445/TEZ/IVA in CF subjects who are heterozygous for the F508del mutation
and a gating (F/G) or residual function (F/RF) mutation.
Study objective
Primary objective (Parts A and B):
To evaluate the long-term safety and tolerability of VX-445/TEZ/IVA in subjects
with CF who are heterozygous for the F508del mutation and a gating (F/G) or
residual function (F/RF) mutation.
Secondary objectives (Parts A only):
- To evaluate the long-term efficacy of VX-445/TEZ/IVA
- To evaluate the pharmacodynamics (PD) of VX-445/TEZ/IVA
Study design
This is a Phase 3, 2-part, multicenter, open label study for subjects who
completed the last Treatment Period visit in the parent study (Study 104) and
meet eligibility criteria.
All subjects in Parts A and B will receive the triple combination (TC) of VX
445/TEZ/IVA at the same dosage as that evaluated in Study 104. Subjects who
complete Part A will have the opportunity to participate in Part B for an
additional 48 weeks. For all subjects, a Safety Follow up Visit is scheduled to
occur 28 (± 7) days after the last dose of study drug in Part A or Part B.
Intervention
Study drug refers to VX-445/TEZ/IVA and IVA. Study drugs will be orally
administered as 2 fixed-dose combination (FDC) film-coated tablets of
VX-445/TEZ/IVA in the morning, and 1 film-coated IVA tablet in the evening.
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: IVA
Activity: CFTR potentiator (increased Cl* secretion)
Strength: 150 mg tablet
Study burden and risks
Risks associated with Eelexacaftor (ELX)/Tezacaftor (TEZ)/Ivacaftor (IVA)
triple combination therapy (referred to as ELX/TEZ/IVA):
To date, ELX/TEZ/IVA has been administered to more than 600 clinical trial
participants with cystic fibrosis age 6 years and greater. In addition, ELX has
been administered alone or in combination with TEZ/IVA to approximately 200
healthy volunteers.
The side effects associated with ELX/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%)
Safety Monitoring in This Study:
In some study participants treated with ELX/TEZ/IVA triple combination therapy,
high liver enzymes in the blood have been observed. Elevated liverenzymes may
be a sign of liver injury. These abnormal liver enzymes may get better after
Study Drug is stopped.
Other than lab test changes, 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.
In severe cases, significant liver injury can potentially become permanent and
even be life-threatening. In patients with advanced liver disease (for example,
cirrhosis and/or portal hypertension), there is a greater risk for worsening of
liver function. The worsening of liver function can lead to a need for liver
transplant.
In some children or adolescents treated with IVA-containing regimens,
abnormality of the eye lens (cataract) has been noted. A link between these
medicines and cataracts is uncertain but cannot be excluded.
In some study participants treated with ELX/TEZ/IVA triple combination therapy,
increases in blood pressure have been observed.
In some study participants treated with ELX/TEZ/IVA triple combination therapy,
rash has been observed. In study participants treated with ELX/TEZ/IVA, rash
was more commonly seen in women, especially those taking hormones to prevent
pregnancy. In some cases, the rashes were severe, required treatment, or led to
stopping of ELX/TEZ/IVA. The rashes got better after Study Drug was stopped.
The Study Drug may contain 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
the amount in one teaspoon of milk. This amount of lactose is unlikely to cause
symptoms in people who have lactose intolerance.
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 subjects. Subjects should tell the
Study Doctor about every medicine, dietary supplement, natural remedy, and
vitamin (or change) while they are in the study. There are certain herbal
medications such as St. John*s Wort, and certain fruits and fruit juices (such
as grapefruit, or products made from them) that they must not take during study.
• Spirometry: When the lungs are tested, the participant may feel the need to
cough, they may feel short of breath or dizzy during or after the test.
• Blood sample collection: When you have your blood taken with a needle, it may
feel like a pinch. It will hurt for a short time, and sometimes the place where
the needle was put might feel sore or look bruised. Some people may experience
dizziness, upset stomach, or fainting when their blood is drawn. There is a
small risk of infection.
• ECG: It might hurt when the study doctor removes the sticky pads, like taking
off a bandage.
• Sweat chloride test: The sweat test may cause tingling on the skin where the
sticky pads are placed. In some cases, blister-like bumps may form, which will
go away within 2-3 hours. There is a chance of minor skin burn. This happens in
less than 1 in 50,000 people. When this happens, it is usually minor and gets
better within one to two weeks with little or no scarring.
Van Swietenlaan 6
Groningen 9728NZ
NL
Van Swietenlaan 6
Groningen 9728NZ
NL
Listed location countries
Age
Inclusion criteria
Part A
Subjects transitioning from Study 104 must meet all of the following criteria
to be eligible for Part A:
1. Subject (or his or her legally appointed and authorized representative) will
sign and date an ICF (informed consent form), 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. Did not withdraw consent from the parent study.
4. Meets at least 1 of the following criteria:
- Completed study drug treatment in the parent study.
- Had study drug interruption(s) in the parent study, but without prematurely
discontinuing study drug in the parent study and completed study visits up to
the last scheduled visit of the Treatment Period of the parent study.
5. Willing to remain on a stable CF treatment regimen through completion of
study participation.
Inclusion criteria for subjects resuming participation in Part A of this study
after enrolling in another qualifying Vertex study include all of the criteria
above AND the following criterion:
6. Completed the ETT visit in another qualified Vertex study before or on same
day as the Returning Visit in this study. If more than 30 days have elapsed
since the ETT visit in the other qualified Vertex study, approval of the
medical monitor is required.
Part B:
Subjects who meet all of the following criteria will be eligible for Part B:
1. Subject (or his or her legally appointed and authorized representative) will
sign and date an 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. Did not withdraw consent from the parent study or Part A of this study.
4. Meets at least 1 of the following criteria:
• Completed study drug treatment in Part A, or
• Had study drug interruption(s) in Part A, but without prematurely
discontinuing study drug and completed study visits up to the last scheduled
visit of the Treatment Period of Part A.
5. Willing to remain on a stable CF treatment regimen (as defined in Section
9.5) through completion of study participation.
Inclusion criteria for subjects resuming participation in Part B of this study
after enrolling in another qualifying Vertex study include all of the criteria
above AND the following criterion:
6. Completed the ETT visit in another qualified Vertex study before or on same
day as the Returning Visit in this study. If more than 30 days have elapsed
since the ETT visit in the other qualified Vertex study, approval of the
medical monitor is required.
Exclusion criteria
Part A
Subjects who meet any of the following criteria will NOT be eligible for Part A:
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 to the subject.
2. Pregnant and breast-feeding females. All female subjects, regardless of
childbearing potential status, must have a negative pregnancy test at the Part
A Day 1 Visit before receiving the first dose of study drug.
3. History of intolerance to study drug in the parent study that would pose an
additional risk to the subject in the opinion of the investigator. (e.g.,
subjects with a history of allergy or hypersensitivity to the study drug).
4. Current participation in an investigational drug study (other than the
parent study). Participation in a non-interventional study (including
observational studies, registry studies, and studies requiring blood
collections without administration of study drug) and screening for another
Vertex study is permitted.
Subjects resuming participation in Part A of this study after enrolling in
another qualifying Vertex study must not meet Exclusion Criteria 1 through 3,
and also must not meet any of the following criteria:
5. Pregnant and nursing females. All female subjects must have a negative
pregnancy test at the Returning Visit before receiving the first dose of study
drug.
6. History of intolerance to study drug that would pose an additional risk to
the subject in the opinion of the investigator. If protocol-defined
interruption criteria is met in another qualified Vertex study, then the
subject must remain on study drug interruption until the subject meets criteria
in Section 9.8 and receives approval by the medical monitor to resume study
drug dosing in this study.
7. Has received the first dose of study drug in the Treatment Period of another
qualified Vertex study.
8. Has access to commercially available VX-445/TEZ/IVA or is receiving managed
access program supplied VX 445/TEZ/IVA.
9. Has departed this study more than once to participate in another qualified
Vertex study.
Part B:
Subjects who meet any of the following criteria will NOT be eligible for this
study:
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 to the subject.
2. Pregnant and breast-feeding females. All female subjects, regardless of
childbearing potential status, must have a negative pregnancy test at the Part
B Day 1 Visit before receiving the first dose of study drug.
3. History of intolerance to study drug that would pose an additional risk to
the subject in the opinion of the investigator (e.g., subjects with a history
of allergy or hypersensitivity to the study drug).
4. Current participation in an investigational drug study (other than the
parent study or the current study). Participation in a non interventional study
(including observational studies, registry studies, and studies requiring blood
collections without administration of study drug) and screening for another
Vertex study is permitted.
Subjects resuming participation in Part B of this study after enrolling in
another qualifying Vertex study must not meet Exclusion Criteria 1 through 4,
and also must not meet any of the following criteria:
5. Pregnant and nursing females. All female subjects must have a negative
pregnancy test at the Returning Visit before receiving the first dose of study
drug.
6. History of intolerance to study drug that would pose an additional risk to
the subject in the opinion of the investigator. If protocol-defined
interruption criteria is met in another qualified Vertex study, then the
subject must remain on study drug interruption until the subject meets criteria
in Section 9.8 and receives approval by the medical monitor to resume study
drug dosing in this study.
7. Has received the first dose of study drug in the Treatment Period of another
qualified Vertex study.
8. Has access to commercially available VX-445/TEZ/IVA or is receiving managed
access program supplied VX 445/TEZ/IVA.
9. Has departed this study more than once to participate in another qualified
Vertex study.
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 | EUCTR2019-000833-37-NL |
| CCMO | NL70512.041.19 |
| Other | tbd |