This study has been transitioned to CTIS with ID 2024-514173-22-00 check the CTIS register for the current data. Primary ObjectiveTo evaluate the long-term safety and tolerability of VNZ/TEZ/D-IVA in subjects with CFSecondary ObjectiveTo evaluate…
ID
Source
Brief title
Condition
- Respiratory disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and tolerability of long-term treatment with VNZ/TEZ/D-IVA based on
adverse events (AEs), clinical laboratory values, ECGs, vital signs, and pulse
oximetry
Secondary outcome
• Absolute change from baseline in percent predicted forced expiratory volume
in 1 second (ppFEV1)
• Absolute change from baseline in sweat chloride (SwCl)
• Number of pulmonary exacerbations (PEx)
Other Endpoints
• Proportion of subjects with SwCl <60 mmol/L
• Proportion of subjects with SwCl <30 mmol/L
• Absolute change from baseline in Cystic Fibrosis Questionnaire Revised
(CFQ-R) respiratory domain (RD) score
• Absolute change in body mass index (BMI)
• Absolute change in BMI z score
• Absolute change in weight
Background summary
Cystic fibrosis (CF) is an autosomal recessive genetic disease with serious
morbidities and frequent premature mortality. CF affects more than 80,000
individuals worldwide (approximately 31,000 in the US and 49,000 in the EU).1-4
CF is caused by decreased quantity and/or function of the CFTR protein due to
mutations in the CFTR gene.5 CFTR is a channel that regulates the flow of
chloride and other anions across epithelia in multiple organs and tissues,
including the lungs, pancreas and other gastrointestinal organs, and sweat
glands.6 Despite progress in the treatment of CF with symptomatic therapies,
the current median age at death among people with CF is approximately 30 years,
and the predicted median age of survival is approximately 47 years.1, 2 More
effective treatments are needed for CF.
The most common disease causing mutation is F508del: approximately 85.3% of
people with CF in the US and 80.6% in Europe have at least one F508del
allele.1, 2
At present CF does not have a cure. CFTR modulators (i.e., correctors and
potentiators) represent a major advancement in the treatment of CF because they
are systemic therapies that target the underlying cause of the disease and have
been shown to improve CF survival by modifying the course of disease.7, 8 The
clinical testing and regulatory approval of CFTR modulators in certain
countries for the treatment of people with CF caused by specific CFTR genotypes
have established the therapeutic value of specific regimens developed by
Vertex. These treatment regimens include ivacaftor (IVA) monotherapy
(Kalydeco*), lumacaftor (LUM)/IVA dual combination therapy (Orkambi*),
tezacaftor (TEZ)/IVA dual combination therapy (Symdeko*, Symkevi*) and
elexacaftor (ELX)/TEZ/IVA triple combination therapy (Trikafta*, Kaftrio*).
Deutivacaftor (D-IVA, VX-561) is a CFTR potentiator and is a deuterated isotope
of IVA with a specific pattern of 9 substituted deuteriums. In vitro data
indicate similar potency of D-IVA in human bronchial epithelial (HBE) cells
relative to IVA. Nonclinical and clinical data demonstrate a similar safety
profile relative to IVA and pharmacokinetic (PK) data support once daily dosing
(refer to VX 121/TEZ/D-IVA Investigator*s Brochure).
VX 121 is a CFTR corrector that improves the processing and trafficking of
mutated CFTR in vitro, thereby increasing the quantity of functional protein at
the cell surface. The effect of VX 121 was additive to the effect of TEZ. The
CFTR protein delivered to the cell surface by VX 121 alone or in combination
with TEZ (VX 121/TEZ) was potentiated by either IVA or D IVA. In HBE cells
derived from people homozygous for F508del and people heterozygous for F508del
and a minimal function (MF) CFTR mutation (F/MF HBE cells) and studied in
vitro, the triple combination (TC) of VX 121, TEZ, and IVA (VX 121/TEZ/IVA)
increased CFTR chloride transport more than the dual combinations of VX 121/TEZ
or VX-121/IVA under most conditions (refer to VX-121/TEZ/D-IVA Investigator*s
Brochure).
Study objective
This study has been transitioned to CTIS with ID 2024-514173-22-00 check the CTIS register for the current data.
Primary Objective
To evaluate the long-term safety and tolerability of VNZ/TEZ/D-IVA in subjects
with CF
Secondary Objective
To evaluate the long-term efficacy of VNZ/TEZ/D-IVA
Study design
This is a Phase 3, multicenter, open label study for subjects who completed the
last Treatment Period visit in a parent study and meet eligibility criteria. A
schematic of the study design is shown in Figure 9 1 of the protocol.
Approximately 850 subjects are expected to enroll in this study.
All subjects will receive VNZ/TEZ/D-IVA at the same dosage that was evaluated
in Study 102 and Study 103. Study drug administration is described in Section
9.6 of the protocol.
Study visits and assessments to be conducted are shown in Table 3 1. All visits
will occur within the windows specified.
Study drug is defined in Section 10 of the protocol.
Intervention
Active substance: VNZ/TEZ/D-IVA
Activity: CFTR corrector, CFTR corrector, and CFTR potentiator (increased Cl-
secretion)
Strength:10-mg VX-121/50-mg TEZ/125-mg D-IVA
Study drug will be orally administered as fixed-dose combination (FDC) film
coated tablets of VNZ/TEZ/D-IVA in the morning.
Study burden and risks
Risks Associated withVNZ/TEZ/D-IVA :
All drugs have the potential to cause side effects; the extent to which this
occurs differs. To date, more than 900 clinical trial participants with cystic
fibrosis ages 12 years and greater have been randomized to either VNZ/TEZ/D-IVA
or elexacaftor (ELX)/TEZ/ivacaftor (IVA) treatment in two large clinical
trials. More than 90 clinical trial participants with cystic fibrosis ages 6 to
11 years have received VNZ/TEZ/D-IVA in a clinical trial. In addition, VNZ has
been administered alone or in combination with TEZ/D-IVA or TEZ/IVA to
approximately 200 healthy volunteers.
The most common side effects occurring in 8% or more of these cystic fibrosis
trial participants are listed in the list below. For these listed side effects,
the percentages of people with cystic fibrosis in a large study who experienced
these side effects are shown.
• Cough, 18%
• Pulmonary exacerbation, 16%
• COVID-19 (coronavirus), 15%
• Rash, 12%
• Stomach ache, 12%
• Common cold, 11%
• Headache, 10%
• Diarrhea, 8%
• Upper respiratory tract infection, 8%
Side effects from the combination of TEZ and ivacaftor (IVA) are listed below.
D-IVA is structurally similar to IVA, which means that it works similarly to
IVA. Thus, the side effects with TEZ/D-IVA are expected to be similar to those
with TEZ/IVA.
Possible Risks of IVA alone, and a combination of TEZ/IVA:
All drugs have the potential to cause side effects; the extent to which this
occurs differs. To date, more than 2500 participants have received at least 1
dose of IVA alone or TEZ/IVA in combination in clinical studies.
The most common side effects associated with IVA or TEZ/IVA in combination are
listed below. The percentages of people with cystic fibrosis who experienced
these side effects are listed below.
Very common side effects occurring in 10% or more of the group include:
• Headache, 24%
• Throat pain, 22%
• Upper respiratory tract infection, 22%
• Nasal congestion, 20%
• Stomach ache, 16%
• Common cold, 15%
• Diarrhea, 13%
• Rash, 13%
Common side effects occurring in 1% or more to less than 10% of the group
include:
• Dizziness (9%)
• Nausea (8%)
• Bacteria in sputum (which may indicate an infection in your respiratory
tract)(7%)
• Sinus congestion (stuffy nose/sinuses) (7%)
• Nasal inflammation (7%)
• Throat redness (5%)
Leidsevaart 20
HA Haarlem 2013
NL
Leidsevaart 20
HA Haarlem 2013
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. Did not withdraw consent from a parent study.
4. Meets at least 1 of the following criteria:
• Completed study drug treatment in a parent study.
• Had study drug interruption(s) in a parent study, but did not permanently
discontinue study drug, and completed study visits up to the last scheduled
visit of the Treatment Period of a parent study.
5. Willing to remain on a stable CF treatment regimen (as defined in Section
9.5) through completion of study participation.
Exclusion criteria
1. New development of a comorbidity during the parent study that might
post an additional risk in administering study drug to the subject. This
includes, but is not limited to, the following:
- Hepatic cirrhosis with portal hypertension, moderate hepatic
impairment, or severe hepatic impairment, that might pose an additional
risk in administering study drug to the subject.
- Solid organ or hematological transplantation.
- Any other comorbidity that, in the opinion of the investigator, might
post an additional risk in administering study drug to the subject.
2. Pregnant or breast-feeding females. All female subjects must have a negative
pregnancy test at the Day 1 Visit before receiving the first dose of study drug.
3. History of drug intolerance in a 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 trial (other than a parent
study). Participation in a noninterventional study (including observational
studies, registry studies, and studies requiring blood collections without
administration of study drug) and screening for another Vertex study is
permitted.
5.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 |
|---|---|
| EU-CTR | CTIS2024-514173-22-00 |
| EudraCT | EUCTR2021-000713-17-NL |
| ClinicalTrials.gov | NCT05076149 |
| CCMO | NL82092.041.22 |