To evaluate the efficacy and pharmacodynamics (PD) of ELX/TEZ/IVA
ID
Source
Brief title
Condition
- Respiratory disorders congenital
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 Week 24
Secondary outcome
• Absolute change from baseline in sweat chloride (SwCl) through Week 24
• Absolute change from baseline in Cystic Fibrosis Questionnaire - Revised
(CFQ-R) respiratory domain (RD) score through Week 24
• Absolute change from baseline in body mass index (BMI) at Week 24
• Absolute change from baseline in weight at Week 24
• Number of pulmonary exacerbations (PEx) through Week 24
• Safety and tolerability assessments based on adverse events (AEs), clinical
laboratory values, ECGs, vital signs, and pulse oximetry
Background summary
Cystic fibrosis (CF) is a rare autosomal recessive disease with serious,
chronically debilitating morbidities and high premature mortality for which
there is currently no cure. CF affects more than 80,000 individuals worldwide,
including more than 49,000 individuals in the EU.
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.
Progressive loss of lung function is the leading cause of mortality.
The most common disease-causing mutation is F508del: approximately 85% of
individuals in the US and 80% of individuals in Europe2 have at least one
F508del mutation. In the EU, patients with one F508del mutation are eligible
for treatment with the CFTR modulator ELX/TEZ/IVA (Kaftrio*/Trikafta*). The
ELX/TEZ/IVA regimen is the first medicine to demonstrate clinical benefit in
patients with a single F508del mutation, regardless of the mutation on the
second allele. The Phase 3 program in CF subjects 6 years of age and older
demonstrated that treatment with ELX/TEZ/IVA results in substantial
improvements in lung function, CFTR function, and nutritional status in this
population, and was generally safe and well tolerated with a low rate of
treatment discontinuation.
The ELX/TEZ/IVA pivotal Phase 3 program demonstrated efficacy in subjects who
have at least one F508del mutation. However, more than 160 additional CFTR
mutations have been shown to be responsive to ELX/TEZ/IVA in vitro. CF patients
with these mutations do not currently have an indicated CFTR modulator
treatment in the EU, nonetheless they are expected to derive clinical benefit
from ELX/TEZ/IVA based on (1) current understanding of the biology of the CFTR
mutations (2) the known mechanism by which CFTR modulators act on defective
CFTR proteins that contain these mutations (3) in vitro evidence indicating
responsiveness of these proteins to ELX/TEZ/IVA and (4) the established
relationship between in vitro responsiveness and clinical benefit.
Study objective
To evaluate the efficacy and pharmacodynamics (PD) of ELX/TEZ/IVA
Study design
This is a Phase 3, randomized, placebo-controlled, double-blind, parallel group
study. Subjects 6 years of age and older with an eligible non-F508del
ELX/TEZ/IVA-responsive CFTR mutation and no exclusionary mutations may be
eligible for enrollment. Eligible ELX/TEZ/IVA-responsive mutations include
minimal function (MF)-like and residual function (RF)-like mutations. MF-like
mutations are either (1) predicted to result in no functional CFTR protein or
(2) are not responsive to IVA or TEZ/IVA. RF-like mutations result in residual
CFTR function. Exclusionary mutations are already indicated for CFTR modulator
treatment.
Subjects will be randomized 2:1 (ELX/TEZ/IVA group: placebo group).
Randomization will be stratified based on ppFEV1 determined during the
Screening Period (<70 versus >=70), age at the Screening Visit (<18 years old
versus >=18 years old) and CFTR mutation group (RF-like mutation versus no
RF-like mutation).
Intervention
Active substance: ELX (VX-445)/TEZ (VX-661)/IVA (VX-770)
Activity: ELX and TEZ are CFTR correctors; IVA is a CFTR potentiator
Strength and route of administration: ELX/TEZ/IVA fixed-dose combination (FDC)
tablets for oral administration at the following strengths:
• ELX 100 mg/TEZ 50 mg/IVA 75 mg
• ELX 50 mg/TEZ 25 mg/IVA 37.5 mg
Active substance: IVA (VX-770)
Activity: CFTR potentiator
Strength and route of administration: IVA tablets for oral administration at
the following strengths:
• IVA 150 mg
• IVA 75 mg
Study burden and risks
Risks associated with Elexacaftor (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 liver enzymes 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 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 the participant. 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 the participant must not take during the study.
Van Swietenlaan 6
Groningen 9728 NZ
NL
Van Swietenlaan 6
Groningen 9728 NZ
NL
Listed location countries
Age
Inclusion criteria
1. Subject (or the subject's 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 (as applicable), and
other study procedures.
. For subjects < 18 years of age: as judged by the investigator, parent or
legal guardian must be able to understand protocol requirements, restrictions,
and instructions and the parent or legal guardian should be able to ensure that
the subject will comply with and is likely to complete the study as planned.
3. Subjects (male or female) 6 years of age and older on the date of informed
consent.
4. Subjects has an eligible ELX/TEZ/IVA-responsive CFTR mutation listed in
Table 15-1 and none of the exclusionary mutations in Table 15-2.
5. Subject has stable CF disease, as deemed by the investigator, before
randomization.
a. Forced expiratory volume in 1 second (FEV1) value >=40% and <=100% of
predicted mean for age, sex, 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).
6. Subject is able to swallow tablets.
Exclusion criteria
1. History of any illness or any clinical condition that might confound the
results of the study or pose an additional risk in administering study drug(s)
to the subject. This may include, but is not limited to:
• History of allergy, intolerance, or hypersensitivity to any component of the
investigational drug product (ELX/TEZ/IVA tablets and IVA tablets) or placebo,
including excipients
• Clinically significant liver 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 (all 3 with no recurrence for the last 5 years).
2. Any clinically significant laboratory abnormalities at the Screening Visit
that would interfere with the study assessments or pose an undue risk for the
subject (as deemed by the investigator).
3. Any of the following abnormal laboratory values at screening:
. Hemoglobin <10 g/dL
. Total bilirubin >=2 × upper limit of normal (ULN)
. AST, ALT, gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) >= 3
x ULN
. Abnormal renal function defined as glomerular filtration rate <=50 mL/min/1.73
m2 (calculated by the Modification of Diet in Renal Disease Study Equation) for
subjects >=18 years of age and <=45 mL/min/1.73 m2 (calculated by the
Counahan-Barratt equation) for subjects < 18 years of age.
4. An acute upper or lower respiratory infection, pulmonary exacerbation, or
changes in therapy (including antibiotics) for sinopulmonary disease within 28
days before Day 1 (first dose of study drug).
5. Lung infection with organisms associated with a more rapid decline in
pulmonary status (including, but not limited to, Burkholderia cenocepacia,
Burkholderia dolosa, and Mycobaterium 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 a respiratory tract culture positive for these
organisms within the 12 months before the date of informed consent, and
. 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.
6. An acute illness not related to CF (e.g., gastroenteritis) within 14 days
before the first dose of study drug (Day 1).
7. Ongoing or prior participation in an investigational drug study within 28
days of the Screening Visit.
. A washout period of 5 terminal half-lives of the previous investigational
study drug, or 28 days, whichever is longer, must elapse before the Screening
Visit.
. The duration of the elapsed time may be longer if required by local
regulations.
8. Pregnant and breast-feeding females. Female subjects of childbearing
potential (Section 11.5.6.1) must have a negative pregnancy test at the
Screening Visit and the Day 1 Visit.
9. Use of restricted medication within specified duration before the first dose
of study drug as defined in Table 9-3.
10. Subject, or 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 | EUCTR2021-005320-38-NL |
| CCMO | NL79770.041.22 |