Primary Objective:To evaluate the efficacy of VX-445 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation (F/F)Secondary Objectives:* To evaluate the…
ID
Source
Brief title
Condition
- Congenital respiratory tract disorders
Synonym
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 at Week 4
Secondary outcome
Key Secondary Endpoints:
* Absolute change in sweat chloride (SwCl) from baseline at Week 4
* Absolute change in CF Questionnaire-Revised (CFQ-R) respiratory domain score
from baseline at Week 4
Other Secondary Endpoints
* Safety and tolerability assessments based on adverse events (AEs), clinical
laboratory values, ECGs, vital signs, and pulse oximetry
* PK parameters of VX-445, TEZ, M1-TEZ, and IVA
Background summary
Cystic fibrosis (CF) is an autosomal recessive chronic disease with serious
morbidities and frequent premature mortality. At present, there is no cure. CF
affects approximately 70,000 individuals worldwide (approximately 30,000 in the
US and 39,000 in the EU). Based on its prevalence, CF qualifies as an orphan
disease.
CF is caused by decreased quantity and/or function of the Cystic Fibrosis
Transmembrane Conductance Regulator (CFTR) protein due to mutations in the CFTR
gene. The CFTR protein is an epithelial chloride channel that aids in
regulating salt and water absorption and secretion and pH balance in sweat
glands and multiple organs, including the lungs, pancreas, and other
gastrointestinal organs. Despite progress in the treatment of CF with
antibiotics and mucolytics, the predicted median age of survival for a person
with CF is approximately 40 years. Progressive loss of lung function is the
leading cause of mortality. More effective treatments are needed for CF.
The most common disease-causing CFTR mutation, F508del, accounts for 70% of the
identified alleles in people with CF, and approximately 40% of people with CF
are homozygous for F508del (F/F).
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 functional CFTR at the cell surface. Potentiators increase the
channel open probability of the CFTR protein delivered to the cell surface to
enhance ion transport. Depending on the amount of residual CFTR channel
activity in the membrane, and the pathophysiology of that activity (reflecting
the CFTR genotype of the patient and possibly other factors), both approaches
may be required.
The therapeutic activity of CFTR correctors and potentiators has been
established with products that were developed by Vertex and approved for the
treatment of CF: ivacaftor (IVA) monotherapy (Kalydeco®), and lumacaftor (LUM)
in combination with IVA (Orkambi®). Kalydeco® and Orkambi® are approved to
treat CF in patients with specific CFTR genotypes. A second
corrector/potentiator combination, tezacaftor (TEZ)/IVA (Symdeko®) is now
approved in the US. An MAA has been submitted and is under review.
VX-445 is a next-generation CFTR corrector being developed for administration
in triple combination (TC) with TEZ/IVA for the treatment of CF.
The purpose of this study is to evaluate the efficacy and safety of VX-445 in
TC with TEZ/IVA in subjects with CF who are homozygous for F508del (F) mutation
(F/F). Patients with this genotype (F/F) usually have severe disease and lack
approved CFTR modulator therapy. Due to this high unmet need, VX-445 is being
developed in TC with TEZ/IVA for F/F subjects. The potential for benefit in
these patients is supported by in vitro data and clinical data in F/F subjects;
in addition, the TC of VX 445/TEZ/IVA is generally safe and well tolerated.
(please refer to VX-445 Investigators Brochure, v3.0 date 20 April 2018).
Study objective
Primary Objective:
To evaluate the efficacy of VX-445 in triple combination (TC) with tezacaftor
(TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are
homozygous for the F508del mutation (F/F)
Secondary Objectives:
* To evaluate the safety of VX-445 in TC with TEZ and IVA
* To evaluate the pharmacodynamics (PD) of VX-445 in TC with TEZ and IVA
* To evaluate the pharmacokinetics (PK) of VX-445, TEZ, and IVA when
administered in TC
Study design
This is a Phase 3, randomized, double-blind, active-controlled, parallel-group,
multicenter study.
The total study duration is approximately 16 weeks (4 weeks for the Screening
Period, 4 weeks for the TEZ/IVA Run-in Period, 4 weeks for the Treatment
Period, and 4 weeks for the Safety Follow-up Period).
Intervention
During the TEZ/IVA Run-in Period, study drug refers to TEZ/IVA and IVA.
During the Treatment Period, study drug refers to VX-445/TEZ/IVA and matching
placebo, TEZ/IVA and matching placebo, and IVA.
Active study drugs will be orally administered as fixed-dose combination (FDC)
film-coated tablets (2 VX-445/TEZ/IVA tablets or 1 TEZ/IVA tablet) in the
morning and as 1 film-coated IVA tablet in the evening.
Active substance: VX-445, TEZ (tezacaftor; VX-661), and IVA (ivacaftor, VX-770)
Activity: CFTR corrector, CFTR corrector, and CFTR potentiator (increased Cl*
secretion)
Strength: 100-mg VX-445/50-mg TEZ/75-mg IVA FDC tablet
Active substance: TEZ (tezacaftor; VX-661) and IVA (ivacaftor; VX-770)
Activity: CFTR corrector and CFTR potentiator (increased Cl* secretion)
Strength: 100-mg TEZ/150-mg IVA FDC tablet
Active substance: IVA (ivacaftor; VX-770)
Activity: CFTR potentiator (increased Cl* secretion)
Strength: 150-mg tablet
Study burden and risks
Risks Associated with VX-445:
All drugs have the potential to cause side effects; the extent to which this
occurs differs. VX-445/TEZ/IVA triple combination has been administered to
subjects with cystic fibrosis. The most common complaints were cough and
increase in sputum; some subjects had a rash. In a study in healthy women, rash
occurred in approximately 4 of the 15 subjects who took birth control pills and
VX-445/TEZ/IVA together. The rashes were not serious and resolved after
treatment was completed or stopped.
VX-445 has been studied in animals. VX-445 was generally well tolerated when
given to dogs and rats for 28 days. Side effects in some animals included:
decreased body weight, decreased blood pressure, damage to the lining of the
stomach, decreased numbers of young red blood cells which may cause anemia,
damage to the testes and sperm, damage to the ovaries and ovarian follicles.
Each of these side effects were only seen at drug levels much higher (2 times
or higher) than expected in current study.
Possible Risks of ivacaftor alone, and a combination of tezacaftor/ivacaftor:
To date, more than 2000 participants have received at least 1 dose of IVA alone
or TEZ/IVA in combination.
The side effects associated with IVA alone or TEZ/IVA in combination are listed
below:
Very common side effects occurring in *10% include:
* Headache;
* Throat pain
* Upper respiratory tract infection
* Nasal congestion
* Abdominal pain
* Common cold
* Diarrhea
* Rash
Common side effects occurring in *1 to <10% include:
* Dizziness
* Nausea
* Bacteria in sputum
* Sinus congestion
* Runny nose
* Throat redness
High liver enzymes (called as ALT or AST) in the blood have been observed in
some participants treated with IVA or TEZ/IVA combination. The very high levels
of these tests could lead to stopping of Study Drug, and these abnormal blood
tests may get better after Study Drug is stopped. In some severe cases, high
liver enzymes may be shown as a sign of liver injury and can become permanent
and even be life-threatening. 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.
Abnormality of the eye lens (cataract) has been noted in some children and
adolescents treated with IVA or TEZ/IVA combination. A link between IVA or
TEZ/IVA combination and cataracts is uncertain but cannot be excluded.
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.
Unknown Risks:
There may be side effects that are not yet known.
Study Procedure Risks:
Blood sample collection: risk of having a bruise (blue mark) or pain where we
take the blood samples. Some people get dizzy or faint from a blood draw. Risk
of an infection (rare), or having bleeding, redness, or bruising at the skin
puncture.
ECG: The sticky pads used for this test may cause skin irritation. Taking the
sticky pads off causes discomfort similar to when taking off a band-aid.
Spirometry: You may feel the need to cough or you may feel short of breath
during or after the test.
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
Utrecht 9728NZ
NL
Van Swietenlaan 6
Utrecht 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, on the date of informed consent.
4. Confirmed diagnosis of CF as determined by the investigator.
5. Subject has the F/F genotype. Note: If the screening CFTR genotype result is not received before Day -28, a previous CFTR genotype laboratory report may be used to establish eligibility. Subjects who have been enrolled and whose screening genotype is not confirmed to be F/F must be discontinued from the study (Section 9.9).
6. Forced expiratory volume in 1 second (FEV1) value *40% and *90% of predicted mean for age, sex, and height (equations of the Global Lung Function Initiative [GLI])9 at the Screening Visit. Spirometry measurements must meet American Thoracic Society/European Respiratory Society criteria10 for acceptability and repeatability.
7. Stable CF disease as judged by the investigator.
8. Willing to remain on a stable CF treatment regimen (as defined in Section 9.5) 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 (all 3 with no recurrence for the last 5 years).
2. Any of the following abnormal laboratory values at screening:
* Hemoglobin <10 g/dL
* Total bilirubin *2 × ULN
* Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) *3 × 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)11, 12 for subjects *18 years of age and *45 mL/min/1.73 m2 (calculated by the Counahan-Barratt equation)13 for subjects aged 12 to 17 years (inclusive)
3. An acute upper or lower respiratory infection, pulmonary exacerbation(s) (PEx), or changes in therapy (including antibiotics) for sinopulmonary disease within 28 days before the first dose of TEZ/IVA in the Run-in Period (Day -28).
4. Lung infection with organisms 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 a 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 TEZ/IVA 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 Table 9-2, within the specified window before the first dose of TEZ/IVA in the Run-in Period (Day -28).
8. Pregnant or nursing females. Females of childbearing potential must have a negative pregnancy test at Screening/Day -56 (serum test) and TEZ/IVA Run-in Period/Day -28 (urine test).
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 | EUCTR2018-000184-89-NL |
| CCMO | NL66316.041.18 |