Primary ObjectivesParts 1 (Subjects with F/MF genotypes) and 2 (Optional; Subjects with the F/F genotype)* To evaluate the safety and tolerability of VX 121 in TC with TEZ/VX 561 (deuterated IVA) * To evaluate the efficacy of VX 121 in TC with TEZ/…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Cystic fibrosis
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoints
* Safety and tolerability, based on the assessment of adverse events (AEs),
laboratory test results, standard 12-lead ECGs, vital signs, and spirometry
* Absolute change in percent predicted forced expiratory volume in 1 second
(ppFEV1) from baseline through Day 29
Secondary outcome
Secondary Endpoints
* Absolute change in sweat chloride concentrations from baseline through Day 29
* Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ R) respiratory
domain score from baseline at Day 29
* PK parameters of VX 121, TEZ, VX 561, IVA (Part 3), and relevant metabolites
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 70,000 people worldwide (around 32,000 in the EU). Based on its
prevalence, CF qualifies as an orphan disease.
CF is caused by reduced quantity and/or function of the 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 (GI) 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.4,5 Progressive loss of lung function is the
leading cause of mortality. More effective treatments are needed for CF.
CFTR modulator therapies have been developed to restore CFTR function. The
modulator combination of VX-121, TEZ, and VX-561 has been tested in cells from
CF patients and shown to be highly effective. This trial will test if
individuals with CF with a single copy of F508del, and a second mutation (a
minimal function mutation) derive clinical benefit from VX121/TEZ/VX-561. This
patient population has no approved CFTR modulator therapies.
VX 561 (formerly known as CTP 656) is a deuterated isotope of IVA with a
specific pattern of 9 substituted deuteriums. In vitro data indicate similar
potency of VX 561 in human bronchial epithelial (HBE) cells relative to IVA.
Safety pharmacology and nonclinical toxicology studies of VX 561 demonstrate a
similar safety profile relative to IVA.
Phase 1 clinical studies in healthy subjects have shown that VX 561 had a
reduced rate of clearance, increased exposure, greater plasma levels at 24
hours, and a longer half-life compared to IVA, thereby supporting once daily
dosing (refer to VX-561 Investigator*s Brochure).
VX 121 is a next generation CFTR corrector. In vitro, VX 121 also improves the
processing and trafficking of mutated CFTR, 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 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 combination of VX 121 and
either TEZ or IVA under most conditions studied (refer to VX-121 Investigator*s
Brochure).
This is the second clinical study of VX 121 and Part 1 is designed to evaluate
the safety and efficacy of VX 121 in TC with TEZ/VX 561 in subjects with CF who
are heterozygous for F508del and a MF CFTR mutation (F/MF genotypes).
Conducting the study in subjects with these genotypes investigates the effect
of treating 1 responsive allele (F508del). Additionally, the safety and
efficacy of VX 121 in TC with TEZ/VX 561 will be evaluated in subjects with CF
who are homozygous for F508del (F/F genotype) in Part 2, or in TC with TEZ/IVA
in subjects with CF with F/MF genotypes in Part 3, if the sponsor chooses to
conduct these optional parts of the study based on overall development goals
for the program and results from other studies.
Study objective
Primary Objectives
Parts 1 (Subjects with F/MF genotypes) and 2 (Optional; Subjects with the F/F
genotype)
* To evaluate the safety and tolerability of VX 121 in TC with TEZ/VX 561
(deuterated IVA)
* To evaluate the efficacy of VX 121 in TC with TEZ/VX 561
Part 3 (Optional; Subjects with the F/MF genotypes)
* To evaluate the safety and tolerability of VX 121 in TC with TEZ/IVA
* To evaluate the efficacy of VX 121 in TC with TEZ/IVA
Secondary Objectives
Parts 1 and 2
* To evaluate the pharmacodynamic (PD) effect of VX 121 in TC with TEZ/VX 561
* To evaluate the pharmacokinetics (PK) of VX 121 when administered in TC with
TEZ/VX 561
* To evaluate the PK of TEZ, VX 561, and their respective metabolites when
administered in TC with VX 121
Part 3
* To evaluate the PD effect of VX 121 in TC with TEZ/IVA
* To evaluate the PK of VX 121 when administered in TC with TEZ/IVA
* To evaluate the PK of TEZ, IVA, and their respective metabolites when
administered in TC with VX 121
Study design
This is a Phase 2, 3 part, proof of concept study of VX 121. Study parts may be
conducted in parallel or sequentially.
Part 1: Subjects with F/MF genotypes - has a randomized, double blind, placebo
controlled, parallel group design and evaluates VX 121 in TC with TEZ/VX
561.The Washout Period (18 ± 3 days) is included to enable a more thorough
evaluation of VX 121 exposure response relationships by conducting PK and PD
assessments during the VX 121 washout.
Planned Doses
* TC-5 mg is optional. The planned VX-121 doses of 5 mg, 10 mg, and 20 mg qd
may be adjusted based on emerging data from subjects with CF in Part D of Study
VX17 121 001 (Study 001). However, no more than 3 dose levels of VX 121 will be
evaluated, and the highest dose will not exceed 20 mg qd.
* The dosage of TEZ and VX 561 will be TEZ 100 mg daily (qd) and VX 561 150 mg
qd.
Part 2 (Optional): Subjects with F/F genotype - has a randomized, double blind,
TEZ/IVA controlled, parallel group design and evaluates VX 121 in TC with
TEZ/VX 561. Part 2 is an optional part of the study, which will be conducted at
the sponsor*s discretion.
All subjects are required to complete the TEZ/IVA Run in Period to establish a
reliable on treatment (TEZ/IVA) baseline. The 4 week Washout Period is included
to evaluate the effect on PD and efficacy endpoints as subjects step down from
TC to TEZ/IVA, after the VX 121 washout.
Planned Doses
* Part 2 will evaluate the same VX-121 dose (20 mg qd) used in Part 1. This
dose may be adjusted downward based on emerging data from Part D of Study 001.
* The dosage of TEZ and VX 561 will be TEZ 100 mg qd and VX 561 150 mg qd.
* The dosage of TEZ/IVA will be TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h).
Part 3 (Optional): Subjects with F/MF genotypes - has a randomized, double
blind, placebo controlled, parallel group design and evaluates VX 121 in TC
with TEZ/IVA. Part 3 is an optional part of the study, which will be conducted
at the sponsor*s discretion.
The Washout Period (18 ± 3 days) is included to enable a more thorough
evaluation of VX 121 exposure response relationships by conducting PK and PD
assessments during the VX 121 washout.
Planned Doses
* Part 3 will evaluate the same VX-121 dose (20 mg qd) used in Part 1. This
dose may be adjusted downward based on emerging data from Part D of Study 001.
* The dosage of TEZ/IVA will be TEZ 100 mg qd/IVA 150 mg q12h.
The Screening Period will occur within 28 days before the first dose of study
drug. The site investigator (or designee) will confirm and document study
eligibility before randomization. Screening assessments may be repeated once to
establish study eligibility. If repeat values of the individual assessment(s)
are within the eligibility criteria and completed within the screening window,
then the subject is eligible for the study.
Part 2 has a Run-In period beore the Treatment Period. The TEZ/IVA Run in
Period of Part 2 is 4 weeks. Subjects will be evaluated as outpatients.
The Treatment Period will last approximately 4 weeks. Subjects will be
evaluated as outpatients.
Subjects in Part 2 must meet both of the following conditions to qualify to
continue into the Treatment Period:
* Must have stable CF disease (as judged by the investigator) and have remained
on a stable CF medication regimen during the 28 days before the Day 1 Visit.
(For example, subjects cannot have an acute upper or lower respiratory
infection, pulmonary exacerbation, or changes in therapy [including
antibiotics] for pulmonary disease within 28 days before the first dose of
study drug in the Treatment Period.)
* Must not have had an acute non-CF illness (e.g., gastroenteritis) within the
14 days before the first dose of study drug in the Treatment Period.
If these conditions are not met, subjects in Part 2 may not be randomized and
enter into the Treatment Period.
Randomization will occur before the first dose of study drug during the
Treatment Period and will occur on the Day 1 Visit (or Day -1) after
eligibility has been confirmed (Parts 1 and 3) or conditions for entry into the
Treatment Period have been confirmed (Part 2).
The Washout Periods will last approximately 18 days (Parts 1 and 3) and 4 weeks
(Part 2).
Subjects will have a Safety Follow up Visit approximately 28 days after the
last study drug dose.
The Safety Follow up is not required for subjects in Part 2 who continue onto a
commercially available, physician prescribed CFTR modulator within 28 days of
completing the Day 57 Visit.
If the subject prematurely discontinues study treatment, an Early Termination
of Treatment (ETT) Visit should be scheduled as soon as possible after the
subject decides to terminate study drug. Subjects who prematurely discontinue
study treatment will also be required to complete the Safety Follow up Visit,
approximately 28 days after their last dose of study drug.
Intervention
Active substance: VX-121
Activity: CFTR corrector (increased Cl* secretion)
Strength and route of administration: 5-mg tablet for oral administration
Active substance: TEZ (VX 661)
Activity: CFTR corrector (increased Cl* secretion)
Strength and route of administration: 50-mg TEZ tablet for oral administration
Active substance: VX-561
Activity: CFTR potentiator (increased Cl* secretion)
Strength and route of administration: 50-mg VX 561 tablet for oral
administration
Active substance: TEZ (VX 661) and IVA (VX 770)
Activity: CFTR corrector and potentiator (increased Cl* secretion)
Strength and route of administration: 100-mg TEZ/150-mg IVA, film coated fixed
dose combination (FDC) tablet for oral administration
Active substance: IVA (VX 770)
Activity: CFTR potentiator (increased Cl* secretion)
Strength and route of administration: 150 mg film-coated tablet for oral
administration
Study burden and risks
All drugs have the potential to cause side effects the extent to which this
occurs differs. Subjects will be monitored for possible side effects during the
study. Possible risks and discomforts are described here, however, there may be
other risks and side effects that are not yet known.
To date, VX-121 alone or VX-121/tezacaftor/ivacaftor triple combination has
been administered to approximately 75 healthy volunteers. The most common
complaints reported were abdominal complaints (gas, nausea, diarrhea,
heartburn) headache, upper respiratory complaints (nasopharyngitis, cough),
dizziness, rash, back pain, fatigue, and the sensation of hair loss. Some of
the subjects stopped taking the study drug as a result of the rash. The rashes
resolved after stopping study drug.
VX-121 has been studied in animals. There were no adverse events noticed.
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 (24%)
* Throat pain (22%)
* Upper respiratory tract infection (22%)
* Nasal congestion (20%)
* Abdominal pain (16%)
* Common cold (15%)
* Diarrhea (13%)
* Rash (13%)
Common side effects, which occurred in *1% to <10%, included:
* Dizziness (9%)
* Nausea (8%)
* Bacteria in sputum (7%)
* Sinus congestion (7%)
* Runny nose (7%)
* Throat redness (5%)
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. While a link between IVA or TEZ/IVA combination
and liver enzyme increase has not been established, blood will be drawn to
check for liver function during the study.
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.
Risks Associated with VX-561:
VX-561 has been studied in animals and a small number of healthy volunteers and
subjects with CF. Based upon these studies, the risks of VX-561 are expected to
be similar to the risks of ivacaftor.
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.There are certain herbal medications such as St. John*s Wort,
and certain fruits and fruit juices (such as grapefruit juice or products made
from it) that subjects must not take during study.
Study Procedure Risks:
Blood sample collection: maybe bruises or pain may appear when blood samples
are taken. Some people get dizzy or faint from a blood draw. In rare cases, an
infection may occur, or bleeding from 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 plaster.
Spirometry: Subjects may feel the need to cough or 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.
There may or may not be a direct benefit for subjects as a result of taking
part in the study. However, what is learned in this study may help in the
treatment of CF or other diseases in the future, and may advance scientific
knowledge.
Van Swietenlaan 6
Groningen 9728NZ
NL
Van Swietenlaan 6
Groningen 9728NZ
NL
Listed location countries
Age
Inclusion criteria
1. Subject will sign and date an informed consent form (ICF).;2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.;3. Subjects (male and female) aged 18 years or older on the date of informed consent.;4. Female subjects must have a negative serum pregnancy test at the Screening Visit.;5. Body weight *35 kg.;6. Subjects must be able to produce a valid (quantity-sufficient) sweat sample at screening. If the initial screening collection results in insufficient sweat volume, then the sweat chloride collection may be repeated once.;Subjects must have a sweat chloride value *60 mmol/L at screening or documented in the form of a laboratory report in the subject*s medical record.;7. Confirmed diagnosis of CF as determined by the investigator.;8. Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR genotype result is not received before the Run-in Period (Part 2) or randomization (Parts 1 and 3), a previous CFTR genotype laboratory report may be used to establisheligibility. Subjects who have been enrolled and whose screening genotype does not confirm study eligibility must be discontinued from the study ;* Parts 1 and 3: Heterozygous for F508del with a second CFTR allele carrying a mutation that does not produce a protein, or produces a protein that is not responsive to TEZ, IVA, or TEZ/IVA therapy;* Part 2: Homozygous for F508del;9. Subjects must have a forced expiratory volume in 1 second (FEV1) *40% and *90% of predicted normal 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.;10. Stable CF disease as judged by the investigator.;11. Willing to remain on a stable CF treatment regimen (other than protocol-specified changes in CFTR modulator regimen) through the Safety Follow-up Visit.
Exclusion criteria
1. History of any comorbidity 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. History of clinically significant cirrhosis with or without portal hypertension.;3. Risk factors for Torsade de Pointes and other ventricular arrhythmias, including but not limited to, history of any of the following: familial long QT syndrome, chronic hypokalemia, heart failure, left ventricular hypertrophy, chronic bradycardia, myocardial infarction, cardiomyopathy, history of arrhythmia (ventricular or atrial fibrillation), obesity, acute neurologic events (subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular accident, or intracranial trauma), or autonomic neuropathy.;4. 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), 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)10,11 for subjects *18 years of age;5. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for sinopulmonary disease within 28 days before the first dose of TEZ/IVA in the Run-in Period (Part 2) or the first dose of study drug in the Treatment Period (Parts 1 and 3).;6. Lung infection with organisms associated with a more rapid decline in pulmonary status (e.g., 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 1 within the 6 months before the date of informed consent.;7. 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 (Part 2) or the first dose of study drug in the Treatment Period (Parts 1 and 3).;8. Standard 12-lead ECG demonstrating QTcF >450 msec at screening. If QTcF exceeds 450 msec, the ECG will be repeated 2 more times, and the average of the 3 QTcF values will be used to determine the subject*s eligibility.;9. History of solid organ or hematological transplantation.;10. History of alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator.;11. Ongoing or prior participation in a study of an investigational treatment with the exception of the following:;* Ongoing or prior participation in an investigational study of a Vertex CFTR modulator. A washout period of 28 days must elapse before Day 1.;* For prospective subjects with ongoing or prior participation in all other interventional studies, a washout period of 28 days or 5 terminal half-lives (whichever is longer) must elapse before screening. The duration of the elapsed time may be longer if required by local regulations.;* Ongoing participation in a noninterventional study (including observational studies and studies requiring assessments without administration of study drug or assignment to other interventions) is permitted.;12. Use of prohibited medications (as defined in Table 9-1 in the Protocol), within the specified window before the first dose of TEZ/IVA in the Run-in Period (Part 2) or the first dose of study drug in the Treatment Period (Parts 1 and 3).;13. 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.;14. Pregnant or nursing female subjects.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-002496-18-NL |
| CCMO | NL68303.091.19 |
| Other | tbd |