Parts D and E: Primary Objectives:• To evaluate the safety and tolerability of VX-445 in TC with TEZ and IVA in subjects with cystic fibrosis (CF)• To evaluate the efficacy of VX-445 in TC with TEZ and IVA in subjects with CFSecondary Objectives• To…
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Parts D and E:
• Safety and tolerability assessments of AEs, clinical laboratory values,
standard 12-lead ECGs, vital signs, pulse oximetry and spirometry
• Absolute change in percent predicted forced expiratory volume in 1 second
(ppFEV1) from baseline through Day 29
Part F (optional)
* To evaluate the safety and tolerability of VX-445 in TC with TEZ and VX-561
(deuterated IVA, also known as CTP-656) in subjects with CF
* To evaluate the efficacy of VX-445 in TC with TEZ and VX-561 in subjects with
CF
Secondary outcome
Parts D and E
• Absolute change in sweat chloride concentrations from baseline through Day 29
• Relative change in ppFEV1 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-445, TEZ, M1-TEZ, IVA, and M1-IVA
Part F (Optional):
* To evaluate the PD effect of VX-445 in TC with TEZ and VX-561 on CFTR
function in subjects with CF
* To evaluate the PK of VX-445 when administered in TC with TEZ and VX-561 in
subjects with CF
* To evaluate the PK of TEZ and metabolite (M1-TEZ), and VX-561 when
administered in TC with VX-445 in subjects with CF
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 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 (CF transmembrane
conductance regulator) 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.
More than 2000 mutations of the CFTR gene have been identified. Most of these
mutations are not associated with CF disease or are very rare. Currently, the
CFTR2 database contains information on only 322 of these identified mutations,
with sufficient evidence to define
281 mutations as disease-causing. The most common disease-causing CFTR mutation,
F508del-CFTR, accounts for 70% of the identified alleles in patients with CF,
with nearly half of
all people with CF are homozygous for F508del.
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 to ameliorate lung disease in patients with CF.
The therapeutic activity of CFTR correctors and potentiators has been
established with products that were developed by Vertex Pharmaceuticals
Incorporated (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. Tezacaftor (TEZ; VX-661), like LUM, is a
first-generation CFTR corrector that improves the processing and trafficking of
the F508del-CFTR protein, resulting in an increase in the quantity of
F508del-CFTR protein at the cell surface. IVA increases the
open-channel probability of the F508del-CFTR protein that has been delivered to
the cell surface by TEZ, thereby enhancing total chloride transport. The
combined effect of TEZ and IVA is
increased quantity and function of F508del-CFTR at the cell surface.
VX-445 is a next-generation CFTR corrector. In vitro, VX-445 improves the
processing and trafficking of F508del-CFTR, thereby increasing the quantity of
functional F508del-CFTR protein at the cell surface. The effect of VX-445 was
additive to the effect of TEZ. The CFTR protein delivered to the cell surface
by VX-445 alone or in combination with TEZ (VX-445/TEZ) was potentiated by IVA.
In human bronchial epithelial (HBE) cells studied 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 (VX-445, TEZ,
and IVA) regimens.
Study objective
Parts D and E: Primary Objectives:
• To evaluate the safety and tolerability of VX-445 in TC with TEZ and IVA in
subjects with cystic fibrosis (CF)
• To evaluate the efficacy of VX-445 in TC with TEZ and IVA in subjects with CF
Secondary Objectives
• To evaluate the pharmacodynamic (PD) effect of VX-445 in TC with TEZ and IVA
on CFTR function in subjects with CF
• To evaluate the PK of VX-445 when administered in TC with TEZ and IVA in
subjects with CF
• To evaluate the PK of TEZ, IVA, and their respective metabolites (M1-TEZ and
M1-IVA) when administered in TC with VX-445 in subjects with CF
Part F (Optional):
Primary Objectives:
* To evaluate the safety and tolerability of VX-445 in TC with TEZ and VX-561
(deuterated IVA, also known as CTP-656) in subjects with CF
* To evaluate the efficacy of VX-445 in TC with TEZ and VX-561 in subjects with
CF
Secondary Objectives
* To evaluate the PD effect of VX-445 in TC with TEZ and VX-561 on CFTR
function in subjects with CF
* To evaluate the PK of VX-445 when administered in TC with TEZ and VX-561 in
subjects with CF
* To evaluate the PK of TEZ and metabolite (M1-TEZ), and VX-561 when
administered in TC with VX-445 in subjects with CF
Study design
Parts D, E and F (Subjects with CF)
Part D, which is comprised of Parts D1 and D2, is randomized, double-blind,
placebo-controlled and evaluates VX-445 in TC with TEZ/IVA in subjects with CF
(F/MF genotypes).
Part E is randomized, double-blind, TEZ/IVA-controlled and evaluates VX-445 in
TC with TEZ/IVA in subjects with CF (F/F genotype).
Part F, an optional part of the study which will be conducted at the sponsor*s
discretion, is randomized, double-blind, placebo-controlled, and evaluates
VX-445 in TC with TEZ and VX-561 in subjects with CF (F/MF genotypes).
Part D may be initiated while Parts A, B, and C are ongoing after review of
safety, tolerability, and PK data. After all Part D1 subjects complete the Day
15 Visit, a blinded review of all available safety and PK data will be
conducted by the Vertex study team and lead investigator(s). Dosing in Parts
D2, E and F will start after this review, if supported by safety and PK data.
VX-445 will be dosed qd.
Part D1 has 1 VX 445 dose level (mid: 100 mg qd). Part D2 has 3 VX 445 dose
levels (low: 50 mg qd; mid: 100 mg qd; high: 200 mg qd). The highest : 200 mg
qd). The TC-high dose of VX 445 in Part D2 does not exceed the highest dose
that was safe and well tolerated in healthy subjects dosed with TC in Part C.
Part E will use the highest dose used in Part D2 (200 mg qd).
Randomization will be stratified by ppFEV1 in Parts D2 and E. Randomization
will not be stratified in Part D1 because of the small number of subjects in
that Part (N ~ 8).
Intervention
See section E4 of the ABR form.
Study burden and risks
Risks Associated with VX-445:
VX-445 will be administered to subjects with CF for the first time in this
study, so it is not known if VX-445 will cause side effects in subjects with CF.
VX-445 has been studied in a small number of healthy subjects without CF.
Review of the safety data has not indicated any major safety findings or
concerns.
VX-445 has been studied in animals. VX-445 was generally well tolerated when
given to dogs and rats for 28 days.
A compound similar to VX-445 caused hemolysis (bursting of red blood cells that
can lead to anemia and brown urine) in a human study. This appears to be due to
a genetic condition, glucose-6-phosphate dehydrogenase (G6PD) enzyme
deficiency. People with this condition may be at risk of hemolysis and kidney
damage if VX-445 is given to them. A blood test for G6PD deficiency will be
performed at screening, and the patient will not be allowed into the study if
he/she have G6PD deficiency.
VX-445 might cause skin damage similar to sunburn. People receiving VX-445 (or
placebo) should limit their exposure to sun and to ultraviolet light while
taking the study drug until 7 days after the last dose.
Possible Risks of tezacaftor alone, ivacaftor alone, and a combination of
tezacftor/ivacaftor
To date, more than 1000 participants with and without cystic fibrosis (CF) have
received 1 dose of tezacaftor either alone or taken with ivacaftor in completed
or ongoing clinical studies. No significant safety risks attributable to
tezacaftor monotherapy or to tezacaftor in combination with ivacaftor have been
identified in these clinical studies either in healthy participants or in CF
participants. Overall, tezacaftor alone or in combination with ivacaftor has
been well tolerated.
One healthy participant who received tezacaftor experienced a serious adverse
event of rhabdomyolysis (muscle injury), several weeks after their last dose of
tezacaftor. The event was considered unrelated to tezacaftor.
Overall, the most common adverse events in studies of CF participants who took
tezacaftor, ivacaftor, or tezacaftor in combination with ivacaftor, are listed
below:
Common adverse events occurring in 10% or more of CF subjects:
• Headache
• Upper respiratory tract infection (common cold)
• Oropharyngeal pain (sore throat)
• Nasal congestion (stuffy nose)
• Infective pulmonary exacerbation of CF (temporary worsening of lung
function due to an infection or inflammation)
• Cough
• Nasopharyngitis (inflammation of the nose and pharynx)
• Abdominal Pain
• Nausea
• Sputum increased
• Diarrhea
• Rash
• Fatigue
Less common adverse events occurring in 5% to 10% of CF subjects:
• Feeling faint
• Bacteria in sputum
• Runny nose
• Coughing up blood
• Vomiting
• An abnormal rattling sound heard when examining unhealthy lungs
• Sinus congestion
• Fever
In CF participants who received tezacaftor, ivacaftor, or tezacaftor and
ivacaftor, as well as placebo, a few participants have shown signs of liver
injury. In these cases, the liver injury was noticed as abnormalities in blood
tests, which are monitored as part of the study which led to stopping of Study
Drug and recovery of the abnormal blood tests. Very severe cases of liver
injury can become permanent and even be life-threatening. While the data do not
support an association between ivacaftor or tezacaftor and liver injury, a
possible link cannot be excluded.
Eye examinations performed in studies involving children receiving ivacaftor,
have identified several participants with cataracts (cloudiness of the lens of
the eye) present from birth, or which developed after birth. While the data do
not support a link between ivacaftor and cataracts, a possible link 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 to the patient. It is very important that the patient tell
his/her Study Doctor about every medicine, dietary supplement, natural remedy,
and vitamin (or change) while he/she is in the study.
There are certain herbal medications such as St. John*s Wort, and certain
fruits and fruit juices (such as grapefruit, Seville oranges, products made
from them) that the patient must not take during study. Study Doctor will
review these with the patient.
Reproductive Risks
The patient should not become pregnant or father a baby while on this study
because it is unknown whether the drugs in this study may adversely affect an
unborn baby. Women should not breastfeed a baby while in this study. It is
important the patient understands that he/she need to use birth control while
in this study. The patient should check with the study doctor about what kind
of birth control methods to use and how long to use them. Some methods might
not be approved for use in this study.
If the patient or his female partner become pregnant during the study the
patient should notify the study doctor right away. If the patient or his female
partner become pregnant, the patient will need to stop Study Drug immediately.
The study doctor will ask to follow the pregnancy to its outcome and until the
infant is one year of age.
Unknown Risks
There may be side effects that are not yet known. The patient should call the
Study Doctor if he/she thinks he/she is having any of the problems listed above
or even if the patient is having problems that are not on this list.
Northern Avenue 50
Boston MA 02210-1862
US
Northern Avenue 50
Boston MA 02210-1862
US
Listed location countries
Age
Inclusion criteria
Parts D and E;1. Subject will sign and date an ICF.
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
3. Subjects will be aged 18 years or older on the date of informed consent.
4. Body weight >=35 kg.
5. Subjects must be able to produce a valid (quantity-sufficient) sweat sample at screening, in addition to having a sweat chloride value >=60 mmol/L documented at screening or in a previous laboratory report. If the initial screening collection results in insufficient sweat volume, then the sweat chloride collection may be repeated once, after approval by the medical monitor. For the laboratory report requirement, it is acceptable to use a sweat chloride value that was obtained before previous treatment with IVA, LUM/IVA, or an investigational CFTR modulator, if applicable.
6. Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR genotype result is not received before randomization, a previous CFTR genotype laboratory report may be used to establish eligibility. Note: Subjects who have been randomized and whose screening genotype does not confirm study eligibility must be discontinued from the study (Section 9.9).
• Part D and F: Heterozygous for F508del with a second CFTR allele carrying a MF mutation that is not expected to respond to TEZ, IVA, and TEZ/IVA (Appendix A)
• Part E: Homozygous for F508del
7. Subjects must have an FEV1 >=40% and <=90% of predicted normal for age, sex, and height (equations of the Global Lung Function Initiative [GLI])12 at the Screening Visit. Spirometry measurements must meet American Thoracic Society/European Respiratory Society criteria13 for acceptability and repeatability.
8. Stable CF disease as judged by the investigator.
9. Willing to remain on a stable CF treatment regimen through the planned end of treatment or, if applicable, the Safety Follow-up Visit.
Exclusion criteria
Parts D and E
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, 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. History of hemolysis.
5. G6PD deficiency, defined as G6PD activity less than the LLN or 70% of the mean of the LLN and the ULN, whichever is greater.
6. 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 transpeptidase (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)14, 15
7. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for sino-pulmonary disease within 28 days before the first dose of study drug.
8. 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 in the past, the investigator will apply the following criteria to establish whether the subject is free of infection with such organisms:
• The subject has had 2 respiratory tract cultures negative for these organisms within the past 12 months, with no subsequent positive cultures.
• These 2 respiratory tract cultures were separated by at least 3 months, and 1 of them was obtained within the past 6 months.
9. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of study drug.
10. A standard digital ECG demonstrating QTc >450 msec at screening. If QTc exceeds 450 msec for the screening ECG, the ECG should be repeated 2 more times during the Screening Period, and the subject will be excluded if the average of the 3 QTc values is
>450 msec. As stated in Section 11.7.5.1, study sites should use QTcF unless they receive
approval in advance from the medical monitor to use QTcB.
11. History of solid organ or hematological transplantation.
12. History of alcohol or drug abuse in the past year, including but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator.
13. Ongoing or prior participation in a study of an investigational treatment other than a 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.
14. Use of prohibited medications as defined in Table 9-4, within the specified window before the first dose of study drug.
15. For female subjects: Pregnant or nursing females. Females of childbearing potential must have a negative pregnancy test at screening, Day -28 (Part E only), and Day 1.
For male subjects: Male subjects with a female partner who is pregnant, nursing, or planning to become pregnant during the study or within 90 days after the last study drug dose.
16. 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. An adult (aged 18 years or older) who is a relative of a study staff member may be randomized 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 | EUCTR2017-000797-11-NL |
| CCMO | NL61792.018.17 |