A Study of VX-445 in Healthy Subjects and Subjects with Cystic Fibrosis

• Register: EUCTR
• Last refreshed on: 7 January 2019
• Main ID: EUCTR2017-000797-11-BE
• Date of registration: 15/06/2017
• Prospective Registration: Yes
• Primary sponsor: Vertex Pharmaceuticals Incorporated
• Public title: A Study of VX-445 in Healthy Subjects and Subjects with Cystic Fibrosis
• Scientific title: A Phase 1/2 Study of VX-445 in Healthy Subjects and Subjects with Cystic Fibrosis
• Date of first enrolment: 28/08/2017
• Target sample size: 104
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-000797-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 12
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Netherlands, United States

Contacts

• Name: Clinical Trials and Medical Info
• Affiliation: Vertex Pharmaceuticals Incorporated

• Name: Clinical Trials and Medical Info
• Affiliation: Vertex Pharmaceuticals Incorporated

Key inclusion & exclusion criteria

Inclusion criteria:
Parts D, E and F
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 aprevious 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).
• Parts 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 104
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Parts D, E and F
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 fe

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Cystic fibrosis
MedDRA version: 20.0 Level: PT Classification code 10011762 Term: Cystic fibrosis System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Intervention(s)

Product Name: VX-445
Pharmaceutical Form: Tablet
INN or Proposed INN: VX-445
Current Sponsor code: VX-445
Other descriptive name: VX-445
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
INN or Proposed INN: VX-445
Current Sponsor code: VX-445
Other descriptive name: VX-445
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: tezacaftor/ivacaftor 100mg/150mg
Product Code: VX-661/VX-770
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: tezacaftor
Current Sponsor code: VX-661
Other descriptive name: VX-661
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
INN or Proposed INN: IVACAFTOR
CAS Number: 873054-44-5
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Kalydeco 150 mg film-coated tablets
Product Name: Ivacaftor
Product Code: VX-770
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: IVACAFTOR
CAS Number: 873054-44-5
Current Sponsor code: VX-770
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: Tezacaftor
Product Code: VX-661
Pharmaceutical Form: Tablet
INN or Proposed INN: Tezacaftor (TEZ)
Current Sponsor code: VX-661
Other descriptive name: VX-661
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: Deuterated Ivacaftor
Product Code: VX-561 (CTP-656)
Pharmaceutical Form: Tablet
INN or Proposed INN: VX-561
Current Sponsor code: VX-561
Other descriptive name: VX-561
Concentration

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Monitored throughout the study

Primary end point(s): Parts D, E and F:
• Safety and tolerability assessments of AEs, clinical laboratory values, standard 12-lead ECGs, vital signs, and pulse oximetry, and spirometry
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through Day 29

Secondary Objective: Parts D and E:
• 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):
• 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

Main Objective: Parts D and E:
• 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

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(s)

Secondary end point(s): 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:
• Absolute change in sweat chloride concentrations from baseline
through Day 29
• Relative change in ppFEV1 from baseline through Day 29
• Absolute change in CFQ-R respiratory domain score from baseline at
Day 29
• PK parameters of VX-445, TEZ, M1-TEZ, and VX-561

Timepoint(s) of evaluation of this end point: Parts D1 and D2: Days 1, 8, 15, 29, 36, ETT
Part E: Days 1, 15, 29, 43, 57, ETT
Part F: Days 1, 8, 15, 29, ETT

Secondary ID(s)

2017-000797-11-NL

VX16-445-001

Source(s) of Monetary Support

Vertex Pharmaceuticals Incorporated