Study to Evaluate the Safety and Efficacy of VX-659 drug in combination with other drugs in Subjects Aged 18 Years and Older With Cystic Fibrosis

• Register: EUCTR
• Last refreshed on: 10 September 2018
• Main ID: EUCTR2016-003585-11-GB
• Date of registration: 10/07/2017
• Prospective Registration: Yes
• Primary sponsor: Vertex Pharmaceuticals Incorporated
• Public title: Study to Evaluate the Safety and Efficacy of VX-659 drug in combination with other drugs in Subjects Aged 18 Years and Older With Cystic Fibrosis
• Scientific title: A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-659 Combination Therapy in Subjects Aged 18 Years and Older With Cystic Fibrosis
• Date of first enrolment: 10/08/2017
• Target sample size: 105
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003585-11
• 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: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Ireland, Israel, United Kingdom, 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:
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 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. 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.
-Parts 1 and 3: 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. If the sweat chloride value cannot be determined from the screening test for a reason other than insufficient sweat volume (i.e., because of laboratory error, damaged specimen, or equipment malfunction), it is acceptable to use a sweat chloride value that was obtained before previous treatment with IVA, LUM/IVA, or an investigational CFTR modulator.
-Part 2: For subjects with a sweat chloride value =60 mmol/L at screening or documented in the form of a laboratory report in the subject’s medical record, medical monitor approval is not required. For subjects with a sweat chloride value <60 mmol/L at screening and no documented historical value =60 mmol/L, medical monitor approval is required based on documented evidence of chronic sinopulmonary disease manifested by at least 1 of the following:
o Persistent colonization/infection with typical CF pathogens, including but not limited to, Staphylococcus aureus, Haemophilus influenzae, and/or Pseudomonas aeruginosa
o Chronic cough and sputum production
o Persistent chest radiograph abnormalities (e.g., bronchiectasis, atelectasis, infiltrates, hyperinflation)
o Nasal polyps, chronic sinusitis, or radiographic or computed tomographic abnormalities of the paranasal sinuses
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 as a source document to establish eligibility and avert the risk of screening period expiration. Note: Subjects who have been randomized and whose screening genotype does not confirm study eligibility must be discontinued from the study.
-Part 1 and Part 3: Heterozygous for F508del with a second CFTR allele carrying an MF mutation that are not expected to respond to TEZ, IVA, or TEZ/IVA (Appendix A)
-Part 2: Homozygous for F508del
7. FEV1 value =40% and =90% 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.
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 105
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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, 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. Current or past history of peptic ulcer disease.
5. History of hemolysis.
6. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, defined as G6PD activity less than the lower limit of normal (LLN) or 70% of the mean of the LLN and the upper limit of normal (ULN), whichever is greater.
7. 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, or alkaline phosphatase =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)
8. 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 study drug.
9. 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 12 months before the screening visit, with no subsequent positive cultures.
-These 2 respiratory tract cultures were separated by at least 3 months, and 1 of them was obtained within 6 months before the screening visit.
10. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of study drug.
11. 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. Study sites should use QTcF unless they receive approval in advance from the medical monitor to use QTcB
12. History of solid organ or hematological transplantation.
13. History of alcohol or drug of abuse in the past year, including but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator.
14. 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.
15. Use of prohibited medications as defined in Table 9-3, within the specified window before the first dose of study drug.
16. Pregnant or nursing females. Females of childbearing potential must have a negativ

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

Health Condition(s) or Problem(s) studied

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

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

Intervention(s)

Product Name: VX-659
Product Code: VX-659
Pharmaceutical Form: Tablet
INN or Proposed INN: VX-659
Current Sponsor code: VX-659
Other descriptive name: VX-659
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 80-
Pharmaceutical form of the placebo: 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/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
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
Current Sponsor code: 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: Deuterated Ivacaftor
Other descriptive name: VX-561 (CTP-656)
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

Primary Outcome(s)

Primary end point(s): • Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, standard 12 lead ECGs, vital signs, and pulse oximetry
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through the Day 29 Visit

Timepoint(s) of evaluation of this end point: 1. Screening Visit, Treatment Period, ETT Visit, Safety Follow-up
2. from baseline through the Day 29 Visit

Secondary Objective: Parts 1 and 2: To evaluate the pharmacodynamic (PD) effects of VX-659 in TC with TEZ and IVA on CFTR function
Part 3 (optional): To evaluate the PD effects of VX-659 in TC with TEZ and VX-561 on CFTR function
All parts:
• To evaluate the pharmacokinetics (PK) of VX-659 when administered in TC with TEZ and either IVA or VX-561
• To evaluate the PK of TEZ, IVA, VX-561 and their respective metabolites when administered with VX-659 (as applicable)

Main Objective: Parts 1 and 2: To evaluate the safety and tolerability of VX-659 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA)
Part 3 (optional): To evaluate the safety and tolerability of VX-659 in TC with TEZ and VX-561 (also known as CTP-656, deuterated IVA)
All parts: To evaluate the efficacy of VX-659 in TC with TEZ and either IVA or VX-561

Secondary Outcome(s)

Secondary end point(s): •Absolute change in sweat chloride concentrations from baseline through the Day 29 Visit
•Relative change in ppFEV1 from baseline through the Day 29 Visit
•Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ R) respiratory domain score from baseline at the Day 29 Visit
•PK parameters of VX 659, TEZ, M1 TEZ, IVA, M1 IVA , and VX-561

Timepoint(s) of evaluation of this end point: 1. from baseline through the Day 29 Visit
2. from baseline through the Day 29 Visit
3. from baseline at the Day 29 Visit
4. Treatment Period, ETT Visit

Secondary ID(s)

2016-003585-11-IE

VX16-659-101

Source(s) of Monetary Support

Vertex Pharmaceuticals Incorporated