A Study Evaluating the Safety and Efficacy of VX-440 Combination Therapy in Subjects With Cystic Fibrosis

• Register: EUCTR
• Last refreshed on: 9 October 2017
• Main ID: EUCTR2016-000454-36-AT
• Date of registration: 07/10/2016
• Prospective Registration: Yes
• Primary sponsor: Vertex Pharmaceuticals Incorporated
• Public title: A Study Evaluating the Safety and Efficacy of VX-440 Combination Therapy in Subjects With Cystic Fibrosis
• Scientific title: A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-440 Combination Therapy in Subjects Aged 12 Years and Older With Cystic Fibrosis
• Date of first enrolment: 03/01/2017
• Target sample size: 198
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000454-36
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: no Number of treatment arms in the trial: 5
• 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, Austria, Belgium, Canada, Denmark, Germany, Italy, Netherlands, Spain, Sweden, 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 (or subject’s 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. Subjects will be aged 18 years or older for Parts 1 and 2, and aged 12 years or older for Part 4, on the date of informed consent and, when appropriate, date of assent.
4. Body weight =35 kg.
5. Sweat chloride value =60 mmol/L from test results obtained during screening. If the value cannot be determined from the screening test, a sweat chloride value documented in the subject’s medical record may be used to establish eligibility. (It is acceptable to use a sweat chloride value that was obtained before previous treatment with IVA, LUM/IVA, or an investigational CFTR modulator).
6. Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR genotype result is not received before randomization (Parts 1 and 4) or before Day -28 (Part 2), 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 9.5).
-Part 1 and Part 4: Heterozygous for F508del with a second CFTR allele carrying an MF mutation that is not likely to respond to TEZ and/or IVA therapy (Appendix A)
-Part 2: Homozygous for F508del
7. Parts 1, 2, and 4 subjects must have an 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.
8. Stable CF disease as judged by the investigator.
9. Willing to remain on a stable CF medication regimen through the planned end of treatment or, if applicable, the Safety Follow-up Visit.
Are the trial subjects under 18? yes
Number of subjects for this age range: 30
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 168
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 might confound the results of the study or pose an additional risk in administering study drug to the subject.
2. History of cirrhosis with 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 , 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 lower limit of normal (LLN) or 70% of the mean of the LLN and the ULN.
6. Any of the following abnormal laboratory values at screening:
-Hemoglobin <10 g/dL
-Total bilirubin =2 × ULN
-Aspartate aminotransferase (AST), alanine aminotransferase (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 for subjects =18 years of age and =45 mL/min/1.73 m2 for subjects aged 12 to 17 years
7. 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 (Day 1 for Parts 1 and 4, Day -28 for Part 2).
8. Lung infection with organisms associated with a more rapid decline in pulmonary status. 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 (Day 1 for Parts 1 and 4, Day -28 for Part 2).
10. A standard digital ECG demonstrating QTc >450 msec at screening.
11. History of solid organ or hematological transplantation.
12. History or evidence of cataract or lens opacity determined to be clinically significant by the ophthalmologist or optometrist based on the ophthalmologic examination during the Screening Period.
13. History of alcohol or drug 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 an investigational drug study with the exception of the following:
-Ongoing or prior participation in an investigational study of TEZ/IVA, IVA, LUM/IVA, or other CFTR modulator. For Parts 1 and 4, a washout period of 28 days must elapse before Day 1. Subjects participating in Study 661-110 may have the Part 1 or Part 4 Screening Period extended by 4 weeks (Section 8.1.1.3). For Part 2, a washout period before Day -28 is not required, and subjects participating in Study 661-110 will transition directly from their prior treatment to the TEZ/IVA Run-in Period providing that they meet eligibility criteria. For all parts, subjects participating in Study 661-110 may have their screening assessments performed while continuing to participate in Study 661-110.
-For prospective subjects

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

Intervention(s)

Product Name: VX-440
Pharmaceutical Form: Tablet
INN or Proposed INN: VX-440
Other descriptive name: VX-440
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
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

Product Name: Tezacaftor
Product Code: VX-661
Pharmaceutical Form: Tablet
INN or Proposed INN: Tezacaftor (TEZ)
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

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

Primary Outcome(s)

Primary end point(s): • Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, standard 12-lead electrocardiograms (ECGs), vital signs, and pulse oximetry
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)

Timepoint(s) of evaluation of this end point: Through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)

Main Objective: • To evaluate the safety and tolerability of VX-440 in dual and triple combination with tezacaftor (TEZ) and ivacaftor (IVA)
• To evaluate the efficacy of VX-440 in dual and triple combination with TEZ and IVA

Secondary Objective: • To evaluate the pharmacodynamic (PD) effect of VX-440 in dual and triple combination with TEZ and IVA on sweat chloride concentrations
• To evaluate the pharmacokinetics (PK) of VX-440 when administered in dual and triple combination with TEZ and IVA
• To evaluate the PK of TEZ, IVA, and their respective metabolites when administered with VX-440

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1. through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
2. through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
3. through Week 12 (Part 4)
4. through Week 12 (Part 4)
5.Week 12 (Part 4)
6. Week 12 (Part 4)
7. Week 12 (Part 4)
8. at Day 29 (Parts 1 and 2) and at Week 12 (Part 4)
9. Day 1, 8, 15, 29, 43 and ETT vist (part 1 Cohort A); Day 1, 15, 29, 43 , ETT visit (Part 1 Cohort B); Day1, 15, 29, 43, ETT vist (Part 2); Day 1, 15, Week 4, Week 8, Week 12, ETT visit (part 4)

Secondary end point(s): 1. Absolute change in sweat chloride concentrations from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
2. Relative change in ppFEV1 from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
3. Number of pulmonary exacerbations through Week 12 (Part 4)
4. Time-to-first pulmonary exacerbation through Week 12 (Part 4)
5. Absolute change in body mass index (BMI) from baseline at Week 12 (Part 4)
6. Absolute change in BMI z-score from baseline at Week 12 (Part 4)
7. Absolute change in weight from baseline at Week 12 (Part 4)
8. Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline at Day 29 (Parts 1 and 2) and at Week 12 (Part 4)
9. PK parameters of VX-440, TEZ, M1-TEZ, IVA, and M1-IVA

Secondary ID(s)

VX15-440-101

2016-000454-36-GB

Source(s) of Monetary Support

Vertex Pharmaceuticals Incorporated