A Phase 3 Study of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)

• Register: EUCTR
• Last refreshed on: 30 June 2019
• Main ID: EUCTR2018-000183-28-GR
• Date of registration: 25/07/2018
• Prospective Registration: Yes
• Primary sponsor: Vertex Pharmaceuticals Incorporated
• Public title: A Phase 3 Study of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)
• Scientific title: A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)
• Date of first enrolment: 01/10/2018
• Target sample size: 360
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-000183-28
• 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: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Greece, Italy, Netherlands, 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 his or her 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. Age 12 years or older, on the date of informed consent.
4. Confirmed diagnosis of CF as determined by the investigator.
5. Heterozygous for F508del and an MF mutation (F/MF genotypes, see Protocol Appendix A for eligible MF mutations). If the screening CFTR genotype result is not received before randomization, a previous CFTR genotype laboratory report may be used to establish eligibility. Subjects who have been randomized and whose screening genotype does not confirm study eligibility must be discontinued from the study (Section 9.9).
6. Forced expiratory volume in 1 second (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.
7. Stable CF disease as judged by the investigator.
8. Willing to remain on a stable CF treatment regimen (as defined in Section 9.5) through completion of study participation.
Are the trial subjects under 18? yes
Number of subjects for this age range: 70
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 290
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. History of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug(s) to the subject. This includes, but is not limited to, the following:
• Clinically significant cirrhosis with or without portal hypertension
• Solid organ or hematological transplantation.
• Alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator.
• Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical carcinoma in situ (all 3 with no recurrence for the last 5 years)
2. History of hemolysis.
3. 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. A documented historical quantitative G6PD activity value measured in an established laboratory that runs the assay routinely and obtained during a prior Vertex study or as part of routine clinical care may be used to establish eligibility.
4. 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 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) for subjects =18 years of age and =45 mL/min/1.73 m2 (calculated by the Counahan-Barratt equation) for subjects aged 12 to 17 years (inclusive)
5. An acute upper or lower respiratory infection, PEx, or changes in therapy (including antibiotics) for sinopulmonary disease within 28 days before the first dose of study drug (Day 1).
6. Lung infection with organisms associated with a more rapid decline in pulmonary status (including, but not limited to, 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 one 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 study drug (Day 1).
8. Ongoing or prior participation in a study of an investigational treatment 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.
9. Use of prohibited medications as defined in Table 9-2, within the specified window before the first dose of stu

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

Health Condition(s) or Problem(s) studied

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: 100-mg VX-445/50-mg TEZ/75-mg IVA FDC
Product Code: VX-445/TEZ/IVA
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Tezacaftor
CAS Number: 1152311-62-0
Current Sponsor code: VX-661
Other descriptive name: VX-661
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
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: 75-
INN or Proposed INN: VX-445
CAS Number: 2216712-66-0
Current Sponsor code: VX-445
Other descriptive name: VX-445
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
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

Primary Outcome(s)

Primary end point(s): Absolute change in ppFEV1 from baseline at Week 4

Timepoint(s) of evaluation of this end point: Week 4

Main Objective: To evaluate the efficacy of VX-445 in Triple Combination (TC) with TEZ and IVA in subjects with CF who are heterozygous for F508del and a minimal function mutation (F/MF subjects)

Secondary Objective: • To evaluate the safety of VX-445 in TC with TEZ and IVA
• To evaluate the pharmacodynamics (PD) of VX-445 in TC with TEZ and IVA
• To evaluate the pharmacokinetics (PK) of VX-445, TEZ, and IVA when administered in TC

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Week 4;
Baseline through Week 24;
At Week 24

Secondary end point(s): Key Secondary Endpoints
Absolute change in ppFEV1 from baseline through Week 24
Number of pulmonary exacerbations (PEx) through Week 24
Absolute change in SwCl from baseline through Week 24
Absolute change in CFQ-R respiratory domain score from baseline through Week 24
Absolute change in body mass index (BMI) from baseline at Week 24
Absolute change in SwCl from baseline at Week 4
Absolute change in CFQ-R respiratory domain score from baseline at Week 4
Other Secondary Endpoints
Time-to-first PEx through Week 24
Absolute change in BMI z-score from baseline at Week 24
Absolute change in body weight from baseline at Week 24
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, ECGs, vital signs, and pulse oximetry
PK parameters of VX-445, TEZ, M1-TEZ, and IVA

Secondary ID(s)

2018-000183-28-SE

VX17-445-102

Source(s) of Monetary Support

Vertex Pharmaceuticals Incorporated

Ethics review

Status: Approved
Approval date:
Contact: