A Phase 3 Study of VX-445 Combination Therapy in Cystic Fibrosis (CF) Subjects Heterozygous for F508del and a Gating or Residual Function Mutation (F/G and F/RF Genotypes)

• Register: EUCTR
• Last refreshed on: 20 July 2020
• Main ID: EUCTR2018-002835-76-DK
• Date of registration: 09/07/2019
• Prospective Registration: Yes
• Primary sponsor: Vertex Pharmaceuticals Incorporated
• Public title: A Phase 3 Study of VX-445 Combination Therapy in Cystic Fibrosis (CF) Subjects Heterozygous for F508del and a Gating or Residual Function Mutation (F/G and F/RF Genotypes)
• 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 Gating or Residual Function Mutation (F/G and F/RF Genotypes)
• Date of first enrolment: 16/10/2019
• Target sample size: 250
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-002835-76
• 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: no; 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, Belgium, Canada, Denmark, France, Germany, Ireland, Italy, Netherlands, Spain, 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, at the date of informed consent.
4. Confirmed diagnosis of CF as determined by the investigator.
5. Subject is heterozygous for F508del and either a gating or residual function mutation (F/G and F/RF genotypes) and is in a region where their genotype and age group are approved indications for treatment with IVA and/or TEZ/IVA (see Appendix A for qualifying mutations).
6. Forced expiratory volume in 1 second (FEV1) value =40% and =90% of predicted mean for age, sex, race, 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. Subjects must be able to produce a valid (quantity-sufficient) sweat sample at screening.
8. Stable CF disease as judged by the investigator.
9. Willing to remain on a stable CF treatment regimen through completion of study participation.
Are the trial subjects under 18? yes
Number of subjects for this age range: 75
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 175
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 (each being disease-free for the last 5 years).
2. Any of the following abnormal laboratory values at screening.
- Hemoglobin <10 g/dL
- Total bilirubin =2 × upper limit of normal (ULN)
- Aspartate transaminase (AST), alanine transaminase (ALT), or gamma-glutamyl transferase (GGT) =3 × ULN
- Abnormal renal function defined as estimated glomerular filtration rate =50 mL/min/1.73 m^2 (calculated by the Modification of Diet in Renal Disease Study Equation) for subjects =18 years of age, or =45 mL/min/1.73 m^2 (calculated by the Counahan-Barratt equation) for subjects 12 to 17 years of age (inclusive)
3. An acute upper or lower respiratory infection, pulmonary exacerbation (PEx), or change in therapy (including antibiotics) for sinopulmonary disease within 28 days before the first dose of study drug in the Run-in Period (Day -28).
4. Lung infection with a microbial pathogen that is 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 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.
5. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of study drug in the Run-in Period (Day -28).
6. Ongoing or prior participation in a study of an investigational treatment other than a Vertex 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.
7. Use of prohibited medications as defined in the protocol within the specified window before the first dose of study drug in the Run-in Period (Day -28).
8. Pregnant or breast-feeding females. All female subjects, regardless of childbearing potential status, must have negative pregnancy tests at the Screening Visit (Day -56) and at the Day -28 Visit, before the first dose of study drug in the Run-in Period.
9. 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 at that site. However, an adult (aged 18 years or older) who is a relative of a study staff member may be enrolled in the study provided that
- the adult lives in

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: 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: elexacaftor
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-
INN or Proposed INN: TEZACAFTOR
CAS Number: 1152311-62-0
Current Sponsor code: VX-661
Other descriptive name: TEZ
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
Other descriptive name: IVA
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 75-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Symkevi 100mg/150mg Film-coated tablets
Product Code: VX-661 / VX-770
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: TEZACAFTOR
CAS Number: 1152311-62-0
Current Sponsor code: VX-661
Other descriptive name: TEZ
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
Other descriptive name: IVA
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 Code: VX-770
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: IVACAFTOR
CAS Number: 873054-44-5
Current Sponsor code: Ivacaftor
Other descriptive name: IVA
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-
Pharmaceutical f

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Run-in period: Day -14; Treatment Period: Day 1, Day 15, Week 4, Week 8; Early Treatment Termination (ETT) visit (if applicable)

Primary end point(s): Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through Week 8 for the VX-445/TEZ/IVA group

Main Objective: To evaluate the efficacy of VX-445/tezacaftor (TEZ)/ivacaftor (IVA) in CF subjects who are heterozygous for F508del and a gating or residual function mutation (F/G and F/RF genotypes)

Secondary Objective: - To evaluate the safety of VX-445/TEZ/IVA
- To evaluate the pharmacodynamics (PD) of VX-445/TEZ/IVA

Secondary Outcome(s)

Secondary end point(s): Key Secondary Endpoints

- Absolute change in sweat chloride (SwCl) from baseline through Week 8 for the VX-455/TEZ/IVA group
- Absolute change in ppFEV1 from baseline through Week 8 for the VX-455/TEZ/IVA group compared to the control group
- Absolute change in SwCl from baseline through Week 8 for the VX-455/TEZ/IVA group compared to the control group

Other Secondary Endpoints

- Absolute change in CF Questionnaire-Revised (CFQ-R) respiratory domain (RD) score from baseline through Week 8 for the VX-455/TEZ/IVA group
- Absolute change in CFQ-R RD score from baseline through Week 8 for the VX-455/TEZ/IVA group compared to the control group
- Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, ECGs, vital signs, and pulse oximetry

Timepoint(s) of evaluation of this end point: Key Secondary Endpoints:
- SwCl: Run-in period: Day -14; Treatment Period: Day 1, Day 15, Week 4, Week 8; ETT visit (if applicable)
- ppFEV1: Run-in period: Day -14; Treatment Period: Day 1, Day 15, Week 4, Week 8; ETT visit (if applicable)

Other Secondary Endpoints
- CFQ-R RD score: Run-In period: Day -28; Treatment Period: Day 1, Day 15, Week 4, Week 8; ETT visit (if applicable)
- Safety and tolerability assessments:
a. AEs: Continuous (signing of ICF until completion of study participation)
b. clinical laboratory values, ECGs, vital signs, pulse oximetry: Day -28; Treatment Period: Day 1, Day 15, Week 4, Week 8; ETT visit (if applicable); SFU visit (if applicable)

Secondary ID(s)

2018-002835-76-GB

VX18-445-104

Source(s) of Monetary Support

Vertex Pharmaceuticals Incorporated

Ethics review

Status: Approved
Approval date: 16/10/2019
Contact: