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: 5 April 2021
• Main ID: EUCTR2018-002835-76-IT
• Date of registration: 12/02/2021
• Prospective Registration: No
• 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) - NA
• Date of first enrolment: 04/10/2019
• 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:
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 liv

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: 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 Name: VX-661 / VX-770
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 Name: Ivacaftor
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)
Concentr

Primary Outcome(s)

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

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)

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)

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

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

Secondary ID(s)

NCT04058353

2018-002835-76-GB

VX18-445-104

Source(s) of Monetary Support

Vertex Pharmaceuticals Incorporated

Ethics review

Status: Approved
Approval date: 17/09/2019
Contact:

Results

• Results available: Yes
• Date Posted: 26/12/2020
• Date Completed: 12/06/2020
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-002835-76/results