A Study to Evaluate the Safety and Efficacy of VX-121 Combination Therapy in Subjects With Cystic Fibrosis

• Register: EUCTR
• Last refreshed on: 30 June 2019
• Main ID: EUCTR2018-002496-18-DE
• Date of registration: 28/01/2019
• Prospective Registration: Yes
• Primary sponsor: Vertex Pharmaceuticals Incorporated
• Public title: A Study to Evaluate the Safety and Efficacy of VX-121 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-121 Combination Therapy in Subjects Aged 18 Years and Older With Cystic Fibrosis
• Date of first enrolment: 02/05/2019
• Target sample size: 108
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-002496-18
• 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: 8
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Germany, Netherlands, Portugal, 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 (male and female) aged 18 years or older on the date of informed consent.
4. Female subjects must have a negative serum pregnancy test at the Screening Visit.
5. Body weight =35 kg.
6. 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.
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.
7. Confirmed diagnosis of CF as determined by the investigator.
8. Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR genotype result is not received before the Run-in Period (Part 2) or randomization (Parts 1 and 3), a previous CFTR genotype laboratory report may be used to establisheligibility. Subjects who have been enrolled and whose screening genotype does not confirm study eligibility must be discontinued from the study
• Parts 1 and 3: Heterozygous for F508del with a second CFTR allele carrying a mutation that does not produce a protein, or produces a protein that is not responsive to TEZ, IVA, or TEZ/IVA therapy
• Part 2: Homozygous for F508del
9. Subjects must have a forced expiratory volume in 1 second (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.
10. Stable CF disease as judged by the investigator.
11. Willing to remain on a stable CF treatment regimen (other than protocol-specified changes in CFTR modulator regimen) through 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 108
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 and other ventricular arrhythmias, 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. 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), 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)10,11 for subjects =18 years of age
5. 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 TEZ/IVA in the Run-in Period (Part 2) or the first dose of study drug in the Treatment Period (Parts 1 and 3).
6. 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, 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 1 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 TEZ/IVA in the Run-in Period (Part 2) or the first dose of study drug in the Treatment Period (Parts 1 and 3).
8. Standard 12-lead ECG demonstrating QTcF >450 msec at screening. If QTcF exceeds 450 msec, the ECG will be repeated 2 more times, and the average of the 3 QTcF values will be used to determine the subject’s eligibility.
9. History of solid organ or hematological transplantation.
10. History of alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator.
11. Ongoing or prior participation in a study of an investigational treatment with the exception of the following:
• Ongoing or prior participation in an investigational study of a Vertex CFTR modulator. A washout period of 28 days must elap

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: VX-121
Pharmaceutical Form: Tablet
INN or Proposed INN: N/A
Current Sponsor code: VX-121
Other descriptive name: VX-121
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: Tezacaftor
Product Code: VX-661
Pharmaceutical Form: Film-coated 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: VX-561
Pharmaceutical Form: Tablet
INN or Proposed INN: N/A
Current Sponsor code: VX-561
Other descriptive name: VX-561
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: Symkevi 100mg/150mg Film-coated tablets

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: TEZ
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
INN or Proposed INN: IVACAFTOR

Primary Outcome(s)

Main Objective: Parts 1 (Subjects with F/MF genotypes) and 2 (Optional; Subjects with the F/F genotype)
• To evaluate the safety and tolerability of VX-121 in triple combination (TC) with tezacaftor (TEZ)/VX-561 (deuterated ivacaftor [IVA])
• To evaluate the efficacy of VX-121 in TC with TEZ/VX-561
Part 3 (Optional; Subjects with the F/MF genotype)
• To evaluate the safety and tolerability of VX-121 in TC with TEZ/IVA
• To evaluate the efficacy of VX-121 in TC with TEZ/IVA

Primary end point(s): • Safety and tolerability, based on the assessment of adverse events (AEs), laboratory test results, standard 12-lead ECGs, vital signs, and spirometry
• Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through Day 29

Secondary Objective: Parts 1 and 2
• To evaluate the pharmacodynamic (PD) effect of VX-121 in TC with TEZ/VX-561
• To evaluate the pharmacokinetics (PK) of VX-121 when administered in TC with TEZ/VX-561
• To evaluate the PK of TEZ, VX-561, and their respective metabolites when administered in TC with VX-121
Part 3
• To evaluate the PD effect of VX-121 in TC with TEZ/IVA
• To evaluate the PK of VX-121 when administered in TC with TEZ/IVA
• To evaluate the PK of TEZ, IVA, and their respective metabolites when administered in TC with VX-121

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

Secondary Outcome(s)

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

Secondary end point(s): • Absolute change in sweat chloride concentrations from baseline through Day 29
• Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline at Day 29
• PK parameters of VX-121, TEZ, VX-561, IVA (Part 3), and relevant metabolites

Secondary ID(s)

VX18-121-101

Source(s) of Monetary Support

Vertex Pharmaceuticals Incorporated

Ethics review

Status: Approved
Approval date:
Contact: