A study to investigate the safety and the movement of the study drug VX- 121 around the body in healthy people and patients with cystic fibrosis

• Register: EUCTR
• Last refreshed on: 3 November 2020
• Main ID: EUCTR2018-000126-55-NL
• Date of registration: 15/05/2018
• Prospective Registration: No
• Primary sponsor: Vertex Pharmaceuticals Incorporated
• Public title: A study to investigate the safety and the movement of the study drug VX- 121 around the body in healthy people and patients with cystic fibrosis
• Scientific title: A Phase 1/2 Study of VX-121 in Healthy Subjects and in Subjects With Cystic Fibrosis
• Date of first enrolment: 15/03/2018
• Target sample size: 120
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-000126-55
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 8
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Netherlands

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:
Parts A, B and C
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 subjects and female subjects of non childbearing potential) will be between the ages of 18 and 55 years, inclusive, and healthy, as defined by no clinically relevant abnormalities identified by a detailed medical history, full physical examination (PE), including blood pressure and pulse rate measurement, standard 12 lead ECG, and clinical laboratory tests.
4. Female subjects must have a negative serum pregnancy test at the Screening Visit.
5. Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, and a total body weight >50 kg.

Part D
1. Subject will sign and date an 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 subjects and female subjects of non childbearing potential) 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 sweat volume at screening is insufficient, then the sweat collection may be repeated once.
7. Confirmed diagnosis of CF as determined by the investigator.
8. Subjects must be heterozygous for F508del with a second CFTR allele carrying a mutation that is not responsive to TEZ, IVA, or TEZ/IVA therapy. If the screening CFTR genotype result is not received before the Run in Period or randomization, as applicable, a previous CFTR genotype laboratory report may be used to establish eligibility. Subjects who have been enrolled and whose screening genotype does not confirm study eligibility must be discontinued from the study (Section 9.9).
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])8 at the Screening Visit. Spirometry measurements must meet American Thoracic Society/European Respiratory Society criteria9 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 120
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Parts A, B and C
1. History of any illness or any clinical condition that, in the opinion of the investigator or the subject’s general practitioner, might confound the results of the study or pose an additional risk in administering study drug to the subject.
2. History of febrile illness or other acute illness within 5 days before the first study drug dose.
3. Any condition possibly affecting drug absorption
4. 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.
5. Blood donation (of approximately 1 pint [500 mL] or more) within 56 days before the first study drug dose or have had any significant loss of blood as determined by the investigator within 60 days before first study drug dose.
6. Use of restricted substances, activities, or devices within the specified duration before the first study drug dose
7. A screen positive for alcohol or drug substances
8. A screen positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) 1 or 2 antibodies.
9. For Part A (Cohorts A3 and A9): a known or suspected lactose intolerance or milk allergy.
10. Subject, or 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.
Part D
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. Abnormal laboratory values at screening, as defined in Section 8.2.2 of the protocol.
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 (Day 28) or the first dose of study drug in the Treatment Period, as applicable.
6. Lung infection with organisms associated with a more rapid decline in pulmonary status (e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus).
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 (Day 28) or the first dose of study drug in the Treatment Period, as applicable.
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

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: VX-121
Pharmaceutical Form: Powder for oral suspension
INN or Proposed INN: Not yet assigned
Current Sponsor code: VX-121
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 10-720
Pharmaceutical form of the placebo: Powder for oral suspension
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
Current Sponsor code: VX-770
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-
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: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Monitored throughout the study

Main Objective: Part A: To evaluate the safety and tolerability of single ascending doses of VX 121 in healthy subjects
Part B: To evaluate the safety and tolerability of multiple ascending doses of VX 121 for 10 days in healthy subjects
Part C: To evaluate the safety and tolerability of multiple ascending doses of VX 121 administered in triple combination (TC) with tezacaftor (TEZ)/ivacaftor (IVA) for 14 days in healthy subjects
Part D: To evaluate the safety and tolerability of VX 121 in TC with TEZ/IVA in subjects with cystic fibrosis (CF)

Primary end point(s): Parts A, B, C, and D: Safety and tolerability, based on the assessment of adverse events (AEs), clinically significant laboratory test results, standard 12-lead ECGs, vital signs, and spirometry (Part D only)

Secondary Objective: Part A: To evaluate the PK of VX-121 after administration of single ascending doses of VX-121 in healthy subjects. To evaluate the relative bioavailability (BA) of a tablet of VX 121 relative to suspension in healthy subjects. To evaluate the effect of milk on the PK of VX 121 after administration of suspension and tablet
Part B: To evaluate the PK of VX-121 after administration of multiple ascending doses of VX-121 for 10 days in healthy subjects
Part C: To evaluate the PK of VX-121 (and PK of TEZ, IVA, and their respective metabolites when administered in TC with VX 121) after administration of multiple ascending doses of VX-121 in TC with TEZ/IVA for 14 days in healthy subjects.
Part D: To evaluate the PK, PD and efficacy of VX 121 when administered in TC with TEZ/IVA in CF subjects. To evaluate the PK, PD and efficacy of TEZ, IVA, and their respective metabolites when administered in TC with VX 121 CF subjects.

Secondary Outcome(s)

Secondary end point(s): • Parts A, B, C, and D: PK parameter estimates of VX-121 derived from plasma concentration time data
• Parts C and D: PK parameter estimates for TEZ and metabolites (M1 TEZ and M2 TEZ) and IVA and metabolites (M1-IVA and M6 IVA) derived from plasma concentration-time data
• Part D: Sweat chloride levels as a biomarker of PD effects
• Part D: Spirometry as preliminary evidence of efficacy

Timepoint(s) of evaluation of this end point: Part A
Cohorts A1, A2, A4, A5, A6: Day -1 to Day 5 +7-10 Day Safety Follow up
Cohort A3: Day -1 to Day 10 + 7-10 Day Safety Follow up
Cohort A9: Day -1 to Day 15 + 7-10 Day Safety Follow up
Part B,
Cohorts B1-B6: Day -1 to Day 14 + 7 -10 Day Safety Follow Up
Part C
Cohorts C1-C2: Day -1 to Day 18 + 7/10 Day Safety Follow up

Secondary ID(s)

VX17-121-001

VER904EC-179041

Source(s) of Monetary Support

Vertex Pharmaceuticals Incorporated

Ethics review

Status: Approved
Approval date: 15/03/2018
Contact:

Results

• Results available: Yes
• Date Posted: 17/05/2020
• Date Completed: 03/05/2019
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-000126-55/results