A Single Ascending and Repeated Dose Study of Oral ZF874 in Healthy Volunteers and PiXZ Subjects
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ClinicalTrials.gov Identifier: NCT04443192 |
Recruitment Status :
Terminated
(Based on the results observed to date, the Sponsor concluded that ZF874 was unlikely to achieve the desired target product profile.)
First Posted : June 23, 2020
Last Update Posted : September 19, 2022
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Tracking Information | |||||||
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First Submitted Date ICMJE | June 16, 2020 | ||||||
First Posted Date ICMJE | June 23, 2020 | ||||||
Last Update Posted Date | September 19, 2022 | ||||||
Actual Study Start Date ICMJE | August 3, 2020 | ||||||
Actual Primary Completion Date | September 12, 2022 (Final data collection date for primary outcome measure) | ||||||
Current Primary Outcome Measures ICMJE |
Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment [ Time Frame: Part A: Day 1 to Day 8; Part B: Day 1 to Day 58 ] Safety and tolerability
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Original Primary Outcome Measures ICMJE | Same as current | ||||||
Change History | |||||||
Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE |
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Current Other Pre-specified Outcome Measures |
Pharmacodynamics (Exploratory) [ Time Frame: Part B: Day 1 to Day 58 ] Serum levels of Z-mutated alpha-1-antitrypsin (Z-A1AT)
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Original Other Pre-specified Outcome Measures | Same as current | ||||||
Descriptive Information | |||||||
Brief Title ICMJE | A Single Ascending and Repeated Dose Study of Oral ZF874 in Healthy Volunteers and PiXZ Subjects | ||||||
Official Title ICMJE | A Double-blind, Randomised, Placebo-controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single Ascending and Repeated Doses of Orally Administered ZF874 in Healthy Volunteers and PiXZ Subjects | ||||||
Brief Summary | This study is composed of two parts. Part A: will test single doses of ZF874 in a double-blind, randomised, placebo-controlled and dose-escalating design (except Group 7, which will be open-label and without placebo). Up to 7 groups of 6-8 healthy volunteers will receive an oral dose of ZF874 or matching placebo (6 active: 2 placebo in Groups 1-6; 6 active in Group 7). The dosing of the first 2 subjects (1 active and 1 placebo) will take place before dosing of the remainder of the group in Groups 1-6, with morning doses given in the fasted state. The dose will be escalated only if the safety and tolerability of the previous highest dose are acceptable, and the plasma concentrations of ZF874 are predicted to remain below the toxicokinetic exposure limit, as determined by the Safety Review Group. Group 7 will consist of 6 subjects, all of whom will receive ZF874 after consuming a standard high-fat breakfast. Dosing of the first 2 subjects before the rest of the group is not required in Group 7, as 6 subjects have already safely received ZF874 at this dose in Group 3 and 12 subjects have already safely received higher doses in Groups 4 and 5. The dose selected for Part A, Group 7 was chosen as the dose has previously been given to subjects fasted in Group 3, and it was safe and well tolerated, allowing for comparison for the food effect, and higher doses have been tested in Part A with no safety concerns. Part B: Multiple Ascending Doses in subjects carrying at least one Z mutated alpha-1-antitrypsin (Z-A1AT) allele (PiXZ subjects): Up to 4 groups of up to 5 PiXZ subjects will be enrolled in Part B (Groups 1-4). In Group 1, up to 4 subjects will receive twice daily doses of either ZF874 or placebo on 28 consecutive days. The dose level (dose and dose regimen) selected for Part B Group 1 will be based on review of the available results from Part A. In Groups 2-4, up to 5 PiXZ subjects will receive ZF874 twice daily by mouth for 28 days; no subjects will receive placebo. The dose for Groups 2 - 4 will not exceed the doses already given in Part A. |
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Detailed Description | Part A: Enrolment of up to 54 healthy men and women is planned, in up to 7 groups. Each of the first 6 groups will consist of 8 subjects and the 7th group will consist of 6 subjects. Subjects will receive either one or two oral dose(s) of either ZF874 or placebo, in the fasted state in the first 6 groups. There will be up to 7 dose levels of ZF874. In each of the first 6 groups, two subjects (one placebo, one ZF874) are to be dosed in a double-blind manner at least 23 hours prior to the remainder of the group. In the absence of any safety concerns in the leading subjects, the remaining subjects will be dosed, at intervals of at least 10 minutes. Dosing of the first 2 subjects before the rest of the group is not required in Group 7, as 6 subjects have already safely received ZF874 at this dose in Cohort 3, and 12 subjects have already safely received higher doses in Cohorts 4 and 5. In Group 7, all subjects will receive a single dose of ZF874 by mouth, after consuming a high-fat breakfast. All subjects will be screened in the 28 days before their dose of trial medication. Subjects will be resident on ward from 1 day before their dose (Day -1) until 48 hours after dosing (Day 3). They will return for a follow-up visit 5-7 days after their dose (Day 6-8). Part B: In Group 1, up to 4 subjects will receive twice daily doses of either ZF874 or placebo on 28 consecutive days (up to 3 active: up to 2 placebo). The dose level (dose and dose regimen) selected for Part B Group 1 will be based on review of the available results from Part A. In Groups 2-4, up to 5 PiXZ subjects will receive ZF874 twice daily by mouth for 28 days; no subjects will receive placebo. The doses will be selected after reviewing the available safety and pharmacokinetic results from previous groups, but will not exceed the doses already given in Part A. Subjects will be pre-screened to confirm PiXZ genotype within 84 days before their dose of trial medication. Once their genotype is confirmed, they will be screened in the 28 days before their dose of study medication. Subjects will be resident on the ward from 1 day before their first dose (Day -1) until 1 hour after they receive their second dose (Day 2). They will then attend 6 outpatient visits before returning to the ward and be resident from Day 27 until 24 hours after the final dose (Day 29). They will return for further outpatient visits on Days 36, 43 and 50, and for a follow-up visit 28-30 days after their final dose (Day 56-58). |
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Study Type ICMJE | Interventional | ||||||
Study Phase ICMJE | Phase 1 | ||||||
Study Design ICMJE | Allocation: Randomized Intervention Model: Single Group Assignment Intervention Model Description: This is a double-blind, randomised, placebo-controlled, single ascending and repeat dose trial in healthy subjects and subjects carrying at least one Z-A1AT allele (PiXZ subjects) Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)Masking Description: Part A Groups 1-6 and Part B Group 1 will be double-blind; Part A Group 7 (food effect) and Part B Groups 2-4 will be open label Primary Purpose: Treatment
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Condition ICMJE | Alpha1 Anti-Trypsin Deficiency | ||||||
Intervention ICMJE |
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Study Arms ICMJE |
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Publications * | Not Provided | ||||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||||
Recruitment Status ICMJE | Terminated | ||||||
Actual Enrollment ICMJE |
69 | ||||||
Original Estimated Enrollment ICMJE |
40 | ||||||
Actual Study Completion Date ICMJE | September 12, 2022 | ||||||
Actual Primary Completion Date | September 12, 2022 (Final data collection date for primary outcome measure) | ||||||
Eligibility Criteria ICMJE | Inclusion Criteria:
Exclusion Criteria:
Part A, Cohort 7 only: - Vegans, vegetarians, or unwilling to eat a high-fat breakfast containing bacon. Part B only: - Undergone liver transplantation |
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Sex/Gender ICMJE |
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Ages ICMJE | 18 Years to 72 Years (Adult, Older Adult) | ||||||
Accepts Healthy Volunteers ICMJE | Yes | ||||||
Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||||
Listed Location Countries ICMJE | United Kingdom | ||||||
Removed Location Countries | |||||||
Administrative Information | |||||||
NCT Number ICMJE | NCT04443192 | ||||||
Other Study ID Numbers ICMJE | ZF-0101 | ||||||
Has Data Monitoring Committee | Yes | ||||||
U.S. FDA-regulated Product |
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IPD Sharing Statement ICMJE |
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Current Responsible Party | Z Factor Limited | ||||||
Original Responsible Party | Same as current | ||||||
Current Study Sponsor ICMJE | Z Factor Limited | ||||||
Original Study Sponsor ICMJE | Same as current | ||||||
Collaborators ICMJE |
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Investigators ICMJE |
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PRS Account | Z Factor Limited | ||||||
Verification Date | September 2022 | ||||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |