Alpha1 Anti-Trypsin Deficiency Clinical Trial
Official title:
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
| Verified date | September 2022 |
| Source | Z Factor Limited |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Terminated |
| Enrollment | 69 |
| Est. completion date | September 12, 2022 |
| Est. primary completion date | September 12, 2022 |
| Accepts healthy volunteers | Accepts Healthy Volunteers |
| Gender | All |
| Age group | 18 Years to 72 Years |
| Eligibility | Inclusion Criteria: - Part A: healthy Caucasian males or females, aged 18-65 years at the time of consent; Part B: males or females of general good health, aged 18-72 years at the time of consent. - Body mass index of 18.0-30.0 kg/m^2 (Part A) and 18.0-35.0 kg/m^2 (Part B). - Able to understand the nature of the trial and any hazards of participating in it. Able to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of the entire trial - Willing to give written fully informed consent to participate - Agree to follow the contraception requirements of the trial - Agree not to donate blood or blood products during the study and for up to 3 months after the trial medication - Registered with a General Practitioner in the United Kingdom - Willing to give written consent to have data entered into The Over-volunteering Prevention System [Part B only] - Confirmed genotype with at least one Z alpha-1-antitrypsin allele (PiXZ) Exclusion Criteria: - Woman who is pregnant or lactating, or woman of child-bearing potential who is sexually active and not using a highly effective method of contraception - Clinically relevant abnormal history, physical findings, ECG, or laboratory values at the pre-trial screening assessment that could interfere with the objectives of the trial or the safety of the volunteer - Acute or chronic illness or history of chronic illness sufficient to invalidate the volunteer's participation in the trial or make it unnecessarily hazardous - Impaired endocrine, thyroid, hepatic, respiratory or renal function, diabetes mellitus, coronary heart disease, or history of any psychotic mental illness - Creatinine clearance <60 mL/min/1.73m2 - Active cancer or to be actively on cancer therapy, or diagnosis of cancer (except for Basal Cell Carcinoma, Squamous Cell Carcinoma (fully excised), or Cervical Intra-epithelial Neoplasia in situ) in the 5 years before the first dose of trial medication. - Surgery (eg stomach bypass) or medical condition that might affect absorption of medicines - Presence or history of severe adverse reaction to any relevant drug - During the 28 days before the first dose of trial medication, the use of prescription medicine judged by the investigator to have the potential to influence the results of the study; or during the 7 days before the first dose of trial medication, the use of a herbal supplement or an over-the-counter medicine, with the exception of ibuprofen - Receipt of a COVID-19 vaccine within 14 days before the first dose of trial medication; exhibition of symptoms suspected to be related to COVID-19 within 28 days before the first dose of trial medication; or receipt of a positive COVID-19 test during the 28 days before the first dose of trial medication - Receipt of an investigational product (including prescription medicines) as part of another clinical trial within 3 months before admission to this study; in the follow-up period of another clinical trial at the time of screening for this study - Recent drug or alcohol abuse (within 2 years before screening), or intake of more than 3 units of alcohol daily (for men) or 2 units of alcohol daily (for women); or use of cigarettes or nicotine-containing products during 30 days before the first dose of trial medication until the end of the study - Blood pressure and heart rate in supine position at the screening examination outside the ranges: blood pressure 90-160 mm Hg systolic, 40-90 mm Hg diastolic; heart rate 40-100 beats/min - Possibility that the volunteer will not cooperate with the requirements of the protocol - Evidence of drug abuse on urine testing - Positive test for hepatitis B virus, hepatitis C virus or human immunodeficiency virus - Loss of more than 400 mL blood during 3 months before the trial, eg as a blood donor - Objection by General Practitioner to volunteer entering trial Part A, Cohort 7 only: - Vegans, vegetarians, or unwilling to eat a high-fat breakfast containing bacon. Part B only: - Undergone liver transplantation |
| Country | Name | City | State |
|---|---|---|---|
| United Kingdom | MAC Clinical Research, Barnsley | Barnsley | |
| United Kingdom | MAC Clinical Research, Leeds | Leeds | |
| United Kingdom | Hammersmith Medicines Research | London | |
| United Kingdom | MAC Clinical Research Manchester | Manchester | Greater Manchester |
| United Kingdom | MAC Clinical Research, Teesside | Stockton-on-Tees |
| Lead Sponsor | Collaborator |
|---|---|
| Z Factor Limited | Centessa Pharmaceuticals plc, Hammersmith Medicines Research |
United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Pharmacodynamics (Exploratory) | Serum levels of Z-mutated alpha-1-antitrypsin (Z-A1AT) | Part B: Day 1 to Day 58 | |
| Primary | Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment | Safety and tolerability | Part A: Day 1 to Day 8; Part B: Day 1 to Day 58 | |
| Secondary | Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects | maximum plasma concentration | Part A: Day 1 to Day 3; Part B: Day 1 to Day 29 | |
| Secondary | Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects | time of maximum plasma concentration | Part A: Day 1 to Day 3; Part B: Day 1 to Day 29 | |
| Secondary | Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects | trough plasma concentration | Part B: Day 1 to Day 29 | |
| Secondary | Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects | maximum plasma concentration / dose | Part A: Day 1 to Day 3; Part B: Day 1 to Day 29 | |
| Secondary | Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects | area under the concentration-time curve during the 24 hours post-dose area under curve to 24 hours post-dose | Part A: Day 1 to Day 2 | |
| Secondary | Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects | area under the concentration-time curve during the 48 hours post-dose area under the concentration-time curve to 48 hours post-dose | Part A: Day 1 to Day 3 | |
| Secondary | Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects | area under the concentration-time curve during the dosing interval | Part B: Day 1 to Day 29 | |
| Secondary | Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects | area under the concentration-time curve to last measurable concentration | Part A: Day 1 to Day 3; Part B: Day 1 to Day 29 | |
| Secondary | Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects | terminal elimination half-life | Part A: Day 1; Part B: Day 28 | |
| Secondary | Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects | terminal rate constant | Part A: Day 1; Part B: Day 28 | |
| Secondary | Food effect on the pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects | maximum plasma concentration / dose | Part A: Day 1 to Day 3 | |
| Secondary | Food effect on the pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects | area under the concentration-time curve to last measurable concentration | Part A: Day 1 to Day 3 | |
| Secondary | Food effect on the pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects | area under the concentration-time curve extrapolated to infinite time | Part A: Day 1 to Day 3 |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Active, not recruiting |
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