A Single Ascending and Repeated Dose Study of Oral ZF874 in Healthy Volunteers and PiMZ Subjects

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Brief Title

A Single Ascending and Repeated Dose Study of Oral ZF874 in Healthy Volunteers and PiMZ Subjects

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 PiMZ 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. Up to 4 groups of 8
      healthy volunteers will receive an oral dose of ZF874 or matching placebo (6 active: 2
      placebo for each group). The dosing of the first 2 subjects (1 active and 1 placebo) will
      take place before dosing of the remainder of the group. 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.

      Part B: Multiple Doses in subjects carrying one Z mutated alpha-1-antitrypsin (Z-A1AT) allele
      (PiMZ subjects): 1 group of 8 subjects will receive daily doses of either ZF874 or placebo on
      28 consecutive days (6 active: 2 placebo). Dose level will depend on review of data from Part
      A and pharmacokinetic modelling as appropriate, but it is anticipated to be the highest dose
      judged to be safe from Part A.
    

Detailed Description

      Part A: Enrolment of up to 32 healthy men and women is planned, in up to 4 groups. Each group
      will consist of 8 subjects. Subjects will receive a single oral dose of either ZF874 or
      placebo, in the fasted state. There will be up to 4 dose levels of ZF874. In each group, 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 sentinel
      subjects, the remaining subjects will be dosed, at intervals of at least 10 minutes. 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 will not start until at least 3 dose levels have been completed in Part A. The dose
      level to be tested in Part B will be selected based on review by the Safety Review Group of
      the available safety and pharmacokinetic results from Part A. One group of 8 PiMZ subjects
      will receive ZF874 or placebo once daily by mouth for 28 days. Six subjects will receive
      active treatment and 2 will receive placebo. Dosing will be staggered: 2 sentinel subjects
      will be dosed first, and the remaining subjects will be dosed at least 71 h later. To
      maintain the blind nature of the study, the 2 sentinel subjects will be randomised to ensure
      that 1 subject receives active treatment and the other receives placebo. The leading subjects
      will be dosed a minimum of 5 min apart. Provided there are no safety concerns, the remaining
      subjects will be dosed, at intervals of at least 10 minutes. Subjects will be pre-screened to
      confirm PiMZ 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 on Days 5, 9, 13, 17, 21 and 25. Subjects will return 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).
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment

Secondary Outcome

 Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiMZ subjects

Condition

Alpha1 Anti-Trypsin Deficiency

Intervention

ZF874

Study Arms / Comparison Groups

 Part A Cohort 1 - ZF874
Description:  Single oral dose of ZF874 by mouth in the fasted state. Dose Level 1

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

40

Start Date

August 10, 2020

Completion Date

January 5, 2021

Primary Completion Date

January 5, 2021

Eligibility Criteria

        Inclusion Criteria:

          -  Caucasian

          -  Body mass index of 18.0-30.0 kg/m^2

          -  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 heterozygous genotype with one Z alpha-1-antitrypsin allele and one
             wild-type (M) allele (PiMZ)

        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 <90 mL/min

          -  Active cancer or to be actively on cancer therapy, or diagnosis of cancer in 12 months
             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 drug

          -  Use of prescription medicine during the 28 days before the first dose of trial
             medication or use of an over-the-counter medicine, with the exception of ibuprofen,
             during the 7 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

          -  Presence or history of drug or alcohol abuse, or intake of more than 21 units of
             alcohol weekly (for men) or 14 units of alcohol weekly (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 90-140 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 B only:

        - Undergone liver transplantation
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Malcolm Boyce, BSc MD FRCP FFPM, 020 8961 4130, [email protected]



Administrative Informations


NCT ID

NCT04443192

Organization ID

ZF-0101


Responsible Party

Sponsor

Study Sponsor

Z Factor Limited

Collaborators

 Hammersmith Medicines Research

Study Sponsor

Malcolm Boyce, BSc MD FRCP FFPM, Principal Investigator, HMR


Verification Date

June 2020