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 PiXZ 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 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 Doses in subjects carrying at least one Z mutated alpha-1-antitrypsin
      (Z-A1AT) allele (PiXZ subjects): 1 group of 14 subjects will receive daily doses of either
      ZF874 or placebo on 28 consecutive days (12 active: 2 placebo). The daily dose level (dose
      and dose regimen) selected for Part B will be based on review of the available results from
      Part A. A lower dose level may be tested.
    

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 will not start until at least 5 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. The data from Part A Group 7
      (food effect) will not be available before the start of Part B. One group of up to 14 PiXZ
      subjects will receive ZF874 or placebo twice daily (12 hours apart) by mouth for 28 days. Up
      to 12 subjects will receive active treatment and 2 will receive placebo. Dosing will be
      staggered: 2 leading subjects will be dosed first, and the remaining subjects will be dosed
      at least 71 h after the first morning dose given to the last leading subject. To maintain the
      blind nature of the study, the 2 leading 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 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
      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). Subjects will consume a standard breakfast
      before their morning dose on Days 1 and 28, and will be offered a meal before any other doses
      given on the ward. 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 PiXZ 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

68

Start Date

August 3, 2020

Completion Date

October 8, 2021

Primary Completion Date

October 8, 2021

Eligibility Criteria

        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 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 relevant drug

          -  Use of prescription medicine, with the exception of inhalers (in Part B only), 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 a COVID-19 vaccine within 14 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
             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 A, Cohort 7 only:

        - Vegans, vegetarians, or unwilling to eat a high-fat breakfast containing bacon.

        Part B only:

        - Undergone liver transplantation
      

Gender

All

Ages

18 Years - 72 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

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

Location Countries

United Kingdom

Location Countries

United Kingdom

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

May 2021