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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 : Recruiting
First Posted : June 23, 2020
Last Update Posted : January 27, 2021
Sponsor:
Collaborator:
Hammersmith Medicines Research
Information provided by (Responsible Party):
Z Factor Limited

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 6 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 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 the same as the highest single dose level that has been given in Part A without any safety concerns. A lower dose level may be tested.


Condition or disease Intervention/treatment Phase
Alpha1 Anti-Trypsin Deficiency Drug: ZF874 Drug: Placebo Phase 1

Detailed Description:

Part A: Enrolment of up to 48 healthy men and women is planned, in up to 6 groups. Each group will consist of 8 subjects. Subjects will receive either one or two oral dose(s) of either ZF874 or placebo, in the fasted state. There will be up to 6 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 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. One group of 14 PiXZ subjects will receive ZF874 or placebo twice daily (12 hours apart) by mouth for 28 days. Twelve 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 after the first morning dose given to the last sentinel subject. 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 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). 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 : Interventional  (Clinical Trial)
Estimated Enrollment : 62 participants
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: Double-blind
Primary Purpose: Treatment
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
Actual Study Start Date : August 3, 2020
Estimated Primary Completion Date : May 6, 2021
Estimated Study Completion Date : May 6, 2021


Arm Intervention/treatment
Active Comparator: Part A Cohort 1 - ZF874
Single oral dose of ZF874 by mouth in the fasted state. Dose Level 1
Drug: ZF874
ZF874 is a novel, first-in-class small molecule. ZF874 is a chemical chaperone that specifically rescues the folding of the Z variant of alpha-1-antitrypsin (A1AT). It is being developed for the treatment of alpha-1-antitrypsin deficiency (AATD) caused by the Z-mutation.

Placebo Comparator: Part A - Placebo to ZF874 - Single Dose
Single oral dose of placebo by mouth in the fasted state
Drug: Placebo
Placebo to ZF874

Active Comparator: Part A Cohort 2 - ZF874
Single oral dose of ZF874 by mouth in the fasted state. Dose Level 2
Drug: ZF874
ZF874 is a novel, first-in-class small molecule. ZF874 is a chemical chaperone that specifically rescues the folding of the Z variant of alpha-1-antitrypsin (A1AT). It is being developed for the treatment of alpha-1-antitrypsin deficiency (AATD) caused by the Z-mutation.

Active Comparator: Part A Cohort 3 - ZF874
Single oral dose of ZF874 by mouth in the fasted state. Dose Level 3
Drug: ZF874
ZF874 is a novel, first-in-class small molecule. ZF874 is a chemical chaperone that specifically rescues the folding of the Z variant of alpha-1-antitrypsin (A1AT). It is being developed for the treatment of alpha-1-antitrypsin deficiency (AATD) caused by the Z-mutation.

Active Comparator: Part A Cohort 4 - ZF874
Single oral dose of ZF874 by mouth in the fasted state. Dose Level 4
Drug: ZF874
ZF874 is a novel, first-in-class small molecule. ZF874 is a chemical chaperone that specifically rescues the folding of the Z variant of alpha-1-antitrypsin (A1AT). It is being developed for the treatment of alpha-1-antitrypsin deficiency (AATD) caused by the Z-mutation.

Placebo Comparator: Part A - Placebo to ZF874 - Two Doses
Two doses of placebo (12 h apart) by mouth in the fasted state
Drug: Placebo
Placebo to ZF874

Active Comparator: Part A Cohort 5 - ZF874 - Two Doses
Two doses of ZF874 (12 h apart) by mouth in the fasted state. Dose Level 5
Drug: ZF874
ZF874 is a novel, first-in-class small molecule. ZF874 is a chemical chaperone that specifically rescues the folding of the Z variant of alpha-1-antitrypsin (A1AT). It is being developed for the treatment of alpha-1-antitrypsin deficiency (AATD) caused by the Z-mutation.

Active Comparator: Part A Cohort 6 - ZF874 - Two Doses
Two doses of ZF874 (12 h apart) by mouth in the fasted state. Dose Level 6
Drug: ZF874
ZF874 is a novel, first-in-class small molecule. ZF874 is a chemical chaperone that specifically rescues the folding of the Z variant of alpha-1-antitrypsin (A1AT). It is being developed for the treatment of alpha-1-antitrypsin deficiency (AATD) caused by the Z-mutation.

Active Comparator: Part B - ZF874
Two doses of ZF874 (12 h apart) by mouth daily for 28 days.
Drug: ZF874
ZF874 is a novel, first-in-class small molecule. ZF874 is a chemical chaperone that specifically rescues the folding of the Z variant of alpha-1-antitrypsin (A1AT). It is being developed for the treatment of alpha-1-antitrypsin deficiency (AATD) caused by the Z-mutation.

Placebo Comparator: Part B - Placebo to ZF874
Two doses of placebo (12 h apart) by mouth daily for 28 days.
Drug: Placebo
Placebo to ZF874




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects [ Time Frame: Part A: Day 1 to Day 3; Part B: Day 1 to Day 29 ]
    maximum plasma concentration

  2. Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects [ Time Frame: Part A: Day 1 to Day 3; Part B: Day 1 to Day 29 ]
    time of maximum plasma concentration

  3. Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects [ Time Frame: Part B: Day 1 to Day 29 ]
    trough plasma concentration

  4. Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects [ Time Frame: Part A: Day 1 to Day 3; Part B: Day 1 to Day 29 ]
    maximum plasma concentration / dose

  5. Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects [ Time Frame: Part A: Day 1 to Day 2 ]
    area under the concentration-time curve during the 24 hours post-dose area under curve to 24 hours post-dose

  6. Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects [ Time Frame: Part A: Day 1 to Day 3 ]
    area under the concentration-time curve during the 48 hours post-dose area under the concentration-time curve to 48 hours post-dose

  7. Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects [ Time Frame: Part B: Day 1 to Day 29 ]
    area under the concentration-time curve during the dosing interval

  8. Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects [ Time Frame: Part A: Day 1 to Day 3; Part B: Day 1 to Day 29 ]
    area under the concentration-time curve to last measurable concentration

  9. Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects [ Time Frame: Part A: Day 1; Part B: Day 28 ]
    terminal elimination half-life

  10. Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects [ Time Frame: Part A: Day 1; Part B: Day 28 ]
    terminal rate constant


Other Outcome Measures:
  1. Pharmacodynamics (Exploratory) [ Time Frame: Part B: Day 1 to Day 58 ]
    Serum levels of Z-mutated alpha-1-antitrypsin (Z-A1AT)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy Caucasian males or females, aged 18-65 years (Part A) and 18-70 years (Part B) 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 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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04443192


Contacts
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Contact: Malcolm Boyce, BSc MD FRCP FFPM 020 8961 4130 mboyce@hmrlondon.com
Contact: Nathalie Hopchet, BSc 020 8961 4130 nhopchet@hmrlondon.com

Locations
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United Kingdom
Hammersmith Medicines Research Recruiting
London, United Kingdom, NW10 7EW
Sponsors and Collaborators
Z Factor Limited
Hammersmith Medicines Research
Investigators
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Principal Investigator: Malcolm Boyce, BSc MD FRCP FFPM HMR
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Responsible Party: Z Factor Limited
ClinicalTrials.gov Identifier: NCT04443192    
Other Study ID Numbers: ZF-0101
First Posted: June 23, 2020    Key Record Dates
Last Update Posted: January 27, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Alpha 1-Antitrypsin Deficiency
Liver Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Emphysema
Pathologic Processes