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Development of AWZ1066S, a Small Molecule Anti-Wolbachia Candidate Macrofilaricide Drug (AWOL)

Primary Purpose

Filariasis, Lymphatic, Onchocerciasis

Status
Terminated
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
AWZ1066S
Placebo
Sponsored by
Liverpool School of Tropical Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Filariasis, Lymphatic focused on measuring Lymphatic filariasis, Onchocerciasis, Wolbachia, Phase 1, Healthy volunteers, Randomized, Double blind, Placebo

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

1. Healthy male and female participants 2 aged 18-65 years 3 BMI 18.0-35.0 kg/m2, maximum weight 100 kg 4 in good health, as determined by: 4a medical history, 4b physical examination, 4c vital signs assessment, 4d 12-lead ECG 4e clinical laboratory evaluations 5 provision of informed consent and abide by study restrictions

Exclusion Criteria:

  1. not willing to abide by contraception restrictions
  2. donated blood in previous 3 months, plasma previous 7 days, platelets previous 6 weeks
  3. consumption >14 units of alcohol/week
  4. tobacco smoking
  5. concomitant medication, apart from treatments for mild asthma, eczema, contraception, paracetamol
  6. herbal remedies
  7. history of anaphylaxis, drug allergy, clinically significant atopic condition as determined by Investigator
  8. clinically significant medical history, as determined by the Investigator
  9. positive hepatitis, HIV serology
  10. live vaccine in previous 3 months, Covid-19 vaccine prior 14 days
  11. Participants who, in the opinion of the Investigator, should not participate in this study.

Sites / Locations

  • Liverpool University Hospitals NHS Foundation Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

AWZ1066S

Placebo

Arm Description

AWZ1066S Part A Cohort A1- 100mg single dose Cohort A2- 200mg single dose Cohort A3- 400mg single dose Cohort A4- 800mg fasted single dose and 800mg fed single dose Cohort A5- 1200mg single dose Cohort A6- 1600mg single dose The doses for part B will be selected following review of data from Part A. Cohort B1- AWZ1066S once daily for 7 days Cohort B2- AWZ1066S once daily for 7 days Cohort B3- AWZ1066S once daily for 7 days Cohort B4- AWZ1066S once daily for 7 days

Placebo Cohort A1- equivalent placebo single dose Cohort A2- equivalent placebo single dose Cohort A3- equivalent placebo single dose Cohort A4- equivalent placebo fasted single dose and equivalent placebo fed single dose Cohort A5- equivalent placebo single dose Cohort A6- equivalent placebo single dose The doses for part B will be selected following review of data from Part A. Cohort B1- equivalent placebo once daily for 7 days Cohort B2- equivalent placebo once daily for 7 days Cohort B3- equivalent placebo once daily for 7 days Cohort B4- equivalent placebo once daily for 7 days

Outcomes

Primary Outcome Measures

Adverse events
Number

Secondary Outcome Measures

Single dose pharmacokinetics Cmax
Pharmacokinetic parameter, maximum plasma concentration (Cmax)
Single dose pharmacokinetics tmax
Pharmacokinetic parameter, time to reach maximum plasma concentration (tmax)
Single dose pharmacokinetics t1/2
Pharmacokinetic parameter, half life (t1/2)
Single dose pharmacokinetics CL/F
Pharmacokinetic parameter, apparent total clearance after oral administration (CL/F)
Multiple dose pharmacokinetics Cmax
Pharmacokinetic parameter, maximum plasma concentration (Cmax)
Multiple dose pharmacokinetics tmax
Pharmacokinetic parameter, time to reach maximum plasma concentration (tmax)
Multiple dose pharmacokinetics t1/2
Pharmacokinetic parameter, half life (t1/2)
Multiple dose pharmacokinetics CL/f
Pharmacokinetic parameter, apparent total clearance after oral administration (CL/F)

Full Information

First Posted
October 5, 2021
Last Updated
September 19, 2023
Sponsor
Liverpool School of Tropical Medicine
Collaborators
Liverpool University Hospitals NHS Foundation Trust, Covance, Subiaco Associates Limited, Sylexis Limited, Eisai Limited
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1. Study Identification

Unique Protocol Identification Number
NCT05084560
Brief Title
Development of AWZ1066S, a Small Molecule Anti-Wolbachia Candidate Macrofilaricide Drug
Acronym
AWOL
Official Title
Development of AWZ1066S, a Small Molecule Anti-Wolbachia Candidate Macrofilaricide Drug
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Terminated
Why Stopped
Safety issues
Study Start Date
December 10, 2021 (Actual)
Primary Completion Date
May 22, 2023 (Actual)
Study Completion Date
May 22, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Liverpool School of Tropical Medicine
Collaborators
Liverpool University Hospitals NHS Foundation Trust, Covance, Subiaco Associates Limited, Sylexis Limited, Eisai Limited

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Lymphatic filariasis and onchocerciasis are a group of neglected tropical diseases caused by the transmission of worm larvae (microfilaria) by biting insects. Once a human is infected, the larvae mature into adult worms that release huge numbers of larvae into the lymphatics for 5-15 years. The larvae cause tissue damage resulting in the disabling diseases of elephantiasis (gross leg and scrotal swelling) and river blindness. These diseases affect 160 million people and are acknowledged major public health problems in the tropics. Current treatments mainly target the larvae but not the adult worms that live for years, meaning that repeated courses of treatment over many years are needed. These repeated courses are usually delivered at population level in the form of mass drug administration programmes. For the adult worms to be able to grow, reproduce and infect more humans they are dependent on a bacterium which lives inside them. This bacterium (Wolbachia) is not naturally found in humans. Some drugs are able to target Wolbachia, however they are unsuitable for mass drug administration programmes because they have to be given for 4-6 weeks and cannot be used in children or pregnant women. AWZ1066S is a novel drug developed in Liverpool that has been shown in experimental models to target Wolbachia and indirectly kill the adult parasitic worms after a 7 day course. After extensive safety testing in animals we are conducting a Phase 1, first in human study, to assess the safety, tolerability and pharmacokinetics of ascending single and multiple oral doses of AWZ1066S in healthy volunteers. The study is a single centre study, will last approximately 1 year and will take place in a dedicated Phase 1 trial unit. Depending on which group they are enrolled into, participants will take either one dose, two doses or seven doses and their involvement will last between 38 and 45 days. Participants will be closely monitored for adverse effects.
Detailed Description
AWZ1066S is in the early stages of clinical development, for safety reasons, a sequential, ascending dose design is being used. The study is double-blind, and placebo controlled. All research activities will be conducted within a dedicated Phase 1 Clinical Research Facility. Part A comprises a single ascending dose design with an overall group total of 48 participants. These will be studied in 6 cohorts (Cohorts A1 to A6), with each cohort consisting of 8 participants (6 randomised to oral dose of AWZ1066S and 2 randomised to placebo). Each participant will receive single dose of AWZ1066S, apart from cohort A4 participants who will take a single dose when fasting and and a single dose when fed, separated by a minimum of 7 days. The planned doses for Part A are: Cohort A1- 100mg Cohort A2- 200mg Cohort A3- 400mg Cohort A4- 800mg fasted and 800mg fed Cohort A5- 1200mg Cohort A6- 1600mg Participants will receive their dose whilst resident in the Clinical Research Facility and will return for outpatient visits on Day 3, 4 and 10 safety assessments and pharmacokinetic blood samples. Part B comprises a multiple ascending dose design, to investigate 4 dose levels in four cohorts (cohorts B1 to B4) with each cohort consisting of 8 participants (6 randomised to oral dose of AWZ1066S and 2 randomized to placebo). The doses investigated will be selected following review of data from the single dosing study (Part A). The intention is to enrol a minimum 32 healthy participants. Each participant will receive single daily dose of AWZ1066S for 7 days. Participants will receive their dose whilst resident in the Clinical Research Facility and will return for outpatient visits on Day 3, 5, 9 and 10 for safety assessments and pharmacokinetic blood samples. A second resident period on Day 6 to Day 8 will allow pharmacokinetic blood samples and safety assessments. Safety and tolerability will be monitored by adverse events, vital signs, ECGs, urinalysis, routine haematology and biochemistry. Escalation of dosing will only take place after examination of safety data by the Dose Escalation Committee.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Filariasis, Lymphatic, Onchocerciasis
Keywords
Lymphatic filariasis, Onchocerciasis, Wolbachia, Phase 1, Healthy volunteers, Randomized, Double blind, Placebo

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
Sequential, ascending dose design, double-blind, placebo controlled. Part A: single ascending dose design with 6 dosing levels. Part B: multiple ascending dose design with 4 dosing levels.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
AWZ1066S
Arm Type
Experimental
Arm Description
AWZ1066S Part A Cohort A1- 100mg single dose Cohort A2- 200mg single dose Cohort A3- 400mg single dose Cohort A4- 800mg fasted single dose and 800mg fed single dose Cohort A5- 1200mg single dose Cohort A6- 1600mg single dose The doses for part B will be selected following review of data from Part A. Cohort B1- AWZ1066S once daily for 7 days Cohort B2- AWZ1066S once daily for 7 days Cohort B3- AWZ1066S once daily for 7 days Cohort B4- AWZ1066S once daily for 7 days
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo Cohort A1- equivalent placebo single dose Cohort A2- equivalent placebo single dose Cohort A3- equivalent placebo single dose Cohort A4- equivalent placebo fasted single dose and equivalent placebo fed single dose Cohort A5- equivalent placebo single dose Cohort A6- equivalent placebo single dose The doses for part B will be selected following review of data from Part A. Cohort B1- equivalent placebo once daily for 7 days Cohort B2- equivalent placebo once daily for 7 days Cohort B3- equivalent placebo once daily for 7 days Cohort B4- equivalent placebo once daily for 7 days
Intervention Type
Drug
Intervention Name(s)
AWZ1066S
Intervention Description
Candidate drug to treat lymphatic filariasis by targeting Wolbachia endosymbiont
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Adverse events
Description
Number
Time Frame
From day of first dose to 10 days after last dose
Secondary Outcome Measure Information:
Title
Single dose pharmacokinetics Cmax
Description
Pharmacokinetic parameter, maximum plasma concentration (Cmax)
Time Frame
From day of first dose to 10 days after last dose
Title
Single dose pharmacokinetics tmax
Description
Pharmacokinetic parameter, time to reach maximum plasma concentration (tmax)
Time Frame
From day of first dose to 10 days after last dose
Title
Single dose pharmacokinetics t1/2
Description
Pharmacokinetic parameter, half life (t1/2)
Time Frame
From day of first dose to 10 days after last dose
Title
Single dose pharmacokinetics CL/F
Description
Pharmacokinetic parameter, apparent total clearance after oral administration (CL/F)
Time Frame
From day of first dose to 10 days after last dose
Title
Multiple dose pharmacokinetics Cmax
Description
Pharmacokinetic parameter, maximum plasma concentration (Cmax)
Time Frame
From day of first dose to 10 days after last dose
Title
Multiple dose pharmacokinetics tmax
Description
Pharmacokinetic parameter, time to reach maximum plasma concentration (tmax)
Time Frame
From day of first dose to 10 days after last dose
Title
Multiple dose pharmacokinetics t1/2
Description
Pharmacokinetic parameter, half life (t1/2)
Time Frame
From day of first dose to 10 days after last dose
Title
Multiple dose pharmacokinetics CL/f
Description
Pharmacokinetic parameter, apparent total clearance after oral administration (CL/F)
Time Frame
From day of first dose to 10 days after last dose

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: 1. Healthy male and female participants 2 aged 18-65 years 3 BMI 18.0-35.0 kg/m2, maximum weight 100 kg 4 in good health, as determined by: 4a medical history, 4b physical examination, 4c vital signs assessment, 4d 12-lead ECG 4e clinical laboratory evaluations 5 provision of informed consent and abide by study restrictions Exclusion Criteria: not willing to abide by contraception restrictions donated blood in previous 3 months, plasma previous 7 days, platelets previous 6 weeks consumption >14 units of alcohol/week tobacco smoking concomitant medication, apart from treatments for mild asthma, eczema, contraception, paracetamol herbal remedies history of anaphylaxis, drug allergy, clinically significant atopic condition as determined by Investigator clinically significant medical history, as determined by the Investigator positive hepatitis, HIV serology live vaccine in previous 3 months, Covid-19 vaccine prior 14 days Participants who, in the opinion of the Investigator, should not participate in this study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Graham Devereux, MD
Organizational Affiliation
Liverpool School of Tropical Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Liverpool University Hospitals NHS Foundation Trust
City
Liverpool
State/Province
Merseyside
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Commercial sensitivity
Citations:
PubMed Identifier
30617067
Citation
Hong WD, Benayoud F, Nixon GL, Ford L, Johnston KL, Clare RH, Cassidy A, Cook DAN, Siu A, Shiotani M, Webborn PJH, Kavanagh S, Aljayyoussi G, Murphy E, Steven A, Archer J, Struever D, Frohberger SJ, Ehrens A, Hubner MP, Hoerauf A, Roberts AP, Hubbard ATM, Tate EW, Serwa RA, Leung SC, Qie L, Berry NG, Gusovsky F, Hemingway J, Turner JD, Taylor MJ, Ward SA, O'Neill PM. AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis. Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1414-1419. doi: 10.1073/pnas.1816585116. Epub 2019 Jan 7.
Results Reference
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Development of AWZ1066S, a Small Molecule Anti-Wolbachia Candidate Macrofilaricide Drug

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