Modulating Endoplasmic Reticulum Stress as a Prophylactic Approach Against Symptomatic Viral Infection

Met-YF-001

To determine the efficacy of metformin in reducing the rate of symptomatic YF17D infection, and to elucidate the effects of metformin on YF17D viremia and the downstream adaptive immune response, we hereby propose a randomised, double-blind, placebo-controlled clinical trial that is coupled with a system biology approach. We plan to recruit 44 healthy volunteers aged 21-40 years, with a Body Mass Index of 20-25 kg/m2, have no known drug allergies and are not currently receiving regular immune-modulating therapy such as metformin, NSAIDs, paracetamol, corticosteroids or statins. The age range that we propose will ensure that our volunteers are likely to be healthy and not be on long-term medication for other concurrent medical conditions. This would abrogate the confounding effect of YF17D infection enhancement by cross reactive antibodies that we have previously shown. Informed written consent will be obtained before any physical examination is performed. All consented subjects will undergo screening which includes a full physical examination, vital signs measurement, clinical laboratory tests and urine pregnancy test (for female subjects of child-bearing potential) Eligible subjects will be randomized 1:1 to either metformin 1000mg or placebo twice daily for 7 consecutive days (Days 1-7). On Day 4, subjects will be administered one dose of YF17D before study drug dosing. Aim 1 tests the hypothesis that prophylactic metformin reduces ER stress and thus attenuates the post-infection pro-inflammatory response for reduced rate of symptomatic outcome. The primary objective for Aim 1 is to determine the efficacy of metformin in reducing the rate of symptomatic YF17D infection using a randomized placebo-controlled clinical trial. Aim 2 explores the effectiveness of metformin, either through its action on ER stress or other pathways that differentially regulate the expression of pro- and anti-viral host factors, in inhibiting live attenuated vaccine infection and downstream adaptive immune responses. The primary objective for Aim 2 is to elucidate the effects of metformin on YF17D viremia and the downstream adaptive immune response.

2021-10-22

2023-07-31

2023-07-31

Completed

Early phase I

32

Inclusion Criteria: 1. Healthy adults, 21-40 years of age at time of screening 2. Body Mass Index of 20-25 kg/m2 3. No known drug allergies and are not currently receiving regular immune-modulating therapy such as metformin, NSAIDs, paracetamol, corticosteroids or statins. 4. Subjects who give written informed consent approved by the Ethical Review Board governing the site. 5. Satisfactory baseline medical assessment as assessed by physical examination and a stable health status. The laboratory values must be within the normal range of the assessing site or show abnormalities that are deemed not clinically significant as judged by the investigator. A stable health status is defined as the absence of a health event satisfying the definition of a serious adverse event. 6. Female subjects of childbearing potential may be enrolled in the study if they have negative urine pregnancy tests on the day of screening. 7. Negative for diabetes mellitus by HbA1c 8. Accessible vein at the forearm for blood collection. 9. Subjects who are willing to comply with the requirements of the study protocol and scheduled visits. (e.g., completion of the subject diary, return for follow-up visits) and who are willing to make themselves available for the duration of the study, with access to a consistent means of telephone contact, which may be either at home or at the workplace, land line, or mobile, but NOT a pay phone or other multiple-user device (i.e. a common-use phone serving multiple rooms or apartments). Exclusion Criteria: 1. History of severe drug and/or food allergies and/or known allergies to the trial product or its components and any ingredients in the placebo pill. 2. Any condition that, in the opinion of the investigator, would complicate or compromise the study or wellbeing of the subject. 3. Woman who is pregnant or breast feeding. 4. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, neuropsychiatric, or immunosuppressive disorders that would be a risk factor when administered the Investigational Product (IP). 5. Diagnosed with cancer or on treatment for cancer within the 3 years prior to the screening. 6. Evidence of clinically significant anemia and other any significant active hematological disease, or having donated \> 450 mL of blood within the past three months. 7. Evidence of substance abuse, or previous substance abuse. 8. Participation in a study involving administration of an investigational compound within the past four months, or planned participation during the duration of this study. 9. Subjects who are on long term immune-modulating therapy (e.g. NSAIDs, Paracetamol, Corticosteroids, Statins etc.) for other medical condition for the last 6 months. 10. Subject who are on long term medication for concurrent medical conditions. 11. Administration of any licensed vaccine within 30 days before the first study vaccine dose. 12. Subject who has been vaccinated with YF vaccine previously.

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2024-04-17