Modulate Cellular Stress in the Immune Cells to Reduce Rate of Symptomatic Viral Infection

NCT04267809 | Completed Phase 2

• 1 other identifier: Met-YF-001
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Endoplasmic Reticulum Stress; Viral Infection; Yellow Fever

Keywords

Metformin; Endoplasmic Reticulum Stress; YF17D infection; Symptomatic; Metabolic; Immunometabolism

Outcome Measures

Primary Outcomes (1)

• Rate of symptomatic outcome

  We will employ the definitions of systemic symptoms, based on the WHO guidelines for surveillance of YF vaccine-related AEs, and graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 as previously published. For pain symptoms (i.e. headache, myalgia, arthralgia), a standardized Numerical pain Rating Scale (NRS) will be used. Subjects will be monitored over a 2-week period starting immediately after YF vaccination

  Day 0 to Day 18

Secondary Outcomes (1)

• Reduction in pro-inflammatory and innate immune responses at day 1 post-infection

  Day 0 to Day 32

Study Arms (2)

Metformin group

EXPERIMENTAL

22 subjects will receive Metformin 1000mg twice daily for 7 consecutive days (Days 1-7). On Day 4, subjects will be administered one dose of YF17D before metformin dosing.

Drug: Metformin Hydrochloride

Placebo group

PLACEBO COMPARATOR

22 subjects will receive placebo twice daily for 7 consecutive days (Days 1-7). On Day 4, subjects will be administered one dose of YF17D before placebo dosing.

Drug: Calcium and Vitamin D

Interventions

Metformin Hydrochloride DRUG

Metformin 500mg tablets are registered and licensed in Singapore. For the study, we will be sourcing the Metformin tablets from Singapore General Hospital Formulary.

Also known as: Metformin

Metformin group

Calcium and Vitamin D DRUG

Calcium and Vitamin D tablets are registered and licensed in Singapore. For the study, we will be sourcing the Calcium and Vitamin D tablets from Singapore General Hospital Formulary.

Placebo group

Eligibility Criteria

• Age: 21 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy adults, 21-40 years of age at time of screening
• Body Mass Index of 20-25 kg/m2
• No known drug allergies and are not currently receiving regular immune-modulating therapy such as metformin, NSAIDs, paracetamol, corticosteroids or statins.
• Subjects who give written informed consent approved by the Ethical Review Board governing the site.
• 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.
• Female subjects of childbearing potential may be enrolled in the study if they have negative urine pregnancy tests on the day of screening.
• Negative for diabetes mellitus by HbA1c
• Accessible vein at the forearm for blood collection.
• 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).

You may not qualify if:

• 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.
• Any condition that, in the opinion of the investigator, would complicate or compromise the study or wellbeing of the subject.
• Woman who is pregnant or breast feeding.
• 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).
• Diagnosed with cancer or on treatment for cancer within the 3 years prior to the screening.
• Evidence of clinically significant anemia and other any significant active hematological disease, or having donated \> 450 mL of blood within the past three months.
• Evidence of substance abuse, or previous substance abuse.
• Participation in a study involving administration of an investigational compound within the past four months, or planned participation during the duration of this study.
• 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.
• Subject who are on long term medication for concurrent medical conditions.
• Administration of any licensed vaccine within 30 days before the first study vaccine dose.
• Subject who has been vaccinated with YF vaccine previously.

Sponsors & Collaborators

• Singapore General Hospital: lead
• Duke-NUS Graduate Medical School: collaborator

Study Sites (1)

Singhealth Investigational Medicine Unit

Singapore, 169608, Singapore

Location

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MeSH Terms

Conditions

Virus Diseases; Yellow Fever

Interventions

Metformin; Calcium; Vitamin D

Condition Hierarchy (Ancestors)

Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Arbovirus Infections; Flavivirus Infections; Flaviviridae Infections; RNA Virus Infections; Hemorrhagic Fevers, Viral

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Metals, Alkaline Earth; Elements; Inorganic Chemicals; Metals; Blood Coagulation Factors; Biological Factors; Secosteroids; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Jenny GH Low, MRCP (UK)

  Singapore General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: This is a randomized, double-blind, placebo-controlled clinical trial of metformin in 44 healthy adults.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Enrolled subjects will be randomized into one of two groups in the same ratio (1:1). As this is an open-label study, random block sizes will be used to avoid selection bias yet ensure balance over time. Randomization will be performed via a web-based randomization system: http://www.randomization.com by an independent person who has no direct contact with the subjects. Randomization opaque envelopes will be prepared by an independent team in accordance to the Master Randomization List generated. The randomization envelopes are to be opened sequentially for each enrollment by the study team and will determine the subject's allocation to one of the two groups.

Study Record Dates

• First Submitted: February 5, 2020
• First Posted: February 13, 2020
• Study Start: October 22, 2021
• Primary Completion: July 31, 2023
• Study Completion: July 31, 2023
• Last Updated: April 17, 2024

Record last verified: 2024-04

Locations

SG (1)