Modulating Endoplasmic Reticulum Stress as a Prophylactic Approach Against Symptomatic Viral Infection
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Rate of symptomatic outcome
研究概览
简要总结
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.
详细描述
Criteria for Recruitment and Recruitment Process: Subjects will be recruited from SingHealth Investigational Medicine Unit (IMU) healthy volunteer database and recruitment posters. Subjects will be given a copy of the Participant Information and Informed Consent Form to read upon their arrival. A briefing session on the study will be conducted by the Investigator. Thereafter, subjects will be ushered into a private room where informed consent is obtained and where questions about the study can be asked freely. Subjects will not be rushed into making a decision to participate in the study. They will be encouraged to speak to their family members about participation in the study; and allowed to defer their decision (without any prejudice) to participate till after discussion with their family members.
Screening Visits and Procedures: Subjects will be recruited via the SingHealth Investigational Medicine Unit (IMU). Informed written consent will be obtained before any study related procedure or assessment is performed. All subjects' eligibility for recruitment into the study must be assessed during screening visit. Subjects must satisfy all inclusion and exclusion criteria outlined in Section 3.3 and Section 3.4 respectively to be eligible for enrolment into the study. Eligibility criteria must be confirmed before dosing. All clinical laboratory tests scheduled for screening will be collected to establish pre-dose baseline. Other procedures that must be completed before the study begins include a full physical examination and urinary pregnancy test (for female subjects of child-bearing potential).
Study Visits and Procedures: All eligible subjects will proceed to Day 1, where they 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. Subjects will report to the SingHealth IMU on Day 1 (pre-study drug), Day 4 (pre-YF17D), Days 5, 7, 11, 14, 18 (only for participants who consent to scRNA-seq and T-cell studies) and Day 32 for research blood sampling. The schedule for blood draws will be identical for all study groups. All research blood samples will be stored at -80oC until recruitment is completed before analysis. Subject recruitment and blood collection will be conducted as an outpatient study in the SingHealth Investigational Medicine Unit (IMU), a dedicated early phase clinical trial facility. From our prior experience, we anticipate we will not have difficulty recruiting the required number of participants into our study necessary to meet our target sample size.
Post Study Follow up and Procedures: There is no requirement for post-study follow-up or procedures.
Safety Monitoring Plan: The study may be evaluated by government inspectors/regulatory authorities who must be allowed access to e-CRFs, source documents, and other study files. The inspectors will review CRFs and compare them with source documents to verify accurate and complete collection of data and confirm that the study is being conducted according to the protocol, ICH-Good Clinical Practices (ICH-GCP) and all applicable regulations.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
盲法说明
This is a randomized, double-blind, placebo-controlled clinical trial of metformin in 44 healthy adults.
入排标准
- 年龄范围
- 21 Years 至 40 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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).
排除标准
- •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.
研究组 & 干预措施
Metformin group
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.
干预措施: Metformin Hydrochloride (Drug)
Placebo group
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.
干预措施: Calcium and Vitamin D (Drug)
结局指标
主要结局
Rate of symptomatic outcome
时间窗: Day 0 to Day 18
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
次要结局
- Reduction in pro-inflammatory and innate immune responses at day 1 post-infection(Day 0 to Day 32)