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

2020-02-17 18:20:55 | BioPortfolio

Summary

To address Aim 1, the investigators will conduct an open-label healthy volunteer study. The study team will recruit 48 healthy adult subjects 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 the investigators propose will ensure that the volunteers are likely to be healthy and not be on long-term medication for other concurrent medical conditions. Informed written consent will be obtained before any physical examination is performed. All consented subjects will undergo health screening, which includes a full physical examination, safety blood tests such as full blood count, renal, lipid and liver panel, C-Reactive Protein (CRP) test and urinary pregnancy test (for female subjects of child-bearing potential), and HbA1c to exclude diabetes mellitus. Eligible subjects will be randomized into 4 groups to receive metformin 850mg or 1000mg once or twice daily for 10 days. Aim 1 tests the hypothesis that metformin reduces ER stress in a dose-dependent manner. The primary objective of aim 1 is to define the dose and kinetics of metformin in modulating ER stress in whole blood of healthy adult volunteers.

Description

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 physical examination is performed. All consented subjects will undergo health screening, which includes a full physical examination, safety blood tests such as full blood count, renal, lipid and liver panel, C-Reactive Protein (CRP) test and urinary pregnancy test (for female subjects of child-bearing potential), and HbA1c to exclude diabetes mellitus.

Study Visits and Procedures: All eligible subjects will proceed to Day 0, where they will be randomized into 4 groups to receive metformin 850mg or 1000mg once or twice daily for 10 days. As this is an open-label trial, both the subject and study team will be made known of the allocated group. Subjects will report to the SingHealth IMU on Days 0, 3, 5, 7 and 10 for research blood sampling. Venous blood will be collected via venepuncture for laboratory analyses immediately before metformin dosing (Day 0), and then at Day 3, 5, 7 and 10. The schedule for blood draws will be identical for all study groups. For our primary end points evaluation, bloods for gene expression, omics-analyses pre-metformin (Day 0) and with metformin (Days 3, 5, 7 and 10) will be assessed. All research blood samples will be stored at -80C 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.

Post Study Follow up and Procedures: Subjects will be monitored over a 2-week period starting immediately after metformin dosing (Day 0). Based on the known pharmacokinetics of metformin, a total duration of 14 days' follow-up would be adequate for side effects monitoring. Subjects will be advised to document any local and systemic symptoms that they may experience after metformin dosing using a standardised symptoms diary. The diary will be collected on the last visit (Day 10) and a copy will be given back to subject. Days 11-14 will be followed up via telephone call by a delegated study team member. Any symptoms experienced by the subject will be documented into the diary by the study team member. Should the subjects develop systemic symptoms that require intervention, they will report to the SingHealth IMU for medical evaluation and receive the appropriate therapy if necessary. Any other concomitant medication use during this period will also be recorded.

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.

Known common adverse events of metformin include diarrhoea, nausea, stomach pain, heartburn and bloatedness. Rare AEs include lactic acidosis and hypoglycaemia. Limiting the duration of metformin dosing to 10 days would further reduce the risk of these serious AEs. Subjects will be trained to look out for early symptoms associated with these AEs and to report to IMU immediately should they experience any of these symptoms. Details of AE event terminology, date and time of event start and end, severity, using the CTCAE or treatment given, impact on work and to the continuation of the study, and final outcome of the event will be recorded on the case report until resolution of the event.

During the study, the investigator will recruit the subjects, as well as perform full history taking and physical examination at both scheduled and unscheduled visits. The investigator will also review the subject's diaries for any potential side effects and manage the AEs based on best clinical practice should they arise. Compliance to study protocol will be checked by taking a medication history, and pill count and inspection of diary as well as measurement of metformin drug level at specific time points.

Data Quality Assurance: The PI and Co-Is will review the study periodically for data and safety monitoring. Internal quality checks will be performed by two CRCs who are study team members. The data entered by one CRC will be checked by another using the source documents. The study may also be picked for monitoring by SingHealth Office of Research Integrity and Compliance (ORIC) or evaluated by government inspectors/regulatory authorities who must be allowed access to e-CRFs, source documents, and other study files. The monitors/inspectors may 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.

Data Entry and Storage: All participant's data will be de-identified upon recruitment. Hardcopy research data collection forms such as CRFs, logs and diaries will be kept in the Investigator's Site File and stored in SingHealth IMU under lock and key, accessible only to delegated study team members. Direct data capture of demographic and clinical data will be captured on source documents. Identifiers will be kept in a separate file in another office and every effort will be made to protect the privacy of the participants. The data to be analysed will contain only de-identified data. An electronic data capture system will be used. All electronic data will be password protected and can only be accessed by study team members. Specimens, test results or pathogen data will be stored at Duke-NUS EID laboratory in a stand-alone PC whereby access is password protected.

Determination of Sample Size: Our preliminary data shows that 750mg once a day with a less efficient formulation of metformin led to about 0.7 SD decline in indicators of ER stress. The investigators hypothesized that in the present study, there will be a 0.7 SD difference between two groups. Using the randomized screening trial design for prioritization of new treatments as candidates for future phase III evaluation (Rubinstein et al. JCO 2005), a sample size of 12 per arm will offer 80% power and 20% one-sided type I error rate. Thus, the total sample size is 48 in total.

From our previous experience with healthy volunteer studies conducted in IMU, there were no dropouts when follow-up period is less than one month. Therefore, the investigators are confident that they can recruit sufficient number of subjects within the trial period and there is no need to inflate the sample size to allow for loss to follow-up for the main analysis.

Statistical analysis: The investigator will assess the change in ER stress variables from day 0 to day 5 and from day 5 to day 10. Diagnostic plots will be used to determine the choice of using the raw data or log-transformed data in parametric analyses or non-parametric analyses. The primary analyses will compare changes from day 0 to day 5 and from day 5 to day 10 between groups. As per Rubinstein's randomized screening trial design, the best treatment will be the candidate for future phase III confirmatory trial. Secondary analyses will pool all groups and time-points into regression modeling of the effects of dose, frequency, time and their interaction.

Gene expression studies: Gene expression in whole blood would be carried out using Nanostring nCounter assay. This assay provides a multiplex approach to identify the genes that the investigator have previously used to validate the hits from the microarray that identified adaptive ER stress as a susceptibility factor for symptomatic YF17D infection (see preliminary data). Importantly, the investigator have worked with Nanostring, to customize a comprehensive set of probes that are able to directly quantify mRNA transcripts in the ER stress and TCA cycle pathways, which would be the target genes in this trial. This approach is also chosen due to the CSA budget constraint. Nonetheless, the study team will collect extra clinical samples as backup and explore the use of RNAseq to discover the pharmacogenomics of metformin through additional funding from other grant sources.

This proposed gene expression study will be carried out at the Viral Research and Experimental Medicine Centre @ SingHealth Duke-NUS (ViREMiCS). ViREMiCS was established by the PI and collaborator, Eng Eong Ooi as a research centre in the SingHealth Duke-NUS Academic Medicine Centre partnership. It has established a suite of molecular and systems biology tools to support and accelerate proof-of concept clinical trials. The investigators thus do not anticipate any problem in using this approach to measure gene expression in blood samples.

Metabolomic profiling: Plasma metabolomics will be examined using capillary electrophoresis/mass spectrometry (CE/MS), as the investigator have previously employed to measure the polar metabolites from glycolysis and TCA cycle [18, 25]. These assays will be outsourced to a Japan-based company (Integrated Human Metabolomics), which the investigators have previously engaged on a fee-for-service basis.

Determination of metformin blood level: Metformin levels will be measured via a liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay method. The assay will be performed on a Shimadzu 8060 LC-MS/MS system, which is available at the Singapore General Hospital.

Study Design

Conditions

Endoplasmic Reticulum Stress

Intervention

Metformin Hydrochloride

Status

Not yet recruiting

Source

Singapore General Hospital

Results (where available)

View Results

Links

Published on BioPortfolio: 2020-02-17T18:20:55-0500

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Medical and Biotech [MESH] Definitions

A system of cisternae in the CYTOPLASM of many cells. In places the endoplasmic reticulum is continuous with the plasma membrane (CELL MEMBRANE) or outer membrane of the nuclear envelope. If the outer surfaces of the endoplasmic reticulum membranes are coated with ribosomes, the endoplasmic reticulum is said to be rough-surfaced (ENDOPLASMIC RETICULUM, ROUGH); otherwise it is said to be smooth-surfaced (ENDOPLASMIC RETICULUM, SMOOTH). (King & Stansfield, A Dictionary of Genetics, 4th ed)

Various physiological or molecular disturbances that impair ENDOPLASMIC RETICULUM function. It triggers many responses, including UNFOLDED PROTEIN RESPONSE, which may lead to APOPTOSIS; and AUTOPHAGY.

A pharmaceutical preparation of sitagliptin phosphate and metformin hydrochloride that is used in the treatment of TYPE 2 DIABETES.

A type of endoplasmic reticulum lacking associated ribosomes on the membrane surface. It exhibits a wide range of specialized metabolic functions including supplying enzymes for steroid synthesis, detoxification, and glycogen breakdown. In muscle cells, smooth endoplasmic reticulum is called SARCOPLASMIC RETICULUM.

One of the BASIC-LEUCINE ZIPPER TRANSCRIPTION FACTORS that is synthesized as a membrane-bound protein in the ENDOPLASMIC RETICULUM. In response to endoplasmic reticulum stress it translocates to the GOLGI APPARATUS. It is activated by PROTEASES and then moves to the CELL NUCLEUS to regulate GENETIC TRANSCRIPTION of GENES involved in the unfolded protein response.

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