Vaccination Efficacy With Metformin in Older Adults (VEME)

Vaccination Efficacy With Metformin in Older Adults: A Pilot Study

With aging the immune system gets weaker. This makes older adults more susceptible to influenza (flu). Vaccinations help to prevent infection from the flu virus, however the immune system of older adults do not respond as well to vaccines compared to young adults and thus, aren't as well protected from the complications from the flu. This research is being done to determine if Metformin, an FDA-approved diabetes medication, is effective at enhancing immune responses to flu vaccine in older men and women. Participants will be randomly assigned to either metformin or placebo treatment for a total of 22 weeks. Participants will be vaccinated with high-dose flu vaccine after 12 weeks of treatment. Immune responses will be evaluated throughout the study at 6 time points.

Study Overview

• Status: Completed
• Conditions: Aging; Vaccine Response Impaired; Age-Related Immunodeficiency
• Intervention / Treatment: Drug: Metformin Hydrochloride Extended-Release Tablets; Biological: Influenza Vaccine

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • UCONN Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 63 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men and women 65 years and older
• Willingness to provide consent and participate in all aspects of the trial including randomization to the intervention group and receiving this year's flu vaccine
• Received previous year's seasonal influenza vaccine

Exclusion Criteria:

• History of severe renal impairment and/or eGFR ≤ 45 mL/min/1.73m2
• Excessive alcohol use (more than 14 alcoholic drinks/week) or clinical/laboratory evidence of hepatic disease (via medical history and/or AST and/or ALT ≥ 3 times upper limit of normal at screening)
• Acute or chronic metabolic acidosis (via medical history and/or low serum bicarbonate (< 22mEq/L), increased anion gap (> 10 mEq/L))
• History of B12 deficiency within the last 10 years
• Known type 2 diabetes or screening of prediabetic (HbA1c 5.7-6.4%) or diabetic (HbA1c ≥ 6.5%)
• Currently taking metformin or other diabetes medications
• Unwilling or unable (due to significant cognitive impairment) to provide informed consent
• Terminal illness with life expectancy less than 12 months
• Advanced neurological disorder (Parkinson's, ALS, MS, dementia)
• Cancer or history of cancer in the past 2 years (excluding non-melanoma skin cancer) or any history of metastatic (stage 4) cancer
• Significant co-morbid disease (severe chronic obstructive pulmonary disease, active rheumatologic diseases, chronic infection (HIV, tuberculosis), severe congestive heart failure (NYHA class 4), myocarditis, etc)
• Myocardial infarction, stroke or hospitalization for heart failure in the last 12 months
• Severe active psychiatric disorder (e.g. bipolar, schizophrenia)
• Unable to complete physical performance testing due to medical conditions (at discretion of the PI)
• Uncontrolled hypertension (systolic/diastolic blood pressure >150/90 mmHg)
• Unintentional weight loss >10% in past 12 months
• Allergy or history of adverse reaction to flu vaccine or any ingredients in flu vaccine, including eggs
• History of Guillain-Barre syndrome following vaccination
• Immunosuppressive disorders or taking immunosuppressive medications (including oral prednisone > 10mg/day)
• Current participation in another interventional study
• Refusal to receive flu vaccine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin Hydrochloride Extended Release Tablets; Patients will consume 3 tablets of 500mg metformin hydrochloride extended-release tablets daily (1500mg/day (after 3 week dose gradation)).	Drug: Metformin Hydrochloride Extended-Release Tablets; Subjects will ingest 1500mg/day of metformin hydrochloride extended release. Immune responses will be examined prior to treatment, prior to flu vaccination, and after flu vaccination.; Other Names: metformin ER; metformin hydrochloride ER; metformin hcl ER; Biological: Influenza Vaccine; All subjects will be vaccinated with high-dose influenza vaccine at the appropriate time of the year per current CDC and FDA recommendations; Other Names: Flu Vaccine
Placebo Comparator: Placebo; Patients will consume 3 identical placebo tablets (after similar 3 week dose gradation).	Biological: Influenza Vaccine; All subjects will be vaccinated with high-dose influenza vaccine at the appropriate time of the year per current CDC and FDA recommendations; Other Names: Flu Vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cell-mediated Flu Vaccine Responses - inducible Granzyme B	Change in inducible Granzyme B levels in peripheral blood mononuclear cells (PBMCs) stimulated ex vivo with live flu virus will be compared between the metformin and placebo group.	Prior to vaccination (week 12) and 5 weeks post vaccination (week 17)
Change in Cell-mediated Flu Vaccine Responses - interferon(IFN)-γ/interleukin(IL)-10 ratio	Change in interferon(IFN)-γ/interleukin(IL)-10 ratio in culture supernatant of peripheral blood mononuclear cells (PBMCs) stimulated ex vivo with live flu virus will be compared between the metformin and placebo group.	Prior to vaccination (week 12) and 5 weeks post vaccination (week 17)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Influenza Antibody Titers	Serum antibody titers will be analyzed via hemagglutination inhibition assays (HI) via established Center for Disease Control (CDC) and World Health Organization (WHO) protocols for each vaccine strain. Change in antibody titer levels over time will be evaluated.	Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22)
Change in T Cell Metabolic Phenotype	T cells will be evaluated for phenotypic differences of glucose transporter expression via flow cytometry and reported as percent positive cells. Change in percent positive cells over time will be evaluated.	Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22)
Change in T Cell Oxygen Consumption Rate	T cells will be evaluated for oxygen consumption rate via Seahorse Agilent Technologies. Change in oxygen consumption rate over time will be evaluated.	Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22)
Change in Frailty Phenotype	Subjects will complete frailty testing via Fried Frailty Phenotype. Change in frailty phenotype over time will be evaluated.	Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22)

Collaborators and Investigators

• Sponsor: UConn Health
• Investigators: Principal Investigator: Jenna M Bartley, PhD, UCONN Health

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2019
• Primary Completion (Actual): February 4, 2020
• Study Completion (Actual): February 4, 2020

Study Registration Dates

• First Submitted: June 19, 2019
• First Submitted That Met QC Criteria: June 20, 2019
• First Posted (Actual): June 24, 2019

Study Record Updates

• Last Update Posted (Actual): July 23, 2020
• Last Update Submitted That Met QC Criteria: July 22, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Immunologic Deficiency Syndromes; Hypoglycemic Agents; Physiological Effects of Drugs; Immunologic Factors; Vaccines; Metformin
• Other Study ID Numbers: 19-205-2; 18155 (AFAR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No