Impact of Metformin on Immunity

Study Overview
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Brief Summary
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To determine whether metformin (MET) can improve the immune response to the pneumococcal conjugate vaccine (PCV-13) in older adults.

Detailed Description
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The objective of this study is to determine whether metformin (MET) can improve the immune response to the pneumococcal conjugate vaccine (PCV-13) in older adults, and if this effect is mediated by the gut microbiota. The proposed research projects will provide the necessary pilot data for future, more definitive, studies that will evaluate the impact of immunomodulatory therapies, such as MET therapy, on the aging immune system. The specific aims are: Aim 1. Compare PCV13 vaccine response in elderly adults (≥63 years of age) treated with MET vs. placebo. For this study, 50 elderly volunteers will be enrolled and randomly assigned to receive MET or placebo. The hypothesis that MET can improve vaccine responsiveness by measuring serotype-specific IgG concentrations before and 30 days after PCV13 administration will be tested. Aim 2. Determine whether the frequencies of immunophenotypes differ between elderly adults treated with MET vs. placebo. The mechanisms of MET's effect on the immune system by comparing immunophenotypes of MET and placebo groups between baseline and prior to PCV13 and between baseline and 30 days after PCV13 administration will be explored.

Official Title
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Metformin and Vaccine Response in Older Adults

Conditions
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Aging, Vaccine Response Impaired

Intervention / Treatment
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* Drug: Metformin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 63 to 89 years of age No history of pneumococcal vaccinations Able to take oral medications Able to provide informed consent Not currently taking metformin Exclusion Criteria: Previous vaccination with any pneumococcal vaccine Metformin within the last 6 months Contraindication for PCV13 History of severe adverse reaction associated with any vaccine component Residence in long-term care facility Diagnosis of diabetes (diagnosis of pre-diabetes okay) Chronic renal disease (or eGFR <50 mL/min) or renal failure (defined as receipt of renal dialysis or transplant) or nephrotic syndrome History of adverse reaction or contraindications associated with metformin Recent history or plan for radiocontrast Self-reported dementia or severe cognitive impairment Receipt of blood products within 6 months before enrollment History of heart disease (New York Heart Classification greater than class II; more than non-specific ST-T wave changes on the ECG) History of chronic obstructive pulmonary disease Poorly controlled blood pressure (systolic BP>160, diastolic BP>90 mmHg) History of an immunodeficiency Use of use of investigational products, antibiotics, probiotics, or systemic immunosuppressive therapy (systemic steroids) within 1 month of study start; patients who are taking these medications chronically, with no expected discontinuation during the study period would not be considered ineligible. Treatment with anticoagulants (warfarin) Donated blood within the last 2 months Subject is considered unsuitable for the study in the opinion of the investigator for any other reason

Ages Eligible for Study
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Minimum Age: 63 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>Dosage is increased over the first 3 weeks up to three 500 mg tablets a day at 3 weeks, then continued on 3 tablets daily for a further 9 weeks. | Drug: Metformin<br>* Total daily dose titrated up to 1500 mg po q day over the course of 3 weeks and continued for a total exposure of 12 weeks.<br>* Other names: Glucophage;|
| Placebo Comparator: Placebo<br>Placebo tablet dosage is increased over the first 3 weeks up to three tablets a day at 3 weeks, then continued on 3 tablets daily for a further 9 weeks. | Drug: Placebo<br>* Placebo tablets titrated up to 3 tablets over the course of 3 weeks and then continued as 3 daily for a total exposure of 12 weeks<br>* Other names: Placebo oral tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in antibody responses to PCV13 | The primary outcome will be antibody responses to PCV13. Antibody levels of each of the 13 different serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) will be compared between the pre-treatment values and the post treatment values. | Change from 4 weeks to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of immunophenotypes | The distribution of immunophenotypes will be presented descriptively at each time point for each treatment group. To determine which immunophenotypes differed between MET and placebo groups, changes will be determined using within-patient cell count ratios for each measured phenotype between baseline and 6-weeks of study drug treatment and between baseline and the 30 days after PCV13. | Baseline, 4 weeks and 8 weeks |