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出境医 / 临床实验 / Vaccination Efficacy With Metformin in Older Adults (VEME)

Vaccination Efficacy With Metformin in Older Adults (VEME)

Study Description
Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Aging Age-Related Immunodeficiency Vaccine Response Impaired Drug: Metformin Hydrochloride Extended-Release Tablets Biological: Influenza Vaccine Phase 1

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description: Metformin and placebo tablets will be identical. Participants and researchers will not know treatment allocation.
Primary Purpose: Basic Science
Official Title: Vaccination Efficacy With Metformin in Older Adults: A Pilot Study
Actual Study Start Date : June 5, 2019
Actual Primary Completion Date : February 4, 2020
Actual Study Completion Date : February 4, 2020
Arms and Interventions
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 hydrochloride ER
  • metformin hcl ER
  • metformin 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 Name: 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 Name: Flu Vaccine
Outcome Measures
Primary Outcome Measures :
  1. Change in Cell-mediated Flu Vaccine Responses - inducible Granzyme B [ Time Frame: Prior to vaccination (week 12) and 5 weeks post vaccination (week 17) ]
    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.

  2. Change in Cell-mediated Flu Vaccine Responses - interferon(IFN)-γ/interleukin(IL)-10 ratio [ Time Frame: Prior to vaccination (week 12) and 5 weeks post vaccination (week 17) ]
    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.


Secondary Outcome Measures :
  1. Change in Influenza Antibody Titers [ Time Frame: Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22) ]
    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.

  2. Change in T Cell Metabolic Phenotype [ Time Frame: Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22) ]
    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.

  3. Change in T Cell Oxygen Consumption Rate [ Time Frame: Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22) ]
    T cells will be evaluated for oxygen consumption rate via Seahorse Agilent Technologies. Change in oxygen consumption rate over time will be evaluated.

  4. Change in Frailty Phenotype [ Time Frame: Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22) ]
    Subjects will complete frailty testing via Fried Frailty Phenotype. Change in frailty phenotype over time will be evaluated.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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
Contacts and Locations

Locations
Layout table for location information
United States, Connecticut
UConn Health
Farmington, Connecticut, United States, 06030
Sponsors and Collaborators
UConn Health
Investigators
Layout table for investigator information
Principal Investigator: Jenna M Bartley, PhD UConn Health
Tracking Information
First Submitted Date  ICMJE June 19, 2019
First Posted Date  ICMJE June 24, 2019
Last Update Posted Date July 23, 2020
Actual Study Start Date  ICMJE June 5, 2019
Actual Primary Completion Date February 4, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 20, 2019)
  • Change in Cell-mediated Flu Vaccine Responses - inducible Granzyme B [ Time Frame: Prior to vaccination (week 12) and 5 weeks post vaccination (week 17) ]
    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.
  • Change in Cell-mediated Flu Vaccine Responses - interferon(IFN)-γ/interleukin(IL)-10 ratio [ Time Frame: Prior to vaccination (week 12) and 5 weeks post vaccination (week 17) ]
    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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 20, 2019)
  • Change in Influenza Antibody Titers [ Time Frame: Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22) ]
    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.
  • Change in T Cell Metabolic Phenotype [ Time Frame: Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22) ]
    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.
  • Change in T Cell Oxygen Consumption Rate [ Time Frame: Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22) ]
    T cells will be evaluated for oxygen consumption rate via Seahorse Agilent Technologies. Change in oxygen consumption rate over time will be evaluated.
  • Change in Frailty Phenotype [ Time Frame: Prior to treatment (week 0), prior to vaccination (week 12), and after vaccination (week 13, 17, and 22) ]
    Subjects will complete frailty testing via Fried Frailty Phenotype. Change in frailty phenotype over time will be evaluated.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Vaccination Efficacy With Metformin in Older Adults
Official Title  ICMJE Vaccination Efficacy With Metformin in Older Adults: A Pilot Study
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description:
Metformin and placebo tablets will be identical. Participants and researchers will not know treatment allocation.
Primary Purpose: Basic Science
Condition  ICMJE
  • Aging
  • Age-Related Immunodeficiency
  • Vaccine Response Impaired
Intervention  ICMJE
  • 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 hydrochloride ER
    • metformin hcl ER
    • metformin 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 Name: Flu Vaccine
Study Arms  ICMJE
  • 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)).
    Interventions:
    • Drug: Metformin Hydrochloride Extended-Release Tablets
    • Biological: Influenza Vaccine
  • Placebo Comparator: Placebo
    Patients will consume 3 identical placebo tablets (after similar 3 week dose gradation).
    Intervention: Biological: Influenza Vaccine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 9, 2020) 		26
Original Estimated Enrollment  ICMJE
 (submitted: June 20, 2019) 		40
Actual Study Completion Date  ICMJE February 4, 2020
Actual Primary Completion Date February 4, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 65 Years and older   (Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03996538
Other Study ID Numbers  ICMJE 19-205-2
18155 ( Other Grant/Funding Number: AFAR )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jenna Bartley, UConn Health
Study Sponsor  ICMJE UConn Health
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jenna M Bartley, PhD UConn Health
PRS Account UConn Health
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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