A Pilot Study of the Effects of Bacillus Calmette-Guérin (BCG) Immunization on Cerebrospinal Fluid and Blood-based Biomarkers in Older Adults.

Sponsor

Massachusetts General Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT04507126

Collaborator

(none)

Enrollment

Location

Arm

Actual Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A pilot study of the effects of Bacillus Calmette-Guérin (BCG) immunization on cerebrospinal fluid and blood-based biomarkers in older adults.

Condition or Disease	Intervention/Treatment	Phase
Mild Cognitive Impairment Healthy	Biological: Bacillus Calmette-Guerin (BCG)	Early Phase 1

Detailed Description

This single-site, open-label clinical trial will investigate the immune and neurobiological effects of BCG vaccination in cognitively unimpaired older adults and older adults with memory and thinking problems by measuring target engagement, pharmacodynamic response, and effect on Alzheimer's disease (AD) pathology and immune response markers. This study will also gather data on study feasibility, tolerability, and safety.

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

Effects of BCG Immunization on Cerebrospinal Fluid and Blood-Based Biomarkers in Older Adults: A Pilot

Actual Study Start Date :

Mar 1, 2021

Actual Primary Completion Date :

Apr 1, 2022

Actual Study Completion Date :

Apr 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BCG Immunization All participants will receive two Bacillus Calmette-Guérin (Japan BCG) vaccine injections spaced four week apart. Each injection will have 1.8-3.9 x 10^6 colony forming units (CFU) reconstituted in 0.1 mL saline.	Biological: Bacillus Calmette-Guerin (BCG) Vaccine

Arm

Intervention/Treatment

Experimental: BCG Immunization

All participants will receive two Bacillus Calmette-Guérin (Japan BCG) vaccine injections spaced four week apart. Each injection will have 1.8-3.9 x 10^6 colony forming units (CFU) reconstituted in 0.1 mL saline.

Biological: Bacillus Calmette-Guerin (BCG)

Vaccine

Outcome Measures

Primary Outcome Measures

CSF biomarkers of pharmacodynamic response- cytokines [Day 84]
Change in concentration of circulating cytokines in CSF from baseline
CSF biomarkers of AD pathology-ATN [Day 84]
Change in concentration of ATN markers of AD pathophysiology (Amyloid-β42/40, phospho-tau, total tau and neurofilament light protein biomarkers) in CSF from baseline.
Blood biomarkers of pharmacodynamic response- cytokines [Day 28]
Change in concentration of circulating cytokines in blood from baseline.
Blood biomarkers of pharmacodynamic response- cytokines [Day 84]
Change in concentration of circulating cytokines in blood from baseline
Blood biomarkers of AD pathology [Day 28]
Change in concentration of ATN markers of AD pathophysiology (Amyloid-β42/40, phospho-tau, total tau and neurofilament light protein biomarkers) in blood from baseline.
Blood biomarkers of AD pathology [Day 84]
Change in concentration of ATN markers of AD pathophysiology (Amyloid-β42/40, phospho-tau, total tau and neurofilament light protein biomarkers) in blood from baseline.

Secondary Outcome Measures

Cognitive Measures (RBANS) [Day 84]
Change from baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score

Eligibility Criteria

Criteria

Ages Eligible for Study:

55 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Study subjects meeting all the following criteria will be allowed to enroll in the study:

Age 55-80 inclusive;
MoCA ≥18;
Normal cognition as defined by MoCA ≥ 26 or MCI as defined by the NIA-AA Workgroup (2011) and MoCA score between 18 and 25 (inclusive);
Education level, English language skills, and literacy indicates subject will be able to complete all assessments;
Ability to provide informed consent;
Willing and able to complete all assessment and study procedures, including blood draws, lumbar punctures, and clinical assessments;
If on cholinesterase inhibitor and/or memantine, doses are stable for 3 months prior to baseline;
Negative test results for HIV antibody and Tuberculosis (QuantiFERON) at screening;
No prior BCG exposure either through birth vaccinations (born in North American) or BCG bladder cancer treatment.
Documentation of current flu season vaccination dated at least 60 days prior to baseline visit.

Exclusion Criteria:

Study subjects meeting any of the following criteria will not be allowed to enroll in the study:

History of chronic infectious disease, such as HIV or untreated or active hepatitis;
History of tuberculosis, positive interferon-gamma release assay (IGRA, also known as the QuantiFERON-TB test), including a test with a high reactivity to mycobacteria of non-tuberculosis variety;
Prior BCG vaccination, positive T-spot tuberculosis test or a T-spot test showing significant Mycobacteria exposure;
A positive SARS-CoV-2 PCR result within 3 months of screening, or known close contact with a confirmed COVID-19 positive person or symptoms highly suspicious for COVID-19 (per CDC guidelines) within 1 month of screening, including fever, cough, shortness of breath, chills, muscle pain, new loss of taste or smell, vomiting or diarrhea, and/or sore throat, based on clinician's judgment;
History of treatment with metformin within the past one year;
Previous participation (ever) in active immunization research for AD or passive immunotherapy or other disease-modifying treatments for AD within the past three months;
Current treatment with immunosuppressants (calcineurin inhibitors, corticosteroids, or biological or cytotoxic immunosuppressants, or disease or condition likely to require high dose steroid or immunosuppressive therapy);
Other conditions or treatments associated with increased risk of infections or treatment with immunosuppressive medications for any reason;
Current treatment with aspirin > 160 mg/day or chronic, daily NSAIDs;
Chronic use of antibiotics;
History of keloid formation;
Living with someone who is immunosuppressed and/or at high risk for infectious diseases (for example, HIV+ or taking immunosuppressive medications for any reason), or in a job (e.g. healthcare) in which the subject works with immunosuppressed populations;
Other/confounding neurological or psychiatric condition, unstable medical or psychiatric conditions, contraindications to BCG use and lab abnormalities or concurrent medication use posing risk for BCG or study procedures;
Laboratory abnormalities in B12, Folate, TSH, or other common laboratory parameters that may contribute to cognitive dysfunction;
Laboratory abnormalities in CBC, electrolytes, LFTs, BUN, Cr, total serum immunoglobulins, ESR, CRP, or urinalysis posing risk to treatment with BCG per clinician judgment;
Laboratory abnormalities in PT-INR, which would pose a risk to performing the lumbar puncture procedure;
Discontinuation of cholinesterase inhibitor or memantine within one month (28 days) prior to baseline visit;
Females who are pregnant, lactating or of child-bearing potential;
If male with female partner(s) of childbearing potential, unwilling or unable to adhere to contraception requirements specified in the protocol.
Administration of live vaccine <60 days prior to Baseline.
Increased intracranial pressure as determined on a fundoscopy/neurological examination performed within 30 days of LP;
COVID-19 vaccination < 60 days prior to baseline or within 14 days of BCG immunizations.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Translational Research Unit	Charlestown	Massachusetts	United States	02124

Sponsors and Collaborators

Massachusetts General Hospital

Investigators

Principal Investigator: Steven E Arnold, MD, Massachusetts General Hospital
Principal Investigator: Denise Faustman, MD, PhD, Massachusetts General Hospital