A Trial to Evaluate the Effects of BCG in Adults With MCI and Mild-to-Moderate AD

An Open-label Trial to Evaluate the Effects of BCG Immunization on Biomarkers of Inflammation/Immune Response and Alzheimer's Disease in Adults With Mild Cognitive Impairment and Mild-to-Moderate Dementia Due to Alzheimer's Disease

A study of the effects of Bacillus Calmette-Guérin (BCG) immunization on cerebrospinal fluid and blood-based biomarkers in older with mild cognitive impairment and mild-to-moderate to Alzheimer's disease.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease; Mild Cognitive Impairment; Mild Dementia; Moderate Dementia
• Intervention / Treatment: Biological: Biological/Vaccine: Bacillus Calmette-Guerin (BCG)

Detailed Description

This single-site, open-label trial will investigate the effects of BCG vaccination on IIR and AD biofluid biomarkers, magnetic resonance imaging (MRI) biomarkers, and neurocognitive/behavioral functioning over a one year period in older adults with mild cognitive impairment (MCI) to mild-to-moderate dementia due to AD. This study will also gather data on tolerability and safety.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Charlestown, Massachusetts, United States, 02129
      • Alzheimer's Clinical and Translational Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Individuals between the ages of 55-85;
2. MCI or moderate dementia due to AD as defined by the 2011 NIA-AA Workgroup recommendations;
3. MoCA ≥ 8 at screening;
4. Global CDR between 0.5-2 (inclusive) at screening;
5. Amyloid and/or tau biomarkers indicative of AD pathology;
6. Education level, English language skills and literacy indicates subject will be able to complete all assessments;
7. Has a study partner who, in the investigator's judgement, has frequent, direct contact with the participant at least several days a week, can accompany the participant to all visits, and is also able to provide information to study investigator/staff;
8. Willing and able to complete all assessment and study procedures, including blood and lumbar punctures, and clinical assessments;
9. If on cholinesterase inhibitor and/or memantine, doses are stable for 3 months prior to baseline;
10. Negative test results for HIV antibody and Tuberculosis (QuantiFERON) at screening;
11. No prior BCG exposure either through birth vaccinations (born in North American) or BCG bladder cancer treatment.

Exclusion Criteria:

1. History of chronic infectious disease, such as HIV or untreated or active hepatitis;
2. 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;
3. Prior BCG vaccination, positive T-spot tuberculosis test or a T-spot test showing significant Mycobacteria exposure;
4. 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;
5. History of treatment with metformin within the past one year;
6. Treatment with other investigational agents which, at the discretion of the investigator, interfere with safety and/or study outcomes;
7. 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);
8. Other conditions or treatments associated with increased risk of infections or treatment with immunosuppressive medications for any reason;
9. Current treatment with aspirin > 160 mg/day or chronic, daily NSAIDs;
10. Current (as of time of study screening) or chronic use of antibiotics;
11. History of keloid formation;
12. 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;
13. 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;
14. Laboratory abnormalities in B12, Folate, TSH, or other common laboratory parameters that may contribute to cognitive dysfunction per clinician judgment;
15. Laboratory abnormalities in CBC, electrolytes, LFTs, BUN, Cr, total serum immunoglobulins, ESR, CRP, or urinalysis posing risk to treatment with BCG per clinician judgment;
16. Laboratory abnormalities in PT-INR, which would pose a risk to performing the lumbar puncture procedure;
17. Discontinuation of cholinesterase inhibitor or memantine within one month (28 days) prior to baseline visit;
18. Females who are pregnant, lactating or of child-bearing potential;
19. If male with female partner(s) of childbearing potential, unwilling or unable to adhere to contraception requirements specified in the protocol.
20. Administration of live vaccine within 30 days of screening visit or BCG immunizations
21. Administration of non-live vaccine within 14 days of screening visit or BCG immunizations
22. If participating in optional MRI: Existing contraindication to MRI per MGH Athinoula A. Martinos Center research guidelines

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BCG; Active BCG immunization	Biological: Biological/Vaccine: Bacillus Calmette-Guerin (BCG); Two Bacillus Calmette-Guérin (Japan BCG) vaccine injections spaced four week apart. Each injection will have 0.36-3.9 x 10^6 colony forming units (CFU) reconstituted in 0.1 mL saline.; Other Names: BCG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Biomarkers of Pharmacodynamic Response- Cytokines	Change in concentration (Average difference) of circulating cytokines in blood from baseline (Average difference).Cytokines include: Plasma IFN-g (pg/ml), Plasma IL-1b (pg/ml), Plasma IL-2 (pg/ml), Plasma IL-6 (pg/ml), Plasma IL-10 (pg/ml), Plasma TNF-a (pg/ml). Mean differences (and standard deviations) from baseline values are presented for the Day 364 (end of study) sample collections for the 4 participants in the study.	Baseline to Day 364
CSF Biomarkers of Pharmacodynamic Response- Cytokines	Change in concentration (Average difference) of circulating cytokines in CSF from baseline (Average difference). Cytokines measured include: CSF IFN-g (pg/ml), CSF IL-1b (pg/ml), CSF IL-2 (pg/ml), CSF IL-6 (pg/ml), CSF IL-10 (pg/ml), CSF TNF-a (pg/ml). Mean differences (and standard deviations) from baseline values are presented for the Day 84 sample collections for the 7 participants with complete data in the study.	Baseline to Day 84
CSF Biomarkers of Pharmacodynamic Response- Cytokines	Change in concentration (Average Difference) of circulating cytokines in CSF from baseline. Cytokines measured include: CSF IFN-g (pg/ml), CSF IL-1b (pg/ml), CSF IL-2 (pg/ml), CSF IL-6 (pg/ml), CSF IL-10 (pg/ml), CSF TNF-a (pg/ml). Mean differences (and standard deviations) from baseline values are presented for the Day 364 (end of study) sample collections for the 4 participants with complete data in the study.	Baseline to Day 364
Blood Biomarkers of AD Pathology-ATN	Change in concentration (Average difference) of ATN markers of AD pathophysiology phospho-tau (217 and 181) and neurofilament light protein biomarkers in blood from baseline. Mean differences (and standard deviations) from baseline values are presented for the Day 364 (end of study) sample collections for the 4 participants in the study at this timepoint.	Baseline to Day 364
CSF Biomarkers of AD Pathology-ATN	Change in concentration (Average difference) of ATN markers of AD pathophysiology (phospho-tau181, total tau, and neurofilament light protein biomarkers in CSF from baseline. Mean differences (and standard deviations) from baseline values are presented Day 364 (end of study) sample collections for the 4 participants in the study at this timepoint.	Baseline to Day 364
Blood Biomarkers of AD Pathology-ATN	Change in concentration (Average difference) of ATN markers of AD pathophysiology (phospho-tau (217 and 181) and neurofilament light protein biomarkers in blood from baseline. Mean differences (and standard deviations) from baseline values are presented for the Day 84 sample collections for the 7 participants in the study at this timepoint.	Baseline to Day 84
CSF Biomarkers of AD Pathology-ATN	Change in concentration (Average difference) of ATN markers of AD pathophysiology (phospho-tau181, total tau, and neurofilament light protein biomarkers in CSF from baseline. Mean differences (and standard deviations) from baseline values are presented for the Day 84 sample collections for the 4 participants in the study at this timepoint.	Baseline to Day 84
Cognitive Measures (RBANS)	Change in Total Scale Index (TSI) of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Mean differences and standard deviations are expressed for the difference between the Day 84 TSI and the baseline TSI for the 7 participants in the study. The RBANS is an assessment commonly used in clinical trials to assess cognitive functioning. Scores range from 40 to 160 with lower scores indicating poorer performance, thus a score decrease would indicate a decrease in cognitive performance. A score under 78 is typically indicative of cognitive impairment.	Baseline to Day 84
Cognitive Measures (RBANS)	Change in Total Scale Index (TSI) of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Mean differences and standard deviations are expressed for the difference between the end of study TSI and the baseline TSI for the 4 participants in the study. The RBANS is an assessment commonly used in clinical trials to assess cognitive functioning. Scores range from 40 to 160 with lower scores indicating poorer performance, thus a score decrease would indicate a decrease in cognitive performance. A score under 78 is typically indicative of cognitive impairment.	Baseline to Day 364
Amyloid-β42/40 Average Difference in Blood	Average difference of ATN markers of AD pathophysiology (Amyloid-β42/40 ratio) in blood from baseline.	Baseline to Day 364
Amyloid-β42/40 Average Difference in CSF	Average difference of ATN markers of AD pathophysiology (Amyloid-β42/40) in CSF from baseline.	Baseline to Day 364
Amyloid-β42/40 Average Difference in Blood - Baseline to Day 84	Average difference of ATN markers of AD pathophysiology (Amyloid-β42/40) in blood from baseline.	Baseline to Day 84
Amyloid-β42/40 Average Difference in CSF - Baseline to Day 84	Average difference of ATN markers of AD pathophysiology (Amyloid-β42/40) in CSF from baseline.	Baseline to Day 84
Blood Biomarkers of Pharmacodynamic Response - Cytokines	Change in concentration of circulating cytokines in blood plasma from baseline. Cytokines include: Plasma IFN-g (pg/ml), Plasma IL-1b (pg/ml), Plasma IL-2 (pg/ml), Plasma IL-6 (pg/ml), Plasma IL-10 (pg/ml), Plasma TNF-a (pg/ml). Mean differences (and standard deviations) from baseline values are presented for the Day 84 sample collections for the 7 participants in the study at that time.	Baseline to Day 84

Collaborators and Investigators

• Sponsor: Steven E Arnold, MD
• Investigators: Principal Investigator: Steven Arnold, MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2022
• Primary Completion (Actual): January 15, 2024
• Study Completion (Actual): January 15, 2024

Study Registration Dates

• First Submitted: August 6, 2021
• First Submitted That Met QC Criteria: August 6, 2021
• First Posted (Actual): August 13, 2021

Study Record Updates

• Last Update Posted (Actual): April 13, 2025
• Last Update Submitted That Met QC Criteria: March 26, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Tauopathies; Neurodegenerative Diseases; Cognitive Dysfunction; Alzheimer Disease; Dementia; Immunologic Factors; Physiological Effects of Drugs; Adjuvants, Immunologic; BCG Vaccine
• Other Study ID Numbers: 2021P002577

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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