Repurposing a Combination Antiretroviral Drug Therapy to Target Retrotransposons and Treat Early Alzheimer's Disease

NCT07795307 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 2026P002048UG3AG104643
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to determine the safety, tolerability, drug levels and biological effects of two doses of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) combination administered daily for 4 weeks in older adults with early Alzheimer's disease. The main questions it aims to answer are:

• Is FTC-TDF combination safe in older adults who have early Alzheimer's disease.
• To measure the FTC-TDF levels at different times.
• To measure the biological effects of FTC-TDF combination.
• To measure the effects of FTC-TDF combination on inflammation. Researchers will compare two doses of FTC-TDF combination to a placebo (a look-alike substance that contains no drug) to see if FTC-TDF combination is safe in older adults who have early Alzheimer's disease. Participants will:
• Take FTC-TDF combination or a placebo every day for 28 days.
• Have 10 clinic visits over approximately 3 months.
• Undergo blood tests, physical exams, cognitive testing, and scans of their brain.

Conditions

Alzheimer's Disease

Keywords

Antiretroviral drug therapy; Retrotransposon; Emtricitabine; Tenofovir disoproxil fumarate

Outcome Measures

Primary Outcomes (7)

• Safety and tolerability

  Treatment-emergent adverse events (AEs).

  28 days

• Safety and tolerability

  Treatment-emergent serious AEs (SAEs)

  28 days

• Safety and tolerability

  Changes in clinical laboratory tests. Specifically, will report the number of participants with abnormal laboratory values and/or AEs that are related to treatment.

  28 days

• Safety and tolerability

  Changes in blood pressure (systolic and diastolic)

  28 days

• Safety and tolerability

  Changes in physical exams. Specifically, this will reflect new or worsening findings on a general physical exam and a neurological exam performed by a study physician.

  28 days

• Safety and tolerability

  Clinical findings of 12-lead electrocardiograms (ECGs). Specifically, change in QTc interval.

  28 days

• Safety and tolerability

  Changes in pulse

  28 days

Secondary Outcomes (10)

• Pharmacokinetics (PK) Concentration average

  28 days

• Pharmacodynamics (PD)

  28 days

• Activity of reverse transcriptase

  28 days

• Markers of systemic inflammation

  28 days

• Pharmacokinetics (PK) Concentration maximum

  28 days

Study Arms (2)

FTC and TDF combination tablet

EXPERIMENTAL

FTC and TDF combination tablets at two dose strengths that are in clinical use: 133 mg FTC plus 200 mg TDF, and 200 mg FTC plus 300 mg TDF. There is a 70% chance participants will receive the FTC-TDF combination.

Drug: Emtricitabine and tenofovir disoproxil fumarate combination

Placebo

PLACEBO COMPARATOR

Placebo tablets. There is a 30% chance participants will receive placebo.

Drug: Placebo

Interventions

Placebo DRUG

Placebo tablets.

Placebo

Emtricitabine and tenofovir disoproxil fumarate combination DRUG

FTC and TDF combination tablets at two dose strengths that are in clinical use: 133 mg FTC plus 200 mg TDF, and 200 mg FTC plus 300 mg TDF.

FTC and TDF combination tablet

Eligibility Criteria

• Age: 55 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Meets National Institute on Aging-Alzheimer's Association clinical diagnostic criteria for mild cognitive impairment (MCI) or AD dementia.
• Has evidence of AD assessed by plasma p-tau217. Prior cerebrospinal fluid (CSF) or positron emission tomography (PET) amyloid testing (obtained clinically or through previous research) from the past 2 years may be used for eligibility with approval from study investigators.
• Clinical Dementia Rating (CDR) global score of 0.5 or 1.
• Mini-Mental State Exam (MMSE) score of 18 to 30 (inclusive).
• item Geriatric Depression Scale (GDS) score of \< 6.
• Impaired memory performance below an education adjusted cut-off score on the Logical Memory II subscale delayed paragraph recall of Wechsler Memory Scale-Revised (WMS-R) (≥16 years: ≤8; 8-15 years: ≤4; 0-7 years: ≤2).
• May take FDA approved medications for the treatment of AD dementia, but if taking such medications, they must be stable for at least 8 weeks before screening (for cholinesterase inhibitors and/or memantine) or 6 months (for lecanemab or donanemab).
• Has adequate visual and auditory acuity to participate in neuropsychological testing and other study outcomes.
• Has availability of a study partner who has regular contact with the participant and knows him/her well.
• Is willing and able to participate in all assessments in English.
• Is capable of providing written informed consent

You may not qualify if:

• Neurologic diseases: Neurologic disease other than AD such as Parkinson's disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia, normal pressure hydrocephalus, corticobasal syndrome, malignant brain tumor (within the last 1 year), multiple sclerosis, or significant head trauma (e.g. with loss of consciousness for 30 minutes or more) followed by persistent neurologic deficits, or significant structural brain abnormalities.
• Neuroimaging: Magnetic resonance imaging (MRI) scan evidence of cortical stroke or macrohemorrhage (\>1 cm), strategically located lacunar stroke, or severe small vessel disease.
• Alcohol or substance use disorder or dependence (Diagnostic and Statistical Manual of Mental Disorders version 5 \[DSM 5\] criteria) within the last 2 years.
• Untreated major depressive disorder (within the last 1 year), bipolar disorder, schizophrenia (DSM 5 criteria), or current major psychotic symptoms or behavioral problems.
• Any systemic illness or unstable medical conditions, which could affect valid cognitive and self-report assessments.
• Excluded medications: Antipsychotic medications; antidepressant medications with anticholinergic side effects. Washout from psychoactive medications for at least 8 weeks before screening.
• Laboratory abnormalities: AST or ALT \> 3 times the upper limit of normal; creatinine clearance \<60 mL/min; HbA1C \> 8.5%.
• Participation in an investigational trial within the past 3 months or 5 half-lives, whichever is shorter
• Conditions which, in the opinion of the investigator, would jeopardize safety or impact the validity of the study results.
• Person who is positive for HBV Surface Antigen.
• Person with a history of osteoporosis or osteomalacia.
• Person taking FTC-TDF for pre-exposure prophylaxis or treatment of HIV.

Sponsors & Collaborators

• Brigham and Women's Hospital: lead

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Related Publications (10)

• Sullivan AC, Zuniga G, Ramirez P, Fernandez R, Wang CP, Li J, Davila L, Pelton K, Gomez S, Sohn C, Gonzalez E, Lopez-Cruzan M, Gonzalez DA, Parker A, Zilli E, de Erausquin GA, Seshadri S, Espinoza S, Musi N, Frost B. A Phase IIa clinical trial to evaluate the effects of anti-retroviral therapy in Alzheimer's disease (ART-AD). NPJ Dement. 2025;1(1):2. doi: 10.1038/s44400-024-00001-z. Epub 2025 Mar 12.

  PMID: 40104524 BACKGROUND

• Wahl D, Smith ME, McEntee CM, Cavalier AN, Osburn SC, Burke SD, Grant RA, Nerguizian D, Lark DS, Link CD, LaRocca TJ. The reverse transcriptase inhibitor 3TC protects against age-related cognitive dysfunction. Aging Cell. 2023 May;22(5):e13798. doi: 10.1111/acel.13798. Epub 2023 Mar 22.

  PMID: 36949552 BACKGROUND

• Wahl D, Grant RA, LaRocca TJ. The reverse transcriptase inhibitor 3TC modulates hippocampal transcriptome signatures of inflammation in tauopathy model mice. Exp Gerontol. 2024 Jul;192:112458. doi: 10.1016/j.exger.2024.112458. Epub 2024 May 21.

  PMID: 38735597 BACKGROUND

• Valles-Saiz L, Avila J, Hernandez F. Lamivudine (3TC), a Nucleoside Reverse Transcriptase Inhibitor, Prevents the Neuropathological Alterations Present in Mutant Tau Transgenic Mice. Int J Mol Sci. 2023 Jul 6;24(13):11144. doi: 10.3390/ijms241311144.

  PMID: 37446327 BACKGROUND

• Frost B, Dubnau J. The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders. Annu Rev Neurosci. 2024 Aug;47(1):123-143. doi: 10.1146/annurev-neuro-082823-020615. Epub 2024 Jul 1.

  PMID: 38663088 BACKGROUND

• Singh S, Borkar MR, Bhatt LK. Transposable Elements: Emerging Therapeutic Targets in Neurodegenerative Diseases. Neurotox Res. 2024 Jan 25;42(1):9. doi: 10.1007/s12640-024-00688-1.

  PMID: 38270797 BACKGROUND

• Roy N, Haq I, Ngo JC, Bennett DA, Teich AF, De Jager PL, Olah M, Sher F. Elevated expression of the retrotransposon LINE-1 drives Alzheimer's disease-associated microglial dysfunction. Acta Neuropathol. 2024 Nov 27;148(1):75. doi: 10.1007/s00401-024-02835-6.

  PMID: 39604588 BACKGROUND

• Mustafin RN, Khusnutdinova EK. Involvement of transposable elements in Alzheimer's disease pathogenesis. Vavilovskii Zhurnal Genet Selektsii. 2024 Apr;28(2):228-238. doi: 10.18699/vjgb-24-27.

  PMID: 38680184 BACKGROUND

• Evering TH, Marston JL, Gan L, Nixon DF. Transposable elements and Alzheimer's disease pathogenesis. Trends Neurosci. 2023 Mar;46(3):170-172. doi: 10.1016/j.tins.2022.12.003. Epub 2022 Dec 30.

  PMID: 36588011 BACKGROUND

• Yushkova E, Moskalev A. Transposable elements and their role in aging. Ageing Res Rev. 2023 Apr;86:101881. doi: 10.1016/j.arr.2023.101881. Epub 2023 Feb 10.

  PMID: 36773759 BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Emtricitabine

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Gad A Marshall, MD

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Danielle M Lavey

CONTACT

617-732-8085; dlavey@bwh.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Study coordinators, cognitive raters, nurses, MRI technicians, lab technicians.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neurology

Model Details: Randomized, double-blind, placebo-controlled, multiple ascending dose trial

Study Record Dates

• First Submitted: August 24, 2026
• First Posted: August 31, 2026
• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: August 31, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will share

Locations

US (1)