Recent studies have identified an association between Alzheimer's Disease (AD) and an expansion of DNA content in the brain (prefrontal cortex). This additional DNA content appears to be derived from reverse transcriptase (RT) activity that incorporates genomic cDNAs (gencDNAs) into chromosomes, resulting in multiple copies of full length and shorter cDNAs involving many genes - including the causal AD gene amyloid precursor protein (APP). Accumulation of these APP gencDNAs is associated with AD. This identifies RT as a promising therapeutic target for the attenuation of AD progression through existing reverse transcriptase inhibitors (RTi's) that have been widely used for treating HIV and hepatitis B. Since this class of drugs has been in the clinic for over 3 decades, there are significant data supporting their post-approval safety for long-term use. However, this has not been specifically addressed in the target population - patients with mild cognitive impairment (MCI), particularly women - who are underrepresented in HIV datasets. This proposed Phase I safety trial will perform a Special Population Study in a cohort of MCI patients who may benefit from the intervention. This study aims to (1) evaluate the safety and tolerability of standard dose FTC or Descovy for 3 months in MCI patients; (2) as secondary aims, collect preliminary data on clinical effects of standard dose FTC or Descovy compared to placebo for 3 months on cogntiive function in MCI patients; and (3) collect preliminary data on clinical effects of standard dose FTC or Descovy compared with placebo on AD-associated inflammatory markers. Participants will be randomized into either Descovy or FTC arms in equal numbers, and receive either active drug or placebo. Participants will orally ingest 1 capsule or tablet (depending on drug arm) daily for the 3 month participation period. The investigators hypothesise that MCI are not at increased risk of adverse effects due to administration of standard dose FTC or Descovy.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
48
Capsule, 200mg FTC. White Opaque Body / Light Blue Opaque Cap with "GILEAD" and Gilead logo on body. "200 mg" on cap printed in black.
Emtricitabine (FTC) 200 mg / Tenofovir Alafenamide (TAF) 25 mg. Tablets, Rectangular-Shaped, Debossed, Film-coated blue.
Placebo to Match Emtricitabine 200mg/Tenofovir Alafenamide 25mg. Tablets, Rectangular-Shaped, Debossed, Film-Coated Blue.
White Opaque Body/Light Blue Opaque Cap with "GILEAD" and Gilead logo on body, "200 mg" on cap printed in black.
National University Hospital
Singapore, Singapore
RECRUITINGNumber of participants with treatment-related Adverse/Serious Adverse Events (AE/SAE)
Number of participants with treatment-related AE/SAEs as assessed on the CTCAE Version 4.0. Incidence rate (n = x, and %), cause, and type of AE/SAE will be compared across the active drug and placebo groups.
Time frame: From enrollment to the end of treatment at 12 weeks (measured from participant's baseline visit).
Change in circulating Beta-Amyloid 40 (Aβ40), Beta-Amyloid 42 (Aβ42) and Aβ-40: Aβ-42 ratio from baseline.
Changes in plasma Aβ-40 and Aβ-42 levels; and Aβ40:Aβ42 ratio from baseline visit to week 12 visit, as assessed on Single Molecular Array (SIMOA). Units: pg/mL. No reference range is reported as significant variation exists across cohorts.
Time frame: From enrollment to the end of treatment at 12 weeks (measured from participant's baseline visit).
Change in Phospho-Tau217 (Ptau217) from baseline.
Change in total plasma Ptau217 levels from baseline visit to week 12 visit, as assessed on Single Molecular Array (SIMOA). Units: pg/mL. No reference range is reported as significant variation exists across cohorts.
Time frame: From enrollment to the end of treatment at 12 weeks (measured from participant's baseline visit).
Change in Interleukin-6 (IL-6) levels from baseline.
Change in serum IL-6 levels from baseline to week 12 visit, as assessed on Luminex Multiplex Analyser. Units: pg/mL. No reference range is reported as significant variation exists across cohorts.
Time frame: From enrollment to the end of treatment at 12 weeks (measured from participant's baseline visit).
Change in Interleukin-8 (IL-8) levels from baseline.
Change in serum IL-8 levels from baseline to week 12 visit, as assessed on Luminex Multiplex Analyser. Units: pg/mL. No reference range is reported as significant variation exists across cohorts.
Time frame: From enrollment to the end of treatment at 12 weeks (measured from participant's baseline visit).
Change in Tumor Necrosis Factor-alpha (TNFα) levels from baseline.
Change in serum TNFα levels from baseline to week 12 visit, as assessed on Luminex Multiplex Analyser. Units: pg/mL. No reference range is reported as significant variation exists across cohorts.
Time frame: From enrollment to the end of treatment at 12 weeks (measured from participant's baseline visit).
Change in Mini Mental State Exam scores (MMSE).
Change in MMSE total scores from baseline visit to week 12 visit, to assess changes in cognitive function. Scores range from 0 - 30, with higher scores indicating better cognitive function.
Time frame: From enrollment to the end of treatment at 12 weeks (measured from participant's baseline visit).
Change in Quick Dementia Rating Scores (QDRS) from baseline.
Change in QDRS total scores from baseline visit to week 12 visit, to assess changes in cognitive function. Scores range from 0 - 30, with higher scores indicating greater cognitive and functional impairment.
Time frame: From enrollment to the end of treatment at 12 weeks (measured from participant's baseline visit).
Change in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scores from baseline.
Change in RBANS total and index scores from baseline to week 12 visit to assess changes in cognitive function. The battery consists of 5 indexes: 1) Immediate Memory, 2) Visuospatial/Constructional, 3) Language, 4) Attention, and 5) Delayed Memory and 12 subtests which are indexed and scored according to standardized RBANS criteria - adjusting for age and education): Immediate Memory: List Learning, Story Memory; Visuospatial/Constructional: Figure Copy, Line Orientation; Language: Picture Naming, Semantic Fluency; Attention: Digit Span, Coding; Delayed Memory: List Recall, List Recognition, Story Recall, Figure Recall. Raw scores of all 12 subtests will be converted to age- and education-adjusted scaled scores before calculating an index score for each domain. Sum of index scores will then be converted to a Total Scale score. Scaled scores range from 40 - 160, with higher scores indicating higher overall cognitive function.
Time frame: From enrollment to the end of treatment at 12 weeks (measured from participant's baseline visit).
Change in Colour Trials Test (CTT) scores from baseline.
Change in CTT (Trial 1 \& 2) completion times from baseline to week 12 visit, to assess changes in attention and sequencing. Units: Time-to-completion (seconds) for each Trial. A range of time-to-completion of 3-8 minutes is reported in the CTT manual, with longer completion times indicative of impaired attention and sequencing.
Time frame: From enrollment to the end of treatment at 12 weeks (measured from participant's baseline visit).
Change in Activities of Daily Living (ADL) scores from baseline.
Change in Independent ADL scores from baseline to week 12 visit, as assessed on the Activities of Daily Living Preventative Instrument (ADCS-ADL-PI) - comprising 15 ADL and 5 physical function questions covering complex activities typically conducted by most during independent living (e.g. handling money, shopping, remembering plans and appointments). ADLs are scored on a 5-point Likert scale. Total scores range from 0 - 45, with higher scores indicating less functional impairment.
Time frame: From enrollment to the end of treatment at 12 weeks (measured from participant's baseline visit).
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