Investigators propose a phase 1b/2a, randomized, double-blind, placebo-controlled, parallel group dose finding and biomarker study to evaluate the safety, tolerability, and biomarker activity of 2-HOBA in 48 MCI/AD participants. Participants will be randomized 1:1:1:1 to receive 250, 500, 750 mg 2-HOBA acetate TID or placebo for 16 weeks. Blood and cerebral spinal fluid (CSF) will be collected to measure markers of protein modification by dicarbonyls (IsoLGs- \& MDA), pTau-181, YKL-40, and NF-L.
This is a phase 1b/2a, randomized, double-blind, placebo-controlled, parallel group dose finding and biomarker study to evaluate the safety, tolerability, and biomarker activity of 2-HOBA in 48 MCI/AD participants. Participants will be randomized 1:1:1:1 to receive 250, 500, 750 mg 2-HOBA acetate TID or placebo for 16 weeks. Blood and CSF will be collected to measure markers of protein modification by dicarbonyls (IsoLGs- \& MDA), pTau-181, YKL-40, and NF-L. Investigators anticipate screening 120 subjects to randomize up to 60 subjects with the goal of 48 patients completing the study (allowing for up to 25% dropout) for the 16-week study. The primary aims of this project are to 1) Provide proof-of-concept that 2-HOBA protects proteins from covalent modification by inhibiting lysine-reacting dicarbonyls in the human brain. Investigators hypothesize that 16 weeks of 2-HOBA treatment will significantly reduce CSF levels of the dilysyl-MDA and IsoLG adduct of CSF proteins in a dose-responsive relationship. 2) Evaluate whether 2-HOBA is safe for extended use in patients with early AD. Investigators hypothesize that 2-HOBA will be safe and well tolerated through 16 weeks of use. Tolerability will be assessed by monitoring symptoms, adverse events, vital signs, ECG, and safety labs during the study. The secondary aims are to evaluate the effect of 2-HOBA treatment on AD biomarkers, brain inflammation, disease severity, and cognitive performance.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
2-hydroxybenzylamine acetate (2-HOBA) is taken three times per day for 16 weeks
Placebo taken three times per day for 16 weeks.
Center for Cognitive Medicine, Vanderbilt University Medical Center
Nashville, Tennessee, United States
Safety/Tolerability (adverse events)
Rates of adverse events will be compared between active and placebo arms and presented as summary statistics.
Time frame: Baseline to week 16
Change in dicarbonyl protein adducts
Change in CSF levels of the dilysyl-malondialdehyde crosslink and the lysyl-levuglandin adduct of CSF proteins in a dose-responsive relationship
Time frame: Baseline to week 16
Compliance
Treatment compliance will be assessed through pill counts at Week 8 and 16
Time frame: Baseline to week 16
Measurement of biomarker, p-Tau181
Change in phosphorylated-Tau-181 levels in CSF and plasma:
Time frame: Baseline to week 16
Measurement biomarker, human cartilage glycoprotein 39 (YKL-4)
Change in plasma concentration of human cartilage glycoprotein 39 (YKL-4)
Time frame: Baseline to week 16
Measurment of biomarker, neurofilaments light chain protein (NF-L)
Change in the concentration of neurofilaments light chain protein (NF-L) in CSF and plasma
Time frame: Baseline to week 16
Measurement of biomarker, F2-Isoprostanes
Change in concentration F2-Isoprostanes in plasma and urine:
Time frame: Baseline to week 16
Measurement of biomarker, 8-hydroxy-2'-deoxyguanosine
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Enrollment
48
Change in concentration of 8-hydroxy-2'-deoxyguanosine in plasma
Time frame: Baseline to week 16