Trial of Oxaloacetate in Alzheimer's Disease (TOAD)

Phase 1

Completed

Brief Summary: The purpose of this study is to determine if oxaloacetate (OAA) is safe and tolerable at doses of up to 2 grams per day in people with Alzheimer's disease (AD).

Detailed Description: Alzheimer's disease (AD) is a progressive brain disorder that causes memory and thinking problems. The exact cause of AD is unknown. Researchers believe mitochondria (the part of your cells that produce energy) might be linked to symptoms of AD. Some studies have shown that the brains in patients with Alzheimer's disease have reduced mitochondrial activity, have fewer mitochondria present in the nerve cells, and have reduced ability to utilize glucose (sugar) for energy.

Oxaloacetate (OAA) is a natural chemical that has been shown to have an effect on brain mitochondrial activity and brain energy in non-human animals.

This study is divided into two parts. In the first part of the study, researchers will test whether a dose of 1 gram per day of OAA, taken for approximately 4 weeks in 15 people with AD is safe and tolerable. After all 15 participants in part 1 have completed their participation, and it is determined that the study drug was safe at this dose, the second part of the study will begin. In part 2, researchers will test a dose of 2 grams per day of OAA, taken for approximately 4 weeks in 15 people with AD, to assess safety at this dose.

Participants will be in this study for about 10 weeks.

Recruitment & Eligibility

Inclusion Criteria

Have a diagnosis of probable Alzheimer's disease (AD) per McKhann et al. criteria [9];
Have a clinical dementia rating (CDR) score of 0.5 or 1 at time of their last University of Kansas Alzheimer's Disease Center (KU ADC) assessment;
Have a Mini Mental Status Exam (MMSE) score of 15-28 at the TOAD screening visit;
Have a reliable and competent study partner who is willing to accompany the participant to all study visits, monitor compliance of study medication administration, and observe/report any changes in the participant's health throughout the study duration;
Are on stable doses of concurrent medications for at least 4 weeks prior to the TOAD screening visit; and
Speaks English as his/her primary language.
If female of child-bearing potential, must have a negative urine pregnancy test at TOAD screening visit (and must agree to use of contraception throughout the trial)

Exclusion Criteria

Dementia due to causes other than AD;
Potentially confounding, serious, or unstable medical conditions such as:
- insulin-dependent diabetes mellitus
- cancer within the past 3 years (except basal cell, squamous cell, or localized prostate cancer)
- a recent cardiac event (i.e. heart attack, angioplasty, etc. within the 6 months prior to screening visit)
- other conditions that pose a potential safety risk or confounding factor in the investigator's opinion;
Any abnormal physical examination assessment or vital sign assessment at TOAD screening visit that is deemed to be clinically significant by the principal investigator;
Any abnormal clinical laboratory test result at TOAD screening visit that is deemed to be clinically significant by the principal investigator.
Any contraindication for undergoing magnetic resonance spectroscopy (MRS), such as the presence of metal implants, a cardiac pacemaker that is not compatible with MRS, or severe claustrophobia

Arm && Interventions

Group	Intervention	Description
Part 1 - Oxaloacetate (OAA) 1 gram/day	Oxaloacetate (OAA) 1g	Participants take 1 gram of OAA per day for period of 4 weeks
Part 2 - Oxaloacetate (OAA)2 gram/day	Oxaloacetate (OAA) 2g	Participants take 2 grams of OAA per day for period of 4 weeks

Primary Outcome Measures

Name	Time	Method
Number of Dose Limiting Toxicity Events	Change from Baseline to Week 4	The number of dose limiting toxicity events will be determined by change in safety labs, physical and neurological exams, vital signs, cognitive measures, signs and symptoms.

Secondary Outcome Measures

Name	Time	Method
Change in Brain Glucose Metabolic Rate as Determined by Fluorodeoxyglucose Positron Emission Tomography (FDG PET)	Change from Baseline to Week 4	Fluorodeoxyglucose positron emission tomography (FDG PET)
Change in Brain Lactate Levels as Determined by Magnetic Resonance Spectroscopy (MRS)	Change from Baseline to Week 4	magnetic resonance spectroscopy (MRS)
Plasma Levels in 500 mg Bid Cohort at Baseline, 60 and 90 Minutes Post-Dose	Change from dose to 60 min post dose and 90 min post dose	For the 1 g/ day (500 mg bid) cohort, baseline blood sample will be obtained just before 500 mg OAA is administered. Blood samples to be drawn again at 60 min and 90 min post administration of dose. The amount of OOA in the blood will be measured at each of the three time points.
Plasma Levels in 1000 mg Bid Cohort at Baseline, 60 and 90 Minutes Post-Dose	Change from dose to 60 min post dose and 90 min post dose	For the 2 g/ day (1000 mg bid) cohort, baseline blood sample will be obtained before 1000 mg OAA is administered. Blood samples to be drawn again at 60 min and 90 min post administration of dose. Plasma levels of OOA will be measured at each of the three timepoints.