Trial of Oxaloacetate in Alzheimer's Disease (TOAD)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Trial of Oxaloacetate in Alzheimer's Disease (TOAD)

Conditions
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Alzheimer's Disease (AD)

Intervention / Treatment
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* Drug: Oxaloacetate (OAA) 1g
* Drug: Oxaloacetate (OAA) 2g


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 - Oxaloacetate (OAA) 1 gram/day<br>Participants take 1 gram of OAA per day for period of 4 weeks | Drug: Oxaloacetate (OAA) 1g<br>* Pills to be taken orally in 500mg dose two times per day<br>* Other names: Ketosuccinic acid;|
| Experimental: Part 2 - Oxaloacetate (OAA)2 gram/day<br>Participants take 2 grams of OAA per day for period of 4 weeks | Drug: Oxaloacetate (OAA) 2g<br>* Pills to be taken orally in 1000mg dose two times per day.<br>* Other names: Ketosuccinic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Dose Limiting Toxicity Events | 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. | Change from Baseline to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Brain Glucose Metabolic Rate as Determined by Fluorodeoxyglucose Positron Emission Tomography (FDG PET) | Fluorodeoxyglucose positron emission tomography (FDG PET) | Change from Baseline to Week 4 | 
| Change in Brain Lactate Levels as Determined by Magnetic Resonance Spectroscopy (MRS) | magnetic resonance spectroscopy (MRS) | Change from Baseline to Week 4 | 
| Plasma Levels in 500 mg Bid Cohort at Baseline, 60 and 90 Minutes 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. | Change from dose to 60 min post dose and 90 min post dose | 
| Plasma Levels in 1000 mg Bid Cohort at Baseline, 60 and 90 Minutes 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. | Change from dose to 60 min post dose and 90 min post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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energy metabolism, oxaloacetate