Conditions: Alzheimer's Disease (AD)
Keywords: energy metabolism oxaloacetate
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 32
Healthy volunteers: no

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.

Arms:
arm 1: Participants take 1 gram of OAA per day for period of 4 weeks arm 2: Participants take 2 grams of OAA per day for period of 4 weeks

Interventions: intervention 1: Oxaloacetate (OAA) 1g intervention 2: Oxaloacetate (OAA) 2g
Intervention descriptions: intervention 1: Pills to be taken orally in 500mg dose two times per day intervention 2: Pills to be taken orally in 1000mg dose two times per day.

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
Trial of Oxaloacetate in Alzheimer’s Disease (TOAD)  
IND # 125788 
 
Amendment 5 
 
08/31/2017 
 
 
 
 
 
Russell H. Swerdlow, MD 
Principal Investigator 
Professor of Neurology 
 
 
 
 
 
 
 
 
 
 
 
Neurology 
University of Kansas Medical Center 
3901 Rainbow Blvd 
Kansas City, KS 66160 
Phone: 913-945-6632 
Fax: 913-945-5035 
Email: rswerdlow@kumc.edu 
 


 
 
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Contents 
1.0 INTRODUCTION ....................................................................................................................................... 3 
2.0 OBJECTIVES ............................................................................................................................................. 3 
3.0 BACKGROUND ......................................................................................................................................... 4 
4.0 PARTICIPANT SELECTION ........................................................................................................................ 5 
5.0 TREATMENT PLAN ................................................................................................................................... 6 
6.0 EXPECTED TOXICITIES AND DOSING DELAY/DOSING MODIFICATIONS ................................................ 11 
7.0 DRUG FORMULATION AND ADMINISTRATION ..................................................................................... 11 
8.0 CORRELATIVE STUDIES .......................................................................................................................... 13 
9.0 STUDY CALENDAR ................................................................................................................................. 15 
10.0 MEASUREMENT OF EFFECT ................................................................................................................. 16 
11.0 ADVERSE EVENT REPORTING REQUIREMENTS ................................................................................... 16 
11.1 Notifying the FDA ............................................................................................................................ 16 
12.0 DATA AND SAFETY MONITORING ....................................................................................................... 16 
13.0 REGULATORY CONSIDERATION........................................................................................................... 17 
14.0 STATISTICAL CONSIDERATION ............................................................................................................ 18 
15.0 PUBLICATION PLAN ............................................................................................................................. 18 
16.0 REFERENCES ........................................................................................................................................ 19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1.0 INTRODUCTION 
Introductory Statement 
 
Since abnormal brain bioenergetic function may contribute to neurodysfunction and 
neurodegeneration in Alzheimer’s disease (AD), manipulating brain bioenergetics may affect the 
symptoms or alter the course of this disease.  Oxaloacetate (OAA) could offer a potential 
approach for manipulating brain bioenergetics.  There is evidence that OAA, a Krebs cycle and 
gluconeogenesis intermediate, enhances glycolysis flux, supports oxidative phosphorylation, and 
favorably modifies bioenergetics-related infrastructures. Our pre-clinical studies have also shown 
that OAA activates the brain’s insulin signaling pathway, reduces neuroinflammation, and 
activates hippocampal neurogenesis [1]. Based on these preclinical findings, a phase I 
pharmacokinetic (PK) study in six human AD subjects (the Pharmacokinetics of Oxaloacetate 
Study, or POX Study; NCT02063308) was performed. The POX Study found AD subjects 
tolerate 100 mg BID of OAA when administered over a one month period.  No adverse events 
were reported.       
 
The next logical step is to conduct a combination safety and target engagement (phase Ib) 
study to define an OAA dose that is safe and which engages brain bioenergetic metabolism. This 
study, the “Trial of OAA in AD” (TOAD) trial, is designed to accomplish these goals.  The 
TOAD trial’s primary endpoint is safety, with OAA doses that have not previously been studied 
in human AD subjects.  One of the secondary endpoints is target engagement of brain 
bioenergetics by OAA.  The TOAD trial will use magnetic resonance spectroscopy (MRS) and 
fluorodeoxyglucose positron emission tomography (FDG PET) to assess brain bioenergetic 
target engagement.  Exploratory target engagement data generated during this study will inform 
future study design. Another secondary endpoint is establishment of a pharmacokinetic profile of 
OAA at doses that have not been previously tested.      
 
It is hypothesized that OAA, when orally ingested in adequate amounts, is safe and will alter 
brain bioenergetics. We further hypothesize that the doubling of the OAA dose will result in a 
doubling of the plasma OAA concentrations and that plasma OAA levels will correlate with our 
brain bioenergetics engagement outcomes (FDG PET and MRS). The following objectives are 
proposed to test these hypotheses.                 
 
2.0 OBJECTIVES 
Primary Objective 
 
The primary objective of the TOAD trial is to determine the safety and tolerability of OAA at 
doses up to 2 g/day.  A dose escalation strategy will be used, which will involve first testing a 1 
g/day OAA dose (500 mg po BID) taken for 4 weeks in 15 AD subjects.  If this dose proves to be 
safe, 2 g/day OAA (1000 mg po BID), taken for 4 weeks in 15 subjects, will be tested.  As part 
of the safety analysis, the following measures will be obtained: pre and post-treatment vital 
signs, safety labs, physical and neurological examinations, and cognitive testing data.  We 
predict both OAA treatment doses will prove to be safe and well-tolerated. 
 
Secondary Objectives 
 
One of the secondary, exploratory objectives will be to test whether OAA (administered at 
500 mg BID or as 1000 mg BID) has an observable effect on brain bioenergetics.  Enhancement 
of brain glucose utilization on FDG PET, and changes in brain metabolism intermediates on 


 
 
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MRS, will be evaluated in both the 1 g/day dose and the 2 g/day dose cohorts.  FDG PET and 
MRS will be measured at pre-treatment (just prior to starting OAA), and at post-treatment (just 
prior to stopping OAA, after approximately one month of treatment).  The pre and post-treatment 
scans will be quantitatively analyzed and compared.  We predict a dose will be found at which 
the post-treatment FDG PET scans show increased cortical glucose utilization, and that a dose 
will be found at which the post-treatment MRS scans show increased lactate and possibly other 
metabolite changes.     
 
Another secondary objective is to define OAA PK properties.  Specifically, we will 
determine plasma OAA levels after 500 mg and 1000 mg doses, to determine if a maximum 
absorption capacity is reached with these doses. We will also test for correlations between 
plasma OAA levels and brain bioenergetic biomarker, as revealed by FDG PET and MRS. 
 
3.0 BACKGROUND 
Prevalence 
 
The elderly constitute a rapidly growing demographic.  This reflects public health initiatives 
and medical advances that reduce risks and provide treatments for many previously terminal 
disorders.  An increasing population of neurodegenerative disease victims is arguably the biggest 
downside to this success.  For several common neurodegenerative diseases incidence rises with 
advancing age and prevalence is quite high [2].  Alzheimer’s disease (AD), the most common 
neurodegenerative disease, affects 5.4 million Americans and one in every eight Americans over 
65 is estimated to have it [3].  Society is also affected, as families and friends of AD patients 
provide most day-to-day care and altogether AD now costs our economy $385 billion annually 
[4].   
 
Rationale for Use 
 
Mitochondrial dysfunction occurs in AD and is felt by many to be disease-relevant and a 
promising therapeutic target [5].  In AD brains various mitochondria-localized enzymes show 
reduced activity, and in most neurons intact mitochondria are numerically reduced [5].  Glucose 
utilization, as demonstrated by FDG PET, is also reduced in the AD brain [6].  For these reasons 
we believe that for AD, increasing mitochondrial mass, mitochondrial respiration, and glucose 
utilization are all well-justified mitochondrial medicine approaches and we are currently 
exploring ways to accomplish these endpoints [7]. Our efforts are informed by caloric restriction, 
which promotes liver mitochondrial biogenesis in some but not all studies, and exercise, which 
promotes muscle mitochondrial biogenesis. While we and others find caloric restriction and 
exercise do affect the brain in specific ways, and may even induce some degree of brain 
mitochondrial biogenesis, our impression is that these interventions at best affect brain 
mitochondrial biogenesis less robustly than they affect liver and muscle. We therefore feel 
approaches that directly and robustly enhance bioenergetic fluxes (glycolysis and respiration-
related) and brain mitochondrial biogenesis pathways are needed, and predict such approaches 
will benefit persons with AD. 
 
The ideal agent would be systemically safe, cross the blood brain barrier, access neurons and 
astrocytes, activate mitochondrial biogenesis, increase respiratory capacity, and increase 
glycolysis capacity.  OAA putatively meets these criteria (see preliminary data in section 8.0 
CORRELATIVE STUDIES).   


 
 
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Description of Study Agent 
 
OAA is a Krebs cycle and gluconeogenesis intermediate.  It forms a redox pair with malate 
and is reduced to malate in a reaction that consumes NADH and generates NAD+.  This would 
predictably shift cell redox balances towards more oxidized states, an effect reported to initiate 
mitochondrial biogenesis and mediate at least some health benefits of caloric restriction and 
exercise. OAA, following its reduction to malate, can also access mitochondria and thereby 
supply carbon to the Krebs cycle and respiratory chain.  Finally, OAA is converted to 
phosphoenolpyruvate (PEP) by PEP carboxykinase (PEPCK), a reaction that comprises part of 
the gluconeogenesis and glyceroneogenesis pathways.  Muscle PEPCK overexpression, possibly 
due to enhanced glyceroneogenesis, induces a profound muscle mitochondrial biogenesis, 
enhances respiratory fitness, and robustly extends lifespan [8]. Currently, OAA is commercially 
available and marketed as a nutritional supplement. 
 
4.0 PARTICIPANT SELECTION 
 
Subjects will be recruited through the University of Kansas Alzheimer’s Disease Center’s 
(KU ADC) Clinical Core Cohort/ Registry program.  As part of their participation in the KU 
ADC Clinical Core Cohort/Registry, individuals receive clinical dementia rating (CDR) and 
Uniform Data Set (UDS) evaluations.  Participant diagnoses, which are primarily based on CDR 
and UDS data, are determined through a consensus conference that includes subspecialty-trained 
cognitive neurologists and an expert neuropsychologist.  Participants diagnosed with AD further 
meet current McKhann el al. criteria for that diagnosis [9].   
 
The TOAD trial will enroll participants with mild AD as determined at the last KU ADC 
Clinical Core/ Registry evaluation.  Each participant must have a study partner.  The study 
partner will be someone who knows the participant well (typically a spouse, relative, or friend of 
the participant) and is able to answer questions about the participant’s changes in health and/or 
behaviors over the course of the study.  In addition, the study partner will administer the study 
medication and agree to accompany the participant to all study visits. 
 
Enrollment Information 
 
The TOAD trial will enroll a total of up to 36 participants, to ensure 15 participants in each 
dose cohort, 1 g/day and 2 g/day, complete the full intervention.  No participant will be enrolled 
into the 2 g/day cohort until all 15 participants have completed the 1 g per day dose and it is 
established that the maximum acceptable dose-limiting toxicity (DLT) event rate has not been 
exceeded and it is safe to test the higher dose (See Safety section). Participants who complete the 
1 g/day dose study may be invited to participate in the 2 g/day dose study, if still eligible and the 
principal investigator deems safe to do so.   
 
Inclusion Criteria 
 
Individuals are eligible if they meet the following criteria:  
 
1. Age 50-85;   
2. Have a diagnosis of probable AD per McKhann et al. criteria [9]; 


 
 
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3. Have a clinical dementia rating (CDR) score of 0.5 or 1 AD at time of their last KU 
ADC assessment; 
4. Have a Mini Mental Status Exam (MMSE) score of 15-28 at the TOAD screening 
visit;  
5. 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;   
6. Are on stable doses of concurrent medications for at least 4 weeks prior to the TOAD 
screening visit; and  
7. Speaks English as his/her primary language. 
8. 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 
 
Individuals are ineligible if they meet any of the following criteria: 
  
1. 
Dementia due to causes other than AD; 
2. 
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; 
3.   
Any abnormal physical examination assessment or vital sign assessment at TOAD 
screening visit that is deemed to be clinically significant by the principal 
investigator; 
4.  
Any abnormal clinical laboratory test result at TOAD screening visit that is 
deemed to be clinically significant by the principal investigator. 
5.   
Any contraindication for undergoing MRS, such as the presence of metal 
implants, a cardiac pacemaker that is not compatible with MRS, or severe 
claustrophobia 
 
 
5.0 TREATMENT PLAN 
Study Design 
 
The TOAD protocol is designed as a phase Ib study that will provide information needed to 
plan a phase II study, or else indicate additional development work that is required before 
pursuing a phase II study.  A dose escalation strategy will be utilized to contribute knowledge to 


 
 
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the safety profile of OAA and to establish an effective target engagement dose. The primary 
outcome measure is the safety of currently untested OAA doses (1 g and 2 g per day) in AD 
subjects, as defined by safety laboratory tests, vital signs, physical and neurological 
examinations, cognitive changes, and reports of adverse events.  Our secondary exploratory 
measures will determine a) whether these OAA doses have an observable effect on brain glucose 
utilization, as determined by FDG PET, and on levels of metabolism-relevant neurochemicals, as 
demonstrated by MRS and b) the PK properties of OAA at 500 mg and 1000 mg doses and 
whether OAA plasma levels at these doses correlate with FDG PET and MRS biomarker data.   
 
Safety Outcomes 
 
1 g/day and 2 g/day doses were selected for the following reasons.  The POX Study has 
already indicated 100 mg BID is well-tolerated in AD subjects.  Higher doses have not been 
specifically tested in AD subjects, but in a 1968 OAA clinical study (in diabetics) OAA dosed to 
1 g/day for up to 44 days was found to be safe [10].  Also, we are aware that humans with 
glioblastoma have tolerated 2-3 grams per day for extended periods (in 2012, OAA was given 
“orphan drug status” for the treatment of gliomas).  Ranging our study between 200 mg/day and 
2 g/day, therefore, seems justified, especially since we are using a dose escalation approach in 
which safety at the 1 g/day dose determines whether we attempt the 2 g/day dose.      
 
Safety will be assessed through pre-and post-treatment collection of:  safety labs, physical 
and neurological exams, cognitive measures, and study partner reports of changes in the 
participant’s health (new medical conditions, symptoms, or changes in functioning).  Clinical 
safety labs will consist of complete blood count, serum electrolytes, serum liver function tests, 
and fasting glucose testing.  To ensure our clinical intervention does not exacerbate cognitive 
decline, we will include pre and post-treatment cognitive testing (ADAS-Cog, MMSE, 
immediate and delayed Logical Memory, and Stroop Color Word Test).  At the time of 
enrollment the participant’s medical history and baseline of current symptoms will be collected 
from the participant (with study partner input).  This symptom checklist will be repeated at the 
end of the ~4 week treatment period, and again ~4 weeks after the treatment is discontinued as a 
structured method to probe for any adverse events. A study clinician will conduct a pre and post-
treatment physical and neurological examination to observe for any change in status. 
 
Adverse events will be collected from the time the informed consent document is signed until 
approximately 4 weeks following the last dose of study medication. The frequency and severity 
of adverse events (AE’s) will be examined and their potential causal relationship to the study 
drug (as determined by the PI) will be assessed at the time of data collection.    
 
Any adverse event that results in the study medication dose being stopped or permanently 
reduced will be considered a dose limiting toxicity (DLT).  The maximum acceptable dose-
limiting toxicity (DLT) event rate will be capped at 13.4% in each cohort.  Based on a sample 
size of 15 subjects per cohort, a binomial distribution analysis indicates if the true probability of 
a DLT event is 5% there is a 99% chance of concluding the dose is safe, with a 10% true 
probability of a DLT event this chance falls to 94%, and with a 25% true probability of a DLT 
event this chance falls to 46%.  Thus, if more than 13.4% of currently enrolled or completed 
participants in a dose cohort experiences a DLT, that dose will be discontinued.  The dose cohort 
will be considered safe if, at its completion, 2 or fewer of the total 15 participants experience a 
DLT.    


 
 
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    The maximum number of subjects in an arm who at any time are at risk of experiencing a dose 
limiting toxicity event will be capped at 3; at no time will the number of subjects that can 
potentially experience a dose limiting toxicity event in an arm exceed 3. This limitation will be 
achieved through curtailment.  If any 2 among the first 6 subjects experiences a dose limiting 
toxicity we will discontinue that arm at that time.  For a given arm, therefore, the risk to our 
subjects will be no greater than the risk of a traditional 3+3 design.  The occurrence of a dose 
limiting toxicity event in 3 subjects in an arm terminates that arm, or 2 dose limiting toxicity 
events if among the first six.  The appearance of even 1 non-serious dose limiting toxicity event 
will put a hold on further enrollment pending review by our Data Safety Monitoring Committee, 
while the appearance of any serious adverse event will require placing the entire study on hold 
pending review by the Data Safety Monitoring Committee, our Institutional Review Board, the 
FDA, and the PI.  In order to advance to the higher dose arm, only up to 1 of the first 6 subjects 
(16.7%) or up to 2 of the planned 15 subjects (13.4%) can experience a dose limiting toxicity; 
the occurrence of dose limited toxicity events in 2 of the first 6 subjects or 3 of the planned 15 
subjects terminates the arm.   
 
No participants will be enrolled into the 2 g/day dose cohort until the 1 g/day cohort is 
completed within the acceptable DLT range.  If the 1 g/day dose is discontinued due to an 
unacceptable rate of DLT events, instead of testing a higher dose we will instead test a lower 
dose (500 mg/day, given as 250 mg BID).  If the 1 g/day cohort is found to be safe but the 2 
g/day cohort is not, remaining subjects will be switched to (if already in the study) or placed on 
(if not already in the study) 750 mg/day (375 mg BID).    
 
Biomarker Outcomes 
 
The TOAD study will utilize FDG PET and MRS as target engagement biomarkers.  FDG 
PET and MRS data interpretation, however, is complicated by the fact that different 
interpretation strategies can be utilized and obviously with MRS there are multiple potential 
outcome measures.  For these reasons, FDG PET and MRS data will be treated as secondary 
outcomes.  Changes in these outcomes will nevertheless greatly inform the design of future OAA 
clinical trials.    
 
In our preclinical mouse MRS studies, pre and post-treatment scans performed on 8 mice 
were sufficient to show treatment-associated lactate differences [1].  Increased lactate levels in 
the brains of mice receiving daily 2 g/kg intraperitoneal (IP) OAA injections could potentially 
reflect an OAA-mediated increase in glucose utilization.  If so, FDG PET may provide a 
reasonably sensitive way to detect increased glucose utilization.  Further, considering MRS and 
FDG PET data together could provide novel insight into bioenergetic fluxes present within the 
brains of AD subjects. 
 
Fifteen participants per cohort is a reasonable enrollment goal to examine this secondary 
objective.  In our preliminary mouse MRS studies, pre and post-treatment scans performed on 8 
mice were sufficient to show treatment-associated lactate differences.  This is not to imply 15 
subjects per group is “conservatively powered”, since there is at best a very limited ability to 
extrapolate data from mice receiving 2 g/kg IP OAA and scanned by a 9.4T magnet to humans 
receiving 500 or 1000 mg po BID and scanned by a 3T magnet.   
 
More applicable are FDG PET data previously reported by Keller et al. [11].  That study was 
able to demonstrate an increase in the FDG PET-determined cerebral metabolic rate of glucose 
(CMRglu) in 13 AD subjects placed on galantamine and subsequently maintained on the drug for 


 
 
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12 months.  If OAA at the doses in the current TOAD study is able to influence glucose 
utilization as robustly as galantamine, an n=15 per group should provide a reasonable chance of 
detecting a treatment-induced change if one exists, while providing a small cushion in the event 
of subject-drop out or if, as is possible, occasional individual scans prove to be of limited quality.  
Moreover, the short study duration (4 weeks) will ideally minimize drop-outs.  In this respect, to 
our knowledge this will be the first study to compare pre and post-treatment PET FDG data at a 4 
week time point.  This is justified given our preliminary data, which indicate OAA rapidly 
affects brain bioenergetics [1].   
 
Assuming safety outcomes are met for a particular cohort, lack of change on both the MRS 
and FDG PET target engagement biomarkers would argue that rather than progressing to a more 
advanced clinical trial phase, we will need to acquire additional very-early stage test data, such 
as the PK of 500 mg and 1000 mg doses to see if there is a linear relationship, and ideally to test 
the safety of higher OAA doses.  If there is a more robust degree of target engagement with 2 
g/day than the 1 g/day dose, further studies will examine safety and target engagement 
biomarkers at doses above 2 g/day to see if the higher doses provide more robust target 
engagement.  If equivalent target engagement biomarker changes are seen at 1 g/day and 2 g/day 
OAA, the 2 g/day dose will move forward in subsequent studies.  Ultimately, future studies will 
utilize the data from the TOAD study to define a specific target engagement biomarker analysis.  
Specifically, if positive MRS data emerge, results from this study will inform which metabolites 
are informative.  Positive FDG PET data will tell us which brain regions are most informative.    
 
Pharmacokinetics (PK) 
  
We recently conducted an OAA PK-Safety study in AD subjects (see section 8.0 Correlative 
Studies / Clinical Studies).  To measure PK in this study, plasma was prepared and analyzed for 
OAA concentration using a commercially-available coupled enzyme assay kit. Our data indicate 
that following oral administration the Tmax for OAA occurs between 1 and 1.5 hours.  
 
We have recently developed a liquid chromatography-tandem mass spectroscopy (LC-
MS/MS) based assay for OAA quantification that will provide sensitivity greater than what can 
be obtained through the coupled enzyme method.  For the TOAD-PK analyses, we will use the 
LC-MS/MS-based assay to quantify OAA across a broader range of plasma concentrations.   
 
Study Procedures 
 
At the initial screening visit (V1), participants will undergo the following procedures:  
informed consent, medical history and symptom inventory, review of concurrent medications, 
Mini Mental Status Examination (MMSE), fasting safety labs (to include complete blood count, 
serum electrolytes, serum liver function tests, glucose) vital signs, and a physical and 
neurological examination. If the participant is a female of childbearing potential, a urine 
pregnancy test must be conducted.  Once eligibility for the study is confirmed and within 14 days 
of this, participants will complete the baseline visit (V2). The baseline visit will include FDG 
PET, MRS, and the safety cognitive battery which consists of the ADAS Cog, Logical Memory I 
and II, and the Stroop Color Word Test.  After all other baseline procedures are completed, study 
medication will be dispensed. 
 
Participants (and their study partners) will be instructed to take the study medication two 
times a day in both the 1 g/day and the 2 g/day cohorts.  In the 1 g/day dose cohort, participants 
will take 500 mg OAA BID for 4 weeks.  The 2 g/day cohort will take 1000 mg OAA BID for 4 


 
 
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weeks. Participants will take their first dose of study medication in the clinic in each cohort and   
blood samples will be drawn just prior to administration of study medication, at 60 minutes post 
ingestion, and at 90 minutes post ingestion. 
 
At the end of weeks 1, 2, and 3 of OAA administration we will place a phone call to enrolled 
subjects and their caregivers to ascertain side effects that could indicate emerging toxicity.  
Approximately 4 weeks (+/- 7 days) after starting study medication, participants will be asked to 
complete V3, which will include a post-treatment FDG PET, MRS, a repeat cognitive battery 
(including MMSE), review of symptoms (to check for adverse events), review of concurrent 
medications, fasting safety labs, vital signs, and  physical/neurological examination.  All used 
and unused study medication will be returned and study medication compliance will be 
calculated.  The V3 FDG PET and MRS will be conducted while still taking study medication 
but just prior (within 7 days) to stopping.   
 
A final phone interview (V4) will be conducted approximately 4 weeks (+/- 7 days) after 
stopping study medication to review the symptom inventory and determine if any adverse events 
were experienced in this time period. 
 
Description of FDG PET Procedures 
 
FDG PET images will be obtained at a satellite location of the University of Kansas Hospital. 
The scanner is accredited by the American College of Radiology (ACR), and our physicists 
perform annual required testing by scanning an Esser PET phantom with 18F to assess SUV 
range, contrast resolution, spatial resolution, and uniformity. In addition to the ACR annual 
testing, the nuclear medicine department routinely performs quality control procedures on a 
daily, weekly, and quarterly basis.  Subjects will arrive for FDG PET after having fasted for a 
minimum of 6 hours and will have a catheter placed for IV administration of FDG.  Subjects will 
receive a single IV bolus of FDG.  After the appropriate amount of time has elapsed, frames are 
reconstructed to a single PET image in native space. Adverse events will be continuously 
monitored during the imaging session. The radiation dose from the two FDG PET scans our 
subjects will receive will not exceed 2100 mrem. While this amount of radioactivity obviously 
exceeds the amount obtained through normal background exposure, it is still considered by 
Radiation Safety to be well below the risk levels acceptable in research and medical practice. 
 
Description of MRS Procedures 
 
MRS scans will be obtained using a 3T system (Skyra, Siemens, Erlangen, Germany) fitted 
with a 12-channel receiver head coil. After positioning the participant supine in the magnet, 
three-plane scout MR images are acquired followed by an oblique-axial MP-RAGE sequence 
oriented parallel to the AC-PC line. We will collect several MRS sequences to sample a large 
spectroscopic imaging slab at the same angle, superior to the lateral ventricles.  From this we will 
determine concentrations of several neurochemicals including lactate, glutamine, and glutamate 
which are of specific relevance to the current proposal.  We will also quantify glutathione from 
the same locations using a double-quantum filtered sequence developed at the Hoglund Brain 
Imaging Center.  In addition, based on our animal results we will also acquire a single voxel 
spectrum that includes the hippocampus.  Scan time will be approximately 1.5 hours, which from 
our experience is feasible in this subject group. Spectra will be analyzed using LCModel and 
corrected for tissue fraction in each voxel using the segmented MP-RAGE images corresponding 
to the spectroscopic imaging slab, and using existing laboratory routines. 


 
 
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Description of Pharmacokinetic Procedures 
 
In each cohort (500 mg OAA bid and 1000 mg OAA bid), the participant will consume the 
first dose of study medication in the clinic, after having fasted for a minimum of 8 hours.  Just 
prior to administration of this first dose, a blood PK sample (approximately 4 mL of blood) will 
be drawn to provide a baseline measurement.  A second PK sample will be drawn at 60 minutes 
post ingestion and a third PK sample will be drawn at 90 minutes post ingestion.  Each PK 
sample will immediately be placed on ice, and will be processed into plasma within 10 minutes 
of collection.  Aliquots of plasma (approximately 0.5 mL each) will be frozen and stored at -
80°C immediately until analyses. Quantitation of OAA in plasma will be performed using the 
LC-MC/MS based assay described above. 
 
Procedure Timeline 
 
The timing of study procedures/schedule of events are summarized in the STUDY 
CALENDAR in Section 9.0 
 
6.0 EXPECTED TOXICITIES  
 
There are no expected toxicities.   
 
7.0 DRUG FORMULATION AND ADMINISTRATION 
Drug Production Site 
 
OAA will be purchased from Terra Biological LLC, which is based in San Diego, CA. OAA 
sold by Terra is produced according to good manufacturing practices.   
 
Drug Transportation 
 
Study medication will be shipped to the study site by express mail. 
 
Drug Formulation 
 
Terra markets OAA as a nutritional supplement in capsules that contain 100 mg of OAA and 
150 mg of ascorbic acid.  To prevent ascorbic acid from complicating interpretations, Terra will 
provide the study site with capsules containing 250 or 500 mg OAA and no ascorbate.  This will 
limit the number of capsules participants must ingest. 
 
Drug Quality Assurance 
Ten of our 250 or 500 mg capsules, from the same lot being dispensed at that time, will be 
randomly selected each month for the duration of our study and will be analyzed according to the protocol 
summarized in the Table below. 
 
 


 
 
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Monthly analysis and quality parameters of our 250/500 mg oxaloacetate capsules. 
Method 
Specification 
HPLC Oxaloacetic Acid Assay 
Greater than 95% 
 
 
If the average oxaloacetate content in ten analyzed oxaloacetate capsules at any point falls 
below 95%, or if any other parameter does not meet our specifications, a new set of capsules will 
be synthesized and reanalyzed.  If meeting this standard requires synthesizing a new batch of 
oxaloacetate, the new batch will also be fully analyzed by the protocol summarized below before 
being packaged into capsules. The new batch will then be dispensed to participants to ensure all 
participants are taking the proper dosage of oxaloacetate above 95%. 
 
Monthly analysis and quality parameters of our 250 mg oxaloacetate capsules. 
Method 
Specification 
HPLC Oxaloacetic Acid Assay 
Greater than 95% 
Appearance 
White to Off-White Crystalline Powder 
Sulfated Ash 
Max: 0.5% 
Loss on Drying 
Max: 1.0% 
Water (Karl Fisher) 
Max: 1.0% 
Solution (10% in Water) 
Clear 
Heavy Metals as Lead (USP <231> 
Max: 0.001% 
Identification (IR) 
Consistent with Structure 
 
Monthly analysis and quality parameters of our 500 mg oxaloacetate capsules. 
Method 
Specification 
HPLC Oxaloacetic Acid Assay 
Greater than 95% 
Appearance 
White to Off-White Crystalline Powder 
Sulfated Ash 
Max: 0.5% 
Water (Karl Fisher) 
Max: 1.0% 
Heavy Metals as Lead (USP <231> 
Max: 0.001% 
Identification (IR) 
Consistent with Structure 
 
 
For the 500 mg capsules, microcrystalline cellulose (MC) has been added to the capsules to 
assist with packing the OAA in the capsules.  With the 500 mg capsules, we allow for cloudiness 
in the solution because the presence of MC renders the solution cloudy, therefore the Solution 
test is not used as a parameter for the 500 mg capsules.  Also with the 500 mg capsules, we will 
define acceptability of the capsules using the Karl Fisher test, as this test is more sensitive to 
water content than the Loss on Drying test.  Levels less than 1.0% on the Karl Fisher test are 
considered acceptable.   


 
 
TOAD 10/25/2016 
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The oxaloacetate capsules we use in these studies will be stored in plastic bottles containing a 
desiccant.  The bottles will be kept in a locked cabinet in the KU Alzheimer’s Disease Center 
which is monitored for temperature changes or in a secure -20 degree freezer in the University of 
Kansas Clinical Research Center building.  Every month 10 capsules from the same lot used for 
dispensing will be delivered to the company that performs the analysis.  The company that will 
perform the analysis is Expert Chemical Analysis (ECA), which is located in San Diego, CA.  
ECA is registered and audited by the FDA (www.ecalab.com).  There is a possibility that loss of 
oxaloacetate integrity could occur as an artifact of the shipping process (when the capsules are 
briefly outside of our controlled environment), but this approach will ensure that the quality of 
the oxaloacetate distributed to our trial subjects meets or exceeds the quality of the assayed 
oxaloacetate capsules.      
 
Drug Administration 
 
Participants in the 1 g/day dose cohort will take 2- 250 mg OAA capsules in the morning and 
2-250 mg OAA capsules in the evening for approximately 4 weeks.  Participants in the 2 g/day 
dose cohort will take 2-500 mg OAA capsules in the morning and 2-500 capsules in the evening 
for approximately 4 weeks. 
 
 
8.0 CORRELATIVE STUDIES 
Pre-Clinical Studies 
 
In one recent study using C. elegans, OAA extended median and maximum lifespan through 
AMP kinase (AMPK) and forkhead O-box (FOXO) transcription factor-dependent pathways 
[12].  In mammals, it can be inferred that systemically administered OAA accesses the brain.  
This inference is based on rodent studies that report OAA prevents kainate-induced seizures and 
neuron damage, decreases ischemia-induced stroke volume, decreases cortical impact-induced 
traumatic brain injury, and slows glioma growth rates [13-16].    
 
Over the past five years we have completed our own preclinical target validation studies.  
Initially, we evaluated the effects of OAA on cell culture bioenergetic fluxes and found that in 
undifferentiated and differentiated human neuronal SH-SY5Y cells OAA increased the 
maximum glycolysis capacity, spare glycolysis capacity, enhanced the mitochondrial respiratory 
flux, and blunted the Crabtree effect.  To extend our studies to animals, we next administered 
OAA to mice in order to test its impact on genes, proteins, and pathways that monitor, regulate, 
and mediate brain bioenergetic fluxes.  We also ascertained the effect of OAA on brain insulin 
signaling, inflammation, and hippocampal neurogenesis as relationships exist between these 
parameters and bioenergetics.  We further probed for changes in metabolic fluxes by using MRS 
to measure in vivo levels of detectable neurochemicals.  
 
In these studies [1], male C57Bl/6 mice received IP OAA, 1-2 g/kg once per day for 1-2 
weeks.  Both doses induced brain changes; we did not determine a minimum effective dose.  
Observed changes were consistent with an activation of mitochondrial biogenesis pathways. 
Brain peroxisome proliferator activated receptor γ coactivator 1α (PGC1α) and peroxisome 
related coactivator (PRC) mRNA levels increased, and brain PGC1α and PRC protein within 
cells redistributed such that their nucleus:cytoplasm ratios increased.  mRNA levels of nuclear 


 
 
TOAD 10/25/2016 
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respiratory factor 1 (NRF1) and transcription factor A of the mitochondria (TFAM) increased. 
OAA treatment also increased cytochrome oxidase subunit 4 isoform 1 (COX4I1) mRNA and 
protein.  AMPK Thr172 phosphorylation, p38 MAPK phosphorylation, and cAMP-response 
element binding (CREB) Ser133 phosphorylation each increased.  
 
OAA treatment enhanced the brain insulin signaling pathway activation state.  Akt Ser473, 
mTOR Ser2448, and P70S6K Thr389 phosphorylation increased.  OAA treatment also reduced 
markers of neuroinflammation.  Hippocampal C-C motif chemokine 11 (CCL11) mRNA, 
hemisphere nuclear factor κB (NFκB) protein levels, and NFκB nucleus-to-cytoplasm ratios 
were lower than in control mice.   
 
It was previously reported in mice that CCL11 retards subgranular layer neurogenesis [17].  
Because CCL11 gene expression was reduced in the hippocampus of OAA-treated mice, and 
because Akt and mTOR activation promotes cell growth, we evaluated hippocampal 
neurogenesis and found enhanced hippocampal neurogenesis.  Hippocampal vascular endothelial 
growth factor A (VEGF) mRNA levels increased.  Hippocampal mRNA and protein levels of 
doublecortin (DCX), which is commonly used as a surrogate measure of new neuron formation, 
increased.  The number of intensely DCX-positive neurons increased.  Relative to the control 
group, DCX-positive neurites were longer in the OAA-treated mice. 
 
1H-MRS was performed on mice before receiving any treatment, and on the same mice after 
they received 2 g/kg/day OAA IP for one week (the 1 g/kg/day dose was not studied).  OAA 
induced changes in several neurochemicals. After one week of OAA, brain lactate, GABA, and 
glutathione (GSH) levels were respectively 21%, 15%, and 27% higher than they were on the 
pre-treatment scans. 
 
Clinical Studies 
 
Prior to our own recent OAA studies, the literature reported only one human study of OAA, a 
1968 study that evaluated its potential anti-hyperglycemic effects.  This study, performed in 
human diabetics, reported OAA was well-tolerated and also limited PK data [10].  Levels were 
not increased 30 minutes but were increased 60 minutes after 200 mg were orally administered to 
three subjects.  On average, OAA levels rose from 0 ug/100 ml to 2.3 ug/100 ml.     
 
We recently conducted an OAA PK-safety study in AD subjects.  OAA 100 mg capsules 
(obtained from Terra, Inc., which markets OAA as a nutritional supplement) were administered 
to 6 subjects recruited from the University of Kansas Alzheimer’s Disease Center (KU ADC) 
clinical cohort.  The first 100 mg capsule was administered at the University of Kansas Clinical 
Translational Science Award (KU CTSA) Clinical Trials Unit (CTU), and over a four hour 
period PK blood samples were obtained at 15, 30, or 60 minute intervals.  Basic safety labs 
(CBC, chemistries) and cognitive tests (MMSE, ADAS-Cog) were performed. Subjects 
continued on 100 mg BID OAA for one month, and then returned to the CTU where blood 
samples were again taken for PK determinations, safety labs and cognitive tests were repeated, 
and a formal side effect query were completed.  There were no drop-outs, pre and post treatment 
cognitive scores were comparable, safety labs were unremarkable, and no side effects were 
reported.  
 Further human experience data are available from the case series of Kesari.  In the Kesari 
case series human subjects with gliomas were administered oxaloacetate at doses far greater than 
500 mg BID.  This case series includes 8 subjects whose single dose amount was 1000 mg and 6 
subjects whose single dose amount was 2000 mg (500 mg doses were not used in this case 


 
 
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series).  Among the subjects maintained at these high doses a single side effect was reported to 
be oxaloacetate-related, and included a single subject who experienced nausea on the 2000 mg 
dose. Neither discontinuation nor a reduction in dosage was required.  Oxaloacetate was 
administered TID in this case series, and the mean treatment duration for the group was over 2 
months. Therefore, well over 2000 doses of over 500 mg have been administered to humans 
without incurring a dose limiting toxicity event.        
In the Kesari case series, the 8 subjects dosed with 1000 mg TID were followed for an 
average of 2.3 months (minimum duration=1 month, maximum duration=8 months).  The 
average cumulative dose for these 8 subjects was therefore ~210,000 mg (minimum=90,000 mg, 
maximum=720,000 mg).  The 6 subjects dosed with 2000 mg TID were followed for an average 
of 4.2 months (minimum duration=1 month, maximum duration=8 months). The only reported 
side effect in this series was one reported case of nausea in the 2000 mg TID group, and this did 
not require discontinuation or a change in dosing. The average cumulative dose for these 6 
subjects was therefore ~756,000 mg (minimum=180,000 mg, maximum=1,440,000 mg); the 
cumulative ~1 month amount at 500 mg BID would be ~30,000 mg.  
It is important to note that oxaloacetate has been available for years as a supplement in the 
United States and other countries, and no toxicity has been reported.  This is consistent with the 
fact that marketed oxaloacetate is produced from tartaric acid, a GRAS compound.  As it is 
produced from a GRAS compound, oxaloacetate itself could also technically be considered to 
meet GRAS status. 
9.0 STUDY CALENDAR 
Trial of Oxaloacetate in Alzheimer’s Disease (TOAD) Schedule of Events 
Procedure 
Visit 1 
(Screening) 
 -14 to 0 days 
Visit 2 
(Baseline)c 
 Day 0 
Visit 3f** 
 Week 4 (+/- 
7 days) 
Visit 4 
 4 weeks post V3 
End Date (+/- 7 
days) 
Informed Consent 
X 
 
 
 
Medical History Review 
X 
 
 
 
Symptom Checklist/ Adverse Event Review 
X 
X 
X 
X 
Concurrent Medication Review 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
 
Physical & Neuro Exam 
X 
 
X 
 
Safety Labs (fasting) 
X 
 
X 
 
Pharmacokinetic labs (fasting) 
 
X 
 
 
Urine pregnancy test* 
X 
 
 
 
MMSE 
X 
 
X 
 
Review of Inclusion / Exclusion Criteria  
X 
 
 
 
ADAS Cog 
 
X 
X 
 
Logical Memory I & II 
 
X 
X 
 
Stroop Color Word Test 
 
X 
X 
 
FDG PETa 
 
X 
X 
 
MRSb 
 
X 
X 
 
Dispense Study Medication/Begin Study 
Medicationd 
 
X 
 
 
Stop Study Medication/ Medication Compliance 
Checke 
 
 
X 
 
aFDG PET=fluorodeoxyglucose positron emission tomography. At V2, FDG PET may be performed any time after participant is deemed eligible 
for study but must be done prior to administration of first dose of study medication. At V3, FDG PET must be completed prior to stopping study 
medication. 


 
 
TOAD 10/25/2016 
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bMRS=magnetic resonance spectroscopy. At V2, MRS may be performed any time after participant is deemed eligible for study but must be 
done prior to first dose of study medication prior to administration of first dose of study medication. At V3, MRS must be completed prior to 
stopping study medication.   
cAll V2 procedures must be completed no later than 14 days after V1. 
dDispensing of study medication and administration of first dose may take place on the same day as other V2 study procedures (such as PET or 
MRS or cognitive testing) but  must be the last procedure completed at V2.     
eStopping study medication/medication compliance check must be the last procedure completed at V3.  
fV3 procedures may be completed on multiple days, but should begin 4 weeks +/- 7 days from Day 0. Once first V3 procedure is completed, all 
other V3 procedures must be completed within 7 days. 
*For females of childbearing potential only 
**Phone call to participant/caregiver will take place at end of Week 1, Week 2, & Week 3 of OAA administrationi to ascertain side effects that 
could indicate emerging toxicity. 
 
10.0 MEASUREMENT OF EFFECT 
 
The primary and secondary outcomes will be assessed as described under section 5.0 
TREATMENT PLAN, Study Design.   
 
11.0 ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 Notifying the FDA 
 
The study sponsor will report adverse events in an expedited fashion to the FDA.  These 
written notifications of adverse events (IND safety reports) will follow the following guidelines:  
• Within 7 calendar days 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening, and  
 
• Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to 
fit the criteria for reporting (reporting within 15 calendar days from when event was 
deemed reportable). 
 
12.0 DATA AND SAFETY MONITORING 
Data Collection 
The PI will oversee all data collection. 


 
 
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Data and Safety Monitoring  
  A medical monitor, Jeffrey Burns, MD, will assess adverse events to determine severity 
and causality.  A protocol for handling adverse events is provided in the Figure below.  Adverse 
events will be reported to the local IRB according to IRB reporting policies and to the FDA 
according to the above requirements.  An internal safety committee will meet quarterly to review 
adverse events and the overall safety of the ongoing trial.  The following individuals will serve 
on this committee: Richard Dubinsky, MD, Michael Abraham, MD, and Kelly Lyons, PhD.   
 
13.0 REGULATORY CONSIDERATION 
Protection of Human Subjects and Informed Consent 
 
Regulations in regard to Human Subjects Protection and Informed Consent will be followed 
in accordance with 21 CFR 50.  All institutional, FDA, state, and federal regulations concerning 
informed consent will be followed.    
Institutional Review Board (IRB) 
 
Regulations regarding initial and continuing review of the study by an Institutional Review 
Board will be followed.  The University of Kansas Medical Center has a federally approved 


 
 
TOAD 10/25/2016 
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Institutional Review Board, which will be involved in all aspects of study planning and 
considerations as per 21 CFR 56.  The KUMC IRB FWA# is FWA00003411.   
 
Financial Disclosure 
 
There are no financial disclosures to be made.   
 
Obligations of Investigators 
 
The Principal Investigator/Sponsor, Dr. Russell Swerdlow, will be responsible for all 
elements of 21 CFR 312 subpart D.  Dr. Swerdlow will maintain oversight of the clinical trial 
ensuring relevant regulatory requirements are met and necessary guidelines are followed.  The 
following are co-investigators: 
• Jeffrey Burns, MD 
• Jonathan Mahnken, PhD 
• William Brooks, PhD 
• Eric Vidoni, PhD 
• Janna Harris, PhD 
 
The Principal Investigator has confirmed all co-investigator credentials, experience, and 
training.  He has also ensured additional personnel will follow the appropriate investigational 
plans and guidelines as submitted in this IND.  All changes to the study, including modifications 
to this IND, will be communicated by the Principal Investigator, and he will be the primary 
liaison to the IRB.   
 
All detected and newly discovered adverse effects and risks will be reported by the involved 
investigator at the time of the event, per institutional guidelines.  Each investigator is also 
responsible for privacy and welfare of his patient.  Record-keeping and data is strictly 
confidential, only to be shared between investigators in the study and only those who are directly 
involved in the care of the patient. 
 
14.0 STATISTICAL CONSIDERATION 
 
The statistical analysis will be conducted as described under 5.0 TREATMENT PLAN, 
Study Design. 
 
15.0 PUBLICATION PLAN 
 
Publications resulting from this study will be prepared by the PI.  Co-authors will include 
personnel from the study site who have meaningfully contributed to study execution or 
development, as well as a project consultant (Dr. Lisa Mosconi, NYU Medical Center).  Only co-
authors who agree with the final manuscript will be listed as authors on the final manuscript. 
   


 
 
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2. 
Swerdlow, R.H., The neurodegenerative mitochondriopathies. J Alzheimers Dis, 2009. 17(4): p. 
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3. 
Hebert, L.E., et al., Alzheimer disease in the US population: prevalence estimates using the 2000 
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4. 
Alzheimer's Association.  2011 Alzheimer’s disease facts and figures. Alzheimer's and Dementia, 
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5. 
Swerdlow, R.H., Mitochondria and cell bioenergetics: increasingly recognized components and a 
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6. 
Mosconi, L., et al., FDG-PET changes in brain glucose metabolism from normal cognition to 
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Swerdlow, R.H., Bioenergetic medicine. Br J Pharmacol, 2014. 171(8): p. 1854-69. 
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McKhann, G.M., et al., The diagnosis of dementia due to Alzheimer's disease: Recommendations 
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Yoshikawa, K., Studies on the anti-diabetic effect of sodium oxaloacetate. Tohoku J Exp Med, 
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Keller, C., et al., Long-term effects of galantamine treatment on brain functional activities as 
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Williams, D.S., et al., Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans 
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Yamamoto, H.A. and P.V. Mohanan, Effect of alpha-ketoglutarate and oxaloacetate on brain 
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Campos, F., et al., Oxaloacetate: a novel neuroprotective for acute ischemic stroke. Int J 
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Ruban, A., et al., Blood glutamate scavengers prolong the survival of rats and mice with brain-
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Zlotnik, A., et al., Effect of glutamate and blood glutamate scavengers oxaloacetate and 
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Villeda, S.A., et al., The ageing systemic milieu negatively regulates neurogenesis and cognitive 
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