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

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).

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease (AD)
• Intervention / Treatment: Drug: Oxaloacetate (OAA) 1g; Drug: Oxaloacetate (OAA) 2g

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 48 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Russell Swerdlow
• Investigators: Principal Investigator: Russell Swerdlow, MD, University of Kansas Medical Center

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Actual): September 1, 2018
• Study Completion (Actual): September 1, 2018

Study Registration Dates

• First Submitted: October 8, 2015
• First Submitted That Met QC Criteria: October 30, 2015
• First Posted (Estimate): November 1, 2015

Study Record Updates

• Last Update Posted (Actual): July 9, 2021
• Last Update Submitted That Met QC Criteria: June 17, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: energy metabolism; oxaloacetate
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: STUDY00002242