Alzheimer's Disease (AD)
Conditions
Keywords
energy metabolism, oxaloacetate
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.
Interventions
DRUGOxaloacetate (OAA) 1g
Pills to be taken orally in 500mg dose two times per day
DRUGOxaloacetate (OAA) 2g
Pills to be taken orally in 1000mg dose two times per day.
Sponsors
Russell Swerdlow
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Pre-assignment details
Original plan was to enroll 30 participants. After enrolling 30 participants, two enrolled participants were withdrawn from the study after assignment to groups but did not complete post treatment data collection. Therefore those two were replaced so that total number of participants who completed post treatment data was 30, increasing the total number of enrolled participants to 32.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 - Oxaloacetate (OAA) 1 Gram/Day Participants take 1 gram of OAA per day for period of 4 weeks
Oxaloacetate (OAA): Pills to be taken orally in 500mg or 1000mg doses two times per day depending on the part of the study | 15 |
| Part 2 - Oxaloacetate (OAA)2 Gram/Day Participants take 2 grams of OAA per day for period of 4 weeks
Oxaloacetate (OAA): Pills to be taken orally in 500mg or 1000mg doses two times per day depending on the part of the study | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Part 1 - Oxaloacetate (OAA) 1 Gram/Day | Part 2 - Oxaloacetate (OAA)2 Gram/Day | Total |
|---|---|---|---|
| Age, Continuous | 70.0 years STANDARD_DEVIATION 5.7 | 71.3 years STANDARD_DEVIATION 8.1 | 70.7 years STANDARD_DEVIATION 6.9 |
| Baseline MMSE | 21.5 Scores on a Scale STANDARD_DEVIATION 4.3 | 21.9 Scores on a Scale STANDARD_DEVIATION 3.2 | 21.7 Scores on a Scale STANDARD_DEVIATION 3.8 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment United States | 15 Participants | 15 Participants | 30 Participants |
| Sex: Female, Male Female | 9 Participants | 11 Participants | 20 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 4 / 15 | 3 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
Primary
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.
Time frame: Change from Baseline to Week 4
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 - Oxaloacetate (OAA) 1 Gram/Day | Number of Dose Limiting Toxicity Events | 0 Dose Limiting Toxicity Events |
| Part 2 - Oxaloacetate (OAA)2 Gram/Day | Number of Dose Limiting Toxicity Events | 0 Dose Limiting Toxicity Events |
Secondary
Change in Brain Glucose Metabolic Rate as Determined by Fluorodeoxyglucose Positron Emission Tomography (FDG PET)
Fluorodeoxyglucose positron emission tomography (FDG PET)
Time frame: Change from Baseline to Week 4
Secondary
Change in Brain Lactate Levels as Determined by Magnetic Resonance Spectroscopy (MRS)
magnetic resonance spectroscopy (MRS)
Time frame: Change from Baseline to Week 4
Secondary
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.
Time frame: Change from dose to 60 min post dose and 90 min post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 - Oxaloacetate (OAA) 1 Gram/Day | Plasma Levels in 1000 mg Bid Cohort at Baseline, 60 and 90 Minutes Post-Dose | 1400 ng/mL | Standard Deviation 962 |
| Part 2 - Oxaloacetate (OAA)2 Gram/Day | Plasma Levels in 1000 mg Bid Cohort at Baseline, 60 and 90 Minutes Post-Dose | 1355 ng/mL | Standard Deviation 690 |
| Part 1 - Oxaloacetate (OAA) 1 Gram/Day - 90 Minutes Post Administration of Dose | Plasma Levels in 1000 mg Bid Cohort at Baseline, 60 and 90 Minutes Post-Dose | 1363 ng/mL | Standard Deviation 759 |
Secondary
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.
Time frame: Change from dose to 60 min post dose and 90 min post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 - Oxaloacetate (OAA) 1 Gram/Day | Plasma Levels in 500 mg Bid Cohort at Baseline, 60 and 90 Minutes Post-Dose | 94 ng/mL | Standard Deviation 102 |
| Part 2 - Oxaloacetate (OAA)2 Gram/Day | Plasma Levels in 500 mg Bid Cohort at Baseline, 60 and 90 Minutes Post-Dose | 63 ng/mL | Standard Deviation 55 |
| Part 1 - Oxaloacetate (OAA) 1 Gram/Day - 90 Minutes Post Administration of Dose | Plasma Levels in 500 mg Bid Cohort at Baseline, 60 and 90 Minutes Post-Dose | 87 ng/mL | Standard Deviation 80 |