Safety with Anhydrous Enol-Oxaloacetate

Safety Information from Clinical Trials

NCT04592354
Anhydrous Enol-Oxaloacetate (AEO) on Improving Fatigue in Post-COVID-19
Survivors (AEO)

https://clinicaltrials.gov/study/NCT04592354

No severe adverse effects were seen in the initial 76 ME/CFS patients and 43 Long COVID patients “proof-of-concept” study. Non-severe adverse effects included Dyspepsia (2/23 in the 500 mg BID group and 2/24 in the 1000 mg BID group) and Insomnia (1/26 in the 500 mg BID group) for ME/CFS patients. In the Long COVID-Fatigue patients, no severe adverse effects were seen. Non-severe adverse effect included stomach upset, headache and constipation in 4/43 patients.

NCT05273372 RESTORE ME -- RCT of Oxaloacetate on Improving Fatigue in ME/CFS

https://clinicaltrials.gov/study/NCT05273372

There were no remarkable changes in vital signs between the two groups. There were no serious treatment-emergent adverse events (TEAE) in the oxaloacetate group. TEAE is defined as any event reported on or after the registration date. There were three serious TEAEs in the control group (including one death). The most common possibly related non-serious TEAEs in the oxaloacetate group (greater than 5%)
were headache and nausea (3 each). The control group had many similar non-serious TEAEs but experienced six severe cases. The oxaloacetate group had two cases of non-serious TEAEs that were severe, with nausea and abdominal pain in one patient. Overall, oxaloacetate was well tolerated by this participant group (Table 3).

Table: Summary of TEAEs by Treatment Group
Oxaloacetate (N=42) Control (N=40)
Total number of TEAEs 41 40
Number (%) of participants reporting at least one TEAE 22 (52.4%) 16 (40.0%)
Serious TEAE 0 3 (7.5%)
Related TEAE 12 (28.6%) 7 (17.5%)
Maximum severity
  Mild 10 (23.8%) 5 (12.5%)
  Moderate 11 (26.2%) 5 (12.5%)
  Severe 2 (4.8%) 6 (15.0%)

Note: The one participant in the oxaloacetate group who experienced severe nausea and abdominal pain dropped due to this TEAE. In contrast, all other oxaloacetate participants dropped for reasons other than TEAEs.

Adverse Events and Study Results
Adverse Events for the 15 participants from each group who contributed pre-and-post intervention data
Intervention AE Number with the AE Likely or Unlikely Related to OAA Comments
500 mg Twice Daily (n=15) Increased confusion 2 Unlikely Began or worsened during post-treatment follow-up period
Cervical stenosis 1 Unlikely
Syncope 1 Unlikely
1000 mg Twice Daily (n=15) Nausea 1 Likely Resolved by taking capsules with food
Sinus infection 1 Unlikely
Breast calcification 1 Unlikely

Linear mixed-model analysis showed significant increase in brain glucose rate dose by time effects across multiple FDG PET SUVR regions. Benefits for the higher dose group were seen in the default mode network (DMN) (p=0.04), rostral anterior cingulate (p=0.03), precuneus (p<0.05), inferior parietal cortex (p=0.03), insula (p<0.05), hippocampus (p=0.02), and parahippocampal gyrus (p=0.03). Other regions, including the posterior cingulate cortex (p=0.08), superior frontal cortex (p=0.06), superior parietal cortex (p=0.08), caudal anterior cingulate (p=0.06), and superior temporal cortex (p=0.11) trended towards a higher dose benefit following the intervention.

The Investigators conclusion was that 1000 mg OAA, taken twice daily for 1 month, is safe in AD patients and engages brain energy metabolism.

NCT02593318 Trial of Oxaloacetate in Alzheimer's Disease (TOAD)

https://clinicaltrials.gov/study/NCT02593318

In this trial of 30 Alzheimer patients there were no DLT events. Both doses of 1,000 mg and 2,000 mg/day were considered safe and tolerated. CBC, electrolyte, LFT, and glucose screening did not reveal any consistent treatment-related alterations. Below lists adverse events for the15 participants from each group who contributed to the full analysis. One participant on the higher dose
experienced nausea, relieved by taking the OAA with food. This was attributed to the study drug. In the lower dose group, one participant with evolving psychotic confusion, documented before starting the OAA, continued to worsen throughout the intervention and the entire one-month post-treatment follow-up period. Because symptom progression was clearly present before and after the treatment period, they did not attribute it to the treatment. Another participant in the lower dose group experienced increased confusion only during the post-treatment follow-up period, while no longer taking OAA, this was not attributed to the study drug.

NCT04204889 Trial of Oxaloacetate in ALS (TOALS)

https://clinicaltrials.gov/study/NCT04204889


A recently completed Investigator IND study at the University of Kansas Medical Center, Omar Jawdat, MD, conducted a Phase 1b prospective 3+3 dose escalation study under the IND 139037. The primary purpose of the study was to determine the safety and the maximal
tolerated dose of Oxaloacetate (OAA) in patients with ALS.

In the study, they screened 19 patients and enrolled 18 clinically definite, probable, or laboratory-supported probable ALS patients according to El Escorial ALS revised criteria. Each cohort received the drug for 28 days. The first 3 patients will receive 1000 mg twice daily, and subsequent cohorts will increase by 500 mg per dose to a maximum of 2500 mg twice daily.  There were 3 patients in dose cohort 1 (1000 mg, BID), 3 patients in dose cohort 2 (1500 mg, BID), 3 patients in dose cohort 3 (2000mg, BID), 3 patients in dose cohort 4 (2500 mg, BID) and 6 patients in dose cohort 5 (2500 mg, BID).

There were no dose-limiting toxicities (DLT). There were no Suspected Unexpected Serious Adverse Reactions (SUSAR’s). There was a total of 34 treatment emergent adverse events across the 18 subjects, see Table 1.

Table 1: Summary of TEAEs by Dose Cohort
Safety Analysis Set
Cohort 1 Dose
1000 mg BID
(N=3)		 Cohort 2 Dose
1500 mg BID
(N=3)		 Cohort 3 Dose
2000 mg BID
(N=3)		 Cohort 4 Dose
2500 mg BID
(N=3)		 Cohort 5 Dose
2500 mg BID
(N=6)		 All Subjects
(N=18)
Total Number of TEAEs 5 1 9 3 16 34
Number (%) of Subjects Reporting at Least One:
  TEAE 3 (100%) 1 (33.3%) 3 (100%) 2 (66.7%) 4 (66.7%) 13 (72.2%)
  Serious TEAE 0 0 0 0 1 (16.7%) 1 (5.6%)
  Related TEAE[1] 3 (100%) 0 3 (100%) 2 (66.7%) 4 (66.7%) 12 (66.7%)
  Maximum Severity[2]
    Mild 3 (100%) 1 (33.3%) 3 (100%) 2 (66.7%) 3 (50.0%) 12 (66.7%)
    Moderate 0 0 0 0 0 0
    Severe 0 0 0 0 1 (16.7%) 1 (5.6%)

Abbreviation: TEAE = treatment-emergent adverse event

Note: A TEAE is defined as any event reported on or after the first dose of study treatment.

[1] Related events include those terms marked as 'Definite,' 'Probable,' or 'Possible;' Not Related events include those terms marked 'Unlikely' or 'Unrelated.'

[2] Subjects reporting more than one adverse event are counted only once using the highest severity.

Table 2: Incidence of TEAEs by System Organ Class, Verbatim Term and Dose Cohort
Safety Analysis Set
System Organ Class
Verbatim Term		 Cohort 1 Dose
1000 mg BID
(N=3)		 Cohort 2 Dose
1500 mg BID
(N=3)		 Cohort 3 Dose
2000 mg BID
(N=3)		 Cohort 4 Dose
2500 mg BID
(N=3)		 Cohort 5 Dose
2500 mg BID
(N=6)		 All Subjects
(N=18)
Number (%) of Subjects Reporting at Least One TEAE 3 (100%) 1 (33.3%) 3 (100%) 2 (66.7%) 4 (66.7%) 13 (72.2%)
Gastrointestinal 3 (100%) 0 3 (100%) 1 (33.3%) 4 (66.7%) 11 (61.1%)
  Nausea 1 (33.3%) 0 0 0 3 (50.0%) 4 (22.2%)
  Heartburn 1 (33.3%) 0 0 1 (33.3%) 1 (16.7%) 3 (16.7%)
  Upset Stomach 0 0 2 (66.7%) 0 1 (16.7%) 3 (16.7%)
  Diarrhea 0 0 0 0 1 (16.7%) 1 (5.6%)
  Episodes of Sporadic Diarrhea 0 0 0 0 1 (16.7%) 1 (5.6%)
  Intermittent Heartburn 1 (33.3%) 0 0 0 0 1 (5.6%)
  Intermittent Indigestion 0 0 1 (33.3%) 0 0 1 (5.6%)
  Stomach Pain 1 (33.3%) 0 0 0 0 1 (5.6%)
  Vomiting 0 0 0 0 1 (16.7%) 1 (5.6%)
General Disorders 0 0 1 (33.3%) 0 1 (16.7%) 2 (11.1%)
  Chills 0 0 0 0 1 (16.7%) 1 (5.6%)
  Fatigue 0 0 1 (33.3%) 0 0 1 (5.6%)
  Fever 0 0 0 0 1 (16.7%) 1 (5.6%)
  Influenza-A 0 0 0 0 1 (16.7%) 1 (5.6%)
Musculoskeletal 0 1 (33.3%) 0 1 (33.3%) 0 2 (11.1%)
  Increased Muscle Cramping 0 0 0 1 (33.3%) 0 1 (5.6%)
  Increased Muscle Fasciculations 0 1 (33.3%) 0 0 0 1 (5.6%)
  Shoulder Aches 0 0 0 1 (33.3%) 0 1 (5.6%)
Respiratory 0 0 0 0 2 (33.3%) 2 (11.1%)
  Cough 0 0 0 0 2 (33.3%) 2 (11.1%)
  Shortness of Breath 0 0 0 0 1 (16.7%) 1 (5.6%)
Cardiac Disorder 0 0 1 (33.3%) 0 0 1 (5.6%)
  Tachycardia 0 0 1 (33.3%) 0 0 1 (5.6%)
Nervous System 0 0 1 (33.3%) 0 0 1 (5.6%)
  Headache 0 0 1 (33.3%) 0 0 1 (5.6%)
Psychiatric Disorder 0 0 0 0 1 (16.7%) 1 (5.6%)
  Insomnia 0 0 0 0 1 (16.7%) 1 (5.6%)
Skin and Subcutaneous Tissue Disorders 0 0 1 (33.3%) 0 0 1 (5.6%)
  Hyperhidrosis 0 0 1 (33.3%) 0 0 1 (5.6%)

Abbreviation: TEAE = treatment-emergent adverse event

Note: A TEAE is defined as any event reported on or after the first dose of study treatment.

Note: At each level of summarization (any event, system organ class, and verbatim term), subjects reporting more than one adverse event are counted only once. There was 1 patient in dose cohort 5 (2500 mg, BID) that had a serious adverse event. While the patient was traveling, they were diagnosed with influenza A and were hospitalized for treatment. The serious adverse event occurred after the end of dosing but before the patient could return to the University of Kansas Medical Center. The Investigator assessed this as “not drug related.” Please see Table 3 Incidence of Serious TEAE’s.

Table 3: Incidence of Serious TEAEs by System Organ Class, Verbatim Term and Dose Cohort
Safety Analysis Set
System Organ Class
Verbatim Term		 Cohort 1 Dose
1000 mg BID
(N=3)		 Cohort 2 Dose
1500 mg BID
(N=3)		 Cohort 3 Dose
2000 mg BID
(N=3)		 Cohort 4 Dose
2500 mg BID
(N=3)		 Cohort 5 Dose
2500 mg BID
(N=6)		 All Subjects
(N=18)
Number (%) of Subjects Reporting at Least One Serious TEAE 0 0 0 0 1 (16.7%) 1 (5.6%)
General Disorders 0 0 0 0 1 (16.7%) 1 (5.6%)
  Influenza-A 0 0 0 0 1 (16.7%) 1 (5.6%)

See Table 4 for Incidence of TEAE's by Drug Relatedness.

Table 4: Incidence of TEAEs by System Organ Class, Verbatim Term, Maximum Relatedness and Dose Cohort
Safety Analysis Set
System Organ Class
Verbatim Term
Maximum Relatedness		 Cohort 1 Dose
1000 mg BID
(N=3)		 Cohort 2 Dose
1500 mg BID
(N=3)		 Cohort 3 Dose
2000 mg BID
(N=3)		 Cohort 4 Dose
2500 mg BID
(N=3)		 Cohort 5 Dose
2500 mg BID
(N=6)		 All Subjects
(N=18)
Number (%) of Subjects Reporting at Least One TEAE 3 (100%) 1 (33.3%) 3 (100%) 2 (66.7%) 4 (66.7%) 13 (72.2%)
  Not Related 0 1 (33.3%) 0 0 0 1 (5.6%)
  Related 3 (100%) 0 3 (100%) 2 (66.7%) 4 (66.7%) 12 (66.7%)
Gastrointestinal 3 (100%) 0 3 (100%) 1 (33.3%) 4 (66.7%) 11 (61.1%)
  Not Related 0 0 0 0 0 0
  Related 3 (100%) 0 3 (100%) 1 (33.3%) 4 (66.7%) 11 (61.1%)
  Nausea 1 (33.3%) 0 0 0 3 (50.0%) 4 (22.2%)
    Not Related 0 0 0 0 0 0
    Related 1 (33.3%) 0 0 0 3 (50.0%) 4 (22.2%)
  Heartburn 1 (33.3%) 0 0 1 (33.3%) 1 (16.7%) 3 (16.7%)
    Not Related 0 0 0 0 0 0
    Related 1 (33.3%) 0 0 1 (33.3%) 1 (16.7%) 3 (16.7%)
  Upset Stomach 0 0 2 (66.7%) 0 1 (16.7%) 3 (16.7%)
    Not Related 0 0 0 0 0 0
    Related 0 0 2 (66.7%) 0 1 (16.7%) 3 (16.7%)
  Diarrhea 0 0 0 0 1 (16.7%) 1 (5.6%)
    Not Related 0 0 0 0 0 0
    Related 0 0 0 0 1 (16.7%) 1 (5.6%)
  Episodes of Sporadic Diarrhea 0 0 0 0 1 (16.7%) 1 (5.6%)
    Not Related 0 0 0 0 1 (16.7%) 1 (5.6%)
    Related 0 0 0 0 0 0
  Intermittent Heartburn 1 (33.3%) 0 0 0 0 1 (5.6%)
    Not Related 0 0 0 0 0 0
    Related 1 (33.3%) 0 0 0 0 1 (5.6%)
  Intermittent Indigestion 0 0 1 (33.3%) 0 0 1 (5.6%)
    Not Related 0 0 0 0 0 0
    Related 0 0 1 (33.3%) 0 0 1 (5.6%)
Stomach Pain 1 (33.3%) 0 0 0 0 1 (5.6%)
  Not Related 0 0 0 0 0 0
  Related 1 (33.3%) 0 0 0 0 1 (5.6%)
  Vomiting 0 0 0 0 1 (16.7%) 1 (5.6%)
    Not Related 0 0 0 0 0 0
    Related 0 0 0 0 1 (16.7%) 1 (5.6%)
  General Disorders 0 0 1 (33.3%) 0 1 (16.7%) 2 (11.1%)
    Not Related 0 0 1 (33.3%) 0 1 (16.7%) 2 (11.1%)
    Related 0 0 0 0 0 0
  Chills 0 0 0 0 1 (16.7%) 1 (5.6%)
    Not Related 0 0 0 0 1 (16.7%) 1 (5.6%)
    Related 0 0 0 0 0 0
  Fatigue 0 0 1 (33.3%) 0 0 1 (5.6%)
    Not Related 0 0 1 (33.3%) 0 0 1 (5.6%)
    Related 0 0 0 0 0 0
  Fever 0 0 0 0 1 (16.7%) 1 (5.6%)
    Not Related 0 0 0 0 1 (16.7%) 1 (5.6%)
    Related 0 0 0 0 0 0
  Influenza-A 0 0 0 0 1 (16.7%) 1 (5.6%)
    Not Related 0 0 0 0 1 (16.7%) 1 (5.6%)
    Related 0 0 0 0 0 0
  Musculoskeletal 0 1 (33.3%) 0 1 (33.3%) 0 2 (11.1%)
    Not Related 0 1 (33.3%) 0 0 0 1 (5.6%)
    Related 0 0 0 1 (33.3%) 0 1 (5.6%)
  Increased Muscle Cramping 0 0 0 1 (33.3%) 0 1 (5.6%)
    Not Related 0 0 0 0 0 0
    Related 0 0 0 1 (33.3%) 0 1 (5.6%)
  Increased Muscle Fasciculations 0 1 (33.3%) 0 0 0 1 (5.6%)
    Not Related 0 1 (33.3%) 0 0 0 1 (5.6%)
    Related 0 0 0 0 0 0
  Shoulder Aches 0 0 0 1 (33.3%) 0 1 (5.6%)
    Not Related 0 0 0 1 (33.3%) 0 1 (5.6%)
    Related 0 0 0 0 0 0
  Respiratory 0 0 0 0 2 (33.3%)/td> 2 (11.1%)
    Not Related 0 0 0 0 1 (16.7%) 1 (5.6%)
    Related 0 0 0 0 1 (16.7%) 1 (5.6%)
  Cough 0 0 0 0 2 (33.3%) 2 (11.1%)
    Not Related 0 0 0 0 1 (16.7%) 1 (5.6%)
    Related 0 0 0 0 1 (16.7%) 1 (5.6%)
  Shortness of Breath 0 0 0 0 1 (16.7%) 1 (5.6%)
    Not Related 0 0 0 0 1 (16.7%) 1 (5.6%)
    Related 0 0 0 0 0 0
  Cardiac Disorders 0 0 1 (33.3%) 0 0 1 (5.6%)
    Not Related 0 0 1 (33.3%) 0 0 1 (5.6%)
    Related 0 0 0 0 0 0
  Insomnia 0 0 0 0 1 (16.7%) 1 (5.6%)
    Not Related 0 0 0 0 0 0
    Related 0 0 0 0 1 (16.7%) 1 (5.6%)
  Skin and Subcutaneous Tissue Disorders 0 0 1 (33.3%) 0 0 1 (5.6%)
    Not Related 0 0 1 (33.3%) 0 0 1 (5.6%)
    Related 0 0 0 0 0 0
  Hyperhidrosis 0 0 1 (33.3%) 0 0 1 (5.6%)
    Not Related 0 0 1 (33.3%) 0 0 1 (5.6%)
    Related 0 0 0 0 0 0
  Tachycardia 0 0 1 (33.3%) 0 0 1 (5.6%)
    Not Related 0 0 1 (33.3%) 0 0 1 (5.6%)
    Related 0 0 0 0 0 0
  Nervous System 0 0 1 (33.3%) 0 0 1 (5.6%)
    Not Related 0 0 1 (33.3%) 0 0 1 (5.6%)
    Related 0 0 0 0 0 0
  Headache 0 0 1 (33.3%) 0 0 1 (5.6%)
    Not Related 0 0 1 (33.3%) 0 0 1 (5.6%)
    Related 0 0 0 0 0 0
  Pschiatric Disorder 0 0 0 0 1 (16.7%) 1 (5.6%)

Abbreviation: TEAE = treatment-emergent adverse event

Note: A TEAE is defined as any event reported on or after the first dose of study treatment.

Note: Related events include those terms marked as 'Definite,' 'Probable,' or 'Possible;' Not Related events include those terms marked 'Unlikely' or 'Unrelated.' At each level of summarization (any event, system organ class, and verbatim term), subjects reporting more than one adverse event are counted only once using the closest relationship to investigational product.