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

NCT05273372 | Completed DMC

• 1 other identifier: TB-2022-AEO ME/CFS v1.6
• Study Type: interventional
• Target: 82
• Locations: 1 country
• Sites: 1

Brief Summary

There is no approved treatment for fatigue in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a condition with as many as 2.5 million people in the US. Initial case studies have shown an improvement in fatigue in ME/CFS with anhydrous enol-oxaloacetate (AEO). This randomized, double blinded, placebo controlled trial will seek to further evaluate the efficacy of AEO to reduce fatigue in ME/CFS, based on change in the Chalder Fatigue Score (Likert Scoring) of the AEO group against the placebo group at 90 days. As secondary evaluations on other core ME/CFS symptoms, the investigators are measuring the health related quality of life as assessed by the SF-36, hours of upright activity, functional capacity (activity, steps, cognition, and heart rate variability), and general health status (global change, vitals) Finally, this test will gain preliminary insights on the safety, tolerability, and efficacy of AEO in ME/CFS patients.

Conditions

Myalgic Encephalomyelitis; Chronic Fatigue Syndrome; Fatigue

Outcome Measures

Primary Outcomes (1)

• Reduction of Fatigue

  Reduction in fatigue, Likert Scoring, on the Chalder Fatigue Scale 0-33 Point Scale, with 0 being no fatigue, and 33 being maximum measurable fatigue

  90 days

Secondary Outcomes (3)

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  90 days

• Physical Functioning on the SF-36

  90 days

• Patient Global Impression of Change Questionnaire, 7 point scale, -3 to +3, with the higher score indicating more improvement

  90 days

Study Arms (2)

Oxaloacetate

EXPERIMENTAL

500 mg anhydrous enol-oxaloacetate in hypromellose capsules (veggie caps). 2 capsules with breakfast and 2 capsules with lunch (1,000 mg BID) for 90 days.

Other: Medical Food - Anhydrous Enol-Oxaloacetate

Placebo

PLACEBO COMPARATOR

500 mg white rice flour in hypromellose capsules (veggie caps). 2 capsules with breakfast and 2 capsules with lunch (1,000 mg BID) for 90 days.

Other: Placebo

Interventions

Placebo OTHER

Placebo treatment with the food white rice flour. 1,000 mg BID

Also known as: White Rice Flour

Placebo

Medical Food - Anhydrous Enol-Oxaloacetate OTHER

Active treatment with oxaloacetate. 1,000 mg BID

Also known as: Oxaloacetate

Oxaloacetate

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients who meet all of the following criteria are eligible to participate in the study:
• Provision of signed and dated informed consent form
• Ability to read, understand or speak English
• Diagnosed with ME/CFS and meet the IOM Diagnostic Criteria for ME/CFS (2015)
• Relatively stable state of illness for the past 3 months that is characterized by \>2 and \<6 hours of daily upright activity
• Male or female, between the ages of 18 and 65 years old
• No evidence of active infection with SARS-CoV-2 documented by a negative test at Visit 1
• Agree to refrain from taking medications that would affect assessment of the effectiveness of study dietary supplement for the duration of the study
• Females of childbearing potential should be on adequate contraception such as oral, implantable, injectable or transdermal hormonal contraceptives (should have been used for a minimum of one full cycle prior to administration of study drug), intrauterine devices (IUD), vasectomized partner, double barrier method (male or female condom, sponge, diaphragm or vaginal ring with simultaneous use of spermicidal jelly or cream)
• Each patient of child-bearing potential must have a negative urine pregnancy test at Visit 1. The urine test at Visit 1 must both be confirmed negative prior to randomization. Women of child-bearing potential will have a urine pregnancy test at each visit (2-4) and it must be negative to continue. Women who are confirmed to be of non-childbearing potential do not require pregnancy testing. To be considered of non-child-bearing potential, the patient must be: post-menopausal (defined as no menses for at least one year); or surgically sterile (s/p hysterectomy, bilateral oophorectomy or bilateral tubal ligation at least 6 months prior to randomization); or at least 3 months s/p a non-surgical permanent sterilization procedure
• History of fatigue and post-exertional malaise (PEM)
• Stated willingness to comply with all study procedures and remain available for the study duration
• Have mobile (smart) phone and access to the internet
• Willingness to wear a device on their ankle

You may not qualify if:

• A patient who meets any of the following criteria will be excluded from participation in this study:
• A positive rapid COVID-19 antigen test at Visit 1
• Alternate medical or psychiatric illness that could explain the ME/CFS symptoms
• Severe ME/CFS with less than 2 hours of upright activity a day
• Body Mass Index \> 35
• Participating in another clinical treatment trial, or symptoms improving as a result of treatment intervention in the past 3 months
• Current treatment with stimulants including methylphenidate, amphetamine-dextroamphetamine, lisdexamfetamine, modafinil, armodafinil
• Pregnancy, or while breast feeding. Women should not be enrolled within 6 months of giving birth and within 3 months of cessation of breast feeding.
• History of:
• Major depression with psychotic or melancholic features before the diagnosis of ME/CFS, or active depression (major depression with psychotic or melancholic features) as determined by self-report
• Untreated endocrine diagnoses including hypothyroidism (Hashimoto's, etc.), Grave's disease, adrenal insufficiency, hypogonadism (testosterone deficiency), diabetes mellitus or insipidus
• Significant head injury in the last 3 years, concussion with loss of consciousness, brain surgery, an automobile accident with head/neck injury, and/or other traumatic brain injury
• A supra-ventricular tachycardia or ventricular tachycardia, e.g., atrial fibrillation or flutter, paroxysmal atrial fibrillation, junctional tachycardia, ventricular tachycardia
• Symptomatic hypotension defined as rested sitting systolic BP \< 100 mmHg or rested sitting diastolic BP \< 60 mmHg
• Substance abuse in the past 12 months as determined by self-report • Improvement in overall ME/CFS symptoms as a result of any treatment intervention in the past 3 months

Sponsors & Collaborators

• Terra Biological LLC: lead
• Bateman Horne Center: collaborator

Study Sites (1)

Bateman Horne Center

Salt Lake City, Utah, 84102, United States

Location

Related Publications (19)

• Germain A, Ruppert D, Levine SM, Hanson MR. Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol Biosyst. 2017 Jan 31;13(2):371-379. doi: 10.1039/c6mb00600k.

  PMID: 28059425 BACKGROUND

• Germain A, Barupal DK, Levine SM, Hanson MR. Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids. Metabolites. 2020 Jan 14;10(1):34. doi: 10.3390/metabo10010034.

  PMID: 31947545 BACKGROUND

• Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington (DC): National Academies Press (US); 2015 Feb 10. Available from http://www.ncbi.nlm.nih.gov/books/NBK274235/

  PMID: 25695122 BACKGROUND

• Keller BA, Pryor JL, Giloteaux L. Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO(2)peak indicates functional impairment. J Transl Med. 2014 Apr 23;12:104. doi: 10.1186/1479-5876-12-104.

  PMID: 24755065 BACKGROUND

• Mandarano AH, Maya J, Giloteaux L, Peterson DL, Maynard M, Gottschalk CG, Hanson MR. Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations. J Clin Invest. 2020 Mar 2;130(3):1491-1505. doi: 10.1172/JCI132185.

  PMID: 31830003 BACKGROUND

• McHorney CA, Ware JE Jr, Lu JF, Sherbourne CD. The MOS 36-item Short-Form Health Survey (SF-36): III. Tests of data quality, scaling assumptions, and reliability across diverse patient groups. Med Care. 1994 Jan;32(1):40-66. doi: 10.1097/00005650-199401000-00004.

  PMID: 8277801 BACKGROUND

• Nagy-Szakal D, Barupal DK, Lee B, Che X, Williams BL, Kahn EJR, Ukaigwe JE, Bateman L, Klimas NG, Komaroff AL, Levine S, Montoya JG, Peterson DL, Levin B, Hornig M, Fiehn O, Lipkin WI. Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics. Sci Rep. 2018 Jul 3;8(1):10056. doi: 10.1038/s41598-018-28477-9.

  PMID: 29968805 BACKGROUND

• Nkiliza A, Parks M, Cseresznye A, Oberlin S, Evans JE, Darcey T, Aenlle K, Niedospial D, Mullan M, Crawford F, Klimas N, Abdullah L. Sex-specific plasma lipid profiles of ME/CFS patients and their association with pain, fatigue, and cognitive symptoms. J Transl Med. 2021 Aug 28;19(1):370. doi: 10.1186/s12967-021-03035-6.

  PMID: 34454515 BACKGROUND

• Ruban A, Berkutzki T, Cooper I, Mohar B, Teichberg VI. Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas. Invest New Drugs. 2012 Dec;30(6):2226-35. doi: 10.1007/s10637-012-9799-5.

  PMID: 22392507 BACKGROUND

• Swerdlow RH, Bothwell R, Hutfles L, Burns JM, Reed GA. Tolerability and pharmacokinetics of oxaloacetate 100 mg capsules in Alzheimer's subjects. BBA Clin. 2016 Mar 10;5:120-3. doi: 10.1016/j.bbacli.2016.03.005. eCollection 2016 Jun.

  PMID: 27051598 BACKGROUND

• Tully L, Humiston J, Cash A. Oxaloacetate reduces emotional symptoms in premenstrual syndrome (PMS): results of a placebo-controlled, cross-over clinical trial. Obstet Gynecol Sci. 2020 Mar;63(2):195-204. doi: 10.5468/ogs.2020.63.2.195. Epub 2020 Feb 25.

  PMID: 32206660 BACKGROUND

• Vernon SD, Whistler T, Cameron B, Hickie IB, Reeves WC, Lloyd A. Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus. BMC Infect Dis. 2006 Jan 31;6:15. doi: 10.1186/1471-2334-6-15.

  PMID: 16448567 BACKGROUND

• Vidoni ED, Choi IY, Lee P, Reed G, Zhang N, Pleen J, Mahnken JD, Clutton J, Becker A, Sherry E, Bothwell R, Anderson H, Harris RA, Brooks W, Wilkins HM, Mosconi L, Burns JM, Swerdlow RH. Safety and target engagement profile of two oxaloacetate doses in Alzheimer's patients. Alzheimers Dement. 2021 Jan;17(1):7-17. doi: 10.1002/alz.12156. Epub 2020 Jul 27.

  PMID: 32715609 BACKGROUND

• Whistler T, Taylor R, Craddock RC, Broderick G, Klimas N, Unger ER. Gene expression correlates of unexplained fatigue. Pharmacogenomics. 2006 Apr;7(3):395-405. doi: 10.2217/14622416.7.3.395.

  PMID: 16610950 BACKGROUND

• Wilkins HM, Harris JL, Carl SM, E L, Lu J, Eva Selfridge J, Roy N, Hutfles L, Koppel S, Morris J, Burns JM, Michaelis ML, Michaelis EK, Brooks WM, Swerdlow RH. Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. Hum Mol Genet. 2014 Dec 15;23(24):6528-41. doi: 10.1093/hmg/ddu371. Epub 2014 Jul 15.

  PMID: 25027327 BACKGROUND

• Williams DS, Cash A, Hamadani L, Diemer T. Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway. Aging Cell. 2009 Dec;8(6):765-8. doi: 10.1111/j.1474-9726.2009.00527.x. Epub 2009 Sep 30.

  PMID: 19793063 BACKGROUND

• Yamano E, Sugimoto M, Hirayama A, Kume S, Yamato M, Jin G, Tajima S, Goda N, Iwai K, Fukuda S, Yamaguti K, Kuratsune H, Soga T, Watanabe Y, Kataoka Y. Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. Sci Rep. 2016 Oct 11;6:34990. doi: 10.1038/srep34990.

  PMID: 27725700 BACKGROUND

• Yoshikawa K. Studies on the anti-diabetic effect of sodium oxaloacetate. Tohoku J Exp Med. 1968 Oct;96(2):127-41. doi: 10.1620/tjem.96.127. No abstract available.

  PMID: 4884771 BACKGROUND

• Cash A, Vernon SD, Rond C, Bateman L, Abbaszadeh S, Bell J, Yellman B, Kaufman DL. RESTORE ME: a RCT of oxaloacetate for improving fatigue in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front Neurol. 2024 Nov 27;15:1483876. doi: 10.3389/fneur.2024.1483876. eCollection 2024.

  PMID: 39664752 DERIVED

Related Links

• Oxaloacetate Acid Supplementation as a Mimic of Calorie Restriction

MeSH Terms

Conditions

Fatigue Syndrome, Chronic; Fatigue

Interventions

Oxaloacetic Acid

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Encephalomyelitis; Neuroinflammatory Diseases; Nervous System Diseases; Neuromuscular Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Oxaloacetates; Oxalates; Dicarboxylic Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Keto Acids

Study Officials

• Suzanne D Vernon, Ph.D.

  Bateman Horne Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 2 sets of bottles will be delivered to the Bateman Horne Center-- Group 1 and Group A. One of the groups will contain the active, the other the placebo.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Placebo-controlled double blinded 2 arm study. 40 patients in treatment arm, 40 patients in placebo arm.

Study Record Dates

• First Submitted: February 18, 2022
• First Posted: March 10, 2022
• Study Start: March 15, 2022
• Primary Completion: June 15, 2024
• Study Completion: November 15, 2024
• Last Updated: February 4, 2025

Record last verified: 2024-11

Locations

US (1)