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NCT Number: NCT07031128

Alpha Ketoglutarate Enhances Geroprotection In Surgery (AEGIS)

One of the most common major surgeries that older patients undergo is coronary artery bypass grafting surgery (CABG), which is performed in approximately 400,000 patients in the United States each year. CABG invokes a massive surgical stress response, with systemic epinephrine increasing 33-fold and norepinephrine increasing 3-fold. Initially, local tissue injury results in a sterile inflammation, releasing damage-associated molecular patterns (DAMPS). DAMPS activate neutrophils, bringing a cascade of cytokines, complement, and coagulation changes. Activation of nociceptors results in a neurometabolic response involving the sympathetic nervous system and hypothalamus-pituitary axis. This brings about systemic effects including changes in basal metabolic rate, hyperglycemia, lipolysis, negative nitrogen balance, and release of cytokines and complement. Although the surgical stress response is essential for wound healing and is usually self-limiting, an exaggerated response may occur resulting in multiple organ dysfunction.

The acute phase of the surgical stress response is often followed by secondary insults that may be either sterile or pathogen-induced (such as postoperative infection).In the "two-hit" model of surgical stress response, there is an exaggerated response even to minor insults in vulnerable individuals who were primed by the initial stress response. Changes in the microbiome may also occur, developing a "pathobiome" that may enter the systemic circulation. If left unchecked, this second hit may result in the development of systemic inflammatory response syndrome (SIRS) and multi-organ failure.

Chronological ageing changes the innate and adaptive immunity of patients. Biological hallmarks of aging such as genomic instability, mitochondrial damage, glycation of proteins, and cellular senescence all result in increased oxidative stress and systemic inflammation. Aging brings about a pro-inflammatory innate immune responsiveness that often occurs even in the absence of an inflammatory threat. This is termed inflammaging. Paradoxically, inflammaging is associated with an increased risk of infection and poor response to stressful events. At the same time, there is an age-associated loss of T-cell function, particularly in naïve CD8 T-cells. This deficit is termed immunosenescence and is characterised by reduced pathogen recognition, chemotaxis, and phagocytosis.

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Key information

Conditions

CABG

Age range

50 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

National University Hospital, Singapore

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About this study

Within 24 hours of surgery, single-cell mass cytometry identified signalling changes in immune cell subsets that characterise the phenotypic and functional immune response to surgery. These signals accounted for 40-60% of observed patient variability, and strong correlations were found between these immune signatures with the speed of recovery from fatigue, pain, and functional impairment. In another study, Fragiadakis found that the preoperative immune state was also predictive of recovery from surgery, with toll-like receptor (TLR) 4 signalling in cluster of differentiation (CD) 14+ monocytes accounting for 50% of observed variance in clinical recovery. Furthermore, the group showed that patients undergoing an intermediate risk cardiac surgery had a significantly higher risk of developing multi-organ failure when their cytokine response profile was highly proinflammatory after stimulation with Escherichia coli-derived lipopolysaccharide . Another study showed that patients' immune response after surgery and immune profile before surgery predicted the development of surgical site complications in abdominal surgery. Taken together, these studies were consistent in suggesting that immune profiles play a major role in surgical resilience.

Therefore, it is postulated that giving a geroprotector in the perioperative period can mitigate the aging-related immune changes and prevent a dysfunctional surgical stress response, directly impacting surgical resilience. AKG is a geroprotector that benefits patients undergoing cardiac surgery. Plasma concentrations of AKG are reduced in patients with ischemic heart disease and it is possible that this aggravates myocardial ischemic injury during CABG. AKG supplementation during cardiopulmonary bypass significantly decreased ischaemic injury markers (creatine kinase MB and troponin T) by 30-50% in patients undergoing heart surgery, secondary to improved myocardial oxygen extraction.

AKG has beneficial effects beyond its cardiac effects. AKG is an intermediate in the Krebs cycle which is involved in various metabolic and cellular pathways as a signalling molecule, energy source, and precursor of amino acid synthesis. AKG is an anti-oxidative agent and a significant source of cellular adenosine triphosphate (ATP). Therefore, AKG plays an important role in multiple metabolic processes, and has been shown to preserve skeletal muscle, improve renal function, and protect neurological function. AKG is also a regulator of cell signalling pathways that maintain energy homeostasis, including mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK). By reducing the triggers of oxidative stress and hypoxia, AKG can moderate inflammation. AKG also has immune-modulatory properties. It modulates monocyte and neutrophil function by increasing phagocytosis and reactive oxygen species (ROS) intermediate production, macrophages by enhancing cytokine production, and lymphocytes by enhancing their proliferation.

Hypothesis Inflammaging and immunosenescence renders the older patient vulnerable to a dysfunctional surgical stress response.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Scheduled for elective CABG with cardiopulmonary bypass
  • Aged 50 years and above
  • Adequate cognitive function to be able to give informed consent

Exclusion criteria

  • Patients already taking AKG as a supplement
  • Substance abuse disorder either untreated or treated
  • Post-traumatic stress disorder, bipolar disorder, Schizophrenia, or any other untreated or poorly controlled mental health or mood disorder, or history of hospitalization due to mental health condition in the past 3 years, cognitively impaired patients
  • HIV/AIDS
  • Patients undergoing or scheduled to undergo chemotherapy or any other treatment for malignancy
  • Patients scheduled for immunosuppressant therapy for transplant
  • Patients with an active infection requiring antibiotic or antiviral therapy
  • Pregnant women / planning to conceive / breastfeeding women
  • Patients who are taking chronic anti-inflammatory drugs e.g., NSAIDS
  • Patients who are hypersensitivity to AKG or placebo or any components of the respective tablets to be administered

Treatment and study plan

Alpha-ketoglutarate

Dietary Supplement

Alpha-ketoglutarate supplements

Placebo

Dietary Supplement

Placebo tablets

Primary outcomes

  1. Composite of systemic inflammatory response syndrome (SIRS) and at least 1 organ system

    Time frame: Postoperative till day 90

    The primary outcome will be a composite of systemic inflammatory response syndrome (SIRS) and at least 1 organ system dysfunction in the systems below.

    • SIRS; and
    • Cardiovascular dysfunction; and/or
    • Neurologic dysfunction; and or
    • Renal dysfunction; and/or
    • Respiratory dysfunction; and or
    • Coagulation dysfunction

Secondary outcomes

  1. Other Clinical Outcomes which may be impacted by AKG - Muscle Mass

    Time frame: Postoperative till day 90

    • Circumferential measurements of arms and calves in cm
    • Triceps fold thickness in cm

  2. Other Clinical Outcomes which may be impacted by AKG - Muscle Strength

    Time frame: Postoperative till day 90

    • Hand grip strength in kg

  3. Other Clinical Outcomes which may be impacted by AKG - Infections Acquired

    Time frame: Postoperative till day 90

    • Surgical site infection: observational & charting review
    • Hospital-acquired infection: observational & charting review

  4. Other Clinical Outcomes which may be impacted by AKG - Long-term Outcomes

    Time frame: Postoperative till day 90

    • Inflammation
    • Cardiac
    • Neurological
    • Renal

    Long-term Outcomes will be determined by charting reviews to determine if there are failure of the above listed organ systems

  5. Other Clinical Outcomes which may be impacted by AKG - Mortality

    Time frame: Postoperative till day 90

    • Mortality from any cause

    To be determined by charting reviews and observation

  6. Resource Utilization - Length of stay

    Time frame: Postoperative till day 90

    • ICU length of stay (days)
    • Hospital length of stay (days)

    To be determined by charting reviews and observation

  7. Resource Utilization - Discharge

    Time frame: Postoperative till day 90

    • Patient discharge location

    To be determined by charting reviews

  8. Resource Utilization - Unplanned readmission

    Time frame: Postoperative till day 90

    • Unplanning readmission from any cause

    To be determined by charting reviews

  9. Resource Utilization - Hospital bill size

    Time frame: Postoperative till day 90

    • Cost of hospital stay (SGD) To be determined by charting reviews and requesting bill information from participants

  10. Biological Ageing - Methylation & Dynamic Clocks

    Time frame: Postoperative till day 90

    Various computer algorithms will be used to determine DNA methylation status

  11. Identification of Immune or Inflammatory Markers

    Time frame: Postoperative till day 90

    Blood samples will be collected and laboratory tests will be conducted to identify immune and inflammatory biomarkers.

    Known inflammatory biomarkers such as CRP, IL-6, TNF-α,IL-1α,IL-10 and IL-8 (not exhaustive) and newly identified biomarkers will be investigated to look at how CABG surgery changes a patient's frailty status and whether AKG has an impact on these biomarkers.

  12. Investigations on Immune Reactivity's Relation with Surgical Resilience

    Time frame: Postoperative till day 90

    • To systematically address the endogenous signalling pathways conferring resilience of immune cells from patients with and without AKG treatments, peripheral blood mononuclear cells (PBMCs) will be stimulated with a panel of agonists that activate different toll-like receptors. Multiplexed cytokine analysis will be conducted on stimulated and control PBMCs. High dimensional, subset-specific, flow cytometry will be utilized at all points to assess changes in surface markers that indicate immune activation, immune regulation and senescence/exhaustion.

  13. Patient-Centred Outcomes - Frailty

    Time frame: Postoperative till day 90

    The study team will determine the patient's frailty based on observation, charting reviews and available clinical information.

  14. Patient-Centred Outcomes - Pain

    Time frame: Postoperative till day 90

    • Self-reported pain scores at rest and on movement using visual analogue scale (0 - 10)

  15. Patient-Centred Outcomes - Disability

    Time frame: Postoperative till day 90

    Study team will determine the patient's diability status base on observation. This will be conducted pre- and post- operation to determine if there is any changes in disability status due to operation, and if and how AKG has impacted this status.

  16. Patient-Centred Outcomes - Quality of Life

    Time frame: Postoperative till day 90

    • EuroQol 5 Dimension (EQ-5D)

  17. Patient-Centred Outcomes - Fatigue

    Time frame: Postoperative till day 90

    • FACIT (Functional Assessment Of Chronic Illness Therapy)

  18. Patient-Centred Outcomes - Depression

    Time frame: Postoperative till day 90

    • Hospital Anxiety and Depression Scale (HADS)

  19. Patient-Centred Outcomes - Patient Satisfaction

    Time frame: Postoperative till day 90

    • Patient satisfaction score using visual analogue scale (0 - 10)

Other outcomes

  1. Changes in Immune Status

    Time frame: Postoperative till day 90

    Comparison between study groups for changes, if any, in gene expression levels using peripheral blood transcriptomics

  2. Changes in Gut Microbiome

    Time frame: Postoperative till day 90

    Comparison between study groups for changes, if any, in gut microbiome via shotgun sequencing to identify microbiome population pre-AKG, pre-op and post-op.

  3. Impact of AKG on Cardiometabolic Status

    Time frame: Postoperative till day 90

    Comparison between study group for changes in cardiometabolic status using metabolic profiling to elucidate the pathway(s) of AKG and ischemic cardio protection.

  4. Investigations into Immune Dysregulation and Inflammation

    Time frame: Postoperative till day 90

    Multiomics platform will be used to identify underlying pathways involved in immune dysregulation and inflammation, if any, and how these pathways are affected by the consumption of AKG pre- and post- operation.

Study contacts

Contact information is provided by the study sponsor or research team.

Lian Kah Ti

CONTACT

[email protected]

6567724200

Sponsors and collaborators

Lead sponsor

National University Hospital, Singapore

Other

Collaborators

  • Wellcome Leap Inc.

Registry information

Official study title

Evaluating the Impact of Alpha Ketoglutarate (AKG), a Geroprotector, in Reducing Morbidity and Improving Patient-Centred Outcomes After Coronary Artery Bypass Grafting Surgery in Resilient and Poorly-Resilient Patients: A Double-Blind Placebo-Controlled Clinical Trial

Important dates

Study start
2024
Primary completion
2026
Study completion
2026
First posted
Jun 22, 2025
Registry last updated
Jun 22, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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