Alpha Ketoglutarate Enhances Geroprotection In Surgery (AEGIS)

NCT07031128 | Recruiting Phase 4

• 1 other identifier: 2023/00747
• Study Type: interventional
• Target: 250
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

CABG

Keywords

Geroprotector; Alpha-ketoglutarate

Outcome Measures

Primary Outcomes (1)

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

  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

  Postoperative till day 90

Secondary Outcomes (19)

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

  Postoperative till day 90

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

  Postoperative till day 90

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

  Postoperative till day 90

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

  Postoperative till day 90

• Other Clinical Outcomes which may be impacted by AKG - Mortality

  Postoperative till day 90

Other Outcomes (4)

• Changes in Immune Status

  Postoperative till day 90

• Changes in Gut Microbiome

  Postoperative till day 90

• Impact of AKG on Cardiometabolic Status

  Postoperative till day 90

Study Arms (2)

AKG

EXPERIMENTAL

To receive AKG tablets (1g a day, once a day, taken orally)

Dietary Supplement: Alpha-ketoglutarate

Placebo

PLACEBO COMPARATOR

To receive placebo tablets (1g a day, once a day, taken orally)

Dietary Supplement: Placebo

Interventions

Alpha-ketoglutarate DIETARY_SUPPLEMENT

Alpha-ketoglutarate supplements

AKG

Placebo DIETARY_SUPPLEMENT

Placebo tablets

Placebo

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• National University Hospital, Singapore: lead
• Wellcome Leap Inc.: collaborator

Study Sites (2)

National University Hospital

Singapore, Singapore, 119074, Singapore

RECRUITING

Singapore General Hospital

Singapore, Singapore

RECRUITING

MeSH Terms

Interventions

Ketoglutaric Acids

Intervention Hierarchy (Ancestors)

Glutarates; Dicarboxylic Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Keto Acids

Study Officials

• Lian Kah Ti

  National University Hospital, Singapore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lian Kah Ti

CONTACT

6567724200; anatilk@nus.edu.sg

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Recruited patients will be randomized 1:1 to either receive AKG or placebo, stratified to each institution. Following successful randomization, each patient will be assigned a unique patient study number and a unique medication kit number.

Study Record Dates

• First Submitted: October 16, 2024
• First Posted: June 22, 2025
• Study Start: June 11, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: June 22, 2025

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

SG (2)