Reducing Inflammatory Syndrome in Surgery - Colorectal (RISIS-CR) Trial (RISIS-CR)

The study proposes to identify inflammatory responsiveness of patients prior to CRC surgery and administer prophylactic anti-inflammatory treatment targeted only to those with an excessive pro-inflammatory response. The study team believe this to be a creative approach as the principles of personalized medicine will be used to treat the appropriate patients, and equally as importantly, to not further suppress the inflammatory response of those who have poor immune function already.

Geroprotectors reduce inflammation, and may reduce postoperative SIR and complications after CRC surgery. In this proposal, we intend to use alpha ketoglutarate (AKG), a geroprotector supplement that enjoys a GRAS (generally regarded as safe) status with the FDA. [12] Apart from reducing inflammation and inhibiting the mTOR pathway, AKG also prevents loss of muscle mass, improves brain oxygenation, has cardioprotective effects, and improves renal function. It also has anti-cancer effects beyond mTOR pathway inhibition, including regulating HIF-1 activity, suppressing secretion of angiogenic factors, and regulating epigenetic processes.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Other: Standard care; Dietary supplement: Placebo; Dietary supplement: Alpha-ketoglutarate

Detailed Description

The incidence of colorectal cancer (CRC) increases exponentially with age, with >50% of CRC first diagnosed at 50 years or older. Surgery is the mainstay of treatment. However, older patients are more likely to develop postoperative ileus and anastomotic leak, longer hospital stays and higher mortality. In the long-term, they are more likely to experience fatigue and slow recovery.

Surgery triggers an inflammatory response. In some cases, the immune system is unable to distinguish between the stimuli of major surgery (ideally a modest response) and trauma or infection. This overshoot manifests as a postoperative systemic inflammatory response (SIR) and may lead to tissue destruction and organ dysfunction. In CRC surgery, SIR as defined by C-reactive protein (CRP) elevation is associated with postoperative Clavien-Dindo grades III and IV complications where intervention is needed. These complications include infection and anastomotic leak, and are linked to reduced overall survival independent of both surgery-related complications and tumour stage. In addition, preoperative systemic inflammation is a marker of poor prognosis. As ageing is often accompanied by a chronic low-grade inflammation, it was not surprising that preoperative systemic inflammation is more common in older patients.

The use of anti-inflammatory drugs to reduce SIR has had mixed successes. Chronic steroid use is a recognized risk factor for anastomotic leak, but in a recent meta-analysis, the use of preoperative corticosteroids lowered markers of SIR and reduced postoperative infective complications. Similarly, although NSAIDs have been shown to reduce hospital stay and hasten recovery in bowel function, a recent meta-analysis indicated that it increases the risk of anastomotic leaks.

Older patients may have impaired immune response to surgical stress from immunosenescence but conversely, some may develop a more intense and prolonged response. In a population study of elderly people, this heterogeneity conferred a survival benefit to those who could mount a pro-inflammatory response, whereas those with poor pro-inflammatory response were more prone to infections. Therefore, suppressing the postoperative SIR in pro-inflammatory patients is likely beneficial but not in patients with low pro-inflammatory potential.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Lian Kah Ti; Phone Number: 6567724200; Email: anatilk@nus.edu.sg

Study Locations

• Singapore
  • Singapore, Singapore
    • Recruiting
    • Singapore General Hospital
    • Contact: Sophia Tsong Huey Chew
  • Singapore, Singapore, 119074
    • Recruiting
    • National University Hospital
    • Contact: Lian Kah Ti; Email: anatilk@nus.edu.sg
    • Contact: Ker Kan Tan
    • Contact: Ne-Hooi Will Loh
    • Contact: Chee Kuan Francis Tan
    • Contact: Chunmei Li
  • Singapore, Singapore
    • Recruiting
    • Sengkang General Hospital
    • Contact: Frederick Koh
  • Singapore, Singapore
    • Recruiting
    • Ng Teng Fong General Hospital
    • Contact: Wee-Sen Choo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients aged at least 45 years old
• Undergoing elective colorectal cancer surgery
• Able to give informed consent

Exclusion Criteria:

• Undergoing emergency colorectal cancer surgery
• Unable to give informed consent
• Females who are pregnant
• Cognitively impaired patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Low inflammatory responder; Low inflammatory responder group - to receive standard care	Other: Standard care; Standard care
Experimental: High inflammatory responder - AKG; High inflammatory responder group - to receive AKG tablets (1g a day, once a day, taken orally)	Dietary supplement: Alpha-ketoglutarate; Alpha-ketoglutarate supplements
Placebo Comparator: High inflammatory responder - placebo; High inflammatory responder group - to receive placebo tablets (1g a day, once a day, taken orally)	Dietary supplement: Placebo; Placebo tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of postoperative CRP levels between the low inflammatory responders, high inflammatory responders with AKG and high inflammatory responders with placebo	Comparison of postoperative CRP levels between the groups.	Postoperative till day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare changes in frailty, cognition, recovery trajectory, clinical outcomes, and surgical complications	Compare changes in frailty, cognition, recovery trajectory, clinical outcomes, and surgical complications	Postoperative till day 30

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: National Medical Research Council (NMRC), Singapore
• Investigators: Principal Investigator: Lian Kah Ti, National University Hospital, Singapore

Study record dates

Study Major Dates

• Study Start (Actual): May 9, 2024
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: July 24, 2023
• First Submitted That Met QC Criteria: October 16, 2024
• First Posted (Actual): October 17, 2024

Study Record Updates

• Last Update Posted (Actual): October 17, 2024
• Last Update Submitted That Met QC Criteria: October 16, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Geroprotector; Alpha-ketoglutarate
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: 2022/00724

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No