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

NCT ID: NCT06646809

Last Updated: 2024-10-17

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-05-09
• Study Completion Date: 2024-12-31

Brief Summary

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.

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.

Conditions

Colorectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Low inflammatory responder

Low inflammatory responder group - to receive standard care

Group Type: OTHER

Standard care

Intervention Type: OTHER

Standard care

High inflammatory responder - AKG

High inflammatory responder group - to receive AKG tablets (1g a day, once a day, taken orally)

Group Type: EXPERIMENTAL

Alpha-ketoglutarate

Intervention Type: DIETARY_SUPPLEMENT

Alpha-ketoglutarate supplements

High inflammatory responder - placebo

High inflammatory responder group - to receive placebo tablets (1g a day, once a day, taken orally)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DIETARY_SUPPLEMENT

Placebo tablets

Interventions

Alpha-ketoglutarate

Alpha-ketoglutarate supplements

Intervention Type: DIETARY_SUPPLEMENT

Placebo

Placebo tablets

Intervention Type: DIETARY_SUPPLEMENT

Standard care

Standard care

Intervention Type: OTHER

Eligibility Criteria

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

• Minimum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Medical Research Council (NMRC), Singapore

OTHER_GOV

Sponsor Role: collaborator

National University Hospital, Singapore

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lian Kah Ti

Role: PRINCIPAL_INVESTIGATOR

National University Hospital, Singapore

Locations

National University Hospital

Singapore, Singapore, Singapore

Site Status: RECRUITING

Ng Teng Fong General Hospital

Singapore, , Singapore

Site Status: RECRUITING

Sengkang General Hospital

Singapore, , Singapore

Site Status: RECRUITING

Singapore General Hospital

Singapore, , Singapore

Site Status: RECRUITING

Countries

Singapore

Central Contacts

Lian Kah Ti

Role: CONTACT

anatilk@nus.edu.sg

6567724200

Facility Contacts

Lian Kah Ti

Role: primary

anatilk@nus.edu.sg

Ker Kan Tan

Role: backup

Ne-Hooi Will Loh

Role: backup

Chee Kuan Francis Tan

Role: backup

Chunmei Li

Role: backup

Wee-Sen Choo

Role: primary

Frederick Koh

Role: primary

Sophia Tsong Huey Chew

Role: primary

Other Identifiers

2022/00724

Identifier Type: -

Identifier Source: org_study_id