Colorectal CancerPhase 3RISIS-CRNCT06646809
Reducing Inflammatory Syndrome in Surgery - Colorectal (RISIS-CR) Trial
A Phase 3 study testing Alpha-ketoglutarate in people with Colorectal Cancer, run by National University Hospital, Singapore at 4 sites in Singapore.
Trial 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. Read more about this study
- Who is it for?
- Ages 45 years and older
- Conditions the study is for
- Colorectal Cancer
- What is being tested?
- Alpha-ketoglutarate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 80 participants
- Where
- 4 sitesSingapore
- Study dates
- 9 May 2024to Dec 2024
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 45 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients aged at least 45 years old
- Undergoing elective colorectal cancer surgery
- Able to give informed consent
Who cannot join
- Undergoing emergency colorectal cancer surgery
- Unable to give informed consent
- Females who are pregnant
- Cognitively impaired patients
Trial locations and contacts
4 sites in 1 country.
Singapore4 sites, 4 recruiting
- Recruiting
National University Hospital
Singapore, Singapore, 119074
Lian Kah Ti, anatilk@nus.edu.sg
Ker Kan Tan
- Recruiting
Ng Teng Fong General Hospital
Singapore
Wee-Sen Choo
- Recruiting
Sengkang General Hospital
Singapore
Frederick Koh
- Recruiting
Singapore General Hospital
Singapore
Sophia Tsong Huey Chew
About this study
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.
Read the 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
- Being tested
- Alpha-ketoglutarate, Placebo, Standard care
- Keywords
- Geroprotector, Alpha-ketoglutarate
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Alpha-ketoglutarateDietary supplement
Alpha-ketoglutarate supplements
PlaceboDietary supplement
Placebo tablets
Standard careOther
Standard care
| Study group | Role | What they receive |
|---|---|---|
| Low inflammatory responder | Other | Low inflammatory responder group - to receive standard care Receives: Other: Standard care |
| High inflammatory responder - AKG | Experimental | High inflammatory responder group - to receive AKG tablets (1g a day, once a day, taken orally) Receives: Dietary Supplement: Alpha-ketoglutarate |
| High inflammatory responder - placebo | Placebo comparator | High inflammatory responder group - to receive placebo tablets (1g a day, once a day, taken orally) Receives: Dietary Supplement: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Postoperative till day 30
Secondary outcomes (1)
Compare changes in frailty, cognition, recovery trajectory, clinical outcomes, and surgical complications
Compare changes in frailty, cognition, recovery trajectory, clinical outcomes, and surgical complications
Measured: Postoperative till day 30
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Oct 2024
- Study start9 May 2024
- Primary completionDec 2024 (estimated)
- Study completionDec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Colorectal CancerStudies of the same condition, open and under way.
- More trials run by National University Hospital, SingaporeThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 3 groups of patients - low inflammatory responder, high inflammatory responder with AKG, high inflammatory responder with placebo
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National University Hospital, Singapore
- Sponsor type
- University, hospital or other
- Collaborators
- NMRC
- Responsible party
- Sponsor
- Investigators
- Lian Kah Ti, Principal investigator, National University Hospital, Singapore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06646809
- Sponsor's protocol ID
- 2022/00724
- Acronym
- RISIS-CR
- Status last verified
- Aug 2024
- First submitted
- 24 Jul 2023
- Last updated
- 17 Oct 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Reducing Inflammatory Syndrome in Surgery - Colorectal (RISIS-CR) Trial
- ClinicalTrials.gov ID
- NCT06646809
- Acronym / sponsor ID
- RISIS-CR / 2022/00724
- Conditions
- Colorectal Cancer
- Keywords
- Geroprotector, Alpha-ketoglutarate
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- National University Hospital, SingaporeUniversity, hospital or other
- Collaborators
- NMRC
- Study start
- 9 May 2024 (actual)
- Primary completion
- Dec 2024 (estimated)
- Study completion
- Dec 2024 (estimated)
- First posted
- 17 Oct 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- 3 groups of patients - low inflammatory responder, high inflammatory responder with AKG, high inflammatory responder with placebo
| Arm | Type | Receives |
|---|---|---|
| Low inflammatory responder | Other | Other: Standard careLow inflammatory responder group - to receive standard care |
| High inflammatory responder - AKG | Experimental | Dietary Supplement: Alpha-ketoglutarateHigh inflammatory responder group - to receive AKG tablets (1g a day, once a day, taken orally) |
| High inflammatory responder - placebo | Placebo comparator | Dietary Supplement: PlaceboHigh inflammatory responder group - to receive placebo tablets (1g a day, once a day, taken orally) |
Who may qualify
- Ages
- 45 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Patients aged at least 45 years old
- Undergoing elective colorectal cancer surgery
- Able to give informed consent
Key exclusion criteria (4 listed)
- Undergoing emergency colorectal cancer surgery
- Unable to give informed consent
- Females who are pregnant
- Cognitively impaired patients
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Alpha-ketoglutarateAlpha-ketoglutarate supplements | Dietary supplement | High inflammatory responder - AKG |
| PlaceboPlacebo tablets | Dietary supplement | High inflammatory responder - placebo |
| Standard careStandard care | Other | Low inflammatory responder |
Primary outcome
Comparison of postoperative CRP levels between the low inflammatory responders, high inflammatory responders with AKG and high inflammatory responders with placebo
Time frame: Postoperative till day 30
Comparison of postoperative CRP levels between the groups.
1 secondary outcome
Compare changes in frailty, cognition, recovery trajectory, clinical outcomes, and surgical complications
Time frame: Postoperative till day 30
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Oct 2024.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lian Kah Ti principal investigator
National University Hospital, Singapore
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Alpha-ketoglutarate in people with Colorectal Cancer, run by National University Hospital, Singapore at 4 sites in Singapore.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 17 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Lian Kah Ti (6567724200, anatilk@nus.edu.sg), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Comparison of postoperative CRP levels between the low inflammatory responders, high inflammatory responders with AKG and high inflammatory responders with placebo (time frame: Postoperative till day 30). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Oct 2024.