Clinical Trials Logo

Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03359681
Other study ID # REG-096-2017
Secondary ID
Status Completed
Phase Phase 2
First received
Last updated
Start date July 10, 2018
Est. completion date October 4, 2021

Study information

Verified date November 2021
Source Zealand University Hospital
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This is a double-blinded placebo controlled randomized trial examining the effect of metformin in non-diabetic patients with colon cancer on cell growth, immunological and metabolic changes. Patients are randomized to receive metformin 20 days before and 10 days after surgery. Tumor samples are examined for changes in level of cell growth and the composition of tumor cells in the tumor is examined. Blood samples are assessed for immunological markers and insulin resistance is measured. Cell proliferation, migration and adhesion are also examined in vitro by adding plasma obtained from the patients to colon cancer cell lines grown in culture.


Description:

Background: Colorectal cancer (CRC) is the third most common cancer worldwide and more than 5000 patients are diagnosed each year in Denmark. Metformin is the drug of choice for treatment of type 2 diabetes. Several studies indicate that the incidence of colorectal cancer is lower among metformin treated diabetic patients than other diabetic patients and survival after CRC is improved for this group as well. Metformin lowers plasma glucose in diabetic patients, but studies suggest that metformin also inhibits cancer cell growth. Tumor cell proliferation and apoptosis can be estimated by determining the expression levels of specific cell cycle related proteins such as Ki67 (proliferation) and cleaved caspase-3 (apoptosis) using immunohistochemistry. The level of cell proliferation and apoptosis is important for tumor development, but growing evidence suggests that the microenvironment of the tumor and the patient's immune response play important roles as well. The immunoscore has been introduced as a prognostic marker for CRC. The immunoscore is determined by staining whole tumor slides for CD3 and CD8 positive lymphocytes using immunohistochemistry, followed by quantitative assessment and scoring of their densities. A high density is associated with better outcome than a low density. It is possible that metformin can influence the composition of immune cells as well. Surgery is known to induce a surgical stress response with hormonal and metabolic changes. The stress response leads to an increased insulin resistance and hyperglycemia postoperatively. The degree of insulin resistance and hyperglycemia is correlated with risk of postoperative complications, reoperation, length of stay and death. Study design: The trial is a randomised, placebo-controlled, double-blinded trial investigating the effect of metformin (intervention group) against placebo (control group) on cell proliferation, metabolic and immunological changes in non-diabetic patients with colon cancer. Patients are recruited at their visit to the out-patient clinic at Slagelse Hospital when surgery is planned. Patients, who agree to participate, will be randomized to receive metformin or placebo for up to 20 days before their operation and 10 days afterwards. Blood samples will be taken at time of randomization and 4 times more during the study. The study is divided into 5 sub-studies: Sub-study 1 - Cell growth on tumor level: The primary outcome is determination of the difference of the level of proliferation after the intervention (time of surgery) adjusted for the level seen at baseline (time of colonoscopy). This is examined by immunohistochemical staining of tumor samples obtained from the colonoscopy and after surgery for Ki67 and cleaved caspase 3. Sub-study 2 - immunological changes: The immunoscore is measured by immunohistochemical staining of tumor samples for CD3 and CD8 positive lymphocytes. Blood samples are analyzed for immune markers. Sub-study 3 - cell growth in vitro: Plasma obtained from the metformin- or placebo-treated patients are added to colorectal cancer cells grown in culture. Cell proliferation, migration and adhesion are determined by in vitro studies and differences between the two groups analyzed. Sub-study 4 - insulin resistance and recovery: Insulin resistance before and after surgery is measured using the homeostatic assessment model (HOMA) from fasting levels of glucose and insulin. Capillary glucose level is measured 4 times a day postoperatively on postoperative day 1 and 2 - before the main meals and before sleeping. Patient perceived quality of recovery is measured using the Danish version of the validated "Quality of recovery-15" questionnaire. Sub-study 5 - microbiota: The microbiota of fecal samples will be measured before and after metformin treatment.


Recruitment information / eligibility

Status Completed
Enrollment 48
Est. completion date October 4, 2021
Est. primary completion date September 2, 2021
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - Patients with adenocarcinoma of the colon planned for elective curative intended surgery at Slagelse hospital - Age of 18 or above - Must be able to understand and sign informed content - Sufficient amount of representative tumor material from the biopsies taken at the initial colonoscopy must be present Exclusion Criteria: - Patients diagnosed with diabetes mellitus - Patients who are receiving or have received metformin or other oral antidiabetics - Impaired kidney function (eGFR < 60mL/min) - Severe liver disease (defined as transaminases above X 3 normal levels) - Participation in another pharmacological intervention trial - Predictable poor compliance (for instance not speaking fluent Danish, mentally impaired) - Presenting with metastatic disease - Patients undergoing neoadjuvant chemotherapy - Pregnancy or lactation (fertile women must have a negative serum or urine pregnancy test to participate) - Fertile women who do not use safe contraception during the study period. - Allergy to metformin or placebo

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Metformin Hydrochloride
metformin 500mg three times a day 20 days before colon cancer surgery and 10 days after.
Placebo oral capsule
placebo 500mg three times a day 20 days before colon cancer surgery and 10 days after.

Locations

Country Name City State
Denmark Department of Surgery, Slagelse Hospital Slagelse

Sponsors (1)

Lead Sponsor Collaborator
Zealand University Hospital

Country where clinical trial is conducted

Denmark, 

Outcome

Type Measure Description Time frame Safety issue
Primary Expression of Ki67 on tumor samples The primary outcome is determination of the difference of the level of proliferation after the intervention (time of surgery) adjusted for the level seen at baseline (time of colonoscopy). This is done using immunohistochemical staining for Ki67 (a marker for proliferation) of biopsies from the tumor. The level of proliferation will be defined as the percentage of tumor nuclei showing Ki67 staining in a specific microscopic field counted at the invasive front. colonoscopy (baseline) and at time of operation (after intervention)
Secondary Expression of cleaved Caspase-3 on tumor samples Determination of the difference in the level of apoptosis after the intervention (time of surgery) adjusted for the level seen at colonoscopy (baseline). Measured by immunohistochemical staining of tumor samples for cleaved Caspase-3 (marker for apoptosis). colonoscopy (baseline) and at time of operation (after intervention)
Secondary immunoscore At time of operation biopsies from the core and from the invasive margin of the tumor will be taken. These biopsies are stained for CD3 and CD8 positive lymphocytes and the density of these are measured. time of operation (after the tumor is removed)
Secondary immunological changes in bloodsamples Bloodsamples are taken at time of inclusion, day of operation and postoperative day 1,2 and 10. These are analysed for immunological markers. At baseline, day of operation and postoperative day 1, 2 and 10.
Secondary insulin resistance Fasting levels of glucose and insulin are measured at the day of operation (before the operation) and at postoperative day 1 and 2. Insulin resistance is measured using the HOMA-score. At the day of surgery and postoperative day 1 and 2.
Secondary blood glucose level Blood glucose (capillary glucose) level is measured 4 times a day on postoperative day 1 and 2. 4 times a day on postoperative day 1 and 2
Secondary Quality of recovery The patients' subjective feeling of recovery is measured using the Danish version of the Quality of recovery-15 questionnaire. The questionnaire includes 15 questions with the possibility of 0 to 150 points (150 being the best possible quality of recovery) At baseline, postoperative day 1, 2, 10 and 30.
Secondary cell growth in vitro - proliferation colon cancer cell lines will be grown in vitro in the presence of plasma from the patients. Differences in proliferation between the two groups are measured. At baseline, postoperative day 1 and 10.
Secondary cell growth in vitro - adhesion colon cancer cell lines will be grown in vitro in the presence of plasma from the patients. Differences in adhesion between the two groups are measured. At baseline, postoperative day 1 and 10.
Secondary cell growth in vitro - invasion colon cancer cell lines will be grown in vitro in the presence of plasma from the patients. Differences in invasion between the two groups are measured. At baseline, postoperative day 1 and 10.
Secondary microbiota The microbiota of fecal samples will be analyzed using 16s rRNA analyses At baseline and the day before surgery
See also
  Status Clinical Trial Phase
Active, not recruiting NCT05551052 - CRC Detection Reliable Assessment With Blood
Completed NCT03457454 - Reducing Rural Colon Cancer Disparities
Recruiting NCT06006390 - CEA Targeting Chimeric Antigen Receptor T Lymphocytes (CAR-T) in the Treatment of CEA Positive Advanced Solid Tumors Phase 1/Phase 2
Active, not recruiting NCT04088955 - A Digimed Oncology PharmacoTherapy Registry
Recruiting NCT06010862 - Clinical Study of CEA-targeted CAR-T Therapy for CEA-positive Advanced/Metastatic Malignant Solid Tumors Phase 1
Terminated NCT01347645 - Irinotecan Plus E7820 Versus FOLFIRI in Second-Line Therapy in Patients With Locally Advanced or Metastatic Colon or Rectal Cancer Phase 1/Phase 2
Completed NCT03390907 - Hybrid APC Assisted EMR for Large Colon Polyps N/A
Recruiting NCT03175224 - APL-101 Study of Subjects With NSCLC With c-Met EXON 14 Skip Mutations and c-Met Dysregulation Advanced Solid Tumors Phase 2
Completed NCT04079478 - The AID Study: Artificial Intelligence for Colorectal Adenoma Detection
Active, not recruiting NCT04057274 - Acute Effect of modeRate-intensity aerOBIc Exercise on Colon Cancer Cell Growth N/A
Recruiting NCT03190941 - Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients Phase 1/Phase 2
Not yet recruiting NCT05147545 - Impact of Exercise and Hyperlipidic Meal on Free Circulating DNA in Patients With Metastatic Colonic Cancer and Healthy Subjects N/A
Recruiting NCT05026268 - The Laparoscopic Right Colectomy With Intracoroporeal Anastomosis N/A
Not yet recruiting NCT03277235 - Effect of a Resilience Model-Based Care Plan in Newly Diagnosed Colorectal Cancer Patients N/A
Active, not recruiting NCT02959541 - PK/PD Investigation of Calciumfolinat in Blood, Tumor and Adjacent Mucosa in Patient With Colon Cancer N/A
Active, not recruiting NCT02730702 - Colon Cancer Risk-stratification Via Optical Analysis of Rectal Ultrastructure
Completed NCT02810652 - Perioperative Geriatrics Intervention for Older Cancer Patients Undergoing Surgical Resection N/A
Recruiting NCT02577627 - Multi-Indication, Retrospective Oncological Study to Validate the Accuracy in Predicting TTP by PrediCare in Patients Under SOC N/A
Terminated NCT02628535 - Safety Study of MGD009 in B7-H3-expressing Tumors Phase 1
Recruiting NCT02526836 - Complete Mesocolic Excision With Central Vessel Ligation Compared With Conventional Surgery for Colon Cancer Phase 2/Phase 3