Effect of the Nutraceutical MICODIGEST 2.0 on the Complications After Surgery for Colorectal Cancer

Study Overview
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Brief Summary
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Most of Colorectal cancer (CRC) diagnosed are candidates for surgical resection with curative intent, although colorectal surgery is associated with some complications that could be life-threatening. Antibiotic prophylaxis is commonly used prior to the admission for the prevention of postoperative complications. However, this intervention can change the composition of intestinal microbiota and promote adverse inflammatory outcomes in CRC patients after surgery. It seems the combination of different fungal extracts could be beneficial because of their role in gut microbiota modulation and their anti-inflammatory activity. Therefore, the fungal extract nutraceutical MICODIGEST 2.0 could be used to reduced the complications after CRC surgery. Based on this hypothesis, we have designed a double-bind randomized clinical trial to evaluate the effect of MICODIGEST 2.0 on the complications after surgery with curative intent for CRC.

Detailed Description
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Colorectal cancer (CRC) is one of the most common malignancies in western countries. Most of the CRC diagnosed are candidates for surgical resection with curative intent. Cure rates after surgery vary between 92 % and 67 % depending on the tumor stage. However, colorectal surgery is associated with some complications that could be life-threatening. Antibiotic prophylaxis is commonly used prior to the admission for the prevention of this postoperative complications. Several studies have shown that antibiotic administration reduces the risk of infections associated with surgery. Nevertheless, this intervention does not modify the mortality and severity of other complications detected. Further, antibiotic prophylaxis could change the intestinal microbiota and promote adverse inflammatory outcomes in CRC patients after surgery. Fungal polysaccharides have attracted attention because of their role in gut microbiota modulation. It seems that this type of polysaccharides could reduce pathogen levels and stimulate the growth of beneficial microorganism. Anti-inflammatory activity has also been described for these fungal polysaccharides. It seems the combination of different fungal extracts would send multiple stimuli to the immune system increasing intracellular reactions and interactions. Thus, the fungal extract nutraceutical MICODIGEST 2.0 could be used to reduced the complications after CRC surgery. MICODIGEST 2.0 is available since 2016 without any adverse effect reported. For all these reasons we have designed a double-bind randomized clinical trial to evaluate the effect of MICODEGIST 2.0 on the complications after surgery with curative intent for CRC. Apart from this purpose, we have also set the following secondary objectives: To evaluate the safety of MICODIGEST 2.0 in CRC patients. To evaluate the effect of MICODIGEST 2.0 on feal microbiome composition and diversity. To evaluate the effect of MICODIGEST 2.0 on inflammatory pattern, dietary pattern and quality of life. To analyze the effect of microbiome, inflammatory and dietary pattern on complications after surgery.

Official Title
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Double-blind Randomized Clinical Trial to Evaluate the Effect of the Nutraceutical MICODIGEST 2.0 on the Complications After Surgery With Curative Intent for Colorectal Cancer

Conditions
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Colorectal Cancer, Surgery--Complications

Intervention / Treatment
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* Dietary Supplement: MICODIGEST 2.0 supplement
* Dietary Supplement: Placebo supplement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CRC patients who are candidates for surgical treatment with curative intent (risk I-III). American Society of Anesthesiologists' Physical Status Classification (ASA) <3. Patients aged between 18 and 85 years. Eastern Cooperative Oncology Group (ECOG) scale between 0-2. Patients with preserved cognitive function. Patient's authorization after reading the study information sheet. Exclusion Criteria: Candidates for neoadjuvant therapy. Patients with concomitant carcinoma. Allergy to the supplied nutraceutical or presence of malabsorption syndrome. Presence of mental disorders Patient with active infection or antibiotic therapy in the last month. Previous colorectal surgery

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: CRC candidates for surgery with curative intent will be considered to include in the study. Patients who fulfill criteria will be screened and randomly allocated to be treated with MICODIGEST 2.0 or placebo previous to the admission. Patients will be also stratified based on tumor location (distal or proximal to splenic flexure). Patients will be followed for 4-6 weeks until surgery intervention.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MICODIGEST 2.0 supplement<br>Treatment with MICODIGEST 2.0 will initiate with 10mL/day (before breakfast or before lunch) for 7 days, and rise to 20mL/day (10mL before breakfast and 10 mL before dinner) for 4-6 weeks. | Dietary Supplement: MICODIGEST 2.0 supplement<br>* MICODIGEST is a nutraceutical which contains 9 different fungal extracts: Ganoderma lucidum, Agaricus blazei, Grifola frondosa, Hericium erinaceus, Cordyceps sinensis, Inonotus obliquus, Pleurotus ostreatus, Polyporus umbellatus y Lentinula edodes<br>|
| Placebo Comparator: Placebo<br>Treatment with placebo will initiate with 10mL/day (before breakfast or before lunch) for 7 days, and rise to 20 mL/day (before breakfast and before dinner) for 4-6 weeks. | Dietary Supplement: Placebo supplement<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complications. | Anastomotic failure, infection, prolonged ileus, systemic complications and other will be measured. Clavien-Dindo classification will be used for grading the severity of these postoperative complications. These analysis will be measured to evaluate the effect of MICODEGIST 2.0 on the complications after surgery with curative intent for CRC. | week 4-6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse effects. | Adverse effects will be considered during follow-up and after surgery using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. This analysis will be measured to evaluate the safety of MICODIGEST 2.0 in CRC patients. | week 1-6 | 
| Fecal microbiome composition. | High-quality DNA extraction will be performed in fecal samples. The bacterial 16S ribosomal ribonucleic acid gene will be sequencing on an Illumina MiSeq. Metagenomic species and a database with >200.000 strains will be used to define the microbiome composition. This analysis will be used to evaluate the effect of MICODIGEST 2.0 on feal microbiome composition. | week 4-6 | 
| Neutrophil/Lymphocyte ratio. | Neutrophil/Lymphocyte will be measured dividing the absolute number of neutrophils by the absolute number of lymphocytes from peripheral blood sample. This inflammatory biomarker will be used to evaluate the effect of MICODIGEST 2.0 on inflammatory pattern. | week 4-6 | 
| C reactive protein (CRP) level. | CRP levels (mg/dL) from peripheral blood samples will be measured to evaluate the effect of MICODIGEST 2.0 on inflammatory pattern. | week 4-6 | 
| Tumor Necrosis Factor alpha (TNF-alpha) and interleukin-6 (IL-6) levels. | TNF-apha (pg/mL) and IL-6 (pg/mL) from peripheral blood samples will be measured to evaluate the effect of MICODIGEST 2.0 on inflammatory pattern. | week 4-6 | 
| Dietary pattern assessment. | Patient-Generated Subjective Global Assessment survey (PG-SGA) will be used to assess the nutritional status. At the end of this survey, the patient will be rated nutritionally in one of three categories: Well-nourished or anabolic (PG-SGA - A), Moderately or suspected of being undernourished (PG-SGA B) and Severely undernourished (PG-SGA C). This analysis will be performed to evaluate the effect of MICODIGEST 2.0 on dietary pattern. | week 4-6 | 
| Quality of life assessment. | The 36-item Short Form Health Survey (SF-36) will be used to measure the health-related quality-of-life. The SF-36 is a 36-item patient-reported questionnaire that covers eight health domains. Scores for each domain range from 0 to 100, with a higher score defining a more favorable health state. This analysis will be perfomed to evaluate the effect of MICODIGEST 2.0 on quality of life. | week 4-6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal Cancer, Surgery Complications, Gut microbiota, Inflammatory pattern, Dietary pattern, Nutraceutical