Digestive System Diseases

Mouth and Tooth Diseases

All Conditions

Neoplasms

Mucositis

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastroenteritis

Gastrointestinal Diseases

Mouth Diseases

Stomatognathic Diseases

Anti-Infective Agents

All Drugs and Chemicals

Other Dietary Supplements

Sulfalene

Acidophilus

Bifidobacterium

Probiotic: VSL#3 is a probiotic formula containing a mixture of 9x10\^10 CFU/g Lactobacilli strains (Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, and Lactobacillus bulgaricus), 8x10\^10 CFU/g Bifidum strains (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis) and 20x10\^10 CFU/g Streptococcus thermophilus. Administred orally

Probiotics (beneficial microorganisms) VSL#3 is a probiotic formula containing a mixture of 9x10\^10 CFU/g Lactobacilli strains (Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, and Lactobacillus bulgaricus), 8x10\^10 CFU/g Bifidum strains (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis) and 20x10\^10 CFU/g Streptococcus thermophilus

Probiotic

Jens R Andersen, MD,MPA

The aim of this study is to test the hypothesis that adjuvant administration of probiotics in cancer patients undergoing chemotherapy can reduce a chemo-induced increased intestinal permeability. Furthermore, we hypothesize that the use of probiotics may reduce the occurrence of gastrointestinal side effects such as diarrhea, abdominal pains, bacterial translocation and infections following chemotherapy.

Treatment of most cancer patients involves radiation and/or chemotherapy which often leads to gastrointestinal toxicity. Cytotoxic chemotherapy in particular often induces several intestinal abnormalities such as mucositis including destruction of intestinal villi, alterations in the gut microbiota, modulation of tight junctions, leading to an increased intestinal permeability. These toxic effects have been observed in several types of chemotherapy and different methods of administering chemotherapy.

The intestinal permeability is regulated and protected by a number factors, including a mucus layer covering the surface of the epithelium. This mucus layer is partly regulated by intestinal bacteria. Therefore it is hypothesized that chemoinduced changes in the intestinal microbiota may possibly affect intestinal permeability. Changes in the intestinal microbiota are seen after only one or a few cycles of chemotherapy treatment in different types of cancers, and could possibly be a contributing factor in the development of mucositis.

It is possible that probiotics may interfere with the ability of pathogenic bacteria to bind to the surface of the intestinal epithelial lining. In vitro studies have shown that probiotics may reduce a post-infective (Escherichia coli) increased intestinal permeability, or increased permeability due to incubation with pro-inflammatory cytokines. VSL#3 is a probiotic formula containing a mixture of 9x10\^10 CFU/g Lactobacilli strains (Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, and Lactobacillus bulgaricus), 8x10\^10 CFU/g Bifidum strains (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis) and 20x10\^10 CFU/g Streptococcus thermophilus. In vitro and ex vivo studies have suggested that the probiotic bacteria found in VSL#3 may have a reducing effect on intestinal permeability as well as a positive modulating effect on tight junction protein expression. Escherichia coli Nissle 1917 is another bacterial strain that has been shown to be able to mediate the modulation of tight junction proteins and thus intestinal permeability. The precise mechanisms behind the effects of probiotics on intestinal epithelial permeability are not yet clear, but some mechanisms have been proposed, including a reduction in bacterial secretion of proinflammatory cytokines as well as other secreted products from probiotic microbial metabolism.

It is not known whether all probiotic strains exert a similar effect on intestinal permeability, as only very limited clinical research has addressed this relation. However, it is very likely that the specific choice of probiotic bacterial species may play a crucial role. We are only familiar with one clinical trial examining the effect of probiotics on intestinal permeability in adults with cancer undergoing treatment in the form of colectomy, but no adjuvant chemotherapy. Probiotics in the form of Lactobacillus plantarum, Lactobacillus acidophilus and Bifidobacterium longum was administered perioperative and postoperative to patients undergoing colectomy, and the study showed that probiotics improved the integrity of the small intestinal mucosal barrier, induced modulation of the intestinal microbiome as well as a reduction in the postoperative rate of infections.The same researchers also measured serum zonulin in the same subjects, and found that the treatment with probiotics also reduced the concentration of postoperative serum zonulin, and thus inhibited the same increase in intestinal permeability as was the case in the control group.

The Effects of Probiotics on Intestinal Permeability in Gastrointestinal Cancer Patients in Chemotherapy

Diarrhea, abdominal pain, abdominal cramps, constipation, etc.

Actial Farmaceutica S.r.l.

Nutricia, Inc.

University of Copenhagen

Associate professor

Blood and Lymph Conditions

Symptoms and General Pathology

Rare Diseases

Leukemia

Preleukemia

Myelodysplastic Syndromes

Cytopenia

Anemia

Syndrome

Neoplasms by Histologic Type

Hematologic Diseases

Precancerous Conditions

Bone Marrow Diseases

Hypoglycemic Agents

Metformin

2000 mg/day metformin for 12 months (1000 mg b.i.d.) with a slow up-titration six weeks prior to full dose treatment.

Kirsten Grønbæk, Professor, MD

Stine Ulrik Mikkelsen, MD

This is a single-arm pilot study of the feasibility and safety of metformin in patients with clonal cytopenia of undetermined significance (CCUS) or lower-risk myelodysplastic neoplasms (LR-MDS).

The research plan is divided into three work packages (WP):

WP0: Bone Marrow Adipose Tissue, Gut Microbiota, and Intestinal Permeability in CCUS and LR-MDS Patients.

The aim of WP0 is to investigate biological features which the investigators hypothesize to be of pathogenetic relevance for MDS progression and may be possible targets of metformin treatment. For this purpose, 20 elderly (≥60 years) healthy controls will be included for comparison to patients with CCUS or LR-MDS from WP1.

The primary objectives are to investigate 1) the abundance and properties of bone marrow adipose tissue (BMAT) and bone marrow (BM) adipocytes, and 2) the gut microbiota and intestinal permeability of patients with CCUS or LR-MDS compared to age-, sex- and body mass index (BMI)-matched healthy controls. Secondary objectives are to characterize DNA methylation and hydroxymethylation (5-mC and 5-hmC) patterns, and hormone and cytokine levels in BM plasma from healthy controls and patients with CCUS or LR-MDS.

WP1: Safety, feasibility, and mechanisms of action of metformin in patients with CCUS or LR-MDS.

In this WP up to 40 patients with CCUS or LR-MDS will receive metformin 2000 mg daily or their maximum tolerated dose (MTD) for 12 months. The aim of WP1 is to investigate safety of metformin and feasibility of the protocol in patients with CCUS or LR-MDS. Potential mechanisms of anti-leukemic action of metformin will also be explored in order to identify a suitable outcome measure and estimate standard deviation of the outcome measure. All in order to inform the design of a future phase 3 RCT of the efficacy of metformin in CCUS and LR-MDS patients. Endpoints of WP1 are specified in the corresponding section.

WP2: Safety and efficacy of metformin compared to placebo. The primary objective of WP2 is to compare safety and preliminary efficacy of metformin in patients with CCUS or LR-MDS to a cohort of patients with CCUS or LR-MDS receiving placebo in context of our EVI-2 randomized, controlled pilot study (NCT03999723).

Data and samples from approximately 50 historical controls will be included from the EVI-2 study in which participants were randomized to receive placebo or oral vitamin C supplement for 12 months.

Repurposing Metformin as a Leukemia-preventive Drug in CCUS and LR-MDS

STOP-LEUKEMIA: Repurposing Metformin as a Leukemia-preventive Drug in CCUS and LR-MDS

To assess safety of metformin treatment in this off-label indication by the type, grade, and number of adverse events and serious adverse events including any suspected unexpected serious adverse reactions in the patients.

To assess safety of metformin treatment in this off-label indication by median maximum tolerated dose and a description of any changes in individual medication doses.

To assess feasibility of the study protocol in terms of recruitment and refusal rates.

To assess feasibility of the study protocol in terms of rate of study completion.

To assess safety of metformin treatment in this off-label indication by the type, grade, and number of adverse events and serious adverse events including any suspected unexpected serious adverse reactions in the patients; drop-out rates; and a description of any changes in individual medication doses including median maximum tolerated dose.

To assess feasibility of the study protocol in terms of rate of adherence to protocol procedures (study medication and study procedures).

Change in variant allele frequency (ΔVAF) by next generation sequencing (NGS)

Change in patient-reported outcome measures (PROM), based on the validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).

Change in patient-reported outcome measures (PROM), based on the validated Short Form 36 Health Survey Questionnaire (SF-36).

Change in patient-reported outcome measures (PROM), based on the validated European Quality of Life Five Dimension questionnaire (EQ-5D).

Change in bone marrow adipose tissue (BMAT) content in bone marrow (BM) measured by MR spectroscopy

Change in bone mineral density (BMD) measured by DEXA scan measured in grams per cubic centimeter with resulting Z score.

Change in body composition measured by DEXA scan presented as whole body bone mass and soft tissue composition with ratios of lean mass, body fat, and bone mass.

Change in gut microbiota by 16S rRNA sequencing or whole genome sequencing of intestinal bacteria.

Change in small intestinal permeability by functional assessment by urine-lactulose/mannitol measurement and ion chromatography or by indirect assessment by qPCR and 16S rRNA sequencing of whole blood.

Change in DNA methylation and hydroxymethylation (5-mC and 5-hmC) patterns in hematopoietic cells by global 5-hmC/5-mC assessment and EPIC arrays.

Change in RNA expression in hematopoietic cells and BM adipocytes.

Change in protein profiles in hematopoietic cells and BM adipocytes by proteomics.

Rates of response and disease progression as according to the International Working Group (IWG) response criteria in myelodysplastic neoplasms.

Change in niche factors in bone marrow by ELISA.

Change in cytokine levels in peripheral blood and bone marrow plasma by ELISA.

Steno Diabetes Center Copenhagen

Zealand University Hospital

Van Andel Research Institute

Herlev Hospital

Technical University of Denmark

Region Hovedstadens Apotek

Kirsten Grønbæk

Professor, MD, DMSc

Disease Progression

Colorectal Neoplasms

Intestinal Neoplasms

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Herbal and Botanical

Cola

Have confirmed colorectal cancer-free and Polyp-free colon using colonoscopy

Have benign or precancerous polyps, including tubulovillous or villous adenomas, using colonoscopy

Have confirmed TNM staging of colorectal cancer

The T refers to the size and extent of the main tumor. The main tumor is usually called the primary tumor.

The N refers to the number of nearby lymph nodes that have cancer. The M refers to whether the cancer has metastasized. This means that the cancer has spread from the primary tumor to other parts of the body.

Have confirmed TNM staging of colorectal cancer

Momchilo Vuyisich, PhD

This is an observational study with the goal to improve the robustness of the scientific evidence linking Fusobacterium nucleatum (Fn) and/or other microorganisms to colorectal cancer (CRC) onset and/or progression. This is an approximately three-year study. There are two phases to this study, including: 1) pilot phase, 2) full study. There are also five arms in this study including cancer-free, pre-cancerous, and Colorectal cancer stages (I-III). The pilot study will include the recruitment of 50 participants per group (i.e., total of 250 participants). The full study will have an additional 150 participants per group (total of 1,000 participants). This study will recruit using clinical sites in the United States.

There are 5 timepoints in this study. If the participants are found to be medically eligible through diagnosis and medical information, they will provide samples (including: saliva, blood, urine, stool and tumor biopsy) at each timepoint and during the study. They will also answer health and wellness questions during this study. Additional data collection, including medical data, biopsies and other biological samples might happen at interim timepoints in case of adenoma/cancer disease progression (recurrence, metastasis). The participant's healthcare provider will determine if additional biopsies are required as a part of the standard of care. If collected, additional samples will be sent for research purposes.

This is an exploratory, longitudinal study that will follow approximately 1,000 participants over 4-6 clinical sites nationwide over a period of 3-4 years and collect molecular and phenotype data to obtain insights into the microbiome and colorectal cancer. Each site will enroll approximately 166-250 participants in total. Those that are polyp/cancer free, pre-cancerous and confirmed primary diagnosis of colorectal cancer (stage I, II and III) will be recruited. Participants will be recruited in primary, secondary, and tertiary care centers, depending on the study inclusion/exclusion criteria.

Participants complete surveys and collect samples including (blood, urine, stool, and saliva) using at-home/in-clinic kits provided by Viome. Participants are also asked to provide tissue or tumor samples if collected by their healthcare provider during a standard of care biopsy procedure. Biopsy samples for this test will be collected by the clinical staff at each study site. Additional data collection, including medical data, biopsies and other biological samples might happen at interim timepoints in case of adenoma/cancer disease progression (recurrence, metastasis). Additionally, participants complete a survey sent on a quarterly basis.

There are 5 timepoints (TP) in this study including: Timepoint 1, Timepoint 2, Timepoint 3, Timepoint 4, and Timepoint 5.

TP1 includes the initial diagnosis where the stage of cancer is determined by imaging (colorectal cancer stages I, II, or III) or colonoscopy results (healthy and pre-cancerous). All participants provide urine, blood, saliva, stool and complete survey.

TP2 includes Post Standard of Care (SOC). For cancer participants, samples will be collected 45 +/- 15 days after all treatments have been completed (this includes chemotherapy, radiation therapy, immunotherapy, and/or surgery). Those that are healthy and pre-cancerous will provide their samples, 90 +/- 15 days after the colonoscopy. All participants provide urine, blood, saliva, stool and complete survey.

TP3, 4, and 5 occur 1, 2 and 3 years respectively after diagnosis (TP1) for cancer-free and precancerous groups and 1, 2 and 3 years respectively after standard of care therapy (TP2) for the cancer groups. All participants provide urine, blood, saliva, stool and complete survey.

Microbiome in Colorectal Cancer Onset and Progression

The Role of the Microbiome in Colorectal Cancer Onset and Progression

Determine Fn species and strains, more specifically the prevalence and relative activity, and the differential gene expression and key pathways. The Investigators will also look at Microbial co-occurrence/abundance with Fn and local tumor microenvironment and tumor marker/mutations and their association with microbiome.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Effects of Probiotics on Intestinal Permeability in Gastrointestinal Cancer Patients in Chemotherapy	NCT03704727	Intestinal Perm... Gastrointestina... Mucositis	Probiotic	18 Years -	University of Copenhagen
Repurposing Metformin as a Leukemia-preventive Drug in CCUS and LR-MDS	NCT04741945	Preleukemia Myelodysplastic... Cytopenia Preleukemic Ane...	Metformin	18 Years -	Rigshospitalet, Denmark
The Effects of Probiotics on Intestinal Permeability in Gastrointestinal Cancer Patients in Chemotherapy	NCT03704727	Intestinal Perm... Gastrointestina... Mucositis	Probiotic	18 Years -	University of Copenhagen
Microbiome in Colorectal Cancer Onset and Progression	NCT05368688	Colorectal Canc... Tumor CRC GI Cancer Gastrointestina...		50 Years - 80 Years	Viome

Spots Global Cancer Trial Database for intestinal permeability