Effects of UNICLA-A2 Dairy Products on Patients at High-risk of Colorectal Cancer Development

• ClinicalTrials.gov Identifier: NCT04824053
• Recruitment Status: Not yet recruiting
• First Posted: April 1, 2021
• Last Update Posted: July 13, 2021
• Sponsor: Instituto de Investigación Sanitaria Aragón
• Collaborators: FEIRACO LACTEOS SL; Hospital Clínico Universitario Lozano Blesa
• Information provided by (Responsible Party): Ángel Lanas Arbeloa, Instituto de Investigación Sanitaria Aragón

Study Description

Brief Summary:

Dietary intervention with UNICLA-A2 milk products containing beta casein A2 protein, and higher levels of omega-3 fatty acids and selenium may contribute to maintain the intestinal integrity, reduce inflammatory processes, normalize the immune system, protect against oxidative damage and equilibrate the gut microbiota in high-risk colorectal cancer patients who have undergone polypectomy

Condition or disease	Intervention/treatment	Phase
Colorectal Polyp	Dietary Supplement: Milk from genetically selected homozygous- β-casein-A2 cows fed with forages and a concentrate enriched on linseed and selenized yeast as sources of PUFAs and selenium; Dietary Supplement: Conventional milk; Dietary Supplement: Yogurt made from milk of genetically selected homozygous- β-casein-A2 cows fed with forages and a concentrate enriched on linseed and selenized yeast as sources of PUFAs and selenium; Dietary Supplement: Conventional yogurt; Dietary Supplement: Fresh cheese made from milk of genetically selected homozygous- β-casein-A2 cows fed with forages and a concentrate enriched on linseed and selenized yeast as sources of PUFAs and selenium; Dietary Supplement: Conventional fresh cheese	Not Applicable

Detailed Description:

Colorectal cancer (CRC) is one of the most frequent cancers in the world and has a significant impact in terms of mortality and health costs. It is estimated that CRC causes around 900,000 deaths annually, mainly due to diagnoses made in advanced stages. Colorectal adenomas (CRA) are precancerous lesions that develop into colorectal cancer following a well-known process into the adenoma-carcinoma sequence. Prevention programs include screening for CRA and removing precancerous lesions by polypectomy, but the high recurrence rates after polypectomy makes it necessary to research on potential chemopreventive agents that may reduce this risk. Dietary recommendations or chemoprevention with different nutritional substances (diets rich in fiber, or poor in red meat, etc) or pharmacological substances including vitamin D, calcium, fatty acids, salicylic acetyl acid, nonsteroidal anti-inflammatory agents (NSAIDs), etc) have been studied. In this way, it seems reasonable to evaluate the effect caused by the administration of certain nutrients that affect lipid and protein metabolism involved in cellular homeostasis, in the preservation of the colonic mucosa or the development of lesions may have in populations at risk.

UNICLA A2 dairy products have a different nutrient profile than conventional ones. UNICLA A2 products have higher content in unsaturated fats, that is to say, increased content of healthy fatty acids such as oleic, linolenic, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and conjugated linoleic acid (CLA). Previous studies have suggested a contribution of ω-3 polyunsaturated fatty acids (PUFAs) to reduce pro-inflammatory markers and, have shown they have antimicrobial and negative properties in relation to biofilm formation. These types of biofilm structures are characteristic of proximal CRC. For these reason, ω-3 PUFAs it is thought that they could modify the altered intestinal microbiota in patients at high risk of CRC towards a less pathogenic environment, correcting the gut dysbiosis. Moreover, they have higher selenium levels (Se), an element with essential biological functions which has been suggested improving effects in combination with other anticancer agents in CRC and taking part in the modulation of several processes, such as the immune response, apoptotic cell death, DNA repair, response to oxidative stress, carcinogenic metabolism, tumorigenesis and angiogenesis. Finally, they contain type A2 beta casein, which differs from A1 beta casein by a single amino acid at position 67 of a 107 amino acid chain. This fact is very important because beta casein contains a chain of amino acids called "beta casomorphin" (BCM7) with negative health effects reported. The proline 67 in beta casein A2 has a strong bond with BCM7 that does not allow it to separate and flow freely in milk to be absorbed. However, the mild bond due to histidine 67 in beta casein A1 allows BCM7 to reach the intestinal wall and be absorbed, being associated with intestinal discomfort, gastrointestinal transit time and stool consistency disturbances, abdominal pain and, increased levels of some inflammatory markers.

For these reasons, in this proposal the investigators aim to determine whether the change from conventional dairy products to UNICLA-A2 products but maintaining the habitual consumption habits in "real life" conditions, without forcing or inducing greater consumption, will have positive effects on maintaining the intestinal integrity by reducing the inflammatory profile, and leading the gut microbiota to a less pathogenic environment in patients at high-risk of CRC development.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Prevention
• Official Title: Comparative Analysis of the Effects of UNICLA-A2 Against Conventional Dairy Products Administered Daily in Patients at High-risk Colorectal Cancer Development Who Have Undergone Polypectomy
• Estimated Study Start Date: November 1, 2021
• Estimated Primary Completion Date: December 30, 2023
• Estimated Study Completion Date: December 15, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: UNICLA-A2 milk and its subproducts; Participants (n=17) ingest milk and dairy products made from cows homozygous for beta casein A2 during 3 months. These products are also enriched in insaturated fatty acids and selenium. The daily intake reflects the habitual consumption habits. Recommended amounts are 250 mL of milk, a yogurt and 50 g fresh cheese per day.	Dietary Supplement: Milk from genetically selected homozygous- β-casein-A2 cows fed with forages and a concentrate enriched on linseed and selenized yeast as sources of PUFAs and selenium; The daily intake should reflect habitual consumption habits in "real life" conditions, without forcing or inducing greater consumption. Therefore, patients will be recommended a daily intake of 250 mL of milk. The intervention duration will be 3 months; Other Name: UNICLA-A2 milk; Dietary Supplement: Yogurt made from milk of genetically selected homozygous- β-casein-A2 cows fed with forages and a concentrate enriched on linseed and selenized yeast as sources of PUFAs and selenium; The daily intake should reflect habitual consumption habits in "real life" conditions, without forcing or inducing greater consumption. Therefore, patients will be recommended a daily intake of one yogurt. The intervention duration will be 3 months; Other Name: UNICLA-A2 yogurt; Dietary Supplement: Fresh cheese made from milk of genetically selected homozygous- β-casein-A2 cows fed with forages and a concentrate enriched on linseed and selenized yeast as sources of PUFAs and selenium; The daily intake should reflect habitual consumption habits in "real life" conditions, without forcing or inducing greater consumption. Therefore, patients will be recommended a daily intake of 50 g of fresh cheese. The intervention duration will be 3 months; Other Name: UNICLA-A2 fresh cheese
Placebo Comparator: Placebo; Participants (n=17) ingest conventional dairy products and milk daily during 3 months. As happens in the UNICLA-A2 arm, the daily intake reflects habitual dairy consumption habits in "real life" conditions, without forcing or inducing greater consumption. Therefore, recommended amounts are 250 mL of milk, a yogurt and 50 g fresh cheese per day.	Dietary Supplement: Conventional milk; The daily intake should reflect habitual consumption habits in "real life" conditions, without forcing or inducing greater consumption. Therefore, patients will be recommended a daily intake of 250 mL of milk. The intervention duration will be 3 months; Dietary Supplement: Conventional yogurt; The daily intake should reflect habitual consumption habits in "real life" conditions, without forcing or inducing greater consumption. Therefore, patients will be recommended a daily intake of one yogurt. The intervention duration will be 3 months; Dietary Supplement: Conventional fresh cheese; The daily intake should reflect habitual consumption habits in "real life" conditions, without forcing or inducing greater consumption. Therefore, patients will be recommended a daily intake of 50 g of fresh cheese. The intervention duration will be 3 months

Outcome Measures

Primary Outcome Measures :

1. Change from baseline levels in pro-inflammatory circulating markers C-reactive protein (CRP), interleukin (IL)-6, macrophage inhibitory cytokine 1 (MIC-1) and tumour necrosis factor alpha (TNFα), as well as in fecal calprotectin. [ Time Frame: At baseline, at 3 months and through study completion, an average of 1 year after the colonoscopy that motivated the patient´s inclusion ]
   The C-reactive protein and calprotectin are measured by conventional methods in the University Clinic Hospital Lozano Blesa and the circulating biomarkers IL-6, MIC-1 and TNFα by enzyme-linked immunosorbent assay

Secondary Outcome Measures :

1. Change from baseline in fecal microbiota. [ Time Frame: At baseline, at 3 months and through study completion, an average of 1 year after the colonoscopy that motivated the patient´s inclusion ]
   Stool samples are collected for DNA extraction and ulterior metagenomic analysis of the fecal microbiota's composition. Library construction is carried out with the Ion 16S™ Metagenomics Kit which permits PCR amplification of hypervariable regions of the 16S rDNA gene from bacteria and the material obtained is subjected to next-generation sequencing (NGS) to see the proportions of the main groups of microorganisms in the sample.
2. To assess the effect of treatment on colorectal adenoma recurrence [ Time Frame: Through study completion, an average of 1 year after the initial colonoscopy that motivated the suitability of patients inclusion. ]
   The number of participants in each arm who develop one or more colorectal adenomas is determined in the follow-up colonoscopy (adenoma detection rate), as well as the presence of advanced or not advanced adenomas, serrated polyps, subtype, location and the total number of adenomas per participant.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Participants diagnosed with high-risk polyps in the colorectal cancer screening programme or in the relative's colon cancer prevention program or patients who are in follow-up due to prior detection of polyps with any of the following characteristics:

   • At least 10 adenomas
   • At least 5 proximal serrated polyps (PSP)
   • At least 2 serrated polyps with diameters ≥10 mm
   • Serrated Polyposis Syndrome (SPS)
   • Early invasive CRC (stage pT1) endoscopically resected (surgery not required)
   • A sessile or flat lesion ≥ 20 mm with fragmented resection
   • Patients with previous resection of polyps in which the resection margin was not assessable and are considered susceptible to repeat colonoscopy
2. Regular consumer of milk and dairy products.
3. Informed consent form signed.

Exclusion Criteria:

1. History of allergic reaction attributed to compounds of similar chemical composition to the study agents.
2. Incomplete colonoscopy or with poor quality criteria, Boston <6.
3. Concomitant acetylsalicylic acid (ASA), NSAIDs, misoprostol, corticosteroids or statins needed on a regular or predictable basis during the time of the study.
4. Previous gastrointestinal surgery (colon or small intestine or gastric) that affects the absorption of nutrients.
5. History of familial adenomatous polyposis.

Contacts and Locations

Contacts

Contact: Angel Lanas Arbeloa, MD, PhD; 0034 976 76 57 86; alanas@unizar.es

Contact: Pilar Irun, PhD; mpirun.uit@gmail.com

Locations

Spain

Angel Lanas Arbeloa

Zaragoza, Spain, 50009

Contact: Angel Lanas Arbeloa, MD, PhD +34 976 76 57 86 alanas@unizar.es

Contact: Pilar Irun, PhD mpirun.uit@gmail.com

Sponsors and Collaborators

Instituto de Investigación Sanitaria Aragón

FEIRACO LACTEOS SL

Hospital Clínico Universitario Lozano Blesa

Investigators

• Principal Investigator: Angel Lanas Arbeloa, MD, PhD; University Hospital Lozano Blesa. IIS Aragón. CIBER de Enfermedades Hepáticas y Digestivas.

More Information

Additional Information:

MedlinePlus is a service of the National Library of Medicine (NLM), the world's largest medical library, which is part of the National Institutes of Health (NIH). 

• Responsible Party: Ángel Lanas Arbeloa, Head of Digestive Service (University Clinic Hospital Lozano Blesa) and Principal Investigator, Instituto de Investigación Sanitaria Aragón
• ClinicalTrials.gov Identifier: NCT04824053
• Other Study ID Numbers: F19-028.0
• First Posted: April 1, 2021
• Last Update Posted: July 13, 2021
• Last Verified: July 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ángel Lanas Arbeloa, Instituto de Investigación Sanitaria Aragón:

polyp; inflammation; fecal microbiota

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Selenium; Caseins; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs; Trace Elements; Micronutrients; Chelating Agents; Sequestering Agents