Oral 2'-Fucosyllactose Supplementation for Bone Marrow Transplant Recipients

Overseen By Celeste Dourson

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Children's Hospital Medical Center, Cincinnati

Must not be taking: Anti-diarrheals, Probiotics

Disqualifiers: Intestinal failure, Breastfeeding, GI infection, Gut damage, IBD, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 5 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a supplement called 2'-fucosyllactose (2'-FL or 2'-Fucosyl-D-lactose) can benefit individuals undergoing bone marrow transplants. Researchers believe this supplement might improve gut health by increasing beneficial gut bacteria and reducing inflammation. They aim to lower the risk of complications such as gut and blood infections. Individuals scheduled for a bone marrow transplant who can take supplements orally might be suitable candidates for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this potentially beneficial supplement.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are taking anti-diarrheal medications or have taken probiotics or prebiotics in the past month.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking anti-diarrheal medications or have taken probiotics or prebiotics in the past month.

Is there any evidence suggesting that 2'-fucosyllactose supplementation is likely to be safe for humans?

Research has shown that 2'-fucosyllactose (2'-FL), a compound commonly found in human milk, is generally safe for people. Studies have demonstrated that it is well-tolerated in foods and supplements. A safety review found that 2'-FL, even when produced using certain bacteria, did not cause harmful effects. This is significant because the compound is often made through a process similar to food production.

In the context of bone marrow transplants, early research suggests that 2'-FL may help maintain healthy gut bacteria without causing major side effects. This is crucial because gut health can be affected during these treatments. Overall, current evidence supports the safety of 2'-FL, offering reassurance to those considering participation in clinical trials involving this supplement. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for bone marrow transplant recipients focus on managing complications and supporting recovery through medications like immunosuppressants and antibiotics. However, 2'-fucosyllactose is unique because it is a type of sugar that naturally occurs in human milk, and it is being explored for its potential to enhance gut health and immune function. Researchers are excited about this treatment because it targets the microbiome, which could help improve outcomes by strengthening the body's defenses and reducing infections. This approach is different from standard treatments, which typically don't address the gut microbiome's role in recovery.

What evidence suggests that 2'-fucosyllactose might be an effective treatment for improving intestinal homeostasis in bone marrow transplant recipients?

Research has shown that 2'-fucosyllactose (2FL) can improve gut health in individuals undergoing stem cell transplants. In this trial, participants will receive 2FL, with dosages adjusted by age group. Studies have found that 2FL may increase beneficial gut bacteria, such as Bifidobacteria, while reducing harmful bacteria, including Firmicutes and Proteobacteria. These gut changes can lead to reduced inflammation and improved immune responses. Early findings suggest that 2FL could lower the risk of complications like graft-versus-host disease (GVHD) and blood infections. Overall, 2FL appears promising in supporting the gut and immune system during challenging treatments like transplants. ^{5 6 7 8 9}

Who Is on the Research Team?

Pooja Khandelwal, MD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Are You a Good Fit for This Trial?

This trial is for patients of any age and diagnosis who are scheduled for an allogeneic stem cell transplant. It's not suitable for those unable to take oral supplements, actively breastfeeding infants, anyone with a recent GI infection or taking anti-diarrheal meds, and people who've used probiotics/prebiotics recently or have had significant gut damage in the past 3 months.

Inclusion Criteria

My treatment plan is flexible regarding age, diagnosis, and stem cell sources.

I am scheduled for a stem cell transplant from a donor.

Exclusion Criteria

I have not had severe gut damage or infections in the last 3 months.

I have a history of inflammatory bowel disease, short bowel syndrome, or bowel surgery.

Actively breastfeeding infants

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

2'-Fucosyllactose (2FL) supplementation administered from day-7 until day+30 after HSCT

5 weeks

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, including incidence of GVHD and bloodstream infections

10 weeks

Visits at day+7, day+14, day+30, and day+100

Dose Finding

Dose escalation or de-escalation based on rates of dose limiting toxicities

Ongoing

What Are the Treatments Tested in This Trial?

Interventions

• 2'-fucosyllactose

Trial Overview The trial tests if adding a supplement called 2'-fucosyllactose (2FL) can help balance gut bacteria and reduce inflammation after bone marrow transplants. The goal is to see if it makes the intestines healthier by day+30 post-transplant and lowers complications like acute GVHD and bloodstream infections by day+100.

How Is the Trial Designed?

Group I: 2'-fucosyllactose for ages >10 years Experimental Treatment 1 Intervention

Dose for ages \>10 years: 10 g/day;

Group II: 2'-fucosyllactose for ages 5.1-10 years Experimental Treatment 1 Intervention

Dose for ages 5.1-10 years: 5 g/day;

Group III: 2'-fucosyllactose for ages 0-5 years Experimental Treatment 1 Intervention

Dose for ages 0-5 years: 2.5 g/day;

2'-fucosyllactose is already approved in European Union, United States for the following indications:

Approved in European Union as 2'-Fucosyllactose for:

• Infant nutrition supplement

Approved in United States as 2'-Fucosyllactose for:

• Infant nutrition supplement

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Published Research Related to This Trial

In a study using neonatal piglets, 2′-fucosyllactose was well tolerated at concentrations up to 2000 mg/L, with no adverse effects on growth, development, or health parameters over a 3-week period.

The research supports the safety of 2′-fucosyllactose for potential use in human infants under 12 weeks of age, as it showed no negative impacts on clinical observations or pathology in the piglet model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 3-week pre-clinical study of 2′-fucosyllactose in farm piglets. Hanlon, PR., Thorsrud, BA.[2017]

Supplementation with blends of Human Milk Oligosaccharides (HMOs) can enhance intestinal barrier function, particularly in the presence of inflammatory challenges, as shown in vitro using Caco-2: HT29 cell line monolayers.

The six-HMO blend (HMO6) was particularly effective in reducing harmful translocation of substances and improving barrier integrity, indicating that specific combinations of HMOs could be beneficial for gut health and protection against inflammatory diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blends of Human Milk Oligosaccharides Confer Intestinal Epithelial Barrier Protection in Vitro. Natividad, JM., Rytz, A., Keddani, S., et al.[2021]

3-Fucosyllactose (3-FL), a prebiotic found in human breast milk, was produced safely using genetically modified E. coli K12, showing no acute toxicity at high doses (5000 mg/kg) and no genetic toxicity in multiple tests.

Subchronic feeding studies in rats revealed that 3-FL did not affect growth, food intake, or health indicators, supporting its safety as a nutritional ingredient in foods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety assessment of the biotechnologically produced human-identical milk oligosaccharide 3-Fucosyllactose (3-FL). Pitt, J., Chan, M., Gibson, C., et al.[2020]

A mixture of five human milk oligosaccharides (HMOs) was tested for safety in rats and found to be non-genotoxic and without adverse effects, establishing a no-observed-adverse-effect-level (NOAEL) of 10% in the diet.

These findings support the safety of HMO MIX I for use in infant formula and other food products, paving the way for its inclusion to better mimic the benefits of human breastmilk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A safety evaluation of mixed human milk oligosaccharides in rats. Parschat, K., Oehme, A., Leuschner, J., et al.[2020]

Disruption of gut microbiota is linked to serious complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT), including infections and acute graft vs. host disease, which can increase mortality rates.

Nutritional strategies, such as modifying diet and using prebiotic supplementation, are being explored as effective methods to improve gut microbiota health and clinical outcomes for allo-HSCT recipients, potentially enhancing survival and reducing complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nutritional modulation of the gut microbiome in allogeneic hematopoietic stem cell transplantation recipients. Muratore, E., Leardini, D., Baccelli, F., et al.[2022]

3-fucosyllactose (3-FL), a novel food derived from a genetically modified strain of E. coli, is considered safe for consumption in various food products, including infant formulas and supplements, based on a comprehensive review by the EFSA involving its manufacturing process and composition.

The anticipated daily intake of 3-FL is unlikely to exceed levels typically consumed by breastfed infants, and while there may be slight exceedances in infants under 1 year, these are not deemed a safety concern due to the natural variability of 3-FL in human milk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of 3-FL (3-Fucosyllactose) as a novel food pursuant to Regulation (EU) 2015/2283. Turck, D., Castenmiller, J., De Henauw, S., et al.[2023]

Oral administration of 2'-Fucosyllactose (2'-FL) in wild-type mice leads to its accumulation in the brain and other organs, suggesting that metabolites derived from gut microbes may play a role in this process rather than the intact 2'-FL itself.

In contrast, when 2'-FL is administered intravenously, it is eliminated through urine without enriching organs, indicating that the method of administration significantly affects its bioavailability and potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic Fate and Distribution of 2´-Fucosyllactose: Direct Influence on Gut Microbial Activity but not on Brain. Kuntz, S., Kunz, C., Borsch, C., et al.[2023]

2'-Fucosyllactose (2'-FL), a sugar found in human milk, was shown to protect small intestinal epithelial cells from damage caused by the chemotherapy drug 5-fluorouracil (5-FU), reducing cell apoptosis and inflammation in mouse models.

Pretreatment with 2'-FL significantly improved outcomes in mice with 5-FU-induced intestinal mucositis, including less body weight loss and reduced intestinal damage, compared to concurrent treatment, highlighting its potential as a preventive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

2'-Fucosyllactose Ameliorates Chemotherapy-Induced Intestinal Mucositis by Protecting Intestinal Epithelial Cells Against Apoptosis. Zhao, G., Williams, J., Washington, MK., et al.[2022]

3-fucosyllactose (3-FL), a novel food derived from a genetically modified strain of E. coli, has been deemed safe for consumption in various food products, including infant formula, based on a comprehensive review by the EFSA involving its manufacturing process and composition.

The anticipated daily intake of 3-FL from proposed uses does not exceed levels found in human milk, suggesting it is safe for the general population, including infants, and poses no safety concerns when consumed alongside other carbohydrate compounds.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of 3-fucosyllactose (3-FL) produced by a derivative strain of Escherichia coli K-12 DH1 as a novel food pursuant to Regulation (EU) 2015/2283. Turck, D., Bohn, T., Castenmiller, J., et al.[2023]

In a study involving 46 children undergoing bone marrow transplant, those who received human milk showed significantly lower levels of inflammatory markers like IL-8, IL-10, and REG3α, suggesting that human milk can help reduce intestinal inflammation during recovery.

The human milk group had a lower abundance of harmful bacteria in their stool compared to the control group, indicating that human milk may support a healthier gut microbiome in post-transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pilot Study of Human Milk to Reduce Intestinal Inflammation After Bone Marrow Transplant. Khandelwal, P., Andersen, H., Romick-Rosendale, L., et al.[2020]

Oral supplementation with the milk oligosaccharide 2-fucosyllactose significantly reduced the severity of colitis in interleukin-10 null (Il10-/-) mice, indicating its potential as a therapeutic agent for gut inflammation.

The treatment led to an increase in beneficial gut bacteria, specifically Ruminococcus gnavus, which helped decrease inflammation by enhancing gut barrier integrity and reducing pro-inflammatory bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alleviation of Intestinal Inflammation by Oral Supplementation With 2-Fucosyllactose in Mice. Grabinger, T., Glaus Garzon, JF., Hausmann, M., et al.[2020]

3-Fucosyllactose (3-FL), a naturally occurring oligosaccharide in breast milk, is important for newborn health and has been shown to be safe, with no acute oral toxicity or genetic toxicity, and is recognized as generally safe (GRAS).

The production of 3-FL can be achieved through enzymatic methods and metabolic engineering strategies, highlighting its potential for use in HMO-fortified products that aim to replicate the benefits of human milk for infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Occurrence, functional properties, and preparation of 3-fucosyllactose, one of the smallest human milk oligosaccharides. Li, Z., Zhu, Y., Ni, D., et al.[2023]

The study demonstrated that synthesized human milk oligosaccharides, specifically 2'-fucosyllactose (2'-FL) and 3-fucosyllactose (3-FL), effectively inhibit the adhesion of various pathogens to human epithelial cells, suggesting their potential role in preventing infections in infants.

Both 2'-FL and 3-FL showed significant reductions in pathogen adhesion, with 2'-FL reducing Campylobacter jejuni and Pseudomonas aeruginosa adhesion by up to 26%, indicating their promising use as supplements in infant formula to enhance health and prevent infectious diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioengineered 2'-fucosyllactose and 3-fucosyllactose inhibit the adhesion of Pseudomonas aeruginosa and enteric pathogens to human intestinal and respiratory cell lines. Weichert, S., Jennewein, S., Hüfner, E., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04263597

Study Details | NCT04263597 | Oral Supplementation of 2'- ... Number of patients able to take 2FL, 6 of 10 patients receiving 2FL able to take 80% of their planned doses, 1 week prior to start of chemotherapy until day+30 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7969390/

The role of the intestinal microbiota in allogeneic HCT This review outlines our current understanding of the relationship between gut bacteria and allo-HCT outcomes, including infection, immune reconstitution, GVHD ...

3. astctjournal.org astctjournal.org/article/S2666-6367(23)01775-X/fulltext

Administration of Human Milk Oligosaccharide (2′ ... Oral supplementation of the most abundant HMO, 2-fucosyllactose (2'-FL), will be safe, well tolerated, and reduce dysbiosis in patients undergoing HSCT. Methods.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40488907/

fucosyllactose alleviate immunodeficiency in vitro and in vivo High doses of GOS or 2'-FL in vivo reversed the adverse effects induced by CTX, modulated the gut microbiota, and boosted the immune response.

5. clinconnect.io clinconnect.io/trials/NCT04263597

Oral Supplementation of 2'-Fucosyllactose in Allogeneic Researchers believe that taking 2FL might help improve gut health by increasing good bacteria while reducing harmful ones. They will measure various indicators ...

6. fda.gov fda.gov/files/food/published/GRAS-Notice-GRN-749-Part-1.pdf

GRAS notice 749 for 2'-O-fucosyllactose Safety assessment of 2'-0 -fulcosyllactose {2'-FL). Republic of Ireland, Dublin,. Ireland. Jennewein Biotechnologie, G., 2015. GRAS Exemption claim for use ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7009083/

Safety of 2'‐fucosyllactose/difucosyllactose mixture as a ... The NF is a mixture of 2'‐fucosyllactose (2'‐FL) and difucosyllactose ... Sum of 2'‐FL, DFL, lactose and fucose [% dry matter], ≥ 92.0 w/w %, HPAEC/PAD.

8. efsa.europa.eu efsa.europa.eu/en/efsajournal/pub/8333

Safety of 2′‐fucosyllactose (2'‐FL) produced by a derivative ... Safety of 2′‐fucosyllactose (2'‐FL) produced by a derivative strain (Escherichia coli SGR5) of E. coli W (ATCC 9637) as a Novel Food ...

9. science.food.gov.uk science.food.gov.uk/article/120875-safety-assessment-of-2-fucosyllactose-2-fl-as-a-novel-food-for-use-in-food-and-food-supplements-rp1476

Safety Assessment of 2'-Fucosyllactose (2'-FL) as a Novel ... The novel food is intended to be used as a source of human identical milk oligosaccharide, 2'-FL, and is manufactured by microbial fermentation.