Prebiotic Therapy to Improve Outcomes of Renal Transplant

Study Overview
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Brief Summary
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An investigator initiated pilot study: two arm, double blind, placebo controlled, randomized, group of approximately 60 patients undergoing a kidney transplant. Participants will be treated with human milk oligosaccharide (HMO) prebiotic versus placebo over 12 weeks from start of the investigational medication date (approximately 3 months) to test whether HMO can improve renal transplant outcomes. Participants will be followed up for 3 months after after they complete the treatment portion of the study. HMO sachets will be administered to determine the safety and efficacy of HMO relative to placebo in improving renal transplant outcomes in patients by reducing delayed graft function and side effects from post transplant therapy.

Detailed Description
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Nearly three million people worldwide suffer from end stage renal disease (ESRD), which has debilitating consequences on the quality of life of patients There is a discrepancy between the availability of organs and the increasing number of patients placed on the waiting list. Canadians with ESRD requiring kidney transplantation has increased by 38% from 2005-2014, whereas the number of transplantable organs has not met this growing need. As clinicians use more marginal donors, the effects of ischemic injury from the procurement process become more pronounced. This ischemia reperfusion injury (IRI) has been linked to increased delayed graft function, rejection and decreased long-term function. Approximately 20% of transplanted patients subsequently return to dialysis due to poor graft function. Therefore, one of the major goals of the transplant community has now shifted to ensuring the longevity of transplanted organs. Research priorities need to shift towards developing ways to ensure the longevity of grafts through modification of recipient factors. Patients are also required to remain on immunosuppressive drugs following transplant in order to maintain the graft. These have a variety of side effects, including diarrhea and intestinal malabsorption, which can lead to a lack of patient compliance with post transplant therapy and a reduced quality of life. Patients with ESRD also have an expansion of bacteria that produce urease and uric acid and produce fewer short-chained fatty acids and vitamins. This is important as it is theorized that the production of short-chained fatty acids by microorganisms in the GI tract are crucial as both the energy source, and to the maintenance of intestinal permeability, which contribute to a healthy gastrointestinal tract. The expansion of bacteria that produce urease and uric acid contribute to toxicity and inflammation in the GI tract that can cause complications in these patients. In order to reduce both delayed graft function and side effects from post transplant therapy, novel support options are required. One option is the use of prebiotics. Non-digestible sugar prebiotics have potential for use in these patients. The Principal Investigator/Sponsor will test this potential in a pilot clinical study with a Human milk oligosaccharides (HMO) prebiotic mix that have been shown to stimulate the production of short chain fatty acids, especially propionate. Propionate has been shown to be important in attenuating hypertrophy, fibrosis, vascular dysfunction and hypertension and is extremely important for the gut kidney axis. Prebiotics offer a safe and well-tolerated therapy, which could have a positive impact by improving systemic inflammatory responses, improving gut barrier function, helping to reduce immunosuppressive drug side effects and stabilizing its dosing. This study will assess blood, and urine samples collected as part of the participant's post-transplant follow up at eight time points to determine graft function. Urine and a faecal sample will be collected at 6 time points for microbiome analyses at baseline, day 7, 30, 60, 120 and 180 from the date of starting the study product. Prior to commencing their treatment, and at days 60,90,150, and 180, the research coordinator (blinded to the randomisation) will assess patients using the SF-36 and GI Health questionnaires during clinic visits, or by telephone interview. Protocol compliance will be tested through product count and interviews at each follow-up visit. Side effects will be assessed using standardized case report forms at each visit. Participants will be encouraged to report any events they may experience directly to the coordinator. Participants who withdraw consent to continue treatments, will be encouraged to undergo the planned assessments. Withdrawal at the request of investigators or medical personnel may include, but are not limited to: Symptoms are deemed to be potentially related to the study product New diagnosis of exclusion criteria; Unacceptable side effects; Death Estimated time to complete recruitment: Averaging 86 weeks, approximately 20 months

Official Title
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Prebiotic Therapy to Improve Outcomes of Renal Transplant

Conditions
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Kidney Transplant; Complications

Intervention / Treatment
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* Dietary Supplement: Human Milk Oligosaccharides (HMO)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age and over receiving a kidney transplant. Exclusion Criteria: Under 18 years of age Inability to give consent Usage of probiotics or other prebiotics. Have had carcinomas during the last 5 years Bowel surgery Crohn ́s disease and other conditions.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: One placebo arm and one active treatment arm, participants will be assigned to each arm equally.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Human Milk Oligosaccharide (HMO)<br>10 g sachet, self-administered for 3 months. 2'-O-fucosyllactose and lacto-N-neotetraose, novel human milk oligosaccharide (HMO) sugars have been shown to stimulate the production of short chain fatty acids, especially propionate. Propionate has been shown to be important in attenuating hypertrophy, fibrosis, vascular dysfunction and hypertension (Bartolomaeus H et al 2019Mar12) and extremely important for the gut kidney axis (Li L et al 2017Dec11). | Dietary Supplement: Human Milk Oligosaccharides (HMO)<br>* Sachet containing 10 grams of HMO<br>* Other names: Prebiotic;|
| Placebo Comparator: Placebo<br>10 g sachet, self-administered for 3 months. Placebo sachets are identical to the HMO sachets in color, taste, smell, size and shape | Other: Placebo<br>* Sachet manufactured to mimic 10g of HMO<br>* Other names: Placebo for HMO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Short Form Health Survey (SF-36) | The Short Form Health Survey will measure participant satisfaction using a scale from 1 - 5, 1 being the best outcome, and 5 being the worst outcome. | 24 weeks | 
| Adverse Events | Adverse events will be recorded through case report forms and reported to the principal investigator. Side effects will be assessed using standardized case report forms at each visit. Participants are encouraged to contact the coordinator to report any concerns. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microbiome changes from baseline to end of treatment | Changes in the entire bacterial community from baseline to end of study will be assessed in the lab from faecal and urine samples collected by the participant. The microbes may vary by participant and the study will be looking at which ones present themselves in each case. Units of measure via culture are colony forming units per g (cfu/g). | 12 weeks | 
| Microbiome changes post intervention | Changes in the entire bacterial community after study intervention will be assessed in the lab from faecal and urine samples collected by the participant. The microbes may vary by participant and this outcome measure will be looking at which ones present themselves in each case. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney, kidney transplant, prebiotic, human milk oligosaccharide, HMO, renal transplant