<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04428190</url>
  </required_header>
  <id_info>
    <org_study_id>PRT01</org_study_id>
    <nct_id>NCT04428190</nct_id>
  </id_info>
  <brief_title>Prebiotic Therapy to Improve Outcomes of Renal Transplant</brief_title>
  <official_title>Prebiotic Therapy to Improve Outcomes of Renal Transplant</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lawson Health Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The W. Garfield Weston Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St. Joseph's Health Care London</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>London Health Sciences Centre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Lawson Health Research Institute</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      An investigator initiated pilot study: two arm, double blind, placebo controlled, randomized,&#xD;
      group of approximately 60 patients undergoing a kidney transplant. Participants will be&#xD;
      treated with human milk oligosaccharide (HMO) prebiotic versus placebo over 12 weeks from&#xD;
      start of the investigational medication date (approximately 3 months) to test whether HMO can&#xD;
      improve renal transplant outcomes. Participants will be followed up for 3 months after after&#xD;
      they complete the treatment portion of the study. HMO sachets will be administered to&#xD;
      determine the safety and efficacy of HMO relative to placebo in improving renal transplant&#xD;
      outcomes in patients by reducing delayed graft function and side effects from post transplant&#xD;
      therapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Nearly three million people worldwide suffer from end stage renal disease (ESRD), which has&#xD;
      debilitating consequences on the quality of life of patients There is a discrepancy between&#xD;
      the availability of organs and the increasing number of patients placed on the waiting list.&#xD;
      Canadians with ESRD requiring kidney transplantation has increased by 38% from 2005-2014,&#xD;
      whereas the number of transplantable organs has not met this growing need.&#xD;
&#xD;
      As clinicians use more marginal donors, the effects of ischemic injury from the procurement&#xD;
      process become more pronounced. This ischemia reperfusion injury (IRI) has been linked to&#xD;
      increased delayed graft function, rejection and decreased long-term function. Approximately&#xD;
      20% of transplanted patients subsequently return to dialysis due to poor graft function.&#xD;
      Therefore, one of the major goals of the transplant community has now shifted to ensuring the&#xD;
      longevity of transplanted organs. Research priorities need to shift towards developing ways&#xD;
      to ensure the longevity of grafts through modification of recipient factors.&#xD;
&#xD;
      Patients are also required to remain on immunosuppressive drugs following transplant in order&#xD;
      to maintain the graft. These have a variety of side effects, including diarrhea and&#xD;
      intestinal malabsorption, which can lead to a lack of patient compliance with post transplant&#xD;
      therapy and a reduced quality of life.&#xD;
&#xD;
      Patients with ESRD also have an expansion of bacteria that produce urease and uric acid and&#xD;
      produce fewer short-chained fatty acids and vitamins.&#xD;
&#xD;
      This is important as it is theorized that the production of short-chained fatty acids by&#xD;
      microorganisms in the GI tract are crucial as both the energy source, and to the maintenance&#xD;
      of intestinal permeability, which contribute to a healthy gastrointestinal tract.&#xD;
&#xD;
      The expansion of bacteria that produce urease and uric acid contribute to toxicity and&#xD;
      inflammation in the GI tract that can cause complications in these patients.&#xD;
&#xD;
      In order to reduce both delayed graft function and side effects from post transplant therapy,&#xD;
      novel support options are required. One option is the use of prebiotics.&#xD;
&#xD;
      Non-digestible sugar prebiotics have potential for use in these patients. The Principal&#xD;
      Investigator/Sponsor will test this potential in a pilot clinical study with a Human milk&#xD;
      oligosaccharides (HMO) prebiotic mix that have been shown to stimulate the production of&#xD;
      short chain fatty acids, especially propionate. Propionate has been shown to be important in&#xD;
      attenuating hypertrophy, fibrosis, vascular dysfunction and hypertension and is extremely&#xD;
      important for the gut kidney axis. Prebiotics offer a safe and well-tolerated therapy, which&#xD;
      could have a positive impact by improving systemic inflammatory responses, improving gut&#xD;
      barrier function, helping to reduce immunosuppressive drug side effects and stabilizing its&#xD;
      dosing.&#xD;
&#xD;
      This study will assess blood, and urine samples collected as part of the participant's&#xD;
      post-transplant follow up at eight time points to determine graft function.&#xD;
&#xD;
      Urine and a faecal sample will be collected at 6 time points for microbiome analyses at&#xD;
      baseline, day 7, 30, 60, 120 and 180 from the date of starting the study product. Prior to&#xD;
      commencing their treatment, and at days 60,90,150, and 180, the research coordinator (blinded&#xD;
      to the randomisation) will assess patients using the SF-36 and GI Health questionnaires&#xD;
      during clinic visits, or by telephone interview.&#xD;
&#xD;
      Protocol compliance will be tested through product count and interviews at each follow-up&#xD;
      visit. Side effects will be assessed using standardized case report forms at each visit.&#xD;
      Participants will be encouraged to report any events they may experience directly to the&#xD;
      coordinator.&#xD;
&#xD;
      Participants who withdraw consent to continue treatments, will be encouraged to undergo the&#xD;
      planned assessments. Withdrawal at the request of investigators or medical personnel may&#xD;
      include, but are not limited to:&#xD;
&#xD;
        1. Symptoms are deemed to be potentially related to the study product&#xD;
&#xD;
        2. New diagnosis of exclusion criteria;&#xD;
&#xD;
        3. Unacceptable side effects;&#xD;
&#xD;
        4. Death&#xD;
&#xD;
      Estimated time to complete recruitment: Averaging 86 weeks, approximately 20 months&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">February 23, 2022</start_date>
  <completion_date type="Anticipated">December 15, 2022</completion_date>
  <primary_completion_date type="Anticipated">October 15, 2022</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>One placebo arm and one active treatment arm, participants will be assigned to each arm equally.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>No other parties will be masked for the study.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Short Form Health Survey (SF-36)</measure>
    <time_frame>24 weeks</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>24 weeks</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Microbiome changes from baseline to end of treatment</measure>
    <time_frame>12 weeks</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Microbiome changes post intervention</measure>
    <time_frame>12 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Number of participants who experience kidney rejection</measure>
    <time_frame>24 weeks</time_frame>
    <description>A kidney rejection will be recorded in the adverse event form for the study.</description>
  </other_outcome>
  <other_outcome>
    <measure>Immunosuppression suppressive drug dose</measure>
    <time_frame>post-operative day 1, 7, 30, 60, 90, 120, 150 and 180</time_frame>
    <description>will be assessed by the clinic on post-operative day 1, 7, 30, 60, 90, 120, 150 and 180</description>
  </other_outcome>
  <other_outcome>
    <measure>Infectious complications</measure>
    <time_frame>post-operative day 30, 60, 90, 120, 150 and 180.</time_frame>
    <description>Cytomegalovirus will be tested by the clinic, typically reported in IU/mL</description>
  </other_outcome>
  <other_outcome>
    <measure>Serum creatinine</measure>
    <time_frame>24 weeks.</time_frame>
    <description>Will be used to determine graft function, and is reported in μmol/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Cystatin-c levels</measure>
    <time_frame>24 weeks.</time_frame>
    <description>Will be used to determine graft function, and is reported in mg/l.</description>
  </other_outcome>
  <other_outcome>
    <measure>Estimated glomerular filtration rate (eGFR)</measure>
    <time_frame>24 weeks.</time_frame>
    <description>Will be used to determine graft function, and is reported in mL/min/1.73m**2.</description>
  </other_outcome>
  <other_outcome>
    <measure>Urine output</measure>
    <time_frame>24 weeks.</time_frame>
    <description>Will be used to determine graft function, and is reported in mL/day.</description>
  </other_outcome>
  <other_outcome>
    <measure>Urine protein/creatinine ratio</measure>
    <time_frame>24 weeks.</time_frame>
    <description>Will be used to determine graft function, and is reported in g/L</description>
  </other_outcome>
  <other_outcome>
    <measure>Dialysis episodes</measure>
    <time_frame>24 weeks.</time_frame>
    <description>Will be used to determine graft function, and will be measured by the amount of times a participant required dialysis.</description>
  </other_outcome>
  <other_outcome>
    <measure>Renal micro-perfusion using Doppler ultrasound</measure>
    <time_frame>24 weeks.</time_frame>
    <description>Will be used to determine graft function by providing an assessment of vascular changes.</description>
  </other_outcome>
  <other_outcome>
    <measure>Search Results Web results Kidney Injury Molecule-1 (Kim-1)</measure>
    <time_frame>24 weeks.</time_frame>
    <description>Will be used to determine graft function, and is reported in ng/ml</description>
  </other_outcome>
  <other_outcome>
    <measure>Neutrophil gelatinase-associated lipocalin (NGAL)</measure>
    <time_frame>24 weeks.</time_frame>
    <description>Will be used to determine graft function, and is reported in ng/ml</description>
  </other_outcome>
  <other_outcome>
    <measure>Immunosuppression drug serum levels (MMF and FK-506)</measure>
    <time_frame>post-operative day 1, 7, 30, 60, 90, 120, 150 and 180</time_frame>
    <description>will be assessed by the clinic, typically reported in mg/ml.</description>
  </other_outcome>
  <other_outcome>
    <measure>Serial viral serologies</measure>
    <time_frame>post-operative day 30, 60, 90, 120, 150 and 180.</time_frame>
    <description>Polyomavirus will be tested by the clinic post-op, typically reported in IU/mL.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Kidney Transplant; Complications</condition>
  <arm_group>
    <arm_group_label>Human Milk Oligosaccharide (HMO)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>10 g sachet, self-administered for 3 months.&#xD;
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).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>10 g sachet, self-administered for 3 months.&#xD;
Placebo sachets are identical to the HMO sachets in color, taste, smell, size and shape</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Human Milk Oligosaccharides (HMO)</intervention_name>
    <description>Sachet containing 10 grams of HMO</description>
    <arm_group_label>Human Milk Oligosaccharide (HMO)</arm_group_label>
    <other_name>Prebiotic</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Sachet manufactured to mimic 10g of HMO</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo for HMO</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  18 years of age and over receiving a kidney transplant.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Under 18 years of age&#xD;
&#xD;
          -  Inability to give consent&#xD;
&#xD;
          -  Usage of probiotics or other prebiotics.&#xD;
&#xD;
          -  Have had carcinomas during the last 5 years&#xD;
&#xD;
          -  Bowel surgery&#xD;
&#xD;
          -  Crohn ́s disease and other conditions.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alp Sener, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>London Health Sciences Centre</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mounirah May</last_name>
    <phone>519-685-8500</phone>
    <phone_ext>34779</phone_ext>
    <email>mounirah.may@lhsc.on.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jeremy P Burton, PhD</last_name>
    <phone>519-646-6000</phone>
    <phone_ext>61365</phone_ext>
    <email>Jeremy.Burton@LawsonResearch.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>London Health Sciences Centre</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A 5A5</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Cadence Baker, MSc</last_name>
      <phone>5196858500</phone>
      <phone_ext>34755</phone_ext>
      <email>cadence.baker@lhsc.on.ca</email>
    </contact>
    <investigator>
      <last_name>Alp Sener, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <reference>
    <citation>Pluznick JL. Gut microbiota in renal physiology: focus on short-chain fatty acids and their receptors. Kidney Int. 2016 Dec;90(6):1191-1198. doi: 10.1016/j.kint.2016.06.033. Epub 2016 Aug 26.</citation>
    <PMID>27575555</PMID>
  </reference>
  <reference>
    <citation>Lee JR, Muthukumar T, Dadhania D, Taur Y, Jenq RR, Toussaint NC, Ling L, Pamer E, Suthanthiran M. Gut microbiota and tacrolimus dosing in kidney transplantation. PLoS One. 2015 Mar 27;10(3):e0122399. doi: 10.1371/journal.pone.0122399. eCollection 2015.</citation>
    <PMID>25815766</PMID>
  </reference>
  <reference>
    <citation>Elison E, Vigsnaes LK, Rindom Krogsgaard L, Rasmussen J, Sorensen N, McConnell B, Hennet T, Sommer MO, Bytzer P. Oral supplementation of healthy adults with 2'-O-fucosyllactose and lacto-N-neotetraose is well tolerated and shifts the intestinal microbiota. Br J Nutr. 2016 Oct;116(8):1356-1368. doi: 10.1017/S0007114516003354. Epub 2016 Oct 10.</citation>
    <PMID>27719686</PMID>
  </reference>
  <reference>
    <citation>Harvie RM, Chisholm AW, Bisanz JE, Burton JP, Herbison P, Schultz K, Schultz M. Long-term irritable bowel syndrome symptom control with reintroduction of selected FODMAPs. World J Gastroenterol. 2017 Jul 7;23(25):4632-4643. doi: 10.3748/wjg.v23.i25.4632.</citation>
    <PMID>28740352</PMID>
  </reference>
  <reference>
    <citation>Dubberke ER, Riddle DJ; AST Infectious Diseases Community of Practice. Clostridium difficile in solid organ transplant recipients. Am J Transplant. 2009 Dec;9 Suppl 4(0 4):S35-40. doi: 10.1111/j.1600-6143.2009.02891.x.</citation>
    <PMID>20070693</PMID>
  </reference>
  <reference>
    <citation>Rayes N, Seehofer D, Theruvath T, Schiller RA, Langrehr JM, Jonas S, Bengmark S, Neuhaus P. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation--a randomized, double-blind trial. Am J Transplant. 2005 Jan;5(1):125-30. doi: 10.1111/j.1600-6143.2004.00649.x.</citation>
    <PMID>15636620</PMID>
  </reference>
  <reference>
    <citation>Sawas T, Al Halabi S, Hernaez R, Carey WD, Cho WK. Patients Receiving Prebiotics and Probiotics Before Liver Transplantation Develop Fewer Infections Than Controls: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2015 Sep;13(9):1567-74.e3; quiz e143-4. doi: 10.1016/j.cgh.2015.05.027. Epub 2015 Jun 2.</citation>
    <PMID>26044318</PMID>
  </reference>
  <reference>
    <citation>Lobb I, Jiang J, Lian D, Liu W, Haig A, Saha MN, Torregrossa R, Wood ME, Whiteman M, Sener A. Hydrogen Sulfide Protects Renal Grafts Against Prolonged Cold Ischemia-Reperfusion Injury via Specific Mitochondrial Actions. Am J Transplant. 2017 Feb;17(2):341-352. doi: 10.1111/ajt.14080. Epub 2016 Nov 29.</citation>
    <PMID>27743487</PMID>
  </reference>
  <reference>
    <citation>Al KF, Bisanz JE, Gloor GB, Reid G, Burton JP. Evaluation of sampling and storage procedures on preserving the community structure of stool microbiota: A simple at-home toilet-paper collection method. J Microbiol Methods. 2018 Jan;144:117-121. doi: 10.1016/j.mimet.2017.11.014. Epub 2017 Nov 16.</citation>
    <PMID>29155236</PMID>
  </reference>
  <reference>
    <citation>Bao Y, Al KF, Chanyi RM, Whiteside S, Dewar M, Razvi H, Reid G, Burton JP. Questions and challenges associated with studying the microbiome of the urinary tract. Ann Transl Med. 2017 Jan;5(2):33. doi: 10.21037/atm.2016.12.14.</citation>
    <PMID>28217698</PMID>
  </reference>
  <results_reference>
    <citation>Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation. Lancet. 2004 Nov 13-19;364(9447):1814-27. doi: 10.1016/S0140-6736(04)17406-0.</citation>
    <PMID>15541456</PMID>
  </results_reference>
  <results_reference>
    <citation>Wong J, Piceno YM, DeSantis TZ, Pahl M, Andersen GL, Vaziri ND. Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD. Am J Nephrol. 2014;39(3):230-237. doi: 10.1159/000360010. Epub 2014 Mar 8.</citation>
    <PMID>24643131</PMID>
  </results_reference>
  <results_reference>
    <citation>Bartolomaeus H, Balogh A, Yakoub M, Homann S, Marko L, Hoges S, Tsvetkov D, Krannich A, Wundersitz S, Avery EG, Haase N, Kraker K, Hering L, Maase M, Kusche-Vihrog K, Grandoch M, Fielitz J, Kempa S, Gollasch M, Zhumadilov Z, Kozhakhmetov S, Kushugulova A, Eckardt KU, Dechend R, Rump LC, Forslund SK, Muller DN, Stegbauer J, Wilck N. Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage. Circulation. 2019 Mar 12;139(11):1407-1421. doi: 10.1161/CIRCULATIONAHA.118.036652.</citation>
    <PMID>30586752</PMID>
  </results_reference>
  <results_reference>
    <citation>Li L, Ma L, Fu P. Gut microbiota-derived short-chain fatty acids and kidney diseases. Drug Des Devel Ther. 2017 Dec 11;11:3531-3542. doi: 10.2147/DDDT.S150825. eCollection 2017.</citation>
    <PMID>29270002</PMID>
  </results_reference>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>May 28, 2020</study_first_submitted>
  <study_first_submitted_qc>June 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>April 5, 2022</last_update_submitted>
  <last_update_submitted_qc>April 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 12, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>kidney</keyword>
  <keyword>kidney transplant</keyword>
  <keyword>prebiotic</keyword>
  <keyword>human milk oligosaccharide</keyword>
  <keyword>HMO</keyword>
  <keyword>renal transplant</keyword>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04428190
org study id: PRT01
nct id: NCT04428190
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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:

        1. Symptoms are deemed to be potentially related to the study product

        2. New diagnosis of exclusion criteria;

        3. Unacceptable side effects;

        4. Death

      Estimated time to complete recruitment: Averaging 86 weeks, approximately 20 months
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: One placebo arm and one active treatment arm, participants will be assigned to each arm equally.
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: No other parties will be masked for the study.
measure: Short Form Health Survey (SF-36)
time frame: 24 weeks
description: 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.
measure: Adverse Events
time frame: 24 weeks
description: 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.
measure: Microbiome changes from baseline to end of treatment
time frame: 12 weeks
description: 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).
measure: Microbiome changes post intervention
time frame: 12 weeks
description: 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.
measure: Number of participants who experience kidney rejection
time frame: 24 weeks
description: A kidney rejection will be recorded in the adverse event form for the study.
measure: Immunosuppression suppressive drug dose
time frame: post-operative day 1, 7, 30, 60, 90, 120, 150 and 180
description: will be assessed by the clinic on post-operative day 1, 7, 30, 60, 90, 120, 150 and 180
measure: Infectious complications
time frame: post-operative day 30, 60, 90, 120, 150 and 180.
description: Cytomegalovirus will be tested by the clinic, typically reported in IU/mL
measure: Serum creatinine
time frame: 24 weeks.
description: Will be used to determine graft function, and is reported in μmol/L.
measure: Cystatin-c levels
time frame: 24 weeks.
description: Will be used to determine graft function, and is reported in mg/l.
measure: Estimated glomerular filtration rate (eGFR)
time frame: 24 weeks.
description: Will be used to determine graft function, and is reported in mL/min/1.73m**2.
measure: Urine output
time frame: 24 weeks.
description: Will be used to determine graft function, and is reported in mL/day.
measure: Urine protein/creatinine ratio
time frame: 24 weeks.
description: Will be used to determine graft function, and is reported in g/L
measure: Dialysis episodes
time frame: 24 weeks.
description: Will be used to determine graft function, and will be measured by the amount of times a participant required dialysis.
measure: Renal micro-perfusion using Doppler ultrasound
time frame: 24 weeks.
description: Will be used to determine graft function by providing an assessment of vascular changes.
measure: Search Results Web results Kidney Injury Molecule-1 (Kim-1)
time frame: 24 weeks.
description: Will be used to determine graft function, and is reported in ng/ml
measure: Neutrophil gelatinase-associated lipocalin (NGAL)
time frame: 24 weeks.
description: Will be used to determine graft function, and is reported in ng/ml
measure: Immunosuppression drug serum levels (MMF and FK-506)
time frame: post-operative day 1, 7, 30, 60, 90, 120, 150 and 180
description: will be assessed by the clinic, typically reported in mg/ml.
measure: Serial viral serologies
time frame: post-operative day 30, 60, 90, 120, 150 and 180.
description: Polyomavirus will be tested by the clinic post-op, typically reported in IU/mL.
arm group label: Human Milk Oligosaccharide (HMO)
arm group type: Active Comparator
description: 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).
arm group label: Placebo
arm group type: Placebo Comparator
description: 10 g sachet, self-administered for 3 months.
Placebo sachets are identical to the HMO sachets in color, taste, smell, size and shape
intervention type: Dietary Supplement
intervention name: Human Milk Oligosaccharides (HMO)
description: Sachet containing 10 grams of HMO
arm group label: Human Milk Oligosaccharide (HMO)
other name: Prebiotic
intervention type: Other
intervention name: Placebo
description: Sachet manufactured to mimic 10g of HMO
arm group label: Placebo
other name: Placebo for HMO
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alp Sener, MD
role: Principal Investigator
affiliation: London Health Sciences Centre
last name: Mounirah May
phone: 519-685-8500
phone ext: 34779
email: mounirah.may@lhsc.on.ca
last name: Jeremy P Burton, PhD
phone: 519-646-6000
phone ext: 61365
email: Jeremy.Burton@LawsonResearch.com
facility: 
status: Recruiting
contact: 
investigator: 
country: Canada
citation: Pluznick JL. Gut microbiota in renal physiology: focus on short-chain fatty acids and their receptors. Kidney Int. 2016 Dec;90(6):1191-1198. doi: 10.1016/j.kint.2016.06.033. Epub 2016 Aug 26.
PMID: 27575555
citation: Lee JR, Muthukumar T, Dadhania D, Taur Y, Jenq RR, Toussaint NC, Ling L, Pamer E, Suthanthiran M. Gut microbiota and tacrolimus dosing in kidney transplantation. PLoS One. 2015 Mar 27;10(3):e0122399. doi: 10.1371/journal.pone.0122399. eCollection 2015.
PMID: 25815766
citation: Elison E, Vigsnaes LK, Rindom Krogsgaard L, Rasmussen J, Sorensen N, McConnell B, Hennet T, Sommer MO, Bytzer P. Oral supplementation of healthy adults with 2'-O-fucosyllactose and lacto-N-neotetraose is well tolerated and shifts the intestinal microbiota. Br J Nutr. 2016 Oct;116(8):1356-1368. doi: 10.1017/S0007114516003354. Epub 2016 Oct 10.
PMID: 27719686
citation: Harvie RM, Chisholm AW, Bisanz JE, Burton JP, Herbison P, Schultz K, Schultz M. Long-term irritable bowel syndrome symptom control with reintroduction of selected FODMAPs. World J Gastroenterol. 2017 Jul 7;23(25):4632-4643. doi: 10.3748/wjg.v23.i25.4632.
PMID: 28740352
citation: Dubberke ER, Riddle DJ; AST Infectious Diseases Community of Practice. Clostridium difficile in solid organ transplant recipients. Am J Transplant. 2009 Dec;9 Suppl 4(0 4):S35-40. doi: 10.1111/j.1600-6143.2009.02891.x.
PMID: 20070693
citation: Rayes N, Seehofer D, Theruvath T, Schiller RA, Langrehr JM, Jonas S, Bengmark S, Neuhaus P. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation--a randomized, double-blind trial. Am J Transplant. 2005 Jan;5(1):125-30. doi: 10.1111/j.1600-6143.2004.00649.x.
PMID: 15636620
citation: Sawas T, Al Halabi S, Hernaez R, Carey WD, Cho WK. Patients Receiving Prebiotics and Probiotics Before Liver Transplantation Develop Fewer Infections Than Controls: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2015 Sep;13(9):1567-74.e3; quiz e143-4. doi: 10.1016/j.cgh.2015.05.027. Epub 2015 Jun 2.
PMID: 26044318
citation: Lobb I, Jiang J, Lian D, Liu W, Haig A, Saha MN, Torregrossa R, Wood ME, Whiteman M, Sener A. Hydrogen Sulfide Protects Renal Grafts Against Prolonged Cold Ischemia-Reperfusion Injury via Specific Mitochondrial Actions. Am J Transplant. 2017 Feb;17(2):341-352. doi: 10.1111/ajt.14080. Epub 2016 Nov 29.
PMID: 27743487
citation: Al KF, Bisanz JE, Gloor GB, Reid G, Burton JP. Evaluation of sampling and storage procedures on preserving the community structure of stool microbiota: A simple at-home toilet-paper collection method. J Microbiol Methods. 2018 Jan;144:117-121. doi: 10.1016/j.mimet.2017.11.014. Epub 2017 Nov 16.
PMID: 29155236
citation: Bao Y, Al KF, Chanyi RM, Whiteside S, Dewar M, Razvi H, Reid G, Burton JP. Questions and challenges associated with studying the microbiome of the urinary tract. Ann Transl Med. 2017 Jan;5(2):33. doi: 10.21037/atm.2016.12.14.
PMID: 28217698
citation: Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation. Lancet. 2004 Nov 13-19;364(9447):1814-27. doi: 10.1016/S0140-6736(04)17406-0.
PMID: 15541456
citation: Wong J, Piceno YM, DeSantis TZ, Pahl M, Andersen GL, Vaziri ND. Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD. Am J Nephrol. 2014;39(3):230-237. doi: 10.1159/000360010. Epub 2014 Mar 8.
PMID: 24643131
citation: Bartolomaeus H, Balogh A, Yakoub M, Homann S, Marko L, Hoges S, Tsvetkov D, Krannich A, Wundersitz S, Avery EG, Haase N, Kraker K, Hering L, Maase M, Kusche-Vihrog K, Grandoch M, Fielitz J, Kempa S, Gollasch M, Zhumadilov Z, Kozhakhmetov S, Kushugulova A, Eckardt KU, Dechend R, Rump LC, Forslund SK, Muller DN, Stegbauer J, Wilck N. Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage. Circulation. 2019 Mar 12;139(11):1407-1421. doi: 10.1161/CIRCULATIONAHA.118.036652.
PMID: 30586752
citation: Li L, Ma L, Fu P. Gut microbiota-derived short-chain fatty acids and kidney diseases. Drug Des Devel Ther. 2017 Dec 11;11:3531-3542. doi: 10.2147/DDDT.S150825. eCollection 2017.
PMID: 29270002
responsible party type: Sponsor
sharing ipd: No