Prebiotics for Spinal Cord Injury Patients With Bowel and Bladder Dysfunction

Use of Novel Human Milk Prebiotics to Improve the Quality of Life for Spinal Cord Injury Patients With Bowel and Bladder Dysfunction

An investigator initiated pilot study: two arm, double blind, placebo controlled, randomized, group of approximately 60 patients with spinal cord injury, and who have evidence of neurogenic bladder. Patients will be treated with human milk oligosaccharide (HMO) versus placebo over 12 weeks from start of the investigational medication date (approximately 3 months) to test whether HMO can improve bowel motility in neurogenic bowel and bladder patients. Patients in the placebo arm of the study will be offered participation in the open label portion of the study immediately after their part in the control group is completed, they will receive HMO for 12 weeks. HMO sachets will be administered to determine the safety and efficacy of HMO relative to placebo in improving quality of life of neurogenic bowel and bladder patients by improving bowel motility and function.

Study Overview

• Status: Completed
• Conditions: Spinal Cord Injuries; Neurogenic Bowel; Bladder Dysfunction
• Intervention / Treatment: Dietary supplement: Human Milk Oligosaccharides (HMO); Other: Placebo

Detailed Description

Spinal cord injury (SCI) is a life changing neurologic diagnosis that affects multiple body systems. Urinary tract infections (UTIs) are almost a universal complication of SCI with bladder dysfunction, and a significant cause of morbidity in those with SCI. Recurrent UTIs requires multiple courses of antibiotic therapy, increasing the incidence of multidrug-resistant bacteria. While curative antibiotic therapy is transiently effective, recurrences are frequent and bladder colonization is inevitable after SCI because of an impaired ability to empty the bladder. Meta-analysis of SCI and UTI have shown there is no evidence to support the use of prophylactic antibiotics. Although the exact mechanism of action is not fully understood, nearly all UTIs are caused by bacteria from the bowel. Therefore, addressing the impaired bowel function in SCI patients would not only improve this debilitating condition but also reduce UTI's and the need for antibiotic therapy.

Since prebiotics are metabolised by bacteria in the colon and their by-products promote intestinal peristalsis and can relieve constipation, they could represent an effective option to treat bowel dysfunction in SCI patients. The study's aim is to improve bowel motility in SCI patients with neurogenic bowel impairments by using 2'-O-fucosyllactose and lacto-N-neotetraose, novel human milk oligosaccharide (HMO) sugars that have already been shown to very specifically modulate intestinal bacteria. In the bowel, the HMO would induce an increase in bifidobacteria, which would further produce short chain fatty acids such that stimulate bowel motility and other beneficially regarded bacteria.

The Principal Investigator/Sponsor will test this potential in a pilot clinical study with a HMO mix that has shown to promote bifidobacteria (Ellison 2016). These HMO compounds are structurally different from the less pure, plant-or bovine dairy-based prebiotics that are currently used in other human applications, and are safe, well tolerated, food grade substances. They have been shown to soften the stools in healthy adults and reduce constipation; therefore, it is expected they will positively impact the quality of life of neurogenic bowel and bladder patients by improving bowel motility, and also reducing the associated co-morbidity of recurrent urinary tract infections. The study will collect data on a sample of up to 60 patients with SCI and neurogenic bowel dysfunction scores of >13.

The Principal Investigator/Sponsor will assess the HMO's effects on the quality of life, intestinal bacterial composition, bowel motility, and associated co-morbidities such as urinary tract infections (UTIs). In the longer term this is expected to reduce UTI occurrence due to reduced pathogen loading; as a consequence, reduce antibiotic use and levels of drug resistant bacteria.If the study If successful, the results outlining its significance could be forwarded to the senior management team at the recruiting hospital to be considered as a potential management tool in the care of patients with SCI.

This study will assess faecal and urine samples at four time points for microbiome and other analyses at baseline, 4 weeks, 8 weeks (approximately 2 months) and 12 weeks (approximately 3 months) from the date of starting the study product. Prior to commencing their treatment, and at weeks 8 and 12, the research coordinator (blinded to the randomisation) will assess patients using various bowel, bladder and quality of life questionnaires during clinic visits, at home or by telephone interview.

The type, level, and completeness of injury will be documented, and the type of bowel and bladder dysfunction (upper or lower motor neuron) will be classified and, if necessary, updated at each in-person visit. Each participant will be provided with instructions and study schedule.

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. Study visits may be in person or over the phone. 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 53 weeks, approximately 12 months

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Alexandria Roa Agudelo; Phone Number: 42696 519-646-6100; Email: Alexandria.RoaAgudelo@sjhc.london.on.ca
• Study Contact Backup: Name: Jeremy P Burton, PhD; Phone Number: 61365 519-646-6000; Email: Jeremy.Burton@LawsonResearch.com

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6C0A7
      • Parkwood Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18 years old
• SCI of at least 3 months duration
• Neurogenic bowel dysfunction scores of >10 OR 4 or less bowel movements per week, OR requires a suppository to have a bowel movement

Exclusion Criteria:

• Pregnancy
• Inability to understand and respond to the provided questionnaires
• Carcinomas during the last 5 years
• Bowel surgery
• Crohn ́s disease or other bowel conditions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Human Milk Oligosaccharide (HMO); 10 g sachet, self-administered for 3 months. 2'-O-fucosyllactose and lacto-N-neotetraose, novel human milk oligosaccharide (HMO) sugars have already been shown to very specifically modulate intestinal bacteria, namely the beneficially viewed bifidobacteria, in clinical studies in adults. Modulating bifidobacteria increases the levels of specific short chain fatty acids (SCFAs), such as butyrate, propionate and acetate.These SCFAs have been shown to stimulate colonic sodium and fluid absorption and exert proliferative effects on the colonocyte in experimental animal studies since the 1990s (Scheppach 1994). Therefore, increasing their levels would lead to an improvement in intestinal motility, as has been summarised previously (Koh 2016)	Dietary supplement: Human Milk Oligosaccharides (HMO); Sachet containing 10 grams of HMO
Placebo Comparator: Placebo; 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; Sachet manufactured to mimic 10g of HMO; Other Names: Placebo for HMO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bowel motility	Improvement of 25-30% in our study population in the neurogenic bowel function of our intervention study group after treatment, will be measured by the Neurogenic Bowel dysfunction score. Neurogenic Bowel Dysfunction score will be measured by a symptom-based questionnaire that scores 10 variables to attain a total score between 0 and 47. It includes frequency of bowel movements, time of defecation, evacuation and incontinence.	12 weeks
Neurogenic bowel dysfunction score (NBD)	The change in this assessment from baseline to end of study will help determine the improvement in bowel motility. It is a symptom-based questionnaire that scores 10 variables to attain a total score between 0 and 47. It includes frequency of bowel movements, time of defecation, evacuation and incontinence.	12 weeks
Change in method of bowel assistance	Medications required, home remedies used, other methods of assistance will be recorded in a study questionnaire.	12 weeks
Duration of bowel routine	Measured by the NBD questionnaire.	12 weeks
Episodes of incontinence	Will be measured in time between bowel movements by the NBD questionnaire.	12 weeks
Frequency of bowel movements per week	Will be measured by the NBD questionnaire.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiome changes from baseline to end of study	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. Of particular interest may be the Enterobacteriaceae like Escherichia coli that cause UTI. Units of measure via culture are colony forming units per g (cfu/g).	12 weeks
Changes in pain	A modified International Spinal Cord Injury Pain Basic Dataset version 2.0 questionnaire will be used. The first part of the questionnaire is a scale that ranges from 1-10, with 1 stating their pain is not interfering with their daily activities, and 10 stating extreme interference. The second part is a table that lists different areas of the body and has the participant check off whether they feel pain in the right, middle, or left side of each body area. Pain type will be assessed by the referring clinician and documented in a study CRF.	12 weeks
Change in sleep	will be documented in the International Spinal Cord Injury Pain Basic Dataset v2.0 questionnaire. The question scales from 1 - 10, 1 stating that pain has had no interference with the participant getting a good night's sleep, and 10 stating major interference.	12 weeks
Change in mood	will be documented in the International Spinal Cord Injury Pain Basic Dataset v2.0 questionnaire. The answer will be measured in a scale from 1-10, 1 stating that pain has had no interference with their mood, and 10 stating major interference.	12 weeks
Quality of Life Measures survey	a general quality of life measures survey will be included in the study. The QOLS is scored by adding up the score on each item to yield a total score for the instrument. The cale includes 16 questions, each question can be answered from a range of 1-7 (1 being very unhappy, 7 being very happy) Scores can range from 16 to 112.	12 weeks
Number of participants reporting unexpected 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.	12 weeks

Collaborators and Investigators

• Sponsor: Lawson Health Research Institute
• Collaborators: St. Joseph's Health Care London; The W. Garfield Weston Foundation; Parkwood Hospital, London, Ontario
• Investigators: Principal Investigator: Jeremy P Burton, PhD, Lawson Health Research Institute

Publications and helpful links

General Publications

• Koh A, De Vadder F, Kovatcheva-Datchary P, Backhed F. From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. Cell. 2016 Jun 2;165(6):1332-1345. doi: 10.1016/j.cell.2016.05.041.
• Taweel WA, Seyam R. Neurogenic bladder in spinal cord injury patients. Res Rep Urol. 2015 Jun 10;7:85-99. doi: 10.2147/RRU.S29644. eCollection 2015.
• Krogh K, Christensen P, Sabroe S, Laurberg S. Neurogenic bowel dysfunction score. Spinal Cord. 2006 Oct;44(10):625-31. doi: 10.1038/sj.sc.3101887. Epub 2005 Dec 13.
• Christensen P, Bazzocchi G, Coggrave M, Abel R, Hultling C, Krogh K, Media S, Laurberg S. A randomized, controlled trial of transanal irrigation versus conservative bowel management in spinal cord-injured patients. Gastroenterology. 2006 Sep;131(3):738-47. doi: 10.1053/j.gastro.2006.06.004.
• Christensen P, Bazzocchi G, Coggrave M, Abel R, Hulting C, Krogh K, Media S, Laurberg S. Outcome of transanal irrigation for bowel dysfunction in patients with spinal cord injury. J Spinal Cord Med. 2008;31(5):560-7. doi: 10.1080/10790268.2008.11754571.
• Tulsky DS, Kisala PA, Tate DG, Spungen AM, Kirshblum SC. Development and psychometric characteristics of the SCI-QOL Bladder Management Difficulties and Bowel Management Difficulties item banks and short forms and the SCI-QOL Bladder Complications scale. J Spinal Cord Med. 2015 May;38(3):288-302. doi: 10.1179/2045772315Y.0000000030.
• 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.
• 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.
• 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.
• Reid G, Burton JP. Urinary incontinence: Making sense of the urinary microbiota in clinical urology. Nat Rev Urol. 2016 Oct;13(10):567-8. doi: 10.1038/nrurol.2016.182. Epub 2016 Sep 20. No abstract available.
• Whiteside SA, Razvi H, Dave S, Reid G, Burton JP. The microbiome of the urinary tract--a role beyond infection. Nat Rev Urol. 2015 Feb;12(2):81-90. doi: 10.1038/nrurol.2014.361. Epub 2015 Jan 20.
• Scheppach W. Effects of short chain fatty acids on gut morphology and function. Gut. 1994 Jan;35(1 Suppl):S35-8. doi: 10.1136/gut.35.1_suppl.s35.

Helpful Links

• The first canadian national atlas of Spinal Cord Injury Rehabilitation from a collaborative community of practice to provide the best care to individuals living with the consequences of spinal cord injury.

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2021
• Primary Completion (Actual): June 29, 2023
• Study Completion (Actual): October 1, 2023

Study Registration Dates

• First Submitted: June 4, 2019
• First Submitted That Met QC Criteria: June 13, 2019
• First Posted (Actual): June 14, 2019

Study Record Updates

• Last Update Posted (Estimated): December 13, 2023
• Last Update Submitted That Met QC Criteria: December 12, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Central Nervous System Diseases; Nervous System Diseases; Gastrointestinal Diseases; Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Trauma, Nervous System; Spinal Cord Diseases; Wounds and Injuries; Spinal Cord Injuries; Neurogenic Bowel
• Other Study ID Numbers: 6170

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No