PediCRaFT: Pediatric Crohn's Disease Fecal Transplant Trial

Crohn Disease Clinical Trial

— PediCRaFT  

Official title:

PediCRaFT: Pediatric Crohn's Disease Fecal Microbiota Transplant Pilot Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03378167
• Other study ID #: 0000
• Status: Completed
• Phase: Phase 1
• Start date: December 1, 2018
• Est. completion date: September 30, 2023

Study information

• Verified date: October 2023
• Source: McMaster Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The objective of this study is to assess the feasibility of a novel colonic and oral fecal microbiota transplantation protocol for the treatment of active pediatric Crohn's disease (CD). Specifically, we will test the hypothesis that a protocol of combination fecal microbiota colonoscopic infusion and oral microbiota capsules (OMC), using live fecal material from anonymous unrelated donors, can improve the disease activity of pediatric CD patients.

Description:

Several recent studies have assessed the role of fecal microbiota transplantation (FMT) in the treatment of inflammatory bowel disease (IBD). IBD is a chronic autoimmune gastrointestinal disorder that has been associated with disease-specific microbial signatures in the host. The vast majority of literature on the therapeutic role of FMT has assessed its role in the treatment of acute Clostridium difficile colitis, but its effectiveness at treating this disease condition suggests a central role of the microbiome in host immune tolerance. A. Alterations in the IBD Microbiome Investigators have characterized specific alterations of the gut microbiota in ulcerative colitis and Crohn's disease, compared to healthy controls. Patients with active IBD may have a relative depletion in anaerobic microbes, such as Bacteroides vulgatus, Lachnospiraceae (p: Firmicutes), and an increase in Proteobacteria and Bacillus (p: Firmicutes). These microbial signatures of IBD have led to several hypotheses about the protective, and pathological roles of different resident intestinal bacterial species. Conte et al have suggested that B. vulgatus may have a protective role against colitis, downregulating inflammation. Other studies have suggested that dysbiosis in IBD leads to decreased production of key short-chain fatty acids, such as butyric acid metabolized by Faecalibacterium prausnitzii. Directly, butyric acid and other short-chain fatty acids are key substrates absorbed by colonocytes, and indirectly, butyrate may inhibit inflammatory processes in the intestinal mucosa by suppressing cytokines, like interleukin-8. These studies have attempted to define canonical "intestinal-microbial-immune axes," supporting the hypothesis that IBD may occur secondary to an altered microbiome in a genetically, immunologically susceptible host. This constant host-microbial cross-talk may thus be altered by the introduction of key bacterial species that are otherwise absent, or decreased as a consequence of active mucosal inflammation, in the IBD gut. While FMT would not provide targeted, species-specific inoculations, whole stool transplant would theoretically introduce a broad range of bacteria, including those that are theoretically "favorable" to the host. B. The Pediatric Microbiome Pediatric IBD, and the pediatric microbiome, have several unique features that suggest microbial-based therapies could be particularly effective. Crohn's disease and ulcerative colitis typically have a much more aggressive course in the pediatric age group, suggesting that the pediatric IBD phenotype may have a pathophysiology that is distinct from adult-onset IBD. In pediatric IBD, the early age of onset makes the cumulative burden of medications, nutritional impairment, and surgery greater. Several standard IBD medication therapies have unique, age-specific toxicities in children. The overlap of pediatric chronic disease with critical periods of growth, bone accretion, and psychosocial development can make disease exacerbations disproportionately affect a child's long-term outcome. The pediatric microbiome itself has key differences. The shorter latency of disease may offer a unique window to reverse an underlying state of "dysbiosis." The pediatric microbiome may be more malleable than a fully defined adult microbiome, and the relatively immature immune system of children may be more influenced by FMT. C. FMT for the Treatment of Pediatric IBD Four case series have been published for the treatment of pediatric ulcerative colitis (UC) and CD using FMT. Protocols varied between all studies, and three main routes of administration were used: serial enemas, serial enemas with supplementary colonoscopic administration, and nasogastric tube. The first published study, involved five enemas administered daily to 9 UC patients, ages 7-21. Outcomes included clinical improvement from baseline using Pediatric Ulcerative Colitis Activity Index (PUCAI) scores, at one-week, and one-month post-treatment. 6/9 patients maintained clinical response at their one-month follow-up assessment. In 2015, two case series of FMT for CD and UC patients were published. A single FMT infusion was administered via nasogastric tube (NGT) to 4 UC, and 9 CD patients. No clinical response was seen in UC through NGT administration. In contrast, remission was induced in 7/9 CD patients within 2-weeks post-treatment, with 5/9 maintaining remission at week 6 and week 12. The most recent pediatric case series from 2015 included a cohort of pediatric UC patients treated with oral 5-ASA monotherapy, who received a combination of serial FMT enemas and colonoscopic infusions. 3 patients were included; 100% went into clinical remission at week 2, sustained clinical remission at week 4, and had complete withdrawal of immunotherapy at time of publication. Within the limitations of this small case series, there was a correlation between the number of FMT administrations, and the duration of remission. Two single-center pediatric case reports have recently been published showing marked clinical improvement in two patients with severe colitis. A 2015 case report describes a 4-month old female presenting with an early-onset colitis with UC-like phenotype. The patient was refractory to treatment with azathioprine and corticosteroids, and did not respond to further treatment with probiotics, a trial of amino-acid based formula, or infliximab. 2 serial FMT infusions with anonymous donor stool were administered via colonoscope, and a subsequent 5 infusions via nasoduodenal tube. These interventions led to clinical improvement, and complete resolution of histopathologic changes 6-months post FMT. A recent, 2016 case report describes an 11-year old female with corticosteroid-dependent UC who was unresponsive to treatment with 5-aminosalicylic acid and tacrolimus14. An initial FMT using her father's donor stool was performed via colonoscopy, and subsequent daily FMTs via fecal retention enema over the next 4 days, followed by 11 additional FMTs via retention enema every 2 to 4 weeks over 10 months. The patient remained in clinical remission at 40 weeks post final FMT, and showed complete endoscopic healing. D. Clinical Observations from Published Pediatric IBD FMT Studies Despite promising results, major drawbacks to these four pediatric studies include small sample sizes and their open label study design. Studies of clinical response demand a blinded study protocol, particularly given that many patients who enrol in FMT studies are a self-selected group, who already believe in the therapeutic value of "natural" treatments. Further, inflammatory bowel disease has well-described associations between clinical symptoms, mucosal disease activity and underlying stressors; thus, patient bias may have a significant influence on self-reported PUCAI/PCDAI (Pediatric Crohn's Disease Activity Index) scores when measuring clinical response. In addition, it is also important to note that success of FMT for IBD reflected in the aforementioned studies may reflect a propensity for studies with positive results to be published and unreported, unsuccessful studies may exist.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: September 30, 2023
• Est. primary completion date: September 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 17 Years

Eligibility

Inclusion Criteria:

• Pediatric patients
• =3yo
• Crohn's disease, or IBD-Unclassified favoring Crohn's disease (as deemed by the patient's primary pediatric gastroenterologist)
• Active symptoms

Exclusion Criteria:

• Currently enrolled in another clinical trial
• Unable to give informed consent or assent
• Severe comorbid medical illness (at discretion of patient's primary pediatric gastroenterologist)
• Concomitant Clostridium difficile infection
• Severe Crohn's disease flare requiring hospitalization
• Commenced new, or temporary medical therapies (ie. corticosteroids, antibiotics, prebiotics) within 4 weeks prior to commencing the trial; NB: Weaning doses of corticosteroid will be permitted (= 0.25mg/kg/day)

Related Conditions & MeSH terms

• Colitis
• Crohn Disease
• Inflammatory Bowel Diseases
• Intestinal Diseases
• Pediatric Crohns Disease

Intervention

Biological:
• MICROBIOTA
Fecal microbiota enema (RBX2660) infused via colonoscope x 1 + oral microbiota capsules (RBX7455) x 6 weeks. The fecal microbiota enema (RBX2660) prepared by Rebiotix has received Health Canada Clinical Trials Application (CTA), and U.S. Food and Drug Administration Investigational New Drug Application (IND) approval for clinical trials in patients with recurrent Clostridium difficile infection, and pediatric inflammatory bowel disease. The human-derived fecal oral microbiota capsule (RBX7455) has received U.S. Food and Drug Administration Investigational New Drug Application (IND) approval for clinical trials in patients with recurrent Clostridium difficile infection.
• PLACEBO
Placebo enema (Normal Saline) infused via colonoscope x 1 + oral placebo capsules (dextrose-containing capsules) x 6 weeks. NOTE: Patients randomized to the control group will be given the option of receiving open-label treatment, with the intervention therapy, either: upon completion of the trial, or if they are removed from the trial due to disease exacerbation or other adverse event, at the discretion of their primary gastroenterologist.

Locations

Country	Name	City	State
Canada	McMaster Children's Hospital	Hamilton	Ontario
Canada	Centre Hospitalier Universitaire Sainte-Justine, University of Montreal	Montréal	Quebec

Sponsors (2)

Lead Sponsor	Collaborator
McMaster Children's Hospital	St. Justine's Hospital

Country where clinical trial is conducted

Canada, 

References & Publications (23)

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Hyams JS, Ferry GD, Mandel FS, Gryboski JD, Kibort PM, Kirschner BS, Griffiths AM, Katz AJ, Grand RJ, Boyle JT, et al. Development and validation of a pediatric Crohn's disease activity index. J Pediatr Gastroenterol Nutr. 1991 May;12(4):439-47. — View Citation

Kellermayer R, Nagy-Szakal D, Harris RA, Luna RA, Pitashny M, Schady D, Mir SA, Lopez ME, Gilger MA, Belmont J, Hollister EB, Versalovic J. Serial fecal microbiota transplantation alters mucosal gene expression in pediatric ulcerative colitis. Am J Gastroenterol. 2015 Apr;110(4):604-6. doi: 10.1038/ajg.2015.19. No abstract available. — View Citation

Kelly CR, Ihunnah C, Fischer M, Khoruts A, Surawicz C, Afzali A, Aroniadis O, Barto A, Borody T, Giovanelli A, Gordon S, Gluck M, Hohmann EL, Kao D, Kao JY, McQuillen DP, Mellow M, Rank KM, Rao K, Ray A, Schwartz MA, Singh N, Stollman N, Suskind DL, Vindigni SM, Youngster I, Brandt L. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014 Jul;109(7):1065-71. doi: 10.1038/ajg.2014.133. Epub 2014 Jun 3. — View Citation

Kunde S, Pham A, Bonczyk S, Crumb T, Duba M, Conrad H Jr, Cloney D, Kugathasan S. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J Pediatr Gastroenterol Nutr. 2013 Jun;56(6):597-601. doi: 10.1097/MPG.0b013e318292fa0d. — View Citation

Lobaton T, Bessissow T, De Hertogh G, Lemmens B, Maedler C, Van Assche G, Vermeire S, Bisschops R, Rutgeerts P, Bitton A, Afif W, Marcus V, Ferrante M. The Modified Mayo Endoscopic Score (MMES): A New Index for the Assessment of Extension and Severity of Endoscopic Activity in Ulcerative Colitis Patients. J Crohns Colitis. 2015 Oct;9(10):846-52. doi: 10.1093/ecco-jcc/jjv111. Epub 2015 Jun 26. — View Citation

Machiels K, Joossens M, Sabino J, De Preter V, Arijs I, Eeckhaut V, Ballet V, Claes K, Van Immerseel F, Verbeke K, Ferrante M, Verhaegen J, Rutgeerts P, Vermeire S. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. 2014 Aug;63(8):1275-83. doi: 10.1136/gutjnl-2013-304833. Epub 2013 Sep 10. — View Citation

Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, Xavier RJ, Teixeira MM, Mackay CR. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009 Oct 29;461(7268):1282-6. doi: 10.1038/nature08530. — View Citation

Orenstein R, Dubberke E, Hardi R, Ray A, Mullane K, Pardi DS, Ramesh MS; PUNCH CD Investigators. Safety and Durability of RBX2660 (Microbiota Suspension) for Recurrent Clostridium difficile Infection: Results of the PUNCH CD Study. Clin Infect Dis. 2016 Mar 1;62(5):596-602. doi: 10.1093/cid/civ938. Epub 2015 Nov 12. — View Citation

Pai N, Popov J. Protocol for a randomised, placebo-controlled pilot study for assessing feasibility and efficacy of faecal microbiota transplantation in a paediatric ulcerative colitis population: PediFETCh trial. BMJ Open. 2017 Aug 21;7(8):e016698. doi: 10.1136/bmjopen-2017-016698. — View Citation

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Shimizu H, Arai K, Abe J, Nakabayashi K, Yoshioka T, Hosoi K, Kuroda M. Repeated fecal microbiota transplantation in a child with ulcerative colitis. Pediatr Int. 2016 Aug;58(8):781-5. doi: 10.1111/ped.12967. Epub 2016 Jun 21. — View Citation

Suskind DL, Brittnacher MJ, Wahbeh G, Shaffer ML, Hayden HS, Qin X, Singh N, Damman CJ, Hager KR, Nielson H, Miller SI. Fecal microbial transplant effect on clinical outcomes and fecal microbiome in active Crohn's disease. Inflamm Bowel Dis. 2015 Mar;21(3):556-63. doi: 10.1097/MIB.0000000000000307. — View Citation

Suskind DL, Singh N, Nielson H, Wahbeh G. Fecal microbial transplant via nasogastric tube for active pediatric ulcerative colitis. J Pediatr Gastroenterol Nutr. 2015 Jan;60(1):27-9. doi: 10.1097/MPG.0000000000000544. — View Citation

Tedelind S, Westberg F, Kjerrulf M, Vidal A. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: a study with relevance to inflammatory bowel disease. World J Gastroenterol. 2007 May 28;13(20):2826-32. doi: 10.3748/wjg.v13.i20.2826. — View Citation

Turner D, Otley AR, Mack D, Hyams J, de Bruijne J, Uusoue K, Walters TD, Zachos M, Mamula P, Beaton DE, Steinhart AH, Griffiths AM. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology. 2007 Aug;133(2):423-32. doi: 10.1053/j.gastro.2007.05.029. Epub 2007 May 21. — View Citation

Vandenplas Y, Veereman G, van der Werff Ten Bosch J, Goossens A, Pierard D, Samsom JN, Escher JC. Fecal Microbial Transplantation in Early-Onset Colitis: Caution Advised. J Pediatr Gastroenterol Nutr. 2015 Sep;61(3):e12-4. doi: 10.1097/MPG.0000000000000281. No abstract available. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Monthly Recruitment Rate	Assessment of recruitment rate (based on patients meeting all eligibility criteria who were approached for trial entry)	30 weeks
Primary	Dropout Rate Post Enrolment	Rate of patients leaving the trial (patient, or protocol directed exclusion) after enrolment	30 weeks
Primary	Rate of Patient Protocol Adherence	Rate of patients providing all required blood, stool and urine samples per protocol	30 weeks
Primary	Rate of Adverse Events	Rate of patients requiring hospitalization, or experiencing PCDAI increase =20 x 2 successive measures	30 weeks
Secondary	Clinical: Improvement in Disease Symptoms	PCDAI decrease =15 from baseline: Week 6, Week 30	Baseline, Week 6, Week 30
Secondary	Clinical: Remission in Disease Symptoms	PCDAI = 10: Week 6, Week 30	Week 6, Week 30
Secondary	Clinical: Improvement in Serum Inflammatory Markers	Decrease C-reactive protein from baseline: Week 6, Week 30	Baseline, Week 6, Week 30
Secondary	Clinical: Improvement in Mucosal Inflammatory Markers	Decrease fecal calprotectin from baseline: Week 6, Week 30	Baseline, Week 6, Week 30
Secondary	Clinical: Change in Urine Metabolomics	Change in urine metabolite profile from baseline: Week 6, Week 30	Baseline, Week 6, Week 30
Secondary	Clinical: Change in Fecal Microbiome	Change in fecal 16s rRNA + metagenomics profile baseline: Week 6, Week 30	Baseline, Week 6, Week 30