Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung's Disease

Hirschsprung's Disease Clinical Trial

— Buty-Hirsch  

Official title:

Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung's

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03660176
• Other study ID #: 2018-02
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: January 2, 2019
• Est. completion date: July 2, 2024

Study information

• Verified date: August 2018
• Source: Assistance Publique Hopitaux De Marseille
• Contact: ANNE DARIEL, MD
• Phone: +33 491964885
• Email: Anne.DARIEL[@]ap-hm.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Hirschsprung's disease (HD) is a rare disease defined as a congenital absence of enteric ganglia, resulting usually in neonatal bowel obstruction. The current treatment is the operative removal of the aganglionic bowel and anastomosis to the ganglionic zone considered as 'healthy'. However, postoperative course remains unpredictable.

Functional intestinal disorders are present in up to 45% of patients and can occur in the immediate postoperative period or few weeks/years later.

Until now, there are neither predictive factors of postoperative digestive complications nor established treatment for postoperative dysmotility in HD. Abnormalities in enteric nervous system (ENS) phenotype and functions in the 'healthy' ganglionic segment are increasingly suspected to be directly responsible for postoperative intestinal dysfunctions in HD. Therefore, approaches aimed at restoring the nitrergic phenotype could be of major therapeutical interest. Among targets regulating the nitrergic phenotype of ENS are the microbiota and/or derived metabolites. Indeed preclinical animal models deficient in bacterial sensing molecules have a loss of nitrergic neurons and reduced colonic transit. Conversely, microbiota transfer to newborn germ-free mice restored colonic transit time. Alternatively the investigators has shown that bacterial metabolites such as short-chain fatty acids, in particular butyrate, can increase nitrergic phenotype and enhance colonic motility in a gut immaturity animal model. Therefore the investigators hypothesize preoperative butyrate enema will reduce postoperative intestinal complications at short-term and medium/long-term.

Description:

Hirschsprung's disease (HD) is a rare disease (1/5000) defined as a congenital absence of enteric ganglia, secondary to developmental defects in colonization of the gut by the enteric nervous system (ENS) and in its maturation, resulting usually in neonatal bowel obstruction. The current treatment is the operative removal of the aganglionic bowel and anastomosis to the ganglionic zone considered as 'healthy'. However, postoperative course remains unpredictable. Functional intestinal disorders, mainly functional obstructive symptoms, are present in up to 45% of patients and can occur in the immediate postoperative period or few weeks/years later. Postoperative enterocolitis also occurs in up to 25% of patients following a similar time course. Until now, there are neither predictive factors of postoperative digestive complications nor established treatment for postoperative dysmotility in HD, in part due to a lack of understanding of the physiopathological mechanisms involved. Abnormalities in ENS phenotype and functions in the 'healthy' ganglionic segment are increasingly suspected to be directly responsible for postoperative intestinal dysfunctions in HD. In an ongoing multicentre study (Ente-Hirsch project), he investigators have identified a reduced density of nitrergic enteric neurons associated with a reduced neuromuscular transmission that could account for digestive dysfunctions in HD. Therefore, approaches aimed at restoring the nitrergic phenotype could be of major therapeutical interest. Among targets regulating the nitrergic phenotype of ENS are the microbiota and/or derived metabolites. Indeed preclinical animal models deficient in bacterial sensing molecules have a loss of nitrergic neurons and reduced colonic transit. Conversely, microbiota transfer to newborn germ-free mice restored colonic transit time. Alternatively he investigators has shown that bacterial metabolites such as short-chain fatty acids, in particular butyrate, can increase nitrergic phenotype and enhance colonic motility in a gut immaturity animal model. Therefore the investigators hypothesize preoperative butyrate enema will reduce postoperative intestinal complications at short-term and medium/long-term.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 58
• Est. completion date: July 2, 2024
• Est. primary completion date: January 2, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 17 Years

Eligibility

Inclusion Criteria:

• Newborn with a diagnosis of Hirschsprung's disease the 2 first months of life,

• Born at or after 35 weeks of gestation (37 weeks of amenorrhea),

• With a short-segment Hirschsprung's disease limited to the rectum and/or sigmoid colon diagnosed on rectal biopsy with established pathological criteria (absence of ganglionic cells +/- hypertrophic extrinsic nerve fibres) (Kapur, Sem Ped Surg 2009),

• Managed successfully with colonic decompressions/irrigations before curative surgery (usually performed 2-3 times a day),

• Uncomplicated form (without enterocolitis and/or diverting colostomy),

• Curative surgery and follow-up in one of the included centres,

• With consent of the 2 parents or legal(s) representative(s),

• Absence of severe or lethal associated malformations,

• Affiliation with the French social security system.

Exclusion Criteria:

• - Long segment Hirschsprung's disease prior to the junction between the left colon and the sigmoid colon,

• Hirschsprung's disease not managed successfully with colonic decompressions/irrigations and requiring a diverting colostomy before the curative surgery,

• Hirschsprung-associated enterocolitis occurring before the randomization,

• Severe or lethal associated malformation, including Down syndrome,

• Intestinal associated malformations (intestinal atresia, gastroschisis, omphalocele, intestinal malrotation and volvulus),

• Any pathological condition that can modify intestinal motility or intestinal transit time (cystic fibrosis, hypothyroidism),

• Refusal of parent(s) or legal representative(s).

• Patients under curatorship or tutorship

Related Conditions & MeSH terms

• Hirschsprung Disease
• Hirschsprung's Disease

Intervention

Drug:
• butyrate enemas + routine management
10ml/kg volume of butyrate enemas in addition to the colonic irrigations

Other:
• routine management
the colonic irrigations

Locations

Country	Name	City	State
France	Assistance Publique Des Hopitaux de Marseille	Marseille	Paca

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique Hopitaux De Marseille

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The time to recovery of bowel function after the curative surgery. A 25% decrease of the time to recovery of bowel function in the experimental group as compared to the control group will be considered as clinically effective.	The recovery of bowel function is defined as follows: Tolerance of 2 feeds at full ration (as before surgery, breast-feeding or bottle-feeding),; And passing stools.; The time to recovery of bowel function will be measured in hours from the end of the curative surgery.	5 YEARS
Secondary	The red carmin total transit time will be measured before the surgery	After randomisation (and before the first butyrate enema) Before the curative surgery	5 YEARS
Secondary	The postoperative medium/long-term efficacy of butyrate enemas	Postoperative functional intestinal obstructive symptoms evaluated at each medical appointment The stool consistency evaluated using the validated 'Amsterdam' infant stool form scale at each medical appointment.	5 YEARS