Hirschsprung's Disease
Conditions
Keywords
Hirschsprung disease, Congenital aganglionosis, Butyrate, Intestinal dysmotility
Brief summary
Hirschsprung's disease (HD) is a rare congenital disorder (1/5000) defined by the absence of ganglion cells in the submucosal and myenteric plexuses along a variable length of the digestive tract. This abnormality most often leads to distal bowel obstruction in newborns with delayed passage of meconium. Treatment is surgical and consists in the resection of the aganglionic and transitional segments. However, the postoperative outcomes remain unpredictable. Despite complete curative surgery, intestinal functional disorders persist in 40-50% of children, mainly obstructive symptoms, and 15-25% of children will also develop postoperative enterocolitis, which remains the leading cause of mortality in HD. There is currently no preventive treatment of these intestinal functional disorders and enterocolitis. Recent preclinical studies have identified butyrate, a short-chain fatty acid, as a regulator of intestinal homeostasis in newborns and adults, particularly involved in maintaining epithelial integrity, regulating the immune response, and regulating the phenotype of the digestive tract and its functions. Butyrate regulates intestinal epithelial barrier functions by strengthening intestinal permeability, and regulates the functions of the enteric nervous system and its phenotype. In newborn rats, butyrate enemas increase the proportion of nitrergic (and also cholinergic) neurons, leading to improved nitrergic neurotransmission and, ultimately, improved colonic transit time. Our main hypothesis is that recto-colonic butyrate enemas administered preoperatively in newborns and infants with HD should reduce postoperative functional intestinal motility disorders and enterocolitis in the short, medium, and long terms. The BUTYHIRSCH project is a phase III, multicenter, national (24 pediatric surgery departments), controlled, randomized, open-label, prospective clinical drug trial. Fifty-eight patients will be included over a period of two years. The primary objective is to determine the short-term efficacy of preoperative butyrate enemas in reducing the time to postoperative bowel recovery. The secondary objectives are to determine the medium- and long-term efficacy of preoperative butyrate enemas on 1) the incidence of postoperative obstructive functional symptoms, 2) the stool consistency, 3) the total postoperative intestinal transit time, 4) the incidence and severity of postoperative enterocolitis, and 5) the intestinal inflammation. Patients will be randomized into 2 groups: the experimental group (29 patients) receiving a sodium butyrate recto-colic enema for 24 days before curative surgery and the control group (29 patients). Postoperative clinical follow-up will be prospective over 3 years in order to collect data on complications such as intestinal motility disorders and enterocolitis. No invasive or radiation-based examinations will be performed postoperatively. Additional investigative procedures will include assessment of total postoperative intestinal transit time using carmine red transit and assessment of intestinal inflammation by measuring fecal calprotectin. examinations will be performed postoperatively. Additional investigative procedures will include assessment of total postoperative intestinal transit time using carmine red transit and assessment of intestinal inflammation by measuring fecal calprotectin.
Interventions
DRUGSodium Butyrate
Daily recto-colonic enemas of sodium butyrate (1.1 g/L solution, 10 mL/kg) administered for 24 days (±4 days) before curative surgery.
OTHERroutine management
Standard preoperative management for Hirschsprung's disease including colonic decompressions/irrigations before curative surgery.
Sponsors
Assistance Publique Hopitaux De Marseille
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomized, controlled, open-label, parallel-group, multicenter phase III study comparing preoperative sodium butyrate enemas plus routine management versus routine management alone.
Eligibility
Sex/Gender
ALL
Age
7 Days to 17 Years
Healthy volunteers
No
Inclusion criteria
The inclusion criteria are: * Newborn with a diagnosis of Hirschsprung's disease the 2 first months of life managed successfully with colonic decompressions/irrigations before curative surgery (usually performed 1-3 times a day) * 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, 2009) * Uncomplicated form (without enterocolitis as defined by the HAEC score 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 The non-inclusion criteria are: * 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 (as defined by the HAEC score) * 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) * Neonates under tutorship or guardianship Minors cannot be excluded because they are the population to be studied. The non-inclusion criteria are: * 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 (as defined by the HAEC score) * 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) * Neonates under tutorship or guardianship Minors cannot be excluded because they are the population to be studied. The non-inclusion criteria are: * 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 (as defined by the HAEC score) * 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) * Neonates under tutorship or guardianship Minors cannot be excluded because they are the population to be studied.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Up to 30 days after surgery | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Postoperative functional intestinal obstructive symptoms evaluated at each medical appointment | 3-4, 5, 6, 9, 12, 18, 24 and 36 months of life | Functional intestinal obstructive symptoms are ongoing severe constipation, abdominal distension, bloating/soiling with or without foul-smelling stools/diarrhoea, functional bowel obstruction without bowel movements, after exclusion of surgical complications. |
| The stool consistency evaluated using the validated 'Bristol' stool form scale modified for children at each medical appointment. | 3-4, 5, 6, 9, 12, 18, 24 and 36 months of life | The stool consistency is evaluated using the 'Bristol' stool form scale modified for children. Stool consistency is correlated with total gastrointestinal transit time in children (Russo et al., 2013). The 'Bristol' stool form scale evaluates the stool consistency and is a six-point scale: 3 and 4 are considered as normal stool consistency and reflect a normal gastrointestinal transit time. |
| The red carmine total intestinal transit time | 1 month after surgery, 6 months of life (after diversification), 18 months of life and 36 months of life. | The red carmine total transit time is an easy, non-invasive, and reproducible method to measure the total transit time in infants. This test consists in the per os administration of the dye (red carmine) by the parents at home. The capsule containing 250mg of red carmine will be opened and the red carmine powder will be mixed with milk (breast milk or formula) or mixed with food. The capsules of red carmine 250 mg will be prepared according to the French ANSM Formulaire National (see appendix). Capsules will be individually packaged in airtight, UV-protected blister packs labelled with the qualitative and quantitative composition. This preparation and the distribution will be realized by the Sponsor according to applicable regulation and Good Practices. |
| HAEC episode(s) defined by the HAEC score (Pastor et al., 2009; Frykman et al., 2017) and grading of HAEC (Gosain et al, 2017). | From surgery up to 3 years postoperatively | HAEC is defined by the HAEC score, a standardized definition for HAEC using clinical, biological, and radiological criteria The most important diagnostic criteria for HAEC were identified from a larger pool of potential diagnostic items through a consensus approach using the Delphi method (Pastor et al., 2009). A HAEC score of 10 or greater was initially chosen to indicate a diagnosis of HAEC, but the cut-off of 10 was not validated in clinical study at that time. Recently, the HAEC score was revised in a multicenter study (Frykman et al., 2017). A HAEC score of 4 maximized the sum of sensitivity (84%) and specificity (98.6%) while the previously cut-off of 10 showed lower sensitivity (42%) with perfect specificity. Grading of HAEC will be also established, from grade I (possible HAEC) to grade III (severe). Grading defines the guidelines for HAEC management (Gosain et al, 2017). |
| The fecal calprotectin | at the time of curative surgery, 1 month after surgery (2-3 months of life) and 6 months of life (after diversification) | The fecal calprotectin concentrations will be measured using an enzyme-linked immunosorbent assay (ELISA). The stool samples will be sent to the laboratory of biochemistry of the Assistance Publique-Hôpitaux de Marseille where the procedure will be performed. The fecal calprotectin is an established biomarker of acute and chronic gut inflammation. However, the fecal calprotectin concentrations have never been studied in HD infants. In necrotizing enterocolitis in premature newborns, current evidence suggests that fecal calprotectin is elevated but its significance as an early screening marker remains unknown and specific cut-off values are needed (Pergialiotis et al., 2016). |
Countries
France
Contacts
CONTACTANNE DARIEL, MD
Outcome results
None listed