Effects of Butyrate Enemas on Postoperative Intestinal Motility Disorders in Hirschsprung's Disease
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 58
- 试验地点
- 2
- 主要终点
- 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.
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 7 Days 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- 未提供
研究组 & 干预措施
routine management
Participants receive routine preoperative management for Hirschsprung's disease before curative surgery, without butyrate enemas.
干预措施: routine management (Other)
EXP GROUP
Participants receive sodium butyrate recto-colonic enemas daily for 24 days before curative surgery in addition to routine preoperative management.
干预措施: routine management (Other)
EXP GROUP
Participants receive sodium butyrate recto-colonic enemas daily for 24 days before curative surgery in addition to routine preoperative management.
干预措施: Sodium Butyrate (Drug)
结局指标
主要结局
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.
时间窗: 5 YEARS
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.
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.
时间窗: 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.
次要结局
- The red carmin total transit time will be measured before the surgery(5 YEARS)
- The postoperative medium/long-term efficacy of butyrate enemas(5 YEARS)
- Postoperative functional intestinal obstructive symptoms evaluated at each medical appointment(3-4, 5, 6, 9, 12, 18, 24 and 36 months of life)
- 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 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.)
- 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)
- 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))