Clinical trial NCT01587846: Lactobacillus Reuteri in Treatment of Functional Abdominal Pain and Chronic Constipation in Children
Official title: Lactobacillus Reuteri in Treatment of Functional Abdominal Pain and Chronic Constipation in Children - Randomized, Double Blind, Placebo Controlled Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Abdominal Pain
Constipation - Functional
Keywords: abdominal pain, constipation, Lactobacillus reuteri
Lead sponsor: Sisters of Mercy University Hospital
Sponsor class: OTHER
Collaborators: name: BioGaia AB
First posted: 2012-04-30
Enrollment: 300
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Beneficial therapeutic effect of probiotics has been reported in children with irritable bowel syndrome, but not consistently in other functional gastrointestinal disorders. Although there is evidence that probiotics increase stool frequency and decrease stool consistency in healthy individuals the evidence for efficacy in constipation is limited.

Children with functional abdominal pain (FAP) and constipation will be included in the study. Children with FAP will be randomized in one of two groups and will receive either L. reuteri in a daily dose of 108 CFU, or placebo during three months. Children with chronic constipation will receive either L. reuteri in a daily dose of 108 CFU and lactulose, or placebo and lactulose. Frequency and intensity of episodes of abdominal pain during and after intervention will be recorded in children with FAP. Frequency of defecation, stool consistency and need for lactulose will be recorded in children with chronic constipation.

Detailed description: Part I. Lactobacillus reuteri in treatment of functional abdominal pain in children

1. Introduction

   Probiotics are defined as live microorganisms which confer a beneficial health effect on a human host. Their beneficial effects are based on: promotion of resistance to enteric pathogens, prevention of small bowel bacterial overgrowth and immune system modulation. The most commonly used probiotics are bacteria of genera Lactobacillus or Bifidobacterium. Other nonpathogenic genera, including Escherichia, Enterococcus and Bacillus, and nonbacterial organisms, such as a nonpathogenic yeast Saccharomyces boulardii, have also been studied.

   A probiotic preparation must contain a certain minimum number of colony-forming units (CFU) per dose (4). Doses used in therapeutic and preventive trials vary. A daily intake of 1.000.000 to 1.000.000.000 CFUs is a reported minimum for therapeutic purposes. There is an increasing number of studies on beneficial effects of probiotics in treatment of acute infectious diarrhoea, and prevention of antibiotic associated diarrhoea. Role of probiotics in the treatment of functional GI disorders is still controversial.

   Recurrent or chronic abdominal pain affects 10-15% of school-age children. Functional abdominal pain (FAP) is defined as occasional or continuous abdominal pain with a frequency of at least once a weak during at least two months; most frequently the pain is located around umbilicus and not related to meals. Although visceral hypersensitivity plays a certain role in pathogenesis of a pain, FAP is probably a complex disorder. Irritable bowel syndrome is defined as abdominal pain or discomfort associated (in at least 25% of time) with two of these criteria: 1) relief after defecation, 2) change in stool frequency or 3) change in stool consistence.

   Pathogenesis of this disorder is complex and included interaction of psychosocial factors, motility disorder and visceral hypersensitivity. Therapeutic possibilities are pepermint oil, serotonin reuptake inhibitors and tricyclic antidepressants. Although there are studies confirming positive effect of probiotics in children and adults with IBS, there is no clear evidence for the effect of probiotics in FAP. The number of studies and the patients included is also relatively small to draw final conclusions.

   Therefore, the aim of this study is to investigate whether Lactobacillus reuteri could have a beneficial role in treatment of functional abdominal pain in children.
2. Study population

   All paediatric patients referred to a pediatric gastroenterologist for functional abdominal pain (age 4-18 years) at the Department of Paediatrics, Children's Hospital Zagreb, University Hospital "Sestre Milosrdnice".

   Their symptoms will be evaluated with the use of Rome III criteria for functional gastrointestinal disorders of children and visual-analogue scale (Wong-Baker faces pain rating scale) for pain.
3. Intervention

   All children with functional abdominal pain whose parents have signed an inform consent; will receive either probiotic or placebo for 3 months.

   As a part of randomized, double blind controlled trail, patients will be randomized into one group (A or B) and none of investigators or patients will know true nature of the product (active product or placebo).
4. Hypothesis

   L. reuteri can effectively treat functional abdominal pain in children.
5. Aims

   To evaluate the effect of L. reuteri on the number and severity of episodes pain in children with functional abdominal pain
6. Sample size for independent cohort study

   Probability of event in control group = 0,5 Difference between groups: 30% (ref. 18) Probability of event in experimental group = 0,35 Controls per case subject = 1 Alpha = 0,05 Power = 0,95

   For Fisher's exact tests:

   N (total) = 2x138 (69 per group)
7. Randomization

The trial will be prospective, randomized, double blind, placebo controlled study. Probiotics, Lactobacillus reuteri and placebo will be supplied by Biogaia, Stockholm, Sweden.

Randomization will be performed using computer generated numbers based on which every patient will get a number and receive the preparation successively. All products, probiotic and placebo will be packed in identical packages and will have identical smell and taste and have only mark "A" or "B", true nature of the preparation would not be revealed to investigators or to participants.

After all calculations and statistical analysis true nature of the preparations will be revealed in front of uninvolved witnesses.

BASELINE (VISIT 1): randomization VISIT 2: 4 weeks after randomization END OF STUDY (VISIT 3): End of study 3 months after baseline VISIT 4: 4 weeks after the end of study (16 weeks after the baseline).

All the symptoms will be monitored using diaries attached to protocol.

In order to achieve adherence to therapeutic protocol parents will be contacted by phone at least once in 7-10 days. Participants will be instructed to keep diary on a daily basis (adherence to therapy, pain diary). All patients will return packages with all used, and unused product.

Part II. Lactobacillus reuteri in treatment of chronic constipation in children - randomized, double blind, placebo controlled study

1. Introduction

   Defecation disorder is a frequent problem in childhood and in 90-95% of children presents a functional problem.

   Chronic constipation in childhood is defined with at least two of these criteria: 1) stools twice a weak of rarer, 2) at least one episode of fecal incontinence per weak after having already achieved toilet control, 3) stool withholding manoeuvres, 4) painful of difficult defecation, 5) presence of large fecal masses in rectum, 6) stool of a large caliber.

   In adults, there is some evidence that chronic constipation is related to a gastrointestinal flora with decreased number of lactobacilli and bifidobacteria and increased potentially pathogenic bacteria, yeast and fungi. Dysbiosis with increased clostridia has also been reported in children with chronic constipation. Majority of infants have higher frequency of defecation and the consistency of stools is softer in breast-fed infants in first months of life. Breast-fed babies produce more lactic acid in colon which decreases intestinal pH. As a result bifidobacteria proliferate. Also, colonic flora has been shown to influence peristalsis. Although there is evidence that lactobacilli and bifidobacteria increase stool frequency and decrease stool consistency in normal individuals the evidence for efficacy in constipation is limited.

   Therefore, the aim of this study is to investigate whether Lactobacillus reuteri could have a beneficial role in treatment of chronic constipation in children.
2. Study population

   All paediatric patients referred to a pediatric gastroenterologist for chronic constipation (age 2-18 years) at the Department of Paediatrics, Children's Hospital Zagreb, University Hospital "Sestre Milosrdnice".

   Their symptoms will be evaluated with the use of Rome III criteria for functional gastrointestinal disorders of children, Bristol scale for stool shape and consistence and visual-analogue scale (Wong-Baker faces pain rating scale) for pain.
3. Intervention

   All children with chronic constipation whose parents have signed an inform consent; will be randomly assigned into one of two following groups: probiotic or placebo.
   1. Group which will receive L. reuteri at a dose 100.000.000 CFU per dose plus lactulose in a dose 1-3 ml/kg, according to the stool frequency and consistency, for 3 months.
   2. Group which will receive placebo plus lactulose in a dose 1-3 ml/kg, according to the stool frequency and consistency, for 3 months.

   All children with a presence of a impacted stool in rectum (on digital rectal exam) at baseline will receive bisacodyl suppository for disimpaction. As a part of randomized, double blind controlled trail, patients will be randomized into one group (A or B) and none of investigators or patients will know true nature of the product (active product or placebo).
4. Hypothesis L. reuteri may effectively treat chronic constipation in children.
5. Aims To evaluate the effect of L. reuteri on the frequency and consistency of stools and episodes of pain in children with chronic constipation
6. Randomization: as in Part I.

BASELINE (VISIT 1): randomization According to the list of patients they will be randomized into two groups (A or B): "probiotic" group and "placebo" group.

VISIT 2: 4 weeks after randomization. END OF STUDY (VISIT 3): End of study 3 months after baseline. VISIT 4: 4 weeks after the end of study (16 weeks after the baseline).

All the symptoms will be monitored using diaries attached to protocol.

ETHICS: as in Part I.

ADHERENCE: as in Part I.

Eligibility criteria: Inclusion Criteria:

* Children with functional abdominal pain (age 4-18 years)
* Children with chronic constipation (age 2-18 years)

Exclusion Criteria:

* Immunodeficiency
* Receiving probiotic and/or prebiotic products 7 days prior to enrolment
* Neoplasms
* Chronic disorders
* Presence of "red flags":

  * Weight loss of more than 10%
  * Growth retardation or growth failure
  * Extraintestinal symptoms (fever, rash, joint pain, aphthae, affection of the urinary system)
  * Frequent vomiting
  * Abnormalities in laboratory findings (anemia, elevated ESR)
  * Abnormalities in clinical findings (organomegaly, perianal disease)

Primary outcomes:
measure: Intensity of abdominal pain
timeFrame: 3 months
measure: Severity of chronic constipation
timeFrame: 3 months
Secondary outcomes:
measure: Intensity of abdominal pain after treatment
timeFrame: 1 month
measure: Severity of chronic constipation after treatment
timeFrame: 1 month
Other outcomes:
Locations:
city: Zagreb
country: Croatia
facility: University Hospital Centre "Sisters of Mercy"
Study officials:
affiliation: Head, Department of Pediatrics, Clinical Professor
name: Sanja Kolaček, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Consultant in Pediatric Gastroenterology
name: Iva Hojsak, MD, PhD
role: STUDY_DIRECTOR
affiliation: Consultant in Pediatric Gastroenterology
name: Oleg Jadrešin, MD, MSc
role: STUDY_CHAIR
References:
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