The Effectiveness of Pleuran in Treatment of Acute Gastroenteritis in Children

Diarrhoea;Acute Clinical Trial

— EPTAGE  

Official title:

The Effectiveness of Pleuran in Treatment of Acute Gastroenteritis in Children- a Randomized, Placebo-controlled, Double-blind Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03988257
• Other study ID #: 5FNUT11
• Secondary ID: KB/45/2018
• Status: Completed
• Phase: Phase 4
• Start date: June 24, 2019
• Est. completion date: December 31, 2022

Study information

• Verified date: October 2021
• Source: Medical University of Warsaw
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Acute gastroenteritis (AGE) is one of the most common causes of children's morbidity and mortality globally. Oral or intravenous rehydration is the only effective treatment in reducing morbidity and mortality rates in AGE. However, new attempts to identify other therapeutic methods to reduce the symptoms of diarrhea are of interest. The administration of pleuran (β- (1,3 / 1,6) -D-glucan) appears to be such an alternative. In Poland, pleuran is being marketed for treating AGE. Its potential immunomodulatory effect is based on the stimulation of both humoral and cellular immunity. The active substance of the product (pleuran) was extracted by unique and patented technology from Pleurotus ostreatus. The substance was previously isolated, identified and chemically characterized by Karacsonyi and Kunia. Pleuran is registered as a diet supplement and distributed in 20 European and non-European countries. The testing for toxicity was performed by the Institute of Preventive and Clinical Medicine of Slovak Medical University (Final Report No. 5-51/04) and the tests were performed in compliance with the criteria of the Directive of Good Laboratory Practice and Directive 2004/10/EC of the European Parliament and the Council of 11th February 2004.

To evaluate the efficacy of pleuran in reducing the duration and the severity of AGE symptoms in children, a randomized, placebo-controlled, fully-blind study has been designed. A total of 120 children will be randomly assigned to receive either Imunoglukan PH4 syrup in the experimental group or matching placebo in the control group. The primary outcome measure will be the duration of diarrhea. The statistical analysis of the results will be conducted in both intention-to-treat and per-protocol approach.

Description:

Study design: This will be a randomized, fully-blind, placebo-controlled trial, with allocation 1:1.

Study population: Children aged 13- 120 months, hospitalized or requiring a visit to the emergency department due to acute gastroenteritis (AGE) lasting at least 24 h, but no longer than 72 h at the time of inclusion to the study.

The setting of the study: The study participants will be recruited from patients requiring hospitalization in 4 paediatric departments or counselling in the emergency department (ED) due to AGE in the Paediatric Teaching Clinical Hospital, the Medical University of Warsaw.

Pre-intervention assessment:

We will evaluate the inclusion and exclusion criteria of the study within 24 hours of hospitalization or ED visit basing on the physical examination and interviews with caregivers. The BMI will be calculated and put on WHO percentiles charts. In order to determine the etiology of AGE, the stool sample will be collected for viral tests (rota-, adeno- and noroviruses markers) before the intervention. If any indication for microbiological stool investigation occurs (the patient in severe condition or with prolonged symptoms in whom specific treatment is considered, or patient with underlying chronic disease), the stool sample will be cultured. The caregivers will be informed about the purpose, methods, safety of the intervention and the course of the study. In order to ensure that the assessed parameters and endpoints are comparable appropriate scales will be applied. To assess the severity of diarrhea, the Modified Vesikari Score will be used. The dehydration degree will be evaluated by means of the WHO scale and the Clinical Dehydration Scale (CDS) recommended by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). The Bristol Stool Form Scale will help to objectify the assessment of stool consistency.

Randomization:

The randomization will involve the random allocation of patients to group A or B. The stratified randomization has been designed with the use of two subgroups. The subgroups will be created depending on the duration of diarrhea at the time of enrolment: 24-48 h (short-lasting diarrhea- SLD) and 48-72 h (long-lasting diarrhea- LLD). The participants of each subgroup will be randomly allocated to the study groups (experimental or control), in blocks of four.

Allocation concealment and blinding:

The active product and placebo will be prepared, weighed, packaged in identical bottles and signed with random numbers by the manufacturer, with the blinded meaning of numbers. The information about the allocation will be deposited in a sealed envelope in a safe place in the administrative part of the department, kept by the independent person not involved in the study. The study product will be delivered to the main researcher in boxes of four, ensuring the contest of 2 active and 2 placebo samples in each box. Subsequent boxes will be used to allocate consecutive patients within the subgroups A and B. By opening each subsequent box, the numbers of bottles in the box will be randomly assigned to the next four patients in a subgroup by the researcher. The contents of the bottles will look and taste the same. Researchers, caregivers, patients, and a person responsible for the statistical analysis will be blinded to the intervention until the completion of the study.

Intervention:

Children allocated to the experimental group will receive Imunoglukan PH4 oral suspension (10 mg of pleuran and 10 mg of vitamin C in 1 ml of syrup) in a dose 1 ml / 5 kg body weight, while patients in the control group will receive a placebo: a vitamin C oral suspension (10 mg of vitamin C in 1 ml of syrup) in a dose 1 ml / 5 kg body weight. Both syrups will be administered once a day in the morning, before the first meal, until signs of AGE subside (< 3 stools / 24 hours and normalization of stool consistency - grade 2-5 according to Bristol Stool Form Scale) or until the 14th day of the intervention.

Concomitant treatment:

To ensure proper rehydration, patients in both groups will receive an oral rehydration solution (ORS) or intravenous fluids if necessary, according to daily fluids requirements. A normal diet will be delivered. Each patient will receive antipyretic, analgesic (Ibuprofen, Acetaminophen), and antiemetic (Ondansetron) if necessary. Patients will not receive other medicines that may interfere with the disease course (probiotics, Diosmectite, Racecadotril). If indications occur, the patient will receive an antibiotic according to the ESPGHAN recommendations

Follow up:

During hospitalization, patients will be examined every day by the physician, with the assessment of dehydration level, the need for intravenous rehydration or concomitant treatment. The results of the evaluation will be recorded in the Case Report Form (CRF). Both during and after the hospitalization, the caregiver will record AGE symptoms in a diary (a number of stools per day, their consistency and accompanying symptoms e.g. fever, vomiting, abdominal pain). Complete diaries will be collected from caregivers via email or by telephone conversation. After discharge, caregivers will have the possibility to contact a physician to receive basic consultation about oral rehydration and eventual side effects.

Data management:

Coded, paper CRF containing all the scales and questionnaires will be created for each patient. After finishing the observation, the data from the symptoms diaries completed by the caregivers will be transferred by the physician to the paper versions of the CRFs. After completing the study, data from the CRFs will be transferred to two electronic databases by two independent persons to confirm the accuracy of the data. Electronic database and CRFs will be prepared in Statistical Analysis System (SAS) software. The collected data will be properly stored to allow for data verification. Confidentiality of data, including personal data of the study participants, will be maintained.

Adverse events (AE) Every AE will be recorded and reported to the investigator and manufacturer, according to a pre-established procedure.

Sample size:

The Altman nomogram was used to estimate the sample size of experimental and control groups. To demonstrate a clinically relevant difference of 24 h in duration of AGE symptoms in experimental and control groups, with 5% significance level and a power of 90%, assuming the standard deviation of the variable in each group of 40 h, a sample of 110 patients will be needed (55 patients in each group). Allowing for 10% attrition of participants during the study, we estimated the sample size as 120 patients (60 patients for each experimental and control group).

Statistical analysis:

Descriptive statistics will be used to summarise baseline characteristics. Intention-to-treat (ITT) and per protocol analyses will be used to present the results of the study. The comparison of group A and B in terms of the primary endpoint (duration of diarrhea) will be performed with Student's t-test if the p-value of the Shapiro-Wilk test will be >0.05. Otherwise, the Mann-Whitney U test will be used. In the case of dropouts or not completed observations before the 14th days of the study, the log-rank test will be performed. The Chi-squared test or Fisher's exact test will be used to compare the groups A and B in terms of the incidence of adverse events and the severity of diarrhea. Statistical significance will be based on two-tailed tests with p-value of 5%. All estimates will be presented with 95% confidence interval.

Amendment No 1:

The presented protocol contains amendments approved by the Bioethics Committee on May 11, 2020. The main reason for those changes was an unsatisfactory pace of recruitment in the first 11 months of study commencement. A detailed analysis revealed the reduction in the number of hospitalizations due to AGE in our Department compared to the previous year and difficulties in meeting the inclusion criteria. In the following months, the COVID pandemic significantly limited the number of patients hospitalized in our hospital. By the time the changes were made we recruited only three patients into the study.

For the listed reasons we have introduced the following changes to the protocol:

1. The first version of the protocol assumed the recruitment of patients among hospitalized children only. The amendment introduced the possibility of recruitment also among children requiring counselling in the emergency department.

2. Initially, patients were recruited only at the Department of Pediatric with Clinical Assessment Unit (the unit initiating and conducting the study). The amendment introduced 4 other clinics of the Pediatric Teaching Clinical Hospital, the Medical University of Warsaw, including the Emergency Department.

3. The age group of recruited patients initially 13- 60 months (up to 6 years of age) was extended to older children 13- 120 months (up to 10 years of age).

Amendment No 2

The presented protocol contains amendments approved by the Bioethics Committee on December 13, 2021. The main reason for those changes was an unsatisfactory pace of recruitment, caused by a significant change in the profile of hospitalized patients due to the SARS-CoV2 pandemic. By the time the changes were made we recruited only ten patients into the study.

1. The amendment introduced two other locations for patient recruitment: The Department of Pediatrics of Warsaw Children's Hospital and The Department of Pediatrics of Hospital of Trzebnica, Poland.

2. The amendment introduced the possibility of recruitment among children requiring outpatient counseling due to acute diarrhea.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. completion date: December 31, 2022
• Est. primary completion date: September 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Months to 120 Months

Eligibility

Inclusion Criteria:

• Children aged 13-120 months, hospitalized or requiring a visit in the emergency department (ED) or outpatient consultation due to AGE, defined as a decrease in the stool consistency (grade 6 or 7 in Bristol Stool Form Scale) and/or an increase in the frequency of stool evacuations > 3 in 24 hours.

• Duration of symptoms 24-72 hours at the time of inclusion.

• Caretaker's written, informed consent.

Exclusion Criteria:

• Duration of symptoms > 72 hours at the time of inclusion.

• Co-occurring other systemic infectious diseases (ex. pneumonia, sepsis).

• Diagnosed immune deficiency.

• Malnutrition (defined as the body mass index (BMI) <-2 SDS (Standard Deviation Scores) or < 3rd percentile based on the World Health Organization (WHO) percentile charts.

• Chronic diarrhoeal gastrointestinal disease (inflammatory bowel disease, short bowel syndrome, cystic fibrosis, celiac disease, food allergy).

• Use of antibiotics, probiotics, prebiotics or anti-diarrhea (Diosmectite, Racecadotril) medicines within 7 days prior to enrolment into the study.

• Use of probiotics, Diosmectite, Racecadotril during the current AGE episode.

• Use of pleuran in the 14 days prior to enrolment into the study.

• Parallel involvement of the patient in other clinical trials, with the exception of observational studies.

• No legal caregivers' consent to participate in the study

Related Conditions & MeSH terms

• Diarrhea
• Diarrhoea;Acute
• Gastroenteritis

Intervention

Dietary Supplement:
• Imunoglukan PH4
Children allocated to experimental group will receive Imunoglukan PH4 syrup (10 mg of pleuran and 10 mg of vitamin C in 1 ml of syrup) in a dose 1 ml / 5 kg body weight, once a day in the morning, before the first meal, until signs of AGE subside (< 3 stools / 24 hours and normalization of stool consistency - grade 2-5 according to Bristol Stool Form Scale) or until the 14th day of the intervention.
• Placebo (vitamin C syrup)
Children allocated to control group will receive a placebo: a vitamin C syrup (10 mg of vitamin C in 1 ml of syrup) in a dose 1 ml / 5 kg body weight, once a day in the morning, before the first meal, until signs of AGE subside (< 3 stools / 24 hours and normalization of stool consistency - grade 2-5 according to Bristol Stool Form Scale) or until the 14th day of the intervention.

Locations

Country	Name	City	State
Poland	The Department of Pediatrics with Clinical Assessment Unit, The Medical University of Warsaw	Warsaw

Sponsors (3)

Lead Sponsor	Collaborator
Medical University of Warsaw	Nutricia Foundation, PLEURAN s.r.o.

Country where clinical trial is conducted

Poland, 

References & Publications (13)

Bergendiova K, Tibenska E, Majtan J. Pleuran (beta-glucan from Pleurotus ostreatus) supplementation, cellular immune response and respiratory tract infections in athletes. Eur J Appl Physiol. 2011 Sep;111(9):2033-40. doi: 10.1007/s00421-011-1837-z. Epub 2011 Jan 20. — View Citation

Bobovcak M, Kuniakova R, Gabriz J, Majtan J. Effect of Pleuran (beta-glucan from Pleurotus ostreatus) supplementation on cellular immune response after intensive exercise in elite athletes. Appl Physiol Nutr Metab. 2010 Dec;35(6):755-62. doi: 10.1139/H10-070. — View Citation

Chan GC, Chan WK, Sze DM. The effects of beta-glucan on human immune and cancer cells. J Hematol Oncol. 2009 Jun 10;2:25. doi: 10.1186/1756-8722-2-25. — View Citation

Di Luzio NR. Update on the immunomodulating activities of glucans. Springer Semin Immunopathol. 1985;8(4):387-400. doi: 10.1007/BF01857392. No abstract available. — View Citation

Freedman SB, Ali S, Oleszczuk M, Gouin S, Hartling L. Treatment of acute gastroenteritis in children: an overview of systematic reviews of interventions commonly used in developed countries. Evid Based Child Health. 2013 Jul;8(4):1123-37. doi: 10.1002/ebch.1932. — View Citation

Guarino A, Ashkenazi S, Gendrel D, Lo Vecchio A, Shamir R, Szajewska H; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; European Society for Pediatric Infectious Diseases. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: update 2014. J Pediatr Gastroenterol Nutr. 2014 Jul;59(1):132-52. doi: 10.1097/MPG.0000000000000375. — View Citation

Hojsak I, Fabiano V, Pop TL, Goulet O, Zuccotti GV, Cokugras FC, Pettoello-Mantovani M, Kolacek S. Guidance on the use of probiotics in clinical practice in children with selected clinical conditions and in specific vulnerable groups. Acta Paediatr. 2018 Jun;107(6):927-937. doi: 10.1111/apa.14270. Epub 2018 Apr 16. — View Citation

Jesenak M, Majtan J, Rennerova Z, Kyselovic J, Banovcin P, Hrubisko M. Immunomodulatory effect of pleuran (beta-glucan from Pleurotus ostreatus) in children with recurrent respiratory tract infections. Int Immunopharmacol. 2013 Feb;15(2):395-9. doi: 10.1016/j.intimp.2012.11.020. Epub 2012 Dec 20. — View Citation

Jesenak M, Urbancek S, Majtan J, Banovcin P, Hercogova J. beta-Glucan-based cream (containing pleuran isolated from pleurotus ostreatus) in supportive treatment of mild-to-moderate atopic dermatitis. J Dermatolog Treat. 2016 Aug;27(4):351-4. doi: 10.3109/09546634.2015.1117565. Epub 2015 Dec 10. — View Citation

Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 1997 Sep;32(9):920-4. doi: 10.3109/00365529709011203. — View Citation

National Collaborating Centre for Women's and Children's Health (UK). Diarrhoea and Vomiting Caused by Gastroenteritis: Diagnosis, Assessment and Management in Children Younger than 5 Years. London: RCOG Press; 2009 Apr. Available from http://www.ncbi.nlm.nih.gov/books/NBK63844/ — View Citation

Szajewska H, Guarino A, Hojsak I, Indrio F, Kolacek S, Shamir R, Vandenplas Y, Weizman Z; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr. 2014 Apr;58(4):531-9. doi: 10.1097/MPG.0000000000000320. Erratum In: J Pediatr Gastroenterol Nutr. 2016 Jan;62(1):188. — View Citation

van den Berg J, Berger MY. Guidelines on acute gastroenteritis in children: a critical appraisal of their quality and applicability in primary care. BMC Fam Pract. 2011 Dec 2;12:134. doi: 10.1186/1471-2296-12-134. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The duration of diarrhoea.	The duration of diarrhoea, defined as the time (hours) until normalization of stool consistency (grade 2, 3, 4 or 5 according to Bristol Stool Form Scale) and until normalization of number of stools per day.	Daily assessment, by the physician and/ or the patient's caregiver during until the 14th day of observation
Secondary	The duration of hospitalization.	The length of hospital stay due to AGE (number of days).	Daily assessment until the 14th day of observation.
Secondary	The number of days with need for intravenous rehydration.	The need for intravenous rehydration will be assessed daily by physician, based on CDC (Centers for Disease Control and Prevention) and WHO dehydration scales.	Daily assessment until the discharge from hospital.
Secondary	The number of hours until normalization of stools consistency ( type 2-5 according to Bristol Stool Consistency Scale).	Assessed on the basis of the diary completed by the physician and the caregiver.	Daily assessment until the 14th day of observation.
Secondary	The number of hours until the normalization of number of stools per day (<3 stools/ day).	Assessed on the basis of the diary completed by the physician and the caregiver.	Daily assessment until the 14th day of observation.
Secondary	The percentage of children with moderate and severe diarrhea.	Assessed by the Modified Vesikari Scale in the end of observation.	Assessed after the 14th day of the observation.
Secondary	The time until the improvement of the child's general condition according to the caregiver's assessment.	Based on the caregiver assessment.	Daily assessment until the 14th day of observation.