The Effectiveness of Pleuran in Treatment of Acute Gastroenteritis in Children
Condition: Diarrhoea;Acute
MeSH terms: Gastroenteritis; Diarrhea
Study type: Interventional
Phase: Phase 4

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.
    

Detailed 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.
    

Intervention name(s): Imunoglukan PH4; Placebo (vitamin C syrup)
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): 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.; 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.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This will be a randomized, double-blind, placebo-controlled trial, with allocation 1:1.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Acute diarrhoea; Infectious diarrhoea; Pleuran; Beta-glucan; Duration of diarrhoea; Severity of diarrhoea; Randomized Controlled Trails as Topic