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Trials structured Study Protocol templateA
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Title: Randomised, placebo-controlled study to assess the safety and efficacy of Enterosgel® in the treatment of functional abdominal pain in children and young people (ENTOPIC): study protocol for a clinical trialNames protocol contributors
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CarolAHowell1
ManjulaVelayudhanNair1
MarcusKarl-HeinzAuth1
ChristineSpray3Phone3Emailchristine.spray@uhbw.nhs.uk
DharamveerBasude3
MatthewDodd4
ElenaMarkaryan1Phone+447860 817365Emailceo@enteromed.co.uk
RadovanHnatič5
StephenJ.Allen2,6EmailStephen.allen@lstmed.ac.uk
HowellCA1
NairMNV2
AuthMKH2
MarkaryanE1Emailemarkaryan@enteromed.co.uk
HnatičR1
AllenSJ.1
1Enteromed Ltd85 Great Portland Street, First FloorW1W 7LTLondonUK
2Paediatric GastroenterologyAlder Hey Children’s NHS Foundation TrustE Prescot RdL14 5ABLiverpoolUK
3Paediatric GastroenterologyBristol Royal Hospital for ChildrenUpper Maudlin StreetBS2 8BJBristolUK
4London School of Hygiene and Tropical MedicineKeppel StreetWC1E 7HTLondonUK
5Bioline Products s.r.o, Pátkova 831182 00Libeň, Prague 8Czech Republic
6Department of Clinical Sciences, Liverpool School of Tropical MedicinePembroke PlaceL3 5QALiverpoolUK
7Alder Hey Children’s NHS Foundation TrustEaton RoadL12 2APLiverpoolUK
8Bristol Royal Hospital for ChildrenBS2 8BJBristolUK, UK
9London School of Hygiene & Tropical MedicineKeppel StreetWC1E 7HTLondonUK
10Liverpool School of Tropical MedicinePembroke PlaceL3 5QALiverpoolUK
Carol A Howell (research@enteromed.co.uk),1 Manjula Velayudhan Nair (Manjula.VelayudhanNair@alderhey.nhs.uk),2 Marcus Karl-Heinz Auth (Marcus.Auth@alderhey.nhs.uk),2 Christine Spray (christine.spray@uhbw.nhs.uk),3 Dharamveer Basude (dharamveer.basude@uhbw.nhs.uk),3 Matthew Dodd (matthew.dodd@lshtm.ac.uk),4 Elena Markaryan (emarkaryan@enteromed.co.uk),1 Radovan Hnatič,5 Stephen J. Allen (Stephen.allen@lstmed.ac.uk)2,6
1. Enteromed Ltd, 85 Great Portland Street, First Floor, London, W1W 7LT, UK
2. Paediatric Gastroenterology, Alder Hey Children's NHS Foundation Trust, E Prescot Rd, Liverpool L14 5AB, UK
3. Paediatric Gastroenterology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ, UK
4. London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
5. Bioline Products s.r.o, Pátkova 831, Libeň, 182 00, Prague 8, Czech Republic
6. Department of Clinical Sciences, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
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Abstract
Background
Functional abdominal pain disorders (FAPDs) comprise of irritable bowel syndrome, functional dyspepsia, abdominal migraine and functional abdominal pain not otherwise specified. FAPDs are common in children worldwide, decrease health related quality of life, reduce attendance and participation in school and after-school activities similar to children with inflammatory bowel disease, and incur significant health care costs. The aetiology is thought to involve structural and/or functional disruptions in one or more elements of the microbiota–gut–brain axis. Several different treatment approaches are available, reflecting that none is proven to have significant efficacy. The medical device Enterosgel®, a silicon-based intestinal absorbent, adsorbs immune proteins, bacterial breakdown products and bile acids and normalises the intestinal microbiota. Enterosgel® is effective in irritable bowel syndrome with diarrhea in adults and is available on prescription and over-the-counter. We plan to evaluate the efficacy, tolerability and safety of Enterosgel® in the treatment FAPDs in children and young people.
Methods
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In a UK two-centre, parallel arm, randomised, double-blind, placebo-controlled trial, we will recruit children aged 3–18 years diagnosed with a FAPD during a routine health facility assessment and in whom other significant gastrointestinal disorders have been excluded. After an initial 2-week observation phase, eligible children will be randomised 1:1 to receive Enterosgel® or a matching placebo drink twice daily for 4 weeks during the double-blind treatment phase, then all children will receive open-label Enterosgel® treatment for a further 4 weeks. With support from parents/carers, children will record abdominal pain daily using the Wong-Baker FACES Pain Rating Scale. The primary outcome is change in mean daily pain score during the initial observation phase and the double-blind phase in the Enterosgel® versus the placebo arm. Secondary outcomes include change in gastrointestinal symptoms (assessed PedsQL™ 3.0 GIS module) and quality of life (KIDSCREEN-27) recorded at baseline and 6 and 10 weeks. After the initial clinical assessment, all procedures will be conducted remotely with study interventions sent by post.Discussion
In the absence of a currently available effective treatment, Enterosgel® may offer an effective, acceptable and safe treatment for children and young people with FAPDs.
Trial registration
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: ISRCTN16474818; registered on 21/05/2025Keywords
Functional abdominal pain
intestinal absorbent
children and young people
clinical trial
Administrative information
Title {1} | Randomised, placebo-controlled study to assess the safety and efficacy of Enterosgel® in the treatment of functional abdominal pain in children and young people (ENTOPIC): study protocol for a clinical trial |
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Trial registration {2a and 2b}. | ISRCTN Registry: ISRCTN16474818 |
Protocol version {3} | Version 3.0; 07/08/2025 |
Funding {4} | Bioline Products s.r.o; Pátkova 831, Libeň, 182 00, Prague 8, Czech Republic |
Author details {5a} | Howell CA,1 Nair MNV,2 Auth MKH,2 Spray C,3 Basude D,3 Dodd M,4 Markaryan E,1 Hnatič R5, Allen SJ.6 1. Enteromed Ltd., 85 Great Portland Street, First Floor, London, W1W 7LT, UK 2. Alder Hey Children's NHS Foundation Trust, Eaton Road, Liverpool L12 2AP, UK 3. Bristol Royal Hospital for Children, Bristol, UK BS2 8BJ, UK 4. London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK 5. Bioline Products s.r.o, Pátkova 831, Libeň, 182 00, Prague 8, Czech Republic 6. Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK |
Name and contact information for the trial sponsor {5b} | Elena Markaryan; Enteromed Ltd., 85 Great Portland Street, First Floor, London, W1W 7LT, UK Email: ceo@enteromed.co.uk Tel: +447860 817365 |
Role of sponsor {5c} | The sponsor and funder contributed to study design and will be involved in supplying interventions and writing study reports. However, the sponsor will have no role in the collection, analysis, and interpretation of data, writing of the report, or the decision to submit the report for publication |
Introduction
Background and rationale {6a}
1.1 Functional abdominal pain
Functional abdominal pain disorders (FAPDs), also known as disorders of gut-brain interaction, [1] are estimated to affect 13.5% of children worldwide and 10.5% of European children [2]. They can result in a decreased health related quality of life (HR-QOL) across all factors (emotional, social and physical) [3], school absenteeism and reduced participation in school and after-school activities, similar to children with inflammatory bowel disease [4] and have significant health care costs [5]. Furthermore, it is estimated that up to 25% of childhood functional gastrointestinal disorders (FGIDs) continue into adulthood [6].
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Clinical practice highlights the limited treatment options. A recent systematic review and meta-analysis of 91 studies (7226 children) evaluated dietary treatments (n = 730), pharmacological treatments (n = 2140), probiotic treatments (n = 1762), and psychosocial treatments (n = 2952) [7]. The study concluded only two treatments with moderate certainty were probably more effective for treatment success than control treatments. These included hypnotherapy and cognitive behavioural therapy, all other treatments were either not effective, or the data were of very low certainty. A small study of melatonin in children with FAPDs also treated with a probiotic showed an initial, modest improvement in abdominal pain but this was not sustained [8]. Another small study of gut-directed hypnotherapy showed decreased pain frequency and intensity in children with functional abdominal pain and irritable bowel syndrome (IBS) but no improvement in quality of life (QOL) or school absence [9]. A recent study of Mebeverine in adolescents showed it was ineffective in the treatment of IBS and functional abdominal pain not otherwise specified [10]. In summary, there is an absence of safe, effective and evidence-based treatments for FAPDs in children.1.2 INTESTINAL ADSORBENTS IN THE TREATMENT OF FAPDs
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Enterosgel® (Bioline Products s.r.o, Czech Republic) is an oral intestinal adsorbent that binds bacterial toxins, viruses, immune chemicals and bile acids in the gut [11, 12]. The active component is polymethylsiloxane polyhydrate. It is classified as a medical device class IIA as it is excreted unchanged being neither absorbed nor metabolised [13]. Enterosgel® is free from preservatives, sugar and other additives and considered to be non-allergenic. It is available over the counter and on prescription as a gel in a tube or sachet. The gel is taken diluted in water and has no taste. The European database of suspected adverse drug reactions reports no adverse reactions since it was certified in 2008 (http://www.adrreports.eu/en/index.html). It is certified for the treatment of acute diarrhoea and IBS with diarrhoea (IBS-D) for all ages.Enterosgel® improves stool frequency and consistency in adults [13] and children with diarrhoea [14–18]. A recent UK randomised, placebo-controlled trial evaluated Enterosgel® in 440 adults with IBS-D (age 16-75yrs) recruited from primary and secondary care, and a virtual site [19]. The primary outcome (percentage of responders for abdominal pain and stool consistency score) was higher in the Enterosgel® (37.4%) than the placebo group (24.3%; NNT:8; odds ratio 1.95 [1.28 to 2.99, p = 0.0020]). Statistically significant benefits in the Enterosgel® arm were also found for diary-based outcomes of stool consistency/frequency, pain, bloating and urgency. Questionnaire scores showed significant differences for the IBS Severity Scoring System and IBS-QOL questionnaires. Following an open-label phase, 75.9% of patients reported adequate relief of symptoms.
In IBS, Enterosgel® is thought to target several factors including immune proteins, bacterial breakdown products and bile acids and normalise the intestinal microflora [19]. Based on its mechanisms of action and the encouraging findings in adult IBS-D, Enterosgel® could be a safe and effective treatment for childhood FAPDs. This trial will be the first placebo-controlled randomised trial with Enterosgel® in children and young people with FAPDs.
Objectives {7}
The primary objective is to test the efficacy (superiority) of Enterosgel® compared with placebo in terms of change in mean abdominal pain score as recorded in the daily diary between the initial observation phase (weeks 1–2) and the double-blind treatment phase (weeks 3–6).
The secondary objectives for the double-blind treatment phase (weeks 3–6) are:
1.
To determine the efficacy of Enterosgel® compared with a parallel placebo group in terms of:
abdominal pain as recorded in the daily diary
change in stomach pain and other gastrointestinal symptoms
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To determine effects of treatment on health-related quality of life
3.
To evaluate safety of Enterosgel® through reported adverse events potentially related to treatment
The secondary objectives for the open-label treatment phase (weeks 7–10) are:
1.
In patients who had received placebo as blinded treatment, to compare the study outcome measures (same as for double-blind phase above) over the open-label Enterosgel® treatment period to the preceding placebo treatment period.
2.
In patients who had received Enterosgel® as the blinded treatment, to test whether the treatment benefits (in terms of study outcome measures; same as for double-blind phase above) can be effectively maintained with Enterosgel®.
3.
To evaluate safety of Enterosgel® through reported adverse events potentially related to treatment.
Trial design {8}
In a UK two-centre, parallel arm, randomised, double-blind, placebo-controlled trial to assess the superiority of Enterosgel® versus placebo, after a 2-week initial observation phase (weeks 1–2), children will be randomised 1:1 to either the control group or the intervention group for the 4-week double-blind phase (weeks 3–6). All children will then receive Enterosgel® daily during the 4-week open-label phase (weeks 7–10). The study design is shown in Fig. 1.
Fig. 1
Study design
Methods: Participants, interventions and outcomes
Study setting {9}
Children aged 3–18 years attending face-to-face or remote general paediatric and paediatric gastroenterology clinics at Alder Hey Children's NHS Foundation Trust and Bristol Royal Hospital for Children, UK over a 12-month period will be reviewed by an experienced paediatrician. Medical records of children previously diagnosed with a FAPD will also be reviewed. Children will only be recruited once a diagnosis of an FAPD has been confirmed according to Rome IV criteria [1, 20]. A thorough clinical assessment including any appropriate investigations (e.g. gastro-intestinal endoscopy; abdominal ultrasound, faecal calprotectin) will be performed with careful attention to potential alarm features in children with chronic abdominal pain to ensure that other diagnoses are excluded [1]. The specific FAPD syndrome will be classified as one or more of:
H2a. Functional Dyspepsia and sub-type: H2a1. Postprandial distress syndrome and H2a2. Epigastric pain syndrome
H2b. Irritable bowel syndrome (IBS) and sub-type: IBS with constipation, IBS with diarrhea, IBS with constipation and diarrhea, and unspecified IBS
H2c. Abdominal Migraine
H2d. Functional Abdominal Pain Not Otherwise Specified
The criteria for each FAPD syndrome and subtype are shown in Additional file 1.
Eligibility criteria {10}
Inclusion Criteria
1)
Written informed consent
2)
Children aged 3–18 years with a clinical diagnosis of FAPD (Group H2a, H2b, H2c, H2d) according to the Rome IV criteria [20] and parent/carer available to provide proxy-reports and/or parent/carer reports
3)
Normal faecal calprotectin concentration at diagnosis (≤ 250ug/g stool age 3–8 yrs, ≤ 100ug/g stool age 9–18 yrs)
4)
Considered suitable to take part in the study by the consenting investigator
5)
Diary completed on at least 11 of 14 days (≥ 75%) during the observational period
6)
Able to complete questionnaires in English
7)
Able to complete e diary and questionnaires on-line
Exclusion Criteria
1)
Previously diagnosed coeliac disease, inflammatory bowel disease or other significant gastro-intestinal disorder
2)
Average number of stools per week < 3
3)
Previous use of Enterosgel®
4)
Use of antidepressant agents, unless used at a stable dose for at least 6 weeks
5)
Use of any probiotic supplements, other intestinal adsorbents, slow-release medications or strong opioids
6)
Participation in any research where treatment is provided in the last three months
7)
Pregnancy or not willing to use contraception for the duration of the study
Criteria regarding avoidance of pregnancy are reported in Additional file 2. A pregnancy kit (if required) will be provided for the subject to use at the baseline appointment, after securing informed consent.
Who will take informed consent? {26a}
Following the initial clinical assessment, participants deemed eligible to join the study by the clinician and/or their parents/carers will be provided with verbal information regarding the trial and an age-appropriate Patient Information Sheet by the study paediatrician or by post for previously diagnosed patients. If they are interested in considering joining the trial, verbal consent to share their contact details and medical information with the Research Nurse will be attained. They will then be contacted by the Research Nurse after they have had 24 hours to consider the study, to arrange the remote recruitment appointment. At the remote recruitment appointment, eligibility will be confirmed, and e-consent and assent will be obtained by the research nurse before any study procedures are conducted.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Participants and/or their parents/carers will be asked to consent to relevant sections of medical notes and data collected during the study to be looked at by the research team, the study monitors, and regulatory authorities or from the NHS Trust, where it is relevant to taking part in this research; for their mobile phone number and email address to be shared with the research team to enable inclusion in the e-diary and for daily reminders to be sent via SMS and email; their name, home address and phone number to be shared with Enteromed Ltd, and for Enteromed Ltd to provide this information to a study supplies warehouse and a courier company to arrange delivery of the study treatment; for information collected to be used to support other research in the future including sharing data anonymously with other researchers; for their General Practitioner being involved in the study, including any necessary exchange of information with the research team; If eligible, to take a pregnancy test; to agree to receive by email the overall study results and an invitation to a study results webinar.
Interventions
Explanation for the choice of comparators {6b}
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All children will receive the same standard care (e.g. information about relaxation techniques) regarding appropriate management of FAPDs. The comparison group will be children with a FAPD who will receive a placebo drink daily during the double-blind phase.Intervention description {11a}
Enterosgel® is an intestinal adsorbent developed for binding toxins and other harmful substances in the gastrointestinal tract. The commercially available Enterosgel® product contains 30% water and 70% polymethylsiloxane polyhydrate, which is a 3-dimensional crosslinked polymer of methylsiliconic acid formed by polycondensation in which hydroxyl groups form stable siloxane bonds. In solution, these form microglobules via cross-linking of the pentameric cyclic structural units created by the siloxane bonds which connect to each other via strong hydrogen bonds [21]. The microglobules contain porous space filled with water. The overall porous structure of Enterosgel® is formed by connecting the microglobules of approximately 50nm in size, which then associate into larger particles ranging from 5-250µm in size, with over 32% in the 20–50 µm range [22]. The porous structure and presence of both hydrophilic and hydrophobic groups on the surface could result in the unique selective adsorptive activity of Enterosgel® towards medium and high-molecular weight substances in the gut. It effectively binds various bacterial toxins (bacterial endotoxin, Clostridioides difficile toxins A and B, shiga toxin II), while showing a lower binding capacity than carbon-based adsorbents for smaller molecules such as vitamin B12 and certain drug compounds [12, 22].
Enterosgel® does not cross the intestinal barrier and is, therefore, classified as a CE Certified medical device. It is free from preservatives, sugar and other additives, has no distinct taste and is easily suspended in water and taken orally. Enterosgel® can be used in children and adults, including pregnant and breastfeeding women. There are no reported adverse reactions in Europe since it was certified in 2011 (European database of suspected adverse drug reaction reports: http://www.adrreports.eu/en/index.html). It is currently sold over the counter in 30 countries in Europe and is available in a tube or sachets from pharmacies and health stores in the UK.
During the double-blind phase (3–6 weeks), participants randomised to the intervention arm will receive either 8, 12 or 18g of Enterosgel® (Bioline Products s.r.o, Czech Republic) pre-diluted with 72-82ml potable water in 90ml tubes depending on age range. Children aged 3–6 years will use ½ the tube in the morning and the remaining ½ tube in the evening. Other ages will use a full tube in the morning and evening. Each dose of treatment is to be taken 2 hours before or after taking oral medications and 1 hour before or after a meal. The daily dose for weeks 3–4 will be 53% of the recommended age-related daily treatment dose for acute diarrhoea; the dose will increase at week 5–6 to 80% of the dose for acute diarrhoea. Study-specific age-related dosage instructions for the double-blind treatment period are provided in Additional file 3.
Participants randomised to the control arm will receive tubes containing an equivalent volume of potable water to be taken twice daily and identical in appearance and taste to the intervention drink.
For the open-label phase, patients will be provided with the standard over-the-counter Enterosgel® in 225g tubes with administration instructions (Additional file 3).
Criteria for discontinuing or modifying allocated interventions {11b}
Enterosgel® is known to result in mild constipation in some people. Participants who develop constipation (no bowel movement for 2 consecutive days), will be advised to increase their fluid intake and discontinue the double-blind treatment, or Enterosgel® during the open-label phase, which can be re-started once the constipation has resolved. No other adverse effects of Enterosgel® are anticipated. However, emergency unblinding during the double-blind phase will be possible should a health professional consider that Enterosgel® may be the cause of worsening symptoms or other adverse effects so that, if required, treatment could be discontinued. Participants are free to withdraw from the trial at any time should they have any concerns.
Strategies to improve adherence to interventions {11c}
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Participants will be provided with detailed information regarding the potential benefits of Enterosgel®, including its efficacy in adults with IBS with diarrhoea, and its excellent safety profile. All participants will be called by the Research Nurse after the first week of the double-blind phase to solve any problems and provide encouragement and support. Participants will report the number of doses of the study interventions taken in the electronic daily diary and reasons for non-compliance; Research Nurses will monitor study treatment compliance in the e-case report form (CRF) and call patients to encourage/help if indicated. Finally, participants can call the Research Nurse at any time to address any issues that may arise.Relevant concomitant care permitted or prohibited during the trial {11d}
Use of probiotic supplements, other intestinal adsorbents (activated charcoal, kaoline, diosmectite), slow-release medications or strong opioids during the study will not be permitted and any participants who require slow-release medications will be withdrawn from the trial. Participants will be advised not to make any changes to their diet during the trial. Participants will be allowed to continue to take antidepressant agents at a stable dose, provided that they had been taking a stable dose for at least 6 weeks before recruitment.
Provisions for post-trial care {30}
Participants will remain under the care of their clinician should further management be required at the end of the trial. The study Sponsor, EnteroMed Ltd, holds Product Liability Insurance for legal liabilities arising from the use of Enterosgel® in the UK and insurance for the conduct of the trial is in place. The NHS legal liability for the negligent acts and omissions of their employees would provide compensation should a patient be harmed as a result of negligence on the part of a member of the study team.
Outcomes {12}
The primary outcome is the change in mean daily Wong-Baker FACES Pain Rating Scale (© 1983 Wong-Baker FACES Foundation, www.WongBakerFACES.org. Used with permission. Originally published in Whaley & Wong’s Nursing Care of Infants and Children. © Elsevier Inc.) limited to abdominal pain during weeks 1–2 (initial observation phase) and the double-blind phase (week 3–6) as recorded in the daily diary in the Enterosgel® versus the placebo arm. Abdominal pain has been selected as it is the predominant symptom in FAPDs and relief of abdominal pain is likely the outcome of most importance to participants. We consider that a daily record of abdominal pain using a well-validated scale is the most effective means of capturing this outcome reliably.
The secondary outcomes for the double-blind and open-label treatment phase are listed in Table 1.
Outcome Measure | Time points and method of assessment | Definition |
|---|---|---|
1. Abdominal pain score | Daily diary | Mean daily Wong-Baker FACES Pain Rating Scale |
2. Frequency of abdominal pain | Daily diary | Proportion of days with any abdominal pain |
3. Days missed nursery/school | Daily diary | Proportion of days missed nursery/school |
4. Change in the Stomach Pain and Hurt total score | Baseline, weeks 6 and 10 (PedsQL™ 3.0 GIS module; comprised of 6 items) | Parent/carer proxy-report for 3-4-year-olds and child self-report from 5–18 years; by parent/carer proxy-report for 3-18-year-olds) |
5. Change in individual components of the PedsQL™ 3.0 GIS module | Baseline, week 6, 10 (PedsQL™ 3.0 GIS module) | Parent/carer proxy-report for 3-4-year-olds and child self-report from 5–18 years; by parent/carer proxy-report for 3–18 years old. Individual components of the PedsQL™ 3.0 GIS module: stomach discomfort when eating (5 items), food and drink limits (6), trouble swallowing (3), heartburn and reflux (4), nausea and vomiting (4), gas and bloating (7), constipation (14), blood in bowel movement (2), diarrhoea (7), worry about bowel movements (5), medicines (4), communication (5). |
6. Change in total PedsQL™ 3.0 GIS module score | Baseline, week 6,10 (PedsQL™ 3.0 GIS module) | Parent/carer proxy-report for 3-4-year-olds and child self-report from 5–18 years; by parent/carer proxy-report for 3–18 years old. |
7. Change in health-related quality of life KIDSCREEN-27 questionnaire | Baseline, week 6, 10 (Health-related quality of life KIDSCREEN-27) | Total Health-related quality of life KIDSCREEN-27 score (parent reported 3–18 years, child self-report 8–18 years) |
8. Change in health-related quality of life KIDSCREEN-27 questionnaire “General Mood and Feelings about Yourself” sub-score | Baseline, week 6, 10 (Health-related quality of life KIDSCREEN-27) | Health-related quality of life KIDSCREEN-27 sub-score for “General Mood and Feelings about Yourself” (7 questions; parent reported 3–18 years, child self-report 8–18 years) |
9. Acceptability of the study interventions | Daily (diary) | Compliance with taking study intervention each day* |
10. Adequate relief | Questionnaire | Opinion of the 1) child and 2) parent/carer whether there has been adequate relief of abdominal pain during the previous 7 days (recorded at end of double-blind and open-label phases) |
11. Use of common analgesics for abdominal pain | Questionnaire | Use of common analgesics (e.g. paracetamol; ibuprofen) for abdominal pain in the last week of the initial observation period (week 2), double blind phase (week 6) and open label phase (week 10) |
12. Adverse Events | When reported | Percentage of patients reporting SAEs and AEs possibly related to treatment Total number of SAEs and AEs reported |
*Participants who develop constipation will be advised to stop treatment for a few days as per study treatment instructions. The diary will capture this information which will not be considered as non-compliance.
Participant timeline {13}
The time schedule of enrolment, interventions, assessments, and visits for participants is shown in table 2.
Procedures | Study period | ||||||
|---|---|---|---|---|---|---|---|
Enrolment | Allocation | Post-allocation | Close-out | ||||
Screening appointment (recruitment site/remote) | Recruitment appointment (remote) | Observation period | Baseline appointment (remote) | Double-blind phase | Open-label phase | Follow-up 2 appointment (remote) | |
TIMEPOINT (weeks) | 0 | 0 | 1–2 | 3 | 3–6 | 7–10 | 10 |
ENROLMENT: | |||||||
Eligibility screen | X | X1 | |||||
Verbal consent to share information with Research Nurse | X | ||||||
Informed consent | X | ||||||
Allocation | X | ||||||
INTERVENTIONS: | |||||||
Enterosgel® | |||||||
Placebo | |||||||
ASSESSMENTS: | |||||||
Daily diary2 | |||||||
PedsQL™ 3.0 GIS module3 | X | X | X | ||||
KIDSCREEN-273 | X | X | X | ||||
Adequate relief question4 | X | X | |||||
Use of analgesics | |||||||
Adverse Events | |||||||
Notes
1.
Eligibility will be re-confirmed based on satisfactory completion of the daily diary, no significant change in clinical status, no use of prohibited medicines and negative pregnancy test (if applicable)
2.
The daily diary will collect information for the Wong-Baker FACES Pain Rating Scale for 10 weeks and study compliance for 8 weeks (weeks 3–10)
3.
These questionnaires will be completed at recruitment and the end of the double blind (week 6) and open-label (week 10) phases
4.
Completed at the end of the double blind (week 6) and open-label (week 10) phases
Sample size {14}
In a previous clinical trial of Mebeverine in the treatment of FAPD in children [10], the mean (SD) change from baseline in the Wong-Baker FACES Pain Rating Scale in the placebo arm was − 1.2 (2.0). We consider that a 1-point larger reduction in the Enterosgel® arm (a mean change from baseline of -2.2) would be clinically significant. The number of patients required to observe this difference with 80% power and α = 0.05 is approximately n = 130 (or n = 65 per arm). We would increase the sample size to n = 154 (77 per arm) to allow for 15% drop-outs.
Recruitment {15}
Based on the clinical audit of children attending paediatric gastroenterology clinics at Alder Hey Hospital during 1 month [23], 40 children fulfilled Rome IV criteria [20] for a FAPD (Group H2). A more recent audit of general paediatric and paediatric gastroenterology clinics at both recruitment sites estimated each site could recruit 5–10 patients from a potential 20–40 eligible patients. Considering difficulties in recruitment to clinical trials especially of older children, recruiting a total of 13 patients per month for 12 months is a realistic target. Regular follow-up meetings will be held to track progress with recruitment. If required, Research Nurses will screen clinical records for children previously diagnosed with an FAPD and send out an invitation to join the study and include the patient information sheets.
Assignment of interventions: allocation
Sequence generation {16a}
Allocation will use a computer-based randomisation tool (Sealed Envelope Ltd, UK). Randomisation will be based on the minimisation method where treatment allocation will be stratified by study centre, sex and age group (3–6, 7–14 and 15–18 years). Minimisation allocates subjects to the treatment group that best maintains balance in stratifying factors. It is effective even at small sample sizes and with multiple stratification variables [24].
Concealment mechanism {16b}
The randomisation tool is built into a secure, restricted access web-based eCRF system (Red Pill) developed and hosted by Sealed Envelope Ltd and will generate a unique randomisation code for each participant. The randomisation code list of the corresponding treatment group is held by the Sponsor’s unblinded study supplies coordinator and separate from the research teams.
Implementation {16c}
Research nurses will enrol participants after they have received the relevant details from the clinician and allocate a unique randomisation code at the baseline appointment for each participant using the eCRF (Sealed Envelope Ltd).
Assignment of interventions: Blinding
Who will be blinded {17a}
The participants and their parents/carers reporting study outcomes and the research team will be blinded to treatment allocation during the double-blind phase. Participants will receive the trial interventions by post but without identifying whether they are active or placebo drinks. Release of the randomisation sequence to the data analysts and research team will only take place after the study database has been cleaned and locked.
Procedure for unblinding if needed {17b}
Unblinding may be requested on the grounds of safety by the Chief Investigator, local Principal Investigator (PI) or authorised delegate or treating physician, a patient/carer or GP. Following submission of the unblinding request form in the eCRF detailing the reason for emergency unblinding, if the PI/sub-PI decides that unblinding is necessary to ensure the patient will receive appropriate medical care, the treatment allocation will be emailed to the person who had requested unblinding and the Trial Manager informed without revealing treatment group. The PI will be responsible for deciding whether the patient should continue on the allocated trial treatment. Unblinded patients will be followed up according to the study protocol until the end of the study.
Data collection and management
Plans for assessment and collection of outcomes {18a}
An electronic diary, developed by Sealed Envelope Ltd. UK, will collect information daily regarding abdominal pain, nursery/school attendance and treatment use but no patient identifiable data. Questions included in the diary are provided in Additional file 4. The Wong-Baker FACES Pain Rating Scale will be used to record the presence and severity of abdominal pain each day. This scale has been well-validated in the self-assessment of physical pain in people aged 3 years and older and used extensively in both research and clinical contexts (https://wongbakerfaces.org/).
The Pediatric Quality of Life Inventory™ (PedsQL™) Gastrointestinal Symptoms Module is a validated questionnaire for patients with FGIDs and organic gastrointestinal diseases. [25, 26] The module consists of a patient self-report for ages 5–18 and parent proxy-report for ages 2–18 years. PedsQL™-3.0-GIS evaluates the intensity of symptoms during the previous one-month period. The modules are separated into age categories; toddlers (2–4 years), young child (5-7yrs), child (8–12 yrs), and teens (13-18yrs). It considers fourteen unidimensional scales measuring stomach pain, stomach discomfort when eating, food and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and bloating, constipation, blood, diarrhea, worry, medicines, and communication. The “worry about bowel movements” (5 questions) will evaluate treatment effects on anxiety/depression. Each question is scored on a scale from 0 to 4, and their sum is then calculated to obtain the total score with higher scores indicating worse symptoms. Data suggests that the PedsQL™-3.0-GIS has good measurement properties and can be used as a common metric for FGIDs to compare GI-specific symptoms in clinical research and practice both within and across patient groups [25].
KIDSCREEN-27 questionnaires will assess the ten health-related quality of life dimensions covering subjective health and psychological, mental and social well-being and can be used in both healthy and ill children [27–29]. The questionnaires take about 10 minutes to complete and will be completed by children themselves, and a corresponding parent version will provide a proxy assessment for age 7 years and below. The questionnaires can be used in hospitals, other medical settings and have been validated in 13 European countries allowing meaningful cross-cultural comparisons [30]. The “General Mood and Feelings about Yourself” sub-score (based on 7 questions) will further assess effects of the study treatment on anxiety/depression.
The diary and questionnaires will be available online for use on any computer, tablet or mobile device. Participants and/or parents/carers will be sent a text and email with a link to the diary and questionnaires and the Research Nurse will explain their use at the recruitment appointment. For the duration of the study, each evening at 6 pm a text and email will be sent with a link to that day’s diary and questionnaires if required. Participants and/or parents/carers will also be able to complete the previous day’s diary if uncompleted.
Plans to promote participant retention and complete follow-up {18b}
Information about the study and frequently asked questions will be available through the study website which will also report recruitment to the study as it progresses. All participants will be called by the Research Nurse after the first week of the double-blind phase to solve any problems and provide encouragement and support. The Sponsor will also check completion of the diaries weekly including the information submitted by participants regarding compliance and inform the Research Nurse to follow-up with participants if indicated. Also, participants can call the Research Nurse at any time to address any issues that may arise. Should a participant decide to discontinue the intervention, we will request that they continue to complete the daily diary and questionnaires for their data to be included in intention-to-treat (ITT) analysis.
Data management {19}
A
All study data will be entered using a validated eCRF system in Red Pill developed by Sealed Envelope Ltd, in which each participant will be identified by a unique study-specific participant number. Data recorded in the eCRFs will contain personal data which will be used to send diary reminders (by email/mobile number) only accessible in the eCRF to study investigators and will not be included in each patient eCRF download provided to sites at the end of the study. The eCRF system will only be accessible to delegated and trained site team personnel, using their individual username and password. Monthly central statistical monitoring reports will be produced by the Data Manager in line with the Data Management and Validation Plan and monitored to check for missing data, ranges of data values, dates of visits and other edit checks.Confidentiality {27}
Personal identifier data will be held on paper in locked cupboards in a locked research offices and on password-protected computers at the study sites. Participants names, home addresses and phone numbers will be sent from sites via encrypted email to the unblinded study coordinators who will use a secure online booking platform at the warehouse facility contracted by the Sponsor (Nivtar Distribution Limited, Duxford, UK) to arrange postage of the trial interventions. Only unique study-specific participant numbers without personal identifiers will be recorded in the eCRF system. All essential documents and trial data will be held by the Sponsor for a minimum of 5 years after the end of the trial. Investigator site files will be archived at the participating sites for 5 years destroyed only after authorisation has been received from the Sponsor.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
No biological samples will be collected in this study.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The trial will be reported according to the CONSORT guidelines for clinical trials (http://www.consort-statement.org/) [31]. Primary data analyses will be based on the ITT principle. The ITT population will include all randomised patients analysed in the groups to which they were randomised to, regardless of whether they received or adhered to the allocated intervention. Recruitment and attrition rates will be calculated as percentages with 95% confidence intervals (CIs). Percentage of patients completing the protocol will be reported and reasons for deviations/study withdrawal collected. Descriptive sub analyses, if numbers allow, will be made based on specific FAPD diagnoses. All statistical analyses will be described in detail in the Statistical Analysis Plan.
The primary outcome will be analysed using an analysis of covariance (ANCOVA) model with treatment assignment and the baseline Stomach Pain and Hurt score as a covariate. In addition, an adjusted ANCOVA model will be performed by including pre-specified covariates (study site, sex and age group) measured at baseline. The unadjusted and adjusted mean difference between two groups in the primary outcome, together with its 95% CI will be calculated. In addition, subgroup analysis of the primary endpoint will be performed on the pre-specified covariates.
Secondary outcome data will be summarised descriptively at each time point, overall and by trial arm. The secondary outcomes will be analysed either by comparing trial arms at week 6 using ANCOVA models adjusting for baseline scores, or by employing mixed effects models for repeated measurements. The baseline scores, treatment group, time point, and treatment group by timepoint interaction terms will be included as covariates. A random effect for participant will be used to account for repeated measurements within participants over time. This will allow efficient use of the data collected, and account for potential within patient correlation.
Interim analyses {21b}
No interim analysis is planned.
Methods for additional analyses (e.g. subgroup analyses) {20b}
Analysis with regards specific FAPD subgroups and ethnicity will be undertaken and described in full in the formal statistical analysis plan [1, 32].
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
The per-protocol analyses will include children who completed the study without reported protocol violations and with 80% or greater treatment compliance. Where appropriate, multiple imputation will be used to impute missing values under a missing at random assumption in order to avoid excluding patients from the analysis. Multiple imputation involves creating multiple copies of the data set, with the missing values replaced by imputed values drawn from their predicted distribution by using the observed data [24].
Plans to give access to the full protocol, participant level-data and statistical code {31c}
A
The full protocol, anonymised participant-level data, and statistical code will be available on reasonable request to the sponsor.Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
A Trial Management Group (TMG) will be responsible for the set-up and conduct of the trial, including monitoring of recruitment and data. It will include at least one Sponsor’s representative, the Chief Investigator, the PI from each site, the trial statistician, the trial manager and a young person from the Generation R Liverpool Young Person’s Advisory Group. The TMG will hold a teleconference once a month and two face-to-face meetings a year.
Composition of the data monitoring committee, its role and reporting structure {21a}
An independent Data Monitoring Committee (DMC) will monitor data collected during the study for efficacy and safety. If any issues emerge, the DMC will make recommendations regarding the continuation of the study. The DMC will consist of a Chair (Paediatric Gastroenterologist) and a statistician with no competing interests. The DMC Charter is available from the sponsor on reasonable request.
Adverse event reporting and harms {22}
The types of adverse events (AEs) associated with medical devices and applicable for this study are defined in accordance with the European Commission guidelines on medical devices [33]. Definitions of AEs are included in Additional file 5.
AEs will be collected throughout the study from baseline appointment until week 10. If an AE is reported by the patient, the relationship of the event to the study treatment or procedures will be assessed by the local PI, or a delegated sub-PI or nurse. The following information will be recorded for all AEs:
Medical term of the AE (SNOMED CT terminology)
Start date and date of resolution
Seriousness
Severity
Study treatment action
Outcome
Relationship with the study treatment
Expectedness
Serious adverse device events, serious AEs (SAEs), and unexpected serious adverse device events USADEs, including any SAEs that occur during the screening period that resulted from the administration of any study procedures and are unexpected, will be recorded in the eCRF and reported to the Sponsor using the SAE reporting form. The reporting form will be emailed to the Trial Manager within 24 hours of the site team becoming aware of the event. If the site does not receive an acknowledgement of the receipt of the report within 24 hours, they will immediately contact the Trial Manager by telephone. The Sponsor will immediately inform the CI of any reported SAEs. The CI will review the SAE to confirm causality and expectedness.
The Sponsor will also report all SAEs to the MHRA, whether or not initially considered to be device related. Any SAEs which indicate an imminent risk of death, serious injury or serious illness, and which requires prompt remedial action for other subjects, will be reported within two calendar days of awareness; any other SAEs will be reported within seven calendar days. The Research Ethics Committee (REC) will be notified of any related and unexpected SAEs within 15 days including details of the participant’s treatment arm. However, investigators will only receive information on the code-break if it is necessary for the safety of the patient.
SAEs will be followed-up until resolution or a final outcome and all follow-up information emailed to the Sponsor as soon as it becomes available. The SAE report form and any related email correspondence will should be filed in the investigator site file and in the electronic Trial Master File.
Frequency and plans for auditing trial conduct {23}
Regular monitoring will be performed by the research team blinded to treatment allocation in accordance with the ICH GCP and a risk-based Trial Monitoring plan, which will define the monitoring schedule and method (on-site, remote) and the details of targeted monitoring. Data will be evaluated for compliance with the protocol and accuracy in relation to source documents. The monitors will verify that the clinical trial is conducted and data are generated, documented and reported in compliance with the protocol, GCP and the applicable regulatory requirements. Any data issues in the eCRF such as missing data or data discrepancies, will be addressed by raising data queries in the eCRF. Any unresolved or outstanding queries will be discussed with the site during the remote/on-site monitoring visits.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Important protocol modifications will be submitted to the REC and MHRA for approval. The study team will be trained accordingly, the participant information sheets and trial registration information revised as needed.
Dissemination plans {31a}
A
Study results will be submitted for presentation at gastroenterology conferences and for publication in international peer-reviewed scientific journals acknowledging that the study was funded by Bioline Products s.r.o (Czech Republic). The main findings will be disseminated to the participants and the public through the study website and an interactive results webinar for all participants and their parents/carers. Results will also be submitted for inclusion into the National Institute for Health and Care Excellence guidance if valuable for NHS.Discussion
We consider that this trial addresses an important issue of direct relevance to many younger people: the lack of an effective treatment for FAPDs which often result in significant morbidity and reduced HR-QoL [1–3] and considerable health care costs. [4] The trial has been designed to try to maximise engagement and then retention of children and young people and their parents/carers. After the initial routine clinic review, there is no requirement for hospital visits which can result in missing nursery or school and time off work for parents and also no sample collection is required. Remote collection of data has been designed to be able to be done on any smart phone, tablet or computer to maximise access for families. However, although the proportion of families in the UK without internet access is low, [34] those without internet access would not be able to participate. Also, given the high cost of translation and potential difficulties in developing symptom and quality of life questionnaires, participation requires adequate English literacy. Finally, the study is based in two tertiary referral hospitals so that children and young people with more severe FAPDs likely resistant to measures such as relaxation techniques will be enrolled. Further research may be needed to assess the efficacy of Enterosgel® in children with less severe FAPDs.
Trial status
Protocol version 3.0 dated 07/08/2025. Recruitment is expected to start in January 2026 and be completed by the end of December 2026.
Abbreviations
AE
adverse events
ANCOVA
analysis of covariance
CI
confidence interval
CRF
case report form
DMC
Data Monitoring Committee
ENTOPIC
Enterosgel® in the treatment of functional abdominal pain in children and young people
FAPD
Functional abdominal pain disorder
FGID
functional gastrointestinal disorder
HR-QOL
health related quality of life
IBS
irritable bowel syndrome
IBS-D
IBS with diarrhoea
ITT
intention-to-treat
PI
Principal Investigator
QOL
quality of life
REC
Research Ethics Committee
SAE
serious adverse event
TMG
Trial Management Group
USADE
Unexpected serious adverse device event
A
A
A
A
Acknowledgement
A
We would like to thank GenerationR Liverpool YPAG for their feedback on research design and review of the study diary, questionnaires and participant information sheets (https://generationr.org.uk/liverpool/) and Professor RM Beattie, Consultant Paediatric Gastroenterologist Southampton Children’s Hospital, UK, who discussed the study design at length with the study team and provided an expert scientific critique report of the protocol.Authors’ contributions {31b}
SA is the Chief Investigator. SA, CH, RH and ME conceived the study, led the proposal and protocol development. MN, MA, CS and DB advised on implementation of the study at the trial sites. MD led on the sample size estimation and statistical analysis. All authors read and approved the final manuscript.
Funding {4}
The study is funded by Bioline Products s.r.o, Pátkova 831, Libeň, 182 00, Prague 8, Czech Republic. The funding body contributed to study design but will have no role in the collection, management, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication.
Availability of data and materials
{29}
The final trial dataset will be available to the research team without limitations.
Ethics approval and consent to participate
{24}
Ethics approval
A
was secured from the UK NHS Health Research Authority Health and Social Care Research Ethics Committee A (HSC REC A) on July 1st 2025 (reference number 25/NI/0085). A
Written informed consent will be obtained from young people aged 16–18 years and from parents/guardians of younger children. A
Additionally, assent to participate in the study will be secured from younger children where possible and informed consent obtained from young people reaching the age of 16 years during the study.Consent for publication
{32}
The participant information sheets and consent forms are available from the sponsor on reasonable request.
A
Competing Interests
E.M. is the founder and director of the study Sponsor, Enteromed Ltd, which is the exclusive distributor of Enterosgel® in the UK. C.H. is employed by Enteromed Ltd. R.H. is employed by the funder Bioline Products s.r.o. S.A., M.N., M.A., C.S., D.B., M.D. declare that they have no competing interests.
EM is the founder and director of the study Sponsor, Enteromed Ltd, which is the exclusive distributor of Enterosgel® in the UK. CH is employed by Enteromed Ltd. RH is employed by the funder Bioline Products s.r.o, SA, MN, MA, CS, DB, MD declare that they have no competing interests.
Electronic Supplementary Material
Below is the link to the electronic supplementary material
A
Author Contribution
S.A. is the Chief Investigator. S.A., C.H., R.H. and M.E. conceived the study, led the proposal and protocol development. M.N., M.A., C.S. and D.B. advised on implementation of the study at the trial sites. M.D. led on the sample size estimation and statistical analysis. All authors read and approved the final manuscript.
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