Packaging, labelling and supply
Both the placebo and Enterosgel® dilutions for double-blind treatment phase are manufactured in accordance with good manufacturing practice (GMP) by Bioline Products s.r.o. (CZ), packed into identical 90ml tubes and labelled In accordance with Annex I of the European Council Directive 93/42/EEC concerning Medical Devices. All study treatment will be stored at a Medicines and Healthcare products Regulatory Agency (MHRA) approved warehouse facility (Wasdell Group, UK). After each randomisation, the site research team will email a request form with a unique randomisation code to a dedicated email address, which can only be accessed by Sponsor’s (Enteromed Ltd, UK) unblinded study coordinators. A coordinator will check the randomisation code against a pre-generated randomisation code list to determine whether it corresponds to placebo or Enterosgel® and will then submit a shipment request to the warehouse through a secure online portal. Supplies will be dispatched for delivery directly to the study participants within 2 calendar days from receiving the request (next day delivery for orders submitted before 2 pm). The supplied treatment will be sufficient to cover the entire 8-week treatment phase even if the maximum dose is taken every day.
Open-label treatment will be provided in sachets containing 15g Enterosgel® and labelled in accordance with regulatory requirements. After a participant has been entered into the open-label phase, the site research team will send a treatment request to the Sponsor who will submit a shipment request to the warehouse as described above.
Treatment use and compliance are monitored through the daily study diary. Participants are not required to return any empty or unused tubes or sachets. Should the participant run out of study treatment during the study, they can request for additional supplies through their research site.
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 providing written informed consent.
Use of probiotic supplements, other intestinal adsorbents (activated charcoal, kaoline, diosmectite), slow-release medications or strong opioids during the study will not be permitted. To minimise the risk that Enterosgel® could adsorb concomitant medications in the gut, it will be recommended to leave at least two hours before and after taking the study treatment and taking any oral medications.
Loperamide will be provided to all study participants for use as a rescue medication during the double-blind and open-label treatment phases.
Primary outcome measure
The primary outcome measure is the percentage of participants defined as responders for abdominal pain and stool consistency during at least 4 weeks in the 8-week treatment period, where:
1) An Abdominal Pain Intensity Weekly Responder is defined as a participant who experiences a decrease in the weekly average abdominal pain score of at least 30 percent compared with baseline. The weekly average abdominal pain score is derived by scoring the worst pain experienced each day and taking the average for one week.
2) A Stool Consistency Weekly Responder is defined as a participant who experiences a 50 percent or greater reduction in the number of days per week with at least one stool that has a consistency of BSFS Type 6 or 7 compared with baseline.
A participant needs to be a responder for both abdominal pain and stool consistency in the same week to be considered a responder that week.
Secondary outcome measures
Secondary outcome measures for the Double-blind treatment phase and Open-label treatment phase are:
- Stool frequency (mean over 8 weeks and the last 4 weeks based on a daily question in study diary)
- Stool consistency assessed as average number of days/week with Bristol Stool Scale type >5 (mean over 8 weeks and the last 4 weeks based on a daily question in study diary, and percentage of responders where responder is defined as participant with 50% reduction in this outcome compared with baseline [i.e. screening period])
- Abdominal pain (mean over 8 weeks and the last 4 weeks based on a daily question in study diary, and percentage of responders where responder is defined as participant with 30% reduction in abdominal score compared with baseline [i.e. screening period]). Scale of abdominal pain is scored on a scale from 0 to 10, where 0 means no pain at all and 10 means the worst possible pain imaginable.
- Bloating (mean weekly score over 8 weeks and the last 4 weeks based on a weekly question in study diary). Scale of bloating is from 0 to 6, where 0 means bloating was not bothersome at all and 6 means bloating was a very great deal bothersome.
- Urgency (mean weekly score over 8 weeks and the last 4 weeks based on a weekly question in study diary). Scale of urgency is from 0 to 6, where 0 means no urgency at all and 6 means a very great deal of urgency with bowel movements.
- Adequate relief of global IBS symptoms (percentage of participants based on a weekly question in study diary)
- IBS Severity Scoring System (IBS-SSS) score (weekly questionnaire)
- IBS-related Work Productivity and Activity Impairment (WPAI:IBS) (weekly questionnaire to assess percent work time missed due to IBS, percent impairment while working due to IBS, percent overall work impairment due to IBS, percent activity impairment due to IBS)
- IBS Quality of Life (IBS-QOL) score (4-weekly questionnaire)
- Patient Health Questionnaire 12 Somatic Symptom (PHQ–12 SS) scale (4-weekly questionnaire to assess total score and individual symptoms headache (e.), tiredness (n.) and sleep (o.))
- Use of rescue medication, i.e. loperamide (total number of days loperamide used each week and average over 8 weeks based on a weekly question in study diary)
- Adverse Events (percentage of participants reporting Serious Adverse Event (SAE) and Adverse Events (AE) possibly related to treatment and total number of SAEs and AEs reported)
Data for secondary outcome measures for the Follow-up phase will be collected at week 24 follow-up call using an investigator questionnaire developed specifically for this study. Data will only be collected from participants who reported adequate relief in the last 4 weeks of open-label treatment phase. The outcomes for the Follow-up phase are:
- Maintenance of treatment benefit (percentage of participants who report increased or maintained treatment benefit at 8 weeks)
- Enterosgel® use (percentage of participants who report having used Enterosgel® during the follow-up period; frequency of use in these participants)
- Loperamide use (percentage of participants who report having used less loperamide during the follow-up period than before the trial)
Exploratory outcome measures
- Qualitative and quantitative data for faecal microorganisms and biomarkers will be collected at baseline and at the end of double-blind treatment period (week 8) in a subgroup of 20 participants using GI-MAP™ assay (Invivo Clinical Ltd, UK). Participants will be selected for stool testing by the randomisation program so that ten participants from each treatment group will be tested. Data will be compared between treatment groups at week 8. Week 8 data will also be compared to baseline in all participants. Depending on the findings, other analyses might be performed in this exploratory dataset.
- Qualitative and quantitative data for intestinal motility, fluid volume, gas content and physiology will be collected at baseline and at 4 weeks of open-label treatment period in a subgroup of 16 participants using Magnetic Resonance Imaging (MRI). MRI data will be analysed using GIQuant image processing software (Motilent Ltd, UK). Only participants recruited to the main study from the University Hospital of North Durham and Newcastle Upon Tyne Hospitals will be invited to take part in this assessment.
Participants will attend 4 study visits and receive 1–2 follow-up calls from their local research team. The schedule of visits and procedures conducted at each visit are summarised in Figure 2.
Screening Visit (–2 weeks)
Informed consent will be obtained before any trial-specific procedures take place. Eligibility will then be determined against all criteria except for the stool consistency and abdominal pain criteria, which will be determined over the next 2 weeks using an electronic diary or a paper diary (for participants unable or unwilling to use the electronic diary). In addition, if a participant is of childbearing potential, a pregnancy test should be conducted after the 2-week screening period if a participant is confirmed to be eligible. Any criteria related to medical history or medication use that cannot be confirmed from the participant’s medical records at screening due to these not being available to the research team, can be initially assessed based on participant-reported information. However, such eligibility criteria must be confirmed against the participant’s medical notes before the participant is randomised. Vital signs (pulse, blood pressure) should be taken and confirmed to be within the following ranges: systolic blood pressure 90–140 mmHg; diastolic blood pressure: 50–90 mmHg; heart rate: 50–105 beats per minute.
Demographic data and current medical conditions and concomitant medications should be recorded in the electronic Case Report Form (eCRF).
If the participant passes all the screening steps above, they are asked to complete a daily diary for 14 days to record stool consistency and abdominal pain. Training on how to use the electronic diary will be provided. If a participant is not able or willing to use an electronic diary, they will receive a paper diary containing identical questions. The participants will be instructed not to use any antidiarrhoeal medication during the screening period.
If the participant fails screening due to lack of screening phase symptoms, they can be re-screened once if the investigator believes the level of symptoms during the initial screening period were atypical for them and that there is a likelihood of achieving symptom thresholds on a further attempt. Participants should not be informed of the detailed reason(s) for why they failed screening, in order not to influence their responses if re-screened. There should be a minimum of 2 weeks from failing screening to re-screening. Participants can be enrolled into re-screening remotely with a phone call unless they need to be re-consented (i.e. if Patient Information has changed). Participants can also be re-screened once if their vital signs were outside accepted range at initial screening.
Baseline Visit (week 0)
After the 14-day screening period, screening diary data will be reviewed to check eligibility against the diary-based eligibility criteria. If an electronic diary was used, the diary system will automatically evaluate eligibility. If a paper diary was used, the site investigators should enter the diary data in the electronic database to allow the system to evaluate eligibility. A negative pregnancy test must also be obtained from any female participants of childbearing potential. Participants whose eligibility is confirmed, will complete study questionnaires (IBS-SSS, IBS-QOL, PHQ–12 SS, WPAI:IBS) and get randomised to blinded treatment. Participants will also receive a pack of paper questionnaires (IBS-SSS, IBS-QOL, PHQ–12 SS, WPAI:IBS) to complete at home during the treatment phase. In total 20 study participants at selected research sites will be selected by the randomisation program for stool sample testing. A separate consent will be sought for the provision of stool samples. The selected participants who consent, will be provided with a stool sample kit and a pre-paid postage envelope to post the sample to the central laboratory where the samples will be analysed. Participants recruited to the main study from pre-selected sites will be invited to take part in MRI assessment. These participants will be provided with a separate MRI information sheet at Baseline visit and will have the opportunity to discuss the assessment with the research team and ask any questions before deciding whether they wish to consent to MRI by signing a separate written informed consent form. If a participant decides not to consent to stool sample testing or MRI assessment, this will not affect their participation in the main study. Participants who consent to MRI will undergo two scans: at Baseline (although not necessarily on the same day as the Baseline Visit) and 12 weeks later, i.e. after 4 weeks of open-label treatment. The scans will take place at Newcastle Upon Tyne Hospitals and will not last longer than 20 minutes involving structural and motility (cine) imaging.
Follow-up call (week 2)
The site research team will contact the participants to ensure that they are continuing in the study and discuss any potential issues with the diary, questionnaires or the study treatments. No data will be recorded on this call, except for any reported AEs or changes in medical history or medications.
Follow-up Visit 1 (week 8)
Participants will complete study questionnaires (IBS-SSS, IBS-QOL, WPAI:IBS, PHQ–12 SS) and AEs and changes in medical history and medications will be reviewed. All participants will receive instructions on how to take Enterosgel® for the next 8 weeks of open label phase. Participants will also be provided with copies of the paper questionnaires for the next 8 weeks. Those participants selected for stool sample testing at Baseline will receive a stool sample kit.
Follow-up Visit 2 (week 16)
Participants will complete study questionnaires (IBS-SSS, IBS-QOL, WPAI:IBS, PHQ–12 SS) and AEs and changes in medical history and medications will be reviewed. All participants will be asked the following question: With regard to your IBS symptoms, compared with the way you felt before you started study treatment, have you, in the past 4 weeks, had adequate relief of your IBS symptoms? a) Yes b) No. Those participants who respond Yes, will receive a follow-up phone call in 8 weeks. Those who respond No, will receive no further follow-up from the research team and will complete the study.
Follow-up call (week 24)
The site research team will contact those participants who had received adequate relief from the open-label treatment for a brief follow-up interview (see Follow-up Visit 2 above). Any AEs and changes in medical history and concomitant medications will be recorded.
Sample size estimation
The sample size calculation was based on demonstrating superiority for the primary outcome, i.e. response to treatment, with 90% power at 5% significance level. Assuming a response rate of 20% in the placebo group and 35% in the active treatment group, 182 participants per treatment group are required. Assuming 15% drop-out rate, in total 430 participants will need to be enrolled. The response rate of 20% in the placebo group is based on previous studies (31, 32). The sample size was calculated using a power calculator for binary outcome superiority trial (Sealed Envelope Ltd).
The study will be conducted at approximately 30 primary and secondary care sites and private gastrointestinal clinics in England. GP surgeries acting as Patient Identification Centres will also refer patients to participating research sites. Sites will identify potential participants opportunistically and through searches of their patient databases, waiting lists, case records and referrals. Some research sites will utilise advanced software (Clinithink Ltd, UK) to identify potentially eligible patients from their clinical databases. The study can be advertised at participating sites and in public with materials approved by the Research Ethics Committee and the Health Research Authority. The study has developed a dedicated website which enables the public to check if they may be eligible and locate the contact details of their closest participating site. Finally, the study will recruit through the ContactME IBS registry (33) which contacts potentially eligible patients with details of the study. All potentially eligible patients will be provided with a Patient Information Sheet either when visiting the GP/hospital/clinic or by post or email. Patients should be allowed at least 24 hours to consider the study information before they are consented into the study.
Eligible participants will be randomised by a delegated member of the site research team to a double-blind treatment group (placebo or Interventional) in a 1:1 ratio. Randomisation will be performed using a computer-based online randomisation tool (Sealed Envelope Ltd, UK). The randomisation algorithm is based on the minimisation method where treatment allocation is stratified by study centre.
Participants randomised to the Control Group will receive placebo for 8 weeks. Participants randomised to the Interventional Group will receive Enterosgel® pre-diluted in water for 8 weeks. Both the participants and the research teams will be blinded to the treatment allocation until the end of the study.
Unblinding (code-break) should only be performed during the trial in a situation where information about the participant’s trial treatment is necessary in order to provide appropriate and optimal medical care. Requests for unblinding will first be reviewed by the PI or sub-PI who evaluates the information and the importance of unblinding in the given circumstances. If they decide that unblinding is necessary to ensure appropriate medical care, an unblinding request form should be submitted through the eCRF system. Unblinded treatment allocation will then be sent to the person who requested the unblinding. In case of emergency unblinding, the PI will be responsible for deciding whether the participant should continue on trial treatment. Unblinded participants should be followed up according to the study protocol until the end of the study.
Data on IBS symptoms and treatment use will be collected using a study-specific diary, which will be available as an electronic version developed by Sealed Envelope Ltd (UK). The electronic diary can be completed online by following a link provided on daily email and text message notification. For participants who are not able or willing to use the electronic diary, a paper diary will be provided. Copies of the paper diary are also provided as a back-up to participants using the electronic diary. For double-blind and open-label diaries completed on paper, the Sponsor’s research team will complete data entry into the electronic diary database. Study data recorded on any other paper source documents (e.g. questionnaires) will be transferred by the site investigators to an eCRF developed by Sealed Envelope Ltd (UK). The eCRF will be accessible via Internet browser and will be password protected to ensure that only authorised site staff and research team members can enter the system to view, add or edit data according to their permissions. Source data will be available at the site to document the existence of the study participants and will include the original documents relating to the study (demographics, medical history, medication, informed consent forms, questionnaires).
Analysis and archiving
After eCRF data entry is completed, all data have been monitored and raised queries have been resolved, the database will be locked. The complete exported dataset will be transferred to the statistical programmers who will complete the analyses in accordance with the Statistical Analysis Plan. 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.
The study will be conducted in accordance with the current approved protocol, International Conference of Harmonisation (ICH) Good Clinical Practice (GCP) guidance, relevant regulations and standard operating procedures. Regular monitoring will be performed in accordance with the ICH GCP and a risk-based Trial Monitoring plan to evaluate compliance with the protocol and accuracy in relation to source documents. In addition, data will be regularly monitored for completeness and quality using automated programmed edit checks. Any data issues are raised as queries in the eCRF system by study monitors.
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.
Detailed methodology statistical analyses of study data will be documented in a Statistical Analysis Plan. This trial will be reported according to the CONSORT guidelines for clinical trials.
Analyses will be conducted following intention-to-treat (ITT) principles with outcomes analysed according to the participant’s original, randomised group irrespective of deviations based on non-compliance. The statistician will remain blind to allocation until after the trial is complete and data locked.
All participant baseline data will be summarised descriptively by trial arm. Continuous measures will be reported as means and standard deviations while the categorical data will be reported as counts and percentages.
The primary outcome measure is the percentage of participants defined as study period responders. Where necessary, multiple imputation will be used to impute missing daily abdominal pain and stool consistency scores before the required derived variables are generated (see Missing data below for further details). Once obtained, the primary outcome data will be summarised descriptively and logistic regression will be used to compare the placebo and Enterosgel® groups, with Odds Ratio and 95% confidence interval reported.
Secondary outcome data will be summarised descriptively at different time points by trial arm. The secondary outcomes will be analysed using either analysis of covariance (ANCOVA) models (for stool consistency and abdominal pain following multiple imputation), linear mixed effects models (continuous secondary outcomes), or mixed effects logistic regression models (binary secondary outcomes). The mixed effects models will contain indicator variables for treatment group and, where appropriate, time plus a time-treatment interaction. The models will be adjusted for the baseline measure of the outcome, where available.
Significance tests will be two-sided at the 5% significance levels unless otherwise stated. All models in the analysis of the double-blind and open-label phases will be adjusted for participant’s age and gender at baseline. Analyses will be undertaken in Stata v13 or later (to be confirmed in the final report).
Multiple imputation by chained equations will be used to impute missing values in daily abdominal pain and stool consistency scores before the primary outcome is derived. A sensitivity analysis will be undertaken to compare the results using multiple imputation with a complete case analysis. The complete case analysis will only use abdominal pain and stool consistency data where participants provided scores on all seven days within a week (i.e. weeks containing at least one missing value of abdominal pain/stool consistency will be excluded).
Quality assurance and control
The principle investigator (PI) will be responsible for ensuring that the site is complying with the study protocol, current version of the World Medical Association Declaration of Helsinki, ICH-GCP guidelines and the applicable regulatory requirements. The PI will be responsible for ensuring that all site staff involved in the study have been appropriately trained and are qualified to conduct their delegated tasks. All medical staff involved in this study are required to have a certificate in GCP.
Data handling and record-keeping/archiving
All study-related paper documents (e.g. paper diaries, questionnaires, consent forms, study logs) will be filed in the study files during the study and archived at the site for 5 years after the end of the study.
Case report forms and source data
Data will be recorded in the eCRF from source documents defined in source data agreement with each site. All participants receive a unique study identification number (participant study ID) and no identifying data such as name, initials or date of birth will be collected in the eCRF. Source data will be available at the sites for monitoring and auditing purposes. Source data will include the original documents relating to the study, including demographics, eligibility checklists, informed consent forms and study questionnaires.
Record-keeping and archiving
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 should be archived at the participating sites for 5 years and should not be destroyed until authorisation to do so has been received from the Sponsor.
Monitoring will be performed according to a risk-based, study-specific Trial Monitoring Plan by monitors delegated by the Sponsor. Monitoring includes checking participant eligibility criteria for all participants and confirming that data have been recorded correctly in the eCRF and any SAEs have been correctly reported and recorded.
Audits and inspections
All study documentation will be accessible to auditors and inspectors. All involved parties must keep the participant data strictly confidential. The Sponsor will conduct internal audits in accordance with a study audit plan.
Confidentiality and data protection
Access to source documents and other essential study documents will be permitted for purposes of audits and inspections. The study participants have consented to relevant sections of their medical notes and data collected during the study to be looked at by the research team, by individuals from Enteromed Ltd or contracted by Enteromed Ltd, from regulatory authorities or from the National Health Service (NHS) Trust, where it is relevant to this research. Participants have also consented to 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 for the purposes of delivery of the study treatment. No identifiable data will be collected in the eCRF or will be published in any abstracts or publications resulting from the study.
Stool samples will be taken by the selected participants at home using a provided kit that includes a postage envelope for sending the sample to the central laboratory where the samples will be received within 6 days from collection and immediately stored at 4C upon arrival in the laboratory. Protein aliquots will be prepared within 24 hours of receipt and stored at –20C until testing within 3 days. All protein testing will be performed using standard enzyme-linked immunosorbent assay (ELISA) methodology. Nucleic acids will be isolated from samples within 1–2 business days after sample receipt and Isolated nucleic acids will be immediately stored at –80C until testing. Analysis reports will be uploaded by the laboratory onto an online portal accessible by the Sponsor’s research team. Results will not be shared with the research sites or the study participants. The stool samples will be destroyed by the central laboratory after the samples have been analysed.
Types of AEs associated with medical devices and applicable for this study are defined in accordance with the European Commission guidelines on medical devices (34). Adverse Events will be collected throughout the study from screening visit until week 24. 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 and expectedness. In case of a SAE related to study treatment(s) or procedures the participant should be withdrawn from the study. Expectedness will be determined based on known side effects listed on the latest Instructions for Use for Enterosgel. Currently listed known side effects of Enterosgel are nausea and constipation.
Reporting of serious adverse events and other safety-related events
The Sponsor must report all SAEs, whether initially considered to be device-related or not, immediately to the MHRA. The Research Ethics Committee should be notified of any related and unexpected SAEs within 15 days. Reports of related and unexpected SAEs in double-blind trials should be unblinded. However, local investigators should only receive information on the code-break if it is necessary for the safety of the participant.
AEs suspected to be related only to an authorised auxiliary medicinal product (i.e. loperamide), and not resulting from a possible interaction with the investigational treatment, should be reported through the Yellow Card Scheme.