The ReVo Study: Low-volume vs High-volume Rectal Irrigation

Rectal irrigation(RI) is introducing warm tap water through the anal canal into the rectum to initiate defaecation. It is recommended that rectal irrigation be considered in patients with evacuation disorders refractory to conservative measures and bio-feedback before performing surgery.

RI is provided either as low-volume(LV) or high-volume(HV). It is unknown if one type of RI is superior to the other and whether one type of RI has better outcomes in patients with a particular pathology.

This randomised controlled trial aims to compare outcomes between two types of RI (LV and HV) and assess efficacy and acceptability of RI as a therapy in patients with Chronic constipation (CC) secondary to evacuation disorders (ED).

Primary Objective To compare the impact of LV RI versus HV RI, upon disease-specific quality of life at three months in patients with CC secondary to ED.

Secondary Objectives

• Improvement in participants' symptoms from RI by measuring symptoms severity score at three months.
• To identify if subgroup of participants with anatomical or pathophysiological variant of ED identified on integrated total pelvic floor ultrasound (TPFUS) will have different outcome from using RI
• Compliance to allocated type of RI and reasons for discontinuation.

Visit 0 (V0): Potentially eligible participants will be identified by the Co-investigator(TG) from Telephone triage assessment clinic, bio-feedback clinic(BFB) and Multi-Disciplinary Meeting in PFU at St. Thomas' Hospital. TG will introduce the research to eligible participants by contacting via telephone or during BFB.

Eligible participants will be provided with an information pack with invitation letter, participant information sheet (PIS) and two consent forms with a return label to post one of the consent forms back for record. PIS will have all details and explanation of the aims, methods, anticipated benefits and possible risks of RI. It will also have contact details of the Principle Investigator (PI) and the TG should eligible participants have any questions regarding the research trial before participating or to escalate concerns during participation. Participants will have at least 48 hours to consider participation.

Telephone Appointment (TA): This will scheduled at least 48 hours after the eligible participant has received the information pack. TG will contact the eligible participant to discuss the trial in detail and answer any queries. After discussion, if eligible participant is happy to participate, both consent forms will be signed. Participants will then be asked to return one consent form to the department for record (return label provided). There is no obligation for eligible participants to give reasons for non-participation.

Participants during the trial can withdraw anytime without giving reasons and return to routine care. However, data collected up to that point will be used to analyse current research as per PIS and consent form.

After consent, a participant journal (PJ) will be posted with instructions to fill it in. PJ will record all participants' medications and visits to healthcare professionals for constipation in the past three months. It will also record bowel frequency two weeks before participants' first face-to-face appointment.

Visit 1, Face-to-face (V1F): Baseline assessment, randomisation, TPFUS and training in RI Participants will have medical history taken and undergo a physical examination of their back passage and vagina (female participants). Participants will be asked to hand over PJ filled at home and fill in four questionnaires which will help investigators assess impact of constipation on participants' daily routine. These are PAC-QOL, PAC-SYM, ICIQ-B and ODS-S as described in outcome measures.

Participants will be randomly assigned 1:1 into two groups; LV RI and HV RI. Investigators will use online software (Clinical trial randomisation tool by National Cancer Institute) for randomisation. Both LV and HV irrigation will be given a code by TG. PI will perform randomisation and will perform allocation concealment using sealed envelopes.

Participants will undergo TPFUS which is routinely performed on all our patients. It uses inaudible sound waves to provide real-time static and dynamic multi-compartmental pelvic floor assessment of anatomical and functional aspects.

The RI systems used in our unit are commercially available on prescription in National Health Service (NHS) practice. Participants will receive training on using RI system from our Nurse Specialist and will be provided equipment to commence RI at home from the next day. Participants will be shown how to record the frequency and volume of RI in the PJ and record any side effects, such as pain, bleeding, etc.

Participants will be contacted via telephone one week later to check for any issues. If necessary, investigators will arrange another training.

Visit 2- face to face (V2F): This appointment will be three months after starting RI where participants will fill in outcome questionnaires as in previous visit and PJ will be collected. This will end participation in the research trial and participants will return to routine care in our department.

During 3-month follow-up, participants may be withdrawn from the trial if become lost to follow-up after at least three failed attempts by TG to make contact via at least two different methods (e.g., telephone, email and letter), choose to withdraw and do not wish to participate in follow-up data collection or lose capacity.

The interventions (LV and HV RI) proposed are those already being offered to patients with CC secondary to ED in the Pelvic Floor Unit(PFU), St. Thomas' Hospital and many specialist centres globally. All interventions pose acceptable risks. TPFUS has been performed routinely in most specialist centres and is considered safe. RI has proven to be a low-risk intervention and has been widely used for a variety of ED. Serious adverse events (SAE) are rare, with one study reporting two non-fatal bowel perforations out of approximately 110,000 irrigation therapy. Other possible side effects include rectal pain, bleeding, painful haemorrhoids and anal fissure. A recent study reported an overall adverse event (AE) rate of 22% with all minor and reversible events considered.

This trial is categorised as Type A i.e. no higher than the risk of standard medical care.

Any AE or SAE reported by participant will be reported to the sponsor and Ethical committee by the PI. The PI may take urgent safety measures to ensure the safety and protection of the participants. The PI will send the Annual Progress Report to the sponsor and Ethical committee.

If the PI determines that, is it within the best interests of the participants to terminate the study, written notification will be given to the sponsor following which participants will be returned to the routine NHS care.

The research team in the PFU will be meeting every two weeks. A trial risk assessment will be conducted in collaboration with the PI and an appropriate trial monitoring and auditing plan will be produced. This will be authorised by the sponsor.

PAC-QOL comprises of 28 questions scored 0-4. Average score of the non-missing questions is calculated by total score divided by number of questions responded, is taken as participant score out of 4. Considering improvement in score of 10% as clinically relevant, we calculated sample size keeping level of significance as 5%, power as 90% and standard deviation of 0.8 in low-volume RI and 0.7 in high-volume RI groups as reported by Emmett CC et al. Adjusting for loss to follow up of 10%, we will need 83 participants in each group. However, should there be a greater than 10% dropout rate which we do not feel will be the case, we will then recruit more participants to be able to analyse with a significance of 5% and power of 90%.

Primary outcome Investigators plan to conduct intention to treat analysis to compare the two types of RI at the end of 3 months. Difference in improvement in PAC-QOL score will be tested using paired sample t-test. Results will be reported as means along with standard deviations of difference in pre and post rectal irrigation for both groups and the mean difference of two interventions along with 95% confidence interval with p-value less than 0.05 will be taken as statistically significant.

Secondary outcomes Investigators plan to conduct stratified analysis based upon findings on TPFUS (anatomical vs functional causes of CC secondary to evacuation disorders). Compliance to RI will be shown via proportion of participants using it at the end of 3 months. Adverse effects from RI will be presented as frequencies. Appropriate regression models will be developed to determine the influence of pre-treatment characteristics on the success of RI in all sub-groups. Analysis will be performed using Statistical Package for the Social Sciences which is an online software platform where P < 0.05 will be taken to indicate statistical significance.

Investigators plan to conduct interim analysis at half the required sample size. At this point, the efficacy outcome will be evaluated and if the difference between two types of RI is statistically significant enough to reach p-value of < 0.01 then that would be considered as sufficient evidence to establish the superiority of one irrigation system over another and continuing the trial further would not be justified.

In the event of a required protocol amendment, details will be submitted to the sponsor for authorisation.

Data Protection: Upon recruitment, identifiable participant data (IPD) will be collected on paper (CRF) to contact participants. CRF will be stored in locked cabinets while electronic data in a password protected file(PPF) on Microsoft access (MA). Only PI and TG will have access to IPD.

TG will generate and assign a unique trial registration code (UTRC) to each participant. Each participant's data will be collected and stored against the UTRC (pseudonymization). CRF will be kept in locked cabinets while electronic data will be recorded in PPF on MA. The participant's general practitioner will be informed of their participation after obtaining consent.

After data collection has ended, TG will create a copy of collected data without the UTRC in a PPF on Microsoft Access, thus completely anonymising data which will be emailed to the Statistician via encrypted email for analysis.

This study is sponsored by Guy's and St Thomas' NHS Foundation Trust (GSTFT) and indemnity is provided through NHS indemnity for clinical negligence. GSTFT is a member of the clinical Negligence Scheme for Trusts.

The project will be under PI and sponsor. The project will be overseen by PI and co-Investigators. The role of the PI will be to provide overall supervision of the study on behalf of the sponsor to ensure that research trial is conducted in accordance with the principles of Good Clinical Practice (GCP) relevant regulations.

A study launch meeting will be conducted. This will include training in the trial protocol, data collection, randomisation and taking informed consent.

The participants will not be identifiable with regards to any future publications. After trial completion, the pseudonymized records will be kept for a further five years and archived with Iron Mountain. All IPD will also be archived for a period of five years in locked cabinets in the Pelvic Floor Unit at St. Thomas' Hospital, therefore no third party will have access to it. At the end of the five-year retention period, permission will be obtained in writing from the sponsor prior to destruction of this material.

Once results are available, they will first be presented in a departmental meeting, followed by submission of a summary to health research authority. A brief summary of the outcomes will be posted to the participants. Finally results will be submitted to scientific journals or presented at a conference not involving any IPD.