DeloRes trial: study protocol for a randomized trial comparing two standardized surgical approaches in rectal prolapse - Delorme’s procedure versus resection rectopexy

DeloRes is a randomized, controlled, observer-blinded multicenter trial with two parallel groups.

DeloRes will be performed in 13 trial centers. All participating centers are cooperating units with a special focus on colorectal surgery and all centers perform between eight and sixty surgical interventions for rectal prolapse per year. In order to minimize performance bias, only surgeons with an adequate experience in performing the approaches investigated operate on patients in this study (minimum number of procedures performed (‘life-time experience’): Delorme’s procedure=20, (laparoscopic) resection rectopexy=20). Each study center provides at least one surgeon with the required experience for Delorme’s procedure and one surgeon with the required experience for (laparoscopic) resection rectopexy (expertise based, best team approach). To ensure standardization for all participating centers an operative manual with standardized video sequences will be prepared. Moreover, consented crucial steps of each procedure will be captured in the clinical record file. In addition, in order to allow confirmation of a certain procedure quality, selected digital photos will be taken.

To reflect current practice and to increase external validity of the trial, perioperative standards (for example, bowel preparation, parenteral nutrition, fast-track, postoperative application of laxatives) will not be strictly standardized. Each trial center, however, will document its own standards in a short questionnaire and agrees not to change this standard during trial recruitment.

Recruitment of participants started in September 2010. The duration of the trial for each patient is expected to be 60 months with follow-up at 6, 12, 24, and 60 months after the primary surgery.

Consecutively screened and eligible patients will be included in the trial. In order to achieve comparable intervention groups, patients will be allocated by preoperative randomization 24 to 48 h prior to surgery after given written informed consent using a centralized web based tool (http://​www.​randomizer.​at). Block randomization stratified by center will be applied to achieve equal group sizes per center.

The laparoscopic approach is considered the standard approach for the transabdominal operation of full-thickness rectal prolapse. Laparoscopic resection rectopexy is suggested to yield better results in the early postoperative phase in comparison to the open approaches with equal recurrence rates in comparison to the open approach. However, the advantages of a laparoscopic approach become somewhat less evident under a fast-track regime, therefore open resection rectopexy is also acceptable via a Pfannenstiel incision. The latter approach has proven to be only moderately invasive in numerous procedures of the lower abdomen. The most frequently used perineal procedure is Delorme’s procedure, which shows low postoperative morbidity. The trial flow is illustrated in Figure1.

The clinically most relevant parameter in the treatment of full-thickness rectal prolapse is the time to recurrence. Therefore this parameter is defined as primary outcome measure, evaluated during the 24 months following primary surgery. Recurrence is defined as the circular protrusion of rectal mucosa through the anal canal and will be examined by standardized history, clinical examination, and photo documentation. To assess the primary outcome, patients are asked to perform a straining maneuver in a sitting position (patients not able to sit will be assessed in a lateral decubitus position). Then a photograph is taken during straining. The primary outcome is finally determined by the independent review board on the basis of the photograph.

Secondary endpoints are time to and incidence of recurrence of full-thickness rectal prolapse during 5-year follow-up, duration of surgical intervention, morbidity, SAE, all causes of mortality within 3 months after primary surgery (this period was chosen to get any mortality possible related to surgery. Patients with rectal prolapse are usually rather old and frail. There are multiple reasons for further morbidity or mortality which are expected to be unrelated to the surgical procedure in case they occur beyond the first 3 months), length of initial hospital stay, reoperation rate for recurrent prolapse, cumulative hospital stay and change in quality of life, constipation, and fecal incontinence as measured by appropriate questionnaires.

The time to and the incidence of recurrence of full-thickness rectal prolapse during a 5-year follow-up after primary surgery will be assessed as explained above. Morbidity occurring during the primary hospital stay is further differentiated into surgical and non-surgical complications, which are specifically defined as following: severity grading is done with the Clavien classification[19] and for anastomotic leakage with the classification of the International Study Group of Rectal Cancer[20]. The definitions of the secondary outcomes are shown in Table 2.

All protocol-required information collected during the trial must be documented in the paper-based CRF by the investigator. Any outstanding entries must be completed immediately after the final examination. The completed CRF must be reviewed and signed by the investigator named in the trial protocol.

In order to ensure that the database reproduces the CRFs correctly a double entry of data will be performed by two different people.

To reduce the number of patients not able or willing to visit the study centers a study nurse will be appointed to visit the patients and to assess the outcome at the specified time (‘flying study-nurse’). Furthermore, the time-to-event method will be applied for the primary analysis to allow for all available information including the observation time of patients who drop out early. Nevertheless, an additional percentage of patients will be recruited to assure a sufficient power for the confirmatory analysis.

Analysis of safety-related data is performed with respect to frequency of serious adverse events, frequency of serious adverse events stratified by intensity and causality, and frequency of morbidity in both treatment groups.

From the day of randomization until the regular end of trial follow-up or until premature withdrawal of the patient, all serious adverse events must be documented on a ‘serious adverse event form’ available in the investigator site file.

A serious adverse event will be defined as an event that results in death, is immediately life-threatening, requires or prolongs hospitalization beyond the 20th postoperative day for any medical reason, requires readmission for any medical reason within 3 months after the operation within this trial, requires readmission for treatment of surgical complications related to the study operation beyond 3 months postoperatively, or results in persistent or significant disability or incapacity. Serious adverse events will be classified in intensity (mild, moderate, severe), outcome (recovered completely, recovered with sequelae, not recovered, death, unknown), and causality (unrelated, possibly related, probably related, definitely related, not assessable).

The assessment is based on surgical findings and the clinical course of the patient. It needs to be done by the investigators. Serious adverse events have to be reported by the attending physician to the coordinating investigator or one of both study supervisors within 24 h after the SAE becomes known.

Participants are allowed to withdraw their written informed consent for the trial at any time and without giving reasons for their decision. If investigators or members of the independent Data Monitoring and Safety Board raise any concerns on an individual patient’s safety, the patient will be withdrawn from the trial.

The surgical interventions applied in this trial are clinically established standard methods for the treatment of rectal prolapse. Therefore, SAEs that will cause a premature end of the trial are not anticipated.

The DSMB will be informed about the recruitment and relevant safety data in regular time intervals. If any safety concerns arise, the DSMB members will confer on the continuation of the trial and can recommend stopping of the trial. The Ethic Committees then have to be informed.

Clinical monitoring will be performed by an institution which is independent from other trial staff and experienced due to participation in many other surgical trials. Monitoring procedures will be adapted to the study specific risks for the patients and standard operating procedures (SOP) will be implemented to ensure patients safety and integrity of the clinical data, for example, primary endpoint in adherence to study protocol. Pre-study visits will be performed in centers interested in participating in the study in order to ensure high compliance quality of the participating centers concerning, for example, patient recruitment and documentation. Prior to study start, all participating centers will be personally trained and introduced into all study specific procedures during individual on site initiation visits. Regular on-site monitoring visits are planned at all sites depending on the recruitment rate and quality of the data (approximately one visit per site and year). The investigator must allow the monitor to look at all essential documents and must provide support at all times to the monitor. For all subjects clinical source data verification (SDV) for all clinical items is planned. The extent of further SDV and/or the frequency of monitoring-visits will be adapted for individual centers in case of bad quality of data or if common protocol violations are observed. In return, frequency of monitoring visits can be reduced for reliable and compliant centers with high data quality. In addition to the SOPs all procedures will be predefined in a study-specific monitoring manual. Queries (for example, in case of missing values, implausibility, et cetera) have to be answered by the investigators in a timely manner in order to avoid that errors in data capture or entry are held on to.

To enable an independent risk assessment for the different surgical procedures, potentially related serious adverse events will be noted and periodically assessed by the independent Data and Safety Monitoring Board (DSMB). Detailed working procedures are defined in a different document.

An independent steering committee will be established. The steering committee will supervise the conduct of the trial and will issue recommendations for early termination, modifications or continuation of the trial, if necessary. The steering committee must be informed in a timely manner of SAE.

Benefit-risk assessment will be critically reviewed and has to be approved by the ethics committees in advance before first recruitment.

All interventions applied in this trial represent clinically established, standard methods of treating full-thickness rectal prolapse. Therefore the applicants do not anticipate any serious adverse event that might be triggered due to the patient’s participation in the trial itself.