Infection control in ERCP using a duodenoscope with a disposable cap (ICECAP): rationale for and design of a randomized controlled trial

This protocol (version 7.0) was written and reported according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) recommendations [16, 17], and a SPIRIT checklist is provided in Supplemental 1. This is a consecutive parallel arm phase IV RCT which will assess 1) the persistent bacterial contamination rate (PBC) of a duodenoscope with a disposable elevator cap (DEC) versus a traditional duodenoscope and 2) the technical and clinical efficacy of the DEC duodenoscope versus a traditional duodenoscope. The study will take place at a single high-volume tertiary ERCP referral center in Calgary, Alberta, Canada, where over 1500 ERCPs are performed annually. Here, ERCP-related care is provided to patients of Calgary (population 1.4 million) and surrounding areas, comprising a total catchment population of close to 2 million. All procedures will be performed by experienced endoscopists having each performed over 1000 ERCPs or by advanced therapeutic endoscopy trainees under direct supervision of the expert endoscopists.

All consecutive patients at the study center who meet the eligibility criteria below will be invited to participate in the study. For cases in which it is determined that the patient failed to meet the eligibility criteria after the patient has agreed to participate in the study and/or has signed the written informed consent form, the study personnel will complete screening forms as well as indicate the specific inclusion/exclusion criterion that was not met. Such a patient will be considered a screen failure and will not be included the final analyses.

This study will be conducted using approved commercially available devices. All devices will be used in accordance with the appropriate Directions for Use (DFU). The Pentax ED34-i10T2 duodenoscope is specifically designed for use with the DEC™ disposable elevator cap. It offers high-definition endoscopic visualization and ergonomic handling while affording the opportunity for complete removal and disposal of the duodenoscope cap, which houses the elevator mechanism. The Pentax ED34-i10T model is a standard high-definition duodenoscope currently used at our centre and will serve as the control instrument. Though it has a detachable tip for ease of manual distal end access, the elevator mechanism remains a part of the scope, and the tip is non-disposable, needing to be reattached to the rest of the scope after cleaning. The interventional and control instruments are shown in Fig. 1. All duodenoscopes used for this study will be less than 24 months old, and their daily use will be comparable. All scopes will undergo scheduled routine maintenance and will be removed from study or clinical use if any damage is known, only being returned once repaired. These steps will be taken acknowledging the association between duodenoscope damage and residual contamination [20]. There are 4 DEC T2 duodenoscopes that will be used throughout this study and 6 standard T1 duodenoscopes. All duodenoscopes will be reprocessed by the same automated endoscope reprocessor and stored in a common cabinet after reprocessing.

Patients will be required to meet all of the following inclusion criteria in order to be eligible for study participation:

Patients meeting any of the following exclusion criteria will not be eligible for study participation:

Consecutive patients undergoing ERCP will be flagged as potentially eligible for study participation. On the day of the procedure, the patient will be approached by a research assistant (RA), who will explain the study, confirm eligibility, and answer any potential questions. If the patient agrees to participate, the relevant written informed consent form is signed and witnessed. If the patient decides not to participate, the ERCP proceeds as per the usual standard of care. Duodenoscopes are stored in a cabinet in the ERCP unit and will be clearly marked and color-coded according to study group assignment.

After the ERCP is complete, the in-room nursing team will carry out standardized post-endoscopy manual cleaning and disinfection of the DEC or traditional duodenoscope. In cases where the DEC was used, the cap will be disposed of. These processes will be timed by the research assistant. Following this, the scope will be portered to the automated reprocessing room for disinfection and reprocessing, which will also be timed.

After reprocessing, staff will then observe the following sequence to determine whether there is any PBC of the duodenoscope after standardized disinfection and reprocessing. These samples will then be shipped for microbiologic analysis. Our unit’s protocol currently dictates that reprocessed scopes undergo point-of-care bioluminescence scans to rule out persistent contamination. Scopes that fail bioluminescence testing are required to be reprocessed anew until the bioluminescence scan is negative. This will take place routinely independent of the study; however, the only change for study scopes will be that our study’s sampling protocol (described below) will take place regardless of the bioluminescence result.

The protocol for duodenoscope sampling that will be utilized for this study is adapted from the Duodenoscope Surveillance Sampling and Culturing Protocols, which were developed jointly by the Department of Health and Human Services (DHHS), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC), and American Society for Microbiology (ASM) [21]. This procedure is summarized here, and will occur within 1 h of the completion of reprocessing.

The presence of any microbial population(s) will be assessed using plating for growth in aerobic conditions. 0.1 mL of wash fluid will be plated to blood agar, MacConkey agar, and Columbia blood agar with colistin-nalidixic acid. If after 72 h there is no growth, the sample will be deemed negative, and will be discarded. Positive samples will be further characterized. Growth will be reported in colony-forming units (CFU)/mL. For Gram-negative bacilli (GNB), these will be reported with CFU/mL and the isolated organism(s) will be reported as identified by matrix-assisted laser desorption/ionization (MALDI). Non-GNB organisms will be reported only if CFU/mL is greater than 20, and a group identification (ie, coagulase-negative Staphylococcus, or Candida) will be provided.

Patients will be contacted by the RA by telephone 30 days following their ERCP to assess for any ongoing symptoms and advise of any adverse events, including unplanned emergency department visits or inpatient admissions. The patient’s medical record is also reviewed at 30 days for complete details of any unplanned emergency department visits, inpatient admissions or prolonged admissions. In accordance with the Declaration of Helsinki and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Practice Guidelines, a participant is free to withdraw from participation in the study at any time, for any reason without prejudice to their future medical care by the physician or the institution. Investigators can also withdraw patients from the study at any time due to potential concerns over safety. Unblinding can occur at this stage if necessary. Data collected up to the time of withdrawal will be analyzed. Study sequences are summarized in Fig. 2.

There are two co-primary outcomes for this study. The first primary outcome is the PBC rate with the ED34-i10T2 duodenoscope and DEC, compared to the currently used ED34-i10T duodenoscope, following standardized disinfection and reprocessing. PBC will be defined as growth of any identifiable microorganism at ≥20 colony forming units (CFU) per 20 mL of solution [22].

The second primary outcome of the study is the ERCP technical success rate with ED34-i10T2/DEC, compared to ED34-i10T. Technical success will be determined in duplicate by two blinded outcome adjudicators with no knowledge of the patient’s study group allocation. The adjudicators will review redacted and de-identified procedure reports for each study patient, and determine the presence or absence of technical success of the overall procedure based on a set of a priori definitions (Tables 1 and 2). Redacted elements will include type of duodenoscope used, specific endoscopists or trainees performing the procedure, and any identifiable patient information including name, date of birth, and health record numbers. Disagreements will be resolved by a third blinded adjudicator. Technical success will also be determined subjectively on a case-by-case basis by the endoscopist performing the procedure, in order to measure correlation with the adjudicator determinations as a secondary analysis, but will not be used in the determination of outcome for the primary analysis. Failure of the procedure due to inability to safely perform the ERCP under conscious sedation will not constitute a technical failure for purposes of this study, in either study arm.

Secondary outcomes include clinical success rates, overall and specific early (intraprocedural) and late (30-day) adverse event rates, 30-day mortality and healthcare utilization rates, procedure and reprocessing times, and ease of device use. Secondary study outcomes and their definitions are listed in Table 3.

The investigators have previously designed and implemented the Calgary Registry for Advanced and Therapeutic Endoscopy, CReATE [26]. CReATE is a high-fidelity prospective database that collects over 300 data fields in real-time for each ERCP procedure, including detailed patient, endoscopist, procedure and post-procedure variables. Therefore, CReATE serves as the ideal data collection platform for this randomized trial. Data are inputted by a full-time research assistant, and stored and managed on a secure encrypted web application specializing in confidential healthcare database implementation and maintenance [27].

De-identified study variables (accessible only to study investigators) will include patient demographics, comorbidities, and relevant medications, endoscopist procedural volume, presence and stage of trainees, degree of procedural involvement of trainees, ERCP indication, procedural details, procedure time, intraprocedural adverse event(s), and sedating medication(s).

For primary outcome 1, a 2018 study [12] demonstrated a PBC rate of over 20% after standard duodenoscope disinfection, but with limited sample size for Pentax scopes. In addition, preliminary results from the FDA in 2019 in real-world settings demonstrated a 9.3% total sample positivity rate among Pentax duodenoscopes [28]. We thus propose that reduction in PBC from 10% with ED34-i10T to 3% with DEC (a relative risk reduction of 67%) would be considered clinically significant. Using a power of 80% with a two-sided alpha of 0.05, 194 subjects in each arm will be required, for a total of 388 patients. Four hundred twenty-six patients will be recruited, accounting for a 10% sample loss rate.

For primary outcome 2, we selected a baseline ERCP technical success rate of 92% based on our centre’s prospective data over the last 12 months. We propose that technical success of DEC within a margin of 7% will result in an ability to conclude non-inferiority based on the importance of avoiding additional MDRO outbreaks. Using a power of 80% with a one-sided alpha of 0.025 [29], 236 subjects in each arm will be required, for a total of 472 patients. Five hundred twenty total patients will be recruited, accounting for a 10% attrition rate. Primary outcome 2 and all secondary outcomes will be determined via both intention to treat (ITT) and per protocol analyses.

Data and safety monitoring will be performed by a committee of two independent study monitors. The monitors will ensure ongoing quality of data collection for the co-primary and secondary outcomes. The monitors will also review safety outcomes in both study arms and inform the investigators if there are any unforeseen trends. Any important safety outcomes or protocol amendments will be reported on clinicaltrials.gov and to our local institutional ethics board.

No industry-related funding has been received to support this study or to compensate study investigators. The temporary use of the DEC duodenoscopes has been granted by Pentax Canada. Our study has received full ethics approval from the Conjoint Health Research Ethics Board (CHREB) at the University of Calgary (REB 19–0983). Our study is registered on clinicaltrials.gov (NCT04040504). There are no planned audits into trial conduct given there is no funding from industry sponsors. Dissemination of study results is planned through publication at medical conferences and/or in peer-reviewed journals.