Trial to compare mixed-use (multi-use and single-use) intermittent catheter management with single-use management over 12 months (The MultICath Trial): protocol for a non-inferiority randomised controlled trial

Aim

The MultICath Trial aims to find out whether mixed-use (multi-use and single-use) catheter management is no worse for safety, acceptability and cost-effectiveness than single-use catheter management.

Trial design

MultICath is a non-inferiority RCT, incorporating an internal pilot. Participants were recruited nationally by two non-NHS (National Health Service) hubs (University of Southampton and Glasgow Caledonian University).

Trial outcomes

Trial intervention: mixed-use (multi-use and single-use) catheter management

This is defined as use of both the participant’s usual single-use catheters and multi-use trial catheters. The trial multi-use catheter is the uncoated, 100% silicone, reusable Cliny catheter (Create Medic Co., Ltd.), with a standard Nelaton tip in Charriere sizes 10–16, and lengths 40 cm, 30 cm and 16.5 cm. These catheters are CE marked for repeated use over 28 days when cleaned between uses with an appropriate disinfectant.20 In the MultICath trial, the cleaning method is based on the Milton cold water method, that is, wash with soapy water followed by a 15 min soak in Milton solution (sodium hypochlorite 0.6%).14 Participants are asked to use, clean and reuse their Cliny catheters, for as many of their catheterisations as they can, and for a maximum of 28 days before replacing with a new one. Participants may also use their single-use catheters at times when they feel unable to use the multi-use catheter, for example, when at work or during the night.

Control: single-use catheter management

Participants allocated to the control arm continue to use their own single-use catheter supplied by their GP or nurse prescribing team (NPT). Control participants who report that they reuse single-use catheters are asked to use them once only during the trial.

Internal pilot

An internal pilot to assess set up, screening and recruitment methods was conducted at the two trial hubs, with defined remedial actions for different levels of recruitment below the target of 30 or more participants over 4 months. Participants recruited during the internal pilot were identified, screened, consented, recruited, randomised and followed up in the same way as proposed for the main trial. Their data will be included in the final analysis. The target number of 30 participants was achieved and progression to the main trial was agreed with the funders (see figure 2: participant flow diagram).

Figure 2

Participant journey through trial and data collection time points including outcome measures used. UTI, urinary tract infection.

Patient identification, recruitment and consent

Patients are screened and approached through GP practices and NPTs acting as patient identification centres who are themselves identified by the National Institute for Health and Care Research (NIHR) Clinical Research Networks (CRN) across England and Wales. In Scotland, potential participants were identified via the Scottish Primary Care Research Network and NHS clinics. Intermittent catheter users who come to know about the trial through other routes such as charities, consumer, or health organisations, or via the MultICath website, contact the MultICath research staff directly.

Potentially eligible patients are sent invitation letters, the participant information sheet (see online supplemental file 1) and an expression of interest form (EOI) either directly by the GP surgery or, on their behalf, by the hybrid mail service Docmail.21 Interested patients return the EOI by post in a prepaid envelope to one of the two hubs or contact the teams by email or phone. Secondary care teams within the two research hubs may directly approach patients and seek verbal consent to pass their contact details directly to the research team.

Consent is obtained in accordance with the principles of the UK policy framework for health and social care research22 by an appropriately qualified and delegated member of the research team. Patients expressing an interest are contacted by a researcher for additional screening. The trial is discussed with the patient, and all questions are answered. Eligible patients who wish to proceed are sent a trial consent form (see online supplemental file 2) and asked to provide written informed consent by signing and dating the consent form. Patients return their signed consent form to the research team for countersigning prior to any research-related tasks taking place and are then sent a fully signed copy.

Following consent and in preparation for randomisation, participants are sent a urine specimen kit and a copy of the data collection tools used at randomisation.

Eligibility criteria

Eligibility criteria for this pragmatic-design trial were developed to include participants from all major groups of IC users.

Inclusion criteria:

• Men and women aged ≥18 years.

• Currently using IC (via the urethra), performed by self or sole carer.

• Patients who have been IC users for ≥6 weeks.

• Patients where IC planned to continue for >12 months and 2 weeks.

• Able and willing to adhere to a 12‐month follow-up period.

• Patient has provided written informed consent for participation in the trial prior to any trial-specific procedures.

Exclusion criteria:

• <18 years.

• Use of IC for self-dilatation of urethral stricture without bladder drainage.

• Non-urethral route for catheterisation, for example, Mitrofanoff.

• Use of less than one catheter per day or seven per week.

• External, non-sole carer required for IC (ie, where sterile technique and catheter are required, eg, visiting community nurse performs IC).

• Inability to give informed consent or have primary outcome information collected.

• Employee or relation of employee of a manufacturer or distributor of IC catheters.

• Women who report they are pregnant or who plan to become pregnant during the trial.

• Participation in another trial.

• Patients in the terminal stages of an illness.

• Anything that, in the opinion of the chief investigator or a delegated member of the research team, prohibits the patient’s participation in the trial.

Randomisation

Randomisation is administered centrally by the Newcastle Clinical Trials Unit (NCTU) secure 24-hour web-based system. Participants are randomised to either mixed-use (intervention arm) or single-use only (control arm) on a 1:1 basis using a method of permuted random blocks of variable length, generated by the system itself, stratified by gender and hub. This is carried out by appropriately delegated members of the research team and access with individual logins.

Blinding

Blinding of the participants and research staff is not possible because of differences in the intervention, trial catheters and processes. Central laboratory staff analysing participant urine samples and the senior statistician are unaware of the allocated group.

Trial processes: intervention arm

Trial processes: control arm

Control participants continue to use only their usual single-use catheters obtained in their normal way and are required to stop reusing catheters if they are doing so. Following randomisation, their start date is delayed by 2 weeks to maintain a similar timeline to the intervention participants. On day 14 participants have a preplanned phone call with a researcher to familiarise them with data collection tools and the processes for sending urine specimens and responding to signs and/or symptoms of UTI.

Follow-up

For participants in both arms, follow-up lasts for 12 months (see online supplemental table 1 for full schedule of events). During this time, data are collected using a range of data collection tools (see table 1).

Process of recording UTI

Participants are asked to take the following actions if they suspect they have a UTI:

1. Send a urine specimen to the trial laboratory. The process for collecting and sending a urine specimen to the trial laboratory is described in the primary outcome section.

2. Record UTI signs and/or symptoms and help-seeking/self-help activities. Participants are asked to complete a self-report UTI questionnaire which is sent directly to the NCTU for data entry. UTI data are also recorded by researchers at monthly follow-ups to ensure all data are captured.

Laboratory analysis

A central laboratory based at The Newcastle upon Tyne Hospitals NHS Foundation Trust is processing urine samples on behalf of the trial. Two types of urine samples are collected from trial participants:

• Routine urine samples—collected at baseline, 6 and 12 months.

• Ad hoc urine samples at the onset of a suspected UTI.

The following outcomes contribute to the trial’s primary and secondary outcomes and are reported to NCTU:

Analysis and storage of trial urine samples is carried out according to the MultICath Laboratory Manual. Results of urine analysis are uploaded to the MACRO database from reports produced by the central laboratory.

Post-trial care

Participants are asked to revert to standard care which is continued use of their usual single-use catheters only.

Qualitative sub-study

Semi-structured qualitative interviews lasting approximately 30–60 min are conducted with up to 40 participants randomised to mixed-use catheter management. The purpose is to understand participants’ experiences of the multi-use catheter and the burden of cleaning catheters in different circumstances and places.

Health economics sub-study

The economic analysis will initially be conducted as a cost–consequence analysis, identifying additional health service and patientborne costs associated with multiuse catheters, potential changes in use of single-use catheters and other health sector resources associated with IC use. The primary economic analysis will be from the NHS and personal social services perspective. Costs will be estimated based on responses to individual patient-reported data including use of resources by treatment group, hospital and community-care use and combined with routine sources such as the Unit Costs for Health and Social Care.23 The economic analysis will report cost-effectiveness over the trial period for the mixed catheter management compared with single-use for intermittent urinary catheterisation using methods appropriate for economic analysis in non-inferiority designs.24 QALYs will be estimated based on responses to the EQ-5D-5L from which the incremental cost per QALY gained will be estimated. Incremental cost-effectiveness ratios will be calculated if one treatment does not dominate (ie, less costly and more effective) by estimating the difference in costs and effects (QALYs) between the two randomised groups. It is not planned for data from this economic analysis to be combined with any other trials.

Withdrawals

Participants can withdraw from the trial at any time without giving a reason. They can partially withdraw (withdrawal from the intervention but continuing to provide follow-up data) or completely withdraw (withdrawal from both the intervention and provision of follow-up data). Consent is sought from participants choosing to completely withdraw from the trial to retain data collected up to the point of withdrawal.

Effort is made to minimise withdrawals by providing support during planned monthly follow-up. The participants’ preferred methods (email, phone, videoconferencing, texting) are used and reminders sent to ensure that meetings are not missed. Between planned follow-ups participants are encouraged to contact the research team if they have any concerns and where possible the same researcher follows up the same participants to help build rapport.

Data management

Participant identification is via a unique trial identifier. Data are collected using case report forms (CRF) and participant-completed questionnaires (paper). CRF and questionnaire data are entered at site into the trial-specific electronic CRFs held within the MACRO database by a delegated hub team member. Participant UTI questionnaires are sent to NCTU for central data entry into the same database. Results of urine analysis are uploaded to the MACRO database from reports produced by the central laboratory.

Access to the trial database is password limited and restricted to delegated staff. The NCTU trial management team have ‘monitor role’ access to the trial database. Data collected within MACRO are regularly reviewed and built-in validation checks are applied regularly to ensure the completeness and accuracy of data reported.

Sample size and analysis

Given that not all IC users will experience UTIs, we aim to demonstrate that the mixed package does not increase the proportion affected. To calculate the sample size, we determined the non-inferiority margin, informed by the clinically important difference or ratio. Clinical importance in this context is not well defined in the literature: but a difference of around 20% in UTI rates has been taken to be important,25 though a smaller difference of 15% would be a safer choice.

As there are no reliable data on the proportion of patients experiencing UTIs in this mixed patient group, the non-inferiority margin is expressed as an OR of 2.0, as otherwise, the sample size calculation is too sensitive to the UTI rate in the control group. Using this non-inferiority margin of OR=2.0 equates to a margin based on a difference in UTI rates being higher in the intervention group by 12% if 70% of controls developed UTIs, higher by 15% if 60% of controls developed UTIs, or higher by 17% if the control risk were 50%.

Data from 208 patients per trial arm would provide 90% power to rule out an increase in UTIs expressed as an OR of 2.0 using a one-sided test (α=0.025). Initially, we aimed to recruit at least 520 in total, assuming an attrition rate of 20%. However, our attrition rate has been higher than anticipated and we have revised our sample size to account for 28% withdrawal and we, therefore, aimed to recruit 578.

The primary outcome (MCS-UTI+HS) will be calculated by the statistician using programming to bring together the various data sources. This will then be compared between the two treatment groups and a two-sided 95% CI will be calculated for the OR of the UTI rates. Non-inferiority will be accepted if the upper bound of the interval is below 2.0. Logistic regression will be used to explore the influence of covariates including gender, age, medical condition, Barthel index,26 carer/no carer and antibiotic prophylaxis on the incidence of UTI in the two groups. Analyses will be carried out on the per-protocol population, and as a secondary analysis, based on intention to treat.27 For participants who are lost to follow-up by 12 months, their information will be included in the ITT analysis up to the point that they are lost to follow-up, but a minimum of 6 months is required for the per-protocol analysis. For a participant to be included in the per-protocol analysis in the intervention group, their percentage reuse must be at least 25% or an average of 0.75 times per day during their potential time on intervention. If more than 10% of participants have missing primary endpoint data then multiple imputation may be attempted, performing at least 10 separate sets of multiple imputations by treatment group using chained equations. In addition, if judged to be appropriate, a tipping point analysis may be performed to test the robustness of the conclusion of the primary outcome analysis. All analyses will be fully described in the Statistical Analysis Plan.

In relation to analysis of the secondary outcomes, the number of MCS-UTI+HSs as an incidence rate, visible blood (from around or on catheter or in urine), antibiotic prescriptions and episodes of microhaematuria per participant will be modelled by Poisson regression comparing rates in single and multi-use trial arms with the exploration of the influence of covariates as above. If the data are overdispersed, negative binomial regression will be used instead. Binary secondary outcomes will be analysed using methods analogous to the primary analysis. Missing secondary outcome data will be considered as described for the primary outcome analysis above. Missing items from a partially completed validated QoL questionnaires will be handled as described in the relevant scoring manual.

There could be substantial attrition during the 12-month follow-up which would have the potential to influence conclusions around the primary outcome. If there were no difference in outcomes between the intervention and control arms at 12 months, this could potentially be due to excessive attrition with few or even no participants continuing by then with reuse. To allow for this possibility the data collected at 6 months will be analysed for the relevant outcome measures. These 6-month measures will be considered to be further secondary outcomes and analyses will be analogous to those performed for the 12-month data.

Safety reporting

AEs are recorded at monthly phone calls or ad hoc phone calls and entered into MACRO. An assessment of seriousness, severity and causality is undertaken for each AE. This assessment must be determined by the PI, subinvestigator or suitably qualified researcher delegated these duties by the principal investigator.

Events or symptoms related to UTI, difficulty or inability to pass the catheter, pain or discomfort passing the catheter, difficulties with catheter removal, pain or discomfort experienced following catheter removal and visible blood associated with catheterisation, are not reportable AEs. They are collected and reported as part of the primary and secondary outcomes of the trial.

Serious adverse events (SAEs) are AEs that meet the definition of serious and are reported to the chief investigator (CI), CTU and sponsor within 24 hours of the research team being made aware of the event. Unexpected serious adverse device effects (USADEs) are reported to the Research Ethics Committee within the required reporting timelines. Pre-existing conditions and any preplanned hospitalisations (eg, elective surgery) not associated with clinical deterioration are not classed as SAEs.

AEs terms are built-in to MACRO with the ability to use the Medical Dictionary for Regulatory Activities (MedDRA) to code AE data. All coded AEs are reviewed by the CI (or a delegated person with sufficient clinical experience) to ensure appropriate MedDRA codes have been assigned to events.

Trial conduct and governance

The trial is conducted in accordance with the UK Policy Framework for Health and Social Care including guidelines for Good Clinical Practice.28 Before any hub could enrol patients into the trial, that hub must have been in receipt of Health Research Authority approval and have issued capacity and capability confirmation (English site) or have local Research and Development approval in place (Scottish site). They must also have been issued the green light to commence recruitment by the sponsor.

The Trial Management Group is responsible for the day-to-day management of the trial, overseeing all aspects of the conduct of the trial to ensure that the protocol is adhered to and taking appropriate actions to ensure patient and data safety. The Trial Steering Committee (TSC) monitors progress and supervises the trial to ensure it is conducted to high standards in accordance with the protocol, relevant regulations and guidelines. The Independent Data Monitoring Committee (IDMC) independently monitors safety and data throughout the trial. The TSC and IDMC include independent experts (clinicians and statisticians) and the TSC also includes an independent patient representative. A charter has been put in place for each committee and clearly outlines each committee’s roles and responsibilities.

Patient and public involvement and engagement

Patient and public involvement and engagement has been integral in the development and design of the intervention and the trial. This active collaboration improved the intervention and research design and aided with the development of trial documentation as well as recruitment of participants. The trial also includes an independent lay member in the TSC.