Objectives
This is a protocol for a Cochrane Review (intervention). The objectives are as follows:
To assess the probability of failure to maintain clinical remission, endoscopic remission, or both, following a switch from SASP or oral 5‐ASA drug (comparator) to another oral 5‐ASA drug (experimental) in adult ulcerative colitis patients at 52 weeks of follow‐up. The intervention of switching to the experimental drug will be compared to the continuation of the comparator drug.
To assess the safety of switching from SASP or oral 5‐ASA to another oral 5‐ASA drug in the aforementioned population.
Background
Description of the condition
Ulcerative colitis (UC) is a chronic inflammatory condition of a part or the whole of the large bowel. It results in lifelong illness that requires medical and, in some cases, surgical intervention [1]. The symptoms of UC include, but are not limited to: diarrhoea with or without blood, fever, abdominal pain, weight loss and fatigue [2]. The medical treatment of UC has seen great improvement in the last 20 years with the introduction of advanced therapies such as biologics and small molecules, but drugs containing 5‐aminosalicylic acid (5‐ASA) remain fundamental in the management of mild to moderate UC [3]. The drugs are administered through oral and rectal routes depending on the disease extension, where rectal formulations are used in distal disease, alone or in combination with oral formulations.
Description of the intervention and how it might work
The intervention being examined in this review is not the efficacy of oral 5‐ASA as this has been extensively examined in previous Cochrane reviews [4, 5]. This review examines whether switching from sulphasalazine (SASP) or oral 5‐ASA drug to another oral 5‐ASA drug in UC patients in clinical remission, endoscopic remission, or both, increases the risk of failure to maintain remission. The switch between these drugs has the potential to contain costs for patients and health care systems, but there is a risk of disrupting the effectiveness of the treatment through increased risk of disease flares and adverse reactions.
The challenge in the utilisation of oral 5‐ASA in the management of UC has historically been ensuring its delivery to the colon with the lowest risk of adverse reactions. Oral 5‐ASA is absorbed and acetylated in the jejunum [6]; without inhibition of this absorption, it will not have any efficacy in the treatment of UC as 5‐ASA acts topically in the colonic mucosa and has no systemic effect [7].
The earliest description of UC treatment with 5‐ASA stems from 1942 [8]. These UC patients were treated with SASP as the drug is composed of 5‐ASA and sulphapyridine molecules joined by an azobond. Sulphapyridine acts as a carrier molecule that inhibits the enteral absorption of 5‐ASA, thereby ensuring its delivery to the colon [9]. The azobond is cleaved by colonic bacteria releasing 5‐ASA to exercise its anti‐inflammatory effects [9, 10]. The use of SASP in the treatment of UC is somewhat limited by intolerance due to adverse hepatic, haematological and dermatological reactions, which approximately 20% of patients experience [11]. Many of these adverse reactions have been linked to the carrier molecule sulphapyridine [12], and once this relation was understood in the late 1970s, new and safer drugs were developed. These new drugs utilise pharmacological techniques other than binding 5‐ASA to sulphapyridine, such as modified‐release formulations [9].
Carrier molecules: e.g. balsalazide, which is formed when 5‐ASA is bonded to the inert molecule 4‐aminobenzoyl‐B‐alanine; and olsalazine, a dimer of 5‐ASA molecules.
Time‐dependent release: 5‐ASA is coated with ethyl cellulose, which dissolves slowly over time in contact with water and extends the release of the drug.
pH‐dependent release: tablets are coated with pH‐resistant methacrylic acid copolymer. The coating dissolves at pH values above 6, depending on the type of methacrylic acid polymer. As the small bowel is mostly acidic, the formulation releases 5‐ASA in the distal part of the ileum and the colon, where the pH is relatively higher.
Most of the above‐mentioned delivery systems were developed, tested and marketed in the 1980s and 1990s [9]. The prodrugs and modified‐release formation drugs have mostly shown their efficacy in comparison to SASP in randomised controlled trials [13], but besides improvement in their dosing regimens with larger tablet strengths [14], once‐daily treatment regimens [15], and more delayed‐release formulations [14, 16], the drugs have seen little development. The drugs with a delayed‐release formulation seem to have the same efficacy in maintaining remission of UC compared to the original formulations [14, 17]. However, differences in their chemical composition, delivery methods and strength mean that it is not feasible to switch between the drugs, thus hindering economic competition between the drugs. The European Crohn's and Colitis Organisation had, in its first two consensus guidelines, recommended 5‐ASA drugs to be prescribed by proprietary names [18, 19], but this topic was not mentioned at all in the two later guidelines [20, 21]. The British National Formulary maintained until 2014 that 5‐ASA drugs are not interchangeable [22], but the later editions did not comment on the topic [23].
The differences in the pharmacokinetics of the drugs described above can theoretically lead to intraindividual differences in the amount of 5‐ASA delivered to the colon. For example, a carrier‐molecule‐based drug can deliver enough 5‐ASA to the colon, but a time‐dependent release drug might release most of its 5‐ASA in the small bowel, leading to a lower amount of 5‐ASA reaching the colon. The amount of 5‐ASA reaching the distal part of the colon, where ulcerative colitis is typically more severe, might be even lower. Switching within the same mode of delivery could also lead to different clinical efficacies as different types of methacrylic acid polymers dissolve at different pH levels. For example, Eudragit L100 dissolves at pH 6 and Eudragit S100 at pH 7 [9].
The considerations described above are primarily based on the pharmacokinetic properties of the different delivery technologies, but the different drugs have also been investigated in regard to their absorption (plasma levels of 5‐ASA), metabolization and excretion (concentrations of 5‐ASA and metabolites in urine and faeces). These pharmacokinetic studies suffer from methodological and statistical shortcomings and, overall, the absorption, metabolization and excretion in urine and faeces seem to be comparable for all 5‐ASA drugs [24]. Lastly, decision‐making should be based on clinical outcomes.
Why it is important to do this review
The current oral 5‐ASA drugs utilise decades‐old pharmaceutical technologies [9]. The first description of the medical use of methacrylic acid copolymer to coat tablets to achieve pH‐dependent drug release was published in 1953 and the first commercial use of these polymers in the chemical industry was with the marketing of Plexiglas in 1933 [25]. Ethylcellulose has been used in the formulation of tablets since the 1970s [26]. Despite the age of these technologies, these drugs are still being sold at high prices with hindered competition because of lack of evidence for the effectiveness and safety of drug switches.
In 2023, mesalazine‐containing drugs were the 22nd most expensive drug measured by gross revenue in Denmark, competing with modern insulins [27]. However, two years earlier, a much cheaper pH‐dependent‐release 5‐ASA drug was marketed in Denmark at half the price of the market‐leading Asacol [28, 29]. This significant difference in price led to a debate on whether all Danish UC patients should be switched to the cheaper drug. The switch would certainly reduce the patients' medical expenses, but also contain cost for the Danish welfare system, as it offers reimbursement of drug expenses based on the cost of yearly drug purchases. While the switch would decrease cost for the patient and the system, the increased incidence of disease flares due to lower effectiveness of the treatment would also be expected to increase the use of health care resources (e.g. endoscopic procedures, inpatient treatment, use of advanced therapies and surgery) burdening the system and maybe even equalising the cost reduction realised from the drug switch.
The English health care system saw a similar debate around 2010 [30]. Primary care trusts initiated a pharmacy‐led switch of 5‐ASA drugs as a cost‐containment initiative. Gastroenterologists in secondary care were not involved in the development of the programme, leading to controversy as the gastroenterologists did not consider that the clinical consequences of the switches were adequately explored. There were concerns about harming patients by increasing the risk of disease flares and adverse reactions, and at the same time, harming the doctor‐patient relationship as the switch was pharmacy‐led. A few years later, an English epidemiological study was published, using data from prescription databases, that investigated the risk of disease flares following the pharmacy‐led switch [31]. It reported no difference in the risk of disease flares in the total investigated population (N = 501), but it found a difference in the subgroup of adherent patients (N = 236; risk of disease flares in people who switched drugs = 26.3%, risk of disease flares in those who did not switch drugs = 7.5%; risk ratio 3.5 (95% confidence interval 1.16 to 10.62)). This study defined a disease flare as a doubling in medication possession ratio as a proxy for disease activity. This debate has, to our knowledge, not been settled using direct and clinically relevant outcomes from interventional studies, neither by performing new studies nor by synthesis of evidence from already published studies. The latest and fifth iteration of the Cochrane review for oral 5‐ASA concluded that there are no differences in the efficacy of the different 5‐ASA drugs in their ability to induce or maintain remission [4, 5]. The review on maintenance of remission does not consider drug switching [5].
If switching to cheaper 5‐ASA drugs is safe and effective, significant savings for UC patients and health care systems can be realised while maintaining the same quality of care.
Objectives
To assess the probability of failure to maintain clinical remission, endoscopic remission, or both, following a switch from SASP or oral 5‐ASA drug (comparator) to another oral 5‐ASA drug (experimental) in adult ulcerative colitis patients at 52 weeks of follow‐up. The intervention of switching to the experimental drug will be compared to the continuation of the comparator drug.
To assess the safety of switching from SASP or oral 5‐ASA to another oral 5‐ASA drug in the aforementioned population.
Methods
We will follow the Cochrane Handbook [32] and the Methodological Expectations for Cochrane Intervention Reviews (MECIR) when conducting the review [33], and PRISMA 2020 when reporting the review [34]. Amendments to this protocol will be documented and dated for later reporting in the final review.
Criteria for considering studies for this review
Types of studies
We aim to include prospective, randomised controlled trials (RCTs) of a parallel design with treatment duration of 12 to 52 weeks. We will not include cross‐over trials as we are investigating the risk of failure to maintain remission, and the washout period in a cross‐over study design is expected to increase the risk of disease activity disrupting the remission criteria. Cluster‐randomised trials will not be eligible because we wish to investigate individual differences in the efficacy of treatments. We will not include quasi‐RCTs due to the risk of selection bias.
Studies will be eligible regardless of publication language, but we will only search for and include studies published in 1980 or later, as no other 5‐ASA drugs beside SASP existed before that year. For studies in languages other than English, we will seek volunteer assistance for review and data extraction via Cochrane Engage, and if this is not possible, we will report the studies as ‘awaiting classification’. We will not include any studies which have been retracted, and will examine any errata for information. A study will only be eligible for inclusion if the two authors reviewing the studies agree.
Types of participants
The participants will be adults (18 years of age or older) suffering from UC whose disease is managed with SASP or 5‐ASA. At the time of enrolment in the studies, the participants must be in clinical remission, endoscopic remission, or both, according to the definition used in each trial. We will include participants of all genders, with any comorbidities, and with any extent of disease.
Types of interventions
The studies to be included must have switched adult UC patients in clinical remission, endoscopic remission, or both, from SASP or oral 5‐ASA to another oral 5‐ASA drug. The duration of the intervention and comparison is 12 to 52 weeks. Based on our prior knowledge of the literature, some studies have switched drugs for most but not all participants. We will include such studies if at least 80% of participants have switched drugs, as these studies still constitute an important part of the evidence. Inclusion of these studies will increase heterogeneity, and we will address this issue in the sensitivity analysis. We have no restrictions on the daily dose, strength of formulation or number of daily doses for SASP and 5‐ASA.
Outcome measures
Outcome measures are dichotomous and are described in the section below. Several scores have been developed to measure clinical and endoscopic activity of UC [35], and different historical periods have used different scores and thereby different definitions of remission; core outcomes have only been established more recently [36]. We expect that most of the included studies were conducted and published in the 1980s and 1990s, so we will use the definition of clinical and endoscopic remission used in each included trial.
Critical outcomes
Failure to maintain clinical remission, endoscopic remission, or both, at 52 weeks of follow‐up
Failure to maintain clinical remission at 52 weeks of follow‐up
Failure to maintain endoscopic remission at 52 weeks of follow‐up
Risk of adverse events at 52 weeks of follow‐up
Important outcomes
Failure to maintain clinical remission, endoscopic remission, or both, at 12 to 26 weeks of follow‐up
Search methods for identification of studies
Electronic searches
The search will be limited to the years 1980 to current as drugs being investigated in this review did not exist before the 1980s [9].
We will search the following databases for relevant studies.
Cochrane Central Register of Controlled Trials (CENTRAL)
MEDLINE Ovid (1980 to current)
Embase Ovid (1980 to current)
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov)
World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch)
To identify RCTs, we will use the latest published Cochrane MEDLINE highly sensitive and precision‐maximising 2023 filter and Embase RCT 2023 filter [37], as described in Supplementary material 1. If the initial search date is more than 12 months old prior to publication, we will rerun the search. If new studies are identified, we will seek to include them in the review. If that is not possible, we will report the studies under 'studies awaiting classification' or under 'ongoing studies' if they are not completed.
Searching other resources
We will search the following resources for other studies not included in the above‐mentioned electronic searches.
Searching within previous relevant systematic reviews on the same topic (see Supplementary material 1 for list of reviews).
Forward and backward citation search of included studies via Scopus.
At this stage, we will investigate if studies to be included have had postpublication amendments (expressions of concern, errata, corrigenda and retractions). We will use publication type terms and free text searches in MEDLINE and Embase, as described in the technical supplement to the Cochrane Handbook [38].
Data collection and analysis
Selection of studies
Two authors will independently review studies for eligibility based on the inclusion criteria. Cases of disagreement will be managed by a discussion between the two authors, in which a consensus must be reached. The unit of interest in the review is the individual study, so we will collate multiple reports of the same study and give a justification for which report is to be used in the review. If a study has incomplete or unobtainable data, we will record it as incomplete and list it in the table of 'Characteristics of studies awaiting classification'. We will add any ongoing studies or studies completed but not yet reported to the ongoing studies table.
We will use a flow diagram based on PRISMA guidance to include details of the flow of studies from the number of identified references in the search to the number of included studies in the review [34]. The process for the selection of studies will be documented sufficiently to enable us to report a table of 'Characteristics of excluded studies'. We will use Covidence to manage the results of our search [39]. Abstracts and articles requiring translation will be reviewed by asking native speakers through Cochrane Engage.
Data extraction and management
Two authors will independently extract the necessary data and, in cases of discrepancies, the two authors will together review the data in order to reach a consensus. For each study, each author will save a filled data collection form, and consensus data will be saved in a third copy. In cases of multiple reports of the same study, we will collect the data from all the reports on the same data extraction form. We will use the most complete report as the main source, and seek to resolve any inconsistencies between the reports by contacting the study authors.
We will extract the following data.
Study: years conducted; publication year of report; setting and type (e.g. parallel, cross‐over)
Participant characteristics: age, gender, disease location; number of randomised patients; definition of remission at study enrolment; proportion in remission and time in remission before enrolment
Intervention and comparison: drug name, active ingredient and dosing; follow‐up time
Outcomes: extraction based on intention to treat; definition of remission at outcome assessment; proportion failing to maintain remission (clinical and endoscopic); adverse reactions
Methodology: recruitment; randomisation process; blinding; missing data and selected reported results
Funding source and conflicts of interest
The data extraction templates will be built in Covidence and data will be exported to RevMan. The templates will be piloted before extraction and data extractors will be trained on their use. The extracted data are expected to have been reported as proportions and thus require no conversion to another format appropriate for meta‐analysis.
Risk of bias assessment in included studies
We intend to assess the risk of bias in the included studies using the Cochrane Risk of Bias 2 (RoB 2) tool [40, 41], using the intention‐to‐treat (ITT) principle to quantify the effect of assignment to the interventions at baseline. All outcomes will be assessed for bias at the aforementioned time point, i.e. after 12 to 52 weeks of follow‐up. Two authors will independently assess the risk of bias and, in cases of disagreement, a consensus must be reached through discussion. The assessment will include the bias domains below, and the risk of bias in the included studies will be reported in three categories: low risk of bias, high risk of bias and 'some concerns' of bias.
Bias arising from the randomisation process
Bias due to deviations from intended interventions
Bias due to missing outcome data
Bias in measurement of the outcome
Bias in the selection of the reported results
Furthermore, we will describe funding information and conflicts of interest for all included studies in the 'Characteristics of included studies' table. The judgement will be noted as: 'notable concern about conflict of interest' or 'no notable concern about conflict of interest', with a description of the reasons for the judgement.
Measures of treatment effect
All the outcomes of this review are dichotomous. For each outcome, we will extract the total number of observations and the total number of events from each included study. An event will be defined as a change in state of the clinical condition of the participant in the studies, i.e. a change from remission to disease activity, and thereby failure to maintain remission. Based on these values, a risk ratio and corresponding 95% confidence interval will be calculated for each study in each outcome analysis. The effect of interest is the ITT effect. We regard a 10 percentage point difference between the experimental and comparison drugs as a minimal clinically important difference.
Unit of analysis issues
For studies with multiple interventions, for example multiple doses, we will combine the experimental groups into a single group for analysis of outcomes, except in subgroup analyses where individual group results can be included. For studies with measurements of outcomes at different time points, we will use the outcome with the longest follow‐up.
Dealing with missing data
To deal with missing data, our analysis will follow the ITT principle, i.e. participants with missing data will be analysed according to the group they were randomised to. We will contact the original investigators to request missing data if possible, and we will use the Cochrane RoB 2 tool to assess bias due to missing data. For all critical outcomes, we plan to perform a best‐case/worst‐case analysis to evaluate the potential impact of missing data by calculating the most extreme possible outcomes. These outcomes will be compared to a complete case analysis. Furthermore, we will address the potential impact of the missing data in the Discussion section of the review.
Reporting bias assessment
Each included study will be assessed for missing results of particular interest for the review. We will compare study register data (if available), study protocols (if available) and abstracts (if available) to the published reports. If possible, we will contact study authors to request the missing results. The methods described in each study report will also be compared with the reported results to assess for selective reporting bias. We plan to assess the overall risk of bias due to missing evidence for all four outcome meta‐analyses using the ROB‐ME tool [42]. Two authors will perform all assessments independently, and in cases of disagreement a consensus must be met. For each meta‐analysis, we will report the overall risk of bias judgement in three categories: 'low', 'high' and 'some concerns'.
If more than 10 studies are included, we will present contour‐enhanced funnel plots for the assessment of reporting biases and assess them according to the guidance in the Cochrane Handbook for Systematic Reviews of Interventions [42].
Synthesis methods
The outcomes described in this review are dichotomous, and we will pool risk ratios from the included studies (with 95% confidence intervals) if the intervention, study population and outcomes are similar. We will conduct the following comparison: continued treatment with SASP or 5‐ASA drug versus switching to another 5‐ASA drug.
We will use a random‐effects model with the inverse‐variance approach incorporating the restricted maximum likelihood (REML), as we are investigating intervention effects that are related but might not be similar [43]. We expect to use the Hartung‐Knapp‐Sidik‐Jonkman‐method to calculate the confidence interval of the effect estimate if there are more than two studies and the between‐study estimate is greater than zero. If the data are reported both as dichotomous and continuous outcomes across the included studies, we will combine the outcomes assuming a logistic distribution and express odds ratios as standardised differences in means [43]. We will use RevMan as the statistical software for the synthesis [44].
To assess the heterogeneity between the studies included in the meta‐analysis, we will use the Chi2 test and report its value on the forest plot. We will regard a P value of 0.10 or lower as statistically significant and evident of statistical heterogeneity, but will not regard a P value above 0.10 as evidence of no heterogeneity. We will also use the I2 statistic to assess heterogeneity, considering a value of 75% or above to be evident of considerable heterogeneity. Heterogeneity will be further explored in the sensitivity analysis, through performing the meta‐analysis with a fixed‐effect model and with/without outlying studies if such can be identified. If we identify considerable heterogeneity, we will not report a meta‐analysis. Heterogeneity will also be taken into account when interpreting the results, especially if there is variation in the direction of effect.
Investigation of heterogeneity and subgroup analysis
We plan to assess the methodological heterogeneity of the included studies by comparing their designs, outcome measurement tools, and the domains of the risk of bias assessment described earlier. To assess clinical heterogeneity, we will compare participant characteristics, definitions of remission, time in remission before enrolment, follow‐up time, characteristics of interventions, and outcomes. Furthermore, we will address methodological and clinical heterogeneity by description in the text, conduct of random‐effects meta‐analysis to allow for variation between studies, conduct of subgroup analysis described below, exclusion of extremely outlying studies, and discussing how heterogeneity might affect the results and conclusions of the review. In case of severe heterogeneity across the included studies, we will not report the meta‐analysis.
If we include at least five studies in the analysis, we will perform the following subgroup analysis for all four critical outcomes.
Switching from one mode of delivery to another: carrier‐molecule to non‐carrier‐molecule delivery; pH‐dependent to non‐pH‐dependent delivery; pH‐dependent to pH‐dependent delivery
Higher versus lower dose before switching, based on molarity, as drugs with carrier molecules have higher molecular weight. High doses are defined as: SASP > 2 g, mesalazine > 1 g, balsalazide ≥ 3 g and olsalazine > 1 g.
Distal disease (which is more difficult to treat through the oral administration route) versus non‐distal UC (extensive and left‐sided).
Long (> 12 weeks) versus short (12 weeks) time in remission before switching drugs.
Publication year: before 2000 and from 2000 onwards.
The first four subgroup analyses will require a combination of study‐ and participant‐level variables. Random effects model will be used within and between subgroups. For the interaction test, we will use a Q‐test based on one‐way analysis of variance.
Sensitivity analysis
We will conduct the following sensitivity analyses for all four critical outcomes.
Model: performance of fixed‐effect meta‐analysis compared to random‐effects meta‐analysis.
Proportion of participants who switched drugs: exclusion of studies which have switched drugs for most (but not all) participants.
Risk of bias: exclusion of studies with high risk of bias, high risk or some concerns of bias arising from the randomisation process and high risk or some concern of bias due to deviations from the intended interventions.
Remission at study enrolment criteria: exclusion of studies using only clinical remission at inclusion before drug switch.
Missing data: as described under Dealing with missing data, we will perform and compare the findings of best‐case/worst‐case and complete case analyses for all four critical outcomes.
Certainty of the evidence assessment
The review will include a summary of findings table that presents all five outcomes [45].
Failure to maintain clinical remission, endoscopic remission, or both, at 52 weeks of follow‐up
Failure to maintain clinical remission at 52 weeks of follow‐up
Failure to maintain endoscopic remission at 52 weeks of follow‐up
Risk of adverse events at 52 weeks of follow‐up
Failure to maintain clinical remission, endoscopic remission, or both, at 12 to 26 weeks of follow‐up
For each of the assessed outcomes in this review, we will utilise the GRADE system to assess and report the certainty of the body of evidence and to draw conclusions about the certainty of evidence within the text of the review [45, 46]. Two authors will perform the assessment independently, and cases of disagreement will be managed by a discussion between the two authors, in which a consensus must be reached. The GRADE system’s five considerations (risk of bias, consistency of effect, imprecision, indirectness and publication bias) will be used in the assessment to downgrade the certainty. We regard an absolute change of at least 10% in risk of failure to maintain remission as clinically significant. We will calculate the optimal information size and use it in the assessment of imprecision. Justifications for the GRADE assessments will be documented and reported in the review. The certainty will be reported as high, moderate, low or very low. We will reach a consensus among all review authors for the final GRADE assessment.
Equity considerations
We plan to assess the included studies for inequity by reviewing and reporting whether they – through design and conduct – have excluded certain populations based on their characteristics (age and gender) and whether the setting of the studies might give rise to consideration of inequity.
Consumer involvement
The Danish patient association for UC, Tarmforeningen, has provided us with feedback on outcomes. They appreciated the use of clinical outcomes and a long‐term follow‐up period of 52 weeks, which they regarded as important for UC patients. We also plan to ask the association to review our plain language summary to ensure that it provides the necessary information and is easily understood by lay readers.
Supporting Information
Supplementary materials are available with the online version of this article: 10.1002/14651858.CD016374.
Supplementary materials are published alongside the article and contain additional data and information that support or enhance the article. Supplementary materials may not be subject to the same editorial scrutiny as the content of the article and Cochrane has not copyedited, typeset or proofread these materials. The material in these sections has been supplied by the author(s) for publication under a Licence for Publication and the author(s) are solely responsible for the material. Cochrane accordingly gives no representations or warranties of any kind in relation to, and accepts no liability for any reliance on or use of, such material.
Supplementary material 1 Search strategies
New
Additional information
Acknowledgements
We thank NN from the Centre for Evidence‐Based Medicine Odense (CEBMO) and Cochrane Denmark (University of Southern Denmark) for providing feedback on the protocol.
Editorial and peer‐reviewer contributions
The following people conducted the editorial process for this article:
Sign‐off Editor (final editorial decision): Grigorios I Leontiadis, McMaster University, Hamilton, Canada;
Managing Editor (selected peer reviewers, provided editorial guidance to authors, edited the article): Sue Marcus, Cochrane Central Editorial Service;
Editorial Assistant (conducted editorial policy checks, selected peer reviewers, collated peer‐reviewer comments and supported editorial team): Cynthia Stafford, Cochrane Central Editorial Service;
Peer‐reviewers (provided comments and recommended an editorial decision): Dr Greco Umberto, UOC Hospital Pharmacy of Ferrara, Italy (patient and public review), Katharina da Silva Lopes, Cochrane Evidence Production and Methods Directorate (methods review), Jo Platt, Central Editorial Information Specialist (search review).
Contributions of authors
OKA conceptualised the review and wrote a protocol draft. AH reviewed, commented on and approved the draft protocol. MMN reviewed, commented on and approved the draft protocol. LKH reviewed, commented on and approved the draft protocol. MML reviewed, commented on and approved the draft protocol. MTJ reviewed, commented on and approved the draft protocol. JK reviewed, commented on and approved the draft protocol.
Declarations of interest
OKA has declared working as a physician in public practice treating ulcerative colitis patients and has no other conflicts of interest. AH: has declared working as a physician in public practice treating ulcerative colitis patients and has no other conflicts of interest. MMN: has declared working as a physician in public practice treating ulcerative colitis patients and has no other conflicts of interest. LKH: has declared working as a physician in public practice treating ulcerative colitis patients and has no other conflicts of interest. MML: has declared working as a physician in public practice treating ulcerative colitis patients and has no other conflicts of interest. MTJ: has declared working as a physician in public practice treating ulcerative colitis patients and received travel, accommodation and conference registration expenses from Tillotts Pharma. JK: has declared working as a physician in public practice treating ulcerative colitis patients and has no other conflicts of interest.
Sources of support
Internal sources
-
None, Other
No internal sources of support received.
External sources
-
None, Other
No external sources of support received.
Registration and protocol
Cochrane approved the proposal for this review in August 2025.
Data, code and other materials
Data sharing is not applicable to this article as it is a protocol, so no datasets were generated or analysed.
Disclosure of artificial intelligence use
Artifical intelligence and automation have not been used in the writing of this protocol.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary material 1 Search strategies
Data Availability Statement
Data sharing is not applicable to this article as it is a protocol, so no datasets were generated or analysed.