Fecal microbiota transplantation for treatment of moderate to severe ulcerative colitis: a living systematic review protocol [version 1; peer review: awaiting peer review]

Background: Several primary studies and systematic reviews (SRs) have been published over the past 10 years to assess the safety and effectiveness of fecal microbiota transplantation (FMT) as a treatment for ulcerative colitis. The objective of this review is to evaluate the efficacy and safety of fecal microbiota transplantation for adult patients with moderate or severe ulcerative colitis. Methods: We will carry out a living systematic review including only randomized controlled trials (RCT) irrespective of publication type, year and language of publication. To prioritize the intervention (TFM administration route), comparisons (placebo, alternative treatment or no treatment) and outcomes (clinical remission, clinical relapse, serious adverse events, clinical response, free time without corticosteroid treatment and health related quality of life) more relevant for supporting the clinical decisions in the treatment of UC patients, we will perform a Delphi process conducted by an expert panel in the field of gastroenterology and colorectal surgery. Searches will be performed in Epistemonikos database and results will be incorporated into the L·OVE platform identified as “Fecal microbiota transplant in ulcerative colitis”. We will evaluate the risk of bias of the included randomized trials using the ROB-2 tool and assess the Open Peer Review Approval Status AWAITING PEER REVIEW Any reports and responses or comments on the article can be found at the end of the article. Open Research Europe Page 1 of 6 Open Research Europe 2022, 2:17 Last updated: 10 FEB 2022


Plain language summary
Research has been carried out over the last few years to evaluate the safety and usefulness of fetal microbiota transplantation as a treatment for ulcerative colitis. The objective of this study is to assess the efficacy and safety of fecal microbiota transplantation for adult patients with moderate or severe ulcerative colitis.
To meet our objective, we will search for all studies that answer our research question which have a design of a randomized controlled trial. We will search for them in the database Epistemonikos and select the studies that meet our criteria for inclusion. We will evaluate the risk of bias of the selected studies and assess the certainty of the evidence using specific tools. We will monitor the new published evidence every two months, searching for relevant studies that could indicate changes in the available evidence. This monitoring process will last 12 months.

Introduction
Condition being studied Ulcerative colitis (UC) is a chronic inflammatory disease that mainly affects the large intestine and rectum, causing ulcers and other damage to the tissue 1 . Typical intestinal symptoms of the disease are abdominal pain and bloody diarrhea. Other symptoms associated with the disease are the presence of tenesmus or urgency, weight loss and fever 1 . The etiology of the UC is still unclear. Different studies propose that the disease could be the result of the interaction of different factors: a genetic predisposition, changes in the composition of the intestinal microbiota and an abnormal immune response to environmental exposures, mainly microbial 2-4 . The peak incidence is in the 15-25-year age group, and there is another peak between 55 and 65 years of age 1,5 . The disease alternates symptomatic episodes with periods of clinical remission or mild activity 2 . Approximately 15% patients may experience an aggressive course, and 20% of these patients may require hospitalization for severe disease activity 6 . Despite recent advances in overall disease management and improved therapeutics, patients with inflammatory bowel diseases still experience a substantial disease burden 5 .
Why it is important to do this review Fecal microbiota transplantation (FMT) consists of the instillation of a fecal solution from a healthy donor to the gastrointestinal tract of a diseased recipient. Thus, natural bacteria are transferred in order to replace other pathological microbiota. It can be performed through different techniques such as colonoscopy, enema, upper endoscopy and nasojejunal or nasogastric tube. FMT is an alternative treatment option for patients with multiple recurrences of clostridium difficile infection for whom appropriate antibiotic treatment has failed 7 . In theory, every disease associated with the impairment of intestinal microflora might benefit from the therapeutic modulation of the gut microbiota. In this regard, several primary studies and systematic reviews (SRs) have been published over the past 10 years to assess the safety and effectiveness of FMT as a treatment for ulcerative colitis. We performed an initial tiered search strategy, beginning with the identification of SRs included in the Epistemonikos Database 8 for mapping the available evidence about this topic. We identified 16 SRs conducted during 2014 and 2021, to assess the effect of FMT in inflammatory bowel diseases including ulcerative colitis. Based on these SRs we developed an evidence matrix that revealed 45 primary studies that have been included in the published reviews, but no review has included all of them 9 . The most recently published SRs, Zhou 2020 10 and Liu X 2021 11 , included 5 and 11 studies, respectively. When reviewing the primary studies, we found that there is great variability in FMT delivery methods, type and dose of microbiota, target population and outcomes of interest.
Considering the characteristics of the available evidence, the wide variability of the SRs currently published, and taking into account that the evidence on this therapy is on the rise (i.e. new studies have been published recently and other studies are going to be published in the near future), we propose to carry out a living systematic review with the aim of updating the estimates of the effect of the FMT on ulcerative colitis patients once new evidence emerges. This SR will be developed as part of the Living Evidence to Inform Health Decisions project, which supports health system organizations in the implementation of the living evidence model for the development of evidence synthesis to inform health decisions 12 .

Objective
To evaluate the efficacy and safety of fecal microbiota transplantation for patients with moderate or severe ulcerative colitis.

Methods
As part of the Living Evidence to inform health decisions project 12 , a common methodological protocol has been defined for developing multiple living systematic reviews and living overviews of reviews. This protocol is reported in line with the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) guidelines 13 . The systematic review has been registered on PROPSERO (CRD42021257579) on 29 th October 2021.

PICO question
To define the research question most relevant to support the clinical decisions in patients with UC, we will ask a group of national experts in the field of gastroenterology and colorectal surgery to compose a panel to select the population, intervention, comparison, and outcomes.
We will perform a one-round consultation, following a modified Delphi process 14 . First, we will elaborate an online questionnaire including different UC diagnostic criteria, TFM administration routes, comparisons and outcomes as described in the Extended data 13 .
Second, we will ask to the panel to rate each item, from 1 to 9 points as follows: low importance (score: 1-3), important but non-critical (score: 4-6), and critical (score: 7-9). The items rated as critical will define the final PICO question.

Eligibility criteria
Types of studies to be included. We will include randomized controlled trials (RCTs).

Types of participants.
Adult patients (>18 years old) diagnosed with moderate or severe ulcerative colitis using the diagnosis criteria selected by the panel.
Setting. Studies including patients in any setting (hospital or community dwelling). No distinctions will be made based on the income of the countries in which the studies were carried out.
Intervention. Treatment with fecal microbiota transplantation for ulcerative colitis including any frequency of administration, or treatment duration, and the administration route selected by the panel.
Comparator. The comparator (placebo, pharmacological treatment, or no treatment) selected by the panel.
Types of outcome measures. We will not consider the outcomes as an inclusion criteria. We will include the studies independently of the reported outcomes.

Methods for identification of studies
The main search source will be the Epistemonikos database, a comprehensive database of systematic reviews and other types of evidence, maintained by screening multiple information sources to identify systematic reviews and their included primary studies, including Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, DARE, HTA Database, Campbell database, JBI Database of Systematic Reviews and Implementation Reports, EPPI-Centre Evidence Library 8 .
An additional search will be performed on MEDLINE in order to identify randomized trials/primary studies not included in reviews. The searches will cover from the inception date of each database. No publication status or language restriction will be applied to the searches in Epistemonikos. We will apply validated filters to identify clinical trials in the MEDLINE database.
Results from these searches will be automatically included in the L.OVE platform of the Epistemonikos Foundation 15 . This platform has been validated showing to be highly comprehensive source of evidence 16,17 .
Our literature search will be devised by the team maintaining the Epistemonikos-L·OVE platform, using the following approach: 1. Identification of terms relevant to the population and intervention components of the search strategy, using Word2vec technology 10 to the corpus of documents available in Epistemonikos Database.
2. Discussion of terms with content and methods experts to identify relevant, irrelevant and missing terms.

Medline. PUBMED.
(((((fecal* OR stool* OR microbi*) AND (transplant* OR bacteriotherapy*)))) AND (((ulcerative* AND colitis*)) AND (((inflammatory AND bowel) OR IBD OR IBDs) OR (crohn*) OR (ulcerative* AND colitis*)))) AND ((randomi* OR RCT OR placebo* OR trial OR "controlled-trial" OR randomly*)) Other sources. In order to identify articles that might have been missed in the electronic searches, and to keep monitoring for the new evidence that arise, we will do a manual search of the reference lists of included studies and will run additional searches in WHO International Clinical Trials Registry Platform and clinicaltrials.gov.

Selection of studies
The results of the literature searches will be automatically incorporated into the L·OVE platform (automated retrieval) identified as "Fecal microbiota transplant in ulcerative colitis".
Firstly, titles and abstracts will be independently screened by at least two reviewers against the inclusion criteria. We will resolve disagreements by consensus or by discussion with a third review author. Secondly, we will obtain the full reports for all records that appear to meet the inclusion criteria (according to the Delphi results). We will record the reasons for excluding studies and show the study selection process in a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram 18 .

Data extraction and management
We will use an excel spreadsheet to extract information about studies characteristics (characteristics of participants; inclusionexclusion criteria; intervention and comparison description, outcomes and results). Data extraction will be performed by two authors.

Data analysis Assessment of risk of bias of included studies.
We will evaluate the risk of bias of the included randomized trials using the ROB-2 tool 19 . Two independent review authors will do this assessment. Discrepancies will be resolved by consensus.

Measures of treatment effect.
Study results will be reported as pooled relative risks (RR), odds ratios (OR) for categorical outcomes or mean differences (MD) (or standardized mean differences, (SMD)) for continuous outcomes with the corresponding 95% confidence intervals (95% CI).

Data synthesis.
We will evaluate the heterogeneity of the included studies with I 2 as follows: I2 < 50% as low, heterogeneity, I2 > 50% and < 90% as high, and > 90% as very high. When heterogeneity is below 90%, we will perform a meta-analysis in RevMan 5.4.

Subgroup analysis.
We will perform the following subgroup analyses if data is available: • Moderate vs severe stage of the disease • Previous surgical treatment versus non-surgical treatment Sensitivity analysis. We will perform a sensitivity analysis excluding the studies with high risk of bias.

Certainty of evidence
We will assess the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach 20 , both for the evidence found as part of the initial or baseline review, and for the updates resulting from the living evidence process.
Two reviewers will independently define the certainty of evidence and discuss any disagreement to reach consensus. We will present the results using summary of findings tables.

Evidence monitoring and surveillance plan
In order to maintain the living evidence process for this review, the Epistemonikos-L.OVE platform 15 will be used as a technological enabler to support the evidence identification, screening, and selection. We will keep a living search in the L·OVE platform to detect systematic reviews and randomized controlled trials. Additionally, each three months, we will manually search for ongoing studies in the WHO International Clinical Trials Registry Platform and the clinicaltrials.gov.
One reviewer will be in charge of assessing the evidence that has entered the specific question in the L.OVE platform every month and apply the selection criteria presented above. If a potentially eligible study is found, a second reviewer will confirm its eligibility by reading the full text. Results of evidence surveillance will be collected and kept as part of the study records. Information for the PRISMA flow diagram will be updated accordingly. The PICO question and criteria for selecting studies will be revised and changed accordingly during the Living Evidence process every time new eligible evidence becomes available.
All new eligible studies will undergo the data extraction process. The data synthesis will be updated immediately after taking into account the predefined subgroups of interest, and the body of evidence for the outcomes of interest will be assessed following the GRADE approach accordingly looking for changes on the certainty assessment results.
The living process for this question will end when the certainty of the evidence on the updated estimates for the desirable and undesirable effects becomes high or after 12 months of surveillance whatever is reached first.

Statistical considerations for the living evidence synthesis
The inclusion of new studies identified as part of evidence surveillance and reporting on the outcomes of interest will follow this approach: We will perform a meta-analysis for each of the outcomes of interest reported by the new studies using a fixed-effect model in order to evaluate the statistical heterogeneity among included studies by using I 2 statistics. If new heterogeneity is detected (i.e. compared to the previous metaanalysis, new heterogeneity appears or increases), we will explore its potential sources by reviewing the new studies against previously included studies in order to identify reasons that may explain inconsistent results among studies. In the presence of unexplained heterogeneity (I2> 70%), we will consider not to meta-analyze them and explain the evidence synthesis narratively. If the I 2 is below 90%, we will perform a meta-analysis by using the fixed effects of the random effects model, whichever pertinent.

Dissemination plan
If during the living process, new relevant results that imply changes in the current clinical practice are identified, we will update the report of this review and disseminate the update among potential users.
We plan to communicate our review results as a publication in a scientific journal. We will also share technical reports to the hospital Health Assessment Committee. We will share the results through our social media channels. All periodical updates will be available in the LE_IHD project website (https://livingevidenceframework.com/en/).

Study status
The searching and screening phases have been completed at the time of this submission.

Data availability
Underlying data No data are associated with this article.