Sacral Neuromodulation for Constipation and Fecal Incontinence in Children and Adolescents – study protocol of a prospective, randomized trial on the application of invasive vs. non-invasive technique

Sacral Neuromodulation for Constipation and Fecal Incontinence in Children and Adolescents – study protocol of a prospective, randomized trial on the application of invasive vs. non-invasive technique | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Sacral Neuromodulation for Constipation and Fecal Incontinence in Children and Adolescents – study protocol of a prospective, randomized trial on the application of invasive vs. non-invasive technique Manuel Besendörfer, Annemarie Kirchgatter, Roman Carbon, Christel Weiss, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3585766/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Mar, 2024 Read the published version in Trials → Version 1 posted 4 You are reading this latest preprint version Abstract Background A therapeutic effect of sacral neuromodulation (SNM) on fecal incontinence (FI) and quality of life has been proven in adults. SNM is, however, rarely used in pediatric cases. The aim of the study is to investigate effects of SNM in pediatric constipation in a prospective parallel-group trial. Methods A monocentric, randomized, unblinded, parallel-group trial is conducted. SNM is conducted in the invasive variant and in an innovative, external approach with adhesive electrodes (enteral neuromodulation, ENM). We include patients with constipation according to the ROME IV criteria and refractory to conventional options. Patients with functional constipation and Hirschsprung’s disease are able to participate. Participants are allocated in a 1:1 ratio to either SNM or ENM group. Clinical data and quality of life is evaluated in regular check-ups. Neuromodulation is applied continuously for 3 months (end point of the study) with follow-up-points at 6 and 12 months. Findings are analyzed statistically considering a 5% significance level (p ≤ 0.05). Outcome variables are defined as change in (1) episodes of abdominal pain, (2) episodes of FI, (3) defecation frequency, (4) stool consistency. Improvement of proprioception, influence on urinary incontinence, quality of life and safety of treatment are assessed as secondary outcome variables. We expect a relevant improvement in both study groups. Discussion This is the first trial, evaluating effects of neuromodulation for constipation in children and adolescents and comparing effects of the invasive and non-invasive application (SNM vs. ENM). Trial registration The study is registered with clinicaltrials.gov, Identifier NCT04713085 (date of registration 01/14/2021). sacral neuromodulation sacral nerve stimulation enteral neuromodulation functional constipation chronic refractory constipation Hirschsprung’s disease fecal incontinence. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Sacral neuromodulation (SNM) has been proven to reduce fecal incontinence (FI), and to improve quality of life in adult patients [ 1 ]. Low-intensity electrical charges are placed in contact with the target nervous tissue to achieve pulsed depolarization of axons [ 2 ]. However, evidence-based knowledge on mechanisms of action and efficacy is still limited. It has been postulated that SNM primarily affects afferent nerve activity [ 2 ]. Beyond that, regions of learning in the central nervous system and even their neuroplasticity are sought to be affected [ 3 ]. Despite these limitations in the understanding of its mode of action, SNM is established as surgical treatment option in adult patients because of its clinical efficacy [ 4 ]. As a minimally invasive approach, it is applied in patients with refractory urological and proctological conditions. Small, rechargeable, and magnetic resonance imaging-safe devices have made the implantation suitable even for children and adolescents. However, SNM is currently only used in highly selected pediatric cases, which does not answer the need for further therapies in refractory cases. Promising results of singular case studies and very small population studies have not yet been transferred to prospective case-control trials to gain evidence-based results. Furthermore, a non-invasive SNM option was developed to offer a quick, cost-effective, and child-friendly approach. Positive effects of SNM on functional constipation in children who continue to be treated conservatively could have been observed [ 5 ], while they remain controversial in adults [ 6 , 7 ]. In a review of 2011, Pauwels et al. observed no significant improvement of constipation in most of the included studies and proposes to apply SNM only in adult patients, refractory to treatment in order to potentially avoid more invasive treatment options [ 8 ]. Long-term outcomes of Gortazar de las Casas and colleagues revealed an efficacy of 38% in adult patients within a follow-up time of 5 years [ 9 ]. However, we see the justification of a potential efficacy of SNM on pediatric constipation due to the following point: We support the hypothesis of a unifying dysfunction of the enteral nervous system [ 10 ], which might even more connect functional/slow-transit-constipation (FC), rectal evacuation disorders, congenital neuro-intestinal dysfunctions with heterogeneous symptoms of constipation and fecal incontinence in children and adolescents. Indication for SNM in children and adolescents might therefore be discussed further. There is currently a lack of randomized trials that are adequately powered and apply validated outcome measures, to allow for firm recommendations on the use of SNM in pediatric patients. We report a protocol of a monocentric, randomized, unblinded, parallel-group trial of SNM in pediatric and adolescent patients with symptoms of refractory chronic constipation. Materials and Design Study objective and hypotheses The aim of the study is to investigate the effects of SNM on symptoms and quality of life in children and adolescents. We intend to demonstrate that SNM is safe and effective in treatment of constipation and FI refractory to conventional therapeutic options. The following hypotheses will be investigated within 3 months of treatment: SNM is superior to ENM regarding treatment of abdominal pain as main symptom of refractory chronic constipation in childhood and adolescence. Further exploratory hypotheses will be evaluated: SNM/ENM is effective and safe in reducing symptoms of chronic constipation and FI in children and adolescents as an additional therapeutic approach while continuing conventional treatment options unchanged. SNM/ENM treatment is effective in the subgroup of patients with Hirschsprung’s disease (HD). Technique Enteral neuromodulation (ENM) ENM is administered non-invasively via two cutaneous adhesive electrodes, placed paravertebrally and periumbilically (Figure 1). The stimulation is applied with a frequency of 15 Hz and a pulse width of 210µs. Detailed stimulation techniques have been described previously [5] and are administered via a pulse generator (Ostimex® ProfiPlus TENS/EMS 335035) [11]. The adhesive electrodes (50x50mm in size) have a conductive surface and adhere to the skin by themselves. The manufacturer makes multiple use possible. Sacral neuromodulation (SNM) SNM is applied via two surgical interventions. First, the flexible electrode lead with four equally spaced electrode contact points (quadripolar tined lead electrode, Medtronic Interstim, Figure 2A) is inserted percutaneously via the sacral foramen close to the sacral spinal nerve S3 or S4. A motor or sensory response can be monitored directly intraoperatively by probatory electrical stimulation and determines the side of the final implantation of the tined electrode. Stimulation is generated externally by a pulse generator and will be started on the first postoperative day with a frequency of 15 Hz and a pulse width of 210µs. The bipolar electrical field is generated between different poles of the tined lead, directly located at the sacral spinal nerves. After a successful trial phase with a neuronal response, an implanted pulse generator (IPG, Medtronic® Interstim Micro) is connected to the implanted electrode (Figure 2B) and subcutaneously implanted (Figure 2C) 4 weeks after the electrode’s implantation to secure optimal electrode positioning and exclusion of postoperative complications. Trial Design This is a monocentric, randomized, unblinded, 2-arm parallel-group trial in a 1:1 allocation ratio. The study is conducted at the University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) from 2019 to 2023. Potential subjects are screened among patients attending pediatric surgical and pediatric gastroenterological clinics. Diagnoses are made according to the ROME IV criteria for FC [12]. Interventions are provided to subjects based on their group assignment of either 3 months of SNM or ENM therapy. Regular checkups and a follow up appointment are conducted within the trial and after 6 and 12 months after the initiation of the intervention. All participants are informed of the purpose of the study and obtain their informed consent before participating in this parallel group study. The subjects may choose to withdraw from the study, or they may be withdrawn from the study, at any time at the discretion of the investigator. If a subject withdraws or is withdrawn, every effort is made to complete and report the observations. The study design is presented in Figure 3. Study population: Eligibility criteria Inclusion criteria To be eligible for participation, subjects are required to fulfill the following criteria: age between 2-17 years informed consent chronic constipation according to the ROME IV criteria for more than 3 months with abdominal pain and with or without FI [12] despite underlying diseases such as FC, rectal evacuation disorders or HD. refractory to conventional treatment in an appropriate weight-adapted application (training for bowel movements, lifestyle changes, pelvic floor training, pharmacological options) in cases of HD: diagnosis confirmed histologically by rectal biopsies and in case of resection of an aganglionic segment: period between surgery and SNM at least 1 year in cases of anorectal malformation or mechanical obstruction: post-surgical status: period between surgery and SNM at least 1 year Exclusion criteria Exclusion criteria are determined as follows: metabolic, inflammatory, and hormonal causes for chronic constipation toxic megacolon or further emergencies, which must be treated surgically sacral fractures or malformations prohibiting SNM access to target nerves inflammatory bowel diseases external rectal prolapse neuronal malignancies under medical and radiation therapy seizures Recruitment Participants are recruited from the outpatients and inpatients clinics of the pediatric surgery and gastroenterology departments. Two or more experts determine the eligibility according to the inclusion and exclusion criteria. Informed consent, especially on treatment modalities and off-label use of SNM/ENM in childhood and adolescence, must be obtained before enrollment in the trial by next-of-kin and participants (6 years and older). Thereafter, a baseline assessment is performed, collecting all baseline information relevant to the study (sociodemographic data, medical history, current defecation status). The study schedule is summarized in Figure 4 and included as the SPIRIT template as Figure 5. At all timepoints, patients are able to withdraw their participation and end therapy with neuromodulation. Randomization Participants are enrolled in the study groups at a 1:1 allocation to either the SNM or ENM group. Furthermore, patients are allocated 1:1 stratified based on HD/FC. Enrollment of subjects (assessment of eligibility, patient contact to obtain informed consent) is done by investigators and clinicians prior to randomization. The study design does not allow blinding of the therapist or further analyses in clinical follow-ups. Data analysis and statistical assessment are conducted separately and anonymously. The statistician performing the statistical analyses is blinded to individual group allocation and treatment. Interventions Non-pharmacological treatment in both study groups All subjects are provided with non-pharmacological management counseling prior to the study inclusion, including lifestyle modifications, such as (1) age-appropriate fluid consumption, (2) balanced diet and (3) regular sportive activity (at least 3 x 30min per week). Education and conduction of toilet training is further advised to improve regular bowel movements. If patients show further symptoms, irresponsive to these measurements, enrollment is conducted and non-pharmacological treatment is continued throughout the trial. Pharmacological treatment in both study groups Pharmacological options are included in the study population as follows: disimpaction with polyethylene glycol (PEG, 1.5-2mg/kg/d for 1-2 weeks) and initiation of maintenance therapy (PEG, 0.2-0.4 mg/kg/d) are conducted prior to the study inclusion. Maintenance therapy is continued throughout the study period in both groups. Supportive local applications such as saline enemas or stimulant laxatives (glycerin, bisacodyl) are applied as needed. Change of pharmacological treatment is not recommended during the study period, especially in case of rectal enemas. Medication due to other diagnoses is not changed during the study period. Group 1: Enteral neuromodulation ENM is continuously applied for 12 weeks in each patient. Stimulation intensity is individually set by each patient to achieve a comfortable stimulation below pain threshold. Group 2: Sacral neuromodulation With the implantation of the electrode, stimulation of S3/4 is continuously applied. Patients are able to set stimulation intensity parameters within a preset range via an external device with or without the IPG. Statistical methods Objectivation and data validation Specialized questionnaires were developed to objectivize symptoms and medical history of patients. These include sociodemographic data, medical history, and current defecation status and were adjusted for time points of “Baseline”, “Treatment with ENM” and “Treatment with SNM”. Quality of life data are assessed according to the ‘Revised Children’s Quality of Life Questionnaire’ (KINDLR) before and after treatment. This reliable and validated questionnaire is a self-report measurement for health-related quality of life in children and adolescents [13, 14]. It consists of 24 5-point Likert-scale items, covering 6 quality of life dimensions: physical well-being, emotional well-being, self-esteem, family, friends, and daily functioning (school or nursery school/kindergarten). Items are partially reversely scored and linearly transformed to a 0 to 100 scale according to the manual. The sub-scales of these six dimensions are combined to produce a total score. Higher scores indicate a better quality of life. The questionnaire is available in three age-specific versions (The Kiddy-KINDLR for 4–7 years of age, the Kid-KINDLR for 8–12 years of age and the Kiddo-KINDLR for 13–16 years of age). Data collection Data is extracted from the bowel movement diaries and specialized questionnaires. Recorded data is stored in case report forms at a secured place. Data is coded and entered in electronical files using Excel 2007 software (Microsoft Cooperation) by at least 2 different data administrators to reduce mistakes. All files are protected with password, which is only known by the investigators. Only the investigators have access to the final trial dataset. The information of the grouping and the results of the study are provided to the participants after the trial. Publications will only report aggregated data, and personal identities will not be disclosed. Sample size calculation As there is still insufficient clinical evidence on neuromodulation treatment in children and adolescents with FC and HD, this study requires only a small sample size. Power analysis is based on abdominal pain as primary outcome variable. A minimum of 78 subjects in total and 39 subjects per group is powered to detect a difference of at least 30 %, with a 95 % confidence interval (α =0.05) and statistical power of 80 % (β = 0.2). Statistical analysis IBM SPSS version 28 (IBM, Armonk, NY) is used to perform statistical analyses by an independent and blinded statistician. Continuous variables are presented as mean ± standard deviation, categorical data are reported as frequencies and percentages. If data losses occur during the study, the last observation is carried forward to adjust the missing data in follow-up evaluations. We compare clinical outcome data using chi-square and Fisher’s exact tests at defined time points pre- and post-treatment in both groups. Quality of life data is compared using unpaired or paired, two-tailed sample t-tests, if applicable. In case of multiple analyses, adjustment of p-values will be conducted accordingly. We set the confidence interval to 95% and all p-values less than 0.05 are considered indicative of statistical significance. Ethical Approval and Registration The study protocol was approved by the local ethics committee (Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), No. B18_20) and complied with the Declaration of Helsinki. Written informed consent is obtained from each subject and next-of-kin by the investigators before the subject enters the trial. The study is registered with clinicaltrials.gov (Identifier NCT04713085). If protocol modifications are required, amendments will be submitted to and approved by the local ethics committee. To disseminate our findings, the clinical trial results will be published in peer-reviewed journals. Additionally, the study’s protocol is in congruence with the SPIRIT 2013 statement [15]. Study Outcomes Participants are required to complete bowel movement diaries throughout the trial to the first target point. Children aged up to 7 years are thereby represented by their next-of-kin, whereas participants ≥ 13 years of age are advised to fill in the questionnaires by themselves. Between age 8 to 12, documentation is conducted together and depending on the child’s autonomy. At routine check-ups at baseline, 4 weeks, 3 and 6 and 12 months, specialized questionnaires must be completed. Quality of life analysis is conducted at baseline and after 3, 6 and 12 months, as described below (Figure 4). Primary outcomes and measurement Primary outcome variables are defined, and change is measured between time points of baseline, 3 and 6 months of therapy as follows: Episodes of abdominal pain: Number of episodes of abdominal pain per week Definition of success: reduction by at least 50% of episodes per week Episodes of FI: Number of episodes of FI per week Definition of success: reduction by at least 50% of episodes per week Defecation frequency: Number of bowel movements per week Definition of success: doubling of episodes per week to at least 3 or more bowel movements per week Stool consistency: Daily assessment of Bristol Stool Scale [16] Definition of success: change of at least 2 points within the scale of 1-7 Patients are classified based on treatment response and efficacy. A “clinically relevant” improvement is defined in cases with at least 2/4 fulfilled criteria, in which symptom control or -reduction is achieved. Secondary outcomes and measurement Secondary outcome variables are defined as follows: Improvement of proprioception: as mentioned in the specialized questionnaires Episodes of urinary incontinence: the number of episodes per week is evaluated with the criterion for a clinically relevant improvement in cases of reduction by at least 50% of episodes per week. Quality of life: assessment based on the KINDLR questionnaires Safety of treatment: adverse events as mentioned in the specialized questionnaires FI is diagnosed at the age of ≥ 4 years in cases of prior adequate toilet training and urinary incontinence at the age of ≥ 6 years with at least 4 episodes per week. Safety analysis and adverse events Former studies on neuromodulation confirm a good safety profile. The participants conduct self-administered neuromodulation therapy at home. The participants are informed about potential adverse events and if any occur, they are instructed to terminate therapy and to immediately communicate with the researchers. Safety problems are reported to the clinical authorities (head of department, ethics committee) as well as to the manufacturers themselves. Appropriate treatment changes are then initiated. Adverse events are additionally recorded as part of the data collection for each session and will be reported to the clinical authorities and the manufacturers. Discussion Neuromodulation is a promising approach in the treatment of chronic constipation and FI in children and adolescents. However, there is a substantial lack of well-planned, prospective clinical trials using an adequate sample size, appropriate methodology and validated outcomes to evaluate indications and efficacy in pediatric patients. Previously published outcomes of invasive and non-invasive sacral neuromodulation do predominantly not allow to draw firm conclusions because of small populations and high heterogeneity in outcome measures and participants. We were able to publish the first prospective randomized trial in 2022 on the efficacy of ENM (non-invasive SNM) in children and adolescents [11]. Patients, refractory to conventional treatment options, were included in the study and were randomized to either an optimization of these conventional options or to ENM under unchanged continuation of conventional options. We saw an improvement in outcome in 39% (conventional options alone) vs. 86% (ENM with conventional therapy, p<0.0001). Conclusively, therapeutic efficacy of ENM could be shown, which serves as a baseline for this present study. We here designed the study protocol of a prospective, monocentric, randomized 2-arm parallel-group trial, which to our knowledge is the first prospective, randomized study assessing SNM in pediatric patients and, above all, the first study assessing treatment differences between the invasive and non-invasive neuromodulatory approach (SNM vs. ENM). We focused on determining appropriate sample size and reproducibility based on robust outcome variables. We accept that the choice of our study design allows the following limitations: Compared to other clinical trials on patients with Hirschsprung’s disease or functional constipation, this study is adequately powered with a comparably small population size. We included patients despite underlying diagnoses of neural enteropathies, such as differentiation of slow-transit constipation, rectal evacuation disorders and aganglionic segments (Hirschsprung’s disease). We accept this as a potential bias of the study, as this heterogeneity might influence results and limit their value. Nevertheless, mechanisms of action of neuromodulation are not fully understood and seem to address multiple neuronal fibers [17]. Influence might be seen despite this heterogeneity based on neural dysfunctions, which unite all defecation disorders [10]. We chose a patient-centered focus and patient-reported outcomes, as we acknowledge the importance of patient’s assessment of treatment benefits. However, this leads to the acceptance of influence of continued conventional treatment options, and to the challenge of objectivation of diverse symptoms and individual perception, which may lead to substantial bias. Additionally, multiple analyses are restrictively valuable, as all p-values are only explorative and therefore not confirmatory. We recognize that the bias due to a placebo effect can only be eliminated using a sham stimulation. To exclude any placebo effects, various considerations were taken when designing the study. In this first comparative prospective trial on pediatric neuromodulation, we accepted data of unblinded patients and treating physicians without sham stimulation, as it was recommended by the local ethics committee. The study focuses on treatment effects of neuromodulation and does not address the long-term clinical effectiveness or cost-effectiveness of SNM and ENM. We hope that our study will help raise awareness of the high percentage of pediatric patients with refractory chronic defecation disorders, who are not treated sufficiently with established conservative and surgical options and will offer these patients a valuable new treatment option. The outcomes of our study will therefore not only be of importance for affected patients, parents and treating physicians, but also for researchers, medical specialist societies and patients’ support groups, as it may complete the treatment algorithm of chronic defecation disorders in pediatric patients. We aim at providing evidence-based conclusions as basis for the routine implementation of neuromodulation in children and adolescents with refractory chronic constipation. Funding has also been obtained to investigate outcome variables in long-term courses. Trial status This is the presentation of study protocol version 1.4 (15 October 2020). Participants are recruited to start since July 2018. Data collection will be finished in December 2023 and study completion is expected to be December 2024. The study is funded by the Deutsche Gesellschaft für Koloproktologie e.V.. The principal investigator and all collaborating physicians have no potential conflict of interests. Abbreviations ENM Enteral neuromodulation FC Functional constipation FI Fecal incontinence HD Hirschsprung’s disease IPG Implanted pulse generator SNM Sacral Neuromodulation Declarations Ethics approval and consent to participate The study protocol was approved by the local ethics committee (Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), No. B18_20) and complied with the Declaration of Helsinki. If protocol modifications are required, amendments will be submitted to and approved by the local ethics committee. Written, informed consent to participate will be obtained from all participants each subject and next-of-kin by the investigators before the subject enters the trial. Consent for publication Written informed consent for publication is obtained by all presented subjects and next-of-kin. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding The study is funded by the Deutsche Gesellschaft für Koloproktologie e.V.. Authors' contributions All the authors contributed to the realization of the study and its publication. SD is the chief investigator; she conceived the study, led the proposal and protocol development. MB, RC, KEM contributed to conception and design of the study. AK and SD organized the database and prepared the analysis. CW and HM conducted the statistical analysis. SD and MB wrote the first draft of the manuscript. KEM and RC revised the manuscript. All authors read and approved the submitted version. Acknowledgements Not applicable. References Maeda Y, O'Connell PR, Lehur PA, Matzel KE, Laurberg S: Sacral nerve stimulation for faecal incontinence and constipation: a European consensus statement . Colorectal Dis 2015, 17 (4):O74-87. 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Carrington EV, Evers J, Grossi U, Dinning PG, Scott SM, O'Connell PR, Jones JF, Knowles CH: A systematic review of sacral nerve stimulation mechanisms in the treatment of fecal incontinence and constipation . Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society 2014, 26 (9):1222-1237. Supplementary Files SPIRITchecklist.docx Cite Share Download PDF Status: Published Journal Publication published 22 Mar, 2024 Read the published version in Trials → Version 1 posted Reviewers agreed at journal 26 Dec, 2023 Reviewers invited by journal 26 Dec, 2023 Editor assigned by journal 15 Dec, 2023 First submitted to journal 10 Nov, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3585766","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":263479385,"identity":"b5fdb311-7968-4b36-9916-325bc0362fd3","order_by":0,"name":"Manuel Besendörfer","email":"","orcid":"","institution":"Friedrich-Alexander-Universität Erlangen-Nürnberg: Friedrich-Alexander-Universitat Erlangen-Nurnberg","correspondingAuthor":false,"prefix":"","firstName":"Manuel","middleName":"","lastName":"Besendörfer","suffix":""},{"id":263479386,"identity":"f33592f0-c874-4395-b694-6cdca93d3edb","order_by":1,"name":"Annemarie Kirchgatter","email":"","orcid":"","institution":"Friedrich-Alexander-Universität Erlangen-Nürnberg: Friedrich-Alexander-Universitat Erlangen-Nurnberg","correspondingAuthor":false,"prefix":"","firstName":"Annemarie","middleName":"","lastName":"Kirchgatter","suffix":""},{"id":263479387,"identity":"c46d4288-b199-4167-bc04-629429ce796c","order_by":2,"name":"Roman Carbon","email":"","orcid":"","institution":"Friedrich-Alexander-Universität Erlangen-Nürnberg: Friedrich-Alexander-Universitat Erlangen-Nurnberg","correspondingAuthor":false,"prefix":"","firstName":"Roman","middleName":"","lastName":"Carbon","suffix":""},{"id":263479388,"identity":"aa2f9e67-a4c4-4d6d-9253-e1c9cc537e90","order_by":3,"name":"Christel Weiss","email":"","orcid":"","institution":"Universität Heidelberg Medizinische Fakultät Heidelberg: Universitat Heidelberg Medizinische Fakultat Heidelberg","correspondingAuthor":false,"prefix":"","firstName":"Christel","middleName":"","lastName":"Weiss","suffix":""},{"id":263479389,"identity":"82e5c3ad-e3b9-44c3-9139-97a62425c4bf","order_by":4,"name":"Hanna Müller","email":"","orcid":"","institution":"University of Marburg: Philipps-Universitat Marburg","correspondingAuthor":false,"prefix":"","firstName":"Hanna","middleName":"","lastName":"Müller","suffix":""},{"id":263479390,"identity":"bcc76e40-0366-4d36-a3c3-42873613a569","order_by":5,"name":"Klaus Matzel","email":"","orcid":"","institution":"Friedrich-Alexander-Universität Erlangen-Nürnberg: Friedrich-Alexander-Universitat Erlangen-Nurnberg","correspondingAuthor":false,"prefix":"","firstName":"Klaus","middleName":"","lastName":"Matzel","suffix":""},{"id":263479391,"identity":"4e86bb5d-3a13-42a0-bcba-b69adef05f5b","order_by":6,"name":"Sonja Diez","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-8864-3240","institution":"Friedrich-Alexander-Universität Erlangen-Nürnberg: Friedrich-Alexander-Universitat Erlangen-Nurnberg","correspondingAuthor":true,"prefix":"","firstName":"Sonja","middleName":"","lastName":"Diez","suffix":""}],"badges":[],"createdAt":"2023-11-09 15:32:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3585766/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3585766/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-024-08052-6","type":"published","date":"2024-03-22T15:03:04+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49088052,"identity":"7f84da08-9a26-4cee-82a4-646a1ff61271","added_by":"auto","created_at":"2024-01-03 01:17:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":370016,"visible":true,"origin":"","legend":"\u003cp\u003eEnteral neuromodulation.\u003c/p\u003e\n\u003cp\u003ePlacement of the cutaneous adhesive electrodes of this non-invasive approach is depicted: the electrical field is built between a paravertebrally and periumbilically placed electrode.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-3585766/v1/db2446bee1e57abe7bf0769c.png"},{"id":49088057,"identity":"5c536db6-f070-45dc-9e30-d8c03ee12840","added_by":"auto","created_at":"2024-01-03 01:17:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3285897,"visible":true,"origin":"","legend":"\u003cp\u003eSacral neuromodulation.\u003c/p\u003e\n\u003cp\u003eFigure 2 illustrates the surgical implantation of sacral neuromodulation. (A) The tined lead electrode is placed at the sacral spinal nerve S3 or S4. (B/C) The previously implanted electrode is connected to a pulse generator, which is then implanted subcutaneously above the gluteal region.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-3585766/v1/4818eb91cc64bf0e6b168b93.png"},{"id":49088478,"identity":"9eaa179a-a41b-46f8-be96-1174095a05a4","added_by":"auto","created_at":"2024-01-03 01:25:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":149391,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design.\u003c/p\u003e\n\u003cp\u003eFigure 3 illustrates the design of the study, highlighting the comparison of the two study groups at different time points.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-3585766/v1/7c7b9e2891e9aad0f31f5c8f.png"},{"id":49088056,"identity":"5218524a-8602-4774-8bcd-63c1b97bc08a","added_by":"auto","created_at":"2024-01-03 01:17:23","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":261796,"visible":true,"origin":"","legend":"\u003cp\u003eStudy schedule.\u003c/p\u003e\n\u003cp\u003eFigure 4 explains evaluation of outcome variables at different time points of the\u003c/p\u003e\n\u003cp\u003estudy.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-3585766/v1/29962d36951049efffc05da6.png"},{"id":49088479,"identity":"c0e05aba-b267-45ed-b2ac-5f4f6d8a693d","added_by":"auto","created_at":"2024-01-03 01:25:23","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":530892,"visible":true,"origin":"","legend":"\u003cp\u003eSPIRIT figure.\u003c/p\u003e\n\u003cp\u003eFigure 5 summarizes the schedule of enrolment, interventions, and assessments according to the SPIRIT figure.\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-3585766/v1/77c58349bfbe16c5b3ff17c2.png"},{"id":53403784,"identity":"abbdddcb-34e7-43fb-97f5-eb2e9e00d136","added_by":"auto","created_at":"2024-03-25 15:14:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2837835,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3585766/v1/9dcc9beb-19fe-4d8a-9de2-4d36dc4c4103.pdf"},{"id":49088053,"identity":"9e11dc1d-322d-43e0-875f-fe1a49e6d9e0","added_by":"auto","created_at":"2024-01-03 01:17:22","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":35061,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITchecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-3585766/v1/2f04a3a4b75df9369fb611fc.docx"}],"financialInterests":"","formattedTitle":"Sacral Neuromodulation for Constipation and Fecal Incontinence in Children and Adolescents – study protocol of a prospective, randomized trial on the application of invasive vs. non-invasive technique","fulltext":[{"header":"Background","content":"\u003cp\u003eSacral neuromodulation (SNM) has been proven to reduce fecal incontinence (FI), and to improve quality of life in adult patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Low-intensity electrical charges are placed in contact with the target nervous tissue to achieve pulsed depolarization of axons [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, evidence-based knowledge on mechanisms of action and efficacy is still limited. It has been postulated that SNM primarily affects afferent nerve activity [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Beyond that, regions of learning in the central nervous system and even their neuroplasticity are sought to be affected [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite these limitations in the understanding of its mode of action, SNM is established as surgical treatment option in adult patients because of its clinical efficacy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. As a minimally invasive approach, it is applied in patients with refractory urological and proctological conditions. Small, rechargeable, and magnetic resonance imaging-safe devices have made the implantation suitable even for children and adolescents. However, SNM is currently only used in highly selected pediatric cases, which does not answer the need for further therapies in refractory cases. Promising results of singular case studies and very small population studies have not yet been transferred to prospective case-control trials to gain evidence-based results. Furthermore, a non-invasive SNM option was developed to offer a quick, cost-effective, and child-friendly approach. Positive effects of SNM on functional constipation in children who continue to be treated conservatively could have been observed [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], while they remain controversial in adults [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In a review of 2011, Pauwels et al. observed no significant improvement of constipation in most of the included studies and proposes to apply SNM only in adult patients, refractory to treatment in order to potentially avoid more invasive treatment options [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Long-term outcomes of Gortazar de las Casas and colleagues revealed an efficacy of 38% in adult patients within a follow-up time of 5 years [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, we see the justification of a potential efficacy of SNM on pediatric constipation due to the following point: We support the hypothesis of a unifying dysfunction of the enteral nervous system [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], which might even more connect functional/slow-transit-constipation (FC), rectal evacuation disorders, congenital neuro-intestinal dysfunctions with heterogeneous symptoms of constipation and fecal incontinence in children and adolescents. Indication for SNM in children and adolescents might therefore be discussed further.\u003c/p\u003e \u003cp\u003eThere is currently a lack of randomized trials that are adequately powered and apply validated outcome measures, to allow for firm recommendations on the use of SNM in pediatric patients. We report a protocol of a monocentric, randomized, unblinded, parallel-group trial of SNM in pediatric and adolescent patients with symptoms of refractory chronic constipation.\u003c/p\u003e"},{"header":"Materials and Design","content":"\u003cp\u003e\u003cu\u003eStudy objective and hypotheses\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe aim of the study is to investigate the effects of SNM on symptoms and quality of life in children and adolescents. We intend to demonstrate that SNM is safe and effective in treatment of constipation and FI refractory to conventional therapeutic options.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe following hypotheses will be investigated within 3 months of treatment:\u003c/p\u003e\n\u003col style=\"list-style-type: upper-alpha;\"\u003e\n \u003cli\u003eSNM is superior to ENM regarding treatment of abdominal pain as main symptom of refractory chronic constipation in childhood and adolescence.\u003c/li\u003e\n \u003cli\u003eFurther exploratory hypotheses will be evaluated:\u003c/li\u003e\n\u003c/ol\u003e\n\u003cul\u003e\n \u003cli\u003eSNM/ENM is effective and safe in reducing symptoms of chronic constipation and FI in children and adolescents as an additional therapeutic approach while continuing conventional treatment options unchanged.\u003c/li\u003e\n \u003cli\u003eSNM/ENM treatment is effective in the subgroup of patients with Hirschsprung\u0026rsquo;s disease (HD).\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cu\u003eTechnique\u003c/u\u003e\u003c/p\u003e\n\u003ch3\u003eEnteral neuromodulation (ENM)\u003c/h3\u003e\n\u003cp\u003eENM is administered non-invasively via two cutaneous adhesive electrodes, placed paravertebrally and periumbilically (Figure 1). The stimulation is applied with a frequency of 15 Hz and a pulse width of 210\u0026micro;s. Detailed stimulation techniques have been described previously\u0026nbsp;[5]\u0026nbsp;and are administered via a pulse generator (Ostimex\u0026reg; ProfiPlus TENS/EMS 335035)\u0026nbsp;[11]. The adhesive electrodes (50x50mm in size) have a conductive surface and adhere to the skin by themselves. The manufacturer makes multiple use possible. \u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eSacral neuromodulation (SNM)\u003c/h3\u003e\n\u003cp\u003eSNM is applied via two surgical interventions. First, the flexible electrode lead with four equally spaced electrode contact points (quadripolar tined lead electrode, Medtronic Interstim, Figure 2A) is inserted percutaneously via the sacral foramen close to the sacral spinal nerve S3 or S4. A motor or sensory response can be monitored directly intraoperatively by probatory electrical stimulation and determines the side of the final implantation of the tined electrode. Stimulation is generated externally by a pulse generator and will be started on the first postoperative day with a frequency of 15 Hz and a pulse width of 210\u0026micro;s. The bipolar electrical field is generated between different poles of the tined lead, directly located at the sacral spinal nerves.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter a successful trial phase with a neuronal response, an implanted pulse generator (IPG, Medtronic\u0026reg; Interstim Micro) is connected to the implanted electrode (Figure 2B) and subcutaneously implanted (Figure 2C) 4 weeks after the electrode\u0026rsquo;s implantation to secure optimal electrode positioning and exclusion of postoperative complications.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eTrial Design\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThis is a monocentric, randomized, unblinded, 2-arm parallel-group trial in a 1:1 allocation ratio. The study is conducted at the University Hospital Erlangen, Friedrich-Alexander-Universit\u0026auml;t Erlangen-N\u0026uuml;rnberg (FAU) from 2019 to 2023. Potential subjects are screened among patients attending pediatric surgical and pediatric gastroenterological clinics. Diagnoses are made according to the ROME IV criteria for FC\u0026nbsp;[12]. Interventions are provided to subjects based on their group assignment of either 3 months of SNM or ENM therapy. Regular checkups and a follow up appointment are conducted within the trial and after 6 and 12 months after the initiation of the intervention. All participants are informed of the purpose of the study and obtain their informed consent before participating in this parallel group study. The subjects may choose to withdraw from the study, or they may be withdrawn from the study, at any time at the discretion of the investigator. If a subject withdraws or is withdrawn, every effort is made to complete and report the observations. The study design is presented in Figure 3.\u003c/p\u003e\n\u003ch2\u003e\u003cu\u003eStudy population: Eligibility criteria\u003c/u\u003e\u003c/h2\u003e\n\u003ch3\u003eInclusion criteria\u003c/h3\u003e\n\u003cp\u003eTo be eligible for participation, subjects are required to fulfill the following criteria:\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eage between 2-17 years\u003c/li\u003e\n \u003cli\u003einformed consent\u003c/li\u003e\n \u003cli\u003echronic constipation according to the ROME IV criteria for more than 3 months with abdominal pain and with or without FI\u0026nbsp;[12]\u0026nbsp;despite underlying diseases such as FC, rectal evacuation disorders or HD.\u003c/li\u003e\n \u003cli\u003erefractory to conventional treatment in an appropriate weight-adapted application (training for bowel movements, lifestyle changes, pelvic floor training, pharmacological options)\u003c/li\u003e\n \u003cli\u003ein cases of HD: diagnosis confirmed histologically by rectal biopsies and in case of resection of an aganglionic segment: period between surgery and SNM at least 1 year\u003c/li\u003e\n \u003cli\u003ein cases of anorectal malformation or mechanical obstruction: post-surgical status: period between surgery and SNM at least 1 year\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch3\u003eExclusion criteria\u003c/h3\u003e\n\u003cp\u003eExclusion criteria are determined as follows:\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003emetabolic, inflammatory, and hormonal causes for chronic constipation\u0026nbsp;\u003c/li\u003e\n \u003cli\u003etoxic megacolon or further emergencies, which must be treated surgically\u003c/li\u003e\n \u003cli\u003esacral fractures or malformations prohibiting SNM access to target nerves\u0026nbsp;\u003c/li\u003e\n \u003cli\u003einflammatory bowel diseases\u003c/li\u003e\n \u003cli\u003eexternal rectal prolapse\u003c/li\u003e\n \u003cli\u003eneuronal malignancies under medical and radiation therapy\u003c/li\u003e\n \u003cli\u003eseizures\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch2\u003e\u003cu\u003eRecruitment\u003c/u\u003e\u003c/h2\u003e\n\u003cp\u003eParticipants are recruited from the outpatients and inpatients clinics of the pediatric surgery and gastroenterology departments. Two or more experts determine the eligibility according to the inclusion and exclusion criteria. Informed consent, especially on treatment modalities and off-label use of SNM/ENM in childhood and adolescence, must be obtained before enrollment in the trial by next-of-kin and participants (6 years and older). Thereafter, a baseline assessment is performed, collecting all baseline information relevant to the study (sociodemographic data, medical history, current defecation status). The study schedule is summarized in Figure 4 and included as the SPIRIT template as Figure 5. At all timepoints, patients are able to withdraw their participation and end therapy with neuromodulation.\u003c/p\u003e\n\u003ch2\u003e\u003cu\u003eRandomization\u003c/u\u003e\u003c/h2\u003e\n\u003cp\u003eParticipants are enrolled in the study groups at a 1:1 allocation to either the SNM or ENM group. Furthermore, patients are allocated 1:1 stratified based on HD/FC. Enrollment of subjects (assessment of eligibility, patient contact to obtain informed consent) is done by investigators and clinicians prior to randomization. The study design does not allow blinding of the therapist or further analyses in clinical follow-ups. Data analysis and statistical assessment are conducted separately and anonymously. The statistician performing the statistical analyses is blinded to individual group allocation and treatment.\u003c/p\u003e\n\u003ch2\u003e\u003cu\u003eInterventions\u003c/u\u003e\u003c/h2\u003e\n\u003ch3\u003eNon-pharmacological treatment in both study groups\u003c/h3\u003e\n\u003cp\u003eAll subjects are provided with non-pharmacological management counseling prior to the study inclusion, including lifestyle modifications, such as (1) age-appropriate fluid consumption, (2) balanced diet and (3) regular sportive activity (at least 3 x 30min per week). Education and conduction of toilet training is further advised to improve regular bowel movements. If patients show further symptoms, irresponsive to these measurements, enrollment is conducted and non-pharmacological treatment is continued throughout the trial.\u003c/p\u003e\n\u003ch3\u003ePharmacological treatment in both study groups\u003c/h3\u003e\n\u003cp\u003ePharmacological options are included in the study population as follows: disimpaction with polyethylene glycol (PEG, 1.5-2mg/kg/d for 1-2 weeks) and initiation of maintenance therapy (PEG, 0.2-0.4 mg/kg/d) are conducted prior to the study inclusion. Maintenance therapy is continued throughout the study period in both groups. Supportive local applications such as saline enemas or stimulant laxatives (glycerin, bisacodyl) are applied as needed. Change of pharmacological treatment is not recommended during the study period, especially in case of rectal enemas. Medication due to other diagnoses is not changed during the study period.\u003c/p\u003e\n\u003ch3\u003eGroup 1: Enteral neuromodulation\u003c/h3\u003e\n\u003cp\u003eENM is continuously applied for 12 weeks in each patient. Stimulation intensity is individually set by each patient to achieve a comfortable stimulation below pain threshold. \u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eGroup 2: Sacral neuromodulation\u003c/h3\u003e\n\u003cp\u003eWith the implantation of the electrode, stimulation of S3/4 is continuously applied. Patients are able to set stimulation intensity parameters within a preset range via an external device with or without the IPG.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e\u003cu\u003eStatistical methods\u003c/u\u003e\u003c/h2\u003e\n\u003ch3\u003eObjectivation and data validation\u003c/h3\u003e\n\u003cp\u003eSpecialized questionnaires were developed to objectivize symptoms and medical history of patients. These include sociodemographic data, medical history, and current defecation status and were adjusted for time points of \u0026ldquo;Baseline\u0026rdquo;, \u0026ldquo;Treatment with ENM\u0026rdquo; and \u0026ldquo;Treatment with SNM\u0026rdquo;.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eQuality of life data are assessed according to the \u0026lsquo;Revised Children\u0026rsquo;s Quality of Life Questionnaire\u0026rsquo; (KINDLR) before and after treatment. This reliable and validated questionnaire is a self-report measurement for health-related quality of life in children and adolescents\u0026nbsp;[13, 14]. It consists of 24 5-point Likert-scale items, covering 6 quality of life dimensions: physical well-being, emotional well-being, self-esteem, family, friends, and daily functioning (school or nursery school/kindergarten). Items are partially reversely scored and linearly transformed to a 0 to 100 scale according to the manual. The sub-scales of these six dimensions are combined to produce a total score. Higher scores indicate a better quality of life. The questionnaire is available in three age-specific versions (The Kiddy-KINDLR for 4\u0026ndash;7 years of age, the Kid-KINDLR for 8\u0026ndash;12 years of age and the Kiddo-KINDLR for 13\u0026ndash;16 years of age).\u003c/p\u003e\n\u003ch3\u003eData collection\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eData is extracted from the bowel movement diaries and specialized questionnaires. Recorded data is stored in case report forms at a secured place. Data is coded and entered in electronical files using Excel 2007 software (Microsoft Cooperation) by at least 2 different data administrators to reduce mistakes. All files are protected with password, which is only known by the investigators. Only the investigators have access to the final trial dataset. The information of the grouping and the results of the study are provided to the participants after the trial. Publications will only report aggregated data, and personal identities will not be disclosed.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eSample size calculation\u003c/h3\u003e\n\u003cp\u003eAs there is still insufficient clinical evidence on neuromodulation treatment in children and adolescents with FC and HD, this study requires only a small sample size. Power analysis is based on abdominal pain as primary outcome variable. A minimum of 78 subjects in total and 39 subjects per group is powered to detect a difference of at least 30 %, with a 95 % confidence interval (\u0026alpha; =0.05) and statistical power of 80 % (\u0026beta; = 0.2).\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eStatistical analysis\u003c/h3\u003e\n\u003cp\u003eIBM SPSS version 28 (IBM, Armonk, NY) is used to perform statistical analyses by an independent and blinded statistician. Continuous variables are presented as mean \u0026plusmn; standard deviation, categorical data are reported as frequencies and percentages. If data losses occur during the study, the last observation is carried forward to adjust the missing data in follow-up evaluations. We compare clinical outcome data using chi-square and Fisher\u0026rsquo;s exact tests at defined time points pre- and post-treatment in both groups. Quality of life data is compared using unpaired or paired, two-tailed sample t-tests, if applicable. In case of multiple analyses, adjustment of p-values will be conducted accordingly. We set the confidence interval to 95% and all p-values less than 0.05 are considered indicative of statistical significance.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e\u003cu\u003eEthical Approval and Registration\u003c/u\u003e\u003c/h2\u003e\n\u003cp\u003eThe study protocol was approved by the local ethics committee (Friedrich-Alexander-Universit\u0026auml;t Erlangen-N\u0026uuml;rnberg (FAU), No. B18_20) and complied with the Declaration of Helsinki. Written informed consent is obtained from each subject and next-of-kin by the investigators before the subject enters the trial. The study is registered with clinicaltrials.gov (Identifier NCT04713085). If protocol modifications are required, amendments will be submitted to and approved by the local ethics committee. To disseminate our findings, the clinical trial results will be published in peer-reviewed journals. Additionally, the study\u0026rsquo;s protocol is in congruence with the SPIRIT 2013 statement\u0026nbsp;[15].\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eStudy Outcomes\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eParticipants are required to complete bowel movement diaries throughout the trial to the first target point. Children aged up to 7 years are thereby represented by their next-of-kin, whereas participants \u0026ge; 13 years of age are advised to fill in the questionnaires by themselves. Between age 8 to 12, documentation is conducted together and depending on the child\u0026rsquo;s autonomy. At routine check-ups at baseline, 4 weeks, 3 and 6 and 12 months, specialized questionnaires must be completed. Quality of life analysis is conducted at baseline and after 3, 6 and 12 months, as described below (Figure 4).\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003ePrimary outcomes and measurement\u003c/h3\u003e\n\u003cp\u003ePrimary outcome variables are defined, and change is measured between time points of baseline, 3 and 6 months of therapy as follows:\u0026nbsp;\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eEpisodes of abdominal pain: Number of episodes of abdominal pain per week\u003cbr\u003eDefinition of success: reduction by at least 50% of episodes per week\u003c/li\u003e\n\u003cli\u003eEpisodes of FI: Number of episodes of FI per week\u003cbr\u003eDefinition of success: reduction by at least 50% of episodes per week\u003c/li\u003e\n \u003cli\u003eDefecation frequency: Number of bowel movements per week\u0026nbsp;\u003cbr\u003eDefinition of success: doubling of episodes per week to at least 3 or more bowel movements per week\u003c/li\u003e\n \u003cli\u003eStool consistency: Daily assessment of Bristol Stool Scale [16]\u003cbr\u003eDefinition of success: change of at least 2 points within the scale of 1-7\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003ePatients are classified based on treatment response and efficacy. A \u0026ldquo;clinically relevant\u0026rdquo; improvement is defined in cases with at least 2/4 fulfilled criteria, in which symptom control or -reduction is achieved.\u003c/p\u003e\n\u003ch3\u003eSecondary outcomes and measurement\u003c/h3\u003e\n\u003cp\u003eSecondary outcome variables are defined as follows:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eImprovement of proprioception: as mentioned in the specialized questionnaires\u003c/li\u003e\n \u003cli\u003eEpisodes of urinary incontinence: the number of episodes per week is evaluated with the criterion for a clinically relevant improvement in cases of reduction by at least 50% of episodes per week.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eQuality of life: assessment based on the KINDLR questionnaires\u003c/li\u003e\n \u003cli\u003eSafety of treatment: adverse events as mentioned in the specialized questionnaires\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eFI is diagnosed at the age of \u0026ge; 4 years in cases of prior adequate toilet training and urinary incontinence at the age of \u0026ge; 6 years with at least 4 episodes per week. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e\u003cu\u003eSafety analysis and adverse events\u003c/u\u003e\u003c/h2\u003e\n\u003cp\u003eFormer studies on neuromodulation confirm a good safety profile. The participants conduct self-administered neuromodulation therapy at home. The participants are informed about potential adverse events and if any occur, they are instructed to terminate therapy and to immediately communicate with the researchers. Safety problems are reported to the clinical authorities (head of department, ethics committee) as well as to the manufacturers themselves. Appropriate treatment changes are then initiated. Adverse events are additionally recorded as part of the data collection for each session and will be reported to the clinical authorities and the manufacturers.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eNeuromodulation is a promising approach in the treatment of chronic constipation and FI in children and adolescents. However, there is a substantial lack of well-planned, prospective clinical trials using an adequate sample size, appropriate methodology and validated outcomes to evaluate indications and efficacy in pediatric patients. Previously published outcomes of invasive and non-invasive sacral neuromodulation do predominantly not allow to draw firm conclusions because of small populations and high heterogeneity in outcome measures and participants. We were able to publish the first prospective randomized trial in 2022 on the efficacy of ENM (non-invasive SNM) in children and adolescents\u0026nbsp;[11]. Patients, refractory to conventional treatment options, were included in the study and were randomized to either an optimization of these conventional options or to ENM under unchanged continuation of conventional options. We saw an improvement in outcome in 39% (conventional options alone) vs. 86% (ENM with conventional therapy, p\u0026lt;0.0001). Conclusively, therapeutic efficacy of ENM could be shown, which serves as a baseline for this present study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe here designed the study protocol of a prospective, monocentric, randomized 2-arm parallel-group trial, which to our knowledge is the first prospective, randomized study assessing SNM in pediatric patients and, above all, the first study assessing treatment differences between the invasive and non-invasive neuromodulatory approach (SNM vs. ENM). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe focused on determining appropriate sample size and reproducibility based on robust outcome variables.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe accept that the choice of our study design allows the following limitations:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eCompared to other clinical trials on patients with Hirschsprung\u0026rsquo;s disease or functional constipation, this study is adequately powered with a comparably small population size.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eWe included patients despite underlying diagnoses of neural enteropathies, such as differentiation of slow-transit constipation, rectal evacuation disorders and aganglionic segments (Hirschsprung\u0026rsquo;s disease). We accept this as a potential bias of the study, as this heterogeneity might influence results and limit their value. Nevertheless, mechanisms of action of neuromodulation are not fully understood and seem to address multiple neuronal fibers\u0026nbsp;[17]. Influence might be seen despite this heterogeneity based on neural dysfunctions, which unite all defecation disorders\u0026nbsp;[10].\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eWe chose a patient-centered focus and patient-reported outcomes, as we acknowledge the importance of patient\u0026rsquo;s assessment of treatment benefits. However, this leads to the acceptance of influence of continued conventional treatment options, and to the challenge of objectivation of diverse symptoms and individual perception, which may lead to substantial bias. Additionally, multiple analyses are restrictively valuable, as all p-values are only explorative and therefore not confirmatory.\u003c/li\u003e\n \u003cli\u003eWe recognize that the bias due to a placebo effect can only be eliminated using a sham stimulation. To exclude any placebo effects, various considerations were taken when designing the study. In this first comparative prospective trial on pediatric neuromodulation, we accepted data of unblinded patients and treating physicians without sham stimulation, as it was recommended by the local ethics committee.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe study focuses on treatment effects of neuromodulation and does not address the long-term clinical effectiveness or cost-effectiveness of SNM and ENM.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eWe hope that our study will help raise awareness of the high percentage of pediatric patients with refractory chronic defecation disorders, who are not treated sufficiently with established conservative and surgical options and will offer these patients a valuable new treatment option. The outcomes of our study will therefore not only be of importance for affected patients, parents and treating physicians, but also for researchers, medical specialist societies and patients\u0026rsquo; support groups, as it may complete the treatment algorithm of chronic defecation disorders in pediatric patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe aim at providing evidence-based conclusions as basis for the routine implementation of neuromodulation in children and adolescents with refractory chronic constipation. Funding has also been obtained to investigate outcome variables in long-term courses.\u0026nbsp;\u003c/p\u003e"},{"header":"Trial status","content":"\u003cp\u003eThis is the presentation of study protocol version 1.4 (15 October 2020). Participants are recruited to start since July 2018. Data collection will be finished in December 2023 and study completion is expected to be December 2024. The study is funded by the Deutsche Gesellschaft f\u0026uuml;r Koloproktologie e.V.. The principal investigator and all collaborating physicians have no potential conflict of interests.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eENM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Enteral neuromodulation\u003c/p\u003e\n\u003cp\u003eFC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Functional constipation\u003c/p\u003e\n\u003cp\u003eFI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Fecal incontinence\u003c/p\u003e\n\u003cp\u003eHD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Hirschsprung\u0026rsquo;s disease\u003c/p\u003e\n\u003cp\u003eIPG\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Implanted pulse generator\u003c/p\u003e\n\u003cp\u003eSNM \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Sacral Neuromodulation\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the local ethics committee (Friedrich-Alexander-Universit\u0026auml;t Erlangen-N\u0026uuml;rnberg (FAU), No. B18_20) and complied with the Declaration of Helsinki. If protocol modifications are required, amendments will be submitted to and approved by the local ethics committee. Written, informed consent to participate will be obtained from all participants each subject and next-of-kin by the investigators before the subject enters the trial.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication is obtained by all presented subjects and next-of-kin.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThe study is funded by the Deutsche Gesellschaft f\u0026uuml;r Koloproktologie e.V..\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eAll the authors contributed to the realization of the study and its publication. SD is the chief investigator; she conceived the study, led the proposal and protocol development. MB, RC, KEM contributed to conception and design of the study. AK and SD organized the database and prepared the analysis. CW and HM conducted the statistical analysis. SD and MB wrote the first draft of the manuscript. KEM and RC revised the manuscript. All authors read and approved the submitted version.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMaeda Y, O\u0026apos;Connell PR, Lehur PA, Matzel KE, Laurberg S: \u003cstrong\u003eSacral nerve stimulation for faecal incontinence and constipation: a European consensus statement\u003c/strong\u003e. \u003cem\u003eColorectal Dis \u003c/em\u003e2015, \u003cstrong\u003e17\u003c/strong\u003e(4):O74-87.\u003c/li\u003e\n\u003cli\u003eMcAlees E, Vollebregt PF, Stevens N, Dudding TC, Emmanuel AV, Furlong PL, Hamdy S, Hooper RL, Jones JFX, Norton C\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eEfficacy and mechanism of sub-sensory sacral (optimised) neuromodulation in adults with faecal incontinence: study protocol for a randomised controlled trial\u003c/strong\u003e. \u003cem\u003eTrials \u003c/em\u003e2018, \u003cstrong\u003e19\u003c/strong\u003e(1):336.\u003c/li\u003e\n\u003cli\u003eAmend B, Matzel KE, Abrams P, de Groat WC, Sievert KD: \u003cstrong\u003eHow does neuromodulation work\u003c/strong\u003e. \u003cem\u003eNeurourol Urodyn \u003c/em\u003e2011, \u003cstrong\u003e30\u003c/strong\u003e(5):762-765.\u003c/li\u003e\n\u003cli\u003eNorton C, Thomas L, Hill J: \u003cstrong\u003eManagement of faecal incontinence in adults: summary of NICE guidance\u003c/strong\u003e. \u003cem\u003eBmj \u003c/em\u003e2007, \u003cstrong\u003e334\u003c/strong\u003e(7608):1370-1371.\u003c/li\u003e\n\u003cli\u003eBesend\u0026ouml;rfer M, Kohl M, Schellerer V, Carbon R, Diez S: \u003cstrong\u003eA Pilot Study of Non-invasive Sacral Nerve Stimulation in Treatment of Constipation in Childhood and Adolescence\u003c/strong\u003e. \u003cem\u003eFrontiers in pediatrics \u003c/em\u003e2020, \u003cstrong\u003e8\u003c/strong\u003e:169.\u003c/li\u003e\n\u003cli\u003eMartellucci J: \u003cstrong\u003eSacral nerve stimulation for constipation: history of an unconsummated marriage\u003c/strong\u003e. \u003cem\u003eTechniques in Coloproctology \u003c/em\u003e2017, \u003cstrong\u003e21\u003c/strong\u003e(4):257-258.\u003c/li\u003e\n\u003cli\u003eThaha MA, Abukar AA, Thin NN, Ramsanahie A, Knowles CH: \u003cstrong\u003eSacral nerve stimulation for faecal incontinence and constipation in adults\u003c/strong\u003e. \u003cem\u003eCochrane Database Syst Rev \u003c/em\u003e2015(8):Cd004464.\u003c/li\u003e\n\u003cli\u003ePauwels N, Willemse C, Hellemans S, Komen N, Van den Broeck S, Roenen J, Van Aggelpoel T, De Schepper H: \u003cstrong\u003eThe role of neuromodulation in chronic functional constipation: a systematic review\u003c/strong\u003e. \u003cem\u003eActa Gastroenterol Belg \u003c/em\u003e2021, \u003cstrong\u003e84\u003c/strong\u003e(3):467-476.\u003c/li\u003e\n\u003cli\u003eGortazar de Las Casas S, Rubio-P\u0026eacute;rez I, Saavedra Ambrosy J, Sancho de Avila A, \u0026Aacute;lvarez-Gallego M, Marijuan Mart\u0026iacute;n JL, Pascual Miguela\u0026ntilde;ez I: \u003cstrong\u003eSacral nerve stimulation for constipation: long-term outcomes\u003c/strong\u003e. \u003cem\u003eTech Coloproctol \u003c/em\u003e2019, \u003cstrong\u003e23\u003c/strong\u003e(6):559-564.\u003c/li\u003e\n\u003cli\u003eWestfal ML, Goldstein AM: \u003cstrong\u003ePediatric enteric neuropathies: diagnosis and current management\u003c/strong\u003e. \u003cem\u003eCurr Opin Pediatr \u003c/em\u003e2017, \u003cstrong\u003e29\u003c/strong\u003e(3):347-353.\u003c/li\u003e\n\u003cli\u003eDiez S, Kirchgatter A, Adam D, F\u0026uuml;ldner A, M\u0026uuml;ller H, Matzel KE, Besend\u0026ouml;rfer M: \u003cstrong\u003eNoninvasive Sacral Neuromodulation in Children and Adolescents: A Case-Control Study of Patients With Chronic Refractory Constipation\u003c/strong\u003e. \u003cem\u003eNeuromodulation \u003c/em\u003e2022.\u003c/li\u003e\n\u003cli\u003eSchmulson MJ, Drossman DA: \u003cstrong\u003eWhat Is New in Rome IV\u003c/strong\u003e. \u003cem\u003eJ Neurogastroenterol Motil \u003c/em\u003e2017, \u003cstrong\u003e23\u003c/strong\u003e(2):151-163.\u003c/li\u003e\n\u003cli\u003eRavens-Sieberer UB, M. : \u003cstrong\u003eKINDL-R English Questionnaire for Measuring Health-Related Quality of Life in Children and Adolescents. Revised Version, Manual.\u003c/strong\u003e 2000.\u003c/li\u003e\n\u003cli\u003eRavens-Sieberer U, Erhart M, Wille N, Bullinger M: \u003cstrong\u003eHealth-related quality of life in children and adolescents in Germany: results of the BELLA study\u003c/strong\u003e. \u003cem\u003eEur Child Adolesc Psychiatry \u003c/em\u003e2008, \u003cstrong\u003e17 Suppl 1\u003c/strong\u003e:148-156.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eSPIRIT 2013 Statement: Defining Standard Protocol Items for Clinical Trials\u003c/strong\u003e. \u003cem\u003eAnnals of Internal Medicine \u003c/em\u003e2013, \u003cstrong\u003e158\u003c/strong\u003e(3):200-207.\u003c/li\u003e\n\u003cli\u003eLewis SJ, Heaton KW: \u003cstrong\u003eStool form scale as a useful guide to intestinal transit time\u003c/strong\u003e. \u003cem\u003eScand J Gastroenterol \u003c/em\u003e1997, \u003cstrong\u003e32\u003c/strong\u003e(9):920-924.\u003c/li\u003e\n\u003cli\u003eCarrington EV, Evers J, Grossi U, Dinning PG, Scott SM, O\u0026apos;Connell PR, Jones JF, Knowles CH: \u003cstrong\u003eA systematic review of sacral nerve stimulation mechanisms in the treatment of fecal incontinence and constipation\u003c/strong\u003e. \u003cem\u003eNeurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society \u003c/em\u003e2014, \u003cstrong\u003e26\u003c/strong\u003e(9):1222-1237.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"sacral neuromodulation, sacral nerve stimulation, enteral neuromodulation, functional constipation, chronic refractory constipation, Hirschsprung’s disease, fecal incontinence.","lastPublishedDoi":"10.21203/rs.3.rs-3585766/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3585766/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eA therapeutic effect of sacral neuromodulation (SNM) on fecal incontinence (FI) and quality of life has been proven in adults. SNM is, however, rarely used in pediatric cases. The aim of the study is to investigate effects of SNM in pediatric constipation in a prospective parallel-group trial.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA monocentric, randomized, unblinded, parallel-group trial is conducted. SNM is conducted in the invasive variant and in an innovative, external approach with adhesive electrodes (enteral neuromodulation, ENM). We include patients with constipation according to the ROME IV criteria and refractory to conventional options. Patients with functional constipation and Hirschsprung\u0026rsquo;s disease are able to participate. Participants are allocated in a 1:1 ratio to either SNM or ENM group. Clinical data and quality of life is evaluated in regular check-ups. Neuromodulation is applied continuously for 3 months (end point of the study) with follow-up-points at 6 and 12 months. Findings are analyzed statistically considering a 5% significance level (p\u0026thinsp;\u0026le;\u0026thinsp;0.05). Outcome variables are defined as change in (1) episodes of abdominal pain, (2) episodes of FI, (3) defecation frequency, (4) stool consistency. Improvement of proprioception, influence on urinary incontinence, quality of life and safety of treatment are assessed as secondary outcome variables. We expect a relevant improvement in both study groups.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThis is the first trial, evaluating effects of neuromodulation for constipation in children and adolescents and comparing effects of the invasive and non-invasive application (SNM vs. ENM).\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eThe study is registered with clinicaltrials.gov, Identifier NCT04713085 (date of registration 01/14/2021).\u003c/p\u003e","manuscriptTitle":"Sacral Neuromodulation for Constipation and Fecal Incontinence in Children and Adolescents – study protocol of a prospective, randomized trial on the application of invasive vs. non-invasive technique","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-03 01:17:18","doi":"10.21203/rs.3.rs-3585766/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2023-12-27T04:38:47+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-12-26T16:42:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-12-15T16:32:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2023-11-10T11:02:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7a6fcb3f-9e20-4a1d-85d5-e14add6c8d4a","owner":[],"postedDate":"January 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-03-25T15:09:29+00:00","versionOfRecord":{"articleIdentity":"rs-3585766","link":"https://doi.org/10.1186/s13063-024-08052-6","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2024-03-22 15:03:04","publishedOnDateReadable":"March 22nd, 2024"},"versionCreatedAt":"2024-01-03 01:17:18","video":"","vorDoi":"10.1186/s13063-024-08052-6","vorDoiUrl":"https://doi.org/10.1186/s13063-024-08052-6","workflowStages":[]},"version":"v1","identity":"rs-3585766","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3585766","identity":"rs-3585766","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}