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Implementation of the ERAS (Enhanced Recovery After Surgery) protocol for colorectal cancer surgery in the Piemonte Region with an Audit and Feedback approach: study protocol for a stepped wedge cluster randomised trial. ForA peerstudy of thereview EASY-NET project.only Journal: BMJ Open

Manuscript ID bmjopen-2020-047491

Article Type: Protocol

Date Submitted by the 03-Dec-2020 Author:

Complete List of Authors: Pagano, Eva; Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Clinical Epidemiology Unit Pellegrino, Luca; Santa Croce e Carle Hospital, Department of Surgery, General and Oncologic Surgery Unit Rinaldi, Federica; University of Turin Palazzo, Valentina; University of Turin Donati, Danilo; Santa Croce e Carle Hospital, Department of Surgery, General and Oncologic Surgery Unit Meineri, Maurizio; Santa Croce e Carle Hospital, Department of http://bmjopen.bmj.com/ Anesthesiology and Intensive Care Palmisano, Sarah; Santa Croce e Carle Hospital, Department of Anesthesiology and Intensive Care Rolfo, Monica; Humanitas, Torino, Healthcare Services Direction Bachini, Ilaria; Ordine Mauriziano Hospital, Unit of Dietetic and Clinical Nutrition Bertetto, Oscar; Dipartimento Interaziendale Interregionale Rete Oncologica Piemonte-Valle d’Aosta Borghi, Felice; ASO Santa Croce e Carle, Department of Surgery, General and Oncologic Surgery Unit on September 29, 2021 by guest. Protected copyright. Ciccone, Giovannino; Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Clinical Epidemiology Unit

AUDIT, Colorectal surgery < SURGERY, Quality in health care < HEALTH Keywords: SERVICES ADMINISTRATION & MANAGEMENT

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4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the terms applicable for US Federal Government officers or employees acting as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author Forunless you peer are acting as review an employee on behalf only of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34 35

36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

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1 2 3 Implementation of the ERAS (Enhanced Recovery After Surgery) protocol for colorectal

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 cancer surgery in the Piemonte Region with an Audit and Feedback approach: study protocol 6 7 for a stepped wedge cluster randomised trial. A study of the EASY-NET project. 8 9 10 Pagano E1, Pellegrino L2, Rinaldi F3, Palazzo V3, Donati D2, Meineri M4, Palmisano S4, Rolfo M5, 11 12 Bachini I6, Bertetto O7, Borghi F2, Ciccone G1 and the ERAS Colon-Rectum Piemonte group 13 14 15 1. Clinical Epidemiology Unit, Città della Salute e della Scienza Hospital, Torino, Italy 16 17 2. Department of Surgery, General and Oncologic Surgery Unit, Santa Croce e Carle Hospital, Cuneo, Italy 18 3. University of Torino, ItalyFor peer review only 19 4. Department of Anesthesiology and Intensive Care, S. Croce e Carle Hospital, Cuneo, Italy 20 21 5. Healthcare Services Direction, Humanitas, Torino, Italy 22 6. Unit of Dietetic and Clinical Nutrition, Ordine Mauriziano Hospital, Torino, Italy 23 24 7. Department of Rete Oncologica del Piemonte e Valle d’Aosta, Città della Salute e della Scienza Hospital, Torino, 25 Italy 26 27 28 Corresponding author 29 30 Eva Pagano 31 Unit of Clinical Epidemiology 32 33 “Città della Salute e della Scienza” Hospital 34 Via Santena 5, 10126, Torino 35

36 Tel. 0039 011 633 68 55 http://bmjopen.bmj.com/ 37 38 [email protected] 39 40 41 42 43

44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Abstract

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 Introduction: The ERAS protocol (Enhanced Recovery After Surgery) is a multimodal pathway 6 7 aimed to reduce surgical stress and to allow a rapid post-operative recovery. Application of the ERAS 8 protocol to colorectal cancer surgery has been limited to a minority of hospitals in Italy. To promote 9 10 the systematic adoption of ERAS in the entire regional hospital network in Piemonte an Audit and 11 12 Feedback approach (A&F) has been adopted together with a cluster randomised trial to estimate the 13 14 true impact of the protocol on a large, unselected population: . 15 Methods: A multicenter stepped wedge cluster randomised trial is designed for comparison between 16 17 standard perioperative management and the management according to the ERAS protocol. The 18 For peer review only 19 primary outcome is the length of hospital stay (LOS). Secondary outcomes are: incidence of post- 20 operative complications, time to patients’ recovery, control of pain and patients’ satisfaction. With 21 22 an A&F approach the adherence to the ERAS items is monitored through a dedicated area in the study 23 24 web site. 25 26 The study includes 28 surgical centers, stratified by activity volume and randomly divided into four 27 groups. Each group is randomly assigned to a different activation period of the ERAS protocol. There 28 29 are four activation periods, one every three months. However, the planned calendar and the total 30 31 duration of the study have been extended by three months due to the COVID-19 pandemic. 32 33 The expected sample size of about 2200 patients has a high statistical power (98%) to detect a 34 reduction of LOS of 1 day and to estimate clinically meaningful changes in the other endpoints. 35

36 Ethics and dissemination: The study protocol has been approved by the Ethical Committee of the http://bmjopen.bmj.com/ 37 38 coordinating Center and by all participating centers. Study results will be timely circulated within the 39 hospital network and published in peer-reviewed journals. 40 41 42 43

44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Trial registration: NCT04037787

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 6 7 Keywords 8 Stepped-wedge cluster-randomised trial, colorectal cancer surgery, ERAS protocol, audit and 9 10 feedback 11 12 13 14 Strengths and limitation of this study 15  The study is designed to confirm that positive clinical outcomes of the application of ERAS 16 17 protocol can be obtained not only when it’s implemented in selected and highly motivated 18 For peer review only 19 centers, but also when implemented in a regional network of surgical centers, supported by a 20 21 careful Audit&Feedback strategy used to improve compliance. 22  The stepped wedge design allows to reach a complete coverage of the participating centers at 23 24 the end of the study with an unbiased assessment of the effects of the clinical practice 25 26 modification. 27 28  In case of low compliance by participating centers with the ERAS protocol, the A&F approach 29 will be considered not effective in promoting change but there will be the chance to analyse 30 31 obstacles and facilitators of the application of the ERAS approach. 32 33 34 Word count: 2994 35

36 Figure: 1 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

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1 2 3 Introduction

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 The ERAS protocol (Enhanced Recovery After Surgery) is a multimodal pathway aimed to reduce 6 7 surgical stress, trying to maintain body homeostasis and to allow a rapid post-operative recovery of 8 the patient undergoing major surgery (1-2). The main targets of the ERAS protocol are: to optimize 9 10 the perioperative management using procedures based on scientific evidence, to favor a better 11 12 recovery of the patient's autonomy in the post-operative period; to favor a reduction in length-of-stay; 13 14 to increase the level of patient satisfaction about treatment received; to reduce the incidence of 15 complications, hospital readmissions and costs (3-5). 16 17 The ERAS Society has developed guidelines for colorectal surgery and has also allowed protocols 18 For peer review only 19 adapted to different surgical disciplines (6-9). The principal items of the ERAS protocol for colorectal 20 cancer are reported as Supplementary Material (Table S1). Literature review and meta-analyses 21 22 confirms that the implementation of the ERAS protocol in colorectal surgery allows for a significant 23 24 reduction of post-operative complications, especially of non-surgical ones, compared to traditional 25 26 perioperative management (10-13). The same meta-analysis confirms that the implementation of an 27 ERAS path allows for a significant reduction in post-operative hospital stays, without increasing the 28 29 rate of hospital readmissions (12). Studies conducted in Alberta, following a national adoption of the 30 31 ERAS pathway in colorectal surgery, have also shown a significant reduction in healthcare costs (14). 32 33 A formal program for the implementation of the ERAS protocol requires three elements (14-16): 34 1) an updated and shared ERAS operating protocol 2) a team dedicated to training operators and to 35

36 increase compliance with the protocol 3) an Audit and Feedback (A&F) system to verify compliance http://bmjopen.bmj.com/ 37 38 with the protocol and to monitor clinical outcomes. 39 In Italy the PeriOperative Italian Society (POIS, http://perioperativeitaliansociety.org) aims to 40 41 disseminatethe ERAS strategy because its mission is to promote the minimally invasive surgical 42 43 procedures and improve the patient's quality of life in the perioperative period.

44 on September 29, 2021 by guest. Protected copyright. 45 The POIS has activated a network of over 70 Italian hospitals and has developed a database for 46 colorectal surgery which has allowed the recent publication of multicenter studies (16-18). 47 48 Although the ERAS protocol has been known for some time, its application has been limited to a 49 50 minority of hospitals, at least in Piemonte (a region of North West of Italy with 4.3 million 51 population). To promote the systematic adoption of ERAS in the entire regional hospital network in 52 53 Pimonte an A&F approach has been adopted together with a cluster randomized controlled study to 54 55 estimate the true impact of the protocol on a large, unselected population: the ERAS Colon-rectum 56 57 Piemonte study. 58 The project was based on two main hypotheses: a) the ERAS protocol has a high probability, based 59 60 on the available evidence, of introducing procedures into clinical practice with a favorable balance

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1 2 3 between benefits and risks (both for patients and for staff); b) the diffusion of the protocol only in

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 selected hospitals, particularly open to change, would have a limited impact on the overall quality of 6 7 the intervention on a regional scale, with an increase in the heterogeneity of services between centers 8 and inequalities among patients. 9 10 This regional project is part of a larger project on the evaluation of effectiveness of A&F interventions 11 12 (EASY-NET), a Network Project founded by the Ministry of Health and the participating Regions 13 14 (NET-2016-02364191). 15 16 17 Methods 18 For peer review only 19 Trial design 20 21 The ERAS Protocol Implementation in Piemonte Region for Colorectal Cancer Surgery (ERAS 22 23 Colon-Rectum Piemonte) (http://www.clinicaltrials.gov, registration number: NCT04037787) is a 24 prospective multicenter cluster randomized controlled study, with a stepped wedge design, for 25 26 comparison between standard perioperative management (usual care) and the management according 27 28 to the ERAS protocol. We hypothesize that the adoption of the protocol will result in a reduction in 29 30 the length of stay, complications, healthcare costs and in improvement of functional recovery and 31 patient satisfaction. 32 33 Clusters are represented by the general surgery units of the regional hospitals with progressive 34 35 adoption of the protocol by groups of units, randomly identified according to a specific calendar. At

36 the end of the study, each cluster will have a period of activity according to standard care ("control http://bmjopen.bmj.com/ 37 38 period") and one period of protocol based practice ("experimental period") with a cross-over like 39 40 design, but with a single transition (from control to experimental). 41 42 The SPIRIT 2013 Checklist (https://www.spirit-statement.org/) is provided in the Supplemental 43 Material. Figure 1 shows the study diagram according to the SPIRIT statement.

44 on September 29, 2021 by guest. Protected copyright. 45 46 47 Study organization 48 49 The study is promoted and coordinate by the “S. Croce e Carle” Hospital (Cuneo) where the surgical 50 51 unit has fully implemented the ERAS protocol for colorectal cancer interventions, having recently 52 obtained the European ERAS certification (https://erassociety.org/). The trial design, data collection 53 54 and monitoring, statistical analyses and feedback activities are under the responsibility of the Clinical 55 56 Epidemiology Unit of the “AOU Città della Salute e della Scienza” hospital (Torino) as part of the 57 58 Work Package 3 of EASY-NET Project. 59 60

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1 2 3 There are not planned preliminary analyses of the study outcomes to be performed before the

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 completion of the study. 6 7 8 Inclusion criteria 9 10 11  All general surgery units of Piemonte Region hospitals that have at least 30 surgical colorectal 12 cancer cases per year. 13 14  All patients undergoing elective colorectal resection for malignancy, with or without 15 16 protective stoma, and both by minimally invasive or laparotomic approach. 17 18 For peer review only 19 Exclusion criteria 20 21 22  Units with less than 30 cases per year of colorectal rectal surgery. 23  Patients requiring an urgent surgical procedure. 24 25  Patients with high complexity or clinical severity, to be documented at the time of admission 26 27 (e.g. patients with ASA score V). 28 29 30 Stratification and randomization of the centers 31 32 33 Ahead of the study starting date, all general surgery units were contacted to assess the level of 34 knowledge of the ERAS protocol for colorectal surgery. Those centers who had already fully adopted 35

36 the protocol before the start of the study were excluded from randomization and included in an http://bmjopen.bmj.com/ 37 38 observational group. All the other centers were stratified by the volume of colorectal interventions 39 40 performed during 2017 and randomly divided into 4 groups, with a similar number of units and 41 procedures. Then, the 4 groups were randomly ordered to activate the protocol according to a 42 43 predefined calendar with 3 months interval between subsequent rounds. This stratified randomization

44 on September 29, 2021 by guest. Protected copyright. 45 was adopted to assure a more homogeneous composition of the groups in each activation period. All 46 randomization procedures were performed by the Clinical Epidemiology unit after anonymizing the 47 48 centers. The calendar date for protocol activation was communicated to each group about two months 49 50 before the starting date to allow sufficient time for the training of the local ERAS team and to organize 51 52 the activity. 53 The centers of the first groupstarted with theprotocol activationafter a 3-months period of baseline, 54 55 during which only standard care was supplied to the enrolled patients. 56 57 58 59 60

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1 2 3 Interventions

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 ERAS group 6 7 8 In the quarter preceding the date of randomization, each group receive specific training on the ERAS 9 principles. Training is provided to a selected group of professionals (surgeons, anesthetists, nurses, 10 11 and dieticians) and consists of a one-day interactive course run by expert POIS trainers. The 12 13 selectedparticipants are required to cascade training to their colleagues at local level. Slides are shared 14 15 for this purpose as well as support is offered by the expert POIS trainers, if required. 16 Each center is asked to identify a "ERAS team", which should include at least one person per 17 18 professional role, with Forthe aim ofpeer providing reviewsupport for the local only implementation of the protocol and 19 20 to be the reference for the center. 21 Once each group enter the experimental period, the ERAS teams have the opportunity to access the 22 23 feedback area on EPICLIN, a dedicated website for the study 24 25 (https://new.epiclin.it/it/eras_colonretto/). The feedback area displays different graphs monitoring 26 27 indicators of adherence to the ERAS procedures. The aim is to verify the centers progress in applying 28 the protocol in order to promptly identify critical issues and address them with corrective actions. 29 30 After the first three months of ERAS adoption, the regional coordinating group organizes a meeting 31 32 with each of the four groups to discuss the feedback indicators, collect the critical issues encountered 33 34 and suggest possible solutions. 35

36 http://bmjopen.bmj.com/ 37 Control group 38 39 Each center belongs to the control group during the three months of baseline and thereafter, until the 40 41 randomization date. During the control period centers are required to continue with their usual 42 43 perioperative care and to fill the Case Report Form (CRF) for the enrolled patients.

44 on September 29, 2021 by guest. Protected copyright. 45 46 Primary outcome 47 48  Mean length of stay (LOS), calculated after excluding lengths exceeding a predefined threshold, 49 50 corresponding to the 94th percentile of the distribution. 51 52 53 Secondary outcome 54 55 56  Percentage of hospital stays exceeding a threshold (> = 22 days) 57 58  Incidence of post-surgical complications, defined according to the Clavien-Dindo classification 59  Intensive care unit access in the post-operative period 60

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1 2 3  Percentage of re-intervention (within 30 days after surgery)

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5  Percentage of Emergency Department (ED) admissions up to 30 days after surgery (regardless of 6 7 diagnosis) 8 9  Percentage of readmissions to hospital within 30 days after surgery (regardless of diagnosis) 10  Post-operative quality of recovery score, measured with the QoR-15 (19) questionnaire around 11 12 48 hours after surgery 13 14  Perceived patient satisfaction score measured with the SSQ-8 (20) questionnaire via telephone 15 16 interview around two weeks after discharge (only in a random sub-sample of patients keen to 17 partecipate) 18 For peer review only 19  Average healthcare costs, calculated from pre-hospitalization up to 30 days after surgery 20 21  Assessment of professionals’ satisfaction, measured qualitatively. 22 23 24 Data collection 25 26 27 The CRF is available in a dedicated area of the EPICLIN electronic platform, developed and managed 28 by the Clinical Epidemiology Unit, compliant with all the security requirements of the General Data 29 30 Protection Regualtion (EU regulation 2016/679). Data related to the peri-operative care are collected 31 32 in the database prospectively and uniformly between study periods. Patients are enrolled and sign a 33 34 consent form after receiving comprehensive oral and written information on the study aims and on 35 the data treatment by the enrolling centre.

36 http://bmjopen.bmj.com/ 37 The post-operative recovery will be measured at 48 hours after surgery through the QoR-15 38 39 questionnaire (available and validated in English) (19). 40 Patients’ satisfaction is measured through the SSQ-8 questionnaire (available and validated in 41 42 English) (20), administered by telephone to a sample of patients or alternatively their caregivers two 43

44 weeks after discharge, by trained personnel. on September 29, 2021 by guest. Protected copyright. 45 46 Professionals’ satisfaction will be qualitatively assessed at the end of the study through questionnaires 47 and focus groups. 48 49 Healthcare costs incurred between the first pre-admission visit and 30 days after hospital discharge 50 51 will be evaluated by including the following categories of resources: pre-intervention visits, hospital 52 stay days (including intensive care days), type of intervention, treatment of complications, re- 53 54 interventions, ED access, new hospitalizations. 55 56 57 58 Patient and Public Involvement 59 60 No patient involved.

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1 2 3 Statistical plan

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 Expected sample size is calculated according to the available data on volume of colorectal cancer 6 7 surgical cases in Piemonte Region in 2018. The total number of centers meeting the inclusion criteria 8 9 of at least 30 surgical colorectal cancer cases per year is 28, with an average of approximately 64 10 11 interventions/year (1790 expected cases in one year). With a randomization calendar including 7 12 centers every quarter, 4 periods (15 months in total, including the 3 months at baseline, before the 13 14 first randomization) are needed to complete the implementation of the ERAS protocol in all the 15 16 enrolled centers. Figure 1 describes the sequence of randomizations of the clusters with the number 17 of centers and patients for the control and experimental periods. The total number of cases expected 18 For peer review only 19 in 15 months is 2240 patients (around 1120 cases in the control period and 1120 in the experimental 20 21 period). The statistical power of the study is calculated for both the main endpoint (length-of-stay), 22 23 and for the dichotomous secondary endpoints, according to the sample size and the study design, 24 applying the Hemming and Girling method with STATA software (v.13). 25 26 The power is calculated assuming that the application of the protocol entails a reduction in the average 27 28 length of stay (calculated after excluding LOS> = 22 days, corresponding to the 94th percentile) of 29 30 at least 1 day (from 9.0 to 8.0), which in relation to the standard deviation (3.7) represents an effect 31 size of about 0.27. 32 33 The parameters used for the calculation are: Mean hospital stay (standard): 9.0 days (DS: 3.7); Mean 34 35 hospital stay (experimental): <= 8.0 days (DS 3.7); Alpha error (two tails): 0.05; Correlation

36 coefficient within clusters (ICC): 0.20; Average clusters sample size in each step: 16; Number of http://bmjopen.bmj.com/ 37 38 randomized clusters per step: 7; Number of steps (excluding the baseline): 4. Total number of cases 39 40 (2240) has a statistical power of 0.98. 41 42 The statistical power of the study is also calculated to highlight as statistically significant absolute 43 differences of at least 10% of the secondary endpoints measurable as percentages (e.g. adherence to

44 on September 29, 2021 by guest. Protected copyright. 45 the ERAS protocol, complications, re-interventions, etc ...). Assuming a reference value of 0.5 (the 46 47 most unfavorable from a statistical point of view), and keeping all the previous parameters the same, 48 49 the study has a power of 0.84. 50 The average LOS (calculated excluding the durations greater than the threshold) will be compared 51 52 between the two study periods using a random-effect linear regression models, adjusting for the study 53 54 period and the surgical technique (laparoscopic vs. open surgery). The center will be included in the 55 model as a random effect. For dichotomous endpoints measured as proportions (e.g. length of stay 56 57 above the threshold, complications, readmissions), the effect of implementing the ERAS protocol 58 59 will be estimated with logistic regression models with random effects, including in the model the 60 same set of covariates used for the analysis of the LOS. 9

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1 2 3 The main analysis will be stratified by characteristics of the centers (classified by volume of activity,

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 degree of adherence to the ERAS protocol at the baseline and other structural characteristics) and by 6 7 patients’ characteristics. Centers with high adherence to the ERAS protocol at the baseline will be 8 excluded from the main analysis. 9 10 To reduce the risk of bias due to patient selection (selection bias, assessed on the basis of the 11 12 percentage of cases included on the total discharge records in the same enrollment period), analyzes 13 14 will be stratified for completeness of enrollment (with the possibility of excluding centers with greater 15 incompleteness). 16 17 To take into account the transition period in each center, a sensitivity analysis is planned which will 18 For peer review only 19 exclude the first month of each implementation period of the ERAS protocol. The adoption of the 20 ERAS protocol will also be analyzed on the basis of the time elapsed since its introduction, to evaluate 21 22 the achievement curve of an acceptable and optimal level of application. 23 24 In addition, it is expected to evaluate the effect of the ERAS implementation analyzing the time trend 25 26 of the average LOS detectable through the regional hospital discharge records in the 5 years preceding 27 the activation of the ERAS protocol and in the following years, through an interrupted time series 28 29 analysis. 30 31 32 33 Ethics and dissemination 34 The study protocol has been approved by the Ethical Committee of the coordinating Center and by 35

36 all participating centers. The study is conducted under the regulations of the Declaration of Helsinki. http://bmjopen.bmj.com/ 37 38 All information collected during the course of the trial will be kept strictly confidential. Information 39 will be held securely at the Clinical Epidemiology Unit, accordingly to all aspects of GDPR 2018. 40 41 The trial staff at the participating centers will be responsible for ensuring that any data or 42 43 documentation sent to the Clinical Epidemiology Unit is appropriately anonymised. At the end of the

44 on September 29, 2021 by guest. Protected copyright. 45 trial, data will be securely archived for a minimum of 20 years. 46 Study results will be timely circulated within the hospital network and published in peer-reviewed 47 48 journals, reported in line with the literature Consolidated Standards of Reporting Trials guidelines 49 50 (21). 51 52 53 Trial Status 54 55 The trial is currently adhering to V.2.0 of the protocol (approved in January 2020). Enrollment was 56 57 initiated the 1st September 2019. Recruitment initially expected to be completed in November 2020, 58 59 due to COVID outbreak is now expected to be completed in February 2021 (three months delay of 60

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1 2 3 the study timetable). At the end of October 2020, the number of patients enrolled is around 2000,

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 45% of which managed according to standard practice. 6 7 8 Discussion 9 10 This paper presents the study protocol of a stepped wedge cluster randomised trial aimed to estimate 11 12 the impact of a quality improvement intervention (the adoption of the ERAS protocol for colorectal 13 14 cancer surgery) in the entire regional hospital network in Piemonte. In 2018 only few selected 15 hospitals were compliant with the ERAS protocol despite it was published several years before. 16 17 Among the reasons for this limited diffusion there is the need for a multiprofessional and 18 For peer review only 19 multidisciplinary management of the patient path besides the requirement to adopt all the items of the 20 protocol. To overcome the usual barriers to innovation in health care, especially at the organization 21 22 level, and to monitor the changes in terms of appropriateness and safety, a structured A&F strategy 23 24 has been planned in parallel to the trial. Even if the use of A&F is strongly recommended within the 25 26 ERAS protocol, it is unusual that this aspect is carefully designed and conducted according to the 27 best practice guidelines (22). 28 29 The chosen study design, a stepped-wedge cluster randomized trial, has several advantages and some 30 31 limits. Randomization at patient level would not be feasible due to the organizational nature of the 32 33 intervention requiring a modification of the care process at center level. However, compared to other 34 study designs such as a before-after cluster randomized trial, the stepped wedge has a lower risk of 35

36 bias due to possible confounding time effect and a complete coverage of the participating centers at http://bmjopen.bmj.com/ 37 38 the end of the study. This last advantage could, at least in theory, also represents a risk in the unlikely, 39 but not impossible, scenario of a detrimental impact of the experimental intervention. 40 41 In case of low or partial compliance by participating centers with the ERAS protocol, the A&F 42 43 approach will be considered not effective in promoting change. Anyway, there will be the chance to

44 on September 29, 2021 by guest. Protected copyright. 45 analyse obstacles and facilitators of the application of the ERAS approach. 46 In conclusion, the main interest of the study results lies in the possibility to demonstrate that positive 47 48 clinical outcomes for the application of ERAS protocol can be obtained not only when it’s 49 50 implemented in selected and highly motivated centers, but also when implemented in a regional 51 network of surgical centers, supported by a careful A&F strategy used to improve compliance. For 52 53 this last aspect the study will contribute useful evidence to the on-going EASY-NET project 54 55 (http://easy-net.info/). 56 57 58 59 60

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1 2 3 Authors’ contributions

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 BF, CG, PE, PL and BO conceived and designed the ERAS Colon-rectum Piemonte study. BF, as 6 7 Study Coordinator, has oversight for the trial. GC and EP have oversight for the study organization 8 and the statistical analysis; BO, DD and PL have oversight for the surgery items; MM and PS have 9 10 oversight for the anesthesiology items; RM has oversight for the nursing items; BI has oversight for 11 12 the nutritional items;. EP, RF and PV drafted the manuscript. The ERAS Colon-Rectum Piemonte 13 14 group will collect data. All authors contributed to, read and approved the final version. 15 16 17 ERAS Colon-Rectum Piemonte study group members: 18 For peer review only 19 Site investigators: AO Alessandria: Federica Borromeo, Fabio Priora; AO Maggiore della Carità, Novara: Sergio Gentilli, 20 Luca Portigliotti; AO Mauriziano, Torino: Paolo Massucco , Marco Palisi; AO S.Croce e Carle, Cuneo: Felice Borghi, 21 Luca Pellegrino; AO San Luigi Gonzaga, Orbassano (TO): Maurizio De Giuli, Aridai Resendiz; Gradenigo - Humanitas, 22 23 Torino: Paola Bellomo, Silvia Marola; IRCCS Candiolo (TO): Alfredo Mellano, Dario Ribero; Nuovo Ospedale degli 24 Infermi, Biella: Roberto Polastri; Ospedale Civile Agnelli, Pinerolo (TO): Andrea Muratore, Nicoletta Sveva Pipitone; 25 26 Ospedale degli Infermi, Rivoli (TO): Mauro Garino; Ospedale Cardinal Massaia, Asti: Elisabetta Castagna, Gabriele 27 Pozzo; Ospedale Castelli, Verbania: Andrea Caneparo; Ospedale Civico, Chivasso (TO): Adriana Ginardi, Reggina 28 29 Lagana; Ospedale Civile, Ciriè (TO): Monica Carrera, Stefania Muzio; Ospedale Civile, Ivrea: Luca Panier Suffat, Ivan 30 Lettini; Ospedale Maggiore, Chieri (TO): Alberto Kiss, Valentina Gentile; Ospedale Martini, Torino: Roberto Saracco, 31 Donatella Scaglione; Ospedale Regina Montis Regalis, Mondovì (CN): Andrea Gattolin, Roberto Rimonda; Ospedale 32 33 S.Biagio, Domodossola (VCO): Francesco Battafarano, Luigi Oragano; Ospedale S.Croce, Moncalieri (TO): Luca 34 Lorenzin, Carlo Palenzona; Ospedale S.Giacomo, Novi Ligure (AL): Carmine Gianfranco Di Somma, Eliana Giaminardi; 35 Ospedale S.Lazzaro, Alba (CN): Marco Calgaro, Marco Naddeo; Ospedale S.Lorenzo, Carmagnola (TO): Piero Cumbo, 36 http://bmjopen.bmj.com/ 37 Emma Marchigiano; Ospedale S.Spirito, Casale M.to (AL): Francesca Cravero, Marco Amisano, Francesco Lemut; 38 39 Ospedale San Giovanni Bosco, Torino: Tiziana Viora, Luciano Bonaccorsi; Ospedale Sant'Andrea, Vercelli: Silvio Testa, 40 Clemente De Rosa; Ospedale SS.Annunziata, Savigliano (CN): Marco Brunetti; Ospedale SS.Trinità, Borgomanero 41 42 (NO): Matteo Gatti, Presidio Cottolengo, Torino: Carlo Bima, Enrico Gibin; Ospedale Maria Vittoria, Torino: Francesco 43 Quaglino, Federico Festa, Luca Bonatti; AOU Città della Salute e della Scienza, Torino: Mario Morino, Marco Ettore

44 on September 29, 2021 by guest. Protected copyright. Allaix, Paolo De Paolis, Ida Marina Raciti, Mauro Santarelli, Gitana Scozzari. 45 46 Study coordination: AO S.Croce e Carle, Cuneo: Felice Borghi, Danilo Donati, Maurizio Meineri, Sarah Palmisano, Luca 47 Pellegrino; AOU Città della Salute e della Scienza, Torino: Giovannino Ciccone, Rosalba Galletti, Eva Pagano, Sergio 48 49 Sandrucci; AO Mauriziano, Torino: Ilaria Bachini, Anna De Magistris, Barbara Mitola, Paolo Massucco, Alessio Rizzo; 50 AO San Luigi Gonzaga, Orbassano and Università degli Studi di Torino (TO): Pietro Caironi; Humanitas, Torino: Monica 51 52 Rolfo; Regione Piemonte: Anna Orlando; Rete Oncologica Piemonte e Valle d'Aosta: Oscar Bertetto. 53 Technical staff: AOU Città della Salute e della Scienza, Torino: Francesco Brunetti, Corinna Defilè, Vitor Hugo Martins, 54 Lisa Giacometti, Matteo Papurello, Fabio Saccona, Danila Turco. 55 56 57 58 59 60

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1 2 3

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 Funding statement 6 7 This work was supported by the Italian Ministry of Health and the Regione Piemonte as part of the 8 Easy-Net Project, grant number NET-2016-02364191. 9 10 11 12 Competing interests statement 13 14 None declared. 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

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1 2 3 References

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 6 1) Kehlet H and Wilmore DW: Evidence-based surgical care and the evolution of fast-track surgery. Ann Surg 7 248(2): 189-198, 2008. 8 9 10 2) Ansari D, Gianotti L, Schroder J and Andersson R: Fast-track surgery: procedure-specific aspects and future 11 direction. Langenbecks Arch Surg 398(1): 29-37, 2013. 12 13 3) O. Ljungqvist, M. Scott, K.C. Fearon, Enhanced recovery after surgery: a review, JAMA Surg. 152 (3) 14 15 (2017 Mar 1) 292–298. 16 17 4) Visioni, R. Shah, E. Gabriel, K. Attwood, M. Kukar, S. Nurkin, Enhanced recovery after surgery for 18 For peer review only 19 noncolorectal surgery?: a systematic review and meta-analysis of major abdominal surgery, Ann. Surg. (2017) 20 (Epub ahead of print). 21 22 23 5) O. Ljungqvist, N.X. Thanh, G. Nelson, ERAS - value based surgery. J Surg Oncol 2017; 116 (5): 608-612. 24 25 6) Gustafsson UO, Scott MJ, Hubner M, Nygren J, Demartines N, Francis N, Rockall TA, Young-Fadok TM, 26 Hill AG, Soop M, de Boer HD, Urman RD, Chang GJ, Fichera A, Kessler H, Grass F, Whang EE, Fawcett 27 28 WJ, Carli F, Lobo DN, Rollins KE, Balfour A, Baldini G, Riedel B, Ljungqvist O. Guidelines for Perioperative 29 Care in Elective Colorectal Surgery: Enhanced Recovery After Surgery (ERAS(®)) Society 30 31 Recommendations: 2018. World J Surg. 2019 Mar;43(3):659-695. 32 33 7) Nygren J, Thacker J, Carli F, Fearon K, Norderval S, Lobo DN, Ljungqvist O, Soop M, Ramirez J. 34 Guidelines for perioperative care in elective rectal/pelvic surgery: Enhanced Recovery After Surgery (ERAS) 35

36 Society recommendations. Clinical Nutrition 2012(31): 801-816. http://bmjopen.bmj.com/ 37 38 8) Nelson G, Altman AD, Nick A, Meyer LA, Ramirez PT, Achtari C, Antrobus J, Huang J, Scott M, Wijk L, 39 40 Acheson N, Ljungqvist O, Dowdy SC. Guidelines for pre- and intra-operative care in gynecologic/oncology 41 surgery: Enhanced Recovery After Surgery (ERAS) Society recommendations--Part I. Gynecol Oncol. 2016 42 43 Feb;140(2):313-22.

44 on September 29, 2021 by guest. Protected copyright. 45 9) Nelson G, Altman AD, Nick A, Meyer LA, Ramirez PT, Achtari C, Antrobus J, Huang J, Scott M, Wijk L, 46 Acheson N, Ljungqvist O, Dowdy SC. Guidelines for postoperative care in gynecologic/oncology surgery: 47 48 Enhanced Recovery After Surgery (ERAS) Society recommendations-- Part II. Gynecol Oncol. 2016 49 Feb;140(2):323-32. 50 51 52 10) Spanjersberg WR, Reurings J, Keus F and van Laarhoven CJ: Fast track surgery versus conventional 53 recovery strategies for colorectal surgery. Cochrane Database Syst Rev 2, 2011. 54 55 11) Zhuang CL, Ye XZ, Zhang XD, Chen BC and Yu Z: Enhanced recovery after surgery programs versus 56 57 traditional care for colorectal surgery: a meta-analysis of randomized controlled trials. Dis Colon Rectum 58 56(5): 667-678, 2013. 59 60 12) Greco M, Capretti G, Beretta L, Gemma M, Pecorelli N, Braga M. Enhanced Recovery Program in 14

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1 2 3 Colorectal Surgery: A Meta-analysis of Randomized Controlled Trials. World J Surg 2014;38:1531–1541. 4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 6 13) Greer NL, Gunnar WP, Dahm P, Lee AE, MacDonald R, Shaukat A, Sultan S, Wilt TJ. Enhanced Recovery 7 Protocols for Adults Undergoing Colorectal Surgery: A Systematic Review and Meta-analysis. Dis Colon 8 9 Rectum. 2018 Sep;61(9):1108-1118. 10 11 14) Thanh NX, Chuck AW, Wasylak T, Lawrence J, Faris P, Ljungqvist O, Nelson G Gramlich LM. An 12 13 economic evaluation of the Enhanced Recovery After Surgery (ERAS) multisite implementation program for 14 colorectal surgery in Alberta. Can J Surg Dec 2016;59(6):415-421. 15 16 15) On behalf of the ERAS Compliance Group. The Impact of Enhanced Recovery Protocol Complianceon 17 18 Elective Colorectal CancerFor Resection. peer Results From review an International only Registry. Ann Surg 2015;261:1153–1159. 19 20 16) Braga M, Borghi F, Scatizzi M, Missana G, Guicciardi MA, Bona S, Ficari F, Maspero M, Pecorelli N; 21 22 PeriOperative Italian Society. Impact of laparoscopy on adherence to an enhanced recovery pathway and 23 readiness for discharge in elective colorectal surgery: Results from the PeriOperative Italian Society registry. 24 Surg Endosc. 2017 Nov;31(11):4393-4399. 25 26 27 17) Braga M, Beretta L, Pecorelli N, Maspero M, Casiraghi U, Borghi F, Pellegrino L, Bona S, Monzani R, 28 Ferrari G, Radrizzani D, Iuliani R, Bima C, Scatizzi M, Missana G, Guicciardi MA, Muratore A, Crespi M, 29 30 Bouzari H, Ceretti AP, Ficari F; PeriOperative Italian Society Group. Enhanced recovery pathway in elderly 31 patients undergoing colorectal surgery: is there an effect of increasing ages? Results from the perioperative 32 33 Italian Society Registry. Updates Surg. 2017 Jun 34 35 18) Braga M, Pecorelli N, Scatizzi M, Borghi F, Missana G, Radrizzani D; PeriOperative Italian Society.

36 Enhanced Recovery Program in High-Risk Patients Undergoing Colorectal Surgery: Results from the http://bmjopen.bmj.com/ 37 38 PeriOperative Italian Society Registry. World J Surg. 2017 Mar;41(3):860-867. 39 40 19) Stark PA, Myles PS, Burke JA. Development and psychometric evaluation of a postoperative quality of 41 42 recovery score: the QoR-15. Anesthesiology. 2013 Jun;118(6):1332-40. 43

44 20) Murphy M, Sternschuss G, Haff R, van Raalte H, Saltz S, Lucente V. Quality of life and surgical on September 29, 2021 by guest. Protected copyright. 45 satisfaction after vaginal reconstructive vs obliterative surgery for the treatment of advanced pelvic organ 46 47 prolapse. Am J Obstet Gynecol. 2008 May;198(5):573.e1-7 48 49 21) Consolidated standards of reporting trials guidelines. Available: http://www.consort-statement.org/ 50 51 [Accessed October 2020] 52 53 22) Brehaut JC, Colquhoun HL, Eva KW, Carroll K, Sales A, Michie S, Ivers N, Grimshaw JM. Practice 54 55 Feedback Interventions: 15 Suggestions for Optimizing Effectiveness Ann Intern Med. 2016 Mar 56 15;164(6):435-41. 57 58 59 60

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1 2 3 Figure 1. Diagram of the ERAS Colon-rectum Piemonte study.

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

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4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 Randomisation Study period (months) 6 7 group Baseline 3 6 9 12 Total 8 Group 1 112 112 112 112 112 9 10 Group 2 112 112 112 112 112 11 12 Group 3 112 112 112 112 112 13 14 Group 4 112 112 112 112 112 15 Number of patients by period: 16 17  Control patients 448 336 224 112 0 1120 18 For peer review only 19  Experimental patients 0 112 224 336 448 1120 20

21 Experimental period 22 Note: Due to COVID-19 outbreak the third period has been extended for three months (lasting 6 rather than 3 23 months) and the further study periods shifted 3-months forward. 24 25 26 27 28 29 30 31 32 33 34 35

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1 2 3 Table S1. ERAS protocol items for colorectal cancer surgery. 4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 6 ERAS protocol items for colorectal cancer surgery 7 Preoperative items  Preadmission counselling 8  No prolonged fasting 9  Carbohydrate loading (maltodextrins administerd 3 hours before 10 11 surgery) 12  Immunonutrition in malnourished patients 13  Bowel preparation only for selected cases (surgery of the middle- 14 lower rectum) 15  Thromboembolism prophylaxis 16 17  Antibiotic prophylaxis 18 For peerNo premedication review only 19 Intraoperative items  Prevention of hypothermia (body warmer/warm intravenous 20 fluids) 21  Adoption of minimally invasive surgical techniques (laparoscopic 22 23 approach is preferable) 24  Surgical drainage only in selected cases 25 Postoperative items  Multimodal analgesia (minimized opioid use) 26  Prevention of nausea and vomiting 27 28  No nasogastric tubes 29  Early removal of urinary catheter 30  Early removal of intravenous infusions 31  Early re-feeding 32  Early mobilization 33 34  Stimulation of gut motility 35  Feedback about compliance and outcomes

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1 2 3

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 6 7 8 9 SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related 10 11 documents* 12 13 14 Section/item ItemNo Description PAG. 15 16 Administrative information 17 18 Title 1For Descriptivepeer title review identifying the studyonly design, population, 2 19 interventions, and, if applicable, trial acronym 20 Trial registration 2a Trial identifier and registry name. If not yet registered, 3 21 name of intended registry 22 23 2b All items from the World Health Organization Trial 24 Registration Data Set 25 26 Protocol version 3 Date and version identifier 11 27 28 Funding 4 Sources and types of financial, material, and other support 12 29 30 Roles and 5a Names, affiliations, and roles of protocol contributors Authors responsibilities 31 5b Name and contact information for the trial sponsor NA 32 33 5c Role of study sponsor and funders, if any, in study design; 12 34 collection, management, analysis, and interpretation of 35 data; writing of the report; and the decision to submit the

36 http://bmjopen.bmj.com/ report for publication, including whether they will have 37 38 ultimate authority over any of these activities 39 5d Composition, roles, and responsibilities of the coordinating 5-6 40 centre, steering committee, endpoint adjudication 41 committee, data management team, and other individuals 42 or groups overseeing the trial, if applicable (see Item 21a 43 for data monitoring committee)

44 on September 29, 2021 by guest. Protected copyright. 45 46 Introduction 47 48 Background and 6a Description of research question and justification for 4-5 49 rationale undertaking the trial, including summary of relevant 50 studies (published and unpublished) examining benefits 51 and harms for each intervention 52 6b Explanation for choice of comparators 5 53 54 Objectives 7 Specific objectives or hypotheses 5 55 56 Trial design 8 Description of trial design including type of trial (eg, 5 57 parallel group, crossover, factorial, single group), 58 allocation ratio, and framework (eg, superiority, 59 equivalence, noninferiority, exploratory) 60

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1 2 3

4 Methods: Participants, interventions, and outcomes BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 6 Study setting 9 Description of study settings (eg, community clinic, 5 7 academic hospital) and list of countries where data will be 8 collected. Reference to where list of study sites can be 9 obtained 10 11 Eligibility criteria 10 Inclusion and exclusion criteria for participants. If 6 12 applicable, eligibility criteria for study centres and 13 individuals who will perform the interventions (eg, 14 surgeons, psychotherapists) 15 16 Interventions 11a Interventions for each group with sufficient detail to allow 7 17 replication, including how and when they will be 18 For administeredpeer review only 19 11b Criteria for discontinuing or modifying allocated NA 20 interventions for a given trial participant (eg, drug dose 21 22 change in response to harms, participant request, or 23 improving/worsening disease) 24 11c Strategies to improve adherence to intervention protocols, 7 25 and any procedures for monitoring adherence (eg, drug 26 tablet return, laboratory tests) 27 28 11d Relevant concomitant care and interventions that are NA 29 permitted or prohibited during the trial 30 31 Outcomes 12 Primary, secondary, and other outcomes, including the 7-8 32 specific measurement variable (eg, systolic blood 33 pressure), analysis metric (eg, change from baseline, final 34 value, time to event), method of aggregation (eg, median, 35 proportion), and time point for each outcome. Explanation

36 of the clinical relevance of chosen efficacy and harm http://bmjopen.bmj.com/ 37 outcomes is strongly recommended 38 39 Participant timeline 13 Time schedule of enrolment, interventions (including any 6; 40 run-ins and washouts), assessments, and visits for Figure 41 participants. A schematic diagram is highly recommended 1 42 (see Figure) 43

44 Sample size 14 Estimated number of participants needed to achieve study 9 on September 29, 2021 by guest. Protected copyright. 45 objectives and how it was determined, including clinical 46 and statistical assumptions supporting any sample size 47 calculations 48 49 Recruitment 15 Strategies for achieving adequate participant enrolment to NA 50 reach target sample size 51 52 Methods: Assignment of interventions (for controlled trials) 53 54 Allocation: 55 56 57 58 59 60

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1 2 3 Sequence 16a Method of generating the allocation sequence (eg, 9 4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 generation computer-generated random numbers), and list of any 6 factors for stratification. To reduce predictability of a 7 random sequence, details of any planned restriction (eg, 8 blocking) should be provided in a separate document that 9 is unavailable to those who enrol participants or assign 10 interventions 11 12 Allocation 16b Mechanism of implementing the allocation sequence (eg, NA 13 concealment central telephone; sequentially numbered, opaque, sealed 14 mechanism envelopes), describing any steps to conceal the sequence 15 until interventions are assigned 16 Implementation 16c Who will generate the allocation sequence, who will enrol NA 17 participants, and who will assign participants to 18 For peer review only 19 interventions 20 Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, NA 21 trial participants, care providers, outcome assessors, data 22 analysts), and how 23 24 17b If blinded, circumstances under which unblinding is NA 25 permissible, and procedure for revealing a participant’s 26 allocated intervention during the trial 27 28 Methods: Data collection, management, and analysis 29 30 Data collection 18a Plans for assessment and collection of outcome, baseline, 8 31 methods and other trial data, including any related processes to 32 promote data quality (eg, duplicate measurements, 33 training of assessors) and a description of study 34 instruments (eg, questionnaires, laboratory tests) along 35 with their reliability and validity, if known. Reference to

36 where data collection forms can be found, if not in the http://bmjopen.bmj.com/ 37 protocol 38 39 18b Plans to promote participant retention and complete NA 40 follow-up, including list of any outcome data to be 41 collected for participants who discontinue or deviate from 42 intervention protocols 43

44 Data management 19 Plans for data entry, coding, security, and storage, NR on September 29, 2021 by guest. Protected copyright. 45 including any related processes to promote data quality 46 (eg, double data entry; range checks for data values). 47 Reference to where details of data management 48 procedures can be found, if not in the protocol 49 50 Statistical methods 20a Statistical methods for analysing primary and secondary 9 51 outcomes. Reference to where other details of the 52 statistical analysis plan can be found, if not in the protocol 53 54 20b Methods for any additional analyses (eg, subgroup and 9 55 adjusted analyses) 56 57 20c Definition of analysis population relating to protocol non- 9 58 adherence (eg, as randomised analysis), and any 59 statistical methods to handle missing data (eg, multiple 60 imputation)

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1 2 3 Methods: Monitoring 4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 Data monitoring 21a Composition of data monitoring committee (DMC); NA 6 summary of its role and reporting structure; statement of 7 whether it is independent from the sponsor and competing 8 interests; and reference to where further details about its 9 charter can be found, if not in the protocol. Alternatively, 10 11 an explanation of why a DMC is not needed 12 21b Description of any interim analyses and stopping NR 13 guidelines, including who will have access to these interim 14 results and make the final decision to terminate the trial 15 16 Harms 22 Plans for collecting, assessing, reporting, and managing NA 17 solicited and spontaneously reported adverse events and 18 For otherpeer unintended review effects of trial only interventions or trial 19 conduct 20 21 Auditing 23 Frequency and procedures for auditing trial conduct, if NR 22 any, and whether the process will be independent from 23 investigators and the sponsor 24 25 Ethics and dissemination 26 27 Research ethics 24 Plans for seeking research ethics committee/institutional 10 28 approval review board (REC/IRB) approval 29 30 Protocol 25 Plans for communicating important protocol modifications NR 31 amendments (eg, changes to eligibility criteria, outcomes, analyses) to 32 relevant parties (eg, investigators, REC/IRBs, trial 33 participants, trial registries, journals, regulators) 34 35 Consent or assent 26a Who will obtain informed consent or assent from potential 8

36 trial participants or authorised surrogates, and how (see http://bmjopen.bmj.com/ 37 Item 32) 38 39 26b Additional consent provisions for collection and use of NA 40 participant data and biological specimens in ancillary 41 studies, if applicable 42 43 Confidentiality 27 How personal information about potential and enrolled 10 participants will be collected, shared, and maintained in 44 on September 29, 2021 by guest. Protected copyright. 45 order to protect confidentiality before, during, and after the 46 trial 47 48 Declaration of 28 Financial and other competing interests for principal 12 49 interests investigators for the overall trial and each study site 50 Access to data 29 Statement of who will have access to the final trial dataset, NR 51 and disclosure of contractual agreements that limit such 52 53 access for investigators 54 Ancillary and post- 30 Provisions, if any, for ancillary and post-trial care, and for NA 55 trial care compensation to those who suffer harm from trial 56 participation 57 58 59 60

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1 2 3 Dissemination 31a Plans for investigators and sponsor to communicate trial 10 4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 policy results to participants, healthcare professionals, the public, 6 and other relevant groups (eg, via publication, reporting in 7 results databases, or other data sharing arrangements), 8 including any publication restrictions 9 31b Authorship eligibility guidelines and any intended use of NA 10 professional writers 11 12 31c Plans, if any, for granting public access to the full protocol, NR 13 participant-level dataset, and statistical code 14 15 16 Appendices 17 Informed consent 32 Model consent form and other related documentation NR 18 materials For givenpeer to participants review and authorised only surrogates 19 20 Biological 33 Plans for collection, laboratory evaluation, and storage of NA 21 specimens biological specimens for genetic or molecular analysis in 22 the current trial and for future use in ancillary studies, if 23 applicable 24 25 *It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 26 Explanation & Elaboration for important clarification on the items. Amendments to the protocol 27 should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the 28 Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” license. 29 30 LEGEND: NA= not applicable; NR= not reported. 31 32 33 34 35

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Manuscript ID bmjopen-2020-047491.R1

Article Type: Protocol

Date Submitted by the 22-Apr-2021 Author:

Primary Subject Surgery Heading:

Secondary Subject Heading: Anaesthesia, Evidence based practice

AUDIT, Colorectal surgery < SURGERY, Quality in health care < HEALTH Keywords: SERVICES ADMINISTRATION & MANAGEMENT

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1 2 3 Implementation of the ERAS (Enhanced Recovery After Surgery) protocol for colorectal

36 Tel. 0039 011 633 68 55 http://bmjopen.bmj.com/ 37 38 [email protected] 39 40 41 42 43

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1 2 3 Abstract

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 Introduction: The ERAS protocol (Enhanced Recovery After Surgery) is a multimodal pathway 6 7 aimed to reduce surgical stress and to allow a rapid post-operative recovery. Application of the ERAS 8 protocol to colorectal cancer surgery has been limited to a minority of hospitals in Italy. To promote 9 10 the systematic adoption of ERAS in the entire regional hospital network in Piemonte an Audit and 11 12 Feedback approach (A&F) has been adopted together with a cluster randomised trial to estimate the 13 14 true impact of the protocol on a large, unselected population. 15 Methods: A multicenter stepped wedge cluster randomised trial is designed for comparison between 16 17 standard perioperative management and the management according to the ERAS protocol. The 18 For peer review only 19 primary outcome is the length of hospital stay (LOS). Secondary outcomes are: incidence of post- 20 operative complications, time to patients’ recovery, control of pain and patients’ satisfaction. With 21 22 an A&F approach the adherence to the ERAS items is monitored through a dedicated area in the study 23 24 web site. 25 26 The study includes 28 surgical centers, stratified by activity volume and randomly divided into four 27 groups. Each group is randomly assigned to a different activation period of the ERAS protocol. There 28 29 are four activation periods, one every three months. However, the planned calendar and the total 30 31 duration of the study have been extended by three months due to the COVID-19 pandemic. 32 33 The expected sample size of about 2200 patients has a high statistical power (98%) to detect a 34 reduction of LOS of 1 day and to estimate clinically meaningful changes in the other endpoints. 35

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1 2 3 Trial registration: NCT04037787

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 6 7 Keywords 8 Stepped-wedge cluster-randomised trial, colorectal cancer surgery, ERAS protocol, audit and 9 10 feedback 11 12 13 14 Strengths and limitation of this study 15  Systematic implementation of the ERAS protocol in an entire regional network of surgical 16 17 centres. 18 For peer review only 19  Use of a cluster stepped wedge design to achieve, by the end of the study, the adoption of the 20 21 ERAS protocol in all the participating centres, followed by an unbiased assessment of the 22 effectiveness of change in clinical practice. 23 24  Development of a comprehensive Audit&Feedback strategy to monitor and encourage 25 26 adoption of the full ERAS protocol. 27 28  Ability to analyse barriers and facilitators to ERAS protocol implementation at both patient 29 and organisational levels. 30 31  COVID-19 pandemic may limit the hospital ability to reorganise according to the ERAS 32 33 protocol and complicate the interpretation of the study results. 34 35

36 Word count: 3260 http://bmjopen.bmj.com/ 37 38 Figure: 1 39 40 41 42 43

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1 2 3 Introduction

36 increase compliance with the protocol 3) an Audit and Feedback (A&F) system to verify compliance http://bmjopen.bmj.com/ 37 38 with the protocol and to monitor clinical outcomes. 39 In Italy the PeriOperative Italian Society (POIS, http://perioperativeitaliansociety.org) aims to 40 41 disseminate the ERAS strategy because its mission is to promote the minimally invasive surgical 42 43 procedures and improve the patient's quality of life in the perioperative period.

44 on September 29, 2021 by guest. Protected copyright. 45 The POIS has activated a network of over 70 Italian hospitals and has developed a database for 46 colorectal surgery which has allowed the recent publication of multicenter studies (16-18). 47 48 Although the ERAS protocol has been known for some time, its application has been limited to a 49 50 minority of hospitals, at least in Piemonte (a region of North West of Italy with 4.3 million 51 population). To promote the systematic adoption of ERAS in the entire regional hospital network in 52 53 Piemonte an A&F approach has been adopted together with a cluster randomized controlled study to 54 55 estimate the true impact of the protocol on a large, unselected population: the ERAS Colon-rectum 56 57 Piemonte study. The A&F strategy is recommended by the ERAS society guidelines for colorectal 58 cancer (quality of evidence: high; recommendation: strong) as an instrument to be applied regularly 59 60 by healthcare providers when driving change or implementing ERAS programmes (6).

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1 2 3 The project was based on two main hypotheses: a) the ERAS protocol has a high probability, based

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 on the available evidence, of introducing procedures into clinical practice with a favorable balance 6 7 between benefits and risks (both for patients and for staff); b) the diffusion of the protocol only in 8 selected hospitals, particularly open to change, would have a limited impact on the overall quality of 9 10 the intervention on a regional scale, with an increase in the heterogeneity of services between centers 11 12 and inequalities among patients. 13 14 This regional project is part of a larger project on the evaluation of effectiveness of A&F interventions 15 (EASY-NET), a Network Project founded by the Ministry of Health and the participating Regions 16 17 (NET-2016-02364191). 18 For peer review only 19 20 Methods 21 22 Trial design 23 24 The ERAS Protocol Implementation in Piemonte Region for Colorectal Cancer Surgery (ERAS 25 26 Colon-Rectum Piemonte) (http://www.clinicaltrials.gov, registration number: NCT04037787) is a 27 28 prospective multicenter cluster randomized controlled study, with a stepped wedge design, for 29 30 comparison between standard perioperative management (usual care) and the management according 31 to the ERAS protocol. We hypothesize that the adoption of the protocol will result in a reduction in 32 33 the length of stay, complications, healthcare costs and in improvement of functional recovery and 34 35 patient satisfaction.

36 Clusters are represented by the general surgery units of the regional hospitals with progressive http://bmjopen.bmj.com/ 37 38 adoption of the protocol by groups of units, randomly identified according to a specific calendar. At 39 40 the end of the study, each cluster will have a period of activity according to standard care ("control 41 42 period") and one period of protocol based practice ("experimental period") with a cross-over like 43 design, but with a single transition (from control to experimental).

44 on September 29, 2021 by guest. Protected copyright. 45 The SPIRIT 2013 Checklist (https://www.spirit-statement.org/) is provided in the Supplemental 46 47 Material. Figure 1 shows the study diagram according to the SPIRIT statement. 48 49 The manuscript has been prepared according to the RECOvER checklist (Supplemental Material), 50 the standardized framework for designing and reporting ERAS-related studies proposed by the ERAS 51 52 and ERAS USA societies (19). 53 54 55 Study organization 56 57 58 The study is promoted and coordinate by the “S. Croce e Carle” Hospital (Cuneo) where the surgical 59 unit has fully implemented the ERAS protocol for colorectal cancer interventions, having recently 60

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1 2 3 obtained the European ERAS certification (https://erassociety.org/). The trial design, data collection

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 and monitoring, statistical analyses and feedback activities are under the responsibility of the Clinical 6 7 Epidemiology Unit of the “AOU Città della Salute e della Scienza” hospital (Torino) as part of the 8 Work Package 3 of EASY-NET Project. 9 10 There are not planned preliminary analyses of the study outcomes to be performed before the 11 12 completion of the study. 13 14 15 Inclusion criteria 16 17 18  All general surgeryFor units peer of Piemonte review Region hospitals onlythat have at least 30 surgical colorectal 19 cancer cases per year. 20 21  All patients undergoing elective colorectal resection for malignancy, with or without 22 23 protective stoma, and both by minimally invasive or laparotomic approach. 24 25 26 Exclusion criteria 27 28 29  Units with less than 30 cases per year of colorectal rectal surgery. 30  Patients requiring an urgent surgical procedure. 31 32  Patients with high complexity or clinical severity, to be documented at the time of admission 33 34 (e.g. patients with ASA score V). 35

36 http://bmjopen.bmj.com/ 37 Stratification and randomization of the centers 38 39 40 Ahead of the study starting date, all general surgery units were contacted to assess the level of 41 knowledge of the ERAS protocol for colorectal surgery. Those centers who had already fully adopted 42 43 the protocol before the start of the study were excluded from randomization and included in an

44 on September 29, 2021 by guest. Protected copyright. 45 observational group. All the other centers were stratified by the volume of colorectal interventions 46 performed during 2017 and randomly divided into 4 groups, with a similar number of units and 47 48 procedures. Then, the 4 groups were randomly ordered to activate the protocol according to a 49 50 predefined calendar with 3 months interval between subsequent rounds. This stratified randomization 51 52 was adopted to assure a more homogeneous composition of the groups in each activation period. All 53 randomization procedures were performed by the Clinical Epidemiology unit after anonymizing the 54 55 centers. The calendar date for protocol activation was communicated to each group about two months 56 57 before the starting date to allow sufficient time for the training of the local ERAS team and to organize 58 59 the activity. 60

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1 2 3 The centers of the first group started with the protocol activation after a 3-months period of baseline,

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 during which only standard care was supplied to the enrolled patients. 6 7 8 Interventions 9 10 11 ERAS group 12 13 In the quarter preceding the date of randomization, each group receive specific training on the ERAS 14 15 principles. Training is provided to a selected group of professionals (surgeons, anesthetists, nurses, 16 and dieticians) and consists of a one-day interactive course run by expert POIS trainers. The selected 17 18 participants are requiredFor to cascade peer training review to their colleagues only at local level. Slides are shared for 19 20 this purpose as well as support is offered by the expert POIS trainers, if required. 21 Each center is asked to identify a "ERAS team", which should include at least one person per 22 23 professional role, with the aim of providing support for the local implementation of the protocol and 24 25 to be the reference for the center. 26 27 28 Control group 29 30 31 Each center belongs to the control group during the three months of baseline and thereafter, until the 32 randomization date. During the control period centers are required to continue with their usual 33 34 perioperative care and to fill the Case Report Form (CRF) for the enrolled patients. 35

36 http://bmjopen.bmj.com/ 37 Audit&Feedback 38 39 The study has a dedicated website (EPICLIN: https://new.epiclin.it/it/eras_colonretto/) for data entry, 40 41 monitoring and feedback. 42 43 From the beginning of the study, all centers can access the “monitoring area” on Epiclin to keep track

44 of data collection progress and visualise graph and tables describing: number of enrolled patients and on September 29, 2021 by guest. Protected copyright. 45 46 expected number in the same period according to cases treated in the previous year, number of 47 48 patients keen to participate to an interview after discharge and number of patients filling the quality 49 50 of recovery questionnaire. 51 Once each group of centers enter the experimental period, its ERAS teams have the opportunity to 52 53 access a feedback area. This area displays various graphs monitoring the indicators of adherence to 54 55 all the ERAS items reported in table S1. The aim is to verify the centers progress in applying the 56 protocol in order to promptly identify critical issues and address them with corrective actions. Each 57 58 indicator of adherence is stratified by study period (control and experimental) to appreciate changes 59 60 in clinical practice. A radar graph allows to compare the adherence of groups of indicators measured

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1 2 3 in three different situations: before randomization, after randomization and in a benchmark setting (a

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 small group of regional hospitals already applying ERAS before the study). 6 7 Two months before ther ERAS adoption, the regional coordinating group organizes a workshop for 8 each of the four groups with the expert POIS trainers and the coordinating/data management team to 9 10 discuss the feedback indicators, the critical issues encountered and find possible solutions. 11 12 A Newsletter is sent every two months to all the ERAS teams to maintain engagement and motivation 13 14 in the overall project and to share information on study progress and relevant news. 15 16 17 Primary outcome 18 For peer review only 19  Mean length of stay (LOS), calculated after excluding lengths exceeding a predefined threshold, 20 21 corresponding to the 94th percentile of the distribution. 22 23 24 25 Secondary outcome 26 27  Percentage of hospital stays exceeding a threshold (> = 12 days) 28 29  Post-operative quality of recovery score, measured with the QoR-15 (19) questionnaire around 30 31 48 hours after surgery 32 33  Incidence of post-surgical complications, defined according to the Clavien-Dindo classification 34  Intensive care unit access in the post-operative period 35

36  Percentage of Emergency Department (ED) admissions up to 30 days after surgery (regardless of http://bmjopen.bmj.com/ 37 38 diagnosis) 39 40  Percentage of readmissions to hospital within 30 days after surgery (regardless of diagnosis) 41  Percentage of re-intervention (within 30 days after surgery) 42 43  Perceived patient satisfaction score measured with the SSQ-8 (20) questionnaire via telephone

44 on September 29, 2021 by guest. Protected copyright. 45 interview around two weeks after discharge (only in a random sub-sample of patients keen to 46 47 participate) 48  Average healthcare costs, calculated from pre-hospitalization up to 30 days after surgery 49 50  Assessment of professionals’ satisfaction, measured qualitatively. 51 52 53 54 Data collection 55 56 The CRF is available in a dedicated area of the EPICLIN electronic platform, developed and managed 57 58 by the Clinical Epidemiology Unit, compliant with all the security requirements of the General Data 59 Protection Regualtion (EU regulation 2016/679). Data related to the peri-operative care are collected 60

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1 2 3 in the database prospectively and uniformly between study periods. Patients are enrolled and sign a

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 consent form after receiving comprehensive oral and written information on the study aims and on 6 7 the data treatment by the enrolling centre. 8 The post-operative recovery will be measured at 48 hours after surgery through the QoR-15 9 10 questionnaire (available and validated in English) (20). 11 12 Patients’ satisfaction is measured through the SSQ-8 questionnaire (available and validated in 13 14 English) (21), administered by telephone to a sample of patients or alternatively their caregivers two 15 weeks after discharge, by trained personnel. 16 17 Professionals’ satisfaction will be qualitatively assessed at the end of the study through questionnaires 18 For peer review only 19 and focus groups. 20 Healthcare costs incurred between the first pre-admission visit and 30 days after hospital discharge 21 22 will be evaluated by including the following categories of resources: pre-intervention visits, hospital 23 24 stay days (including intensive care days), type of intervention, treatment of complications, re- 25 26 interventions, ED access, new hospitalizations. 27 28 29 Patient and Public Involvement 30 31 No patient involved. 32 33 34 35 Statistical plan

36 http://bmjopen.bmj.com/ 37 Expected sample size is calculated according to the available data on volume of colorectal cancer 38 39 surgical cases in Piemonte Region in 2018. The total number of centers meeting the inclusion criteria 40 of at least 30 surgical colorectal cancer cases per year is 28, with an average of approximately 64 41 42 interventions/year (1790 expected cases in one year). With a randomization calendar including 7 43

44 centers every quarter, 4 periods (15 months in total, including the 3 months at baseline, before the on September 29, 2021 by guest. Protected copyright. 45 46 first randomization) are needed to complete the implementation of the ERAS protocol in all the 47 enrolled centers. Figure 1 describes the sequence of randomizations of the clusters with the number 48 49 of centers and patients for the control and experimental periods. The total number of cases expected 50 51 in 15 months is 2240 patients (around 1120 cases in the control period and 1120 in the experimental 52 period). The statistical power of the study is calculated for both the main endpoint (length-of-stay), 53 54 and for the dichotomous secondary endpoints, according to the sample size and the study design, 55 56 applying the Hemming and Girling method with STATA software (v.13). 57 58 The power is calculated assuming that the application of the protocol entails a reduction in the average 59 length of stay (calculated after excluding LOS> = 22 days, corresponding to the 94th percentile) of 60

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1 2 3 at least 1 day (from 9.0 to 8.0), which in relation to the standard deviation (3.7) represents an effect

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 size of about 0.27. 6 7 The parameters used for the calculation are: Mean hospital stay (standard): 9.0 days (DS: 3.7); Mean 8 hospital stay (experimental): <= 8.0 days (DS 3.7); Alpha error (two tails): 0.05; Correlation 9 10 coefficient within clusters (ICC): 0.20; Average clusters sample size in each step: 16; Number of 11 12 randomized clusters per step: 7; Number of steps (excluding the baseline): 4. Total number of cases 13 14 (2240) has a statistical power of 0.98. 15 The statistical power of the study is also calculated to highlight as statistically significant absolute 16 17 differences of at least 10% of the secondary endpoints measurable as percentages (e.g. adherence to 18 For peer review only 19 the ERAS protocol, complications, re-interventions, etc ...). Assuming a reference value of 0.5 (the 20 most unfavorable from a statistical point of view), and keeping all the previous parameters the same, 21 22 the study has a power of 0.84. 23 24 The average LOS (calculated excluding the durations greater than the threshold) will be compared 25 26 between the two study periods using a random-effect linear regression models, adjusting for the study 27 period and the surgical technique (laparoscopic vs. open surgery). The center will be included in the 28 29 model as a random effect. For dichotomous endpoints measured as proportions (e.g. length of stay 30 31 above the threshold, complications, readmissions), the effect of implementing the ERAS protocol 32 33 will be estimated with logistic regression models with random effects, including in the model the 34 same set of covariates used for the analysis of the LOS. 35

36 The main analysis will be stratified by characteristics of the centers (classified by volume of activity, http://bmjopen.bmj.com/ 37 38 degree of adherence to the ERAS protocol at the baseline and other structural characteristics) and by 39 patients’ characteristics. Centers with high adherence to the ERAS protocol at the baseline will be 40 41 excluded from the main analysis. 42 43 To reduce the risk of bias due to patient selection (selection bias, assessed on the basis of the

44 on September 29, 2021 by guest. Protected copyright. 45 percentage of cases included on the total discharge records in the same enrollment period), analyzes 46 will be stratified for completeness of enrollment (with the possibility of excluding centers with greater 47 48 incompleteness). 49 50 To take into account the transition period in each center, a sensitivity analysis is planned which will 51 exclude the first month of each implementation period of the ERAS protocol. The adoption of the 52 53 ERAS protocol will also be analyzed on the basis of the time elapsed since its introduction, to evaluate 54 55 the achievement curve of an acceptable and optimal level of application. 56 57 In addition, it is expected to evaluate the effect of the ERAS implementation analyzing the time trend 58 of the average LOS detectable through the regional hospital discharge records in the 5 years preceding 59 60

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1 2 3 the activation of the ERAS protocol and in the following years, through an interrupted time series

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 analysis. 6 7 8 Ethics and dissemination 9 10 The study protocol has been approved by the Ethical Committee of the coordinating Center and by 11 12 all participating centers. The study is conducted under the regulations of the Declaration of Helsinki. 13 14 All information collected during the course of the trial will be kept strictly confidential. Information 15 will be held securely at the Clinical Epidemiology Unit, accordingly to all aspects of GDPR 2018. 16 17 The trial staff at the participating centers will be responsible for ensuring that any data or 18 For peer review only 19 documentation sent to the Clinical Epidemiology Unit is appropriately anonymised. At the end of the 20 trial, data will be securely archived for a minimum of 20 years. 21 22 Study results will be timely circulated within the hospital network and published in peer-reviewed 23 24 journals, reported in line with the literature Consolidated Standards of Reporting Trials guidelines 25 26 (22). 27 28 29 Trial Status 30 31 The trial is currently adhering to V.2.0 of the protocol (approved in January 2020 n.28-2020). 32 33 Enrollment was initiated the 1st September 2019. Recruitment initially expected to be completed in 34 35 November 2020, due to COVID outbreak is now expected to be completed in February 2021 (three

36 months delay of the study timetable). At the end of October 2020, the number of patients enrolled is http://bmjopen.bmj.com/ 37 38 around 2000, 45% of which managed according to standard practice. 39 40 41 42 Discussion 43 This paper presents the study protocol of a stepped wedge cluster randomised trial aimed to estimate

44 on September 29, 2021 by guest. Protected copyright. 45 the impact of a quality improvement intervention (the adoption of the ERAS protocol for colorectal 46 47 cancer surgery) in the entire regional hospital network in Piemonte. In 2018 only few selected 48 49 hospitals were compliant with the ERAS protocol despite it was published several years before. 50 Among the reasons for this limited diffusion there is the need for a multiprofessional and 51 52 multidisciplinary management of the patient path besides the requirement to adopt all the items of the 53 54 protocol. To overcome the usual barriers to innovation in health care, especially at the organization 55 level, and to monitor the changes in terms of appropriateness and safety, a structured A&F strategy 56 57 has been planned in parallel to the trial. Even if the use of A&F is strongly recommended within the 58 59 ERAS protocol, it is unusual that this aspect is carefully designed and conducted according to the 60 best practice guidelines (23). 11

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1 2 3 The chosen study design, a stepped-wedge cluster randomized trial, has several advantages and some

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 limits. Randomization at patient level would not be feasible due to the organizational nature of the 6 7 intervention requiring a modification of the care process at center level. However, compared to other 8 study designs such as a before-after cluster randomized trial, the stepped wedge has a lower risk of 9 10 bias due to possible confounding time effect and a complete coverage of the participating centers at 11 12 the end of the study. This last advantage could, at least in theory, also represents a risk in the unlikely, 13 14 but not impossible, scenario of a detrimental impact of the experimental intervention. 15 In case of low or partial compliance by participating centers with the ERAS protocol, 16 17 the effectiveness of A&F should be interpreted considering the disruptive COVID-19 pandemic 18 For peer review only 19 impact on hospital activity. Anyway, there will be the chance to carefully analyse obstacles and 20 facilitators of the application of the ERAS approach at both patient and organisational levels. 21 22 In conclusion, the main interest of the study results lies in the possibility to demonstrate that positive 23 24 clinical outcomes for the application of ERAS protocol can be obtained not only when it’s 25 26 implemented in selected and highly motivated centers, but also when implemented in a regional 27 network of surgical centers, supported by a careful A&F strategy used to improve compliance. For 28 29 this last aspect the study will contribute useful evidence to the on-going EASY-NET project 30 31 (http://easy-net.info/). 32 33 34 35

36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

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1 2 3 Authors’ contributions

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 BF, CG, PE, PL and BO conceived and designed the ERAS Colon-rectum Piemonte study. BF, as 6 7 Study Coordinator, has oversight for the trial. CG and PE have oversight for the study organization 8 and the statistical analysis; BO, DD and PL have oversight for the surgery items; MM and PS have 9 10 oversight for the anesthesiology items; RM has oversight for the nursing items; BI has oversight for 11 12 the nutritional items; PE, RF and PV drafted the manuscript. The ERAS Colon-Rectum Piemonte 13 14 group will collect data. All authors contributed to, read and approved the final version. 15 16 17 ERAS Colon-Rectum Piemonte study group members: 18 For peer review only 19 Site investigators: AO Alessandria: Federica Borromeo, Fabio Priora; AO Maggiore della Carità, Novara: Sergio Gentilli, 20 Luca Portigliotti; AO Mauriziano, Torino: Paolo Massucco , Marco Palisi; AO S.Croce e Carle, Cuneo: Felice Borghi, 21 Luca Pellegrino; AO San Luigi Gonzaga, Orbassano (TO): Maurizio De Giuli, Aridai Resendiz; Gradenigo - Humanitas, 22 23 Torino: Paola Bellomo, Silvia Marola; IRCCS Candiolo (TO): Alfredo Mellano, Dario Ribero; Nuovo Ospedale degli 24 Infermi, Biella: Roberto Polastri; Ospedale Civile Agnelli, Pinerolo (TO): Andrea Muratore, Nicoletta Sveva Pipitone; 25 26 Ospedale degli Infermi, Rivoli (TO): Mauro Garino; Ospedale Cardinal Massaia, Asti: Elisabetta Castagna, Gabriele 27 Pozzo; Ospedale Castelli, Verbania: Andrea Caneparo; Ospedale Civico, Chivasso (TO): Adriana Ginardi, Reggina 28 29 Lagana; Ospedale Civile, Ciriè (TO): Monica Carrera, Stefania Muzio; Ospedale Civile, Ivrea: Luca Panier Suffat, Ivan 30 Lettini; Ospedale Maggiore, Chieri (TO): Alberto Kiss, Valentina Gentile; Ospedale Martini, Torino: Roberto Saracco, 31 Donatella Scaglione; Ospedale Regina Montis Regalis, Mondovì (CN): Andrea Gattolin, Roberto Rimonda; Ospedale 32 33 S.Biagio, Domodossola (VCO): Francesco Battafarano, Luigi Oragano; Ospedale S.Croce, Moncalieri (TO): Luca 34 Lorenzin, Carlo Palenzona; Ospedale S.Giacomo, Novi Ligure (AL): Carmine Gianfranco Di Somma, Eliana Giaminardi; 35 Ospedale S.Lazzaro, Alba (CN): Marco Calgaro, Marco Naddeo; Ospedale S.Lorenzo, Carmagnola (TO): Piero Cumbo, 36 http://bmjopen.bmj.com/ 37 Emma Marchigiano; Ospedale S.Spirito, Casale M.to (AL): Francesca Cravero, Marco Amisano, Francesco Lemut; 38 39 Ospedale San Giovanni Bosco, Torino: Tiziana Viora, Luciano Bonaccorsi; Ospedale Sant'Andrea, Vercelli: Silvio Testa, 40 Clemente De Rosa; Ospedale SS.Annunziata, Savigliano (CN): Marco Brunetti; Ospedale SS.Trinità, Borgomanero 41 42 (NO): Matteo Gatti, Presidio Cottolengo, Torino: Carlo Bima, Enrico Gibin; Ospedale Maria Vittoria, Torino: Francesco 43 Quaglino, Federico Festa, Luca Bonatti; AOU Città della Salute e della Scienza, Torino: Mario Morino, Marco Ettore

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1 2 3

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1 2 3 References

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 1. Kehlet H, Wilmore DW. Evidence-based surgical care and the evolution of fast-track surgery. Ann 6 7 Surg. 2008;248(2):189–98. 8 9 2. Ansari D, Gianotti L, Schröder J, Andersson R. Fast-track surgery: procedure-specific aspects and 10 future direction. Langenbecks Arch Surg. 2013;398(1):29–37. 11 12 3. Ljungqvist O, Scott M, Fearon KC. Enhanced Recovery After Surgery: A Review. JAMA Surg. 13 2017;152(3):292–8. 14 15 4. Visioni A, Shah R, Gabriel E, Attwood K, Kukar M, Nurkin S. Enhanced Recovery After Surgery for 16 Noncolorectal Surgery?: A Systematic Review and Meta-analysis of Major Abdominal Surgery. Ann Surg. 17 2018;267(1):57–65. 18 For peer review only 19 5. Ljungqvist O, Thanh NX, Nelson G. ERAS-Value based surgery. J Surg Oncol. 2017;116(5):608–12. 20 21 6. Gustafsson UO, Scott MJ, Hubner M, Nygren J, Demartines N, Francis N, et al. Guidelines for 22 Perioperative Care in Elective Colorectal Surgery: Enhanced Recovery After Surgery (ERAS®) Society 23 Recommendations: 2018. World J Surg. 2019;43(3):659–95. 24 25 7. Nygren J, Thacker J, Carli F, Fearon KCH, Norderval S, Lobo DN, et al. Guidelines for perioperative 26 care in elective rectal/pelvic surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations. 27 28 Clin Nutr Edinb Scotl. 2012;31(6):801–16. 29 8. Nelson G, Altman AD, Nick A, Meyer LA, Ramirez PT, Achtari C, et al. Guidelines for pre- and intra- 30 31 operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society 32 recommendations--Part I. Gynecol Oncol. 2016;140(2):313–22. 33 34 9. Nelson G, Altman AD, Nick A, Meyer LA, Ramirez PT, Achtari C, et al. Guidelines for postoperative 35 care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations-

36 -Part II. Gynecol Oncol. 2016;140(2):323–32. http://bmjopen.bmj.com/ 37 38 10. Spanjersberg WR, Reurings J, Keus F, van Laarhoven CJ. Fast track surgery versus conventional 39 recovery strategies for colorectal surgery. Cochrane Database Syst Rev. 16 2011;(2):CD007635. 40 41 11. Zhuang C-L, Ye X-Z, Zhang X-D, Chen B-C, Yu Z. Enhanced recovery after surgery programs versus 42 traditional care for colorectal surgery: a meta-analysis of randomized controlled trials. Dis Colon Rectum. 43 2013;56(5):667–78.

44 on September 29, 2021 by guest. Protected copyright. 45 12. Greco M, Capretti G, Beretta L, Gemma M, Pecorelli N, Braga M. Enhanced recovery program in 46 47 colorectal surgery: a meta-analysis of randomized controlled trials. World J Surg. 2014;38(6):1531–41. 48 13. Greer NL, Gunnar WP, Dahm P, Lee AE, MacDonald R, Shaukat A, et al. Enhanced Recovery 49 50 Protocols for Adults Undergoing Colorectal Surgery: A Systematic Review and Meta-analysis. Dis Colon 51 Rectum. 2018;61(9):1108–18. 52 53 14. Thanh NX, Chuck AW, Wasylak T, Lawrence J, Faris P, Ljungqvist O, et al. An economic evaluation of 54 the Enhanced Recovery After Surgery (ERAS) multisite implementation program for colorectal surgery in 55 Alberta. Can J Surg J Can Chir. 2016;59(6):415–21. 56 57 15. ERAS Compliance Group. The Impact of Enhanced Recovery Protocol Compliance on Elective 58 Colorectal Cancer Resection: Results From an International Registry. Ann Surg. 2015;261(6):1153–9. 59 60

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1 2 3 16. Braga M, Borghi F, Scatizzi M, Missana G, Guicciardi MA, Bona S, et al. Impact of laparoscopy on 4 adherence to an enhanced recovery pathway and readiness for discharge in elective colorectal surgery: BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 6 Results from the PeriOperative Italian Society registry. Surg Endosc. 2017;31(11):4393–9. 7 17. Braga M, Beretta L, Pecorelli N, Maspero M, Casiraghi U, Borghi F, et al. Enhanced recovery 8 9 pathway in elderly patients undergoing colorectal surgery: is there an effect of increasing ages? Results 10 from the perioperative Italian Society Registry. Updat Surg. 2018;70(1):7–13. 11 12 18. Braga M, Pecorelli N, Scatizzi M, Borghi F, Missana G, Radrizzani D, et al. Enhanced Recovery 13 Program in High-Risk Patients Undergoing Colorectal Surgery: Results from the PeriOperative Italian Society 14 Registry. World J Surg. 2017;41(3):860–7. 15 16 19. Elias KM, Stone AB, McGinigle K, Tankou JI, Scott MJ, Fawcett WJ, et al. The Reporting on ERAS 17 Compliance, Outcomes, and Elements Research (RECOvER) Checklist: A Joint Statement by the ERAS® and 18 ERAS® USA Societies. WorldFor J Surg. peer 2019;43(1):1–8. review only 19 20 20. Stark PA, Myles PS, Burke JA. Development and psychometric evaluation of a postoperative quality 21 22 of recovery score: the QoR-15. Anesthesiology. 2013;118(6):1332–40. 23 21. Murphy M, Sternschuss G, Haff R, van Raalte H, Saltz S, Lucente V. Quality of life and surgical 24 25 satisfaction after vaginal reconstructive vs obliterative surgery for the treatment of advanced pelvic organ 26 prolapse. Am J Obstet Gynecol. 2008;198(5):573.e1-7. 27 28 22. Consolidated standards of reporting trials guidelines. Available: http://www.consort- 29 statement.org/ [Accessed April 2021] 30 31 23. Brehaut JC, Colquhoun HL, Eva KW, Carroll K, Sales A, Michie S, et al. Practice Feedback 32 Interventions: 15 Suggestions for Optimizing Effectiveness. Ann Intern Med. 15 2016;164(6):435–41. 33 34 35

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1 2 3 Figure 1. Diagram of the ERAS Colon-rectum Piemonte study.

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1 2 3 Table S1. ERAS protocol items for colorectal cancer surgery. 4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 ERAS protocol items for colorectal cancer surgery 6 7 Preoperative items  Preadmission counselling 8  No prolonged fasting 9  Carbohydrate loading (maltodextrins administerd 3 hours before 10 surgery) 11  Immunonutrition in malnourished patients 12  Bowel preparation only for selected cases (surgery of the middle-lower 13 rectum) 14 15  Thromboembolism prophylaxis 16  Antibiotic prophylaxis 17  No premedication 18 Intraoperative items For peerPrevention ofreview hypothermia (body only warmer/warm intravenous fluids) 19  Adoption of minimally invasive surgical techniques (laparoscopic 20 approach is preferable) 21  Surgical drainage only in selected cases 22 Postoperative items  Multimodal analgesia (minimized opioid use) 23 24  Prevention of nausea and vomiting 25  No nasogastric tubes 26  Early removal of urinary catheter 27  Early removal of intravenous infusions 28  Early re-feeding 29  Early mobilization 30  Stimulation of gut motility 31  Feedback about compliance and outcomes 32 33 34 35

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1 2 3

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 6 7 8 9 SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related 10 11 documents* 12 13 14 Section/item ItemNo Description PAG. 15 16 Administrative information 17 1, line 1 18 Title 1 ForDescriptive peer title review identifying the studyonly design, population, 19 interventions, and, if applicable, trial acronym 20 Trial registration 2a Trial identifier and registry name. If not yet registered, 3, line 1 21 name of intended registry 22 23 2b All items from the World Health Organization Trial NR 24 Registration Data Set 25 26 Protocol version 3 Date and version identifier 11, line 17 27 28 Funding 4 Sources and types of financial, material, and other 5, line 7 29 support 30 31 Roles and 5a Names, affiliations, and roles of protocol contributors 1, line 5 32 responsibilities 5b Name and contact information for the trial sponsor NA 33 34 5c Role of study sponsor and funders, if any, in study NA 35 design; collection, management, analysis, and

36 http://bmjopen.bmj.com/ interpretation of data; writing of the report; and the 37 38 decision to submit the report for publication, including 39 whether they will have ultimate authority over any of 40 these activities 41 5d Composition, roles, and responsibilities of the 5, line 32 42 coordinating centre, steering committee, endpoint 43 adjudication committee, data management team, and

44 on September 29, 2021 by guest. Protected copyright. 45 other individuals or groups overseeing the trial, if 46 applicable (see Item 21a for data monitoring committee) 47 48 Introduction 49 50 Background and 6a Description of research question and justification for 4, line 2 51 rationale undertaking the trial, including summary of relevant 52 studies (published and unpublished) examining benefits 53 and harms for each intervention 54 4, line 29 55 6b Explanation for choice of comparators 56 Objectives 7 Specific objectives or hypotheses 5, line 1 57 58 59 60

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1 2 3 Trial design 8 Description of trial design including type of trial (eg, 5, line 15 4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 parallel group, crossover, factorial, single group), 6 allocation ratio, and framework (eg, superiority, 7 equivalence, noninferiority, exploratory) 8 9 10 Methods: Participants, interventions, and outcomes 11 5, line 20 12 Study setting 9 Description of study settings (eg, community clinic, 13 academic hospital) and list of countries where data will 14 be collected. Reference to where list of study sites can 15 be obtained 16 6, line 8 17 Eligibility criteria 10 Inclusion and exclusion criteria for participants. If 18 Forapplicable, peer eligibility review criteria for onlystudy centres and 19 individuals who will perform the interventions (eg, 20 surgeons, psychotherapists) 21 Interventions 11a Interventions for each group with sufficient detail to allow 7, line 4 22 replication, including how and when they will be 23 24 administered 25 11b Criteria for discontinuing or modifying allocated NA 26 interventions for a given trial participant (eg, drug dose 27 change in response to harms, participant request, or 28 improving/worsening disease) 29 30 11c Strategies to improve adherence to intervention 7, line 20 31 protocols, and any procedures for monitoring adherence 32 (eg, drug tablet return, laboratory tests) 33 34 11d Relevant concomitant care and interventions that are NA 35 permitted or prohibited during the trial

36 http://bmjopen.bmj.com/ 37 Outcomes 12 Primary, secondary, and other outcomes, including the 8, line 9 38 specific measurement variable (eg, systolic blood 39 pressure), analysis metric (eg, change from baseline, 40 final value, time to event), method of aggregation (eg, 41 median, proportion), and time point for each outcome. 42 Explanation of the clinical relevance of chosen efficacy 43 and harm outcomes is strongly recommended

44 on September 29, 2021 by guest. Protected copyright. 45 Participant timeline 13 Time schedule of enrolment, interventions (including any 6, line 20; 46 run-ins and washouts), assessments, and visits for 47 participants. A schematic diagram is highly Figure 1 48 recommended (see Figure) 49 50 Sample size 14 Estimated number of participants needed to achieve 9, line 19 51 study objectives and how it was determined, including 52 clinical and statistical assumptions supporting any 53 sample size calculations 54 55 Recruitment 15 Strategies for achieving adequate participant enrolment NA 56 to reach target sample size 57 58 Methods: Assignment of interventions (for controlled trials) 59 Allocation: 60

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1 2 3 Sequence 16a Method of generating the allocation sequence (eg, 9, line 21 4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 generation computer-generated random numbers), and list of any 6 factors for stratification. To reduce predictability of a 7 random sequence, details of any planned restriction (eg, 8 blocking) should be provided in a separate document 9 that is unavailable to those who enrol participants or 10 assign interventions 11 NA 12 Allocation 16b Mechanism of implementing the allocation sequence (eg, 13 concealment central telephone; sequentially numbered, opaque, 14 mechanism sealed envelopes), describing any steps to conceal the 15 sequence until interventions are assigned 16 Implementation 16c Who will generate the allocation sequence, who will NA 17 enrol participants, and who will assign participants to 18 For peer review only 19 interventions 20 Blinding (masking) 17a Who will be blinded after assignment to interventions NA 21 (eg, trial participants, care providers, outcome 22 assessors, data analysts), and how 23 24 17b If blinded, circumstances under which unblinding is NA 25 permissible, and procedure for revealing a participant’s 26 allocated intervention during the trial 27 28 Methods: Data collection, management, and analysis 29 30 Data collection 18a Plans for assessment and collection of outcome, 8, line 29 31 methods baseline, and other trial data, including any related 32 processes to promote data quality (eg, duplicate 33 measurements, training of assessors) and a description 34 of study instruments (eg, questionnaires, laboratory 35 tests) along with their reliability and validity, if known.

36 Reference to where data collection forms can be found, http://bmjopen.bmj.com/ 37 if not in the protocol 38 39 18b Plans to promote participant retention and complete NA 40 follow-up, including list of any outcome data to be 41 collected for participants who discontinue or deviate from 42 intervention protocols 43

44 Data management 19 Plans for data entry, coding, security, and storage, NR on September 29, 2021 by guest. Protected copyright. 45 including any related processes to promote data quality 46 (eg, double data entry; range checks for data values). 47 Reference to where details of data management 48 procedures can be found, if not in the protocol 49 50 Statistical methods 20a Statistical methods for analysing primary and secondary 9, line 27 51 outcomes. Reference to where other details of the 52 statistical analysis plan can be found, if not in the 53 protocol 54 55 20b Methods for any additional analyses (eg, subgroup and 10, line 20- 56 adjusted analyses) 31 57 58 20c Definition of analysis population relating to protocol non- 10, line 24 59 adherence (eg, as randomised analysis), and any Missing data NR 60 statistical methods to handle missing data (eg, multiple imputation)

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28 Ethics and dissemination 29 Research ethics 24 Plans for seeking research ethics committee/institutional 11, line 5 30 approval review board (REC/IRB) approval 31 32 Protocol 25 Plans for communicating important protocol NR 33 amendments modifications (eg, changes to eligibility criteria, 34 outcomes, analyses) to relevant parties (eg, 35 investigators, REC/IRBs, trial participants, trial registries, 36 journals, regulators) http://bmjopen.bmj.com/ 37 38 Consent or assent 26a Who will obtain informed consent or assent from 9 line 1 39 potential trial participants or authorised surrogates, and 40 how (see Item 32) 41 42 26b Additional consent provisions for collection and use of NA 43 participant data and biological specimens in ancillary

44 studies, if applicable on September 29, 2021 by guest. Protected copyright. 45 46 Confidentiality 27 How personal information about potential and enrolled 11, line 12 47 participants will be collected, shared, and maintained in 48 order to protect confidentiality before, during, and after 49 the trial 50 51 Declaration of 28 Financial and other competing interests for principal 14, line 6 52 interests investigators for the overall trial and each study site 53 NR 54 Access to data 29 Statement of who will have access to the final trial 55 dataset, and disclosure of contractual agreements that 56 limit such access for investigators 57 Ancillary and post- 30 Provisions, if any, for ancillary and post-trial care, and for NA 58 59 trial care compensation to those who suffer harm from trial 60 participation

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1 2 3 Dissemination 31a Plans for investigators and sponsor to communicate trial 11, line 9 4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 policy results to participants, healthcare professionals, the 6 public, and other relevant groups (eg, via publication, 7 reporting in results databases, or other data sharing 8 arrangements), including any publication restrictions 9 31b Authorship eligibility guidelines and any intended use of NA 10 professional writers 11 12 31c Plans, if any, for granting public access to the full NR 13 protocol, participant-level dataset, and statistical code 14 15 16 Appendices 17 Informed consent 32 Model consent form and other related documentation NR 18 materials Forgiven peer to participants review and authorised only surrogates 19 20 Biological 33 Plans for collection, laboratory evaluation, and storage of NA 21 specimens biological specimens for genetic or molecular analysis in 22 the current trial and for future use in ancillary studies, if 23 applicable 24 25 *It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 26 Explanation & Elaboration for important clarification on the items. Amendments to the protocol 27 should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the 28 Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” license. 29 30 LEGEND: NA= not applicable; NR= not reported. 31 32 33 34 35

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1 2 3 RECOvER Checklist for reporting of enhanced recovery research

4 BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 6 7 Section ItemNo Recommendation PAG. 8 Title 9 Title 1 Indicate that this is an enhanced recovery study in 1, line 1 10 the title 11 12 13 Introduction 14 15 16 Background 2 Explain the area of uncertainty that the study seeks 4, line 1 17 to address 18 For peer review only 19 Guidelines 3 If a published set of enhanced recovery guidelines 4, line 9 20 exists for this procedure, include a reference to the 21 guidelines 22

23 8, line 9 24 Outcomes 4 Define the primary outcome and any key 25 prespecified secondary outcomes for the study 26 27 Methods 28 29 30 IRB approval 5 Give the Institutional Review Board/Ethics 11, line 5 31 Committee name and approval number. If 32 permission was not required, reasons should be 33 stated 34 35 Study design 6 Indicate what type of study is presented (randomized 5, line 15

36 controlled trial, cohort, cross-sectional, etc.) The SPIRIT in http://bmjopen.bmj.com/ 37 individual guidelines for the type of study should be Supplemental 38 followed (e.g., CONSORT for randomized controlled materials 39 trial, STROBE for cohort studies, etc.) 40 41 Setting 7 Describe whether this is a single or multicenter 5, line 15 42 study, the type of practice (academic vs. community, 43 tertiary vs. primary), and the providers (limited group

44 on September 29, 2021 by guest. Protected copyright. 45 or all providers on a service) 46 47 Timing 8 Describe periods of recruitment, time points at which NR 48 outcomes assessed, and follow-up 49 50 Partecipants 9 Define study inclusion and exclusion criteria 6, line 8 51 52 53 Enhanced 10 Describe when the enhanced recovery protocol was 6, line 26 54 recovery protocol implemented relative to the study period 55 56 11 Provide a flow diagram or table through the NR 57 continuum of care detailing the enhanced recovery 58 protocol including the following elements: 59 (a) Preadmission patient education regarding the 60 protocol (b) Preadmission screening and optimization as

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1 2 3 indicated for nutritional deficiency, frailty, anemia,

4 HbA1c, tobacco cessation, and ethanol use BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 (c) Fasting and carbohydrate loading guidelines (d) 6 Preemptive analgesia (dose, route, timing) (e) Anti- 7 emetic prophylaxis (dose, route, timing) (f) 8 Intraoperative fluid management strategy 9 (g) Types, doses, and routes of anesthetics 10 administered (h) Patient warming strategy 11 12 (i) Management of postoperative fluids 13 (j) Postoperative analgesia and anti-emetic plans 14 (k) Plan for opioid minimization 15 (l) Drain and line management 16 (m) Early mobilization strategy 17 (n) Postoperative diet and bowel regimen 18 For managementpeer review (o) Criteria for discharge only 19 (p) Tracking of post-discharge outcomes 20 21 Enhanced 12 Describe the audit system for compliance with the 7, line 20 22 recovery auditing enhanced recovery protocol and how compliance 23 data are measured 24 25 Outcomes 13 (a) Explain the criteria for assessing primary and 8, line 9 26 secondary outcomes 27 (b) Distinguish among clinical, functional, 28 administrative, and quality of life outcome measures 29

30 8, line 23 31 PROs 14 If patient questionnaires are used, provide

32 references to validation of these study instruments 33 34 Results 35

36 http://bmjopen.bmj.com/ 37 Patient population 15 Use a flow diagram to explain the derivation of the NA 38 study population 39 (a) Provide a Table I with the key demographic and 40 clinical features of the study population (b) Indicate 41 number of participants with missing data for each 42 variable of interest 43

44 Enhanced 16 Provide a Table II with average compliance for each NA on September 29, 2021 by guest. Protected copyright. 45 recovery enhanced recovery protocol element and present a 46 compliance comparison of the variation in enhanced recovery 47 compliance among the study groups 48

49 Correlations 17 Perform logistic regression to correlate the change in NA 50 51 primary outcome with the study intervention 52 53 Discussion 54 55 56 Context 18 Explain what the study adds to the body of 12, line 12 57 knowledge regarding the study intervention within 58 the context of enhanced recovery after surgery care 59 60

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1 2 3 Limitations 19 Discuss the limitations of the study and how these 12, line 8

4 might temper the findings BMJ Open: first published as 10.1136/bmjopen-2020-047491 on 3 June 2021. Downloaded from 5 6 Other information 7 8 9 Funding 20 Document all sources of funding and potential 14, line 2 10 conflicts of interest for the study authors 11 12 13 LEGEND: NA= not applicable; NR= not reported. 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

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