Background: Following total hip- and knee arthroplasty (THA and TKA), post-discharge physical rehabilitation is common practice, but varies significantly regarding content, duration, intensity and mode of delivery. Recent systematic reviews have found home-based rehabilitation to be as good as outpatient rehabilitation in terms of pain and physical function. We therefore wonder if physical rehabilitation “works” at all when compared to no physical rehabilitation after THA and TKA – “no rehabilitation” defined as no prescribed therapeutic rehabilitation exercises. The purpose of this trial is to compare the effectiveness of home-based telerehabilitation, home-based rehabilitation and no physical rehabilitation following THA and TKA. Methods: This pragmatic, randomized controlled trial will include 168 patients following discharge after THA or TKA, in Bornholm Denmark. Patients will be randomized into one of the three 6-week rehabilitation strategies: home-based telerehabilitation, home-based rehabilitation or no physical rehabilitation. The trial is designed as a superiority trial to test the hypothesis that rehabilitation (home-based telerehabilitation and home-based rehabilitation) is superior to no physical rehabilitation. The primary outcome will be the hip disability and osteoarthritis outcome score (HOOS)/ the knee injury and osteoarthritis outcome score (KOOS)-subscale: function of daily living at first follow-up (end of the 6-weeks' intervention). Additional follow-ups are scheduled at 3 and 12 months. Outcome assessors and data analysts are blinded to group allocation.Conclusions: Knowledge about the effectiveness of the three investigated rehabilitation strategies will help guide the future organization of post-discharge rehabilitation after THA and TKA.Trial registration: Clinicaltrials.govNCT03750448 (23/11/2018) Total hip and knee arthroplasty  are considered effective for end-stage osteoarthritis in restoring function of the affected joint, relieve symptoms and improving quality of life. Post-discharge physical rehabilitation following THA and TKA is widely promoted to restore function and mobility of the affected joint6. However, the practices of post-discharge physical rehabilitation following THA and TKA vary significantly in content, duration and intensity, where the current practices are ranging from a single session of professional advice while still in hospital to several weeks of intensive in- or outpatient physical rehabilitation or home-based interventions.Osteoarthritis is the leading cause of disability and pain among adults. Generally, home-based rehabilitation after initial instruction is as effective as more closely supervised outpatient rehabilitation in the long term, even in patients at risk of a poor outcome after TKA17. When compared to no or minimal physical rehabilitation, physiotherapy exercises seem superior for improvements in physical function, pain and range of motion up to 3–6 months following TKA7. We recently undertook a systematic review18 of RCTs that compared physical rehabilitation strictly to a “no physical rehabilitation” comparator on patient-reported outcomes for function and pain and identified only two trials20. The review was inconclusive, and we – along with others7 – call for sufficiently powered trials that investigate physical rehabilitation after THA and TKA against no physical rehabilitation comparators.Several systematic reviews and meta-analyses of randomized controlled trials (RCTs) have examined the effectiveness of different types of post-discharge rehabilitation delivery strategies following THA and TKA7, as reviewed above. So, a natural next step for us is to challenge our own belief that physical rehabilitation (in itself) is important – and surely better than “no physical rehabilitation” – when it comes to enhancing postoperative recovery of functional performance after these surgeries.Traditionally, the type of physical rehabilitation exercise and degree of supervision are regarded as important factors for postoperative recovery of functional performance; however, this does not seem to be the case. Rehabilitation with little supervision has been shown to be as equally effective as rehabilitation with much more supervision following THA and TKA in terms of self-reported function, physical performance and pain7. The primary endpoint is at the 6-week follow up, as it represents current clinical practice in terms of rehabilitation duration for the municipality of Bornholm, Denmark. When we collected stakeholder input for the trial design, the municipality’s main interest in the trial was related to this time point firstly and the other time points secondarily.In the DRAW 1 trial, we will investigate three different rehabilitation strategies after THA and TKA. We will use two rehabilitation strategies that are commonly used in the community rehabilitation setting in Denmark; home-based telerehabilitation and home-based rehabilitation after initial instruction and compare them to a strategy of no physical rehabilitation as defined in the methods section below. Our primary outcome is the hip disability and osteoarthritis outcome score (HOOS)/knee injury and osteoarthritis outcome score (KOOS)-subscale: function of daily living at the end of the 6-weeks' intervention. This is chosen to be the primary outcome as it is usually physical function that prescribed rehabilitation is targeted to improveBecause the DRAW1 trial is a pragmatic trial, we have made no efforts to modify current clinical practice, as it represents “real  life” and interpretation of the available scientific evidence in one municipality in Denmark. We ask if the commonly used practice of a post-operative rehabilitation plan and corresponding out-patient physical rehabilitation in the patient’s own municipality is superior to no physical rehabilitation.The objective of the trial is to compare the effectiveness of home-based telerehabilitation, home-based rehabilitation and no physical rehabilitation following THA and TKA.21 and the SPIRIT checklist23. The trial report will adhere to the Consolidated Standards of Reporting Trials (CONSORT) using the extension for non-pharmacological treatments24. The interventions will be described in details using the recommended generic template for intervention description and replication (TIDieR)25. For a detailed exercise-specific description of the intervention, the consensus on exercise reporting template (CERT)26 will be used. The trial is pre-registered at ClinicalTrials.gov (NCT03750448 on 23rd November 2018)27 and ethical approvals was obtained from the ethics committee of the Capital Region Denmark28 and the Danish Data Protection Agency29 before the first participant was recruited. The first participant was enrolment in January 2019. The research question, objective, and trial design were developed using stakeholder input from patients, orthopaedic surgeons, physiotherapists and policymakers.This trial is named the “Does rehabilitation after total hip and knee arthroplasty “work”? ”. It uses a superiority, three-arm, parallel group, RCT design with blinded outcome assessments at baseline (before intervention), at 6 weeks (end of intervention) and follow-ups at 3 and 12 months. The trial protocol is based on the PREPARE trial guide31. While usual care consisted of supervised exercises twice weekly during 6 weeks , the telerehabilitation intervention received 6 supervised exercise classes during the 6-week intervention, limiting what conclusions can be drawn regarding the true efficacy of telerehabilitation. Before investing in the telerehabilitation technology, the municipality of Bornholm wants an estimate of the effectiveness of telerehabilitation during a 6-week interventionwithout supervised exercise sessions to explore the full potential of telerehabilitation (please see the description of the different interventions below).The municipality of Bornholm , where the trial takes place, has been involved in the formulation of the research question and study design. They are considering full-scale implementation of the home-based telerehabilitation-solution based on cost-benefit considerations when compared to their current practice, which is home-based rehabilitation (no tele-setup). The effectiveness of this type of technology-assisted exercise intervention has already been compared to usual care in four municipalities in Copenhagen, Denmark, where comparable effects regarding physical performance and self-reported physical function were seen in both the usual care and telerehabilitation group after a 6-week intervention23. Written trial information and the patients’ rights as a potential trial participant will be included in this letter, including the right to have a bystander present during the first consultation at our rehabilitation centre.All patients will be included by consecutive sampling from three outpatient rehabilitation trial sites on the isle of Bornholm, Denmark. This consecutive sampling, along with the use of few eligibility criteria, will ensure generalizability of the results. All patients, who receive a THA or TKA and reside on the island, are referred to postoperative, free-of-charge rehabilitation at our institution, reflecting the current clinical practice in Eastern Denmark for patients undergoing THA or TKA. Before discharge from the hospital, patients with hip- or knee arthroplasties have obtained independent basic mobility  with appropriate walking assistant device and experiencing acceptable pain levels. Patients referred to our institution will receive a letter of invitation to initiate outpatient rehabilitation following their surgery23. Patients who are willing to participate will sign an informed consent form before any study related procedures are performed. Patients deemed eligible for study inclusion will be introduced to the trial individually by an experienced physiotherapist, serving as the intervention deliverer, during the first consultation. The consultation will take place in a room with no external interruptions, where patients will be given thorough written and oral information about the nature of the trial by the physiotherapist. Eligible patients will be informed that the trial includes random allocation to one of three intervention groups  with the purpose of investigating the effectiveness of the three different rehabilitation strategies following THA and TKA. Before deciding to participate in the trial, the patients will be informed about their rights as a trial participant, including the right to have timely consideration before enrolling in the trial. The patients may consider trial participation in the study up to 10 days after they have received oral and written trial information. Patients interested in participating in the trial will be asked to provide written consent according to the template provided by the Ethics Committee of the Capital Region Denmark32, eligible patients are blinded to the trial hypothesis. The physiotherapist attending the first consultation will conduct baseline assessment immediately after the patient has provided written consent and before randomization. Baseline assessment is performed before randomization and before the allocated intervention is reveal to the patient and the attending physiotherapist. All outcome assessors dedicated to the trial are licensed physiotherapists. They will be trained by the primary investigator to ensure standardized outcome assessment and exercise instruction. Patients will be informed that they can, without the need to provide any reason, withdraw their consent and stop their participation in the trial. If written consent is not provided, the patient will be offered usual care at our rehabilitation facility, which is home-based rehabilitation with regular follow-ups. After the baseline assessment has been performed and information about the allocated intervention has been provided, the consultation ends and the attending physiotherapist who conducted the baseline outcome assessment has no further role in the study.To prevent ascertainment biasIn order to increase the external validity and improve the generalizability of this trial, only few eligibility criteria will be used. This will furthermore reflect current clinical practice and enhance the pragmatic nature of the trial.Inclusion criteria:-Patients having had primary, unilateral THA or TKA due to osteoarthritis.-Patients being referred to receive postoperative rehabilitation at our institution.-Patients being able to speak, read and understand Danish language.-Patients aged ≥ 18 years.Exclusion criteria:-Patients not able to comply with exercise instructions.-Patients who are discharged to a nursing-home facility or receiving in-home rehabilitation by home care.When baseline assessment is completed, the patients will be randomly allocated to one of the three rehabilitation strategies (see assignment of interventions). The attending physiotherapist will then instruct the patients individually according to their allocated group assignment. Once the initial instruction is completed and the patients are comfortable with the intervention to which they are assigned, the session is completed, and no further direct supervision will be given during the 6-week intervention. All patients - no matter their allocation - will receive pamphlets where postoperative information such as recommendations regarding the return to activities of daily living, possible complications and expected discomforts is outlined.33 and encouragements to gradually return to activities of daily living. There will be no specific exercise-encouragement given to the no physical rehabilitation group. The two other intervention groups will be prescribed specific exercises for restoring function following THA or TKA. The detailed intervention description and the exercise description are further outlined in our extended data23.All patients will be given similar pamphlets as mentioned above. The pamphlets will include information of encouragement to stay active as recommended by the Danish National Health BoardHome-based telerehabilitation. Patients randomized to this group will receive interactive virtual rehabilitation using a mobile app. The home-based telerehabilitation is based on sensor technology, developed byICURA34 , their participation in the study will be discontinued. The patients will then receive appropriate care and offered outpatient rehabilitation as needed. Study participants will be retained in the trial (unless they withdraw their consent) to enable follow-up data collection and to prevent missing data.Only patients who receive home-based telerehabilitation and home-based rehabilitation are given instructions to modify their allocated intervention. Should any of these patients experience severe hip- or knee symptoms, they will be instructed to lessen the intensity of the prescribed exercise intervention, until the pain has subsided. If this is not sufficient in relieving pain symptoms, the patients are instructed to reduce the volume of the exercise, until the pain has subsided. If the pain persists, the patients are instructed to stop performing the exercises, until the pain has reduced. The patients will then be instructed to gradually progress to the physical intervention to which they are assigned. Detailed, written information will be given to all patients during the first consultation where expected discomfort following THA and TKA will be explained thoroughly. During the first consultation, the importance of following the study guidelines and adhering to the allocated group will be highlighted. Exercise adherence will be recorded as a percentage of completed exercises (based on adherence to the prescribed exercise frequency and repetitions) during the first follow up (after the 6-week intervention) for both the home-based telerehabilitation and home-based rehabilitation groups. Exercise adherence will be taken into consideration when performing the per-protocol analysis .All enrolled patients will be encouraged to contact the principal investigator directly, if experiencing problems related to their recent surgery or to their allocated group intervention. The principal investigator will then fill out a standardized form at these calls. Patients can use pain-relief products as needed, prescribed by their physician after their surgery. To avoid study-contamination, patients will be asked to adhere to the allocated rehabilitation intervention and not to seek alternative health-care services specific to their hip- or knee arthroplasty during the course of the study. Patients will be advised to contact their general practitioner or the principal investigator as needed.This trial is designed with four outcome assessments:-0), during the first consultation following the patient’s THA or TKA .At baseline (t-1), at our outpatient rehabilitation facility.After the 6-week intervention (t-2), follow-up assessment at our outpatient rehabilitation facility.3 months postoperatively (t-3), final follow-up assessment at our outpatient rehabilitation facility.12 months postoperatively  at the end of the 6-week intervention. This is chosen as the primary outcome as it is usually physical function that prescribed rehabilitation is targeted to improve7 and therefore the best suited outcome to measure rehabilitation effectiveness. Secondly, restoration of function is often a crucial element of treatment success, which makes this subscale a suitable outcome measure to indicate the restoration of function. The ADL-subscale was identified through semi-structured patient-interviews; patients found the HOOS/KOOS subscale most relevant in order to measure postoperative progress. The outcome will not be calculated as a change score using the baseline value. We do not consider it possible to obtain a valid HOOS/KOOS ADL score before 6 weeks after surgery, because some of the items in the HOOS/KOOS ADL subscale have most often not been sufficiently addressed or experienced by the participants within the first 6 weeks after surgery.Secondary outcomes. Secondary outcome measurements include the difference between intervention groups during all follow-ups of three subscales from HOOS/KOOS 36. Patient global assessment will be evaluated using a standard question: “How would you rate your current level of function during your usual activities of daily living?” quantified on a 0–100 visual rating scale37. Performance-based assessment will be measured by the 30-s chair stand test, and 40 meters walking test as recommended by the Osteoarthritis Research Society International (OARSI)38. Furthermore, patient satisfaction39 and exercise adherence will be assessed at the end of the 6-week intervention. Current use of analgesics, current use of walking assistant devices and adverse events will be registered within each group  at each follow-up assessment. Outcome assessors will document the time of each individual consultation to investigate the total time of each patient’s rehabilitation and within each of the three rehabilitation strategies. The additional time spent during monitoring of the homebased telerehabilitation intervention will also be documented. Data from medical records. All the above-mentioned outcome measurements will be passed on from medical record files in collaboration with the responsible physiotherapist. All data will first be recorded and passed onafter the patient has provided oral and written consent to participate in the trial.37.Outcome measurement will adhere to OARSI clinical trials recommendationsThe patients will complete all questionnaires at each follow up on paper and in individual consultation rooms with no external interruptions. The score of each questionnaire will be calculated by the consulting physiotherapist. The 30s chair-stand-test will be conducted in the consultation room using a test-chair, while the 40 metres walking test will be performed on a test-track near the consultation rooms. All outcome data will finally be reported in the patient’s electronically stored medical record.Primary outcome.Hip disability and osteoarthritis outcome score (HOOS) / knee injury and osteoarthritis outcome score (KOOS) subscale: function in daily living (ADL). This patient-reported outcome measurement (PROM) has proven to be a valid, reliable and responsive outcome measurement following THA and TKA. This subscale consists of 17 questions related to the patient’s function in activities of daily living such as “descending stairs”, “standing” and “getting in/out of car”. The subscale is scored by the degree of difficulty that the patient experienced in the last week on a 5-point Likert scale  and calculated to a score ranging from 0 (worst/extreme difficulties) to 100 (best/ no problems). The total questionnaire takes about 10 minutes to complete. At least 50% of the questionnaire items are required to be answered to permit calculation of a mean score.Secondary outcomes.Remaining three sub-scales of HOOS/KOOS: symptoms, pain, and hip- or knee related quality of life. A fourth subscale, sport and recreation, was excluded as an outcome measurement at 6 weeks, as most of the items in the HOOS/KOOS sport and recreation subscale often will not have been sufficiently addressed or experienced by the participants within the first 6 weeks after surgery.36.Like the above-mentioned subscale, these subscales are scored by the degree of difficulty the patient has experienced in the last week on a 5-point Likert scale. Each subscale provides a score, which can be calculated to a total score ranging from 0 (worst/extreme difficulties) to 100 (best/ no problems). At least 50% of the questionnaire items in each subscale are required to be answered to permit calculation of a mean score. A total score of the questionnaires has not been validated and is therefore not recommendedPatient global assessment. At baseline the patient’s perception of his or her overall functional ability will be assessed using a single numeric rating scale, as recommended by OARSI37. The patient will be asked a single question: “How would you rate your current level of function during your usual activities of daily living?” During follow-up assessment patients will be asked the same question as at baseline. Their answer will be rated on a 0–100 visual rating scale with end-points anchored as “Inability to perform any daily activities” (0) and “No problem with any daily activity” (100)37.30-s chair stand test. Performance-based assessment will be performed using the 30-s chair-stand test, which represents thesit-to-stand activity. The test counts the number of sit-to-stand repetitions the patient can perform in 30 seconds. The straight-back chairs used for testing during all outcome assessments will be of the same model, same height (approximately 43 cm) and will be placed against a wall. Any other adaptations (i.e. the use of armrests or assistive devices) will be reported. To assure understanding, two slow-paced repetitions will be practiced before the test initiates. The 30-s chair stand test has proven good reliability to measure functional performance following THA and TKA44.40 meters walking test. This performance-based assessment measures short distance walking activity. The patient will be instructed to walk as quickly as safely possible to a mark 10 meters away, return and repeat for a total distance of 40 meters. Each walk of 10 meters (excluding the turn time) is recorded and expressed as speed m/s by dividing distance by time in seconds. A practice walk up and back will be performed to assure understanding. Any assistive devices used will be recorded.Analgesics. The use of analgesics will be recorded at baseline and at all follow-up assessments, using a nominal scale (yes/no) regarding the daily consumption of opioids, non-steroid-anti inflammatorily drug (NSAID) and paracetamol. If the patient is not aware of his or her use of analgesics, a medical record will be obtained to assess the use of analgesics. Walking assistant devices. The type and number (e.g. one or two elbow crutches) will be recorded at baseline and at all follow-up assessments. The need for walking assistant devices will be assessed by the number of walking assistant devices the patient uses during normal activities of daily living.Patient satisfaction. Patient satisfaction will be assessed at the end of the 6-week intervention, where patients will be asked to answer four questions to indicate their level of satisfaction. The answers will be based on a 4-Likert ordinal scale with the categories: very satisfied (100 points), somewhat satisfied (75 points), somewhat dissatisfied (50 points), and very dissatisfied (25 points). The score is the unweighted mean of the combined scores. The four questions are: “How satisfied are you with the results of your surgery and rehabilitation?”, “How satisfied are you with your surgery and rehabilitation for improving your pain?”, “How satisfied are you with the results of your surgery and rehabilitation for improving your ability to do home or yard work?” and “How satisfied are you with the results of surgery and rehabilitation for improving your ability to do recreational activities?”. The questions are modified from the self-administered patient satisfaction scale for primary hip and knee arthroplasty39 and have in its original form proven to be a valid and reliable outcome measurement for patient satisfaction following THA and TKA39.Exercise adherence. Exercise adherence will be measured as a percentage (0–100), where 0 % indicates total non-adherence and 100 % indicates total adherence to the exercise prescription. Exercise adherence in the home-based telerehabilitation and home-based rehabilitation group will be measured as a self-reported outcome, where patients will be asked: “What percentage of the prescribed 42 exercise sessions  have you completed the past 6 weeks?”Adverse events. Adverse event during enrolment of the trial will be recorded, regardless of the relation to the trial.Time usage. We wish to explore the economic resources required for each of the three rehabilitation strategies. We intend to use this data in our cost-benefit considerations compared to the current practise (home-based rehabilitation).Patients deemed eligible for study participation and provided written consent will be randomly assigned to one of the three interventions, after the completion of baseline assessment. A physiotherapist, not otherwise involved in the study, will perform a computer-generated random allocation sequence  concealed in 168 consecutively numbered, opaque, sealed envelopes determining allocation to home-based telerehabilitation, home-based rehabilitation or no physical rehabilitation. Blocked randomisation will be used to achieve balanced group allocations and to ensure concealment; the block sizes will not be disclosed.1 + t2 + t3) at our outpatient facilities. The patients will be asked not to disclose any information that could give away the group allocation, and the physiotherapist will be instructed not to ask questions that could be used to identify the allocated group of the patient, before follow-up assessment has taken place.Before intervention allocation, baseline measures will be performed and recorded. Experienced physiotherapists, who are blinded to group allocation, will record the follow-up outcome measurements  and obtain the HOOS or KOOS questionnaire from the patient on a standardized form during the first consultation, which will take place approximately 3–7 days after discharge. The performance-based outcome assessments will be performed thereafter and also recorded on the standardized form. This procedure will be repeated at the following follow-ups by different physiotherapists to keep outcome assessors blinded for group allocation. Four questions regarding patient satisfaction will be included in the online questionnaire before the 6-week follow-up.All original written information and case report forms will be stored in a secured room and kept for three years after the trial completion. Electronic data will be anonymized, coded and saved on a secured server in the Capital Region of Denmark, Bornholm. A complete backup of the data entries will be performed every month until trial completion.Exercise data from the home-based telerehabilitation will be coded and saved on a secured server in the Capital Region of Denmark. The stored data set will be coded in a way so that group allocation is concealed, allowing for blinding of the data analyst.Participant retention and completion of follow-up assessments are expected to be relatively high due to the comprehensive follow-up assessment of this trial. While standard of care usually includes a 3 months’ follow up, patients included in this trial are invited to follow-up assessments at 6 weeks, 3 and 12 months postoperatively, which includes a free-of-charge consultation with a physiotherapist.23.The main analysis plan is outlined below, while a detailed analysis can be found in our extended dataThe trial is designed to test the hypothesis that physical rehabilitation (home-based telerehabilitation and home-based rehabilitation combined) is superior to no physical rehabilitation following THA and TKA or if one of the physical rehabilitation strategies is superior to no physical rehabilitation. Superiority of physical rehabilitation over no physical rehabilitation will be claimed if the between-group contrast at the 6 weeks follow-up is 10 HOOS/KOOS ADL-subscale points or greater in favour of the physical rehabilitation. Superiority of an individual physical rehabilitation strategy over no physical rehabilitation will be claimed if the same criteria are met and in favour of that physical rehabilitation. 1), secondary endpoints being differences at second follow-up (t2) and final follow up (t3) .The primary outcome is the mean difference in the HOOS/KOOS subscale: function in daily living (ADL). Primary endpoint will be differences between groups at first follow up  and no physical rehabilitation. This will be assessed by independent two-sample t-tests if normality assumptions are acceptable, otherwise the Wilcoxon sum rank-test will be used. The same tests will also be used to compare the individual physical rehabilitations to no physical rehabilitation.The secondary analysis will test differences in the mean score of all continuous secondary outcomes at the primary, secondary and final endpoints and will be performed in the same way as the primary analysis. Nominal outcomes will be analysed by the chi-squared test or in cases with less than five expected counts for any observation, Fishers exact test will be used.23).At baseline descriptive statistics will be presented. At each endpoint, mean scores, standard deviations, between-groups mean  and p-values will be reported  principle . Additionally, per protocol (PP) analysis will be done for the primary outcome. All patients with an exercise adherence of at least 80 % will be considered adherent to the rehabilitation strategy and included in the PP analysis. All patients in the no rehabilitation group will be included in the PP analysis. Missing values in both ITT and PP analysis will be imputed by multiple imputation. Imputation models will be based on all other available variables in the data.No data monitoring committee will be composed, as the interventions pose little or no known risk for the participating patients. Likewise, no auditing procedures are expected to take place.45 is used as our superiority margin, with an expected standard deviation of 20 points, a power of 0.80 and a significance level of 0.05 resulting in a sample size of 50 patients in each group. With 10% loss to follow up46 this results in 56 patients in each group. This calculation will be used for each comparison of individual physical rehabilitations to no physical rehabilitation; therefore, 56 patients are needed for each of the three groups resulting in 168 patients included in total (3 groups of 56 patients). Comparison of any physical rehabilitation to no physical rehabilitation is done under the same clinically important difference and expected standard deviation as the individual comparisons. With a sample size of 100  and 50  the expected power is 0.89.A clinically important difference of 10 points on the HOOS/KOOS subscale function in daily living (ADL)We expect a relatively low inclusion rate of 50%, since one of the interventions includes “no physical rehabilitation”, compared to standard rehabilitation. Furthermore, based on the expected patient flow at our trial sites and the need to conduct the trial within a realistic timeframe, we do not initially intend to stratify THA and TKA for subgroup analysis. There will not be any specific strategies for increasing participant enrolment related to this trial.28 and the Danish Data Protection Agency29 and was registered in a public trial registry before the first participant was enrolled. Written consent from each trial participant will be obtained during the first consultation at our outpatient facility by an experienced physiotherapist.This trial obtained approvals from the Ethics Committee of the Capital Region DenmarkAll study-related information about the participants will be stored securely on the study site. Paper forms will in stored in locked cabinets, while electronic data will be stored on a password protected drive at the study site. Only persons involved in the trial will have access to the study-related information. Individual study information will not be released outside of the study without permission of the individual participant. This study will be handled in accordance with the Data Protection Act from the Danish Protection Agency.It is not expected that the allocated interventions will cause any harm to the participants. If any harm is caused, at the end of the 6-week intervention, the patients will be offered free-of-charge in- or outpatient rehabilitation as deemed clinically needed.The principal investigator (TMC) and the principal supervisor (TB) will have full access to the data set. The full-anonymized data set will be made available for the journal reviewing the manuscript.The trial is planned to be reported in four manuscripts and expected to be published in international, peer-reviewed journals. The first manuscript will be the trial protocol. The second manuscript will be the primary report on the investigated effectiveness of the three rehabilitation strategies under investigation. The third manuscript will report the result of the trial from an economic perspective, while the fourth manuscript will report exploratory analyses depending on the primary trial findings. All results, including positive, negative or inconclusive results, will be presented at relevant scientific conferences and symposiums.All patients will be offered to receive an information letter with the results of this trial when the trial is completed and published. Trial data can be requested by contacting the principal investigator.Study status: Active, not recruiting. Participant no. 168 was recruited on the 27th of January 2021. The final follow-up data are expected to be obtained by January 2022.47 and over 9,000 TKAs48 were performed in Denmark. The number of these procedures is expected to increase50, which puts further emphasis on the importance of finding the optimal rehabilitation strategy for this group of patients. As there are significant variations in the rehabilitation practices following THA and TKA both nationally and internationally, investigations of different rehabilitation strategies and their effectiveness are warranted.In 2018, over 10,000 THAs51 we consider the research question feasible, interesting, novel, ethical and relevant. We believe this clinical trial to be highly useful, as we have conducted a thorough literature review of the problem base, included context placement and information gain in the background section, according to the essay published by Ioannidis in 201652. Additionally, with careful methodological considerations such as few exclusion criteria and PROM’s we have also ensured a pragmatic and patient-centred trial52. As we will pre-register the trial; use the TIDieR-framework for intervention description25 and publish the trial protocol, we consider the trial design and intent to be as transparent as possible.Using the FINER-criteriaIn summary, the objective of this trial is to investigate the effectiveness of three different rehabilitation strategies following THA and TKA in terms of function in daily living. Knowledge about the effectiveness of the three investigated rehabilitation strategies will help guide the future organization of post-discharge rehabilitation after THA and TKA.This trial has several strengths. Firstly, this trial will be the first trial to compare the effectiveness of two commonly used postoperative rehabilitation strategies to a “no physical rehabilitation”-intervention following THA and TKA. Secondly, the trial will be conducted at a geographically ideal setting. The Isle of Bornholm, Denmark, offers a unique opportunity to control study contamination, as our institution is the only one of this kind on the isle. Thirdly, home-based telerehabilitation and home-based rehabilitation-interventions will be given the exact same rehabilitation exercise instructions in terms of exercise type, dosage and intensity, which will make the two physical rehabilitation interventions comparable. Fourthly, randomization and the blinding of outcome assessors and data analysts will greatly decrease the risk of bias of this trial. The consecutive sampling and the relatively unrestricted inclusion criteria increase the external validity.23, CERT26, and TIDieR25, allowing replication and direct clinical use of the described exercise interventions. Furthermore, the adherence to the clinical recommendations from OARSI37 will permit comparison to other trials, eventually allowing meta-analysis.Lastly, this protocol follows the clinical recommendations from SPIRITA noteworthy limitation to this study is the lack of a preoperative outcome assessment. Many patients choose to have their surgery performed at a hospital not located on the island of Bornholm. This means it is not practically possible to obtain preoperative data of these patients before their surgery.Due to the nature of this trial, there is a risk of selection bias, where active patients will be more likely to participate, compared to inactive patients who are expected to more likely feel the need for supervised rehabilitation. Likewise, the use of a single centre study design represents a common limitation for the external validity of rehabilitation intervention trials. We also anticipate that patient-perceived lack of technical understanding will present some selection bias. However, the current study will nevertheless provide level-one evidence of the effectiveness of the three investigated rehabilitation strategies.No data are associated with this article.https://doi.org/10.7910/DVN/BUNJQV23Harvard Dataverse: DRAW1.This project contains the following extended data:-Flowchart of enrolment, randomization, treatment and follow-up-Schedule for enrolment, intervention and outcome assessments-Analysis outline for primary and secondary analysis-Template for intervention description and replication (TIDier) checklist for trial interventions-Exercise description-Participant information sheet-Participant letter of invitation-Participant consent formhttps://doi.org/10.7910/DVN/BUNJQV23Harvard Dataverse: DRAW1.This project contains the following reporting guidelines:- SPIRIT checklistCreative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).Data are available under the terms of theTrial registration: Clinicaltrials.gov: NCT03750448 (23/11/2018)Trial protocol draft version: 5 (05.01.2021)Protocol amendments: None The authors have addressed my comments to my satisfaction. This manuscript is well structured. The authors additionally provided details as to why they chose not to add additional information or content based on my comments. These explanations have satisfied me and I have no other comments to make other than great job.Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?Not applicableReviewer Expertise:Orthopedic and sports rehabilitation, spinal manipulation for cervical and thoracic spine pathologies and health services researchI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. I criticized the article called "Physical rehabilitation versus no physical rehabilitation after total hip and knee arthroplasties: Protocol for a pragmatic, randomized, controlled, superiority trial ".Participants aged ≥18 are specified in the inclusion criteria, but this is a very wide age range, and accordingly, the responses of the participants to rehabilitation vary and affect the results of the study. The lack of preoperative evaluations also contributes to this variability. Therefore, I recommend performing age-related subgroup analyzes or specifying the age of the participants in the inclusion criteria.Secondly, participants' involvement in other exercise or treatment programs affects the clinical process. Therefore, 'participating in any program outside of study' should be added to the exclusion criteria.The other thing not mentioned in the study is the discharge criteria. Whether or not the same discharge criteria are used for each participant and the details of these criteria contribute to the clarification of the clinical process. Therefore, I recommend including this in the method.Since THA and TKA are two different joints and surgeries, rehabilitation procedures and interventions are also different. In the study, these two different interventions were not clearly explained. The type, intensity and dosage of planned interventions or exercises should be detailed. My opinions are as follows:Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?PartlyAre the datasets clearly presented in a useable and accessible format?PartlyReviewer Expertise:Orthopedic Physiotherapy and RehabilitationI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. We would like to thank the reviewer for the helpful comments provided. We found the comments to be fair and the provided input to be very valuable. Our response to the comments are as follows:Reviewer 3, comment 1: I criticized the article called "Physical rehabilitation versus no physical rehabilitation after total hip and knee arthroplasties: Protocol for a pragmatic, randomized, controlled, superiority trial ". Participants aged ≥18 are specified in the inclusion criteria, but this is a very wide age range, and accordingly, the responses of the participants to rehabilitation vary and affect the results of the study. The lack of preoperative evaluations also contributes to this variability. Therefore, I recommend performing age-related subgroup analyzes or specifying the age of the participants in the inclusion criteria.Author response: We initially planned to have very wide, pragmatic inclusion criteria, but we do appreciate and acknowledge the reviewers comment on the inclusion criteria. We will therefore, as recommended, perform an age-relate subgroup analysis.Action taken: Sentence added on page 13, line 422-423: “As the age of the participants may vary and affect the results of the study, we will undertake an age-related subgroup analysis.”Reviewer 3, comment 2: Secondly, participants' involvement in other exercise or treatment programs affects the clinical process. Therefore, 'participating in any program outside of study' should be added to the exclusion criteria.Author response: We do very much agree with the reviewers comment on participants involvement in other exercise/treatments, which may affect the clinical process. We do however ask participant to adhere to the allocated rehabilitation intervention and not to seek other health-care services specific to their THA or TKA during the course of the study  and to contact their general practitioner or study principle as needed. Furthermore, one of the exclusion criteria of the trial is: “(…) receiving in-home rehabilitation by home care”. We believe this is the most pragmatic way to avoid study contamination and improve adherence to the study protocol. Lastly, as patient recruitment is finished, no alterations can be applied to the experimental procedures of the trialAction taken: No action taken.Reviewer 3, comment 3: The other thing not mentioned in the study is the discharge criteria. Whether or not the same discharge criteria are used for each participant and the details of these criteria contribute to the clarification of the clinical process. Therefore, I recommend including this in the method.Author response: We do agree with the reviewer’s comment. In Denmark the discharge criteria follow a fast-track pathway, which is standardised across the country. Discharge criteria are: obtainment of basic mobility  and acceptable pain levels.Action taken: Sentence added on page 5, line 95-97: “Before discharge from the hospital, patients with hip- or knee arthroplasties have obtained independent basic mobility  with appropriate walking assistant and experiencing acceptable pain levels.”Reviewer 3, comment 4: Since THA and TKA are two different joints and surgeries, rehabilitation procedures and interventions are also different. In the study, these two different interventions were not clearly explained. The type, intensity and dosage of planned interventions or exercises should be detailed.Author response: The different rehabilitation procedures and interventions are described in detail in extended data, including the type, intensity and dosage.Action taken: No action taken. Thank you for the opportunity to review this well-written study protocol. The protocol utilises reporting guidelines appropriately, and as such is thorough and transparent.  The research question and aim is valid and needed, and we agree that to our knowledge this will be the first to compare the effectiveness of physical rehabilitation (either home-based tele-rehab or home-based self guided rehab) vs no physical rehabilitation.  We have the following general points that we encourage the authors to consider when reporting the outcomes and drawing conclusions from this study .et al., 20171). Primary outcome measure - Use of the KOOS/HOOS is valid and justified by the authors, but please can it's use as the primary outcome measure instead of performance based function tests (which are secondary outcome measures) be explained in light of research that shows early functional recovery post TKA/THA does not always correlate with PROMs  outcome measure - Within the rationale for the study, the authors explain the need for the local health service to understand the cost benefits/comparisons of the interventions. We feel that more explanation of how the economic analysis will be performed is required. Do the authors intend to include a health resource use measure in addition to comparing physio time? Such health resource questionnaires can account for total related costs of interventions, experienced by both the health service and the personal health related costs of the individual patient.  The inclusion of both THA and TKA - From a pragmatic and recruitment perspective we understand why they are grouped together. However, these are two different procedures on different joints with different rehab needs. The early functional recovery (at 6 weeks) of THA and TKA patients can differ, therefore we feel there is a strong need to include a sub-group analysis. From our reading of the text, it is not clear to us whether this is planned or not, for example on page 8 in the "additional analysis" section a subgroup analysis with stratification is discussed, but on page 9 in the "sample size" section it says that an initial subgroup analysis is not planned. Please can this be clarified? In summary, this is a well-designed study, and I look forward to learning the findings, and implications for future research and clinical practice. We hope our feedback is useful.Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?Not applicableReviewer Expertise:Physiotherapy, Rehabilitation, Orthopaedics, Exercise TherapyWe confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. We would like to thank the reviewers for the helpful comments provided. We found the comments to be fair and the provided input to be very valuable. Our response to the comments are as follows:Reviewer 2, comment 1: Thank you for the opportunity to review this well-written study protocol. The protocol utilises reporting guidelines appropriately, and as such is thorough and transparent.  The research question and aim is valid and needed, and we agree that to our knowledge this will be the first to compare the effectiveness of physical rehabilitation (either home-based tele-rehab or home-based self guided rehab) vs no physical rehabilitation. et al., 20171). We have the following general points that we encourage the authors to consider when reporting the outcomes and drawing conclusions from this study Primary outcome measure - Use of the KOOS/HOOS is valid and justified by the authors, but please can it's use as the primary outcome measure instead of performance based function tests (which are secondary outcome measures) be explained in light of research that shows early functional recovery post TKA/THA does not always correlate with PROMs .Action taken: No action taken.Reviewer 2, comment 2: Time usage  outcome measure - Within the rationale for the study, the authors explain the need for the local health service to understand the cost benefits/comparisons of the interventions. We feel that more explanation of how the economic analysis will be performed is required. Do the authors intend to include a health resource use measure in addition to comparing physio time? Such health resource questionnaires can account for total related costs of interventions, experienced by both the health service and the personal health related costs of the individual patient. Author response: Thank you very much for bringing up this issue. The municipality intends to investigate health resource use by taking the physiotherapists time into account. No other resource use item is intended to be applied. We do, however, acknowledge the need for a more thorough economic assessment of the interventions applied, if the primary aim of this trial was in a health economic perspective. As patient recruitment is finished, no alterations can be applied to the experimental procedures of the trial. However, in hindsight, additional health resource questionnaires should have been included.    Action taken: No action taken.Reviewer 2, comment 3: The inclusion of both THA and TKA - From a pragmatic and recruitment perspective we understand why they are grouped together. However, these are two different procedures on different joints with different rehab needs. The early functional recovery (at 6 weeks) of THA and TKA patients can differ, therefore we feel there is a strong need to include a sub-group analysis. From our reading of the text, it is not clear to us whether this is planned or not, for example on page 8 in the "additional analysis" section a subgroup analysis with stratification is discussed, but on page 9 in the "sample size" section it says that an initial subgroup analysis is not planned. Please can this be clarified? In summary, this is a well-designed study, and I look forward to learning the findings, and implications for future research and clinical practice. We hope our feedback is useful.Author response: Thank you for bringing this to our attention. We do agree that THA and TKA are different procedures on different joints with different rehab needs, which is why we also intent to include a subgroup analysis between THA and TKA. As the initial sample size does not allow for stratified analysis, it was our intention to double the sample size of the trial by continuing the study setup in a supplementary trial if possible. After the trial inclusion was completed and the target sample size was obtained, an opportunity to continue the trial were presented and at the same time the municipality asked for stratified data to help guide their rehabilitation practice. This first trial (DRAW1) will therefore not include stratified analyses, while a following trial (DRAW2) eventually will allow for stratified analysis. A detailed description of DRAW2 can be found here:https://clinicaltrials.gov/ct2/show/NCT04960241?term=mark-christensen&draw=2&rank=1Action taken: Sentence deleted on page 8 : “We will undertake exploratory subgroup analyses with stratification on THA or TKA similar to that outlined for the non-stratified analysis.” Thank you for the opportunity to review this important manuscript. Overall, this is one of the better manuscripts I have reviewed in some time. This is an important topic and the writing is concise, clear, and easy to follow. Of course another read-through is always worth it.  As this is a protocol, my comments will be specific to the information in this manuscript, however, other comments I make can be applicable to the pending RCT that can have huge implications for physical therapy. First, I think the title of this paper needs to clearly specify that this is tele-rehabilitation or home rehabilitation and not simply say rehabilitation. I strongly suggest this as depending on the results we would want all readers to clearly know the type of rehabilitation provided up front, especially since no group is getting formal outpatient physical therapy. Second, it appears that the initial PT making the introduction to the patients about the trial has no other role in the study? If this is the case, I would like to see that made more explicitly clear. Third, my biggest concern is two fold. First, why was the word rehabilitation used as opposed to physical therapy? Are there going to be providers who are not physical therapists in this study? If the authors want to use the word rehabilitation, I think it is important to operationally define why this was chosen rather than physical therapy. Perhaps, this can be specific to Denmark, but in the US, these terms are not synonymous and can have implications and be interpreted differently. If is specific to Denmark, and the authors feel there would be no miscommunication or confusion, my comment can be ignored. Secondly and more importantly, my concern is the term rehabilitation and how the interventions are being applied. Physical therapy/rehabilitation is not only about exercise. There are other components, such as manual therapy, and motor control/movement training that can be just as important if not more important following THA or TKA. Depending on the results it may be more appropriate to conclude that exercise and education in isolation are no better/better  than no physical rehabilitation. It is important to clarify this because in the US physical therapy is not only exercise. It is a combination of manual therapy, exercise, and movement training, along with possible modalities at times. It is the clinical reasoning that is important in how these interventions are put together and in what dosage they are prescribed at.  Lastly, I would suggest assessing some form of strength measure for the quadriceps and hip abductors as research continues to discuss the long term strength deficits for the quadriceps after TKA and gluteus medius following THA depending on the approach used.Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?Not applicableReviewer Expertise:Orthopedic and sports rehabilitation, spinal manipulation for cervical and thoracic spine pathologies and health services researchI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. We would like to thank the reviewer for the helpful comments provided. We found the comments to be fair and the provided input to be very valuable. Our response to the comments are as follows:Reviewer 1, comment 1: Thank you for the opportunity to review this important manuscript. Overall, this is one of the better manuscripts I have reviewed in some time. This is an important topic and the writing is concise, clear, and easy to follow. Of course another read-through is always worth it.  As this is a protocol, my comments will be specific to the information in this manuscript, however, other comments I make can be applicable to the pending RCT that can have huge implications for physical therapy. I think the title of this paper needs to clearly specify that this is tele-rehabilitation or home rehabilitation and not simply say rehabilitation. I strongly suggest this as depending on the results we would want all readers to clearly know the type of rehabilitation provided up front, especially since no group is getting formal outpatient physical therapy.Author response: We initially want to emphasize that the trial was designed firstly as a superiority trial for the comparison of physical rehabilitation versus no physical rehabilitation, which is also reflected in the pre-defined plan for the analyses. This is the main focus and rationale of trial and, hence, what we want to emphasize transparently in the title. We do, however, clarify the different types of rehabilitation provided in the abstract so that anyone who does a title/abstract screen will see this. We hope the reviewer can appreciate the reasons for this choice.Action taken: NoneReviewer 1, comment 2: Second, it appears that the initial PT making the introduction to the patients about the trial has no other role in the study? If this is the case, I would like to see that made more explicitly clear. Author response: We agree. The introducing PTs role is to conduct baseline assessment first and deliverer of intervention second, and should be explicitly stated.Action taken: Sentence added on page 6, line 119-121: “Baseline assessment is performed before randomization and the allocated intervention is reveal to the patient and the attending physiotherapist”. Sentence added on page 6, line 121-122: “All outcome assessors dedicated to the trial are licensed physiotherapists”. Lastly, sentence added on page 6, line 126-129: “After the baseline assessment has been performed and information about the allocated intervention has been provided, the consultation ends and the attending physiotherapist who conducted the baseline outcome assessment has no further role in the study. Reviewer 1, comment 3: Third, my biggest concern is two fold. First, why was the word rehabilitation used as opposed to physical therapy? Are there going to be providers who are not physical therapists in this study? If the authors want to use the word rehabilitation, I think it is important to operationally define why this was chosen rather than physical therapy. Perhaps, this can be specific to Denmark, but in the US, these terms are not synonymous and can have implications and be interpreted differently. If is specific to Denmark, and the authors feel there would be no miscommunication or confusion, my comment can be ignoredAuthor response: In Denmark, hospital discharge following THA or TKA is combined with a postoperative “rehabilitation plan” which is essentially a prescription of an outpatient health care service  to be delivered in the patient’s own municipality. In most cases, the service deliverer are physical therapists. There are, however, regional differences in how that municipality rehabilitation is organized and constructed - but it reflects the context-specific interpretation of the available scientific evidence. It typically includes both exercise and non-exercise components. Because the DRAW1 trial is a pragmatic trial, we have made no efforts to modify current clinical practice, as it represents “real  life” in one municipality in Denmark. We simply ask if the commonly used practice of a post-operative rehabilitation plan and corresponding out-patient physical rehabilitation in the patient’s own municipality is superior to no physical rehabilitation. So, to reflect this organization of health care service and the terms used to describe if, we think “physical rehabilitation” is the best fit.  Action taken: We have added a section on page 4, sentence 47-51 outlining parts of the answer above: “Because the DRAW1 trial is a pragmatic trial, we have made no efforts to modify current clinical practice, as it represents “real  life” and interpretation of the available scientific evidence in one municipality in Denmark. We ask if the commonly used practice of a post-operative rehabilitation plan and corresponding out-patient physical rehabilitation in the patient’s own municipality is superior to no physical rehabilitation”.Reviewer 1, comment 4: Secondly and more importantly, my concern is the term rehabilitation and how the interventions are being applied. Physical therapy/rehabilitation is not only about exercise. There are other components, such as manual therapy, and motor control/movement training that can be just as important if not more important following THA or TKA. Depending on the results it may be more appropriate to conclude that exercise and education in isolation are no better/better  than no physical rehabilitation. It is important to clarify this because in the US physical therapy is not only exercise. It is a combination of manual therapy, exercise, and movement training, along with possible modalities at times. It is the clinical reasoning that is important in how these interventions are put together and in what dosage they are prescribed at. Author response: In our response to comment 3 above, we provide our reasoning for the choice of wording. We do not agree that particular components of physical therapy/rehabilitation or single modalities offer superior effects in the rehabilitation efforts following THA or TKA, neither on short nor long term. The supporting evidence is now quite substantial .  As physical rehabilitation in the form of physical activity and exercise prescription is currently recommended despite its lack of clear superiority over a range of different comparators, we have decided to investigate if such prescription is superior to no prescription of physical rehabilitationAction taken: No action taken.  Reviewer 1, comment 5: Lastly, I would suggest assessing some form of strength measure for the quadriceps and hip abductors as research continues to discuss the long term strength deficits for the quadriceps after TKA and gluteus medius following THA depending on the approach used.Author response: We did consider to include some form of strength measure, but since we wanted to design a pragmatic trial with a simple outcome assessment (to increase uptake and fidelity). As patients are concerned about their functional performance, and not their strength (even though is can be used as a surrogate outcome measure), we prioritized a functional assessment. And finally, as recruitment has been concluded, inclusion of another outcome measure is not possible. Action taken: No action taken.


Brugia pahangi. However, the local environment of rubber or oil palm plantations, which would increase their exposure to risk factors of the infection due to mosquito transmission, is unclear. The present study first sought to determine the extent to which variations in the local landscape, such as the elevated versus low-lying ecotope of rubber or oil palm plantations, in a 2-km radius of the geographically defined landscape in a rural area of Suratthani, Southern Thailand could influence the abundance of Armigeres subalbatus and its susceptibility to zoonotic filarial parasite infections compared to Mansonia, Aedes, and Culex, and Coquillettidia. Thereafter, the filarial larvae found in the infected mosquitoes were molecularly investigated. Ar. subalbatus plantation ecotype was not only found to outnumber the local mosquitoes, but was identified as the predominant species that adapted well to the elevated ecotopes of the rubber or oil palm plantations, which existed at altitudes of 60–80 m. The overall rate of zoonotic filarial parasite infections  of Ar. subalbatus was 2.5% , with an average L3 load of 2.3 larvae per infected Ar. subalbatus ; this is because the infections were found to be concentrated in the elevated ecotopes alone. Based on filarial orthologous β-tubulin gene-specific touchup-nested PCR and sequence analysis using 30 L3 larva clones as representatives of 9 Ar. subalbatus infectious pools, Ar. subalbatus either carried B. pahangi or Dirofilaria immitis, or both species. Such findings suggest that Ar. subalbatus might have played an imperative role in the transmission of B. pahangi in the plantation areas infested with Ar. subalbatus.In recent years, children in Thailand have been infected with zoonotic   •Ar. subalbatus is the natural vector for zoonotic Brugia pahangi.•Ar. subalbatus plantation ecotype adapted to rubber or oil palm plantations.•Local landscape variation influencing its abundance and susceptibility to zoonotic filarial infection.•3 larvae present in Ar. subalbatus.Touchup-nested PCRs specific for amplifying filarial beta-tubulin genes of L•Ar. subalbatus carried either B. pahangi or D. immitis, or both.Implying that  As a o humans . Of noteia (SEA) ,8. Owingia (SEA) ,10, the B. pahangi infections in children younger than 2 years of age in Thailand (see the supplementary Table S1). Thus, addressing the risk at the interface of human, animal, and the environment, and understanding the vulnerability of children and how they acquire these infections locally through mosquito transmission, are urgently required. Children might be vulnerable to infection with B. pahangi owing to poor social or environmental conditions [Armigeres, Anopheles, Mansonia, Aedes, and Culex [B. pahangi [Mansonia mosquitoes, such as Ma. uniformis, Ma. indiana, Ma. annulifera, and Ma. bonneae, are the main vectors for B. malayi in Thailand [Armigeres subalbatus is the natural vector for zoonotic B. pahangi [B. pahangi to humans in SEA [Ar. subalbatus that share common characteristics: the forest and plantation ecotypes. The forest ecotype is indigenous to the forest and forest fringe and can breed in natural containers with organic substances. In contrast, the plantation ecotype is well adapted to plantation areas where breeding can occur in either artificial or natural containers with organic substances. The present study attempted to clarify some ecologic and epidemiologic questions regarding the occurrence of zoonotic B. pahangi infections in children by determining the fitness of Ar. subalbatus plantation ecotype  and its potential to transmit epizootic B. pahangi parasites.In recent years, there has been an emergence of zoonotic nditions ; the infnd Culex ; and the pahangi  within aThailand  and otheThailand . Armiger pahangi ,16 and ms in SEA . There aB. pahangi in the plantation areas of Suratthani, Southern Thailand (case no. 1), and Rayong, Eastern Thailand (case no. 2) (Table S1) by employing a 2-km radius of geographically defined local landscape as the study area. This study area covered four different ecotopes, which served as the study sites in Suratthani. Thereafter, we sought to empirically determine the extent to which variations in the local landscape could influence the infestation of Ar. subalbatus plantation ecotypes and zoonotic filarial infections (with L1/L2/L3 juveniles) of Ar. subalbatus compared to other local mosquitoes; and to investigate the representative L3 larva clones of B. pahangi, originally derived from any infectious mosquito pool using a newly developed touchup-nested PCR specific for the amplification of filarial orthologous β-tubulin genes and sequence analysis [We mimicked local environmental conditions of cases infected with analysis .22.1B. pahangi and human blood-seeking mosquitoes inhabit). The selection criteria were based on field data obtained using field surveys. A topographical survey was conducted to gather spatial information and to locate both natural and man-made land surface features using land use maps with elevation contours and geographical positioning system (GPS). This provided the correct information of the scaled and detailed boundary of the selected study area and the GPS coordinates of the ecotopes, which were the selected study sites, based on spatial considerations such as latitude, longitude, altitude, rubber or oil palm plantation polygons, roads, water bodies, building, built-up land, and potential larval breeding sites [Mansonia, Armigeres, Aedes, Culex, Coquillettidia, or Anopheles). Parasitological survey was carried out to examine zoonotic filarial infections in domestic cats or dogs within the boundary of the selected study area. Blood samples collected from cats or dogs at night were used for this survey. Larval survey was carried out to assess the availability of larval habitats of local mosquitoes within, or proximal to, the selected ecotopes. Household survey was conducted to assess the physical environmental conditions inside and outside houses with domestic animals.Prior to the study carried out in 2013, the local environmental conditions of the receptive plantation areas (Table S1) were considered ideal for the establishment of the selection criterion  grid cell . The elevated ecotopes  that were mainly covered with either rubber or oil palm plantations were located approximately 70 m above sea level (MASL), whereas the low-lying ecotope  with only 10% rubber plantation was located at 40 MASL in a disturbed swamp, which is the breeding habitat of Mansonia mosquitoes  collection method was used to detect the species and numbers of mosquitoes, both indoors and outdoors, between 18:00 h and 21:00 h for 3 consecutive nights . The taxonomic identification of individual adult female mosquitoes was blindly performed by two expert entomologists. The abundance of local mosquitoes was expressed as man landing rate (MLR), which infers the number of human blood-seeking mosquitoes per night per person for each ecotope.1, L2, or L3 larval stages by dissection under a stereomicroscope , thorax (L2), and head and proboscis (L3) was tallied [3 per infected mosquito were presented. The infectious mosquito pool must have had at least one adult female mosquito infected with any of the L1, L2, or L3 larval stages. For example, the abundance of the Ar. subalbatus infectious pool was expressed as infectious MLR, which infers the infectious number of human blood-seeking Ar. subalbatus per night per person for each ecotope. The infection rate (%) for each ecotope was expressed as the number of Ar. subalbatus adult female mosquitoes infected with any larval stages  in the total number of Ar. subalbatus adult female mosquitoes collected by HLC, multiplied by 100. The 95% confidence interval (CI) was used to estimate the infection rate for Ar. subalbatus in all ecotopes and the L3 load for the Ar. subalbatus infectious pools.All identified adult female mosquitoes were individually examined for the presence of Lcroscope . None ofbalbatus . The num tallied , and the2.33 larva clones originally obtained from the 9 Ar. subalbatus infectious pools of ecotopes A to C were isolated under carefully controlled conditions in the field. Of the 56 L3 larva clones obtained, 30 were used as representatives of the L3 gDNA templates: AAP1 (L01 to L12 clones), AAP2 (L13 to L15 clones), AAP3 (L16 to L18 clones), BAP1 (L19 to L22 clones), BAP2 (L23 clone), BAP3 (L24 to L25 clones), CAP1 (L26 clone), CAP2 (L27 clone), and CAP3 (L28 to L30 clones). These clones were separately prepared for gDNA extraction using the QIAamp® Blood Mini Kit , as described elsewhere [3 gDNA solution (approximate 100–200 μl), which had a 260/280 absorbance ratio of 1.8–2.0, contained the average gDNA content per L3 clone of 994.6 ng, or 7.4 to 12.5 ng/μl.Immediately after mosquito dissection , single Wuchereria bancrofti MMO7 (1246), MDA1 (252), and MMO6 (13) patient isolates [Brugia malayi NT01 (673), NT02 (166), and NT08 (367) patient isolates; B. pahangi DA08 (167) dog isolate and CA12 (300) cat isolate; and Dirofilaria immitis Di106 (>5000) and Di101 (2633) dog isolates. All purified Mf gDNA samples were prepared using the QIAamp® Blood Mini Kit  according to the methods described elsewhere [The positive controls included purified gDNA templates of microfilaremic (Mf) bloods harboring a wide range of microfilarial densities (Mf/ml): isolates ; Brugia lsewhere ,19. Nega2.42.4.1β-tubulin genes were retrieved from the genome databases, GenBank, EMBL, DDBJ, and DFCI. Their homology was analyzed using multiple sequence alignment  program was carried out empirically using a bracket of specific primer-template annealing temperatures in a 25-μl reaction volume, as described elsewhere , except Brugia-specific primer sets, the PCR ingredients were similar to those of the first reaction, except that 2 μl of the primary TUPCR products was used as a template. A touchup program (or TU5660) was performed with initial denaturation at 95 °C for 1 min, followed by 5 cycles with successive annealing temperature increments of 1 °C in every cycle. For the first 5 cycles, the reaction mixture was heated at 95 °C for 1 min, followed by annealing at 56 °C → 60 °C for 1 min and polymerization at 72 °C for 1 min. The subsequent 30 cycles of amplification were similar, except that the annealing temperature was 60 °C for 1 min. Lastly, the extension was performed at 72 °C for 4 min. TUPCRs containing both positive controls (approximately 20–30 ng of Mf gDNA templates) and negative controls were performed in the same manner as those containing the L3 gDNA templates.For the secondary TUPCRs containing species-specific or 2.5W. bancrofti (MT674270-MT674272), B. malayi (MT674273- MT674275), B. pahangi (MT674276- MT674279), and D. immitis (MT674280- MT674288).Electrophoresis of the PCR products with expected sizes and the determination of the homology of all sequenced amplicons at the DNA and protein levels were accomplished using the methods described elsewhere ,19. The 33.1Ar. subalbtus (953), Cx. vishnui (133), Cx. gelidus (105), Ae. albopictus (80), Ma. uniformis (58), Ae. aegypti (23), Ma. indiana (15), Ma. bonneae (10), Cq. crassipes (6), Cx. quinquefasciatus (5), Cx. sp. (4), and Cx. nigropunctatus (1) were collected using the HLC method , B (pi = 0.829), and C (pi = 0.543), but not the low-lying ecotope, D (pi = 0.103) when compared to other locally adapted mosquitoes such as Cx. vishnui, Cx. gelidus, Ae. albopictus, and Ma. uniformis , B (31.83), and C (16.90), tended to exhibit an average MLR of 19.85, which was 4-fold to 20-fold greater than that of other mosquito species: Culex spp. (5.17), Aedes spp. (2.15), and Mansonia spp. (1.73)  .Table 2SCulex (n = 248), Aedes (n = 103), Mansonia (n = 83), and Coquillettidia (n = 6)  alone, there were 24 infected mosquitoes  of varying filarial parasite infections in ecotope C (2.96%), B (2.62%), and A (2.25%) , 0.67 (ecotope A), and 0.50 (ecotope C) . Further, Ar. subalbatus tended to harbor 56 infective L3, which was found to be three-fold greater than the amount of L1 (29) and L2 (25) harbored (Table S3).All 440 HLC-collected adult female mosquitoes belonging to the genera  (n = 6)  were neg (2.25%) . Howeverotope C) . All 9 A3.2β-tubulin gene-specific TUPCR amplification carried out using gDNA templates of 30 representative L3 larva clones, the Ar. subalbatus infectious pool, AAP1, corresponded to infections with both B. pahangi (468-bp amplicons of L02 clone) and D. immitis (477-bp amplicons of the L07 clone)  . The CAP4Armigeres subalbatus, the natural vector for B. pahangi and D. immitis, is commonly found in urban and rural areas in SEA [Ar. subalbatus plantation ecotype was found to be the predominant species carrying zoonotic B. pahangi and D. immitis, and may have played an imperative role in circulating these parasites in the local landscape assessed in the rural area of Suratthani. Based on the results obtained herein, variation in the local landscape and environment influenced the infestation of Ar. subalbatus, enabling them to adapt well to the elevated ecotopes of rubber or oil palm plantations at 60–80 MASL. Rubber or oil palm plantations and not disturbed swamp, which was found in ecotope D, might be the ideal places for the breeding of Ar. subalabatus in both artificial and natural containers with organic matters. Its adaptability markedly contributed to its outnumbering of its counterpart species, such as Mansonia, Aedes, and Culex, and foraging blood meals in human dwellings with domestic cats or dogs. Further, there were high abundances of Ar. subalbatus in the elevated ecotopes as shown in s in SEA ,14,22,23s in SEA ,25. In tAr. subalbatus. However, an accurate estimate of the B. pahangi infection in Ar. subalbatus was not established. When filarial orthologous beta-tubulin gene-specific TUPCR was carried out using representative L3 larva clones, any Ar. subalbatus infectious pool might have carried either B. pahangi or D. immitis, or both B. pahangi and D. immitis. This finding strongly suggests that Ar. subalbatus is susceptible to these zoonotic filarial parasites [3 loads. Ar. subalbatus might have a disproportionate L3 load of B. pahangi relative to D. immitis, despite its infection rate being estimated to be less than 1% in the natural population. Such finding might be explained by the feeding behaviors of Ar. subalbatus that more likely carried out a vicious attack on dogs in the outdoor settings than cats when seeking animal blood meals during the peak hour of 18:30–19:30 h. Moreover, Ar. subalbatus might have a flight range longer than 100 m, even up to 1000 m. However, this might not relate B. pahangi infected cats to B. pahangi infections in Ar. subalbatus in the elevated ecotopes of A to C owing to its animal host range [B. pahangi might be due to the fitness of the Ar. subalbatus vectors, their ability to produce large numbers, and the source of infections in domestic cats [In the local landscape examined herein, the zoonotic filarial infection rate was approximately 2.5% or up to 4% in the natural population of arasites  with a wst range . Similartic cats ,8,12; a B. pahangi infections in children. However, several factors, including the variation in the local landscape and environment, availability of Ar. subalbatus breeding sites proximal to the dwellings of domestic animals, the abundance of Ar. subalbatus, and the prevalence of B. pahangi infection in domestic animals, might be important.Collectively, our findings are general considerations of the epidemiological catchment area comprised of designated sites scalable for vector surveillance and case investigation of 5Ar. subalbatus plantation ecotypes and higher rates of zoonotic filarial parasite infections of B. pahangi and D. immitis in Ar. subalbatus than other local mosquitoes belonging to the genera Mansonia, Aedes, Culex, and Coquillettidia. Based on the molecular investigation of the L3 larva clones, which were representatives of the Ar. subalbatus infectious pools, Ar. subalbatus could either carry B. pahangi or D. immitis, or both species. Such findings imply the potential role of Ar. subalbatus in the natural transmission of not only zoonotic B. pahangi infection, but also D. immitis in plantation areas in Thailand, regardless of altitude.Variations in the local landscape and environment, such as elevated instead of a low-lying ecotope of rubber plantations or oil palm plantations, could influence higher abundances of The authors assert that all procedures contributing to this work complied with the ethical standards and were approved by the Institutional Review Board at the Faculty of Veterinary Medicine, Mahanakorn University of Technology .10.13039/501100004396Thailand Research Fund; 10.13039/100012527Office of the Higher Education Commission; and 10.13039/501100001831Mahanakorn University of Technology, Bangkok, Thailand .The research was supported by The Apiradee Intarapuk: Conceptualiation; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Validation; Writing - original draft.Adisak Bhumiratana: Conceptualiation; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Validation; Visualization; Writing - original draft; Writing - review & editing.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


In non-inferiority trials, there is a concern that intention-to-treat (ITT) analysis, by including participants who did not receive the planned interventions, may bias towards making the treatment and control arms look similar and lead to mistaken claims of non-inferiority. In contrast, per protocol (PP) analysis is viewed as less likely to make this mistake and therefore preferable in non-inferiority trials. In a systematic review of antibiotic non-inferiority trials, we compared ITT and PP analyses to determine which analysis was more conservative.In a secondary analysis of a systematic review, we included non-inferiority trials that compared different antibiotic regimens, used absolute risk reduction (ARR) as the main outcome and reported both ITT and PP analyses. All estimates and confidence intervals (CIs) were oriented so that a negative ARR favored the control arm, and a positive ARR favored the treatment arm. We compared ITT to PP analyses results. The more conservative analysis between ITT and PP analyses was defined as the one having a more negative lower CI limit.p = 0.0402). CIs were slightly wider in ITT analyses than in PP analyses . The median success rate was 89% (interquartile range IQR 82 to 93%) in the PP population and 44% (IQR 23 to 60%) in the patients who were included in the ITT population but excluded from the PP population (p < 0.0001).The analysis included 164 comparisons from 154 studies. In terms of the ARR, ITT analysis yielded the more conservative point estimate and lower CI limit in 83 (50.6%) and 92 (56.1%) comparisons respectively. The lower CI limits in ITT analysis favored the control arm more than in PP analysis (median of − 7.5% vs. -6.9%, Contrary to common belief, ITT analysis was more conservative than PP analysis in the majority of antibiotic non-inferiority trials. The lower treatment success rate in the ITT analysis led to a larger variance and wider CI, resulting in a more conservative lower CI limit. ITT analysis should be mandatory and considered as either the primary or co-primary analysis for non-inferiority trials.CRD42020165040.PROSPERO registration number The online version contains supplementary material available at 10.1186/s12874-021-01260-7. In randomized controlled trials (RCTs), the most commonly analyzed populations are the intention-to-treat (ITT) and per protocol (PP) populations , 2. The ITT and PP analyses may differ in terms of how conservative the results are. Risk differences are usually calculated as success rate in the treatment arm minus the control arm, which is the absolute risk reduction (ARR). For the ARR point estimate and confidence interval (CI), the more conservative estimate would be smaller (more negative), which would favor the control arm more. Most non-inferiority trials use the lower CI limit to conclude on non-inferiority . The treITT analysis is considered more conservative (less likely to find a difference between groups) than PP analysis in superiority RCTs, because the estimated treatment effect using ITT analysis may be diluted by inclusion of participants who did not receive the intervention . In non-Recent studies have challenged the notion that PP analysis is more conservative in non-inferiority trials. Simulation studies have identified scenarios where PP analysis was more conservative and other scenarios where it was not , 11. HowOf non-inferiority RCTs on drug therapy, anti-infective agents are the most common type of drug being evaluated . For nonThis was a secondary analysis of a previously conducted systematic review (PROSPERO CRD42020165040) . The revWe searched MEDLINE, Embase and the Cochrane Database of Systematic Reviews from inception to November 22, 2019. The detailed search strategy is described in Additional file We included studies published in English that were identified as non-inferiority RCTs in humans comparing two or more systemic antibiotic regimens used to treat a bacterial infection. Studies were included if the treatment and control arms were specific antibiotic regimens. Each arm within the trial should have a different antibiotic regimen.Commentaries, reviews, study protocols, secondary analysis, and conference proceedings were excluded. We also excluded trial registrations where the results were not published in a journal article. Phase 2 and pilot studies were identified and excluded after full text reading.To be included in this secondary analysis, the studies must have reported both ITT and PP analyses, and the outcomes in percentage absolute risk differences.Six reviewers screened abstracts after a training session to identify potentially relevant studies and extract full texts for reading. In the training session, all reviewers screened a sample batch of abstracts together and reached consensus on inclusion versus exclusion. The first 300 abstracts that each reviewer screened were double checked by another independent reviewer for consistency. If consistent, the reviewer then screened abstracts independently.For full text review, two independent reviewers read and extracted the data in duplicate onto a standardized extraction form. Disagreements were resolved by discussion to reach consensus, and adjudication by a third reviewer if necessary.We extracted the following data from each journal article: journal, year of study, sample size, inclusion and exclusion criteria for ITT as well as PP population, treatment of missing data, and the primary outcome including the absolute numbers  and reported CI.The co-primary outcomes were the point estimate and lower CI. We converted all risk differences to the standard ARR calculated as the success rate in treatment arm minus the success rate in the control arm, such that a negative ARR means that the results favor the control arm and a positive ARR means that the results favor the treatment arm. Based on this orientation, the lower CI limit can be interpreted as representing the worst plausible treatment effect for the treatment arm. A conclusion of non-inferiority was based on a comparison of this lower CI limit to the non-inferiority margin Fig. .Fig. 1OWe extracted the number of successes and total number of patients in the treatment and control arms to calculate the two-sided 95% CI for the ARR using the method described by Agresti and Caffo . The AgrThe more conservative approach between PP and ITT analyses was defined as the one with the smaller (more negative) lower CI limit, as the smaller limit is less likely to exclude a non-inferiority margin.We used the calculated two-sided 95% CI to determine whether the treatment arm was non-inferior to the control arm based on the lower CI limit relative to the non-inferiority margin specified in the study. We then examined the concordance between the ITT and PP analyses. ITT and PP analyses would be concordant if both analyses reached the same conclusion. The analyses would be discordant if non-inferiority was proven in one analysis but inconclusive in the other analysis.In the rare cases where a study that had two or more comparisons, we did not take into account the correlation of comparisons within studies.Two independent reviewers assessed the risk of bias in duplicate based on the Cochrane Collaboration’s tool for assessing risk of bias in randomized trials . AttritiThe ITT and PP analyses were displayed on the funnel plot to assess for publication bias. Consider a scenario where non-inferiority was inconclusive in the ITT analysis and proven in the PP analysis. The authors may choose to omit the ITT analysis and publish only the PP analysis results. Therefore, it is possible that authors only report both ITT and PP analyses when both analyses successfully demonstrated non-inferiority. If this were the case, then there may be asymmetry in the funnel plot of ITT and PP analyses results.Descriptive analyses included number (percentage) for categorical variables and median (interquartile range IQR) for continuous variables. For comparison of point estimates, lower CI limits and CI widths between ITT and PP analyses in the same study, a paired Wilcoxon signed-rank test was used .P < 0.2 were entered into a multivariable linear regression model.As an exploratory analysis, an univariate linear regression was used to estimate associations between study-level characteristics and the difference between the lower CI limit of the ITT and PP analyses. Possible predictors included the methods of dealing with missing data, risk for bias as well as inclusion and exclusion criteria for ITT and PP populations as binary variables. Variables with univariate The excluded population is defined as patients in the ITT population who were excluded from the PP population. The total number of patients and treatment successes in each arm of the excluded population was calculated by subtraction, using the number of patients and treatment successes reported in each arm of the ITT and PP populations.P < 0.05 significance level. All analyses were done with R version 3.6.3 . Funnel plots and Egger’s regression test for funnel plot asymmetry were done using the metafor package [All tests were two sided with a  package . CI for  package .Of the 227 antibiotic non-inferiority trials, 41 (18.1%) studies reported only ITT analysis, 22 (9.7%) studies reported only PP analysis, and 164 (72.2%) studies reported both ITT and PP analyses. Furthermore, nine studies were excluded for reporting primary outcomes that were not proportions. One study was excluded because it did not report the numbers required to calculate the treatment success rates. Therefore, 154 (67.8%) studies met the inclusion criteria  studies defined non-inferiority based on the lower CI limit with respect to the non-inferiority margin. Study characteristics with respect to the description and analysis of ITT and PP populations are described in Table Risk of bias is summarized in Table p < 0.0001) and more conservative lower CI limits   cases    for the excluded population and − 0.2% (IQR − 2.6 to 2.2%) for the PP population (p-value of 0.9132. The funnel plots for ITT analyses only and PP analyses only are shown in Additional file The Egger’s regression test for funnel plot asymmetry of all ITT and PP analyses (Additional file In this systematic review of antibiotic non-inferiority trials, ITT analysis was more conservative than PP analysis in the majority of cases. In general, ITT analysis had wider CIs and more conservative lower CI limits than PP analysis. Although the difference between the lower CI limits of the ITT and PP analyses were small on average, there was a substantial variation at the individual trial level. For example, in two studies, this difference was larger than the non-inferiority margin itself. The substantial variation at the individual study level led to different conclusions on non-inferiority by ITT and PP analyses in approximately 12% of studies if non-inferiority was determined based on our calculated two-sided 95% CI relative to the specified non-inferiority margin in the study.Although one might expect that the larger sample size in ITT would result in a narrower CI, the opposite was true in our study. The success rate of the excluded population was on average half that in the PP population in both the treatment and control arms, as shown in Additional file From a study design perspective, ITT and PP analyses measure two different treatment effects. ITT analysis measures the effect based on allocated intervention. In contrast, PP analysis measures the treatment effect of patients who started, adhered to and completed follow-up. From this perspective, it is expected that the treatment effect from the ITT analysis would have a lower success rate and be more conservative.The multivariable linear regression model showed two noteworthy correlations. A more conservative ITT lower CI limit was associated with a lower proportion of the ITT population included in the PP population for the treatment arm and a higher proportion of the ITT population in the PP population for the control arm. These variables determine the proportion of the excluded population, which would then affect the CI width as described above. The linear regression model was only an exploratory analysis for the following reasons. First, for predictors used in the model, the methods were frequently not described in detail in the journal articles. For example, only 39% of studies described how they handled missing data. Second, many other factors may have contributed to which analysis would be more conservative such as pattern of missingness and non-compliance . Data caPrior to our study, only two studies have compared ITT and PP analyses. These two studies included 11 and 20 trials, respectively , 13, wheOur study raises questions about whether ITT or PP analysis is more conservative in non-inferiority trials. While PP analysis may be more conservative than ITT analysis in theory, the empirical evidence here suggests that ITT analysis can be more conservative than PP analysis in practice. The difference in results between the two analysis strategies will depend on many factors and as a result, there is no justification for the omission of ITT analysis in non-inferiority trials. The PP population excludes patients based on post-randomization information such as missingness and compliance, introducing the potential for bias . These cSince the success rate of the ITT population that was excluded from the PP population significantly impacts the CI for the ITT analysis, the handling of missing data in ITT analysis has important consequences on conservatism. Future non-inferiority trials should pay attention to the methodology of how to handle missing data and describe it in detail in the publication. In our study, only 39% studies described how missing data was handled. Of the ways to handle and impute missing data, counting missing data as failure is the most common method. This would decrease the success rate in the ITT population and likely lead to a wider and more conservative CI. From the perspective of conservatism, this is likely an appropriate method in most studies. It should be noted that the tipping point analysis where missing data were counted as failures in the treatment arm and successes in the control arm has been used in trials and likely yields an even more conservative result.The strength of our study is in the systematic and comprehensive literature search that includes the largest number of non-inferiority trials to date for comparison of ITT and PP analyses.The study has several limitations. First, most abstracts were screened by a single person. However, the first 300 abstracts screened by each reviewer were doubled checked by another person to ensure consistency in the screening process. Second, there may be publication bias. We were only able to analyze studies that reported both ITT and PP analyses. For studies that reported either ITT or PP analysis only, it may be possible that the other analysis was omitted on purpose because it was too conservative and resulted in the study being a negative study. However, the funnel plots (Additional file Our systematic review of antibiotic non-inferiority trials showed that ITT analysis on average produced wider CIs and was more conservative than PP analysis. Given that ITT is less prone to bias when an appropriate method for handling missing data is used, reporting of ITT analysis should be mandatory and ITT analysis should be the primary or co-primary analysis for non-inferiority trials on antibiotics.Additional file 1.Additional file 2.