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Background | MINOR, MUSCULOSKELETAL DISORDERS | Advanced practice physiotherapy (APP) models of care where physiotherapists are primary contact emergency department (ED) providers are promising models of care to improve access, alleviate physicians’ burden, and offer efficient centered patient care for patients with minor musculoskeletal disorders (MSKD). | PMC9900999 | |
Objectives | MINOR | To compare the effectiveness of an advanced practice physiotherapist (APPT)-led model of care with usual ED physician care for persons presenting with a minor MSKD, in terms of patient-related outcomes, health care resources utilization, and health care costs. | PMC9900999 | |
Methods | Pain | ADVERSE EVENT, MINOR | This trial is a multicenter stepped-wedge cluster randomized controlled trial (RCT) with a cost analysis. Six Canadian EDs (clusters) will be randomized to a treatment sequence where patients will either be managed by an ED APPT or receive usual ED physician care. Seven hundred forty-four adults with a minor MSKD will be recruited. The main outcome measure will be the Brief Pain Inventory Questionnaire. Secondary measures will include validated self-reported disability questionnaires, the EQ-5D-5L, and other health care utilization outcomes such as prescription of imaging tests and medication. Adverse events and re-visits to the ED for the same complaint will also be monitored. Health care costs will be measured from the perspective of the public health care system using time-driven activity-based costing. Outcomes will be collected at inclusion, at ED discharge, and at 4, 12, and 26 weeks following the initial ED visit. Per-protocol and intention-to-treat analyses will be performed using linear mixed models with a random effect for cluster and fixed effect for time. | PMC9900999 |
Discussion | MSKD have a significant impact on health care systems. By providing innovative efficient pathways to access care, APP models of care could help relieve pressure in EDs while providing efficient care for adults with MSKD. | PMC9900999 | ||
Keywords | PMC9900999 | |||
Administrative information | EMERGENCY |
Matifat, E.: Maisonneuve-Rosemont Hospital Research Center, University of Montreal Affiliated Research Center, Montréal, Québec, Canada.Berger Pelletier, E.: Faculty of Medicine, Université Laval Québec, Québec, CanadaBrison, R.: Department of Emergency Medicine, Queen’s University, Kingston, Ontario, Canada.Hébert, L.J.: Center for Interdisciplinary Research in Rehabilitation and Social Integration (Cirris); Department of Rehabilitation, Faculty of Medicine, Laval University, Québec, Québec, Canada.Roy, J.-S.: Center for Interdisciplinary Research in Rehabilitation and Social Integration (Cirris); Department of Rehabilitation, Faculty of Medicine, Université Laval Québec, Québec, Canada.Woodhouse, L.: Tufts University School of Medicine, Public Health and Community Medicine, Arizona, USA.Berthelot, S.: Department of Family Medicine and Emergency Medicine, Faculty of Medicine, Laval University, Québec, Québec, Canada.Daoust, R.: Department of Family Medicine and Emergency Medicine, Faculty of Medicine, Montreal University, Montréal, Québec, Canada.Sirois, M.-J. : Department of Rehabilitation, Faculty of Medicine, Laval University, Québec, Québec, Canada.Booth, R.: School of Rehabilitation Therapy, Faculty of Health Sciences, Queen’s University, Kingston, Ontario, Canada.Gagnon, R.: Center for Interdisciplinary Research in Rehabilitation and Social Integration (CIRRIS), Québec, Québec, Canada; Department of Rehabilitation, Faculty of Medicine, Laval University, Québec, Québec, Canada.Miller, J. : School of Rehabilitation Therapy, Faculty of Health Sciences, Queen’s University, Kingston, Ontario, Canada.Tousignant-Laflamme, Y. : School of Rehabilitation, Faculty of Medicine and Health Sciences, Sherbrooke University, Sherbrooke, Québec, Canada.Emond, M. : Department of Family Medicine and Emergency Medicine, Faculty of Medicine, Laval University, Québec, Québec, Canada.Perreault, K.: Center for Interdisciplinary Research in Rehabilitation and Social Integration (Cirris), Québec, Québec, Canada; Department of Rehabilitation, Faculty of Medicine, Laval University, Québec, Québec, Canada.Desmeules, F.: Maisonneuve-Rosemont Hospital Research Center, University of Montreal Affiliated Research Center, Montréal, Québec, Canada; School of Rehabilitation, Faculty of Medicine, University of Montréal, Montréal, Québec, Canada. | PMC9900999 | |
Introduction | PMC9900999 | |||
Background and rationale {6a} | CHRONIC DISORDERS | Overcrowding in emergency departments (ED) is one of the biggest concerns in several health care systems. This challenge will worsen in years to come given the aging populations, the increasing prevalence of chronic disorders, and physician shortages [Traditionally, ED physicians are the primary contact practitioners who manage patients with MSKD, although a high proportion of physicians report limited knowledge and confidence in taking charge of these patients [ | PMC9900999 | |
Objectives {7} | disability, Pain, pain | ADVERSE EVENTS, MINOR | Thus, the aim of our project is to evaluate the impact of an APP-led model of care compared to usual physician ED care for persons presenting with minor MSKD. The specific objectives are:To compare the effectiveness of both types of care in terms of patient-related outcomes for patients with minor MSKD in six Canadian EDs, at discharge from the ED and 4, 12, and 26 weeks after the ED consultation, on the following outcomes:Primary outcome: the Brief Pain Inventory (BPI) – Interference of pain on function subscaleSecondary outcomes: pain intensity, disability, patient satisfaction with care, and adverse events.To compare health care resource utilization between both types of care at ED discharge and at 4, 12, and 26 weeks after the initial consultation, including proportion of ED return visits for the same complaint, medication prescriptions, prescriptions for imaging and laboratory tests, and referral to other health care providersTo compare both types of care in terms of health care costs from the public payer’s perspective and perform a cost-utility analysis, at ED discharge and at 4, 12, and 26 weeks after the initial consultationTo compare wait to initial assessment and ED length of stay between both types of care for the evaluation and treatment of participants during their ED visitWe hypothesize that integrating APP-led care in the ED will be at least as effective as usual ED physician care for patients with a MSKD, in terms of patient-related and health care resource utilization-related outcomes. Furthermore, health care costs will be lower in the APP-led care arm. | PMC9900999 |
Trial design {8} | This project is a multicenter pragmatic stepped-wedge (3 steps with 4 periods of 6 weeks each) cluster RCT with a cost analysis conducted in six Canadian EDs. | PMC9900999 | ||
Methods: participants, interventions, and outcomes | PMC9900999 | |||
Study setting {9} | Patients will be recruited from the following six Canadian EDs: Maisonneuve-Rosemont Hospital (MRH) (CIUSSS-de-l’Est-de-l’Ile-de-Montréal, Montréal, Québec), Centre Hospitalier Universitaire de l’Université Laval (CHUL) and Enfant-Jésus Hospital (EJH) (CHU de Québec, Québec), Hotel-Dieu Hospital (Kingston Health Sciences Center-KHSC, Kingston, Ontario), Hôtel-Dieu Hospital (CIUSSS-de-l’Estrie-CHUS, Sherbrooke, Québec), and Rockyview General Hospital (Calgary, Alberta). | PMC9900999 | ||
Eligibility criteria {10} | dislocations, musculoskeletal injury, pain, fractures, muscle pain, psychiatric, tendinopathy, neurological deficits, joint sprain, trauma | OSTEOARTHRITIS, MINOR, INFLAMMATORY ARTHRITIS, VEHICLE ACCIDENT | The inclusion criteria are (1) patients presenting with complaints related to minor MSKD (e.g., back pain, joint sprain, osteoarthritis, muscle pain, or tendinopathy) triaged as level 3, 4, or 5 on the Canadian Triage and Acuity Scale (CTAS); (2) aged 18 years or more; (3) legally able to consent; (4) able to understand/speak French or English; and (5) be a beneficiary of a provincial universal health insurance coverage.The exclusion criteria are (1) having injury resulting from major trauma (e.g., high-velocity trauma or major motor vehicle accident); (2) presenting a major musculoskeletal injury (e.g., open fractures, unreduced dislocations, open wounds, or a condition that needs an urgent surgical intervention); (3) presenting a red flag (e.g., progressive neurological deficits or infection-related symptoms); (4) consulting for a diagnosed inflammatory arthritis or other active/unstable non-musculoskeletal condition (e.g., pulmonary, cardiac, digestive or psychiatric condition); and (5) consulting for a work-related MSKD eligible for workers’ compensation benefits. | PMC9900999 |
Who will take informed consent? {26a} | Research professionals in each site will explain the study, including the purpose and the required implication by participants, to eligible patients and will answer any remaining questions. Research professionals will then obtain written informed consent from patients who agree to enroll in this study. Information and consent forms will be available in both French and English, depending on the participants’ preferred language. | PMC9900999 | ||
Additional consent provisions for collection and use of participant data and biological specimens {26b} | N/A, no ancillary studies | PMC9900999 | ||
Interventions | PMC9900999 | |||
Explanation for the choice of comparators {6b} | In the Canadian health care system, patients presenting to EDs will receive the usual care from an ED physician. As this is the most prevalent model of care for patients with MSKD, this will be used as our control arm. | PMC9900999 | ||
Intervention description {11a} | The experimental arm will receive APP-led care. Patients will be independently managed (assessment and intervention) by a PT (The control arm will receive the usual ED physician care delivered by an ED physician. This will include independent assessment, treatment, and discharge by an ED physician with no physiotherapy within the ED but a physician’s referral to outpatient physiotherapy or other professionals/medical specialists will be possible. Overall care offered by the ED physician will not be standardized but will be systematically documented.Participants in both arms presenting a non-MSKD condition after assessment will be excluded from the study. The proportion of excluded participants per group, as well as the reasons for exclusion, will be systematically collected and analyzed (Fig. Trial flow chart | PMC9900999 | ||
Criteria for discontinuing or modifying allocated interventions {11b} | No specific criteria for modifying allocated interventions were defined since this is a punctual intervention. However, participants in both arms presenting a non-MSKD condition after assessment will be excluded from the study and will receive usual ED physician care outside the trial according to their condition. | PMC9900999 | ||
Strategies to improve adherence to interventions {11c} | This pragmatic trial will evaluate the impact of an assessment and intervention offered only within the ED either by a PT or a physician. | PMC9900999 | ||
Relevant concomitant care permitted or prohibited during trial {11d} | There will be no restriction in terms of care during this trial. Participants will be asked to complete a treatment diary regarding compliance with ED treatments and any health services or interventions they sought for their initial problem during the follow-up period. | PMC9900999 | ||
Provisions for post-trial care {30} | ADVERSE EVENTS | The main potential risk in this trial is a diagnostic error by PTs or physicians. Any adverse events will be documented within the current study, and we will ensure study participants receive the appropriate care if needed. | PMC9900999 | |
Outcomes {12} | PMC9900999 | |||
Baseline data collection | depression | DISORDER, AIDS | At trial inclusion, eligible participants will answer a series of questions covering socio-demographic characteristics, such as age, sex, gender, education level, household income, and living status. Clinical variables such as anthropometric data, affected body area, reason for consultation, CTAS level, duration of symptoms, type of disorder (traumatic/atraumatic), use of walking aids, and presence of any comorbidities will also be documented. Participants will also respond to the Patient Health Questionnaire (PHQ-9), a multipurpose instrument for screening and measuring depression [ | PMC9900999 |
Primary outcome measure | Pain, pain | The main outcome measure will be the Brief Pain Inventory–Short Form, Pain Interference Scale (BPI), and the primary endpoint at 4 weeks after discharge. The BPI is a self-administered questionnaire that includes seven items where the patient is asked to rate the impact of pain on various functional activities (pain interference scale) using a 10-point scale. The BPI is valid, reliable, and responsive to change in MSKD populations [ | PMC9900999 | |
Other patient-related outcomes | neck-related disorders, disability | In order to further assess the impact of MSKD on function, participants will complete self-reported validated and reliable disability questionnaires relevant to the affected body area. Depending on the affected body area(s), participants will complete one or more of the following questionnaires: Neck Disability Index (NDI) for neck-related disorders [ | PMC9900999 | |
Health care resource utilization outcomes | ADVERSE EVENTS | The ED physician or PT will complete a standardized form following their assessment and interventions, indicating diagnoses, requests for additional medical imaging or laboratory tests (if relevant), treatment plan (e.g., conservative treatment options, medication or physiotherapy care), discharge plan, and referral to other professional or medical specialists, if relevant. Providers in both arms will have access to the patient’s full medical record. Proportion of medical imaging tests or other laboratory tests, drug prescriptions/recommendations for analgesics and for opioids, and referral to other providers after initial assessment will be recorded with this form and confirmed with the participants’ medical file. Any adverse events, re-visits to the ED for the same complaint, and any incidents associated with care will be questioned at each time point during follow-up and completed by consulting patients’ medical files. | PMC9900999 | |
Health care costs | The EQ-5D-5L will be the primary outcome measure for the cost analysis outcomes. It is a generic health-related quality of life questionnaire for which validity has been established. It has been widely used in economic evaluations, including in trials with patients suffering from MSKD and in our pilot RCT [ | PMC9900999 | ||
Wait to initial assessment and ED length of stay measures | Wait in the ED, which is defined as the time between the arrival in the ED and the initial evaluation by a physician or a PT will be recorded. The total length of stay in the ED will also be recorded in minutes by research professionals onsite. | PMC9900999 | ||
Participant timeline {13} | The participant timeline is presented in Table | PMC9900999 | ||
Sample size {14} | The main hypothesis is that APP-led care will be at least as effective as usual ED physician care based on the results of our literature review [ | PMC9900999 | ||
Recruitment {15} | All new patients presenting to participating EDs and triaged by nurses (based on the usual triage process used in each ED) as having a possible MSKD will be considered for this study. In addition, a research professional in each site will screen the triage lists to identify any other potential participants for the trial and ensure none are omitted. Eligibility of ED patients will subsequently be assessed regarding the inclusion and exclusion criteria during an in-person interview with a research professional and review of medical records. Research professionals will explain the study to eligible patients and obtain their informed consent.For patients who decline participation in the project, demographic data, such as age, sex, reason for consultation, and reason to refuse to participate, will be collected to calculate participation proportions and establish comparisons between participants and non-participants. | PMC9900999 | ||
Assignment of interventions: allocation | PMC9900999 | |||
Sequence generation {16a} | All eligible and consenting sites will be randomly assigned to a sequence of models of care (APP-led or usual). All sites will begin the trial with a baseline period where no site is in the intervention arm. Then, during 6-week intervals, two sites (clusters) will move to the intervention arm with this timing randomized at the outset of the trial. After the third step in the sequence, all six sites will be in the intervention arm. | PMC9900999 | ||
Concealment mechanism {16b} | Sites will be informed at the beginning of the trial of the intervention sequence as this will allow efficient planning of the intervention arm at each ED. | PMC9900999 | ||
Implementation {16c} | Randomization procedures will be performed by an independent research professional not involved in other aspects of the trial. | PMC9900999 | ||
Assignment of interventions: blinding | PMC9900999 | |||
Who will be blinded {17a} | Neither participants nor providers will be blinded in this study in the context of this pragmatic RCT. Even if the patient’s perception can be influenced by the type of provider they see, this approach is necessary because of the pragmatic nature of the proposed care model, and it is important that patients know which provider and models of care they are exposed to as this increases the external validity of the current trial. An independent statistician not involved in any other parts of this trial and blinded to the participants’ allocation will conduct the statistical analyses. | PMC9900999 | ||
Procedure for unblinding if needed {17b} | Neither participants nor providers are blinded. | PMC9900999 | ||
Data collection and management | PMC9900999 | |||
Plans for assessment and collection of outcomes {18a} | All data will be collected using the REDCap platform. Outcome measures will be collected at inclusion, before ED discharge, and at 4-week, 12-week, and 26-week follow points (Table | PMC9900999 | ||
Plans to promote participant retention and complete follow-up {18b} | In order to limit loss to follow-up, we will validate with participants at each time point their contact information and preferred means of communication. | PMC9900999 | ||
Data management {19} | The databases will be centralized at the coordination center (Maisonneuve-Rosemont Hospital - MRH - Research Center). MRH will store all data captured in REDCap on its own servers. All data is therefore stored and hosted at MRH, and no project information is ever transmitted at any time by REDCap from MRH to any other institution. | PMC9900999 | ||
Confidentiality {27} | Data will be kept in REDCap at the end of the study in a de-identified form using an identification code. Only the investigators will have access to the link key linking codes to individuals. The data will be kept for seven years. | PMC9900999 | ||
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} | No biological specimens were collected. | PMC9900999 | ||
Statistical methods | PMC9900999 | |||
Statistical methods for primary and secondary outcomes {20a} | Descriptive statistics will be used to present the participants’ characteristics. Baseline demographic data will be compared across groups and the participating EDs to establish the comparability of study samples across intervention arms and clusters. If differences are observed, statistical models will be adjusted, and any difference will be considered. Descriptive statistics will be computed for all outcome measures at different measurement times. Per-protocol and intention-to-treat analysis will be performed. Outcomes will be analyzed at the individual level using mixed models as recommended for stepped-wedge designs [ | PMC9900999 | ||
Interim analyses {21b} | Interim analyses will be conducted at the 1-month follow-up to ensure no safety issue is detected and final analyses will be conducted at the end of the trial. | PMC9900999 | ||
Methods for additional analyses (e.g., subgroup analyses) {20b} | SECONDARY, RECRUITMENT | Secondary analyses will be performed according to the affected body area (upper limb, lower limb, neck, or back) and will consider site recruitment clustering, since these factors can impact care utilization as well as other outcomes measured in the study. The same is also true for sex and gender for which secondary analyses will also be conducted. | PMC9900999 | |
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} | Participants withdrawing from the study and reasons for withdrawal will be analyzed. Characteristics of participants and non-participants will also be compared. Multiple imputation will be used for missing data handling. | PMC9900999 | ||
Plans to give access to the full protocol, participant-level data, and statistical code {31c} | The protocol, data, and statistical code that support the findings of this study will be available from the corresponding author, upon reasonable request. | PMC9900999 | ||
Oversight and monitoring | PMC9900999 | |||
Composition of the coordinating center and trial steering committee {5d} | TSC | The trial steering committee (TSC) will include co-PIs Drs. Desmeules, Perreault, and Émond, with co-Is and assistants hired in each site. They will be at the core of trial management (as described above). The TSC will meet at the beginning of the study to plan/organize, to ensure the study integrates well within each site’s local reality. Twice a year, the TSC will meet to produce an executive summary of the research program. The research team from Maisonneuve-Rosemont Research Center, under Dr. Desmeules’ supervision, will coordinate the study. | PMC9900999 | |
Composition of the data monitoring committee, its role, and reporting structure {21a} | Since this is a low-risk intervention and not required by the Ethics Committee, there is no external data monitoring committee. | PMC9900999 | ||
Adverse event reporting and harms {22} | ADVERSE EVENTS | The current literature on the safety of ED physiotherapy care with MSKD patients found no increase in adverse events associated with ED physiotherapist-led care [ | PMC9900999 | |
Frequency and plans for auditing trial conduct {23} | TSC | RECRUITMENT | The TSC will meet every month to discuss issues with recruitment, protocol adherence, and follow-up of participants. | PMC9900999 |
Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25} | If any important protocol amendments are required, the TSC will meet to discuss the relevance of the proposed changes. Ethics committees of all participating sites will be informed of potential changes. Amendments will be undertaken only after approval of all committees. | PMC9900999 | ||
Dissemination plans {31a} | trauma | Several stakeholders and knowledge users, such as patients, administrators, health care practitioners, and decision-makers, have been engaged in the entire process from project inception to preparation of this protocol. They will pursue their active involvement until project completion and dissemination of the results. The results of this study will be adapted for presentation and exchange with collaborators in the different trial settings. A set of recommendations based on the results will be developed and shared. The results of this study, with the involvement of our collaborators and knowledge users, will be presented in each participating hospital through formal on-site or distance meetings and symposiums. Other usual means of dissemination will include communications in conferences related to ED and trauma research and practice (e.g., emergency medicine), rehabilitation or health service organization, and scientific publications in peer-reviewed journals. Outcomes will also be shared with stakeholders (medical and patients’ associations and governments) by producing and sharing policy briefs and synthesis documents. | PMC9900999 | |
Discussion | Current evidence shows that an increasing number of MSKD patients turn to EDs for care [ | PMC9900999 | ||
Strength and limitations | APPTs | STILL | This study is the first multicenter pragmatic trial with a cost analysis assessing APP-led ED care. The trial has been designed by a group of experts with expertise in the management of MSKD, public health, epidemiology, cost analyses, health services, ED medicine, interprofessional collaboration, rehabilitation, and designing and performing RCTs. The stepped-wedge design is an emerging and original methodology that facilitates the evaluation and implementation of new models of care [Although this trial is a pragmatic design, because of its experimental nature, it may not fully represent usual care that APPTs or ED physicians offer as they are aware of the objective of the trial. Moreover, patients are not blinded to providers that will offer care, and it may influence their perceptions. Still, this approach is necessary because of the pragmatic nature of the proposed trial, and it is important that patients know which provider and models of care they are exposed to as this increases the external validity of the current trial. Also, only a limited number of APPTs (12) will be assessing patients within this study across six EDs across Canada.While APP-led ED models of care are emerging globally, none of these models has been evaluated across Canada where these models are also becoming more prominent. MSKD not only represent a significant economic burden for Canadians, but also have a significant impact on population health, the Canadian workforce, and our health care system. As such, new models of care that result in more efficient care are needed. Given the high consultation rates for MSKD and known overcrowding in EDs, this trial has the potential to improve access and efficiency of ED care. | PMC9900999 |
Trial status | RECRUITMENT | Recruitment for this trial should start in the fall of 2022 and be completed by the spring of 2023. | PMC9900999 | |
Acknowledgements | Not applicable. | PMC9900999 | ||
Authors’ contributions {31b} | FD, KP, ME, and co-principal investigators for this study were involved in the study protocol development and revision as well as the funding proposal. All authors reviewed, edited, and approved the final version of this protocol. | PMC9900999 | ||
Authors’ information | Not provided. | PMC9900999 | ||
Funding {4} | This research is funded by the Canadian Institutes of Health Research (CIHR) (202010PJT-451693-CIB-CFCC-130299). | PMC9900999 | ||
Availability of data and materials {29} | After all analyses have been conducted and results published, the data that support the findings of this trial will be available upon reasonable request. | PMC9900999 | ||
Declarations | PMC9900999 | |||
Ethics approval and consent to participate {24} | This study was approved by the Research Ethics Committee of the CIUSSS-de-l’Est-de-l’Ile-de-Montréal (MP-12-2022-2730). This study will be undertaken following approval from the ethics review boards of all participating EDs.In regard to participants’ consent, research professionals in each site will explain the study, including the purpose and the required implication by participants, to eligible patients and will answer any remaining questions. Research professionals will then obtain written informed consent from patients who agree to enroll in this study. Information and consent forms will be available in both French and English, depending on the participants’ preferred language. | PMC9900999 | ||
Consent for publication {32} | Not applicable. No identifying images or other personal or clinical details of participants are presented here nor will be presented in reports of the trial results. Informed consent materials are available from the corresponding author upon request. | PMC9900999 | ||
Competing interests {28} | The authors declare that they have no competing interests. | PMC9900999 | ||
References | PMC9900999 | |||
Purpose | SBS-IF, intestinal failure, short bowel syndrome | INTESTINAL FAILURE, SHORT BOWEL SYNDROME | The short- and long-term efficacy, safety, and pharmacokinetics of teduglutide were analyzed in adult Japanese patients with short bowel syndrome and intestinal failure (SBS-IF). | PMC9950205 |
Methods | Patients received teduglutide 0.05 mg/kg/day in clinical trials (TED-C14-004, SHP633-306, and extension SHP633-307). Data were analyzed at 24 weeks and an interim data cut-off of 4.5 years. | PMC9950205 | ||
Results | ADVERSE EVENTS, DISEASE, ADVERSE DRUG REACTIONS | The parenteral support (PS) volume decreased by ≥ 20% for 9/18 patients at 24 weeks and in all 11 patients by data cut-off in SHP633-307. The mean (standard deviation) PS volume decreased from baseline at 24 weeks in TED-C14-004 (−30.1 ± 25.9%) and SHP633-306 (−25.6 ± 25.5%), and at data cut-off in SHP633-307 (−57.08 ± 28.49%). Teduglutide was absorbed quickly. The adverse events were consistent with the underlying disease and known adverse drug reactions. Anti-teduglutide antibody titers declined with long-term treatment. | PMC9950205 | |
Conclusions | In Japanese adults with SBS-IF, teduglutide treatment was associated with clinically meaningful reductions in PS requirements, similar to findings in prior international studies. No new safety concerns specific to the Japanese SBS-IF patient population were identified with short- or long-term teduglutide treatment. Anti-teduglutide antibody titers disappeared in most Japanese adults with long-term treatment. These results constitute the longest evaluation of teduglutide treatment within clinical trials reported to date. | PMC9950205 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s00595-022-02587-4. | PMC9950205 | ||
Keywords | PMC9950205 | |||
Introduction | intestinal failure, malignancy, Short bowel syndrome, Crohn’s disease, mesenteric ischemia, SBS, SBS-IF | INTESTINAL FAILURE, INTESTINAL OBSTRUCTION, SHORT BOWEL SYNDROME, MESENTERIC ISCHEMIA, PATHOLOGY | Short bowel syndrome (SBS) is a rare condition resulting from significant physical or functional loss of portions of the bowel and is the most common cause of intestinal failure (IF) [Patients with SBS-IF comprise a heterogeneous population differing in underlying pathology, the function of the remnant bowel, and demographic characteristics [SBS in adults is commonly caused by extensive intestinal resection for recurrent Crohn’s disease, mesenteric ischemia, intestinal obstruction, or malignancy, and may involve partial or complete colonic resection [Severe reductions in the intestinal absorptive capacity may render patients with chronic SBS-IF dependent on life-sustaining parenteral support (PS; parenteral nutrition and/or intravenous fluids) [Teduglutide is a GLP-2 analogue approved in several countries and continents, including the United States and Europe (2012), for the treatment of patients ≥ 1 year old with SBS-IF (0.05 mg/kg subcutaneously [SC] once daily) who are dependent on PS [The benefits and risks associated with teduglutide in Japanese patients with SBS-IF have not been previously reported. We therefore report herein the efficacy, safety, and pharmacokinetic (PK) findings for teduglutide from two multicenter phase III clinical trials and their extension study in adult Japanese patients with SBS-IF: the up to 30-month TED-C14-004 study; the 24-week SHP633-306 pivotal study; and the SHP633-307 long-term extension study (involving ≥ 12 months’ and 24 weeks’ participation in studies TED-C14-004 and SHP633-306, respectively). These three studies were conducted with the goal of achieving marketing approval for teduglutide in Japan. | PMC9950205 |
Methods | PMC9950205 | |||
Study design | SBS-IF, Crohn’s disease, SBS | STERILE, REMISSION | Two open-label, multicenter phase III clinical trials of teduglutide in adult patients with SBS-IF and their extension study were conducted in Japan: TED-C14-004 (ClinicalTrials.gov identifier NCT02340819) involved short-term (24 weeks) and long-term (up to 30 months) treatment with teduglutide; SHP633-306 (ClinicalTrials.gov identifier NCT03663582) involved only short-term (24 weeks) treatment with teduglutide; and SHP633-307 (ClinicalTrials.gov identifier NCT03596164) was a long-term extension study that enrolled patients who completed TED-C14-004 or SHP633-306.TED-C14-004 was conducted between December 2014 and November 2018, and SHP633-306 was conducted between July 2018 and August 2019. SHP633-307 is ongoing at the time of this analysis, so February 2020 was used as the interim data cut-off point. The studies were conducted in accordance with the principles of the World Medical Association Declaration of Helsinki and applicable laws and standards of good clinical practice in Japan. Upon approval of the study protocol from institutional review boards or ethics committees, written informed consent from patients was obtained prior to their involvement in any study activities. The inclusion and exclusion criteria, dose of teduglutide, and treatment duration used for studies TED-C14-004 and SHP633-306 were based on those used in the pivotal multinational STEPS-1 study [Patients who entered TED-C14-004 or SHP633-306 had to be ≥ 16 years old, have SBS as a result of major intestinal resection, and have been dependent on PS ≥ 3 times per week for ≥ 12 months before enrollment, with a < 10% change in weekly PS volume for ≥ 4 consecutive weeks before the start of treatment with teduglutide. Patients with a history of Crohn’s disease could participate if they had been in clinical remission (inactive Crohn’s disease demonstrated by clinical assessment) for ≥ 12 weeks before teduglutide dosing. Key exclusion criteria included use of native GLP-2 or human growth hormone in the 6 months before study start or any prior use of teduglutide. To be eligible for SHP633-307, patients had to have completed SHP633-306 or had ongoing participation in TED-C14-004 at the time of study closure.An overview of the study designs for TED-C14-004, SHP633-306, and SHP633-307 is given in Fig. In TED-C14-004, there was no training for patients or caregivers on how to administer teduglutide at home. However, for SHP633-306 and SHP633-307, patients or caregivers were provided a detailed training manual and a quick reference guide. The first dose was administered by a study physician, who then observed the patient or caregiver administering teduglutide at least twice in compliance with an administration checklist prior to patients or caregivers administering the drug unsupervised. To ensure teduglutide continued to be administered correctly and safely at home, the study physician supervised administration at select study visits during the treatment period. To facilitate the preparation and administration of teduglutide, a vial adaptor was also implemented in SHP633-306 and SHP633-307 for reconstitution of lyophilized teduglutide with sterile water for injection and drawing of the reconstituted drug into a dosing syringe with a safety lock.Study design of TED-C14-004, SHP633-306 | PMC9950205 |
Data collection | BLOOD | For TED-C14-004 and SHP633-306, patient demographic and clinical characteristics were captured at baseline, defined as the last visit before initiation of treatment with teduglutide. The baseline for the analysis of the efficacy and PK assessments for each patient was the baseline from core studies TED-C14-004 or SHP633-306. Data collected at each clinic visit included the daily PS volume, safety parameters, clinical laboratory test results, vital signs, body weight, and body mass index (BMI).Concentrations of plasma citrulline, a biomarker of intestinal epithelial mass, were measured at baseline; weeks 4, 8, 16, and 24; and then every 2 months thereafter up to 30 months of treatment. Patients who continued into SHP633-307 from SHP633-306 had measurements taken at month 12, while those continuing from TED-C14-004 had measurements taken every 3 months.In TED-C14-004 and SHP633-306, blood samples for PK evaluations were taken pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h post-dose during the first 12 weeks of treatment with teduglutide. In SHP633-307, patients continuing from study TED-C14-004 had blood samples for PK evaluations taken pre-dose and at 0.25 and 0.5 min, and 1, 2, 3, 4, 6, 8, 10, and 12 h post-dose at the first extension study visit. Patients continuing from SHP633-306 had blood samples taken pre-dose and 1 and 2 h post-dose at the first extension study visit. Blood samples to test for the presence of antibodies to teduglutide were taken at baseline and weeks 12 and 24 in SHP633-306; ≥ 14 h after dosing at baseline and weeks 12 and 24, and then every 6 months thereafter in TED-C14-004; and every 3 months in SHP633-307. | PMC9950205 | |
Data analyses | stoma, Crohn’s disease | ADVERSE EVENTS | The intent-to-treat (ITT) population consisted of patients who enrolled and were eligible at baseline (i.e., after PS optimization and stabilization) to receive teduglutide. Efficacy analyses were based on the ITT population, all of whom received teduglutide. The safety population comprised all patients in the ITT population who received ≥ 1 dose of teduglutide and the PK population included all patients in the safety analysis population for whom PK data were sufficient and interpretable. In these studies, the ITT population was the same as the safety population. Treatment compliance was defined as patients receiving ≥ 80% of the planned study drug doses, assessed by site investigators counting used/unused vials at every clinic visit.Efficacy endpoints were defined in an analogous manner to previous pivotal studies [Efficacy was evaluated between baseline and 24 weeks in TED-C14-004 and SHP633-306 and between baseline and 30 months in TED-C14-004. Among patients who entered SHP633-307, the total follow-up periods, including the prior studies, were up to 14–57 months of total teduglutide exposure for patients from SHP633-306 and TED-C14-004.Post hoc analyses of PS volume reductions in patients with Crohn’s disease, with and without a stoma, were performed for TED-C14-004.Single-dose PK parameters were estimated using a non-compartmental analysis and included the maximum plasma concentration of teduglutide (CSafety analyses included the monitoring of adverse events (AEs), body weight, BMI, vital signs, 12-lead electrocardiogram (ECG), serum biochemistry, hematology, and presence of antibodies to teduglutide. AEs were coded using the Medical Dictionary for Regulatory Activities versions 17.1 (TED-C14-004) and 21.0 (SHP633-306 and SHP633-307) [ | PMC9950205 |
Statistical analyses | The small size of the study populations precluded any formal statistical testing; data were summarized using descriptive statistics. All data values are reported as the mean ± standard deviation (SD) unless otherwise stated. | PMC9950205 | ||
Results | PMC9950205 | |||
Mean exposure to teduglutide | Patients who completed the extension study until the interim data cut-off point received teduglutide up to a maximum of 14 months (SHP633-306) or 57 months (TED-C14-004). The mean extents of teduglutide exposure only in TED-C14-004 and SHP633-306 were 26.8 ± 17.0 months and 4.8 ± 1.6 months, respectively. The mean cumulative extents of exposure to teduglutide for patients who completed both the core and the extension study treatments were 54.3 ± 1.7 and 12.7 ± 1.0 months for patients from TED-C14-004 and SHP633-306, respectively. | PMC9950205 | ||
Efficacy | Crohn’s disease, teduglutidePatients |
Short-term treatment with teduglutideThe first 24 weeks of treatment with teduglutide were considered short-term use.Change in PS requirementsA reduction in weekly PS volume of ≥ 20% from baseline at both weeks 20 and 24 was achieved by 9 of 18 patients (50%) (5 of 11 patients [45.5%] in TED-C14-004 and 4 of 7 patients [57.1%] in SHP633-306). At 24 weeks, the PS volume decreased from baseline by 4.9 ± 4.8 L/week (−30.1% ± 25.9%; Change in plasma citrulline levelAt 24 weeks, the level of plasma citrulline increased from baseline by 15.0 ± 17.4 µM (86.9% ± 112.3%, Urine outputAt 24 weeks, the 48 h urine output increased from a baseline of 2933.0 ± 563.0 mL/day (Long-term treatment with teduglutidePatients who participated in TED-C14-004 received up to 30 months of treatment. By the interim cut-off point of the extension study (SHP633-307), patients from SHP633-306 and TED-C14-004 received a maximum of 14 and 57 months of treatment, respectively.Change in PS requirementsAll patients who participated in the extension study following SHP633-306 maintained ≥ 20% reduction from baseline at each scheduled visit to the last visit before the data cut-off. After 30 months of treatment, 6 of 7 patients (85.7%) in TED-C14-004 achieved ≥ 20% reduction in weekly PS volume from baseline. By the end of TED-C14-004, all patients had achieved ≥ 20% reduction in weekly PS volume, which was maintained to the last visit before the data cut-off in the extension study.Reductions in PS volume continued with long-term treatment with teduglutide. Patients from SHP633-306 had notable and progressive reductions in PS from baseline; at 12 months, the PS volume had decreased by 7.3 ± 6.5 L/week (−51.6% ± 28.5%; In TED-C14-004, 2 of 8 patients (25%) achieved enteral autonomy by 30 months of treatment. Both had Crohn’s disease recorded as the reason for small bowel resection, an ileostomy, no remaining colon, and a remaining small intestinal length of 100 cm in one and 120 cm in the other. Furthermore, both remained off PS throughout SHP633-307 until its interim data cut-off. During SHP633-307, 1 patient from SHP633-306 almost achieved enteral autonomy at the interim data cut-off point, which occurred 14 months after this patient had begun treatment. Based on diary data, this individual received 0.5 L/day of PS for 2 days/week during the 2 weeks prior to their visit at month 14, but did not receive PS during the 7 days following this visit.Change in plasma citrulline levelThe levels of plasma citrulline continued to increase with long-term treatment, showing an increase of 13.0 ± 5.6 µM (79.1% ± 33.5%) from baseline for patients from SHP633-306 at the interim cut-off of the extension study (Online Resource 2). For patients in TED-C14-004, the plasma citrulline level continued to increase through 24 months of treatment and plateaued thereafter. After 30 months of treatment, the increase from baseline was 28.3 ± 24.1 µM (135.0% ± 84.2%; Urine outputMean percent change in the PS volume from baseline up to 24 weeks (For patients who advanced to SHP633-307 from SHP633-306, further increases from baseline (1242.5 ± 374.1 mL/day; | PMC9950205 | |
Post hoc analyses of TED-C14-004 | Crohn’s disease | Post hoc analyses of TED-C14-004 were performed for both short- and long-term treatment of patients in this study. In the subgroup of patients with Crohn’s disease, the mean baseline PS volume requirement was 16.3 ± 8.4 L/week ( | PMC9950205 | |
PK analyses | In TED-C14-004, data for PK analyses were available for 8 patients (72.7%); teduglutide was undetectable in the plasma of the other 3 patients at all time points, most likely because of dosing errors (improved training of patients or caregivers to administer teduglutide was then implemented in SHP633-306 and SHP633-307). PK analyses of teduglutide showed that a CPatients in SHP633-307 from TED-C14-004 achieved a C | PMC9950205 | ||
Safety | colon or gastrointestinal cancers | There were no clinically meaningful changes during any of the studies concerning the clinical laboratory measures, vital signs, body weight, BMI, or ECG findings. There were also no AEs related to growth of pre-existing polyps of the colon or gastrointestinal cancers observed during the studies. | PMC9950205 | |
Anti-teduglutide antibodies | hypersensitivity | HYPERSENSITIVITY, HYPERSENSITIVITY REACTION | At 24 weeks, 5 out of 14 patients (35.7%; Detection of anti-teduglutide antibodies from baseline to the interim data cut-off pointThe patient with the highest titer of anti-teduglutide antibodies (1:650 at month 12) had sustained reductions in PS volume at the time of the interim data cut-off (28.6% reduction in PS volume), and there were no signs of hypersensitivity. Among the 7 patients who tested positive for anti-teduglutide antibodies, 1 (14.3%) did not achieve a reduction in PS volume greater than 20% and discontinued treatment after week 24; this patient had a low titer of anti-teduglutide antibodies (1:20) at week 24. Overall, no association with AEs of hypersensitivity or teduglutide-related hypersensitivity reaction was observed among the patients in whom anti-teduglutide antibodies were detected. Furthermore, no association between anti-teduglutide antibodies and a lack of efficacy was observed. | PMC9950205 |
Discussion | DISEASE, DISEASE CHARACTERISTIC | Teduglutide is the first and only GLP-2 analogue currently available worldwide for treatment of SBS-IF [The efficacy and safety profile of teduglutide observed in Japanese patients was generally consistent across these studies as well as with the previously reported values in pivotal multinational STEPS studies [As well as differing in disease characteristics, patients in these studies were all Japanese, whereas those who participated in the STEPS international phase III studies conducted in Europe and North America were mostly Caucasian. Differences in race or ethnicities can result in variabilities in the efficacy, PK, and/or safety of some therapies; these variations can be attributed to differences in certain aspects, such as physiological and socio-cultural factors [The PK data overall were consistent with expected values for teduglutide [Generally, anti-drug antibodies can reduce the efficacy of drugs as well as cause AEs in patients, resulting in such treatments not being a viable option for patients [Limitations associated with these current studies include the small population size and the homogeneity of the population disease etiology, which are a result of the rarity of the condition of focus. The studies lacked a comparator arm, so the possibility cannot be ruled out that reductions in PS might be affected partially by spontaneous intestinal adaptation. However, a period of PS stabilization was required before enrollment, and patients in our studies had been diagnosed with SBS-IF for many years (over 5 years on average) prior to enrollment, well past the expected period of spontaneous adaptation after intestinal resection [ | PMC9950205 | |
Conclusion | In adult Japanese patients with SBS-IF, treatment with teduglutide 0.05 mg/kg SC once daily elicited clinically meaningful reductions in PS requirements. Teduglutide was quickly absorbed and did not accumulate following multiple doses. The effects of teduglutide continued during long-term treatment. No new safety concerns were identified within these short- and long-term studies. These three studies demonstrate that adult Japanese patients with SBS-IF benefit from short- and long-term treatment with teduglutide in a similar manner to patients from North America and Europe. Anti-teduglutide antibody titers, if developed, generally declined to undetectable levels with long-term treatment. These results constitute the longest evaluation of teduglutide treatment within clinical trials reported to date. | PMC9950205 | ||
Author contributions | All authors contributed to the conception and design of the research and to the analysis and interpretation of the data. All authors critically revised the manuscript, agreed to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript. | PMC9950205 | ||
Funding | The clinical trials were funded by Shire Human Genetic Therapies, Inc., a Takeda company (Cambridge, MA, USA). The sponsor of the studies participated in the study design, data collection, data analysis, data interpretation, and review and approval of the final clinical study reports and provided the study drug. | PMC9950205 | ||
Data availability | The datasets generated are not publicly available due to the limited number of study participants, such that there is a reasonable likelihood of re-identification of individual patients. | PMC9950205 | ||
Declarations | PMC9950205 | |||
Conflict of interest | S.N. received Honoraria from Mitsubishi Tanabe Pharma, EA Pharma Co., Ltd., Janssen Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and AbbVie Inc., and has received research funding from Mitsubishi Tanabe Pharma. M.W. received research funding from Shire, a Takeda company. T.M. received research funding from Shire International GmbH, Takeda Pharmaceuticals; Asahi Kasei Pharma; Taiho Pharmaceutical; Chugai Pharmaceutical; Yakult Honsha; Eli Lilly Japan; Ono Pharmaceutical; Sanofi; Kaken Pharmaceutical; and Mitsubishi Tanabe Pharma; and holds a chair endowed by Kinshukai Medical Corporation. E.U. and R.K.S. are employees of Takeda Pharmaceutical Company Limited, Tokyo, Japan. M.Y. and S.C. are employees of Takeda Pharmaceutical Company, Cambridge, MA, USA. A.G. was a former employee of Shire Human Genetic Therapies, Inc., a Takeda company, MA, USA. A.S., Y.T., H.O., and H.I. have no conflicts to disclose. | PMC9950205 | ||
Ethical approval | RECRUITMENT | These studies were performed in accordance with the World Medical Association Declaration of Helsinki and applicable laws and standards of good clinical practice in Japan. The study protocols, any protocol amendments, the final approved informed consent documents, relevant supporting information, and all types of patient recruitment information were approved by the institutional review boards of Hospital of Hyogo College of Medicine, Osaka University Hospital, Yokohama Municipal Citizen’s Hospital | PMC9950205 | |
References | PMC9950205 | |||
1. Introduction | fatigue, PLF, impaired judgment [Until now, collecting a small, hypoglycemia, irritability | HYPOGLYCEMIA, BLOOD | This study examined the effects of continuous carbohydrate intake during a golf round on interstitial glucose, golf performance, and the cognitive performance of competitive golfers. Eleven competitive golfers participated and played 18 holes of golf in this study. Participants were randomly assigned to the group indicated to consume the test food (CHO intake) or the group required to not consume it (NOT intake). Here, gummies were used as the test food, and the amount of carbohydrates was 30 g per h. Blood glucose levels were evaluated using interstitial glucose. Golf performance was measured in five tests, including scores, 2.5 m putting test, club head speed, driving distance, and accuracy. Cognitive performance was measured in three tests, including self-perceived levels of fatigue (PLF), self-perceived levels of concentration (PLC), and self-perceived levels of relaxation (PLR). Interstitial glucose (Golf is reported to be a moderate-intensity sport with a physical activity level of 4.8 METs, with an extended duration of 18 holes (a round) lasting anywhere from 4 to 5 h while covering distances over 10 km [The American College of Sports Medicine (ACSM) recommends endurance athletes to engage in exercise longer than 1 h and ingest carbohydrates at a rate of 30–60 g per hour to maintain carbohydrate oxidation and delay fatigue [Research indicates that hypoglycemia during golf can lead to concentration loss, irritability, impaired judgment [Until now, collecting a small amount of capillary blood from the fingertip by puncture is a simple method of measuring blood glucose during exercise. Therefore, this measurement method is not possible in ongoing golf play. To solve this problem, continuous glucose monitoring (CGM) for blood glucose measurement was employed in this study. These CGM systems can be easily worn on the body and can automatically and constantly measure the glucose concentration in the interstitial fluid. The glucose concentration in the interstitial fluid of the subcutaneous tissue closely correlates with the glucose concentration in the blood [This study aimed to examine the effects of continuous carbohydrate intake during a golf round on interstitial glucose, golf performance, and the cognitive performance of healthy male competitive golfers. The hypothesis is that continuous carbohydrate intake will attenuate the decline in interstitial glucose level and cognitive performance and improve golf performance. | PMC10384188 |
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