Pragmaticism in Cancer Clinical Trials.

Clinical trials are essential for advancing oncology treatment strategies and have contributed significantly to the decline in cancer mortality rates over the past decades. Traditional explanatory trials, focused on establishing intervention efficacy in ideal settings, often lack generalizability and may not reflect real-world patient care scenarios. Furthermore, increasing complexity in cancer clinical trial design has led to challenges such as protocol deviations, slow enrollment leading to lengthened durations of trial, and escalating costs. By contrast, pragmatic trials aim to assess intervention effectiveness in more representative patient populations under routine clinical conditions. Here, we review the principles, methodologies, challenges, and advantages of incorporating pragmatic features (PFs) into cancer clinical trials. We illustrate the application of pragmatic trial designs in oncology and discuss the QUASAR collaborative, TAPUR study, and the ongoing PRAGMATICA-LUNG trial. Although not all oncology trials may be amenable to adopting fully pragmatic designs, integration of PFs when feasible will enhance trial generalizability and real-world applicability. Project Pragmatica and similar initiatives advocate for the integration of real-world practice with clinical trials, fostering a nuanced approach to oncology research that balances efficacy and effectiveness assessments, ultimately with a goal of improving patient outcomes.

SurLym trial: study protocol for a multicentre pragmatic randomised controlled trial on the added value of reconstructive lymphatic surgery to decongestive lymphatic therapy for the treatment of lymphoedema.

INTRODUCTION: Lymphoedema is a chronic condition caused by lymphatic insufficiency. It leads to swelling of the limb/midline region and an increased risk of infection. Lymphoedema is often associated with mental and physical problems limiting quality of life. The first choice of treatment is a conservative treatment, consisting of exercises, skin care, lymph drainage and compression. Reconstructive lymphatic surgery is also often performed, that is, lymphovenous anastomoses, lymph node transfer or a combination. However, robust evidence on the effectiveness of reconstructive lymphatic surgery is missing. Therefore, the objective of this trial is to investigate the added value of reconstructive lymphatic surgery to the conservative treatment in patients with lymphoedema. METHODS AND ANALYSIS: A multicentre randomised controlled and pragmatic trial was started in March 2022 in three Belgian university hospitals. 90 patients with arm lymphoedema and 90 patients with leg lymphoedema will be included. All patients are randomised between conservative treatment alone (control group) or conservative treatment with reconstructive lymphatic surgery (intervention group). Assessments are performed at baseline and at 1, 3, 6, 12, 18, 24 and 36 months. The primary outcome is lymphoedema-specific quality of life at 18 months. Key secondary outcomes are limb volume and duration of wearing the compression garment at 18 months. The approach of reconstructive lymphatic surgery is based on presurgical investigations including clinical examination, lymphofluoroscopy, lymphoscintigraphy, lymph MRI or CT angiography (if needed). All patients receive conservative treatment during 36 months, which is applied by the patient's own physical therapist and by the patient self. From months 7 to 12, the hours a day of wearing the compression garment are gradually decreased. ETHICS AND DISSEMINATION: The study has been approved by the ethical committees of University Hospitals Leuven, Ghent University Hospital and CHU UCL Namur. Results will be disseminated via peer-reviewed journals and presentations. TRIAL REGISTRATION NUMBER: NCT05064176.

Flexor Injury Rehabilitation Splint Trial (FIRST): protocol for a pragmatic randomised controlled trial comparing three splints for finger flexor tendon repairs.

BACKGROUND: Without surgical repair, flexor tendon injuries do not heal and patients' ability to bend fingers and grip objects is impaired. However, flexor tendon repair surgery also requires optimal rehabilitation. There are currently three custom-made splints used in the rehabilitation of zone I/II flexor tendon repairs, each with different assumed harm/benefit profiles: the dorsal forearm and hand-based splint (long), the Manchester short splint (short), and the relative motion flexion splint (mini). There is, however, no robust evidence as to which splint, if any, is most clinical or cost effective. The Flexor Injury Rehabilitation Splint Trial (FIRST) was designed to address this evidence gap. METHODS: FIRST is a parallel group, superiority, analyst-blind, multi-centre, individual participant-randomised controlled trial. Participants will be assigned 1:1:1 to receive either the long, short, or mini splint. We aim to recruit 429 participants undergoing rehabilitation following zone I/II flexor tendon repair surgery. Potential participants will initially be identified prior to surgery, in NHS hand clinics across the UK, and consented and randomised at their splint fitting appointment post-surgery. The primary outcome will be the mean post-randomisation score on the patient-reported wrist and hand evaluation measure (PRWHE), assessed at 6, 12, 26, and 52 weeks post randomisation. Secondary outcome measures include blinded grip strength and active range of movement (AROM) assessments, adverse events, adherence to the splinting protocol (measured via temperature sensors inserted into the splints), quality of life assessment, and further patient-reported outcomes. An economic evaluation will assess the cost-effectiveness of each splint, and a qualitative sub-study will evaluate participants' preferences for, and experiences of wearing, the splints. Furthermore, a mediation analysis will determine the relationship between patient preferences, splint adherence, and splint effectiveness. DISCUSSION: FIRST will compare the three splints with respect to clinical efficacy, complications, quality of life and cost-effectiveness. FIRST is a pragmatic trial which will recruit from 26 NHS sites to allow findings to be generalisable to current clinical practice in the UK. It will also provide significant insights into patient experiences of splint wear and how adherence to splinting may impact outcomes. TRIAL REGISTRATION: ISRCTN: 10236011.

Effectiveness of a community-based multicomponent lifestyle intervention (the ADA programme) to improve the quality of life of French breast cancer survivors: protocol for a pragmatic cluster randomised trial and embedded qualitative study.

INTRODUCTION: Breast cancer survivors (BCSs) are often faced with multiple mental and physical sequelae and are at increased risk of emotional distress, degraded health-related quality of life (HRQoL), chronic pain and fatigue.Physical activity is strongly associated with improved HRQoL and survival rates; however, adherence rates to recommendations for a healthy lifestyle are seldom satisfactory among BCSs. Also, few studies have examined the effectiveness of multicomponent and personalised interventions that integrate physical activity and motivational techniques to improve the HRQoL of BCS. METHOD AND ANALYSIS: "Activité physique adaptée Doublée d'un Accompagnement d'après cancer" (ADA) is an integrated programme of physical activity enriched with a dietary and supportive care approach targeting BCS in the early post-treatment phase. The effectiveness of the ADA intervention will be evaluated using a cluster randomised controlled trial design with two arms (ADA programme vs usual care; 1:1 ratio).The ADA intervention aims to recruit 160 participants and will be implemented by Siel Bleu, a non-profit association specialised in health prevention via adapted physical activity. Measurements will be performed at baseline, 3, 6 and 12 months after the start of the intervention. The primary outcome will be participants' HRQoL, at 12 months measured by the Functional Assessment of Chronic Illness Therapy-Fatigue global score. Secondary outcome will include participants' physical, social, emotional and functional well-being. The effect of the intervention on physical activity level, motivation for physical activity, relation to food and self-efficacy will also be evaluated. ETHICS AND DISSEMINATION: The study was approved by the 'CPP Paris XI' Institutional Review Board on 5 May 2022 (Ref no.: 21.04512.000048-22004). The study's findings will be shared through various channels, including academic publications, simplified reports for wider audiences and active engagement with medical and institutional organisations as well as patients' associations. TRIAL REGISTRATION NUMBER: NCT05658341.

Strategies for secondary use of real-world clinical and administrative data for outcome ascertainment in pragmatic clinical trials.

BACKGROUND: Pragmatic trials are gaining popularity as a cost-effective way to examine treatment effectiveness and generate timely comparative evidence. Incorporating supplementary real-world data is recommended for robust outcome monitoring. However, detailed operational guidelines are needed to inform effective use and integration of heterogeneous databases. OBJECTIVE: Lessons learned from the Veterans Affairs (VA) Diuretic Comparison Project (DCP) are reviewed, providing adaptable recommendations to capture clinical outcomes from real-world data. METHODS: Non-cancer deaths and major cardiovascular (CV) outcomes were determined using VA, Medicare, and National Death Index (NDI) data. Multiple ascertainment strategies were applied, including claims-based algorithms, natural language processing, and systematic chart review. RESULTS: During a mean follow-up of 2.4 (SD = 1.4) years, 907 CV events were identified within the VA healthcare system. Slight delays (∼1 year) were expected in obtaining Medicare data. An additional 298 patients were found having a CV event outside of the VA in 2016 - 2021, increasing the CV event rate from 3.5 % to 5.7 % (770 of 13,523 randomized). NDI data required âˆ¼2 years waiting period. Such inclusion did not increase the number of deaths identified (all 894 deaths were captured by VA data) but enhanced the accuracy in determining cause of death. CONCLUSION: Our experience supports the recommendation of integrating multiple data sources to improve clinical outcome ascertainment. While this approach is promising, hierarchical data aggregation is required when facing different acquisition timelines, information availability/completeness, coding practice, and system configurations. It may not be feasible to implement comparable applications and solutions to studies conducted under different constraints and practice. The recommendations provide guidance and possible action plans for researchers who are interested in applying cross-source data to ascertain all study outcomes.

Practical Guide to Pragmatic Clinical Trials in Surgical Education Research.

This Guide to Statistics and Methods provides an overview of the key features of pragmatic trials within the context of surgical education research using examples from the Flexibility in Duty-Hour Requirements for Surgical Trainees trial.

Bridging research gaps in geriatric oncology: unraveling the potential of pragmatic clinical trials.

PURPOSE OF REVIEW: This review examines the role of pragmatic clinical trials (PCTs) in addressing the underrepresentation of older adults with cancer (OAC) in clinical trials. Focusing on real-world evidence (RWE), it aims to provide a comprehensive overview of PCT utilization, emphasizing their potential to enhance treatment decisions and patient outcomes. Existing knowledge gaps in PCT implementation are also discussed. RECENT FINDINGS: PCTs are identified as effective tools to include OACs with comorbidities and complex conditions in research, bridging the representation gap. Despite their proven value in healthcare provision, their application in OAC contexts remains limited, hindering comprehensive understanding and inclusivity in clinical trials. SUMMARY: While randomized controlled trials (RCTs) are considered the gold standard in oncology research, OACs have historically been excluded, perpetuating underrepresentation. Furthermore, even in current oncology clinical development trials, this demographic continues to be underrepresented. PCTs offer a valuable avenue for the identification and evaluation of therapies within authentic RW contexts, encompassing various healthcare settings, such as hospitals, clinics, and physician practices. RCTs and PCTs complement one another, and the utilization of PCTs has the potential to inform clinical decision-making across the OACs entire treatment trajectory.

Effectiveness of general anaesthesia with remimazolam tosilate on intraoperative haemodynamics and postoperative recovery: study protocol for a randomised, positive-controlled, pragmatic clinical trial (GARTH trial).

INTRODUCTION: It is encouraged to estimate the effectiveness of components within the enhanced recovery after surgery (ERAS) protocol through patient-reported outcomes, alongside doctor-reported outcomes and length of hospital stay. At present, studies on the contributions of optimal anaesthetic drugs within the ERAS protocol to patient-reported and doctor-reported outcomes are limited. Therefore, this study aims to pragmatically evaluate the effectiveness and safety of general anaesthesia (GA) with remimazolam tosilate within the ERAS protocol on intraoperative haemodynamics and postoperative recovery in adults undergoing elective surgeries, compared with propofol. METHODS AND ANALYSIS: This study is a single-centre, randomised, blinded, positive-controlled, pragmatic clinical trial. A total of 900 patients, aged ≥18 years old, scheduled for an elective surgical procedure under GA will be included. Patients will be randomised in a 1:1 ratio to the remimazolam group (the GA with remimazolam tosilate within the ERAS protocol group) or propofol group (the GA with propofol within the ERAS protocol group), stratified by general surgery, thoracic surgery and other surgeries (including urological surgery and otolaryngology surgery). The primary outcomes include the 24-hour postoperative quality of recovery-40 score and the rate of intraoperative hypotension. Secondary endpoints include the rate of sedative hypotension requiring treatment, the haemodynamic profiles, the 72-hour postoperative quality of recovery-40 score, the functional anaesthetic capability, adverse events and complications, quality of life within 3 months as well as economic health outcomes. ETHICS AND DISSEMINATION: This study protocol has been approved by the ethics committee of Guangdong Provincial People's Hospital (KY-H-2022-005-03-08). Dissemination plans will be presented at scientific meetings and in scientific publications. TRIAL REGISTRATION NUMBER: ChiCTR2200062520.

Protocol of the Comparison of Intravesical Therapy and Surgery as Treatment Options (CISTO) study: a pragmatic, prospective multicenter observational cohort study of recurrent high-grade non-muscle invasive bladder cancer.

BACKGROUND: Bladder cancer poses a significant public health burden, with high recurrence and progression rates in patients with non-muscle-invasive bladder cancer (NMIBC). Current treatment options include bladder-sparing therapies (BST) and radical cystectomy, both with associated risks and benefits. However, evidence supporting optimal management decisions for patients with recurrent high-grade NMIBC remains limited, leading to uncertainty for patients and clinicians. The CISTO (Comparison of Intravesical Therapy and Surgery as Treatment Options) Study aims to address this critical knowledge gap by comparing outcomes between patients undergoing BST and radical cystectomy. METHODS: The CISTO Study is a pragmatic, prospective observational cohort trial across 36 academic and community urology practices in the US. The study will enroll 572 patients with a diagnosis of recurrent high-grade NMIBC who select management with either BST or radical cystectomy. The primary outcome is health-related quality of life (QOL) at 12 months as measured with the EORTC-QLQ-C30. Secondary outcomes include bladder cancer-specific QOL, progression-free survival, cancer-specific survival, and financial toxicity. The study will also assess patient preferences for treatment outcomes. Statistical analyses will employ targeted maximum likelihood estimation (TMLE) to address treatment selection bias and confounding by indication. DISCUSSION: The CISTO Study is powered to detect clinically important differences in QOL and cancer-specific survival between the two treatment approaches. By including a diverse patient population, the study also aims to assess outcomes across the following patient characteristics: age, gender, race, burden of comorbid health conditions, cancer severity, caregiver status, social determinants of health, and rurality. Treatment outcomes may also vary by patient preferences, health literacy, and baseline QOL. The CISTO Study will fill a crucial evidence gap in the management of recurrent high-grade NMIBC, providing evidence-based guidance for patients and clinicians in choosing between BST and radical cystectomy. The CISTO study will provide an evidence-based approach to identifying the right treatment for the right patient at the right time in the challenging clinical setting of recurrent high-grade NMIBC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03933826. Registered on May 1, 2019.

Protocol to evaluate sequential electronic health record-based strategies to increase genetic testing for breast and ovarian cancer risk across diverse patient populations in gynecology practices.

BACKGROUND: Germline genetic testing is recommended by the National Comprehensive Cancer Network (NCCN) for individuals including, but not limited to, those with a personal history of ovarian cancer, young-onset (< 50 years) breast cancer, and a family history of ovarian cancer or male breast cancer. Genetic testing is underused overall, and rates are consistently lower among Black and Hispanic populations. Behavioral economics-informed implementation strategies, or nudges, directed towards patients and clinicians may increase the use of this evidence-based clinical practice. METHODS: Patients meeting eligibility for germline genetic testing for breast and ovarian cancer will be identified using electronic phenotyping algorithms. A pragmatic cohort study will test three sequential strategies to promote genetic testing, two directed at patients and one directed at clinicians, deployed in the electronic health record (EHR) for patients in OB-GYN clinics across a diverse academic medical center. We will use rapid cycle approaches informed by relevant clinician and patient experiences, health equity, and behavioral economics to optimize and de-risk our strategies and methods before trial initiation. Step 1 will send patients messages through the health system patient portal. For non-responders, step 2 will reach out to patients via text message. For non-responders, Step 3 will contact patients' clinicians using a novel "pend and send" tool in the EHR. The primary implementation outcome is engagement with germline genetic testing for breast and ovarian cancer predisposition, defined as a scheduled genetic counseling appointment. Patient data collected through the EHR (e.g., race/ethnicity, geocoded address) will be examined as moderators of the impact of the strategies. DISCUSSION: This study will be one of the first to sequentially examine the effects of patient- and clinician-directed strategies informed by behavioral economics on engagement with breast and ovarian cancer genetic testing. The pragmatic and sequential design will facilitate a large and diverse patient sample, allow for the assessment of incremental gains from different implementation strategies, and permit the assessment of moderators of strategy effectiveness. The findings may help determine the impact of low-cost, highly transportable implementation strategies that can be integrated into healthcare systems to improve the use of genomic medicine. TRIAL REGISTRATION: ClinicalTrials.gov. NCT05721326. Registered February 10, 2023. https://www. CLINICALTRIALS: gov/study/NCT05721326.

A Multilevel Primary Care Intervention to Improve Follow-Up of Overdue Abnormal Cancer Screening Test Results: A Cluster Randomized Clinical Trial.

Importance: Realizing the benefits of cancer screening requires testing of eligible individuals and processes to ensure follow-up of abnormal results. Objective: To test interventions to improve timely follow-up of overdue abnormal breast, cervical, colorectal, and lung cancer screening results. Design, Setting, and Participants: Pragmatic, cluster randomized clinical trial conducted at 44 primary care practices within 3 health networks in the US enrolling patients with at least 1 abnormal cancer screening test result not yet followed up between August 24, 2020, and December 13, 2021. Intervention: Automated algorithms developed using data from electronic health records (EHRs) recommended follow-up actions and times for abnormal screening results. Primary care practices were randomized in a 1:1:1:1 ratio to (1) usual care, (2) EHR reminders, (3) EHR reminders and outreach (a patient letter was sent at week 2 and a phone call at week 4), or (4) EHR reminders, outreach, and navigation (a patient letter was sent at week 2 and a navigator outreach phone call at week 4). Patients, physicians, and practices were unblinded to treatment assignment. Main Outcomes and Measures: The primary outcome was completion of recommended follow-up within 120 days of study enrollment. The secondary outcomes included completion of recommended follow-up within 240 days of enrollment and completion of recommended follow-up within 120 days and 240 days for specific cancer types and levels of risk. Results: Among 11 980 patients (median age, 60 years [IQR, 52-69 years]; 64.8% were women; 83.3% were White; and 15.4% were insured through Medicaid) with an abnormal cancer screening test result for colorectal cancer (8245 patients [69%]), cervical cancer (2596 patients [22%]), breast cancer (1005 patients [8%]), or lung cancer (134 patients [1%]) and abnormal test results categorized as low risk (6082 patients [51%]), medium risk (3712 patients [31%]), or high risk (2186 patients [18%]), the adjusted proportion who completed recommended follow-up within 120 days was 31.4% in the EHR reminders, outreach, and navigation group (n = 3455), 31.0% in the EHR reminders and outreach group (n = 2569), 22.7% in the EHR reminders group (n = 3254), and 22.9% in the usual care group (n = 2702) (adjusted absolute difference for comparison of EHR reminders, outreach, and navigation group vs usual care, 8.5% [95% CI, 4.8%-12.0%], P < .001). The secondary outcomes showed similar results for completion of recommended follow-up within 240 days and by subgroups for cancer type and level of risk for the abnormal screening result. Conclusions and Relevance: A multilevel primary care intervention that included EHR reminders and patient outreach with or without patient navigation improved timely follow-up of overdue abnormal cancer screening test results for breast, cervical, colorectal, and lung cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03979495.

Analysis of the characteristics and the degree of pragmatism exhibited by pragmatic-labelled trials of antineoplastic treatments.

BACKGROUND: Pragmatic clinical trials (PCTs) are designed to reflect how an investigational treatment would be applied in clinical practice. As such, unlike their explanatory counterparts, they measure therapeutic effectiveness and are capable of generating high-quality real-world evidence. However, the conduct of PCTs remains extremely rare. The scarcity of such studies has contributed to the emergence of the efficacy-effectiveness gap and has led to calls for launching more of them, including in the field of oncology. This analysis aimed to identify self-labelled pragmatic trials of antineoplastic interventions and to evaluate whether their use of this label was justified. METHODS: We searched PubMed® and Embase® for publications corresponding with studies that investigated antitumor therapies and that were tagged as pragmatic in their titles, abstracts and/or index terms. Subsequently, we consulted all available source documents for the included trials and extracted relevant information from them. The data collected were then used to appraise the degree of pragmatism displayed by the PCTs with the help of the validated PRECIS-2 tool. RESULTS: The literature search returned 803 unique records, of which 46 were retained upon conclusion of the screening process. This ultimately resulted in the identification of 42 distinct trials that carried the 'pragmatic' label. These studies examined eight different categories of neoplasms and were mostly randomized, open-label, multicentric, single-country trials sponsored by non-commercial parties. On a scale of one (very explanatory) to five (very pragmatic), the median PCT had a PRECIS-2 score per domain of 3.13 (interquartile range: 2.57-3.53). The most and least pragmatic studies in the sample had a score of 4.44 and 1.57, respectively. Only a minority of trials were described in sufficient detail to allow them to be graded across all domains of the PRECIS-2 instrument. Many of the studies examined also had features that arguably precluded them from being pragmatic altogether, such as being monocentric or placebo-controlled in nature. CONCLUSION: PCTs of antineoplastic treatments are generally no more pragmatic than they are explanatory.

Efficacy and safety of different antimicrobial DURATions for the treatment of Infections associated with Osteosynthesis Material implanted after long bone fractures (DURATIOM): Protocol for a randomized, pragmatic trial.

BACKGROUND: Infection associated with osteosynthesis material (IOM) is one of the most feared and challenging complications of trauma surgery and can cause significant functional loss, requiring multiple interventions and excessive consumption of antimicrobials. Evidence is needed about the best surgical procedure and the duration of antibiotic treatment according to the age of the implant or onset of infection symptoms, as it considers the biofilm formation and the state of fracture healing. There were not clinical trials evaluating the optimal duration of antibiotic therapy in IOM when implant is retained. Because there are antibiotics that have proven to be effective for the treatment of infection associated to implant, mainly in PJI, these antibiotics could be used in these infections. Investigating whether shorter duration of treatment is a priority in infectious diseases, as a way to reduce the exposure to antibiotics and help in controlling antimicrobial resistance and avoiding unnecessary adverse events and cost. We aim to describe the hypothesis, objectives, design, variables and procedures for a pragmatic randomized controlled trial comparing different durations of antibiotic treatment in IOM after long bone fractures treated with debridement and implant retention. METHODS AND DESIGN: This is a multicenter, open-label, non-inferiority, randomized, controlled, pragmatic phase 3 trial, comparing different durations of antibiotic treatment in IOM after long bone fractures treated with debridement and implant retention. Patients with microbiologically confirmed IOM will be included. Eligible patients are those older than 14 years, with early IOM (up to 2 weeks after the implant surgery) and delayed IOM (between 3 and 10 weeks after the implant surgery) with stabilized fracture and absence of bone exposure who sign the informed consent. Randomization will be 1:1 to receive a short-term antibiotic treatment (8 weeks in early IOM and 12 weeks in delayed IOM) or a long-term antibiotic treatment (12 weeks in early IOM or until fracture healing or implant removal in delayed IOM). The antibiotic treatment will be that used in routine practice by the specialist in infectious diseases. The primary outcome is the composited variable "cure" that includes clinical cure, radiological healing, and definitive soft tissue coverage, which will be evaluated in the test of cure at 12 months after the end of antibiotic therapy. Adverse events, resistance development during therapy and functional status will be collected. A total of 364 patients are needed to show a 10% non-inferiority margin, with 80% power and 5% one-sided significance level. DISCUSSION: If the hypothesis of non-inferiority of short vs. long antibiotic treatments is demonstrated, and the efficacy of antibiotics with less ecological impact in long treatments, the impact on reduction of bacterial resistance, toxicity and health costs will be observed. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT05294796) on Jan 26th 2022 and at the European Union Drug Regulating Authorities Clinical Trials (EUDRACT) (2021-003914-38) on Jul 16th 2021. The Sponsor Study Code is DURATIOM.

An anesthesia-centered bundle to reduce postoperative pulmonary complications: The PRIME-AIR study protocol.

BACKGROUND: Postoperative pulmonary complications (PPCs) are a major cause of morbidity and mortality after open abdominal surgery. Optimized perioperative lung expansion may minimize the synergistic factors responsible for the multiple-hit perioperative pulmonary dysfunction. This ongoing study will assess whether an anesthesia-centered bundle focused on perioperative lung expansion results in decreased incidence and severity of PPCs after open abdominal surgery. METHODS: Prospective multicenter randomized controlled pragmatic trial in 750 adult patients with at least moderate risk for PPCs undergoing prolonged (≥2 hour) open abdominal surgery. Participants are randomized to receive either a bundle intervention focused on perioperative lung expansion or usual care. The bundle intervention includes preoperative patient education, intraoperative protective ventilation with individualized positive end-expiratory pressure to maximize respiratory system compliance, optimized neuromuscular blockade and reversal management, and postoperative incentive spirometry and early mobilization. Primary outcome is the distribution of the highest PPC severity by postoperative day 7. Secondary outcomes include the proportion of participants with: PPC grades 1-2 through POD 7; PPC grades 3-4 through POD 7, 30 and 90; intraoperative hypoxemia, rescue recruitment maneuvers, or cardiovascular events; and any major extrapulmonary postoperative complications. Additional secondary and exploratory outcomes include individual PPCs by POD 7, length of postoperative oxygen therapy or other respiratory support, hospital resource use parameters, Patient-Reported Outcomes Measurements (PROMIS®) questionnaires for dyspnea and fatigue collected before and at days 7, 30 and 90 after surgery, and plasma concentrations of lung injury biomarkers (IL6, IL-8, RAGE, CC16, Ang-2) analyzed from samples obtained before, end of, and 24 hours after surgery. DISCUSSION: Participant recruitment for this study started January 2020; results are expected in 2024. At the conclusion of this trial, we will determine if this anesthesia-centered strategy focused on perioperative lung expansion reduces lung morbidity and healthcare utilization after open abdominal surgery. TRIAL REGISTRATION: ClinicalTrial.gov NCT04108130.

Effect of Fu's subcutaneous needling for cancer pain management: protocol for a pragmatic randomised controlled trial.

INTRODUCTION: Pain is a common symptom in patients with cancer, and pain management is crucial for these patients. Fu's subcutaneous needling (FSN) is a modern acupuncture therapy based on basic medicine commonly used in patients with pain. However, evidence of its effectiveness in treating cancer pain has not been systematically proven. Therefore, this pragmatic randomised controlled trial aims to evaluate the effectiveness and safety of FSN for cancer pain management. METHODS AND ANALYSIS: Overall, 120 eligible patients will be recruited and randomly assigned into two groups using block randomisation. Both groups will be administered analgesic drugs according to the National Comprehensive Cancer Network guidelines. The treatment group will receive FSN therapy one time a day for 6 days. Additionally, we will assess analgesic consumption as the primary outcome and the Numerical Rating Scale, outbreak pain, symptom assessment and adverse events as secondary outcomes to evaluate the effect and safety of FSN in treating cancer pain. The incidence of adverse events will be monitored to assess the safety of FSN. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (approval No: K(2021)096). The results will be published in a peer-reviewed journal, and trial participants will be informed via email and/or phone calls. TRIAL REGISTRATION NUMBER: ChiCTR2200056348.

Feasibility and first results of the 'Trials-within-Cohorts' (TwiCs) design in patients undergoing radiotherapy for lung cancer.

Background: 'Trials-within-Cohorts' (TwiCs), previously known as 'cohort multiple randomized controlled trials' is a pragmatic trial design, supporting an efficient and representative recruitment of patients for (future) trials. To our knowledge, the 'COhort for Lung cancer Outcome Reporting and trial inclusion' (COLOR) is the first TwiCs in lung cancer patients. In this study we aimed to assess the feasibility and first year results of COLOR.Material and Methods: All patients diagnosed with lung cancer referred to the Radiotherapy department were eligible to participate in the ongoing prospective COLOR study. At inclusion, written informed consent was requested for use of patient data, participation in patient-reported outcomes (PROs), and willingness to participate in (future) trials. Feasibility was studied by assessing participation and comparing baseline PROs to EORTC reference values. First-year results of PROs at baseline and 3 months after inclusion were evaluated separately for stereotactic body radiotherapy (SBRT) and conventional radiotherapy patients.Results: Of the 338 eligible patients between July 2020 and July 2021, 169 (50%) participated. Among these, 127 (75%) gave informed consent to PROs participation and 110 (65%) were willing to participate in (future) trials. The inclusion percentage dropped from 77% to 33% when the information procedure was switched from in-person to by phone (due to COVID-19 pandemic measures). Baseline PROs for physical and cognitive functioning were comparable in COLOR patients compared to the EORTC reference values. No significant changes in PROs were observed 3 months after inclusion, except for a slight increase in pain scores in the SBRT group (n = 97).Conclusions: The TwiCs-design appears feasible in lung cancer patients with fair participation rates (although negatively impacted by the COVID-19 pandemic). With a planned expansion to other centers, the COLOR-study is expected to enable multiple (randomized) evaluations of experimental interventions with important advantages for recruitment, generalizability, and long-term outcome data collection.

Acupuncture for chronic low back pain in older adults: Design and protocol for the BackInAction pragmatic clinical trial.

BACKGROUND: Back pain prevalence and burden increase with age; approximately one-third of U.S. adults 65 years of age and older experience lower back pain (LBP). For chronic low back pain (cLBP), typically defined as lasting three months or longer, many treatments for younger adults may be inappropriate for older adults given their greater prevalence of comorbidities with attendant polypharmacy. While acupuncture has been demonstrated to be safe and effective for cLBP in adults overall, few studies of acupuncture have either included or focused on adults ≥65 years old. METHODS: The BackInAction study is a pragmatic, multi-site, three-arm, parallel-groups randomized controlled trial designed to test the effectiveness of acupuncture needling for improving back pain-related disability among 807 older adults ≥65 years old with cLBP. Participants are randomized to standard acupuncture (SA; up to 15 treatment sessions across 12 weeks), enhanced acupuncture (EA; SA during first 12 weeks and up to 6 additional sessions across the following 12 weeks), and usual medical care (UMC) alone. Participants are followed for 12 months with study outcomes assessed monthly with the primary outcome timepoint at 6 months. DISCUSSION: The BackInAction study offers an opportunity to further understand the effectiveness, dose-dependence, and safety of acupuncture in a Medicare population. Additionally, study results may encourage broader adoption of more effective, safer, and more satisfactory options to the continuing over-reliance on opioid- and invasive medical treatments for cLBP among older adults. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04982315. Clinical trial registration date: July 29, 2021.

Biologic Abatement and Capturing Kids' Outcomes and Flare Frequency in Juvenile Spondyloarthritis (BACK-OFF JSpA): study protocol for a randomized pragmatic trial.

BACKGROUND: The effectiveness of biologic therapies, primarily tumor necrosis factor inhibitors (TNFi), for children with spondyloarthritis (SpA) has made inactive disease a realistic patient outcome. However, biologic therapies are costly, primarily delivered by subcutaneous or intravenous route, and have non-trivial side effects. Many patients and families want to know if biologic medications can be discontinued after inactive disease is achieved. It remains unclear whether medication dose should remain unchanged, tapered (increase the time between doses), or discontinued once when inactive disease is attained. METHODS: The Biologic Abatement and Capturing Kids' Outcomes and Flare Frequency in Juvenile SpA (BACK-OFF JSpA) trial is a multicenter pragmatic trial that will randomize 198 participants ages 8-21 years old with SpA and sustained inactive disease on standard TNFi dosing to (1) continue standard TNFi dosing, (2) fixed longer dosing intervals of TNFi, or (3) stop TNFi. The trial will compare the hazard rate of protocol-defined flare and participants' emotional health among the 3 groups over 12 months. Innovative aspects of this trial are the involvement of patient and parent stakeholders in the design and conduct of the study as well as an electronic health record-based enhanced recruitment strategy. DISCUSSION: This is the first randomized pragmatic trial to assess the efficacy of TNFi de-escalation strategies in children with JSpA with sustained inactive disease. This research will improve the evidence base that patients, caregivers, and rheumatologists use to make shared decisions about continued treatment versus de-escalation of TNFi therapy in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04891640. Registered on 18 May 2021.

Impact of a machine learning algorithm on time to palliative care in a primary care population: protocol for a stepped-wedge pragmatic randomized trial.

BACKGROUND: As primary care populations age, timely identification of palliative care need is becoming increasingly relevant. Previous studies have targeted particular patient populations with life-limiting disease, but few have focused on patients in a primary care setting. Toward this end, we propose a stepped-wedge pragmatic randomized trial whereby a machine learning algorithm identifies patients empaneled to primary care units at Mayo Clinic (Rochester, Minnesota, United States) with high likelihood of palliative care need. METHODS: 42 care team units in 9 clusters were randomized to 7 wedges, each lasting 42 days. For care teams in treatment wedges, palliative care specialists review identified patients, making recommendations to primary care providers when appropriate. Care teams in control wedges receive palliative care under the standard of care. DISCUSSION: This pragmatic trial therefore integrates machine learning into clinical decision making, instead of simply reporting theoretical predictive performance. Such integration has the possibility to decrease time to palliative care, improving patient quality of life and symptom burden. TRIAL REGISTRATION: Clinicaltrials.gov NCT04604457 , restrospectively registered 10/26/2020. PROTOCOL: v0.5, dated 9/23/2020.