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Clinical Trials (London, England) Jun 2024There is growing interest in using embedded research methods, particularly pragmatic clinical trials, to address well-known evidentiary shortcomings afflicting the...
There is growing interest in using embedded research methods, particularly pragmatic clinical trials, to address well-known evidentiary shortcomings afflicting the health care system. Reviews of pragmatic clinical trials published between 2014 and 2019 found that 8.8% were conducted with waivers of informed consent; furthermore, the number of trials where consent is obtained is increasing with time. From a regulatory perspective, waivers of informed consent are permissible when certain conditions are met, including that the study involves no more than minimal risk, that it could not practicably be carried out without a waiver, and that waiving consent does not violate participants' rights and welfare. Nevertheless, when research is conducted with a waiver of consent, several ethical challenges arise. We must consider how to: address empirical evidence showing that patients and members of the public generally prefer prospective consent, demonstrate respect for persons using tools other than consent, promote public trust and investigator integrity, and ensure an adequate level of participant protections. In this article, we use examples drawn from real pragmatic clinical trials to argue that prospective consultation with representatives of the target study population can address, or at least mitigate, many of the ethical challenges posed by waivers of informed consent. We also consider what consultation might involve to illustrate its feasibility and address potential objections.
PubMed: 38916109
DOI: 10.1177/17407745241259360 -
Journal of Korean Medical Science Jun 2024Currently, non-vitamin K-antagonist oral anticoagulant (NOAC) monotherapy has been suggested as the optimal antithrombotic therapy for atrial fibrillation (AF) beyond...
BACKGROUND
Currently, non-vitamin K-antagonist oral anticoagulant (NOAC) monotherapy has been suggested as the optimal antithrombotic therapy for atrial fibrillation (AF) beyond one year after coronary revascularization. The aim of this study was to compare the outcomes between NOAC monotherapy and NOAC plus antiplatelet combination therapy using real-world data.
METHODS
Between 2015 and 2020, patients with AF who had received NOACs beyond one year after coronary revascularization were enrolled from Korean national insurance data. We emulated a pragmatic sequence of trials between the NOAC monotherapy and the antiplatelet combination therapy followed by propensity score matching. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCEs), a composite of all-cause death, myocardial infarction, and stroke.
RESULTS
Among 206,407 person-trials from 4,465 individuals, we compared 3,275 pairs of the monotherapy and the matched combination therapy. During a median follow-up of 1.24 years, the incidence rate of MACCE was 19.4% and 20.0% per patient-year in the monotherapy group and the antiplatelet combination group, respectively (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.88-1.05; = 0.422). Compared with the antiplatelet combination group, the monotherapy group had a significantly lower incidence rate of major bleeding, defined as intracranial bleeding or gastrointestinal bleeding requiring hospitalization (2.8% vs. 3.6% per patient-year; HR, 0.78; 95% CI, 0.62-0.97; = 0.024).
CONCLUSION
As an antithrombotic therapy for AF beyond one year after coronary revascularization, NOAC monotherapy was associated with a similar risk of MACCE and a lower risk of major bleeding compared to NOAC plus antiplatelet combination therapy.
Topics: Humans; Atrial Fibrillation; Male; Female; Aged; Middle Aged; Platelet Aggregation Inhibitors; Anticoagulants; Drug Therapy, Combination; Stroke; Fibrinolytic Agents; Myocardial Infarction; Hemorrhage; Myocardial Revascularization; Proportional Hazards Models; Propensity Score; Incidence; Republic of Korea
PubMed: 38915283
DOI: 10.3346/jkms.2024.39.e191 -
Pilot and Feasibility Studies Jun 2024Dental caries remains a significant problem in England, affecting 11% of 3-year-olds and 23% of 5-year-olds. While current approaches have been extensively investigated,...
BACKGROUND
Dental caries remains a significant problem in England, affecting 11% of 3-year-olds and 23% of 5-year-olds. While current approaches have been extensively investigated, their ability to (1) control pain and infection; (2) prevent hospital admissions, and (3) be implemented within the National Health Service (NHS) contractual arrangements, remains unsatisfactory. Silver diamine fluoride (SDF) is an alternative, non-invasive approach that has proven efficacy in arresting caries progression in primary teeth, principally from studies conducted outside of Europe. Its use in primary dental care in the UK is limited, despite the acknowledged need. The clinical and cost-effectiveness of SDF has not been compared to usual care in the UK. Before a pragmatic randomised controlled trial (RCT) can be conducted to compare SDF to usual care for caries management in young children, there are several uncertainties that require investigation. This study aims to establish whether such an RCT is feasible.
METHODS
This mixed-method parallel design study is a feasibility study with an embedded process evaluation, to compare SDF with usual treatment in primary dental care in the UK. It will be individually randomised, with 13 dentists and therapists, in 8 different dental primary care sites with a sample size of 80 child participants aged 1-8 years old. The aim will be to recruit ten participants per site with equal arm allocation. Follow-up will be for 1 year. The study will inform whether an RCT is feasible by resolving several key uncertainties. The acceptability and implementation of SDF and the research processes will be explored. Patient and Public Involvement and Engagement representatives will be involved throughout recruitment and retention strategies, participant documentation, analysis, engagement and dissemination.
DISCUSSION
The ability to conduct an RCT will be evaluated. If feasible, this RCT has the potential to evaluate the effectiveness of a non-invasive approach for the management of untreated caries in young children. A feasibility study also offers the opportunity to consider factors associated with the implementation of SDF at an early stage through a process evaluation that will inform the definitive trial and an implementation strategy for SDF by identifying relevant barriers and facilitators.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT06092151. Date: 19/10/2023.
PubMed: 38915111
DOI: 10.1186/s40814-024-01519-y -
Clinical Journal of the American... Jun 2024Tunneled hemodialysis catheters often have infectious or mechanical complications that require unplanned removal and replacement, but the optimal replacement strategy is...
BACKGROUND
Tunneled hemodialysis catheters often have infectious or mechanical complications that require unplanned removal and replacement, but the optimal replacement strategy is unknown. This study described the real-world use of two strategies in Australia and compared the survival of replacement catheters inserted by either strategy.
METHODS
Observational data from the REDUCCTION trial, which enrolled a nationwide cohort of 6400 adults who received an incident hemodialysis catheter (2016-2020) was used for this secondary analysis. Tunneled catheters were replaced by either catheter exchange through the existing tunnel tract or removal and replacement through a new tract. The effect of the replacement strategy on the time to catheter removal due to infection or dysfunction was estimated by emulating a hypothetical pragmatic randomized trial among a subset of 434 patients with mechanical tunneled catheter failure.
RESULTS
Out of 9974 tunneled hemodialysis catheters inserted during the trial, 380 had infectious and 945 had mechanical complications that required replacement. Almost all infected hemodialysis catheters (97%) were removed and separately replaced through a new tunnel tract, whereas nephrology services differed widely in their replacement practices for catheters with mechanical failure (median = 50% guidewire exchanged, interquartile range= 30%-67%). Service-level differences accounted for 29% of the residual variation after adjusting for patient factors. In the target trial emulation cohort of mechanical failure (N=434 patients), catheter exchange was not associated with lower complication-free survival at one, six, or 12 months (counterfactual survival difference at one month = 5.9%, 95% CI = -2%, 14%).
CONCLUSION
Guidewire exchange for mechanical failure of catheter was not associated with lower catheter survival and may be preferable for patients.
PubMed: 38913437
DOI: 10.2215/CJN.0000000000000495 -
Intensive Care Medicine Jun 2024The efficacy of the 1-h bundle for emergency department (ED) patients with suspected sepsis, which includes lactate measurement, blood culture, broad-spectrum...
PURPOSE
The efficacy of the 1-h bundle for emergency department (ED) patients with suspected sepsis, which includes lactate measurement, blood culture, broad-spectrum antibiotics administration, administration of 30 mL/kg crystalloid fluid for hypotension or lactate ≥ 4 mmol/L, remains controversial.
METHODS
We carried out a pragmatic stepped-wedge cluster-randomized trial in 23 EDs in France and Spain. Adult patients with Sepsis-3 criteria or a quick sequential organ failure assessment (SOFA) score ≥ 2 or a lactate > 2 mmol/L were eligible. The intervention was the implementation of the 1-h sepsis bundle. The primary outcome was in-hospital mortality truncated at 28 days. Secondary outcomes included volume of fluid resuscitation at 24 h, acute heart failure at 24 h, SOFA score at 72 h, intensive care unit (ICU) length of stay, number of days on mechanical ventilation or renal replacement therapy, vasopressor free days, unnecessary antibiotic administration, and mortality at 28 days. 1148 patients were planned to be analysed; the study period ended after 873 patients were included.
RESULTS
872 patients (mean age 66, 42% female) were analyzed: 387 (44.4%) in the intervention group and 485 (55.6%) in the control group. Median SOFA score was 3 [1-5]. Median time to antibiotic administration was 40 min in the intervention group vs 113 min in the control group (difference - 73 [95% confidence interval (CI) - 93 to - 53]). There was a significantly higher rate, volume, and shorter time to fluid resuscitation within 3 h in the intervention group. There were 47 (12.1%) in-hospital deaths in the intervention group compared to 61 (12.6%) in the control group (difference in percentage - 0.4 [95% CI - 5.1 to 4.2], adjusted relative risk (aRR) 0.81 [95% CI 0.48 to 1.39]). There were no differences between groups for other secondary endpoints.
CONCLUSIONS
Among patients with suspected sepsis in the ED, the implementation of the 1-h sepsis bundle was not associated with significant difference in in-hospital mortality. However, this study may be underpowered to report a statistically significant difference between groups.
PubMed: 38913098
DOI: 10.1007/s00134-024-07509-1 -
Annals of Surgery Open : Perspectives... Jun 2024
Response to: Comment on "Effects of a Pragmatic Home-Based Exercise Program Concurrent With Neoadjuvant Therapy on Physical Function of Patients With Pancreatic Cancer: The PancFit Randomized Clinical Trial".
PubMed: 38911649
DOI: 10.1097/AS9.0000000000000435 -
Evidence & Policy : a Journal of... Feb 2024Implementing evidence-based practices (EBPs) within service systems is critical to population-level health improvements - but also challenging, especially for complex...
BACKGROUND
Implementing evidence-based practices (EBPs) within service systems is critical to population-level health improvements - but also challenging, especially for complex behavioral health interventions in low-resource settings. "Mis-implementation" refers to poor outcomes from an EBP implementation effort; mis-implementation outcomes are an important, but largely untapped, source of information about how to improve knowledge exchange.
AIMS AND OBJECTIVES
We present mis-implementation cases from three pragmatic trials of behavioral health EBPs in U.S. Federally Qualified Health Centers (FQHCs).
METHODS
We adapted the Consolidated Framework for Implementation Research and its Outcomes Addendum into a framework for mis-implementation and used it to structure the case summaries with information about the EBP and trial, mis-implementation outcomes, and associated determinants (barriers and facilitators). We compared the three cases to identify shared and unique mis-implementation factors.
FINDINGS
Across cases, there was limited adoption and fidelity to the interventions, which led to eventual discontinuation. Barriers contributing to mis-implementation included intervention complexity, low buy-in from overburdened providers, lack of alignment between providers and leadership, and COVID-19-related stressors. Mis-implementation occurred earlier in cases that experienced both patient- and provider-level barriers, and that were conducted during the COVID-19 pandemic.
DISCUSSION AND CONCLUSION
Multi-level determinants contributed to EBP mis-implementation in FQHCs, limiting the ability of these health systems to benefit from knowledge exchange. To minimize mis-implementation, knowledge exchange strategies should be designed around common, core barriers but also flexible enough to address a variety of site-specific contextual factors and should be tailored to relevant audiences such as providers, patients, and/or leadership.
PubMed: 38911233
DOI: 10.1332/17442648y2023d000000016 -
Hepatobiliary Surgery and Nutrition Jun 2024Immune checkpoint inhibitor (ICI)-based therapy has achieved impressive success in various cancer types. Several ICIs have been unprecedentedly approved as the treatment... (Review)
Review
BACKGROUND AND OBJECTIVE
Immune checkpoint inhibitor (ICI)-based therapy has achieved impressive success in various cancer types. Several ICIs have been unprecedentedly approved as the treatment regimens for advanced hepatocellular carcinoma (HCC) in recent decade. Meanwhile, numerous clinical trials are being performed to exploit more ICIs into initially unresectable HCC and postoperative HCC to expectantly induce adequate tumor downstaging for further resection or implement adjuvant treatment for relapse-free survival, respectively. In this review, we aim to summarize some pragmatic histomorphologic, immunohistochemical, and molecular pathologic parameters which promisingly indicate the response of neoadjuvant/conversion ICI-related therapy and predict the efficacy of adjuvant/therapeutic ICI-related therapy for HCC.
METHODS
We searched PubMed using the terms hepatocellular carcinoma, immunotherapy, immune checkpoint inhibitor, immune checkpoint blockade, conversion therapy, neoadjuvant therapy, adjuvant therapy, biomarker, pathologic evaluation, pathologic assessment till February 2023.
KEY CONTENT AND FINDINGS
Although there is no consensus regarding the pathologic evaluation of relevant HCC specimens, it is encouraging that a few of studies have concentrated on this field, and moreover, the methods and parameters noted on other cancer types are also worthy of reference. For the pathologic assessment of HCC specimens underwent immunotherapy, a suitable sampling scheme, identifying immunotherapy-related pathologic response, and quantification of pathologic response rate should be emphasized. For the patients of HCC who are scheduled to receive immunotherapy, tumor-infiltrating lymphocyte, intratumoral tertiary lymphoid structure, programmed cell death ligand 1, , microsatellite instability and mismatch repair, tumor mutational burden and tumor neoantigen, as well as some other signaling pathways are the potential predictive biomarkers of treatment response of ICI.
CONCLUSIONS
The management of HCC in the era of immunotherapy arises a brand-new pathological challenge that is to provide an immunotherapy-related diagnostic report. Albeit many related researches are preclinical or insufficient, they may tremendously alter the immunotherapy strategy of HCC in future.
PubMed: 38911201
DOI: 10.21037/hbsn-22-527 -
Acta Oncologica (Stockholm, Sweden) Jun 2024The Precision Oncology Platform (POP) trial represents the effort of the Portuguese Oncology Institute of Porto (IPO Porto) for joining other leading European...
BACKGROUND AND PURPOSE
The Precision Oncology Platform (POP) trial represents the effort of the Portuguese Oncology Institute of Porto (IPO Porto) for joining other leading European institutions in both 'Personalised Cancer Medicine for all EU citizens' (PCM4EU), and 'PRecisIon Cancer MEdicine RepurpOsing SystEm Using Pragmatic Clinical Trials' (PRIME-ROSE) consortia, enabling the development of the Portuguese version of the Drug Rediscovery Protocol (DRUP)-like Clinical Trial (DLCT), based on the experience of the DRUP trial developed in The Netherlands.
PATIENTS/MATERIAL AND METHODS
The POP trial is a phase II, pragmatic multicentric, non-randomised, open-label study, designed entirely like the other DLCTs. Its primary objective is to describe anti-tumour activity of targeted anticancer drugs in patients with advanced malignancies harbouring actionable molecular alterations. The primary endpoint is disease control rate (DCR). Secondary endpoints encompass treatment-related grade ≥3 adverse events, objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory objectives will assess biomarkers, resource use and costs, and patient-reported outcome measures (PROMs).
INTERPRETATION
The POP trial will offer access to innovative treatments for patients without further therapeutic options and provide evidence on efficacy and safety of molecularly-guided treatments. Methodologically, it represents a pioneer approach in Portugal, including a pay-for-performance model embedded in the clinical trial. The POP trial represents a unique opportunity to integrate clinical research within cancer care, pursuing an evidence-based precision oncology strategy, and facilitating its rational and cost-effective implementation into the Portuguese healthcare system.
Topics: Humans; Precision Medicine; Portugal; Neoplasms; Antineoplastic Agents; Medical Oncology; Clinical Trials, Phase II as Topic; Molecular Targeted Therapy
PubMed: 38910310
DOI: 10.2340/1651-226X.2023.33322 -
BMJ Open Jun 2024Biological disease-modifying antirheumatic drugs (bDMARDs) have revolutionised the treatment of inflammatory arthritis (IA). However, many people with IA still require...
PERI-operative biologic DMARD management: Stoppage or COntinuation during orthoPaEdic operations (the PERISCOPE trial) - a study protocol for a pragmatic, UK multicentre, superiority randomised controlled trial with an internal pilot, economic evaluation and nested qualitative study.
INTRODUCTION
Biological disease-modifying antirheumatic drugs (bDMARDs) have revolutionised the treatment of inflammatory arthritis (IA). However, many people with IA still require planned orthopaedic surgery to reduce pain and improve function. Currently, bDMARDs are withheld during the perioperative period due to potential infection risk. However, this predisposes patients to IA flares and loss of disease control. The question of whether to stop or continue bDMARDs in the perioperative period has not been adequately addressed in a randomised controlled trial (RCT).
METHODS AND ANALYSIS
PERISCOPE is a multicentre, superiority, pragmatic RCT investigating the stoppage or continuation of bDMARDs. Participants will be assigned 1:1 to either stop or continue their bDMARDs during the perioperative period. We aim to recruit 394 adult participants with IA. Potential participants will be identified in secondary care hospitals in the UK, screened by a delegated clinician. If eligible and consenting, baseline data will be collected and randomisation completed. The primary outcome will be the self-reported PROMIS-29 (Patient Reported Outcome Measurement Information System) over the first 12 weeks postsurgery. Secondary outcome measures are as follows: PROMIS - Health Assessment Questionnaire (PROMIS-HAQ), EQ-5D-5L, Disease activity: generic global Numeric Rating Scale (patient and clinician), Self-Administered Patient Satisfaction scale, Health care resource use and costs, Medication use, Surgical site infection, delayed wound healing, Adverse events (including systemic infections) and disease-specific outcomes (according to IA diagnosis). The costs associated with stopping and continuing bDMARDs will be assessed. A qualitative study will explore the patients' and clinicians' acceptability and experience of continuation/stoppage of bDMARDs in the perioperative period and the impact postoperatively.
ETHICS AND DISSEMINATION
Ethical approval for this study was received from the West of Scotland Research Ethics Committee on 25 April 2023 (REC Ref: 23/WS/0049). The findings from PERISCOPE will be submitted to peer-reviewed journals and feed directly into practice guidelines for the use of bDMARDs in the perioperative period.
TRIAL REGISTRATION NUMBER
ISRCTN17691638.
Topics: Humans; Orthopedic Procedures; United Kingdom; Antirheumatic Agents; Pragmatic Clinical Trials as Topic; Perioperative Care; Qualitative Research; Multicenter Studies as Topic; Pilot Projects; Cost-Benefit Analysis; Biological Products
PubMed: 38910007
DOI: 10.1136/bmjopen-2024-084997