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PloS One 2023Postoperative pulmonary complications (PPCs) are a major cause of morbidity and mortality after open abdominal surgery. Optimized perioperative lung expansion may...
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.
Topics: Adult; Humans; Anesthesia; Lung; Lung Diseases; Multicenter Studies as Topic; Positive-Pressure Respiration; Postoperative Complications; Prospective Studies; Randomized Controlled Trials as Topic; Pragmatic Clinical Trials as Topic
PubMed: 37023031
DOI: 10.1371/journal.pone.0283748 -
Malawi Medical Journal : the Journal of... Sep 2022Pragmatic clinical trials generally rely on real world data and have the potential to generate real world evidence. This approach arose from concerns that many trial...
BACKGROUND
Pragmatic clinical trials generally rely on real world data and have the potential to generate real world evidence. This approach arose from concerns that many trial results did not adequately inform real world practice. However, maintaining the real world setting during the conduct of a trial and ensuring adequate protection for research participants can be challenging. Best practices in research oversight for pragmatic clinical trials are nascent and underdeveloped, especially in developing countries.
METHODS
We use the PRECIS-2 tool to present a case study from Lilongwe in Malawi to describe ethical and regulatory challenges encountered during the conduct of a pragmatic trial and suggest possible solutions.
RESULTS
In this article, we highlight the following six issues: (1) one public facility hosting several pragmatic trials within the same period; (2) research participants refusing financial incentives; (3) inadequate infrastructure and high workload to conduct research; (4) silos among partner organisations involved in delivery of health care; (5) individuals influencing the implementation of revised national guidelines; (6) difficulties with access to electronic medical records.
CONCLUSION
Multiple stakeholder engagement is critical to the conduct of pragmatic trials, and even with careful stakeholder engagement, continuous monitoring by gatekeepers is essential. In the Malawian context, active engagement of the district research committees can complement the work of the research ethics committees (RECs).
Topics: Humans; Delivery of Health Care; Malawi; Pragmatic Clinical Trials as Topic; Organizational Case Studies
PubMed: 36406092
DOI: 10.4314/mmj.v34i3.12 -
BMJ Open Sep 2023Incorrect penicillin allergy records are recognised as an important barrier to the safe treatment of infection and affect an estimated 2.7 million people in England....
Penicillin allergy status and its effect on antibiotic prescribing, patient outcomes and antimicrobial resistance (ALABAMA): protocol for a multicentre, parallel-arm, open-label, randomised pragmatic trial.
INTRODUCTION
Incorrect penicillin allergy records are recognised as an important barrier to the safe treatment of infection and affect an estimated 2.7 million people in England. Penicillin allergy records are associated with worse health outcome and antimicrobial resistance. The ALlergy AntiBiotics And Microbial resistAnce (ALABAMA) trial aims to determine if an intervention package, centred around a penicillin allergy assessment pathway (PAAP) initiated in primary care, is safe and effective in improving patient health outcomes and antibiotic prescribing.
METHODS AND ANALYSIS
The ALABAMA trial is a multicentre, parallel-arm, open-label, randomised pragmatic trial with a nested pilot study. Adults (≥18 years) with a penicillin allergy record and who have received antibiotics in the previous 24 months will be eligible for participation. Between 1592 and 2090 participants will be recruited from participating National Health Service general practices in England. Participants will be randomised to either usual care or intervention to undergo a pre-emptive PAAP using a 1:1 allocation ratio. The primary outcome measure is the percentage of treatment response failures within 28 days of an index prescription. 2090 and 1592 participants are estimated to provide 90% and 80% power, respectively, to detect a clinically important absolute difference of 7.9% in primary outcome at 1 year between groups. The trial includes a mixed-methods process evaluation and cost-effectiveness evaluation.
ETHICS AND DISSEMINATION
This trial has been approved by London Bridge Research Ethics Committee (ref: 19/LO/0176). It will be conducted in compliance with Good Clinical Practice guidelines according to the Declaration of Helsinki. Informed consent will be obtained from all subjects involved in the study. The primary trial results will be submitted for publication to an international, peer-reviewed journal.
TRIAL REGISTRATION
ISRCTN20579216.
Topics: Adult; Humans; Alabama; Anti-Bacterial Agents; Drug Hypersensitivity; Drug Resistance, Bacterial; Hypersensitivity; Multicenter Studies as Topic; Penicillins; Pilot Projects; Randomized Controlled Trials as Topic; State Medicine; Pragmatic Clinical Trials as Topic
PubMed: 37666558
DOI: 10.1136/bmjopen-2023-072253 -
Journal of Orthopaedic Trauma Mar 2021The insights that real-world data (RWD) can provide, beyond what can be learned within the traditional clinical trial setting, have gained enormous traction in recent...
The insights that real-world data (RWD) can provide, beyond what can be learned within the traditional clinical trial setting, have gained enormous traction in recent years. RWD, which are increasingly available and accessible, can further our understanding of disease, disease progression, and safety and effectiveness of treatments with the speed and accuracy required by the health care environment and patients today. Over the decades since RWD were first recognized, innovation has evolved to take real-world research beyond finding ways to identify, store, and analyze large volumes of data. The research community has developed strong methods to address challenges of using RWD and as a result has increased the acceptance of RWD in research, practice, and policy. Historic concerns about RWD relate to data quality, privacy, and transparency; however, new tools, methods, and approaches mitigate these challenges and expand the utility of RWD to new applications. Specific guidelines for RWD use have been developed and published by numerous groups, including regulatory authorities. These and other efforts have shown that the more RWD are used and understood and the more the tools for handling it are refined, the more useful it will be.
Topics: Big Data; Delivery of Health Care; Humans; Pragmatic Clinical Trials as Topic
PubMed: 33587539
DOI: 10.1097/BOT.0000000000002037 -
Health Expectations : An International... Jun 2022Better transparency of research results and participant engagement may help address poor participant accrual in paediatric clinical research. We conducted formative... (Review)
Review
INTRODUCTION
Better transparency of research results and participant engagement may help address poor participant accrual in paediatric clinical research. We conducted formative research to assess the acceptability of lay summaries and thank you notes, as well as to refine and expand guidance on participant and family engagement in Pediatric Trials Network's (PTN) pragmatic paediatric clinical research.
METHODS
Informed by draft PTN guidance, we conducted in-depth qualitative interviews with adolescent clinical trial participants and caregivers of paediatric participants in four trials conducted by PTN across eight sites. Participants were shown multiple versions of mock lay summaries and thank you notes and asked questions on their preferences for content and layout, and on trial communications. We used applied thematic analysis to analyse the data.
RESULTS
We interviewed 27 individuals engaged in PTN research: 24 caregivers and 3 adolescents. During a trial, participants want regular updates on study progress, reminders of the study purpose and reassurances of data confidentiality. After the trial, participants want to learn the aggregated results, particularly medication effectiveness. Participants reported that lay summaries should include a review of the study's purpose, methods and length, and that they expect to learn individual-level results. Participants stated that thank you notes must be of sufficient length to be meaningful.
CONCLUSIONS
This is the first study to describe stakeholder preferences for thank you note content and layout. Using these findings, we finalized PTN's trial communication guidance for use in future PTN trials. Research is needed to determine the effect of lay summaries and thank you notes on improving public transparency regarding clinical trials and paediatric trial recruitment and completion.
PATIENT OR PUBLIC CONTRIBUTION
By design, stakeholders (adolescent trial participants and caregivers of pediatric trial participants) contributed to PTN's guidance on the content and layout of lay summaries and thank you notes through their participation in the in-depth interviews.
Topics: Adolescent; Caregivers; Communication; Humans; Pragmatic Clinical Trials as Topic
PubMed: 35246906
DOI: 10.1111/hex.13448 -
American Journal of Kidney Diseases :... Nov 2019A pragmatic cluster-randomized trial (CRT) is a research design that may be used to efficiently test promising interventions that directly inform dialysis care. While... (Review)
Review
A pragmatic cluster-randomized trial (CRT) is a research design that may be used to efficiently test promising interventions that directly inform dialysis care. While the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials provides general ethical guidance for CRTs, the dialysis setting raises additional considerations. In this article, we outline ethical issues raised by pragmatic CRTs in dialysis facilities. These issues may be divided into 7 key domains: justifying the use of cluster randomization, adopting randomly allocated individual-level interventions as a facility standard of care, conducting benefit-harm analyses, gatekeepers and their responsibilities, obtaining informed consent from research participants, patient notification, and including vulnerable participants. We describe existing guidelines relevant to each domain, illustrate how they were considered in the Time to Reduce Mortality in End-Stage Renal Disease (TiME) trial (a prototypical pragmatic hemodialysis CRT), and highlight remaining areas of uncertainty. The following is the first step in an interdisciplinary mixed-methods research project to guide the design and conduct of pragmatic CRTs in dialysis facilities. Subsequent work will expand on these concepts and when possible, argue for a preferred solution.
Topics: Ethics, Medical; Humans; Kidney Failure, Chronic; Personal Autonomy; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Renal Dialysis
PubMed: 31227227
DOI: 10.1053/j.ajkd.2019.04.019 -
Mayo Clinic Proceedings Nov 2023Pragmatic randomized clinical trials (pRCTs) have a unique set of considerations for data and safety monitoring. Because of their unconventional trial designs coupled... (Review)
Review
Pragmatic randomized clinical trials (pRCTs) have a unique set of considerations for data and safety monitoring. Because of their unconventional trial designs coupled with collection of multilevel data and implementation outcomes in real-world settings, thoughtful consideration is needed on the presentation of the trial design and accruing data to facilitate review and decision-making by the trial's data and safety monitoring board (DSMB). To our knowledge, there is limited information available in practical guidelines for generalists and medical general practitioners on what to monitor and to report to the DSMB during the conduct of pRCTs and what the DSMB should focus on in its review of reports. This article discusses these matters in the context of 3 case studies focusing on a set of critical data and safety monitoring questions that would be of interest to the generalist conducting pRCTs. In considering these questions, we provide tabular and graphical illustrations of how data can be presented to the DSMB while drawing attention to those areas that the DSMB should focus on in its review of the trial. The strategies and viewpoints discussed herein provide practical guidelines and can serve as a resource for the generalist conducting pRCTs.
Topics: Humans; Randomized Controlled Trials as Topic; Clinical Trials Data Monitoring Committees
PubMed: 37923529
DOI: 10.1016/j.mayocp.2023.02.019 -
Journal of Clinical Epidemiology Oct 2021Feasibility studies are increasingly being used to support the development of, and investigate uncertainties around, future large-scale trials. The future trial can be...
BACKGROUND AND OBJECTIVE
Feasibility studies are increasingly being used to support the development of, and investigate uncertainties around, future large-scale trials. The future trial can be designed with either a pragmatic or explanatory mindset. Whereas pragmatic trials aim to inform the choice between different care options and thus, are designed to resemble conditions outside of a clinical trial environment, explanatory trials examine the benefit of a treatment under more controlled conditions. There is existing guidance for designing feasibility studies, but none that explicitly considers the goals of pragmatic designs. We aimed to identify unique areas of uncertainty that are relevant to planning a pragmatic trial.
RESULTS
We identified ten relevant domains, partly based on the pragmatic-explanatory continuum indicator summary-2 (PRECIS-2) framework, and describe potential questions of uncertainty within each: intervention development, research ethics, participant identification and eligibility, recruitment of individuals, setting, organization, flexibility of delivery, flexibility of adherence, follow-up, and importance of primary outcome to patients and decision-makers. We present examples to illustrate how uncertainty in these domains might be addressed within a feasibility study.
CONCLUSION
Researchers planning a feasibility study in advance of a pragmatic trial should consider feasibility objectives specifically relevant to areas of uncertainty for pragmatic trials.
Topics: Biomedical Research; Feasibility Studies; Guidelines as Topic; Humans; Pilot Projects; Pragmatic Clinical Trials as Topic; Research Design; Uncertainty
PubMed: 34229091
DOI: 10.1016/j.jclinepi.2021.06.029 -
Clinical Trials (London, England) Dec 2020Standard approaches to trial design and analyses can be inefficient and non-pragmatic. Failure to consider a range of outcomes impedes evidence-based interpretation and...
BACKGROUND/AIMS
Standard approaches to trial design and analyses can be inefficient and non-pragmatic. Failure to consider a range of outcomes impedes evidence-based interpretation and reduces power. Traditional approaches synthesizing information obtained from separate analysis of each outcome fail to incorporate associations between outcomes and recognize the cumulative nature of outcomes in individual patients, suffer from competing risk complexities during interpretation, and since efficacy and safety analyses are often conducted on different populations, generalizability is unclear. Pragmatic and efficient approaches to trial design and analyses are needed.
METHODS
Approaches providing a pragmatic assessment of benefits and harms of interventions, summarizing outcomes experienced by patients, and providing sample size efficiencies are described. Ordinal outcomes recognize finer gradations of patient responses. Desirability of outcome ranking is an ordinal outcome combining benefits and harms within patients. Analysis of desirability of outcome ranking can be based on rank-based methodologies including the desirability of outcome ranking probability, the win ratio, and the proportion in favor of treatment. Partial credit analyses, involving grading the levels of the desirability of outcome ranking outcome similar to an academic test, provides an alternative approach. The methodologies are demonstrated using the acute stroke or transient ischemic attack treated with aspirin or ticagrelor and patient outcomes study (SOCRATES; NCT01994720), a randomized clinical trial.
RESULTS
Two 5-level ordinal outcomes were developed for SOCRATES. The first was based on a modified Rankin scale. The odds ratio is 0.86 (95% confidence interval = 0.75, 0.99; = 0.04) indicating that the odds of worse stroke categorization for a trial participant assigned to ticagrelor is 0.86 times that of a trial participant assigned to aspirin. The 5-level desirability of outcome ranking outcome incorporated and prioritized survival; the number of strokes, myocardial infarction, and major bleeding events; and whether a stroke event was disabling. The desirability of outcome ranking probability and win ratio are 0.504 (95% confidence interval = 0.499, 0.508; = 0.10) and 1.11 (95% confidence interval = 0.98, 1.26; = 0.10), respectively, implying that the probability of a more desirable result with ticagrelor is 50.4% and that a more desirable result occurs 1.11 times more frequently on ticagrelor versus aspirin.
CONCLUSION
Ordinal outcomes can improve efficiency through required pre-specification, careful construction, and analyses. Greater pragmatism can be obtained by composing outcomes within patients. Desirability of outcome ranking provides a global assessment of the benefits and harms that more closely reflect the experience of patients. The desirability of outcome ranking probability, the proportion in favor of treatment, the win ratio, and partial credit can more optimally inform patient treatment, enhance the understanding of the totality of intervention effects on patients, and potentially provide efficiencies over standard analyses. The methods provide the infrastructure for incorporating patient values and estimating personalized effects.
Topics: Adult; Aspirin; Humans; Ischemic Attack, Transient; Odds Ratio; Platelet Aggregation Inhibitors; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Research Design; Stroke; Ticagrelor; Treatment Outcome
PubMed: 32666831
DOI: 10.1177/1740774520941441 -
Journal of Neurosurgical Anesthesiology Jan 2022The coronavirus disease 2019 (COVID-19) pandemic incited a global clinical trial research agenda of unprecedented speed and high volume. This expedited research activity...
The coronavirus disease 2019 (COVID-19) pandemic incited a global clinical trial research agenda of unprecedented speed and high volume. This expedited research activity in a time of crisis produced both successes and failures that offer valuable learning opportunities for the scientific community to consider. Successes include the implementation of large adaptive and pragmatic trials as well as burgeoning efforts toward rapid data synthesis and open science principles. Conversely, notable failures include: (1) inadequate study design and execution; (2) data reversal, fraud, and retraction; and (3) research duplication and waste. Other challenges that became highlighted were the need to find unbiased designs for investigating complex, nonpharmaceutical interventions and the use of routinely collected data for outcomes assessment. This article discusses these issues juxtaposing the COVID-19 trials experience against trials in anesthesiology and other fields. These lessons may serve as a positive catalyst for transforming future clinical trial research.
Topics: COVID-19; Humans; Pandemics; Randomized Controlled Trials as Topic; SARS-CoV-2
PubMed: 34870631
DOI: 10.1097/ANA.0000000000000804