Pragmatic-Explanatory Continuum Indicator Research Articles

Evaluating India’s Position in Pragmatic Clinical Trial for Public Healthcare: A Key to Real World Healthcare Solutions

Pragmatic Clinical Trials (PCTs) are valuable tools for evaluating interventions in real-world settings, providing insights for clinical practice. Unlike traditional randomized controlled trial (RCTs), PCTs generate real-world evidence for better decision-making. With 615 reported globally between 1967 and 2017, a 58% increase from 2013 to 2017, India has only one registered PCT, indicating a gap in its adoption. This review examines national clinical trial registries, PubMed database for PCTs till 2024, comparing data across different nations. The study reveals a significant shortage of PCTs in India and a lack of awareness of frameworks like Pragmatic Explanatory Continuum Indicator Summary 2. India faces challenges in implementing PCTs due to low awareness, inadequate infrastructure, and logistical hurdles. However, with regulatory reforms, international collaboration, and infrastructure improvements, India can become a key player in advancing PCTs. Increased awareness and researcher training will contribute to better healthcare outcomes both domestically and globally.

Recommendations for monitoring adherence and fidelity in pragmatic trials based on experience in the Pain Management Collaboratory.

Most pragmatic trials follow the PRagmatic Explanatory Continuum Indicator Summary (PRECIS-2) criteria. The criteria specify unobtrusive measurement of participants' protocol adherence and practitioners' intervention fidelity but suggest no special monitoring strategies to assure trial integrity. We present experience with adherence/fidelity monitoring in the Pain Management Collaboratory (PMC) and provide recommendations for their monitoring in pragmatic trials to preserve inferences of treatment comparisons. In November 2021, we surveyed 10 of 11 originally funded PMC pragmatic trials to determine the extent to which adherence and fidelity data were being monitored. Of the 10 PMC trials, 8 track adherence/fidelity. The electronic health record is the most frequent source for monitoring adherence (7/10) and fidelity (5/10). Most adherence data are used to monitor participant engagement with the trial intervention (4/10) and are reviewed by study teams (8/10) and often with a data and safety monitoring board (DSMB) (5/10). Half of the trials (5/10) reported using fidelity data for feedback/training; such data are not shared with a DSMB (0/10). Only 2 of 10 trials reported having prespecified guidance or rules around adherence/fidelity (eg, stopping rules or thresholds for corrective action, such as retraining). As a best practice for pragmatic trials, we recommend early and regular adherence/fidelity monitoring to determine whether intervention delivery is as intended. We propose a 2-stage process with thresholds for intervening and triggers for conducting a formal futility analysis if adherence and fidelity are not maintained. The level of monitoring should be unobtrusive for both participants and those delivering the intervention; resulting data should be reviewed by an independent DSMB.

Are pragmatism and ethical protections in clinical trials a zero-sum game?

Randomized controlled trials with pragmatic intent aim to generate evidence that directly informs clinical decisions. Some have argued that the ethical protection of informed consent can be in tension with the goals of pragmatism. But the impact of other ethical protections on trial pragmatism has yet to be explored. In this article, we analyze the relationship between additional ethical protections for vulnerable participants and the degree of pragmatism within the PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2) domains of trial design. We analyze three example trials with pragmatic intent that include vulnerable participants. The relationship between ethical protections and trial pragmatism is complex. In some cases, additional ethical protections for vulnerable participants can promote the pragmatism of some of the PRECIS-2 domains of trial design. When designing trials with pragmatic intent, researchers ought to look for opportunities wherein ethical protections enhance the degree of pragmatism.

Comments, suggestions, and criticisms of the Pragmatic Explanatory Continuum Indicator Summary-2 design tool: a citation analysis

IntroductionThe pragmatic explanatory continuum indicator summary (PRECIS) tool, initially published in 2009 and revised in 2015, was created to assist trialists to align their design choices with the intended purpose of their randomised controlled trial (RCT): either to guide real-world decisions between alternative interventions (pragmatic) or to test hypotheses about intervention mechanisms by minimising sources of variation (explanatory). There have been many comments, suggestions, and criticisms of PRECIS-2. This summary will be used to facilitate the development of to the next revision, which is PRECIS-3. MethodsWe used Web of Science to identify all publication types citing PRECIS-2, published between May 2015 and July 2023. Citations were eligible if they contained ‘substantive’ suggestions, comments, or criticism of the PRECIS-2 tool. We defined ‘substantive’ as comments explicitly referencing at least one PRECIS-2 domain or a concept directly linked to an existing or newly proposed domain.Two reviewers independently extracted comments, suggestions, and criticisms, noting their implications for the update. These were discussed among authors to achieve consensus on the interpretation of each comment and its implications for PRECIS-3. ResultsThe search yielded 885 publications, and after full-text review, 89 articles met the inclusion criteria. Comments pertained to new domains, changes in existing domains, or were relevant across several or all domains. Proposed new domains included assessment of the comparator arm and a domain to describe blinding. There were concerns about scoring eligibility and recruitment domains for cluster trials. Suggested areas for improvement across domains included the need for more scoring guidance for explanatory design choices. DiscussionPublished comments recognise PRECIS-2's success in aiding trialists with pragmatic or explanatory design choices. Enhancing its implementation and widespread use will involve adding new domains, refining domain definitions, and addressing overall tool issues. This citation review offers valuable user feedback, pivotal for shaping the upcoming version of the PRECIS tool, PRECIS-3.

Benchmarking Human–AI collaboration for common evidence appraisal tools

Background and ObjectiveIt is unknown whether large language models (LLMs) may facilitate time- and resource-intensive text-related processes in evidence appraisal. The objective was to quantify the agreement of LLMs with human consensus in appraisal of scientific reporting (Preferred Reporting Items for Systematic reviews and Meta-Analyses [PRISMA]) and methodological rigor (A MeaSurement Tool to Assess systematic Reviews [AMSTAR]) of systematic reviews and design of clinical trials (PRagmatic Explanatory Continuum Indicator Summary 2 [PRECIS-2]) and to identify areas where collaboration between humans and artificial intelligence (AI) would outperform the traditional consensus process of human raters in efficiency. Study Design and SettingFive LLMs (Claude-3-Opus, Claude-2, GPT-4, GPT-3.5, Mixtral-8x22B) assessed 112 systematic reviews applying the PRISMA and AMSTAR criteria and 56 randomized controlled trials applying PRECIS-2. We quantified the agreement between human consensus and (1) individual human raters; (2) individual LLMs; (3) combined LLMs approach; (4) human–AI collaboration. Ratings were marked as deferred (undecided) in case of inconsistency between combined LLMs or between the human rater and the LLM. ResultsIndividual human rater accuracy was 89% for PRISMA and AMSTAR, and 75% for PRECIS-2. Individual LLM accuracy was ranging from 63% (GPT-3.5) to 70% (Claude-3-Opus) for PRISMA, 53% (GPT-3.5) to 74% (Claude-3-Opus) for AMSTAR, and 38% (GPT-4) to 55% (GPT-3.5) for PRECIS-2. Combined LLM ratings led to accuracies of 75%–88% for PRISMA (4%–74% deferred), 74%–89% for AMSTAR (6%–84% deferred), and 64%–79% for PRECIS-2 (29%–88% deferred). Human–AI collaboration resulted in the best accuracies from 89% to 96% for PRISMA (25/35% deferred), 91%–95% for AMSTAR (27/30% deferred), and 80%–86% for PRECIS-2 (76/71% deferred). ConclusionCurrent LLMs alone appraised evidence worse than humans. Human–AI collaboration may reduce workload for the second human rater for the assessment of reporting (PRISMA) and methodological rigor (AMSTAR) but not for complex tasks such as PRECIS-2.

PRECIS-2 analysis of pragmatic acupuncture trials: a systematic review

BackgroundPragmatic acupuncture trials (PATs) are a research tool for assessing the effectiveness of acupuncture treatments in a real-world setting. This study aimed to provide a comprehensive methodological analysis of PATs using the PRECIS-2(PRagmatic Explanatory Continuum Indicator Summary-2) tool to determine their pragmatism.MethodsThe MEDLINE, EMBASE, Cochrane Central Register for Controlled Trials, CINAHL, Allied and Complementary Medicine Database, China National Knowledge Infrastructure, VIP, WANFANG, Taiwan Periodical Literature Database, KoreaMed, KMbase, Research Information Service System, Oriental Medicine Advanced Searching Integrated System, CiNii and ClinicalTrials.gov were searched. The search included randomised controlled trials (RCTs) and protocols of RCTs that investigated all types of acupuncture and used self-declared pragmatic design. Two authors independently collected the basic information and characteristics of the studies and assessed their pragmatism using the nine PRECIS-2 domains and the additional domain of control.ResultsA total of 93 studies were included. The means of eligibility, recruitment, organisation, primary outcome, primary analysis, and control domains were statistically larger than three and were shown to be pragmatic. The means of setting, flexibility:delivery, and follow-up domains were not greater than three and were shown to be non-pragmatic. For flexibility:adherence domain was inappropriate for assessment owing to insufficient information in the studies.ConclusionsPATs were pragmatic in the domain of eligibility, recruitment, organisation, primary outcome, primary analysis, and control and were not pragmatic in the domain of setting, flexibility:delivery, and follow-up. Future PATs need to strengthen the pragmatism in the setting, flexibility:delivery, and follow-up domains and to describe the flexibility:adherence domain in more detail.Trial registrationCRD42021236975.

Vaccine communication training using the Brief Motivational Interviewing for Maternal Immunization intervention: A PRISM implementation evaluation.

Improving clinician-patient communication can increase uptake of recommended vaccinations during pregnancy. To evaluate adaptations to and pragmatism of the brief Motivational Interviewing for Maternal Immunizations (MI4MI) intervention and to use the Practical Robust Implementation and Sustainability Model (PRISM) to describe context and implementation outcomes among clinician and staff participants. We incorporated data from study team members, clinicians and staff participants, pregnant patients at participating clinics, and patient medical records. Quantitative and qualitative data were collected using surveys, chart reviews, study team notes, interviews, and focus groups. Adaptations were evaluated using the Framework for Reporting Adaptations and Modifications-Enhanced (FRAME) and pragmatism was measured with PRagmatic Explanatory Continuum Indicator Summary (PRECIS-2). MI4MI was effective at improving participants' vaccine communication experiences. Adoption was limited by our recruitment approach. MI4MI implementation was shaped by contextual factors and associated adaptations related to the COVID pandemic and clinic and participant characteristics. Virtual asynchronous intervention delivery had mixed effects on adoption and implementation that varied across clinics and participants. Participants expressed interest in maintaining the MI4MI intervention moving forward; however, identification of sustainability infrastructure was limited. MI4MI was evaluated to be relatively pragmatic. Contextual factors strongly shaped implementation of MI4MI. Future iterations of MI4MI should include training delivery modes and incentives that accommodate a range of participants across job roles and organizational settings. Future studies including control clinics are needed to measure effectiveness for increasing vaccination and comparing virtual versus hybrid implementation strategies.

Use of pragmatic randomized trials in multiple sclerosis: A systematic overview.

Pragmatic trials are increasingly recognized for providing real-world evidence on treatment choices. The objective of this study is to investigate the use and characteristics of pragmatic trials in multiple sclerosis (MS). Systematic literature search and analysis of pragmatic trials on any intervention published up to 2022. The assessment of pragmatism with PRECIS-2 (PRagmatic Explanatory Continuum Indicator Summary-2) is performed. We identified 48 pragmatic trials published 1967-2022 that included a median of 82 participants (interquartile range (IQR) = 42-160) to assess typically supportive care interventions (n = 41; 85%). Only seven trials assessed drugs (15%). Only three trials (6%) included >500 participants. Trials were mostly from the United Kingdom (n = 18; 38%), Italy (n = 6; 13%), the United States and Denmark (each n = 5; 10%). Primary outcomes were diverse, for example, quality-of-life, physical functioning, or disease activity. Only 1 trial (2%) used routinely collected data for outcome ascertainment. No trial was very pragmatic in all design aspects, but 14 trials (29%) were widely pragmatic (i.e. PRECIS-2 score ⩾ 4/5 in all domains). Only few and mostly small pragmatic trials exist in MS which rarely assess drugs. Despite the widely available routine data infrastructures, very few trials utilize them. There is an urgent need to leverage the potential of this pioneering study design to provide useful randomized real-world evidence.

Meta-research on pragmatism of randomized trials: rationale and design of the PragMeta database

BackgroundPragmatic trials provide decision-oriented, real-world evidence that is highly applicable and generalizable. The interest in real-world evidence is fueled by the assumption that effects in the “real-world” are different to effects obtained under artificial, controlled, research conditions as often used for traditional explanatory trials. However, it is unknown which features of pragmatism, generalizability, and applicability would be responsible for such differences. There is a need to provide empirical evidence and promote meta-research to answer these fundamental questions on the pragmatism of randomized trials and real-world evidence. Here, we describe the rationale and design of the PragMeta database which pursues this goal (www.PragMeta.org).MethodsPragMeta is a non-commercial, open data platform and infrastructure to facilitate research on pragmatic trials. It collects and shares data from published randomized trials that either have a specific design feature or other characteristic related to pragmatism or they form clusters of trials addressing the same research question but having different aspects of pragmatism. This lays the foundation to determine the relationship of various features of pragmatism, generalizability, and applicability with intervention effects or other trial characteristics.The database contains trial data actively collected for PragMeta but also allows to import and link existing datasets of trials collected for other purposes, forming a large-scale meta-database. PragMeta captures data on (1) trial and design characteristics (e.g., sample size, population, intervention/comparison, outcome, longitudinal structure, blinding), (2) effects estimates, and (3) various determinants of pragmatism (e.g., the use of routinely collected data) and ratings from established tools used to determine pragmatism (e.g., the PRagmatic–Explanatory Continuum Indicator Summary 2; PRECIS-2).PragMeta is continuously provided online, inviting the meta-research community to collaborate, contribute, and/or use the database. As of April 2023, PragMeta contains data from > 700 trials, mostly with assessments on pragmatism.ConclusionsPragMeta will inform a better understanding of pragmatism and the generation and interpretation of real-world evidence.

Study design and baseline profile for adults with type 2 diabetes in the once-weekly subcutaneous SEmaglutide randomized PRAgmatic (SEPRA) trial

IntroductionOnce-weekly subcutaneous semaglutide, a glucagon-like peptide-1 analog, is approved in the USA as an adjunct to diet and exercise for adults with inadequately controlled type 2 diabetes (T2D) to improve...

Integrating pragmatic and implementation science randomized clinical trial approaches: a PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2) analysis

BackgroundOver the past two decades, pragmatic and implementation science clinical trial research methods have advanced substantially. Pragmatic and implementation studies have natural areas of overlap, particularly relating to the goal of using clinical trial data to leverage health care system policy changes. Few investigations have addressed pragmatic and implementation science randomized trial methods development while also considering policy impact.MethodsThe investigation used the PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2) and PRECIS-2-Provider Strategies (PRECIS-2-PS) tools to evaluate the design of two multisite randomized clinical trials that targeted patient-level effectiveness outcomes, provider-level practice changes and health care system policy. Seven raters received PRECIS-2 training and applied the tools in the coding of the two trials. Descriptive statistics were produced for both trials, and PRECIS-2 wheel diagrams were constructed. Interrater agreement was assessed with the Intraclass Correlation (ICC) and Kappa statistics. The Rapid Assessment Procedure Informed Clinical Ethnography (RAPICE) qualitative approach was applied to understanding integrative themes derived from the PRECIS-2 ratings and an end-of-study policy summit.ResultsThe ICCs for the composite ratings across the patient and provider-focused PRECIS-2 domains ranged from 0.77 to 0.87, and the Kappa values ranged from 0.25 to 0.37, reflecting overall fair-to-good interrater agreement for both trials. All four PRECIS-2 wheels were rated more pragmatic than explanatory, with composite mean and median scores ≥ 4. Across trials, the primary intent-to-treat analysis domain was consistently rated most pragmatic (mean = 5.0, SD = 0), while the follow-up/data collection domain was rated most explanatory (mean range = 3.14–3.43, SD range = 0.49–0.69). RAPICE field notes identified themes related to potential PRECIS-2 training improvements, as well as policy themes related to using trial data to inform US trauma care system practice change; the policy themes were not captured by the PRECIS-2 ratings.ConclusionsThe investigation documents that the PRECIS-2 and PRECIS-2-PS can be simultaneously used to feasibly and reliably characterize clinical trials with patient and provider-level targets. The integration of pragmatic and implementation science clinical trial research methods can be furthered by using common metrics such as the PRECIS-2 and PRECIS-2-PS. Future study could focus on clinical trial policy research methods development.Trial registrationDO-SBIS ClinicalTrials.gov NCT00607620. registered on January 29, 2008. TSOS ClinicalTrials.gov NCT02655354, registered on July 27, 2015.

Intervention Fidelity in Pain Pragmatic Trials for Nonpharmacologic Pain Management: Nuanced Considerations for Determining PRECIS-2 Flexibility in Delivery and Adherence

Nonpharmacological treatments are considered first-line pain management strategies, but they remain clinically underused. For years, pain-focused pragmatic clinical trials (PCTs) have generated evidence for the enhanced use of nonpharmacological interventions in routine clinical settings to help overcome implementation barriers. The Pragmatic Explanatory Continuum Indicator Summary (PRECIS-2) framework describes the degree of pragmatism across 9 key domains. Among these, “flexibility in delivery” and “flexibility in adherence,” address a key goal of pragmatic research by tailoring approaches to settings in which people receive routine care. However, to maintain scientific and ethical rigor, PCTs must ensure that flexibility features do not compromise delivery of interventions as designed, such that the results are ethically and scientifically sound. Key principles of achieving this balance include clear definitions of intervention core components, intervention monitoring and documentation that is sufficient but not overly burdensome, provider training that meets the demands of delivering an intervention in real-world settings, and use of an ethical lens to recognize and avoid potential trial futility when necessary and appropriate. PerspectiveThis article presents nuances to be considered when applying the PRECIS-2 framework to describe pragmatic clinical trials. Trials must ensure that patient-centered treatment flexibility does not compromise delivery of interventions as designed, such that measurement and analysis of treatment effects is reliable.

Implementation of e-Mental Health Interventions for Informal Caregivers of Adults With Chronic Diseases: Mixed Methods Systematic Review With a Qualitative Comparative Analysis and Thematic Synthesis.

Informal caregivers commonly experience mental health difficulties related to their caregiving role. e-Mental health interventions provide mental health support in a format that may be more accessible to informal caregivers. However, e-mental health interventions are seldom implemented in real-world practice. This mixed methods systematic review aimed to examine factors associated with the effectiveness and implementation of e-mental health interventions for informal caregivers of adults with chronic diseases. To achieve this aim, two approaches were adopted: combinations of implementation and intervention characteristics sufficient for intervention effectiveness were explored using qualitative comparative analysis, and barriers to and facilitators of implementation of e-mental health interventions for informal caregivers were explored using thematic synthesis. We identified relevant studies published from January 1, 2007, to July 6, 2022, by systematically searching 6 electronic databases and various secondary search strategies. Included studies reported on the effectiveness or implementation of e-mental health interventions for informal caregivers of adults with cancer, chronic obstructive pulmonary disease, dementia, diabetes, heart disease, or stroke. Randomized controlled trials reporting on caregivers' mental health outcomes were included in a crisp-set qualitative comparative analysis. We assessed randomized controlled trials for bias using the Risk of Bias 2.0 tool, and we assessed how pragmatic or explanatory their trial design was using the Pragmatic Explanatory Continuum Indicator Summary 2 tool. Studies of any design reporting on implementation were included in a thematic synthesis using the Consolidated Framework for Implementation Research to identify barriers to and facilitators of implementation. Overall, 53 reports, representing 29 interventions, were included in the review. Most interventions (27/29, 93%) focused on informal cancer or dementia caregivers. In total, 14 reports were included in the qualitative comparative analysis, exploring conditions including the presence of peer or professional support and key persuasive design features. Low consistency and coverage prevented the determination of condition sets sufficient for intervention effectiveness. Overall, 44 reports were included in the thematic synthesis, and 152 barriers and facilitators were identified, with the majority related to the intervention and individual characteristic domains of the Consolidated Framework for Implementation Research. Implementation barriers and facilitators in the inner setting (eg, organizational culture) and outer setting (eg, external policies and resources) domains were largely unexplored. e-Mental health interventions for informal caregivers tend to be well-designed, with several barriers to and facilitators of implementation identified related to the intervention and individual user characteristics. Future work should focus on exploring the views of stakeholders involved in implementation to determine barriers to and facilitators of implementing e-mental health interventions for informal caregivers, focusing on inner and outer setting barriers and facilitators. PROSPERO (International Prospective Register of Systematic Reviews) CRD42020155727; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020155727. RR2-10.1136/bmjopen-2019-035406.

Primary Decompressive Craniectomy After Traumatic Brain Injury: A Literature Review.

Traumatic brain injuries (TBIs) still put a high burden on public health worldwide. Medical and surgical treatment strategies are continuously being studied, but the role and indications of primary decompressive craniectomy (DC)remain controversial. In medically refractory intracranial hypertension after severe traumatic brain injury, secondary decompressive craniectomy is a last resort treatment option to control intracranial pressure (ICP). Randomized controlled studies have been extensively performed on secondary decompressive craniectomy and its role in the management of severe traumatic brain injuries. Indications, prognostic factors, and long-term outcomes in primary decompressive craniectomy during the evacuation of an epidural, subdural, or intracerebral hematoma in the acute phase are still a matter of ongoing research and controversy to this day. Prospective trials have been designed, but the results are yet to be published. In isolated epidural hematoma without underlying brain injury, osteoplastic craniotomy is likely to be sufficient. In acute subdural hematoma (ASDH) with relevant brain swelling and preoperative CT signs such as effaced cisterns, overly proportional midline-shift compared to a relatively small acute subdural hematoma, and accompanying brain contusions as well as pupillary abnormalities, intraventricular hemorrhage, and coagulation disorder, primary decompressive craniectomy is more likely to be of benefit for patients with traumatic brain injury. The role of intracranial pressure monitoring after primary decompressive craniectomy is recommended, but prospective trials are pending. More refined guidelines and hopefully class I evidence will be established with the ongoing trials: randomized evaluation of surgery with craniectomy for patients undergoing evacuation of acute subdural hematoma (RESCUE-ASDH), prospective randomized evaluation of decompressive ipsilateral craniectomy for traumatic acute epidural hematoma (PREDICT-AEDH), and pragmatic explanatory continuum indicator summary (PRECIS).

Generalizability of randomized controlled trials in primary health care: Applying the PRECIS-2 tool on published protocols.

Pragmatic design may facilitate the generalizability of effectiveness of randomized controlled trials (RCTs) in primary health care (PHC). The aim of this study was to investigate whether published protocols in PHC were designed pragmatically and to explore whether specific trial characteristics may be related to a pragmatic design. Using the Pragmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2), we assessed pragmatism for 123 published RCT protocols. For each domain, we calculated the mean score with the 95% confidence interval (95% CI). Interrater reliability was assessed by weighted κ-coefficient with 95% CI. We examined potential associations of published protocol characteristics with overall pragmatism by performing univariate and multivariate analyses. We observed the highest score for primary analysis (4.66, 95%CI: 4.51, 4.82). The eligibility score was intermediate (3.16, 95%CI: 3.01, 3.32). Domains with scores towards the explanatory side included organization (2.50, 95%CI: 2.36, 2.63), flexibility of delivery (2.74, 95%CI: 2.60, 2.88) and flexibility of adherence (3.00, 95%CI: 2.83, 3.17). Interrater agreement was good (κ = 0.61; 95%CI: 0.34, 0.80; p < 0.001). Higher sample sizes were correlated to a pragmatic design (odds ratio: 6.86, 95%CI: 1.64, 28.75; p = 0.04). Most RCT protocols were rated as intermediate in the pragmatic-explanatory continuum. Future research may guide all stakeholders on how best to incorporate the level of pragmatism in the interpretation of the resultsso that the trials are more likely to be applicable in real-world settings.

An analysis of published trials found that current use of pragmatic trial labels is uninformative

ObjectivesRandomized trials labelled as “pragmatic” are attractive to funders, patients, and clinicians as the label implies that the results are directly applicable to clinical care. We examined how authors justify use of the label (e.g., by referring to one or more PRECIS [PRagmatic Explanatory Continuum Indicator Summary]-2 domains). Study Design and SettingWe reviewed primary trial reports published 2014–2019, registered in ClinicalTrials.gov and using the pragmatic label anywhere in the report. ResultsAmong 415 trials, the label was justified by reference to at least one design element in 282 (68.0%); of these, 240 (85.1%) referenced trial characteristics that can be mapped to one or more of the PRECIS-2 domains, most commonly eligibility (91, 32.3%), setting (90, 31.9%), flexibility delivery (89, 31.6%), and organization (75, 26.6%); 42 (14.9%) referenced characteristics that are not PRECIS-2 domains, most commonly type of intervention/comparator (48, 17%), recruitment without consent (22, 7.8%), routinely collected data (22, 7.8%), and cluster randomization (20, 7.1%). Most reports referenced only one or two design elements. Overall, 9/415 (2.2%) provided PRECIS wheels. ConclusionCurrent use of pragmatic labels is uninformative. Authors should clarify the decision the trial is intended to support and include a PRECIS-2 table to make the design transparent.

Comparison of explanatory and pragmatic design choices in a cluster-randomized hypertension trial: effects on enrollment, participant characteristics, and adherence

BackgroundExplanatory trials are designed to assess intervention efficacy under ideal conditions, while pragmatic trials are designed to assess whether research-proven interventions are effective in “real-world” settings without substantial research support.MethodsWe compared two trials (Hyperlink 1 and 3) that tested a pharmacist-led telehealth intervention in adults with uncontrolled hypertension. We applied PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2) scores to describe differences in the way these studies were designed and enrolled study-eligible participants, and the effect of these differences on participant characteristics and adherence to study interventions.ResultsPRECIS-2 scores demonstrated that Hyperlink 1 was more explanatory and Hyperlink 3 more pragmatic. Recruitment for Hyperlink 1 was conducted by study staff, and 2.9% of potentially eligible patients enrolled. Enrollees were older, and more likely to be male and White than non-enrollees. Study staff scheduled the initial pharmacist visit and adherence to attending this visit was 98%. Conversely for Hyperlink 3, recruitment was conducted by clinic staff at routine encounters and 81% of eligible patients enrolled. Enrollees were younger, and less likely to be male and White than non-enrollees. Study staff did not assist with scheduling the initial pharmacist visit and adherence to attending this visit was only 27%. Compared to Hyperlink 1, patients in Hyperlink 3 were more likely to be female, and Asian or Black, had lower socioeconomic indicators, and were more likely to have comorbidities. Owing to a lower BP for eligibility in Hyperlink 1 (>140/90 mm Hg) than in Hyperlink 3 (>150/95 mm Hg), mean baseline BP was 148/85 mm Hg in Hyperlink 1 and 158/92 mm Hg in Hyperlink 3.ConclusionThe pragmatic design features of Hyperlink 3 substantially increased enrollment of study-eligible patients and of those traditionally under-represented in clinical trials (women, minorities, and patients with less education and lower income), and demonstrated that identification and enrollment of a high proportion of study-eligible subjects could be done by usual primary care clinic staff. However, the trade-off was much lower adherence to the telehealth intervention than in Hyperlink 1, which is likely to reflect uptake under real-word conditions and substantially dilute intervention effect on BP.Trial registrationThe Hyperlink 1 study (NCT00781365) and the Hyperlink 3 study (NCT02996565) are registered at ClinicalTrials.gov.

752-P: Study Design and Baseline Profile for Patients with Type 2 Diabetes in the Semaglutide Once-Weekly Randomized Pragmatic Trial (SEPRA)

SEPRA (NCT03596450) is a 2-yr, multicenter, open-label, randomized pragmatic clinical trial comparing the long-term effects of once-weekly subcutaneous semaglutide vs. standard of care (both added to ≤2 oral antidiabetic medications) in US health-insured adults with T2D and physician-determined inadequate glycemic control. SEPRA will assess glycemic control, weight loss, healthcare utilization, and patient-reported outcomes by collecting individual-level data from routine clinical practice and health insurance claims. The primary endpoint is the proportion of patients achieving HbA1c &amp;lt;7.0% at yr 1. The study design was evaluated using the Pragmatic Explanatory Continuum Indicator Summary (PRECIS) -2 assessment; it scored 4-5 in all 9 domains, suggesting a highly pragmatic study. Of 1,278 patients enrolled, 54% were male with mean (± SD) age 57.4 ± 11.1 yrs, BMI 35.7± 8.0 kg/m2, diabetes duration 7.4 ± 6.0 yrs, HbA1c 8.48 ± 1.6%, and mean individualized HbA1c target 6.66 ± 0.5%. Of note, 86.9% of patients had HbA1c &amp;gt;7.0% and most required sizeable reductions in HbA1c to reach the clinician-assigned individualized target. SEPRA will provide real-world evidence on the long-term effectiveness of semaglutide in a population with a broad range of HbA1c levels and other clinical characteristics when used as intensification early on in usual T2D care practice settings. Disclosure V.Willey: Employee; HealthCore Inc. J.B.Buse: Consultant; Alkahest, Anji, AstraZeneca, Boehringer Ingelheim International GmbH, Cirius Therapeutics, Inc., Eli Lilly and Company, Fortress biotech, GentiBio, Glycadia, Glyscend, Janssen Pharmaceuticals, Inc., Mellitus Health, Moderna, Inc., Pendulum Therapeutics, Praetego, LLC, Stability Health, Valo, Zealand Pharma A/S, Other Relationship; Adocia, AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. B.Harty: None. J.L.Mitchell: None. B.P.Soule: Employee; Bristol-Myers Squibb Company, Novo Nordisk. H.N.Christensen: Employee; Novo Nordisk. M.J.Cziraky: None. S.Skibsted: Employee; Novo Nordisk. Funding Funded by Novo Nordisk Inc

Pragmatic clinical trial design in emergency medicine: Study considerations and design types.

Pragmatic clinical trials (PCTs) focus on correlation between treatment and outcomes in real-world clinical practice, yet a guide highlighting key study considerations and design types for emergency medicine investigators pursuing this important study type is not available. Investigators conducting emergency department (ED)-based PCTs face multiple decisions within the planning phase to ensure robust and meaningful study findings. The PRagmatic Explanatory Continuum Indicator Summary 2 (PRECIS-2) tool allows trialists to consider both pragmatic and explanatory components across nine domains, shaping the trial design to the purpose intended by the investigators. Aside from the PRECIS-2 tool domains, ED-based investigators conducting PCTs should also consider randomization techniques, human subjects concerns, and integration of trial components within the electronic health record. The authors additionally highlight the advantages, disadvantages, and rationale for the use of four common randomized study design types to be considered in PCTs: parallel, crossover, factorial, and stepped-wedge. With increasing emphasis on the conduct of PCTs, emergency medicine investigators will benefit from a rigorous approach to clinical trial design.

An application of PRECIS-2 to evaluate trial design in a pilot cluster randomised controlled trial of a community-based smoking cessation intervention for women living in disadvantaged areas of Ireland

Background“We Can Quit2” (WCQ2) was a pilot cluster randomised controlled trial with an embedded process evaluation assessing the feasibility and acceptability of ‘We Can Quit’ (WCQ, a peer-delivered community-based stop-smoking programme for women in disadvantaged communities. The control group comprised ‘enhanced usual care’ offered by the Irish Health Service Executive (HSE). The PRagmatic Explanatory Continuum Indicator Summary (PRECIS-2) is a tool to assess whether a trial design is more explanatory (working under ideal conditions) or pragmatic (working under ‘real-world’ conditions). The aim of this paper was to retrospectively evaluate the WCQ2 pilot trial using PRECIS-2 to inform the decision-making process on progression to a future definitive trial (DT).MethodsThe WCQ2 trial protocol and HSE standard stop-smoking service were described across the nine PRECIS-2 domains: eligibility, recruitment, setting, organisation, flexibility-delivery, flexibility-adherence, follow-up and primary outcome. Team members scored the domains as pragmatic or explanatory for each arm in a half-day workshop.ResultsSeven team members (practitioners and researchers) assessed the overall trial design as more explanatory than pragmatic. Important differences emerged between the two arms. WCQ targeted adult women from disadvantaged communities whereas HSE run a limited enhanced service for all quitters. Trial recruitment was challenging, intense efforts were needed as the trial proceeded. WCQ was delivered in a non-clinical community setting, HSE services in a clinical setting. WCQ organisation was co-designed with community partners and comprises peer-to-peer group support delivered by trained lay community facilitators, whereas HSE one-to-one support is delivered by Smoking Cessation Officers with a clinical background. Only WCQ allowed flexibility in delivery and adherence. Follow-up was more intensive in WCQ. Greater efforts to improve participant retention will be required in a future DT.ConclusionsPRECIS-2 allowed the reflection of practitioners and researchers on similarities and differences between intervention and control arms. Results will inform the decision on progression to an effectiveness DT, which will require more a pragmatic and less explanatory design. This novel use of PRECIS-2 to retrospectively evaluate a complex community-based pilot trial in advance of a full DT will also support learning for those undertaking hybrid trials of implementation and effectiveness.Trial registrationThis trial is registered with the ISRCTN registry (No. 74721694).