Registry-based Clinical Trials Research Articles

Cohort profile: the European Unified Registries On Heart Care Evaluation and Randomized Trials (EuroHeart)-acute coronary syndrome and percutaneous coronary intervention.

The European Unified Registries On Heart Care Evaluation and Randomized Trials (EuroHeart) aims to improve the quality of care and clinical outcomes for patients with cardiovascular disease. The collaboration of acute coronary syndrome/percutaneous coronary intervention (ACS/PCI) registries is operational in seven vanguard European Society of Cardiology member countries. Adults admitted to hospitals with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) are included, and individual patient-level data collected and aligned according to the internationally agreed EuroHeart data standards for ACS/PCI. The registries provide up to 155 variables spanning patient demographics and clinical characteristics, in-hospital care, in-hospital outcomes, and discharge medications. After performing statistical analyses on patient data, participating countries transfer aggregated data to EuroHeart for international reporting. Between 1st January 2022 and 31st December 2022, 40021 admissions (STEMI 46.7%, NSTEMI 53.3%) were recorded from 192 hospitals in the seven vanguard countries: Estonia, Hungary, Iceland, Portugal, Romania, Singapore, and Sweden. The mean age for the cohort was 67.9 (standard deviation 12.6) years, and it included 12628 (31.6%) women. The EuroHeart collaboration of ACS/PCI registries prospectively collects and analyses individual data for ACS and PCI at a national level, after which aggregated results are transferred to the EuroHeart Data Science Centre. The collaboration will expand to other countries and provide continuous insights into the provision of clinical care and outcomes for patients with ACS and undergoing PCI. It will serve as a unique international platform for quality improvement, observational research, and registry-based clinical trials.

Multicentre implementation of a quality improvement initiative to reduce delirium in adult intensive care units: An interrupted time series analysis

PurposeThe ABCDEF bundle may improve delirium outcomes among intensive care unit (ICU) patients, however population-based studies are lacking. In this study we evaluated effects of a quality improvement initiative based on the ABCDEF bundle in adult ICUs in Alberta, Canada. Material and methodsWe conducted a pre-post, registry-based clinical trial, analysed using interrupted time series methodology. Outcomes were examined via segmented linear regression using mixed effects models. The main data source was a population-based electronic health record. Results44,405 consecutive admissions (38,400 unique patients) admitted to 15 general medical/surgical and/or neurologic adult ICUs between 2014 and 2019 were included. The proportion of delirium days per ICU increased from 30.24% to 35.31% during the pre-intervention period. After intervention implementation it decreased significantly (bimonthly decrease of 0.34%, 95%CI 0.18–0.50%, p < 0.01) from 33.48% (95%CI 29.64–37.31%) in 2017 to 28.74% (95%CI 25.22–32.26%) in 2019. The proportion of sedation days using midazolam demonstrated an immediate decrease of 7.58% (95%CI 4.00–11.16%). There were no significant changes in duration of invasive ventilation, proportion of partial coma days, ICU mortality, or potential adverse events. ConclusionsAn ABCDEF delirium initiative was implemented on a population-basis within adult ICUs and was successful at reducing the prevalence of delirium.

A NSQIP-Based Randomized Clinical Trial Evaluating Choice of Prophylactic Antibiotics for Pancreaticoduodenectomy.

Surgical site infection is a common complication following pancreaticoduodenectomy and is a major source of postoperative morbidity. Surgical site infection is more common among patients who undergo preoperative biliary instrumentation, likely because of the introduction of intestinal flora into the normally sterile biliary tree. Frequently, bacterial isolates from surgical site infections after pancreaticoduodenectomy demonstrate resistance to the antibiotic agents typically used for surgical prophylaxis, suggesting that broad-spectrum coverage may be beneficial. This chapter summarizes the current evidence regarding surgical site infection following pancreatic surgery and describes the rationale and methodology underlying a multicenter randomized trial evaluating piperacillin-tazobactam compared with cefoxitin for surgical site infection prevention following pancreaticoduodenectomy. As the first U.S. randomized surgical trial to utilize a clinical registry for data collection, this study serves as proof of concept for registry-based clinical trials. The trial has successfully completed patient accrual, and study results are forthcoming.

Leveraging Comprehensive Cancer Registry Data to Enable a Broad Range of Research, Audit and Patient Support Activities.

Simple SummaryRegistry data has the potential to support a broad range of research, audit and education initiatives. Here, we describe the experience and learnings of a series of large multi-institutional cancer registries that leverage real-world clinical data for a range of purposes, that informs the conduct and output of each registry in a virtuous cycle. Lessons learnt include the need for careful and continuous curation of information being collected, regular database updates, and the need for a continued focus on data quality. As a standalone resource, each registry has supported numerous projects, but linkage with external datasets with patients in common has enhanced the research potential. Multiple projects have linked registry data with matched tissue specimens to support the discovery and valiation of prognostic and predictive markers in the tumour and blood specimens. Registry-based biomarker trials have been successfully supported, generating novel and practice-changing data. Registry-based clinical trials, particularly studies exploring the best use of drug options are now complementing the research conducted in traditional clinical trials. More recent projects supported by the registries include health economic studies, personalised patient education material, and increased consumer engagement, including consumer entered data.Traditional cancer registries have often been siloed efforts, established by single groups with limited objectives. There is the potential for registry data to support a broad range of research, audit and education initiatives. Here, we describe the establishment of a series of comprehensive cancer registries across the spectrum of common solid cancers. The experience and learnings of each registry team as they develop, implement and then use collected data for a range of purposes, that informs the conduct and output of other registries in a virtuous cycle. Each registry is multi-site, multi-disciplinary and aims to collect data of maximal interest and value to a broad range of enquiry, which would be accessible to any researcher with a high-quality proposal. Lessons learnt include the need for careful and continuous curation of data fields, with regular database updates, and the need for a continued focus on data quality. The registry data as a standalone resource has supported numerous projects, but linkage with external datasets with patients in common has enhanced the audit and research potential. Multiple projects have linked registry data with matched tissue specimens to support prognostic and predictive biomarker studies, both validation and discovery. Registry-based biomarker trials have been successfully supported, generating novel and practice-changing data. Registry-based clinical trials, particularly randomised studies exploring the optimal use of available therapy options are now complementing the research conducted in traditional clinical trials. More recent projects supported by the registries include health economic studies, personalised patient education material, and increased consumer engagement, including consumer entered data.

Patient Engagement in a Multi-Stakeholder Workshop to Plan the Collection of Patient-Oriented Outcomes for Children with Inherited Metabolic Diseases.

Building on a study to develop core outcome sets for children with rare inherited metabolic diseases, the purpose of this workshop was to inform the design of longitudinal pediatric registries that support registry-based clinical trials. This workshop was co-designed by two patient/family partner investigators and attended by two family advisors who received preparatory training. Patient partners and advisors recommended integrating the collection of registry data into everyday life and highlighted the importance of transparent communication and attention to the issue of integration of patient-reported data into clinical care. We propose a need to explore strategies for engaging patients in post-project knowledge translation.

A NSQIP-based randomized clinical trial evaluating choice of prophylactic antibiotics for pancreaticoduodenectomy.

Surgical site infection after pancreaticoduodenectomy is often caused by pathogens resistant to standard prophylactic antibiotics, suggesting that broad-spectrum antibiotics may be more effective prophylactic agents. This article describes the rationale and methodology underlying a multicenter randomized trial evaluating piperacillin-tazobactam compared with cefoxitin for surgical site infection prevention following pancreaticoduodenectomy. As the first US randomized surgical trial to utilize a clinical registry for data collection, this study serves as proof of concept for registry-based clinical trials.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

ENSAT registry-based randomized clinical trials for adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

Interleukin-1 Blockade in Polygenic Autoinflammatory Disorders: Where Are We now?

Polygenic autoinflammatory diseases (AIDs), such as systemic juvenile idiopathic arthritis (sJIA), adult-onset Still's disease, Kawasaki disease, idiopathic recurrent pericarditis (IRP), Behçet’s Syndrome, Crystal-induced arthropatihes such as gout or Calcium pyrophosphate deposition disease are characterized by the overexpression of inflammasome-associated genes, leading to a dysregulation of the innate immune response. The IL-1 cytokine family (IL-1α, IL-1β, IL-1Ra, IL-18, IL-36Ra, IL-36α, IL-37, IL-36β, IL-36g, IL-38, IL-33) was defined to be principally responsible for the inflammatory nature of polygenic AIDs. Several clinical trials were initiated, and IL-1 blockade has been proven to cause a rapid reduction of clinical symptoms and normalization of laboratory parameters in the majority of cases. Randomized, placebo-controlled, clinical trials, together with registry-based clinical trials and open-label, retrospective and prospective observational studies, supported the efficacy and safety of IL-1 inhibitors in the treatment of polygenic AIDs. Most of the current data are focused on the therapeutic use of anakinra, an IL-1 receptor antagonist, canakinumab, an anti-IL-1β monoclonal antibody, and rilonacept, a soluble decoy receptor. However, other promising agents, such as gevokizumab, IL-1β blocking monoclonal antibody, tadekinig alfa, a human recombinant IL-18-binding protein, and tranilast, an analog of a tryptophan metabolite, are currently being tested. Anakinra, canakinumab and rilonacept caused impressive improvements in both systemic and musculoskeletal symptoms. Furthermore, the anti-IL-1 therapy allowed corticosteroid tapering and, in some cases, even withdrawal. This article reviews the current IL-1 inhibitors and the results of all clinical trials in which they have been tested for the management of broad spectrum of polygenic AIDs.

Mortality with Paclitaxel-Coated Devices in Peripheral Artery Disease

BackgroundThe results of a recent meta-analysis aroused concern about an increased risk of death associated with the use of paclitaxel-coated angioplasty balloons and stents in lower-limb endovascular interventions for symptomatic peripheral artery disease.MethodsWe conducted an unplanned interim analysis of data from a multicenter, randomized, open-label, registry-based clinical trial. At the time of the analysis, 2289 patients had been randomly assigned to treatment with drug-coated devices (the drug-coated–device group, 1149 patients) or treatment with uncoated devices (the uncoated-device group, 1140 patients). Randomization was stratified according to disease severity on the basis of whether patients had chronic limb-threatening ischemia (1480 patients) or intermittent claudication (809 patients). The single end point for this interim analysis was all-cause mortality.ResultsNo patients were lost to follow-up. Paclitaxel was used as the coating agent for all the drug-coated devices. During a mean follow-up of 2.49 years, 574 patients died, including 293 patients (25.5%) in the drug-coated–device group and 281 patients (24.6%) in the uncoated-device group (hazard ratio, 1.06; 95% confidence interval, 0.92 to 1.22). At 1 year, all-cause mortality was 10.2% (117 patients) in the drug-coated–device group and 9.9% (113 patients) in the uncoated-device group. During the entire follow-up period, there was no significant difference in the incidence of death between the treatment groups among patients with chronic limb-threatening ischemia (33.4% [249 patients] in the drug-coated–device group and 33.1% [243 patients] in the uncoated-device group) or among those with intermittent claudication (10.9% [44 patients] and 9.4% [38 patients], respectively).ConclusionsIn this randomized trial in which patients with peripheral artery disease received treatment with paclitaxel-coated or uncoated endovascular devices, the results of an unplanned interim analysis of all-cause mortality did not show a difference between the groups in the incidence of death during 1 to 4 years of follow-up. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT02051088.)

Developments in evidence creation for treatments of inborn errors of metabolism.

Inborn errors of metabolism (IEM) represent the first group of genetic disorders, amenable to causal therapies. In addition to traditional medical diet and cofactor treatments, new treatment strategies such as enzyme replacement and small molecule therapies, solid organ transplantation, and cell‐and gene‐based therapies have become available. Inherent to the rare nature of the single conditions, generating high‐quality evidence for these treatments in clinical trials and under real‐world conditions has been challenging. Guidelines developed with standardized methodologies have contributed to improve the practice of care and long‐term clinical outcomes. Adaptive trial designs allow for changes in sample size, group allocation and trial duration as the trial proceeds. n‐of‐1 studies may be used in small sample sized when participants are clinically heterogeneous. Multicenter observational and registry‐based clinical trials are promoted via international research networks. Core outcome and standard data element sets will enhance comparative analysis of clinical trials and observational studies. Patient‐centered outcome‐research as well as patient‐led research initiatives will further accelerate the development of therapies for IEM.

Determining the Suitability of Registries for Embedding Clinical Trials in the United States: A Project of the Clinical Trials Transformation Initiative

BackgroundPatient registries are organized systems that use observational methods to collect uniform data on specified outcomes in a population defined by a particular disease, condition, or exposure. Data collected in registries often coincide with data that could support clinical trials. Integrating clinical trials within registries to create registry-embedded clinical trials offers opportunities to reduce duplicative data collection, identify and recruit patients more efficiently, decrease time to database lock, accelerate time to regulatory decision-making, and reduce clinical trial costs. This article describes a project of the Clinical Trials Transformation Initiative (CTTI) intended to help clinical trials researchers determine when a registry could potentially serve as the platform for the conduct of a clinical trial.MethodsThrough a review of registry-embedded clinical trials and commentaries, semi-structured interviews with experts, and a multi-stakeholder expert meeting, the project team addressed how to identify and describe essential registry characteristics, practices, and processes required to for conducting embedded clinical trials intended for regulatory submissions in the United States.ResultsRecommendations, suggested practices, and decision trees that facilitate the assessment of whether a registry is suitable for embedding clinical trials were developed, as well as considerations for the design of new registries. Essential registry characteristics include relevancy, robustness, reliability, and assurance of patient protections.ConclusionsThe project identifies a clear role for registries in creating a sustainable and reusable infrastructure to conduct clinical trials. Adoption of these recommendations will facilitate the ability to perform high-quality and efficient prospective registry-based clinical trials.

Early continuous ultrafiltration in Chinese patients with congestive heart failure (EUC-CHF): study protocol for an open-label registry-based prospective clinical trial

BackgroundConventional pharmacologic therapies aim to reduce fluid overload in advanced heart failure (HF) represented by intravenous (IV) loop diuretics (LDs) have sometimes not so efficacious and been reported to have side effects such as unpredictable removal of water and sodium and electrolyte disturbance. It is not certain whether early ultrafiltration (UF) is effective than LDs in relieving edema. Given the weakness of evidence for early UF in patients with fluid overload, recommendations of UF in guidelines is considered as second-line therapy only for patients with refractory congestion, who failed to respond to LD-based strategies.MethodsThe early continuous ultrafiltration in Chinese patients with congestive heart failure (EUC-CHF) trial is an open-label, registry-based, prospective study, recruiting patients with severe acute decompensated HF who are hospitalized for HF worsening due to overt fluid overload 24 h from hospital admission. Forty patients will be enrolled to two treatment groups (n = 20 for each group). The primary outcomes are the changes of weight loss and dyspnea severity score after treatment, as well as the occurrence of clinically overt major bleeding.DiscussionEUC-CHF trial was primarily designed to evaluate the efficacy and safety of early UF in patients with acute decompensated HF to reduce volume overload and improve clinical outcome. The trial aims to determine if early UF in acute HF is superior to IV LDs in clinical parameter improvement without adverse events and prevents rehospitalization up to 30 days. Also the trial is expected to establish a scoring system based on Chinese population to guide early UF treatment in appropriate patients. EUC-CHF is one of the first controlled trials tailored to determine the benefit of UF with 24 h from hospital admission.Trial registrationwww.chictr.org.cn, ChiCTR1800019556. Registered on 18 November 2018.

Use of the CANHEART ‘big data’ registry to conduct a large randomized registry clinical trial to improve lipid management in Ontario, Canada

IntroductionCreation of registries using linked population-based databases could potentially be used to conduct large registry-based clinical trials. As part of the CANHEART-Strategy for Patient-Oriented Research (SPOR) innovative clinical trials initiative, we explored the practicality of using the linked CANHEART registry to conduct a cluster-randomized trial aimed at improving lipid management.&#x0D; Objectives and ApproachThe CANHEART registry (www.canheart.ca) was created through the linkage of 19 population-based health databases in Ontario, Canada, providing individual-level socio-demographic, geographic, hospitalization, disease testing/screening, mortality, prescription medication, and behavior/lifestyle information. Using CANHEART defined eligibility criterion, small and medium-sized, high cardiovascular-risk health regions (defined as having acute myocardial infarction, stroke or cardiovascular death rates greater than the Ontario average) are being randomly allocated to receive either the intervention (availability of a lipid management ‘toolbox’) or standard care. Cohort linkages to additional years of data will occur regularly over the 3-year trial to ascertain the primary outcome of appropriate statin prescribing rates.&#x0D; &#x0D; \section*{Results}&#x0D; Record linkage enabled us to determine baseline characteristics of 835,345 patients aged 40-75 as of January 2016, being treated in the 28 study-eligible regions by 2,012 family physicians. Preceding the study, the baseline statin use rate was 35.7\% (in 66-75 year olds) across these regions and the cardiovascular event rate ranged from 3.78-5.64 events/1000 person-years. A randomization procedure yielded 14 regions in both the intervention and control arms which did not differ significantly in socio-demographic characteristics, traditional cardiovascular risk factors, disease history, prevalence of statin use, or access to healthcare indicators. Working groups have been established to operationalize the lipid management tools that will be made available in the intervention regions. Analysis of newly linked participant data will permit outcome ascertainment at trial completion.&#x0D; &#x0D; \section*{Conclusion/Implications}&#x0D; Our work demonstrates the feasibility of using the CANHEART ‘big data’ registry to conduct a large, cluster-randomized clinical trial aimed at improving lipid management, without requiring any primary data collection. Broader use of this methodology has the potential to change the existing paradigm for conducting pragmatic clinical trial research.