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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 -
Injury Oct 2023Recent decades have seen marked advances in the quality of clinical orthopaedic trauma research, and with this has come a rise in the number of randomised clinical... (Review)
Review
Recent decades have seen marked advances in the quality of clinical orthopaedic trauma research, and with this has come a rise in the number of randomised clinical trials (RCTs) being conducted in orthopaedic trauma. These trials have been largely valuable in driving evidence-based management of injuries which previously had clinical equipoise. However, though RCTs are traditionally seen as the 'gold standard' of high-quality research, this research method is comprised primarily of two entities, explanatory and pragmatic designs, each with its own strengths and limitations. Most orthopaedic trials lie within a continuum between these designs, with varying degrees of both pragmatic and explanatory features. In this narrative review we provide a summary of the nuances within orthopaedic trial design, the advantages and limitations of such designs, and suggest tools which may aid clinicians in the appropriate selection and evaluation of trial designs.
Topics: Humans; Orthopedics; Research Design; Orthopedic Procedures
PubMed: 37400326
DOI: 10.1016/j.injury.2023.110905 -
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 Intensive Care Medicine Nov 2023Implementation of the "B" element-both spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs)-of the ABCDEF bundle improves the outcomes for...
BACKGROUND
Implementation of the "B" element-both spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs)-of the ABCDEF bundle improves the outcomes for mechanically ventilated patients. In 2021, the Pragmatic Investigation of optimal Oxygen Targets (PILOT) trial investigating optimal oxygenation targets in patients on mechanical ventilation was completed.
OBJECTIVES
To compare SAT and SBT conduct between a randomized controlled trial and current clinical care.
METHODS
The 2008 Awakening and Breathing Controlled (ABC) Trial (2003-2006) randomized mechanically ventilated patients to paired SATs and SBTs versus sedation per usual care plus SBTs. The PILOT trial (2018-2021) enrolled patients years later where SAT + SBT conduct was observed. We compared SAT and SBT conduct in ABC's interventional group (SAT + SBT; n = 167, 1140 patient days) to that in PILOT (n = 2083, 8355 patient days).
RESULTS
Spontaneous awakening trial safety screens were done in all 1140 ABC patient-days on sedation and/or analgesia and in 3889 of 4228 (92%) in PILOT. Spontaneous awakening trial safety screens were passed in 939 of 1140 (82%) instances in ABC versus only 1897 of 3889 (49%) in PILOT. Interestingly, SAT was performed in ≥95% of passed SAT safety screens in both trials and was passed in 837 of 895 (94%) in ABC versus 1145 of 1867 (61%) in PILOT. SBT safety screens were performed in all 983 ABC instances and 8031 of 8370 (96%) in PILOT. SBT safety screens were passed in 647 of 983 (66%) in ABC versus 4475 of 8031 (56%) in PILOT. Spontaneous breathing trial was performed in ≥93% of passed SBT safety screens in both trials and was passed in 319 of 603 (53%) in ABC versus 3337 of 4454 (75%) in PILOT.
CONCLUSION
This study compared SAT/SBT conduction in an ideal setting to real-world practice, 13 years later. Performance of SAT/SBT safety screens, SATs, and SBTs between a definitive clinical trial (ABC) as compared to current clinical care (PILOT) remained high.
PubMed: 37981753
DOI: 10.1177/08850666231213337 -
Trials Jan 2024In an era focused on value-based healthcare, the quality of healthcare and resource allocation should be underpinned by empirical evidence. Pragmatic clinical trials... (Review)
Review
Pragmatic randomized controlled trials: strengthening the concept through a robust international collaborative network: PRIME-9-Pragmatic Research and Innovation through Multinational Experimentation.
In an era focused on value-based healthcare, the quality of healthcare and resource allocation should be underpinned by empirical evidence. Pragmatic clinical trials (pRCTs) are essential in this endeavor, providing randomized controlled trial (RCT) insights that encapsulate real-world effects of interventions. The rising popularity of pRCTs can be attributed to their ability to mirror real-world practices, accommodate larger sample sizes, and provide cost advantages over traditional RCTs. By harmonizing efficacy with effectiveness, pRCTs assist decision-makers in prioritizing interventions that have a substantial public health impact and align with the tenets of value-based health care. An international network for pRCT provides several advantages, including larger and diverse patient populations, access to a broader range of healthcare settings, sharing knowledge and expertise, and overcoming ethical and regulatory barriers. The hypothesis and study design of pRCT answers the decision-maker's questions. pRCT compares clinically relevant alternative interventions, recruits participants from diverse practice settings, and collects data on various health outcomes. They are scarce because the medical products industry typically does not fund pRCT. Prioritizing these studies by expanding the infrastructure to conduct clinical research within the healthcare delivery system and increasing public and private funding for these studies will be necessary to facilitate pRCTs. These changes require more clinical and health policy decision-makers in clinical research priority setting, infrastructure development, and funding. This paper presents a comprehensive overview of pRCTs, emphasizing their importance in evidence-based medicine and the advantages of an international collaborative network for their execution. It details the development of PRIME-9, an international initiative across nine countries to advance pRCTs, and explores various statistical approaches for these trials. The paper underscores the need to overcome current challenges, such as funding limitations and infrastructural constraints, to leverage the full potential of pRCTs in optimizing healthcare quality and resource utilization.
Topics: Humans; Randomized Controlled Trials as Topic; Research Design; Sample Size; Administrative Personnel; Evidence-Based Medicine
PubMed: 38263138
DOI: 10.1186/s13063-024-07935-y -
Journal of Clinical Medicine Sep 2023Heart failure (HF) is a significant clinical and financial burden worldwide. Remote monitoring (RM) devices capable of identifying early physiologic changes in... (Review)
Review
Heart failure (HF) is a significant clinical and financial burden worldwide. Remote monitoring (RM) devices capable of identifying early physiologic changes in decompensation have the potential to reduce the HF burden. However, few trials have discussed at length the practical aspects of implementing RM in real-world clinical practice. The present paper reviews current RM devices and clinical trials, focusing on patient populations, outcomes, data collection, storage, and management, and describes the implementation of an RM device in clinical practice, providing a pragmatic and adaptable framework.
PubMed: 37834845
DOI: 10.3390/jcm12196200 -
BMJ Open Sep 2023Corneal blindness is the third most frequent cause of blindness globally. Damage to the corneal endothelium is a leading indication for corneal transplantation, which is...
Belgian Endothelial Surgical Transplant of the Cornea (BEST cornea) protocol: clinical and patient-reported outcomes of Ultra-Thin Descemet Stripping Automated Endothelial Keratoplasty (UT-DSAEK) versus Descemet Membrane Endothelial Keratoplasty (DMEK) - a multicentric, randomised, parallel group...
OBJECTIVES
Corneal blindness is the third most frequent cause of blindness globally. Damage to the corneal endothelium is a leading indication for corneal transplantation, which is typically performed by lamellar endothelial keratoplasty. There are two conventional surgical techniques: Ultra-Thin Descemet Stripping Automated Endothelial Keratoplasty (UT-DSAEK) and Descemet Membrane Endothelial Keratoplasty (DMEK). The purpose of this study is to compare both techniques.
METHODS AND ANALYSIS
The trial compares UT-DSAEK and DMEK in terms of clinical and patient reported outcomes using a pragmatic, parallel, multicentric, randomised controlled trial with 1:1 allocation with a sample size of 220 participants across 11 surgical centres. The primary outcome is the change in best-corrected visual acuity at 12 months. Secondary outcomes include corrected and uncorrected vision, refraction, proportion of high vision, quality of life (EQ-5D-5L and VFQ25), endothelial cell counts and corneal thickness at 3, 6 and 12 months follow-up appointments. Adverse events will also be compared 12 months postoperatively.
ETHICS AND DISSEMINATION
The protocol was reviewed by ethical committees of 11 participating centres with the sponsor centre issuing the final definitive approval. The results will be disseminated at clinical conferences, by patient partner groups and open access in peer-reviewed journals.
GOVERNANCE OF THE TRIAL
Both, trial management group and trial steering committee, are installed with representatives of all stakeholders involved including surgeons, corneal bankers, patients and external experts.
TRIAL REGISTRATION NUMBER
NCT05436665.
Topics: Humans; Endothelium, Corneal; Belgium; Descemet Membrane; Quality of Life; Corneal Diseases; Corneal Transplantation; Cornea; Patient Reported Outcome Measures; Blindness; Randomized Controlled Trials as Topic
PubMed: 37714670
DOI: 10.1136/bmjopen-2023-072333 -
BMJ Open Dec 2023Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol,...
Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B Trial): protocol for a multicentre phase 3 pragmatic clinical and cost-effectiveness randomised trial in the UK.
INTRODUCTION
Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care.
METHODS AND ANALYSIS
Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of -2 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40-50 UK ICUs.
ETHICS AND DISSEMINATION
The Scotland A REC approved the trial (18/SS/0085). We use a surrogate decision-maker or deferred consent model consistent with UK law. Dissemination will be via publications, presentations and updated guidelines.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov NCT03653832.
Topics: Adult; Humans; Propofol; Dexmedetomidine; Cost-Benefit Analysis; Clonidine; Critical Illness; Quality of Life; Adrenergic alpha-2 Receptor Agonists; Hypnotics and Sedatives; Pain; Intensive Care Units; United Kingdom; Respiration, Artificial; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Clinical Trials, Phase III as Topic
PubMed: 38072483
DOI: 10.1136/bmjopen-2023-078645 -
Trials Aug 2023Medical complications during pregnancy, including anaemia, gestational diabetes mellitus and hypertensive disorders of pregnancy place women are at higher risk of...
A community-based intervention to improve screening, referral and follow-up of non-communicable diseases and anaemia amongst pregnant and postpartum women in rural India: study protocol for a cluster randomised trial.
BACKGROUND
Medical complications during pregnancy, including anaemia, gestational diabetes mellitus and hypertensive disorders of pregnancy place women are at higher risk of long-term complications. Scalable and low-cost strategies to integrate non-communicable disease screening into pregnancy care are needed. We aim to determine the effectiveness and implementation components of a community-based, digitally enabled approach, "SMARThealth Pregnancy," to improve health during pregnancy and the first year after birth.
METHODS
A pragmatic, parallel-group, cluster randomised, type 2 hybrid effectiveness-implementation trial of a community-based, complex intervention in rural India to decrease anaemia (primary outcome, defined as haemoglobin < 12g/dL) and increase testing for haemoglobin, glucose and blood pressure (secondary outcomes) in the first year after birth. Primary Health Centres (PHCs) are the unit of randomisation. PHCs are eligible with (1) > 1 medical officer and > 2 community health workers; and (2) capability to administer intravenous iron sucrose. Thirty PHCs in Telangana and Haryana will be randomised 1:1 using a matched-pair design accounting for cluster size and distance from the regional centre. The intervention comprises (i) an education programme for community health workers and PHC doctors; (ii) the SMARThealth Pregnancy app for health workers to support community-based screening, referral and follow-up of high-risk cases; (iii) a dashboard for PHC doctors to monitor high-risk women in the community; (iv) supply chain monitoring for consumables and medications and (v) stakeholder engagement to co-develop implementation and sustainability pathways. The comparator is usual care with additional health worker education. Secondary outcomes include implementation outcomes assessed by the RE-AIM framework (reach, effectiveness, adoption, implementation, maintenance), clinical endpoints (anaemia, diabetes, hypertension), clinical service delivery indicators (quality of care score), mental health and lactation practice (PHQ9, GAD7, EuroQoL-5D, WHO IYCF questionnaire).
DISCUSSION
Engaging women with screening after a high-risk pregnancy is a challenge and has been highlighted as a missed opportunity for the prevention of non-communicable diseases. The SMARThealth Pregnancy trial is powered for the primary outcome and will address gaps in the evidence around how pregnancy can be used as an opportunity to improve women's lifelong health. If successful, this approach could improve the health of women living in resource-limited settings around the world.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05752955. Date of registration 3 March 2023.
Topics: Female; Humans; Pregnancy; Anemia; Diabetes, Gestational; Follow-Up Studies; Hypertension; India; Noncommunicable Diseases; Postpartum Period; Referral and Consultation; Randomized Controlled Trials as Topic
PubMed: 37559158
DOI: 10.1186/s13063-023-07510-x -
Trials Jul 2023Each year, 1 million children develop TB resulting in over 200,000 child deaths. TB preventive treatment (TPT) is highly effective in preventing TB but remains poorly... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Each year, 1 million children develop TB resulting in over 200,000 child deaths. TB preventive treatment (TPT) is highly effective in preventing TB but remains poorly implemented for household child contacts. Home-based child contact management and TPT services may improve access to care. In this study, we aim to evaluate the effectiveness and cost-effectiveness of home-based contact management with TPT initiation in two TB high-burden African countries, Ethiopia and South Africa.
METHODS
This pragmatic cluster randomized trial compares home-based versus facility-based care delivery models for contact management. Thirty-six clinics with decentralized TB services (18 in Ethiopia and 18 in South Africa) were randomized in a 1:1 ratio to conduct either home-based or facility-based contact management. The study will attempt to enroll all eligible close child contacts of infectious drug-sensitive TB index patients diagnosed and treated for TB by one of the study clinics. Child TB contact management, including contact tracing, child evaluation, and TPT initiation and follow-up, will take place in the child's home for the intervention arm and at the clinic for the control arm. The primary outcome is the cluster-level ratio of the number of household child contacts less than 15 years of age in Ethiopia and less than 5 years of age in South Africa initiated on TPT per index patient, comparing the intervention to the control arm. Secondary outcomes include child contact identification and the TB prevention continuum of care. Other implementation outcomes include acceptability, feasibility, fidelity, cost, and cost-effectiveness of the intervention.
DISCUSSION
This implementation research trial will determine whether home-based contact management identifies and initiates more household child contacts on TPT than facility-based contact management.
TRIAL REGISTRATION
NCT04369326 . Registered on April 30, 2020.
Topics: Child; Humans; Child, Preschool; Tuberculosis; South Africa; Ethiopia; Ambulatory Care Facilities; Clinical Protocols; Contact Tracing
PubMed: 37491264
DOI: 10.1186/s13063-023-07514-7