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Trials Feb 2023The effectiveness of biologic therapies, primarily tumor necrosis factor inhibitors (TNFi), for children with spondyloarthritis (SpA) has made inactive disease a...
BACKGROUND
The effectiveness of biologic therapies, primarily tumor necrosis factor inhibitors (TNFi), for children with spondyloarthritis (SpA) has made inactive disease a realistic patient outcome. However, biologic therapies are costly, primarily delivered by subcutaneous or intravenous route, and have non-trivial side effects. Many patients and families want to know if biologic medications can be discontinued after inactive disease is achieved. It remains unclear whether medication dose should remain unchanged, tapered (increase the time between doses), or discontinued once when inactive disease is attained.
METHODS
The Biologic Abatement and Capturing Kids' Outcomes and Flare Frequency in Juvenile SpA (BACK-OFF JSpA) trial is a multicenter pragmatic trial that will randomize 198 participants ages 8-21 years old with SpA and sustained inactive disease on standard TNFi dosing to (1) continue standard TNFi dosing, (2) fixed longer dosing intervals of TNFi, or (3) stop TNFi. The trial will compare the hazard rate of protocol-defined flare and participants' emotional health among the 3 groups over 12 months. Innovative aspects of this trial are the involvement of patient and parent stakeholders in the design and conduct of the study as well as an electronic health record-based enhanced recruitment strategy.
DISCUSSION
This is the first randomized pragmatic trial to assess the efficacy of TNFi de-escalation strategies in children with JSpA with sustained inactive disease. This research will improve the evidence base that patients, caregivers, and rheumatologists use to make shared decisions about continued treatment versus de-escalation of TNFi therapy in this population.
TRIAL REGISTRATION
ClinicalTrials.gov NCT04891640. Registered on 18 May 2021.
Topics: Adolescent; Adult; Child; Humans; Young Adult; Antirheumatic Agents; Arthritis, Juvenile; Biological Products; Multicenter Studies as Topic; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Spondylarthritis; Spondylitis, Ankylosing; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha
PubMed: 36755328
DOI: 10.1186/s13063-022-07038-6 -
American Journal of Respiratory and... Oct 2021
Topics: Clinical Trials as Topic; Critical Care; Critical Illness; Hospitalization; Humans; Outcome Assessment, Health Care; Patient-Centered Care; Quality Indicators, Health Care
PubMed: 34319848
DOI: 10.1164/rccm.202104-1063PP -
Circulation Mar 2016Randomized, clinical trials are commonly regarded as the highest level of evidence to support clinical decisions. Good Clinical Practice guidelines have been constructed... (Review)
Review
Randomized, clinical trials are commonly regarded as the highest level of evidence to support clinical decisions. Good Clinical Practice guidelines have been constructed to provide an ethical and scientific quality standard for trials that involve human subjects in a manner aligned with the Declaration of Helsinki. Originally designed to provide a unified standard of trial data to support submission to regulatory authorities, the principles may also be applied to other studies of human subjects. Although the application of Good Clinical Practice principles generally led to improvements in the quality and consistency of trial operations, these principles have also contributed to increasing trial complexity and costs. Alternatively, the growing availability of electronic health record data has facilitated the possibility for streamlined pragmatic clinical trials. The central tenets of Good Clinical Practice and pragmatic clinical trials represent potential tensions in trial design (stringent quality and highly efficient operations). In the present article, we highlight potential areas of discordance between Good Clinical Practice guidelines and the principles of pragmatic clinical trials and suggest strategies to streamline study conduct in an ethical manner to optimally perform clinical trials in the electronic age.
Topics: Clinical Trials as Topic; Humans; Practice Guidelines as Topic; Research Design
PubMed: 26927005
DOI: 10.1161/CIRCULATIONAHA.115.019902 -
Trials Dec 2019All clinical trial investigators have ethical and regulatory obligations to monitor participant safety and trial integrity. Specific procedures for meeting these...
BACKGROUND
All clinical trial investigators have ethical and regulatory obligations to monitor participant safety and trial integrity. Specific procedures for meeting these obligations, however, may differ substantially between pragmatic trials and traditional explanatory clinical trials.
METHODS/RESULTS
Appropriate monitoring of clinical trials typically includes assessing rate of recruitment or enrollment; monitoring safe and effective delivery of study treatments; assuring that study staff act to minimize risks; monitoring quality and timeliness of study data; and considering interim analyses for early detection of benefit, harm, or futility. Each of these responsibilities applies to pragmatic clinical trials. Just as design of pragmatic trials typically involves specific and necessary departures from methods of explanatory clinical trials, appropriate monitoring of pragmatic trials typically requires specific departures from monitoring procedures used in explanatory clinical trials. We discuss how specific aspects of pragmatic trial design and operations influence selection of monitoring procedures and illustrate those choices using examples from three ongoing pragmatic trials conducted by the Mental Health Research Network.
CONCLUSIONS
Pragmatic trial investigators should not routinely adopt monitoring procedures used in explanatory clinical trials. Instead, investigators should consider core principles of trial monitoring and design monitoring procedures appropriate for each pragmatic trial.
Topics: Adolescent; Adult; Aged; Data Accuracy; Humans; Middle Aged; Pragmatic Clinical Trials as Topic; Research Design; Young Adult
PubMed: 31815644
DOI: 10.1186/s13063-019-3869-3 -
Trials Oct 2022Rifampicin-resistant tuberculosis (RR-TB) remains an important global health problem. Ideally, the complete drug-resistance profile guides individualized treatment for...
Sequencing Mycobacteria and Algorithm-determined Resistant Tuberculosis Treatment (SMARTT): a study protocol for a phase IV pragmatic randomized controlled patient management strategy trial.
BACKGROUND
Rifampicin-resistant tuberculosis (RR-TB) remains an important global health problem. Ideally, the complete drug-resistance profile guides individualized treatment for all RR-TB patients, but this is only practised in high-income countries. Implementation of whole genome sequencing (WGS) technologies into routine care in low and middle-income countries has not become a reality due to the expected implementation challenges, including translating WGS results into individualized treatment regimen composition.
METHODS
This trial is a pragmatic, single-blinded, randomized controlled medical device trial of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Subjects are 18 years or older and diagnosed with pulmonary RR-TB in four of the five health districts of the Free State province in South Africa. Participants are randomized in a 1:1 ratio to either the intervention (a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB) or control (RR-TB treatment according to the national South African guidelines). The primary effectiveness outcome is the bacteriological response to treatment measured as the rate of change in time to liquid culture positivity during the first 6 months of treatment. Secondary effectiveness outcomes include cure rate, relapse rate (recurrence of RR-TB disease) and TB free survival rate in the first 12 months following RR-TB treatment completion. Additional secondary outcomes of interest include safety, the feasibility of province-wide implementation of the strategy into routine care, and health economic assessment from a patient and health systems perspective.
DISCUSSION
This trial will provide important real-life evidence regarding the feasibility, safety, cost, and effectiveness of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Given the pragmatic nature, the trial will assist policymakers in the decision-making regarding the integration of next-generation sequencing technologies into routine RR-TB care in high TB burden settings.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05017324. Registered on August 23, 2021.
Topics: Algorithms; Antitubercular Agents; Clinical Trials, Phase IV as Topic; Humans; Mycobacterium; Neoplasm Recurrence, Local; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Multidrug-Resistant
PubMed: 36209235
DOI: 10.1186/s13063-022-06793-w -
Trials Aug 2022Explanatory trials are designed to assess intervention efficacy under ideal conditions, while pragmatic trials are designed to assess whether research-proven...
BACKGROUND
Explanatory 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.
METHODS
We 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.
RESULTS
PRECIS-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.
CONCLUSION
The 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 REGISTRATION
The Hyperlink 1 study (NCT00781365) and the Hyperlink 3 study (NCT02996565) are registered at ClinicalTrials.gov.
Topics: Adult; Female; Humans; Hypertension; Male; Pharmacists; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Telemedicine
PubMed: 35978336
DOI: 10.1186/s13063-022-06611-3 -
BMC Public Health Feb 2022Daily physical activity is critical during the early years of life for facilitating children's health and development. A large proportion of preschool children do not...
Evaluating the effectiveness of the Play Active policy intervention and implementation support in early childhood education and care: a pragmatic cluster randomised trial protocol.
BACKGROUND
Daily physical activity is critical during the early years of life for facilitating children's health and development. A large proportion of preschool children do not achieve the recommended 3 h of daily physical activity. Early childhood education and care (ECEC) services are a key setting to intervene to increase physical activity. There is a significant need for ECEC specific physical activity policy, including clearer guidelines on the amount of physical activity children should do during care, and strategies for implementation of these guidelines.
METHODS
This study is a pragmatic cluster randomised trial to evaluate the effectiveness of the Play Active physical activity policy intervention to improve early childhood education and care educator's physical activity-related practices. The central component of Play Active is an evidence-informed physical activity policy template which includes 25 practices to support nine age-specific recommendations on the amount of physical activity and sedentary time, including screen time, young children should do while in care. There are six implementation support strategies to facilitate physical activity policy implementation: (i) personalise policy (services select at least five of the 25 practices to focus on initially); (ii) policy review and approval; (iii) a resource guide; (iv) a brief assessment tool for monitoring children's energetic play; (v) professional development; and (vi) Project Officer implementation support (phone calls). A total of 60 early childhood education and care services will be recruited from metropolitan Perth, Western Australia. After baseline assessment, services will be randomly allocated to either intervention or wait-listed comparison conditions. Primary (educator-reported frequency and amount of daily time provided for children's physical activity, sedentary and screen time) and secondary (educator physical activity-related practices, self-efficacy, motivation, attitudes and beliefs, social support, and supportive physical environment) outcomes will be assessed at baseline and post-intervention, after intervention services have had a minimum 3 months of policy implementation within their service.
DISCUSSION
The Play Active trial will rigorously evaluate a novel physical activity policy intervention with implementation support that promotes positive physical activity behaviours in educators and children attending ECEC. If effective, the program could be adapted, scaled-up and delivered in ECEC services nationally.
TRIAL REGISTRATION
Australian New Zealand Clinical Trials Registry ACTRN12620001206910 (date of registration 13/11/2020).
Topics: Australia; Child; Child Health; Child, Preschool; Exercise; Health Promotion; Humans; Policy; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Self Efficacy
PubMed: 35164729
DOI: 10.1186/s12889-022-12729-5 -
Neurology Apr 2016We aimed to provide recommendations for addressing comorbidity in clinical trial design and conduct in multiple sclerosis (MS).
OBJECTIVE
We aimed to provide recommendations for addressing comorbidity in clinical trial design and conduct in multiple sclerosis (MS).
METHODS
We held an international workshop, informed by a systematic review of the incidence and prevalence of comorbidity in MS and an international survey about research priorities for studying comorbidity including their relation to clinical trials in MS.
RESULTS
We recommend establishing age- and sex-specific incidence estimates for comorbidities in the MS population, including those that commonly raise concern in clinical trials of immunomodulatory agents; shifting phase III clinical trials of new therapies from explanatory to more pragmatic trials; describing comorbidity status of the enrolled population in publications reporting clinical trials; evaluating treatment response, tolerability, and safety in clinical trials according to comorbidity status; and considering comorbidity status in the design of pharmacovigilance strategies.
CONCLUSION
Our recommendations will help address knowledge gaps regarding comorbidity that interfere with the ability to interpret safety in monitored trials and will enhance the generalizability of findings from clinical trials to "real world" settings where the MS population commonly has comorbid conditions.
Topics: Clinical Trials as Topic; Comorbidity; Humans; Multiple Sclerosis
PubMed: 26888986
DOI: 10.1212/WNL.0000000000002471 -
BMJ Open Mar 2022Nearly one-quarter of patients discharged from the hospital with heart failure (HF) are readmitted within 30 days, placing a significant burden on patients, families and...
Using Mobile Integrated Health and telehealth to support transitions of care among patients with heart failure (MIGHTy-Heart): protocol for a pragmatic randomised controlled trial.
INTRODUCTION
Nearly one-quarter of patients discharged from the hospital with heart failure (HF) are readmitted within 30 days, placing a significant burden on patients, families and health systems. The objective of the 'Using obile nterated ealth and elehealth to support transitions of care among patients with failure) study is to compare the effectiveness of two postdischarge interventions on healthcare utilisation, patient-reported outcomes and healthcare quality among patients with HF.
METHODS AND ANALYSIS
The MIGHTy-Heart study is a pragmatic comparative effectiveness trial comparing two interventions demonstrated to improve the hospital to home transition for patients with HF: mobile integrated health (MIH) and transitions of care coordinators (TOCC). The MIH intervention bundles home visits from a community paramedic (CP) with telehealth video visits by emergency medicine physicians to support the management of acute symptoms and postdischarge care coordination. The TOCC intervention consists of follow-up phone calls from a registered nurse within 48-72 hours of discharge to assess a patient's clinical status, identify unmet clinical and social needs and reinforce patient education (eg, medication adherence and lifestyle changes). MIGHTy-Heart is enrolling and randomising (1:1) 2100 patients with HF who are discharged to home following a hospitalisation in two New York City (NY, USA) academic health systems. The coprimary study outcomes are all-cause 30-day hospital readmissions and quality of life measured with the Kansas City Cardiomyopathy Questionnaire 30 days after hospital discharge. The secondary endpoints are days at home, preventable emergency department visits, unplanned hospital admissions and patient-reported symptoms. Data sources for the study outcomes include patient surveys, electronic health records and claims submitted to Medicare and Medicaid.
ETHICS AND DISSEMINATION
All participants provide written or verbal informed consent prior to randomisation in English, Spanish, French, Mandarin or Russian. Study findings are being disseminated to scientific audiences through peer-reviewed publications and presentations at national and international conferences. This study has been approved by: Biomedical Research Alliance of New York (BRANY #20-08-329-380), Weill Cornell Medicine Institutional Review Board (20-08022605) and Mt. Sinai Institutional Review Board (20-01901).
TRIAL REGISTRATION NUMBER
Clinicaltrials.gov, NCT04662541.
Topics: Aftercare; Aged; Heart Failure; Humans; Medicare; New York City; Patient Discharge; Pragmatic Clinical Trials as Topic; Quality of Life; Randomized Controlled Trials as Topic; Telemedicine; United States
PubMed: 35273051
DOI: 10.1136/bmjopen-2021-054956 -
BMC Infectious Diseases Jul 2022Sepsis is still a major public health concern and a medical emergency due to its high morbidity and mortality. Accurate and timely etiology diagnosis is crucial for...
Evaluation of droplet digital PCR rapid detection method and precise diagnosis and treatment for suspected sepsis (PROGRESS): a study protocol for a multi-center pragmatic randomized controlled trial.
BACKGROUND
Sepsis is still a major public health concern and a medical emergency due to its high morbidity and mortality. Accurate and timely etiology diagnosis is crucial for sepsis management. As an emerging rapid and sensitive pathogen detection tool, digital droplet PCR (ddPCR) has shown promising potential in rapid identification of pathogens and antimicrobial resistance genes. However, the diagnostic value and clinical impact of ddPCR tests remains to be studied in patients with suspected sepsis. PROGRESS trial is aimed to evaluate the clinical effectiveness of a novel ddPCR assay compared with standard practice.
METHODS
PROGRESS is a multicenter, open-label, pragmatic randomized controlled trial (pRCT) set in ten hospitals, including departments of infectious disease and intensive care units. In this study, a total of 2292 patients with suspected sepsis will be randomly assigned to two arms: the ddPCR group and the control group with a ratio of 3:1. The primary outcome is the diagnostic efficacy, that is, the sensitivity and specificity of the ddPCR assay compared with the synchronous blood culture. Secondary outcomes include the mortality rates and the mean Sequential Organ Failure Assessment (SOFA) score at follow-up time points, the length of stay in the hospital, the time to directed antimicrobial therapy, duration of broad-spectrum antibiotic use, and the EQ-5D-5L score on day 90.
DISCUSSION
It is the first multicenter pragmatic RCT to explore the diagnostic efficacy and clinical impact of the ddPCR assay in patients with suspected sepsis, taking advantage of both RCT's ability to establish causality and the feasibility of pragmatic approaches in real-world studies (RWS). This trial will help us to get a comprehensive view of the assay's capacity for precise diagnosis and treatment of sepsis. It has the potential to monitor the pathogen load change and to guide the antimicrobial therapy, making a beneficial impact on the prognosis of sepsis patients.
TRIAL REGISTRATION
ClinicalTrial.gov, NCT05190861. Registered January 13, 2022-'Retrospectively registered', https://clinicaltrials.gov/ct2/show/NCT05190861 .
Topics: Humans; Multicenter Studies as Topic; Organ Dysfunction Scores; Polymerase Chain Reaction; Pragmatic Clinical Trials as Topic; Prognosis; Randomized Controlled Trials as Topic; Sepsis; Treatment Outcome
PubMed: 35854212
DOI: 10.1186/s12879-022-07557-2