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Anesthesiology Jan 2020Large randomized trials provide the highest level of clinical evidence. However, enrolling large numbers of randomized patients across numerous study sites is expensive... (Review)
Review
Large randomized trials provide the highest level of clinical evidence. However, enrolling large numbers of randomized patients across numerous study sites is expensive and often takes years. There will never be enough conventional clinical trials to address the important questions in medicine. Efficient alternatives to conventional randomized trials that preserve protections against bias and confounding are thus of considerable interest. A common feature of novel trial designs is that they are pragmatic and facilitate enrollment of large numbers of patients at modest cost. This article presents trial designs including cluster designs, real-time automated enrollment, and practitioner-preference approaches. Then various adaptive designs that improve trial efficiency are presented. And finally, the article discusses the advantages of embedding randomized trials within registries.
Topics: Clinical Trials as Topic; Humans; Research Design
PubMed: 31809323
DOI: 10.1097/ALN.0000000000002989 -
BMC Public Health Aug 2022While effective physical activity referral schemes (PARSs) and related structures for promoting physical activity (PA) already exist in several countries, in Germany,...
BACKGROUND
While effective physical activity referral schemes (PARSs) and related structures for promoting physical activity (PA) already exist in several countries, in Germany, PARSs have not yet been implemented systematically and nationwide. Through a co-production approach with relevant actors in the German healthcare system, a PARS was developed, and an implementation plan was created (e.g. financing). This study protocol aims to evaluate the developed PARS for people with non-communicable diseases (NCDs) in Germany regarding its potential effectiveness and implementation success.
METHODS
To evaluate the effectiveness and implementation success of the PARS, we will apply a pragmatic cluster-randomised controlled trial (cRCT) in Hybrid II design by comparing two intervention groups (PARS vs PA advice [PAA]). The trial will take place in the Nürnberg metropolitan region, with 24 physician practices recruiting 567 people with NCDs. Both groups will receive brief PA advice from a physician to initially increase the participants' motivation to change their activity level. Subsequently, the PARS group will be given individualised support from an exercise professional to increase their PA levels and be transferred to local exercise opportunities. In contrast, participants in the PAA group will receive only the brief PA advice as well as information and an overview of regional PA offerings to become more active at their own initiative. After 12 and 24 weeks, changes in moderate to vigorous PA and in physical activity-related health competence (movement competence, control competence, self-regulation competence) will be measured as primary outcomes. Secondary outcomes will include changes in quality of life. To measure implementation success, we refer to the RE-AIM framework and draw on patient documentation, interviews, focus groups and surveys of the participating actors (physicians, exercise professionals).
DISCUSSION
Through a between-group comparison, we will investigate whether additional individual support by an exercise professional compared to brief PA advice alone leads to higher PA levels in people with NCDs. The acceptance and feasibility of both interventions in routine care in the German healthcare system will also be evaluated.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT04947787 . Registered 01 June 2021.
Topics: Delivery of Health Care; Exercise; Germany; Humans; Pragmatic Clinical Trials as Topic; Quality of Life; Randomized Controlled Trials as Topic; Referral and Consultation
PubMed: 35964042
DOI: 10.1186/s12889-022-13833-2 -
BMC Public Health Mar 2023The growing number of patients with type 2 diabetes and prediabetes is a major public health concern. Physical activity is a cornerstone of diabetes management and may...
mHealth intervention delivered in general practice to increase physical activity and reduce sedentary behaviour of patients with prediabetes and type 2 diabetes (ENERGISED): rationale and study protocol for a pragmatic randomised controlled trial.
BACKGROUND
The growing number of patients with type 2 diabetes and prediabetes is a major public health concern. Physical activity is a cornerstone of diabetes management and may prevent its onset in prediabetes patients. Despite this, many patients with (pre)diabetes remain physically inactive. Primary care physicians are well-situated to deliver interventions to increase their patients' physical activity levels. However, effective and sustainable physical activity interventions for (pre)diabetes patients that can be translated into routine primary care are lacking.
METHODS
We describe the rationale and protocol for a 12-month pragmatic, multicentre, randomised, controlled trial assessing the effectiveness of an mHealth intervention delivered in general practice to increase physical activity and reduce sedentary behaviour of patients with prediabetes and type 2 diabetes (ENERGISED). Twenty-one general practices will recruit 340 patients with (pre)diabetes during routine health check-ups. Patients allocated to the active control arm will receive a Fitbit activity tracker to self-monitor their daily steps and try to achieve the recommended step goal. Patients allocated to the intervention arm will additionally receive the mHealth intervention, including the delivery of several text messages per week, with some of them delivered just in time, based on data continuously collected by the Fitbit tracker. The trial consists of two phases, each lasting six months: the lead-in phase, when the mHealth intervention will be supported with human phone counselling, and the maintenance phase, when the intervention will be fully automated. The primary outcome, average ambulatory activity (steps/day) measured by a wrist-worn accelerometer, will be assessed at the end of the maintenance phase at 12 months.
DISCUSSION
The trial has several strengths, such as the choice of active control to isolate the net effect of the intervention beyond simple self-monitoring with an activity tracker, broad eligibility criteria allowing for the inclusion of patients without a smartphone, procedures to minimise selection bias, and involvement of a relatively large number of general practices. These design choices contribute to the trial's pragmatic character and ensure that the intervention, if effective, can be translated into routine primary care practice, allowing important public health benefits.
TRIAL REGISTRATION
ClinicalTrials.gov (NCT05351359, 28/04/2022).
Topics: Humans; Diabetes Mellitus, Type 2; Exercise; General Practice; Multicenter Studies as Topic; Prediabetic State; Randomized Controlled Trials as Topic; Sedentary Behavior; Telemedicine; Pragmatic Clinical Trials as Topic
PubMed: 36997936
DOI: 10.1186/s12889-023-15513-1 -
Journal of Comparative Effectiveness... Nov 2016Clinical trial designs often fail to deliver data that jointly satisfy evolving demands of both regulatory and reimbursement authorities. We propose a new multi-tiered...
Clinical trial designs often fail to deliver data that jointly satisfy evolving demands of both regulatory and reimbursement authorities. We propose a new multi-tiered trial design to integrate efficacy and effectiveness, and address the evolving needs of authorities. The mixed randomized trial allocates patients first to trial arm - randomized controlled, pragmatic (randomized) or observational - and then to treatment group - experimental, placebo, active comparator, best available therapy or standard of care. Trial arms may be staggered over time to reflect the current state of randomized and non-randomized data of the experimental drug, and thereby still prioritize safety. At the same time, the mixed randomized trial allows for the collection of real-world data in a randomized setting, and thereby reduces selection bias.
Topics: Observational Studies as Topic; Randomized Controlled Trials as Topic; Research Design
PubMed: 27618500
DOI: 10.2217/cer-2016-0034 -
Journal of Clinical Pharmacology Oct 2018Almost half of recent pediatric trials failed to achieve labeling indications, in large part because of inadequate study design. Therefore, innovative study methods are... (Review)
Review
Almost half of recent pediatric trials failed to achieve labeling indications, in large part because of inadequate study design. Therefore, innovative study methods are crucial to optimizing trial design while also reducing the potential harms inherent with drug investigation. Several methods exist to optimize the amount of pharmacokinetic data collected from the smallest possible volume and with the fewest number of procedures, including the use of opportunistic and sparse sampling, alternative and noninvasive matrices, and microvolume assays. In addition, large research networks using master protocols promote collaboration, reduce regulatory burden, and increase trial efficiency for both early- and late-phase trials. Large pragmatic trials that leverage electronic health records can capitalize on central management strategies to reduce costs, enroll patients with rare diseases on a large scale, and augment study generalizability. Further, trial efficiency and safety can be optimized through Bayesian adaptive techniques that permit planned protocol changes based on analyses of prior and accumulated data. In addition to these trial design features, advances in modeling and simulation have paved the way for systems-based and physiologically based models that individualize pediatric dosing recommendations and support drug approval. Last, given the low prevalence of many pediatric diseases, collecting deidentified genetic and clinical data on a large scale is a potentially transformative way to augment clinical pharmacology research in children.
Topics: Biomedical Research; Child; Clinical Trials as Topic; Humans; Infant; Models, Biological; Pharmacology, Clinical; Research Design
PubMed: 30248192
DOI: 10.1002/jcph.1053 -
Trials Nov 2022Acute pancreatitis (AP) is a common digestive disease with increased incidence globally but without internationally licenced pharmacological therapy. Moderately severe...
AGI grade-guided chaiqin chengqi decoction treatment for predicted moderately severe and severe acute pancreatitis (CAP trial): study protocol of a randomised, double-blind, placebo-controlled, parallel-group, pragmatic clinical trial.
BACKGROUND
Acute pancreatitis (AP) is a common digestive disease with increased incidence globally but without internationally licenced pharmacological therapy. Moderately severe and severe acute pancreatitis (MSAP/SAP) contributes predominately for its morbidities and mortality and has been managed in West China Hospital for decades using the traditional Chinese medicinal formula chaiqin chengqi decoction (CQCQD). The current study tests whether the early administration of CQCQD will result in improved clinical outcomes in predicted MSAP/SAP patients.
METHODS
This is a single-centre, randomised, controlled, double-blind pragmatic clinical trial. AP patients aged 18-75 admitted within 72 h of onset will be assessed at admission for enrolment. We excluded the predicted mild acute pancreatitis (Harmless Acute Pancreatitis Score > 2 at admission) and severe organ failure (Sequential Organ Failure Assessment [SOFA] score of respiratory, cardiovascular, or renal systems > 3) at admission. Eligible patients will be randomly allocated on a 1:1 basis to CQCQD or placebo control administration based on conventional therapy. The administration of CQCQD and placebo is guided by the Acute Gastrointestinal Injury grade-based algorithm. The primary outcome measure will be the duration of respiratory failure (SOFA score of respiratory system ≥ 2) within 28 days after onset. Secondary outcome measures include occurrence of new-onset any organ failure (SOFA score of respiratory, cardiovascular, or renal system ≥ 2) and new-onset persistent organ failure (organ failure lasts > 48 h), dynamic surrogate biochemical markers and clinical severity scores, gut-centred treatment modalities, local complications status, intensive care need and duration, surgical interventions, mortality, and length of hospital stay. Follow-up will be scheduled on 6, 12, and 26 weeks after enrolment to assess AP recurrence, local complications, the requirement for surgical interventions, all-cause mortality, and patient-reported outcomes.
DISCUSSION
The results of this study will provide high-quality evidence to appraise the efficacy of CQCQD for the early management of AP patients.
TRIAL REGISTRATION
Chictr.org.cn Registry ( ChiCTR2000034325 ). Registered on 2 July, 2020.
Topics: Humans; Acute Disease; Drugs, Chinese Herbal; Lung; Pancreatitis; Randomized Controlled Trials as Topic; Pragmatic Clinical Trials as Topic
PubMed: 36348365
DOI: 10.1186/s13063-022-06792-x -
Implementation Science : IS Jan 2021The prescribing of high-risk medications to older adults remains extremely common and results in potentially avoidable health consequences. Efforts to reduce prescribing...
Rationale and design of the Novel Uses of adaptive Designs to Guide provider Engagement in Electronic Health Records (NUDGE-EHR) pragmatic adaptive randomized trial: a trial protocol.
BACKGROUND
The prescribing of high-risk medications to older adults remains extremely common and results in potentially avoidable health consequences. Efforts to reduce prescribing have had limited success, in part because they have been sub-optimally timed, poorly designed, or not provided actionable information. Electronic health record (EHR)-based tools are commonly used but have had limited application in facilitating deprescribing in older adults. The objective is to determine whether designing EHR tools using behavioral science principles reduces inappropriate prescribing and clinical outcomes in older adults.
METHODS
The Novel Uses of Designs to Guide provider Engagement in Electronic Health Records (NUDGE-EHR) project uses a two-stage, 16-arm adaptive randomized pragmatic trial with a "pick-the-winner" design to identify the most effective of many potential EHR tools among primary care providers and their patients ≥ 65 years chronically using benzodiazepines, sedative hypnotic ("Z-drugs"), or anticholinergics in a large integrated delivery system. In stage 1, we randomized providers and their patients to usual care (n = 81 providers) or one of 15 EHR tools (n = 8 providers per arm) designed using behavioral principles including salience, choice architecture, or defaulting. After 6 months of follow-up, we will rank order the arms based upon their impact on the trial's primary outcome (for both stages): reduction in inappropriate prescribing (via discontinuation or tapering). In stage 2, we will randomize (a) stage 1 usual care providers in a 1:1 ratio to one of the up to 5 most promising stage 1 interventions or continue usual care and (b) stage 1 providers in the unselected arms in a 1:1 ratio to one of the 5 most promising interventions or usual care. Secondary and tertiary outcomes include quantities of medication prescribed and utilized and clinically significant adverse outcomes.
DISCUSSION
Stage 1 launched in October 2020. We plan to complete stage 2 follow-up in December 2021. These results will advance understanding about how behavioral science can optimize EHR decision support to improve prescribing and health outcomes. Adaptive trials have rarely been used in implementation science, so these findings also provide insight into how trials in this field could be more efficiently conducted.
TRIAL REGISTRATION
Clinicaltrials.gov ( NCT04284553 , registered: February 26, 2020).
Topics: Aged; Electronic Health Records; Health Personnel; Humans; Inappropriate Prescribing; Randomized Controlled Trials as Topic; Research Design
PubMed: 33413494
DOI: 10.1186/s13012-020-01078-9 -
BMJ Open Apr 2023The ongoing ageing population is associated with an increase in the number of patients suffering a stroke, transient ischaemic attack (TIA) or myocardial infarction...
Efficiency and effectiveness of intensive multidisciplinary follow-up of patients with stroke/TIA or myocardial infarction compared to usual monitoring: protocol of a pragmatic randomised clinical trial. DiVa (Dijon vascular) study.
INTRODUCTION
The ongoing ageing population is associated with an increase in the number of patients suffering a stroke, transient ischaemic attack (TIA) or myocardial infarction (MI). In these patients, implementing secondary prevention is a critical challenge and new strategies need to be developed to close the gap between clinical practice and evidence-based recommendations. We describe the protocol of a randomised clinical trial that aims to evaluate the efficiency and effectiveness of an intensive multidisciplinary follow-up of patients compared with standard care.
METHODS AND ANALYSIS
The DiVa study is a randomised, prospective, controlled, multicentre trial including patients >18 years old with a first or recurrent stroke (ischaemic or haemorrhagic) or TIA, or a type I or II MI, managed in one of the participating hospitals of the study area, with a survival expectancy >12 months. Patients will be randomised with an allocation ratio of 1:1 in two parallel groups: one group assigned to a multidisciplinary, nurse-based and pharmacist-based 2-year follow-up in association with general practitioners, neurologists and cardiologists versus one group with usual follow-up. In each group for each disease (stroke/TIA or MI), 430 patients will be enrolled (total of 1720 patients) over 3 years. The primary outcome will be the incremental cost-utility ratio at 24 months between intensive and standard follow-up in a society perspective. Secondary outcomes will include the incremental cost-utility ratio at 6 and 12 months, the incremental cost-effectiveness ratio at 24 months, reduction at 6, 12 and 24 months of the rates of death, unscheduled rehospitalisation and iatrogenic complications, changes in quality of life, net budgetary impact at 5 years of the intensive follow-up on the national health insurance perspective and analysis of factors having positive or negative effects on the implementation of the project in the study area.
ETHICS AND DISSEMINATION
Ethical approval was obtained and all patients receive information about the study and give their consent to participate before randomisation. Results of the main trial and each of the secondary analyses will be submitted for publication in a peer-reviewed journal.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov Identifier: NCT04188457. Registered on 6 December 2019.
Topics: Adolescent; Humans; Follow-Up Studies; Ischemic Attack, Transient; Multicenter Studies as Topic; Myocardial Infarction; Prospective Studies; Quality of Life; Randomized Controlled Trials as Topic; Stroke; Pragmatic Clinical Trials as Topic
PubMed: 37185649
DOI: 10.1136/bmjopen-2022-070197 -
BMJ Open Apr 2022Cervical cancer screening in general practice could be a routine moment to provide female smokers with stop smoking advice and support. The aim of this study is to...
Smoking cessation strategy in the national cervical cancer screening program (SUCCESS): study protocol for a pragmatic cluster randomised trial and process evaluation in Dutch general practice.
INTRODUCTION
Cervical cancer screening in general practice could be a routine moment to provide female smokers with stop smoking advice and support. The aim of this study is to assess the effect of a stop smoking strategy delivered by trained practice assistants after the cervical smear, and to evaluate the implementation process.
METHODS AND ANALYSIS
The study is a two-arm, pragmatic cluster randomised trial, in Dutch general practice. Randomisation takes place 1:1 at the level of the general practice. Practices either deliver the SUCCESS stop smoking strategy or the usual care condition. The strategy consists of brief stop smoking advice based on the Ask-Advise-Connect method and is conducted by trained practice assistants after routine cervical cancer screening. The primary outcome is the performance of a serious quit attempt in the 6 months after screening. Secondary outcomes are 7-day point prevalence abstinence, reduction in the number of cigarettes per day and transition in motivation to quit smoking. Follow-up for these measurements takes place after 6 months. Analysis on the primary outcome aims to detect a 10% difference between treatment arms (0.80 power, p=0.05, using a one-sided test), and will be performed according to the intention to treat principle. The process evaluation will assess feasibility, acceptability and barriers or enablers to the strategy's implementation. For this purpose, both qualitative and quantitative data will be collected via questionnaires and in-depth interviews, respectively, in both individual study participants and involved staff.
ETHICS AND DISSEMINATION
The Dutch Ministry of Health, Welfare and Sport approved of the trial after an advisory report from the Health Council (Nr. 2018/17). A licence was provided to conduct the study under the Population Screening Act. Study results will be disseminated through publications in peer-reviewed journals and conference presentations.
TRIAL REGISTRATION NUMBER
NL5052 (NTR7451).
Topics: Early Detection of Cancer; Family Practice; Female; General Practice; Humans; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Smoking Cessation; Uterine Cervical Neoplasms
PubMed: 35379626
DOI: 10.1136/bmjopen-2021-055812 -
Trials Aug 2022Total hip arthroplasty is considered an efficacious procedure for relieving pain and disability, but despite that objectively measured physical activity level remains...
Effectiveness of promotion and support for physical activity maintenance post total hip arthroplasty-study protocol for a pragmatic, assessor-blinded, randomized controlled trial (the PANORAMA trial).
BACKGROUND
Total hip arthroplasty is considered an efficacious procedure for relieving pain and disability, but despite that objectively measured physical activity level remains unchanged compared to pre-surgery and is still considerably lower than that of a healthy age- and sex-matched population 6-12 months post-surgery. Since there is a graded relationship between physical activity level and functional performance, increasing physical activity may enhance the outcome of the procedure. This study aims to investigate whether promotion and support of physical activity initiated 3 months after total hip arthroplasty complementary to usual rehabilitation care can increase objective measured physical activity 6 months post-surgery.
METHODS
The trial is designed as a pragmatic, parallel group, two-arm, assessor-blinded, superiority, randomized (1:1), controlled trial with post intervention follow-up 6 and 12 months after total hip arthroplasty. Home-dwelling, independent, and self-reliant patients with hip osteoarthritis are provisionally enrolled prior to surgery and re-screened about 2-3 months post-surgery to confirm eligibility. Baseline assessment is conducted 3 months post-surgery. Subsequently, patients (n=200) are randomized to either a 3-month, multimodal physical activity promotion/education intervention or control (no further attention). The intervention consists of face-to-face and telephone counselling, patient education material, pedometer, and step-counting journal. The primary outcome is objectively measured physical activity, specifically the proportion of patients that complete on average ≥8000 steps per day 6 months post-surgery. Secondary outcomes include core outcomes (i.e., physical function, pain, and patient global assessment) and health-related quality of life. Furthermore, we will explore the effect of the intervention on self-efficacy and outcome expectations (i.e., tertiary outcomes).
DISCUSSION
By investigating the effectiveness of a pedometer-driven, face-to-face, and telephone-assisted counselling, behavior change intervention in complementary to usual rehabilitation, we hope to deliver applicable and generalizable knowledge to support physical activity after total hip arthroplasty and potentially enhance the outcome of the procedure.
TRIAL REGISTRATION
www.
CLINICALTRIALS
gov NCT04471532 . Registered on July 15, 2020.
Topics: Arthroplasty, Replacement, Hip; Exercise; Humans; Osteoarthritis, Hip; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 35964101
DOI: 10.1186/s13063-022-06610-4