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Obesity (Silver Spring, Md.) Apr 2021Little is known about the predictors of response to obesity interventions.
OBJECTIVE
Little is known about the predictors of response to obesity interventions.
METHODS
In 450 participants with obesity, body composition, resting energy expenditure, satiety, satiation, eating behavior, affect, and physical activity were measured by validated studies and questionnaires. These variables were used to classify obesity phenotypes. Subsequently, in a 12-month, pragmatic, real-world trial performed in a weight management center, 312 patients were randomly assigned to phenotype-guided treatment or non-phenotype-guided treatment with antiobesity medications: phentermine, phentermine/topiramate, bupropion/naltrexone, lorcaserin, and liraglutide. The primary outcome was weight loss at 12 months.
RESULTS
Four phenotypes of obesity were identified in 383 of 450 participants (85%): hungry brain (abnormal satiation), emotional hunger (hedonic eating), hungry gut (abnormal satiety), and slow burn (decreased metabolic rate). In 15% of participants, no phenotype was identified. Two or more phenotypes were identified in 27% of patients. In the pragmatic clinical trial, the phenotype-guided approach was associated with 1.75-fold greater weight loss after 12 months with mean weight loss of 15.9% compared with 9.0% in the non-phenotype-guided group (difference -6.9% [95% CI -9.4% to -4.5%], P < 0.001), and the proportion of patients who lost >10% at 12 months was 79% in the phenotype-guided group compared with 34% with non-phenotype-guided treatment group.
CONCLUSIONS
Biological and behavioral phenotypes elucidate human obesity heterogeneity and can be targeted pharmacologically to enhance weight loss.
Topics: Anti-Obesity Agents; Clinical Trials as Topic; Female; Humans; Male; Obesity; Precision Medicine; Weight Loss
PubMed: 33759389
DOI: 10.1002/oby.23120 -
Pharmacoepidemiology and Drug Safety Oct 2020There is a need to develop hybrid trial methodology combining the best parts of traditional randomized controlled trials (RCTs) and observational study designs to... (Review)
Review
PURPOSE
There is a need to develop hybrid trial methodology combining the best parts of traditional randomized controlled trials (RCTs) and observational study designs to produce real-world evidence (RWE) that provides adequate scientific evidence for regulatory decision-making.
METHODS
This review explores how hybrid study designs that include features of RCTs and studies with real-world data (RWD) can combine the advantages of both to generate RWE that is fit for regulatory purposes.
RESULTS
Some hybrid designs include randomization and use pragmatic outcomes; other designs use single-arm trial data supplemented with external comparators derived from RWD or leverage novel data collection approaches to capture long-term outcomes in a real-world setting. Some of these approaches have already been successfully used in regulatory decisions, raising the possibility that studies using RWD could increasingly be used to augment or replace traditional RCTs for the demonstration of drug effectiveness in certain contexts. These changes come against a background of long reliance on RCTs for regulatory decision-making, which are labor-intensive, costly, and produce data that can have limited applicability in real-world clinical practice.
CONCLUSIONS
While RWE from observational studies is well accepted for satisfying postapproval safety monitoring requirements, it has not commonly been used to demonstrate drug effectiveness for regulatory purposes. However, this position is changing as regulatory opinions, guidance frameworks, and RWD methodologies are evolving, with growing recognition of the value of using RWE that is acceptable for regulatory decision-making.
Topics: Decision Making; Drug Approval; Humans; Observational Studies as Topic; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Research Design
PubMed: 31823482
DOI: 10.1002/pds.4932 -
Epidemiology (Cambridge, Mass.) Mar 2023Observational studies are often the only option to estimate effects of interventions during pregnancy. Causal inference from observational data can be conceptualized as...
BACKGROUND
Observational studies are often the only option to estimate effects of interventions during pregnancy. Causal inference from observational data can be conceptualized as an attempt to emulate a hypothetical pragmatic randomized trial: the target trial.
OBJECTIVE
To provide a step-by-step description of how to use healthcare databases to estimate the effects of interventions initiated during pregnancy. As an example, we describe how to specify and emulate a target trial of COVID-19 vaccination during pregnancy, but the framework can be generally applied to point and sustained strategies involving both pharmacologic and non-pharmacologic interventions.
METHODS
First, we specify the protocol of a target trial to evaluate the safety and effectiveness of vaccination during pregnancy. Second, we describe how to use observational data to emulate each component of the protocol of the target trial. We propose different target trials for different gestational periods because the outcomes of interest vary by gestational age at exposure. We identify challenges that affect (i) the target trial and thus its observational emulation (censoring and competing events), and (ii) mostly the observational emulation (confounding, immortal time, and measurement biases).
CONCLUSION
Some biases may be unavoidable in observational emulations, but others are avoidable. For instance, immortal time bias can be avoided by aligning the start of follow-up with the gestational age at the time of the intervention, as we would do in the target trial. Explicitly emulating target trials at different gestational ages can help reduce bias and improve the interpretability of effect estimates for interventions during pregnancy.
Topics: Female; Humans; Pregnancy; COVID-19; COVID-19 Vaccines; Databases, Factual; Gestational Age; Vaccination; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic
PubMed: 36722806
DOI: 10.1097/EDE.0000000000001562 -
Clinical Infectious Diseases : An... Oct 2022A positive follow-up blood culture for methicillin-resistant Staphylococcus aureus (MRSA) while on seemingly appropriate therapy is a common and ominous development....
A positive follow-up blood culture for methicillin-resistant Staphylococcus aureus (MRSA) while on seemingly appropriate therapy is a common and ominous development. However, the definition and management of persistent MRSA bacteremia is unstandardized. In this Opinion Paper, we identify the presence of bacteremia for > 1 calendar day as a "worry point" that should trigger an intensive diagnostic evaluation to identify metastatic infection sites. Next, we define the duration of MRSA bacteremia that likely constitutes antibiotic failure and outline a potential management algorithm for such patients. Finally, we propose pragmatic clinical trial designs to test treatment strategies for persistent MRSA bacteremia.
Topics: Humans; Anti-Bacterial Agents; Bacteremia; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Pragmatic Clinical Trials as Topic
PubMed: 35535790
DOI: 10.1093/cid/ciac364 -
Circulation Mar 2021Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative...
BACKGROUND
Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative (Randomized, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology) uses a structured process to design RWE studies emulating randomized, controlled trials (RCTs) and compare results. We report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications.
METHODS
We selected 3 active-controlled and 7 placebo-controlled RCTs for replication. Using patient-level claims data from US commercial and Medicare payers, we implemented inclusion and exclusion criteria, selected primary end points, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 preexposure confounders. All study measures were prospectively defined and protocols registered before hazard ratios and 95% CIs were computed. Success criteria for the primary analysis were prespecified for each replication.
RESULTS
Despite attempts to emulate RCT design as closely as possible, differences between the RCT and corresponding RWE study populations remained. The regulatory conclusions were equivalent in 6 of 10. The RWE emulations achieved a hazard ratio estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled. The largest differences in effect estimates were found for RCTs where second-generation sulfonylureas were used as a proxy for placebo regarding cardiovascular effects. Nine of 10 replications had a standardized difference between effect estimates of <2, which suggests differences within expected random variation.
CONCLUSIONS
Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly. More trial emulations are needed to understand how often and in what contexts RWE findings match RCTs. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03936049, NCT04215523, NCT04215536, NCT03936010, NCT03936036, NCT03936062, NCT03936023, NCT03648424, NCT04237935, NCT04237922.
Topics: Aged; Female; Humans; Male; Middle Aged; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic
PubMed: 33327727
DOI: 10.1161/CIRCULATIONAHA.120.051718 -
American Society of Clinical Oncology... Jun 2024Clinical trials are essential for advancing oncology treatment strategies and have contributed significantly to the decline in cancer mortality rates over the past... (Review)
Review
Clinical trials are essential for advancing oncology treatment strategies and have contributed significantly to the decline in cancer mortality rates over the past decades. Traditional explanatory trials, focused on establishing intervention efficacy in ideal settings, often lack generalizability and may not reflect real-world patient care scenarios. Furthermore, increasing complexity in cancer clinical trial design has led to challenges such as protocol deviations, slow enrollment leading to lengthened durations of trial, and escalating costs. By contrast, pragmatic trials aim to assess intervention effectiveness in more representative patient populations under routine clinical conditions. Here, we review the principles, methodologies, challenges, and advantages of incorporating pragmatic features (PFs) into cancer clinical trials. We illustrate the application of pragmatic trial designs in oncology and discuss the QUASAR collaborative, TAPUR study, and the ongoing PRAGMATICA-LUNG trial. Although not all oncology trials may be amenable to adopting fully pragmatic designs, integration of PFs when feasible will enhance trial generalizability and real-world applicability. Project Pragmatica and similar initiatives advocate for the integration of real-world practice with clinical trials, fostering a nuanced approach to oncology research that balances efficacy and effectiveness assessments, ultimately with a goal of improving patient outcomes.
Topics: Humans; Neoplasms; Clinical Trials as Topic; Research Design; Pragmatic Clinical Trials as Topic; Medical Oncology
PubMed: 38771997
DOI: 10.1200/EDBK_100040 -
International Journal of Nursing Studies Aug 2019Despite clear evidence for the lack of effectiveness and safety, physical restraints are frequently applied in nursing homes. Multicomponent interventions addressing... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Despite clear evidence for the lack of effectiveness and safety, physical restraints are frequently applied in nursing homes. Multicomponent interventions addressing nurses' attitudes and organizational culture have been effective in reducing physical restraints.
OBJECTIVE
To evaluate the effectiveness of two versions of a guideline and theory-based multicomponent intervention to reduce physical restraints in nursing homes.
DESIGN
Pragmatic cluster randomized controlled trial.
SETTING
The study was conducted in 120 nursing homes in four regions in Germany.
PARTICIPANTS
All residents living in the participating nursing home during follow-up, newly admitted residents were also included. A total of 12,245 residents included in the primary analysis (4126 and 3547 residents in intervention group 1 and 2 and 4572 residents in the control group).
METHODS
Intervention group 1 received an updated version of a successfully tested guideline-based multicomponent intervention (comprising brief education for the nursing staff, intensive training of nominated key nurses in each cluster, introduction of a least-restraint policy and supportive material), intervention group 2 received a concise version of the original program and the control group received optimized usual care (i.e. supportive materials only). Primary outcome was physical restraint prevalence at twelve months, assessed through direct observation by blinded investigators. Intervention and control groups were compared using baseline-adjusted linear regression on cluster level, Bonferroni-adjusted for double testing. Secondary outcomes included falls, fall-related fractures, and quality of life. We also described intervention costs and performed a comprehensive process analysis.
RESULTS
At baseline, mean physical restraint prevalence was 17.4% and 19.6% in intervention groups 1 and 2, and 18.8% in the control group. After twelve months, mean prevalence was 14.6%, 15.7%, and 17.6%. Baseline-adjusted differences between mean prevalences were 2.0% (97.5% CI, -5.8 to 1.9) lower in intervention group 1 and 2.5% (97.5% CI, -6.4 to 1.4) lower in intervention group 2 compared to controls. Physical restraint prevalence showed a pronounced variation between the different clusters in all study groups. We found no significant differences in the secondary outcomes. According to the process evaluation, the intervention was mainly implemented as planned, but the expected change towards a least restraint culture of care was not achieved in all clusters.
CONCLUSIONS
Neither intervention showed a clear advantage compared to control. The pronounced center variation in physical restraint prevalence indicates that other approaches like governmental policies are needed to sustainably change physical restraint practice and reduce center variations in nursing homes.
TRIAL REGISTRATION
ClinicalTrials.gov : NCT02341898.
Topics: Cluster Analysis; Humans; Nursing Homes; Pragmatic Clinical Trials as Topic; Restraint, Physical
PubMed: 31014546
DOI: 10.1016/j.ijnurstu.2019.03.017 -
The British Journal of General Practice... Feb 2022
Topics: General Practice; Humans; Pragmatic Clinical Trials as Topic
PubMed: 35091399
DOI: 10.3399/bjgp22X718289 -
Pain Jul 2023Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled...
Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions.
Topics: Humans; Analgesics; Consensus; Pain; Pain Management; Research Design; Pragmatic Clinical Trials as Topic
PubMed: 36943273
DOI: 10.1097/j.pain.0000000000002888 -
BMJ Open Mar 2023Registry randomised clinical trials (RRCTs) have the potential to provide pragmatic answers to important clinical questions. RRCTs can be embedded into large... (Review)
Review
Registry randomised clinical trials (RRCTs) have the potential to provide pragmatic answers to important clinical questions. RRCTs can be embedded into large population-based registries or smaller single site registries to provide timely answers at a reduced cost compared with traditional randomised controlled trials. RRCTs can take a number of forms in addition to the traditional individual-level randomised trial, including parallel group trials, platform or adaptive trials, cluster randomised trials and cluster randomised stepped-wedge trials. From an implementation perspective, initially it is advantageous to embed RRCT into well-established registries as these have typically already overcome any issues with end point validation and adjudication. With advances in data linkage and data quality, RRCTs can play an important role in answering clinical questions in a pragmatic, cost-effective way.
Topics: Humans; Data Accuracy; Randomized Controlled Trials as Topic; Registries
PubMed: 36858472
DOI: 10.1136/bmjopen-2022-068057