Efficacy In Randomized Control Trials Research Articles

Identification and inference for subgroups with differential treatment efficacy from randomized controlled trials with survival outcomes through multiple testing.

With the uptake of targeted therapies, instead of the "one-fits-all" approach, modern randomized controlled trials (RCTs) often aim to develop treatments that target a subgroup of patients. Motivated by analyzing the Age-Related Eye Disease Study (AREDS) data, a large RCT to study the efficacy of nutritional supplements in delaying the progression of an eye disease, age-related macular degeneration (AMD), we develop a simultaneous inference procedure to identify and infer subgroups with differential treatment efficacy in RCTs with time-to-event outcomes. Specifically, we formulate the multiple testing problem through contrasts and construct their simultaneous confidence intervals, which appropriately control both within- and across-marker multiplicity. Realistic simulations are conducted using real genotype data to evaluate the method performance under various scenarios. The method is then applied to AREDS to assess the efficacy of antioxidants and zinc combination in delaying AMD progression. Multiple gene regions including ESRRB-VASH1 on chromosome 14 have been identified with subgroups showing differential efficacy. We further validate our findings in an independent subsequent RCT, AREDS2, by discovering consistent differential treatment responses in the targeted and non-targeted subgroups identified from AREDS. This multiple-testing-based simultaneous inference approach provides a step forward to confidently identify and infer subgroups in modern drug development.

Treatment strategies for mosaic overgrowth syndromes of the PI3K-AKT-mTOR pathway.

Mosaic overgrowth syndromes (OS) are a proteiform ensemble of rare diseases displaying asymmetric overgrowth involving any tissue type, with degrees of severity ranging from isolated malformation to life-threatening conditions such as pulmonary embolism. Despite discordant clinical presentations, all those syndromes share common genetic anomalies: somatic mutations of genes involved in cell growth and proliferation. The PI3K-AKT-mTOR signaling pathway is one of the most prominent regulators of cell homeostasis, and somatic oncogenic mutations affecting this pathway are responsible for mosaic OS. This review aims to describe the clinical and molecular characteristics of the main OS involving the PI3K-AKT-mTOR pathway, along with the treatments available or under development. This review summarizes available data regarding OS in scientific articles published in peer-reviewed journals. OS care requires a multidisciplinary approach relying on clinical and radiological follow-up along with symptomatic treatment. However, no specific treatment has yet shown efficacy in randomized control trials. Clinical classifications of OS led to frequent misdiagnosis. Moreover, targeted therapies directed at causal mutated proteins are developing in OSs through cancer drugs repositioning, but the evidence of efficacy and tolerance is still lacking for most of them. The genetic landscape of OS is constantly widening and molecular classifications tend to increase the accuracy of diagnosis, opening opportunities for targeted therapies. OS are a dynamic, expanding field of research. Studies focusing on the identification of genetic anomalies and their pharmacological inhibition are needed.

Differences in patients' population and efficacy/effectiveness of biologic disease-modifying antirheumatic drugs between randomized controlled trials and real-world settings in patients with rheumatoid arthritis - using the IORRA cohort.

To evaluate the differences in patients' population and efficacy/effectiveness of biological disease-modifying antirheumatic drugs (bDMARDs) between randomized controlled trials (RCTs) and clinical practice in patients with rheumatoid arthritis. We reviewed inclusion criteria in Phase II or III RCTs of bDMARDs conducted in Japan. The Institute of Rheumatology, Rheumatoid Arthritis study participants during the period when each RCT was conducted (Cohort A) and new bDMARD users at our institute in 2016 (Cohort B) were assessed for the fulfilment of the inclusion criteria. The effectiveness of bDMARDs in our cohort and their efficacy in RCTs were compared using the inverse-variance method. Nineteen RCTs were selected. The mean proportions of patients fulfilling all inclusion criteria of each RCT in Cohorts A and B were 2.3% and 7.6%, respectively. The pooled proportion ratios (95% confidence interval) for achieving the American College of Rheumatology 20 (ACR20), ACR50, ACR70, and disease activity score 28 remission in non-eligible cases for eight RCTs versus all corresponding RCTs were 0.38 (0.30-0.51), 0.41 (0.30-0.57), 0.54 (0.35-0.82), and 1.28 (1.10-1.56), respectively. Few rheumatoid arthritis patients fulfilled the inclusion criteria of the RCTs in clinical settings. There was a difference in the efficacy/effectiveness of bDMARDs between RCTs and clinical practice.

The Efficacy of Early Start Denver Model Intervention in Young Children with Autism Spectrum Disorder Within Japan: A Preliminary Study.

ObjectivesAmong the many intervention programs for children with autism spectrum disorder (ASD), the Early Start Denver Model (ESDM) is one of the few approaches that has succeeded in demonstrating clinical efficacy in randomized control trials. Here, we investigate the clinical efficacy of ESDM intervention in young children with ASD in a community setting within Japan.MethodsAll subjects were children with ASD who received ESDM intervention during the study period. Each ESDM session lasted 75 min and occurred once per week for at least 12 weeks. The outcome measures consisted of the Kyoto Scale of Psychological Development (K-test), Aberrant Behavior Checklist-Japanese version (ABC-J), and the Clinical Global Impression-Severity scale (CGI-S).ResultsTwenty-seven subjects (29.4±6.4 months old) received ESDM intervention that lasted for 8.0±2.6 months on average. The score on Language and Social developmental quotient on the K-test increased significantly after the intervention. The total scores on the ABC-J and CGI-S significantly decreased after completion of the ESDM intervention.ConclusionOur results suggest that ESDM intervention could reduce the severity of distinct clinical features of ASD, such as impairments in social interaction and communication assessed by the K-test, and maladaptive behavior rated by the ABC-J and CGI-S. We believe that the ESDM adapted to each institution might become one of the standard options for children with ASD in Japan.

An efficacy evaluation method for non-normal outcomes in randomized controlled trials

Randomized controlled trials (RCT) are widely used in clinical efficacy evaluation studies. Linear regression is a general method to evaluate treatment efficacy considering the existence of confounding variables. However, when residuals are not normally distributed, parameter estimation based on ordinary least squares (OLS) is inefficient. This study introduces an exponential squared loss (ESL) model to evaluate treatment effect. The proposed method provides robust estimation for non-normal data. Simulation results show that it outperforms ordinary least squares regression with contaminated data. In the mild cognitive impairment (MCI) efficacy evaluation study with traditional Chinese medicine, our method is applied to construct a linear efficacy evaluation model for the difference in Alzheimer’s disease assessment scale-cognitive (ADAS-cog) scores between the final and baseline records (ADASFA), with the existence of confounding factors and non- normal residuals. The results coincide with existing medical literatures. This proposed method overcomes the limitation of confounding variables and non-normal residuals in RCT efficacy studies. It outperforms OLS on estimation efficiency in situations where the percentage of non-normal contamination reaches 30%. These advantages make it a good method for real-world clinical studies.

Diabetes Mellitus Management Among Patients with Limited English Proficiency: A Systematic Review and Meta-Analysis.

Patients with limited English proficiency (LEP) and type 2 diabetes mellitus (T2DM) have several health disparities, including suboptimal patient-provider interactions, poorer glycemic control, and T2DM complications. Understanding existing interventions for improving T2DM outcomes in this population is critical for reducing disparities. We performed a systematic review of randomized controlled trials (RCTs) and observational studies examining the effectiveness of interventions in improving T2DM outcomes among patients with LEP in North America. Quality was assessed using the Cochrane risk of bias tool for RCTs and the Newcastle-Ottawa Scale for non-RCT studies. Meta-analysis was conducted using the random-effects model. Fifty-four studies, 39 of which reported sufficient data for meta-analysis of glycemic control, were included. The interventions were associated with a statistically significant reduction in hemoglobin A1c (HbA1c) (weighted difference in means, -0.84% [95% CI, -0.97 to -0.71]) that was, however, very heterogeneous across studies (I2= 95.9%). Heterogeneity was explained by study design (lower efficacy in RCTs than non-RCTs) and by intervention length and delivery mode (greater reduction in interventions lasting <6months or delivered face-to-face); P < 0.05 for all three covariates. The interventions were also associated in most studies with improvement in knowledge, self-efficacy in diabetes management, quality of life, blood pressure, and low-density lipoprotein cholesterol. Multiple types of interventions are available for T2DM management in patients with LEP. Multicomponent interventions delivered face-to-face seem most effective for glycemic control. More research is needed to better understand other aspects of multicomponent interventions that are critical for improving important outcomes among patients with T2DM and LEP.

Understanding the Gap Between Efficacy in Randomized Controlled Trials and Effectiveness in Real-World Use of GLP-1 RA and DPP-4 Therapies in Patients With Type 2 Diabetes

The objective of this study was to estimate and explain the gap between clinical efficacy and real-world (RW) effectiveness of type 2 diabetes medications. This mixed-methods quasi-experimental study used retrospective claims (Optum/Humedica) to compare the change in HbA1c of RW patients with type 2 diabetes 12 months after starting a glucagon-like peptide 1 receptor agonist (GLP-1 RA) or dipeptidyl peptidase 4 (DPP-4) inhibitor with published findings from randomized controlled trials (RCTs) evaluating these drugs. Selected RW patients were similar to RCT patients, and regression analysis was used in the RW data to adjust for differences between poorly adherent and adherent patients to explain why RCT and RW findings may differ. RW patients initiating a GLP-1 RA (n = 221) or a DPP-4 (n = 652) experienced smaller reductions in HbA1c (GLP-1 RA: -0.52% [-6 mmol/mol], DPP-4: -0.51% [-6 mmol/mol])than reported in RCTs (-1.30% [-14 mmol/mol] from seven GLP-1 RA RCTs, n = 2,600; -0.68% [-8 mmol/mol] from four DPP-4 RCTs, n = 1,889). Baseline HbA1c, additional medications, and adherence were significant explanatory factors in the RW HbA1c change. Modeled estimates of RCT efficacy (-1.04% GLP-1 RA [-12 mmol/mol], -0.69% DPP-4 [-8 mmol/mol]) were within the RCTs' reported range (GLP-1 RA: -0.84% to -1.60% [-9 to -18 mmol/mol], DPP-4: -0.47% to -0.90% [-5 to -10 mmol/mol]). Poor medication adherence accounted for approximately three-fourths of the gap between RW and expected RCT results (gap = 0.51% [6 mmol/mol] GLP-1 RA; 0.18% [3 mmol/mol] DPP-4). Poor medication adherence is primarily why RW effectiveness is significantly less than RCT efficacy, suggesting an urgent need to effectively address adherence among patients with type 2 diabetes.

A clinical evaluation of the XIENCE V everolimus eluting stent in the treatment of patients with coronary artery disease: Result from Thailand Registry – XIENCE V performance evaluation (THRIVE study)

ObjectiveTo evaluate the 2-year clinical outcomes of XIENCETM V everolimus eluting stent (EES) for the treatment of coronary artery disease. BackgroundPercutaneous coronary intervention with a drug eluting stent has become the preferred treatment in patients with coronary artery disease. Everolimus eluting stent had proven efficacy in randomized control trials but those trials may not represent daily practice of interventional cardiology. MethodsThe THRIVE study was a prospective, multicenter, real-world, single-arm registry. Included in the registry were 400 patients in Thailand with coronary artery disease suitable for treatment with the XIENCETM V. ResultsAt 30 days, 1 year, and 2 years, the respective rate of all-cause mortality, myocardial infarction (MI), and target lesion revascularization (TLR) was 0.7, 1.0, and 0.5 %. 2.1, 2.1, and 1.0 %, and 2.2, 3.0, and 2.1 %. The cumulative rate for stent thrombosis was 1.6 % at 2 years. ConclusionsThe THRIVE study demonstrated that use of EES yielded a rate for 2 years of major adverse cardiac events comparable to the randomized controlled trial of EES in the SPIRIT trials. This result supports the efficacy and safety of XIENCETM V everolimus eluting for daily interventional cardiology practice.

Predicting real-world effectiveness using overall survival and progression-free survival-based clinical trial efficacy measures.

6564Background: Efficacy measured in cancer medication randomized controlled trials (RCTs) may not accurately predict real-world effectiveness. We measured the relationship between RCT efficacy and...

Comparing Effectiveness with Efficacy: Outcomes of Palliative Chemotherapy for Non-Small-Cell Lung Cancer in Routine Practice

Randomized controlled trials (rcts) are the "gold standard" for establishing treatment efficacy; however, efficacy does not automatically translate to a comparable level of effectiveness in routine practice. Our objectives were to □ describe outcomes of palliative platinum-doublet chemotherapy (ppdc) in non-small-cell lung cancer (nsclc) in routine practice, in terms of survival and well-being; and□ compare the effectiveness of ppdc in routine practice with its efficacy in rcts. Electronic treatment records were linked to the Ontario Cancer Registry to identify patients who underwent ppdc for nsclc at Ontario's regional cancer centres between April 2008 and December 2011. At each visit to the cancer centre, a patient's symptoms are recorded using the Edmonton Symptom Assessment System (esas). Score on the esas "well-being" item was used here as a proxy for quality of life (qol). Survival in the cohort was compared with survival in rcts, adjusting for differences in case mix. Changes in the esas score were measured 2 months after treatment start. The proportion of patients having improved or stable well-being was compared with the proportion having improved or stable qol in relevant rcts. We identified 906 patients with pre-ppdcesas records. Median survival was 31 weeks compared with 28-48 weeks in rcts. After accounting for deaths and cases lost to follow-up, we estimated that, at 2 months, 62% of the cohort had improved or stable well-being compared with 55%-63% who had improved or stable qol in rcts. The effectiveness of ppdc for nsclc in routine practice in Ontario is consistent with its efficacy in rcts, both in terms of survival and improvement in well-being.

Respiratory Guidelines—Which Real World?

Clinical practice guidelines are usually developed by a group of experts coming together to review the evidence in a field to make evidence-based recommendations on how to integrate new evidence into practice. The development process often draws on strict methodological rules to assess and assign quality grades to the evidence used to underpin the recommendations. Yet the goal of clinical practice guidelines--to help guide clinicians to understand, translate, and apply new evidence into everyday practice--can be thwarted by a lack of diversity and plurality of committee members, by limitations in the published evidence base, and by the design of the randomized controlled trials (RCTs) that largely underpin their pronouncements. Asthma and chronic obstructive pulmonary disease (COPD) RCTs often represent only a minority (5 to 10%) of the routine care population in whom licensed interventions will be applied. Thus, the implications of extrapolating RCT efficacy (based on idealized patients and management settings) to real-life treatment effectiveness (achieved in broad patient populations being managed in routine care) is unclear. Although RCTs can adequately demonstrate efficacy of a specific treatment, pragmatic trials and postmarketing observational studies are usually required to evaluate the long-term safety of therapeutic interventions. The practical usefulness of clinical practice guidelines may be enhanced by ensuring representation of a broad stakeholder group within guideline committees (e.g., patients, primary and secondary care clinicians, policy makers, and health insurers) and by integrating effectiveness as well as efficacy data. Only in this way can clinical practice guidelines achieve their goal of guiding the meaningful implementation of new research into practice, for the benefit of all stakeholders.

More Outcomes than Trials: A Call for Consistent Data Collection across Stroke Rehabilitation Trials

Stroke survivors experience complex combinations of impairments, activity limitations, and participation restrictions. The essential components of stroke rehabilitation remain elusive. Determining efficacy in randomized controlled trials (RCTs) is challenging; there is no commonly agreed primary outcome measure for rehabilitation trials. Clinical guidelines depend on proof of efficacy in RCTs and meta-analyses. However, diverse trial aims, differing methods, inconsistent data collection, and use of multiple assessment tools hinder comparability across trials. Consistent data collection in acute stroke trials has facilitated meta-analyses to inform trial design and clinical practice. With few exceptions, inconsistent data collection has hindered similar progress in stroke rehabilitation research. There is an urgent need for the routine collection of a core dataset of common variables in rehabilitation trials. The European Stroke Organisation Outcomes Working Group, the National Institutes of Neurological Disorders and Stroke Common Data Elements project, and the Collaborative Stroke Audit and Research project have called for consistency in data collection in stroke trials. Standardizing data collection can decrease study start up times, facilitate data sharing, and inform clinical guidelines. Although achieving consensus on which outcome measures to use in stroke rehabilitation trials is a considerable task, perhaps a feasible starting point is to achieve consistency in the collection of data on demography, stroke severity, and stroke onset to inclusion times. Longer term goals could include the development of a consensus process to establish the core dataset. This should be endorsed by researchers, funders, and journal editors in order to facilitate sustainable change.

Observational Studies versus Randomized Controlled Trials of Behavioral Interventions in Field Settings

This article considers research designs that evaluate outcomes of behavioral interventions in field settings. It focuses on differences in efficacy estimates between observational studies (OSs) and randomized controlled trials (RCTs). The article contends that pretreatment motivation and in-treatment compliance both contribute to treatment outcomes. It proposes a 3-variable causal model in which pretreatment motivation produces positive treatment outcomes directly, and also indirectly, via in-treatment compliance. The article challenges the common notion that RCTs represent the gold standard in designs for evaluating the efficacy of behavioral interventions in field settings. The article's causal model predicts that OSs governed by self-assignment and RCTs of the same behavioral interventions both yield biased estimates of efficacy, although these effect-size biases are generally in opposite directions. OS estimates of efficacy are typically too large because of group differences in pretreatment motivation favoring the treated group over the untreated group. RCT efficacy estimates are typically too small because noncompliance in treatment conditions dilutes the impact of field interventions. Taken together, motivation and compliance thus account for the 2 expected efficacy biases: overestimation of effect sizes in OSs and underestimation in RCTs. Accordingly, the causal model predicts that, under most conditions, OSs will generate larger effect sizes than RCTs and thus a higher proportion of significant results. The article examines published outcome evaluations in 3 psychological domains: vocational counseling, precollege academic programs and home-visiting programs. Consistent with the model's directional prediction, studies in all 3 domains document a systematic efficacy difference between OSs and RCTs.

Radiation necrosis following treatment of high grade glioma—a review of the literature and current understanding

Radiation therapy is an integral part of the standard treatment paradigm for malignant gliomas, with proven efficacy in randomized control trials. Radiation treatment is not without risk however, and radiation injury occurs in a certain proportion of patients. Difficulties in differentiating recurrence from radiation injury complicate the treatment course and can compromise care. These complexities are compounded by the recent distinction of two types of radiation injury: pseudoprogression and radiation necrosis, which are likely the result of radiation injury to the tumor and normal tissue, respectively. A thorough understanding of radiation-induced injury offers insights to guide further therapies. We detail the current knowledge of the mechanisms of radiation injury, along with potential targets for therapeutic intervention. Various diagnostic modalities are also described, in addition to the multiple options for treatment within the context of their pathophysiology and clinical efficacy. Radiation therapy is an integral part of the multidisciplinary management of gliomas, and the optimal diagnosis and management of radiation injury is paramount to improving patient outcomes.

Randomized trials are also essential for device therapy: reply

Randomized trials are also essential for device therapy: reply

For want of a control

For want of a control