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Biostatistics (Oxford, England) Dec 2023Trial-level surrogates are useful tools for improving the speed and cost effectiveness of trials but surrogates that have not been properly evaluated can cause...
Trial-level surrogates are useful tools for improving the speed and cost effectiveness of trials but surrogates that have not been properly evaluated can cause misleading results. The evaluation procedure is often contextual and depends on the type of trial setting. There have been many proposed methods for trial-level surrogate evaluation, but none, to our knowledge, for the specific setting of platform studies. As platform studies are becoming more popular, methods for surrogate evaluation using them are needed. These studies also offer a rich data resource for surrogate evaluation that would not normally be possible. However, they also offer a set of statistical issues including heterogeneity of the study population, treatments, implementation, and even potentially the quality of the surrogate. We propose the use of a hierarchical Bayesian semiparametric model for the evaluation of potential surrogates using nonparametric priors for the distribution of true effects based on Dirichlet process mixtures. The motivation for this approach is to flexibly model relationships between the treatment effect on the surrogate and the treatment effect on the outcome and also to identify potential clusters with differential surrogate value in a data-driven manner so that treatment effects on the surrogate can be used to reliably predict treatment effects on the clinical outcome. In simulations, we find that our proposed method is superior to a simple, but fairly standard, hierarchical Bayesian method. We demonstrate how our method can be used in a simulated illustrative example (based on the ProBio trial), in which we are able to identify clusters where the surrogate is, and is not useful. We plan to apply our method to the ProBio trial, once it is completed.
Topics: Humans; Bayes Theorem; Treatment Outcome; Clinical Trials as Topic
PubMed: 36610075
DOI: 10.1093/biostatistics/kxac053 -
Current Hypertension Reports Oct 2023PURPOSE OF REVIEW: Resistant hypertension (RH) defined as uncontrolled blood pressure despite the use of a combination of a renin-angiotensin system blocker, a calcium... (Review)
Review
PURPOSE OF REVIEW: Resistant hypertension (RH) defined as uncontrolled blood pressure despite the use of a combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic at maximally tolerated doses is associated with a substantially increased risk of cardiovascular and renal events. Despite targeting relevant pathophysiological pathways contributing to elevated blood pressure, approximately 10-15% of hypertensive patients remain above recommended blood pressure targets. Further optimization of blood pressure control is particularly challenging in patient populations who frequently present with RH such as elderly and patients with chronic kidney disease, due to the unfavorable safety profile of the recommended fourth-line therapy with mineralocorticoid receptor antagonists. This review explores the potential role of endothelin antagonists as an alternative fourth-line therapy. RECENT FINDINGS: Despite the well-described role of the endothelin pathway in the pathogenesis of hypertension, it is currently not targeted therapeutically. Recently however, main outcome data from the PRECISION study, a randomized placebo-controlled phase 3 trial, in patients with RH on guideline-recommended standardized single-pill background therapy convincingly demonstrated the safety and blood pressure-lowering efficacy of the dual endothelin antagonist Aprocitentan. Findings from the phase 3 PRECISION study could signify a turning point in the utilization of endothelin receptor antagonists as a standard treatment for patients with RH.
Topics: Humans; Aged; Hypertension; Endothelin Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Endothelins; Randomized Controlled Trials as Topic; Clinical Trials, Phase III as Topic
PubMed: 37566184
DOI: 10.1007/s11906-023-01259-z -
JACC. Cardiovascular Interventions Oct 2023
Review
Topics: Humans; Treatment Outcome; Informed Consent; Deception; Randomized Controlled Trials as Topic
PubMed: 37879809
DOI: 10.1016/j.jcin.2023.08.015 -
Sexual Medicine Reviews Dec 2023Lasers are commonly used for treating various vaginal/vulvar conditions. To date, there is to our knowledge no available literature review on the effects of different... (Review)
Review
INTRODUCTION
Lasers are commonly used for treating various vaginal/vulvar conditions. To date, there is to our knowledge no available literature review on the effects of different types of lasers for the treatment of women with vulvodynia, a condition that causes chronic pain in the vulvar area.
OBJECTIVES
We sought to review the literature and summarize the existing published evidence regarding the effects of lasers for the treatment of women with vulvodynia.
METHODS
A scoping review with a systematic search was conducted that included studies investigating the use of laser treatment in women with vulvodynia. The National Heart, Lung, and Blood Institute Study Quality Assessment Tools were used for the quality assessment. The type of laser, effects on pain and function, and participants' perceived improvement as well as adverse events were analyzed.
RESULTS
Eight studies investigating laser therapy were included in the analysis: 1 randomized controlled trial, 5 before-after studies, 1 nonrandomized intervention study, and 1 case report. Several types of laser therapies were identified, ranging from mild noninvasive photobiomodulation to more invasive ablative procedures. Of the 6 studies that included pain outcomes, 3 studies showed statistically significant improvements from baseline to follow-up, and 3 demonstrated a reduction in pain from subjectively interpreted data. Similarly, each of the 2 studies investigating sexual function also reported an improvement (based only on subjective interpretation). Of the 2 studies with a comparison group, neither study was adequately powered to detect between-group differences. Furthermore, 57%-78% of participants reported improvement, with 1 study showing a greater statistically significant improvement in the low-level laser therapy patient group compared to the sham laser group. Outcomes and adverse events varied depending on the type of laser used.
CONCLUSIONS
Although these studies demonstrated some benefits of laser therapy for the treatment of vulvodynia, these findings should be interpreted with caution given the scarcity of the included studies that were robust and sufficiently powered. Future research should focus on conducting well-designed randomized controlled trials to evaluate the efficacy of different types of lasers in the treatment of vulvodynia.
Topics: Female; Humans; Lasers; Low-Level Light Therapy; Pain; Pain Measurement; Vulvodynia; Clinical Trials as Topic; Case Reports as Topic
PubMed: 37794569
DOI: 10.1093/sxmrev/qead039 -
BMC Cardiovascular Disorders Aug 2023To achieve potential financial savings and avoid exposing the patients to unnecessary risk, an optimal diagnostic strategy to identify low risk individual who may derive...
Comparison of two diagnostic strategies for patients with stable chest pain suggestive of chronic coronary syndrome: rationale and design of the double-blind, pragmatic, randomized and controlled OPERATE Trial.
BACKGROUND
To achieve potential financial savings and avoid exposing the patients to unnecessary risk, an optimal diagnostic strategy to identify low risk individual who may derive minimal benefit from further cardiac imaging testing (CIT) is important for patients with stable chest pain (SCP) suggestive of chronic coronary syndrome (CCS). Although several diagnostic strategies have been recommended by the most recent guidelines, few randomized controlled trials (RCTs) have prospectively investigated the actual effect of applying these strategies in clinical practice.
METHODS
OPERATE (OPtimal Evaluation of stable chest pain to Reduce unnecessAry utilization of cardiac imaging TEsting) trial is an investigator-initiated, multicenter, coronary computed tomography angiography (CCTA)-based, 2-arm parallel-group, double-blind, pragmatic and confirmative RCT planning to include 800 subjects with SCP suggestive of CCS. After enrollment, all subjects will be randomized to two arms (2016 U.K. National Institute of Health and Care Excellence guideline-determined and 2019 European Society of Cardiology guideline-determined diagnostic strategy) on a 1:1 basis. According to each strategy, CCTA should be referred and deferred for a subject in high and low risk group, respectively. The primary (effectiveness) endpoint is CCTA without obstructive coronary artery disease. Safety of each strategy will be mainly assessed by 1-year major adverse cardiovascular event rates.
DISCUSSION
The OPERATE trial will provide comparative effectiveness and safety evidences for two different diagnostic strategies for patients with SCP suggestive of CCS, with the intension of improving the diagnostic yield of CCTA at no expense of safety.
CLINICAL TRIAL REGISTRATION
ClinicalTrial.org Identifier NCT05640752.
Topics: Humans; Heart; Chest Pain; Coronary Artery Disease; Patients; Computed Tomography Angiography; Syndrome; Randomized Controlled Trials as Topic
PubMed: 37612631
DOI: 10.1186/s12872-023-03424-3 -
Translational Neurodegeneration May 2024The use of biomarker-led clinical trial designs has been transformative for investigating amyloid-targeting therapies for Alzheimer's disease (AD). The designs have... (Review)
Review
The use of biomarker-led clinical trial designs has been transformative for investigating amyloid-targeting therapies for Alzheimer's disease (AD). The designs have ensured the correct selection of patients on these trials, supported target engagement and have been used to support claims of disease modification and clinical efficacy. Ultimately, this has recently led to approval of disease-modifying, amyloid-targeting therapies for AD; something that should be noted for clinical trials investigating tau-targeting therapies for AD. There is a clear overlap of the purpose of biomarker use at each stage of clinical development between amyloid-targeting and tau-targeting clinical trials. However, there are differences within the potential context of use and interpretation for some biomarkers in particular measurements of amyloid and utility of soluble, phosphorylated tau biomarkers. Given the complexities of tau in health and disease, it is paramount that therapies target disease-relevant tau and, in parallel, appropriate assays of target engagement are developed. Tau positron emission tomography, fluid biomarkers reflecting tau pathology and downstream measures of neurodegeneration will be important both for participant recruitment and for monitoring disease-modification in tau-targeting clinical trials. Bespoke design of biomarker strategies and interpretations for different modalities and tau-based targets should also be considered.
Topics: Alzheimer Disease; Humans; tau Proteins; Biomarkers; Clinical Trials as Topic
PubMed: 38773569
DOI: 10.1186/s40035-024-00417-w -
Journal of Clinical Epidemiology Dec 2023To inform clinical practice guidelines, randomized controlled trials (RCTs) of the management of pneumonia need to address the outcomes that are most important to...
OBJECTIVES
To inform clinical practice guidelines, randomized controlled trials (RCTs) of the management of pneumonia need to address the outcomes that are most important to patients and health professionals using consistent instruments, to enable results to be compared, contrasted, and combined as appropriate. This systematic review describes the outcomes reported in clinical trials of pneumonia management and the instruments used to measure these outcomes.
STUDY DESIGN AND SETTING
Based on a prospective protocol, we searched MEDLINE/PubMed, Cochrane CENTRAL and clinical trial registries for ongoing or completed clinical trials evaluating pneumonia management in adults in any clinical setting. We grouped reported outcomes thematically and classified them following the COMET Initiative's taxonomy. We describe instruments used for assessing each outcome.
RESULTS
We found 280 eligible RCTs of which 115 (41.1%) enrolled critically ill patients and 165 (58.9%) predominantly noncritically ill patients. We identified 43 distinct outcomes and 108 measurement instruments, excluding nonvalidated scores and questionnaires. Almost all trials reported clinical/physiological outcomes (97.5%). Safety (63.2%), mortality (56.4%), resource use (48.6%) and life impact (11.8%) outcomes were less frequently addressed. The most frequently reported outcomes were treatment success (60.7%), mortality (56.4%) and adverse events (41.1%). There was significant variation in the selection of measurement instruments, with approximately two-thirds used in less than 10 of the 280 RCTs. None of the patient-reported outcomes were used in 10 or more RCTs.
CONCLUSION
This review reveals significant variation in outcomes and measurement instruments reported in clinical trials of pneumonia management. Outcomes that are important to patients and health professionals are often omitted. Our findings support the need for a rigorous core outcome set, such as that being developed by the European Respiratory Society.
Topics: Adult; Humans; Pneumonia; Treatment Outcome; Clinical Trials as Topic
PubMed: 37898460
DOI: 10.1016/j.jclinepi.2023.10.011 -
Journal of Drugs in Dermatology : JDD Aug 2023Topical treatments remain the foundation of psoriasis management. Tapinarof (VTAMA®; Dermavant Sciences, Inc.) is a first-in-class, non-steroidal, topical, aryl...
Topical treatments remain the foundation of psoriasis management. Tapinarof (VTAMA®; Dermavant Sciences, Inc.) is a first-in-class, non-steroidal, topical, aryl hydrocarbon receptor (AhR) agonist approved by the US Food and Drug Administration for the treatment of plaque psoriasis in adults and is under investigation for the treatment of psoriasis in children, and atopic dermatitis in adults and children down to 2 years old. Here, we review the mechanism of action of tapinarof and the PSOARING phase 3 trial program in mild to severe psoriasis. AhR is a ligand-dependent transcription factor involved in maintaining skin homeostasis. Tapinarof specifically binds to AhR to decrease proinflammatory cytokines, decrease oxidative stress, and promote skin barrier normalization. In two identical, randomized, 12-week pivotal phase 3 trials, PSOARING 1 and 2, tapinarof cream 1% once daily (QD) demonstrated significant efficacy versus vehicle and was well tolerated in adults with mild to severe psoriasis. In the PSOARING 3 long-term extension trial of repeated, intermittent tapinarof cream in eligible patients completing the pivotal trials, a high rate of complete disease clearance (40.9%) and a remittive effect of approximately 4 months off therapy were demonstrated over 52 weeks, with no tachyphylaxis. The most common adverse event, folliculitis, was mostly mild or moderate and resulted in a low trial discontinuation rate in PSOARING 1 and 2 (≤1.8%). Tapinarof cream 1% QD provides a novel, non-steroidal, topical treatment option for patients with psoriasis and is highly effective and well tolerated with long-term use including when applied to sensitive and intertriginous skin. Bobonich M, Gorelick J, Aldredge L, et al. Tapinarof, a novel, first-in-class, topical therapeutic aryl hydrocarbon receptor agonist for the management of psoriasis. J Drugs Dermatol. 2023;22(8):779-784. doi:10.36849/JDD.7317.
Topics: Humans; Dermatitis, Atopic; Emollients; Psoriasis; Receptors, Aryl Hydrocarbon; Skin; Treatment Outcome; Clinical Trials, Phase III as Topic; Randomized Controlled Trials as Topic
PubMed: 37556512
DOI: 10.36849/jdd.7317 -
Future Oncology (London, England) Sep 2023The prognosis of locally advanced colon cancer (LACC) with surgical resection followed only by adjuvant chemotherapy is poor. Preoperative chemotherapy for LACC...
The prognosis of locally advanced colon cancer (LACC) with surgical resection followed only by adjuvant chemotherapy is poor. Preoperative chemotherapy for LACC patients with risk factors such as cT4bN+ or cT3-4aN2-3 has attracted attention. Here, the authors describe the rationale and design of JCOG2006, a randomized phase II study comparing preoperative chemotherapy with mFOLFOX6 versus FOLFOXIRI for LACC. Their efficacy and safety are evaluated and a determination of which is the more promising treatment will be conducted in a subsequent phase III trial. A total of 86 patients will be accrued from 44 institutions over 2 years. The primary end point is the proportion of patients with a Tumor Regression Score of 0-2, and secondary end points include overall survival, response rate and adverse events. : jRCTs031210365 (https://jrct.niph.go.jp/).
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Colonic Neoplasms; Fluorouracil; Leucovorin; Neoadjuvant Therapy; Neoplasm Staging; Randomized Controlled Trials as Topic
PubMed: 37750332
DOI: 10.2217/fon-2023-0091 -
Circulation Jul 2023Health status outcomes, including symptoms, function, and quality of life, are worse for Black compared with White patients with heart failure. Sodium-glucose... (Meta-Analysis)
Meta-Analysis
Racial Differences in Quality of Life in Patients With Heart Failure Treated With Sodium-Glucose Cotransporter 2 Inhibitors: A Patient-Level Meta-Analysis of the CHIEF-HF, DEFINE-HF, and PRESERVED-HF Trials.
BACKGROUND
Health status outcomes, including symptoms, function, and quality of life, are worse for Black compared with White patients with heart failure. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce cardiovascular mortality and improve health status in patients with heart failure, but whether the health status benefit of SGLT2is is similar across races is not established. The objective of this study was to compare the treatment effect of SGLT2is (versus placebo) on health status for Black compared with White patients with heart failure.
METHODS
We combined patient-level data from 3 randomized clinical trials of SGLT2is: DEFINE-HF (Dapagliflozin Effect on Symptoms and Biomarkers in Patients With Heart Failure; n=263), PRESERVED-HF (Dapagliflozin in Preserved Ejection Fraction Heart Failure; n=324), and CHIEF-HF (A Study on Impact of Canagliflozin on Health Status, Quality of Life, and Functional Status in Heart Failure; n=448). These 3 United States-based trials enrolled a substantial proportion of Black patients, and each used the Kansas City Cardiomyopathy Questionnaire (KCCQ) to measure health status at baseline and after 12 weeks of treatment. Among 1035 total participants, selecting self-identified Black and White patients with complete information yielded a final analytic cohort of 935 patients. The primary endpoint was KCCQ Clinical Summary score. Twelve-week change in KCCQ with SGLT2is versus placebo was compared between Black and White patients by testing the interaction between race and treatment using multivariable linear regression models adjusted for trial, baseline KCCQ (as a restricted cubic spline), race, and treatment. The data that support the findings of this study are available from the corresponding author upon reasonable request.
RESULTS
Among 935 participants, 236 (25%) self-identified as Black, and 469 (50.2%) were treated with an SGLT2i. Treatment with an SGLT2i, compared with placebo, resulted in KCCQ Clinical Summary score improvements at 12 weeks of +4.0 points (95% CI, 1.7-6.3; =0.0007) in White patients and +4.7 points (95% CI, 0.7-8.7; =0.02) in Black patients, with no significant interaction by race and treatment (=0.76). Other KCCQ scales showed similar results.
CONCLUSIONS
Treatment with an SGLT2i resulted in consistent and significant improvements in health status for both Black and White patients with heart failure.
Topics: Humans; Quality of Life; Race Factors; Heart Failure; Glucose; Sodium; Stroke Volume; Randomized Controlled Trials as Topic
PubMed: 37191040
DOI: 10.1161/CIRCULATIONAHA.122.063263