Cardiac Adverse Events and Remdesivir in Hospitalized Patients with Coronavirus Disease 2019 (COVID-19): A Post Hoc Safety Analysis of the Randomized DisCoVeRy Trial.

BACKGROUND: We aimed to evaluate the cardiac adverse events (AEs) in hospitalized patients with Coronavirus Disease 2019 (COVID-19) receiving remdesivir plus standard of care (SoC) compared to SoC alone (control), as an association was noted in some cohort studies and disproportionality analyses of safety databases. METHODS: This post-hoc safety analysis is based on data from the multicenter, randomized, open-label, controlled DisCoVeRy trial in hospitalized patients with COVID-19 (NCT04315948). Any first AE occurring between randomization and day 29 in the modified intention-to-treat (mITT) population randomized to either remdesivir or control group was considered. Analysis was performed using Kaplan-Meier survival curves and Kaplan-Meier estimates were calculated for event rates. RESULTS: Cardiac AEs were reported in 46 (11.2%) of 410 and 48 (11.3%) of 423 patients in the mITT population (n = 833) enrolled in the remdesivir and control groups, respectively. The difference between both groups was not significant (HR 1.0, 95% CI 0.7-1.5, p = 0.98), even when evaluating serious and non-serious cardiac AEs separately. The majority of reports in both groups were of arrhythmic nature (remdesivir, 84.8%; control, 83.3%) and were associated with a favorable outcome. There was no significant difference between remdesivir and control groups in the occurrence of different cardiac AE subclasses, including arrhythmic events (HR 1.1, 95% CI: 0.7-1.7, p = 0.68). CONCLUSIONS: Remdesivir treatment was not associated with an increased risk of cardiac AEs, whether serious or not, and regardless of AE severity, compared to control, in patients hospitalized with moderate or severe COVID-19. This is consistent with the results of other randomized controlled trials and meta-analyses.

More Than a Decade Since the Latest CONSORT Non-inferiority Trials Extension: Do Infectious Diseases Trials Do Enough?

More than a decade after the Consolidated Standards of Reporting Trials group released a reporting items checklist for non-inferiority randomized controlled trials, the infectious diseases literature continues to underreport these items. Trialists, journals, and peer reviewers should redouble their efforts to ensure infectious diseases studies meet these minimum reporting standards.

A meta-analysis of randomized controlled clinical trials for implications of acute treatment effects on glomerular filtration rate for long-term kidney protection.

Pharmacologic interventions to slow chronic kidney disease progression, such as ACE-inhibitors, angiotensin receptor blockers, or sodium glucose co-transporter 2 inhibitors, often produce acute treatment effects on glomerular filtration rate (GFR) that differ from their long-term chronic treatment effects. Observational studies assessing the implications of acute effects cannot distinguish acute effects from GFR changes unrelated to the treatment. Here, we performed meta-regression analysis of multiple trials to isolate acute effects to determine their long-term implications. In 64 randomized controlled trials (RCTs), enrolling 154,045 participants, we estimated acute effects as the mean between-group difference in GFR slope from baseline to three months, effects on chronic GFR slope (starting at three months after randomization), and effects on three composite kidney endpoints defined by kidney failure (GFR 15 ml/min/1.73m2 or less, chronic dialysis, or kidney transplantation) or sustained GFR declines of 30%, 40% or 57% decline, respectively. We used Bayesian meta-regression to relate acute effects with treatment effects on chronic slope and the composite kidney endpoints. Overall, acute effects were not associated with treatment effects on chronic slope. Acute effects were associated with the treatment effects on composite kidney outcomes such that larger negative acute effects were associated with lesser beneficial effects on the composite kidney endpoints. Associations were stronger when the kidney composite endpoints were defined by smaller thresholds of GFR decline (30% or 40%). Results were similar in a subgroup of interventions with supposedly hemodynamic effects that acutely reduce GFR. For studies with GFR 60 mL/min/1.73m2 or under, negative acute effects were associated with larger beneficial effects on chronic GFR slope. Thus, our data from a large and diverse set of RCTs suggests that acute effects of interventions may influence the treatment effect on clinical kidney outcomes.

Acupuncture for hot flashes in hormone receptor-positive breast cancer: A pooled analysis of individual patient data from parallel randomized trials.

BACKGROUND: Hot flashes are a common side effect of endocrine therapy (ET) that contribute to poor quality of life and decreased treatment adherence. METHODS: Patients with breast cancer wo were receiving ET and experiencing hot flashes were enrolled through three parallel, randomized trials conducted in the United States, China, and South Korea. Participants were randomized to either immediate acupuncture (IA) or delayed acupuncture control (DAC). IA participants received 20 acupuncture sessions over 10 weeks, whereas DAC participants received usual care, then crossed over to acupuncture with a reduced intensity. The primary end point was a change in score on the endocrine symptom subscale of the Functional Assessment of Cancer Therapy (FACT)-Endocrine Symptoms between baseline and week 10. Secondary end points included the hot flash score and the FACT-Breast score. A planned pooled analysis of individual patient data was performed using longitudinal mixed models. RESULTS: In total, 158 women with stage 0-III breast cancer were randomized (United States, n = 78; China, n = 40; South Korea, n = 40). At week 10, IA participants reported statistically significant improvements in the endocrine symptom subscale score (mean change ± standard error: 5.1 ± 0.9 vs. 0.2 ± 1.0; p = .0003), the hot flash score (-5.3 ± 0.9 vs. -1.4 ± 0.9; p < .003), and the FACT-Breast total score (8.0 ± 1.6 vs. -0.01 ± 1.6; p = .0005) compared with DAC participants. The effect of the acupuncture intervention differed by site (p = .005). CONCLUSIONS: Acupuncture led to statistically and clinically meaningful improvements in hot flashes, endocrine symptoms, and breast cancer-specific quality of life in women undergoing ET for breast cancer in the United States, China, and South Korea.

Lost in the plot: missing visual elements in Kaplan-Meier plots of phase III oncology trials.

Missing visual elements (MVE) in Kaplan-Meier (KM) curves can misrepresent data, preclude curve reconstruction, and hamper transparency. This study evaluated KM plots of phase III oncology trials. MVE were defined as an incomplete y-axis range or missing number at risk table in a KM curve. Surrogate endpoint KM curves were additionally evaluated for complete interpretability, defined by (1) reporting the number of censored patients and (2) correspondence of the disease assessment interval with the number at risk interval. Among 641 trials enrolling 518 235 patients, 116 trials (18%) had MVE in KM curves. Industry sponsorship, larger trials, and more recently published trials were correlated with lower odds of MVE. Only 3% of trials (15 of 574) published surrogate endpoint KM plots with complete interpretability. Improvements in the quality of KM curves of phase III oncology trials, particularly for surrogate endpoints, are needed for greater interpretability, reproducibility, and transparency in oncology research.

Influence of lack of blinding on the estimation of medication-related harms: a retrospective cohort study of randomized controlled trials.

BACKGROUND: Empirical evidence suggests that lack of blinding may be associated with biased estimates of treatment benefit in randomized controlled trials, but the influence on medication-related harms is not well-recognized. We aimed to investigate the association between blinding and clinical trial estimates of medication-related harms. METHODS: We searched PubMed from January 1, 2015, till January 1, 2020, for systematic reviews with meta-analyses of medication-related harms. Eligible meta-analyses must have contained trials both with and without blinding. Potential covariates that may confound effect estimates were addressed by restricting trials within the comparison or by hierarchical analysis of harmonized groups of meta-analyses (therefore harmonizing drug type, control, dosage, and registration status) across eligible meta-analyses. The weighted hierarchical linear regression was then used to estimate the differences in harm estimates (odds ratio, OR) between trials that lacked blinding and those that were blinded. The results were reported as the ratio of OR (ROR) with its 95% confidence interval (CI). RESULTS: We identified 629 meta-analyses of harms with 10,069 trials. We estimated a weighted average ROR of 0.68 (95% CI: 0.53 to 0.88, P < 0.01) among 82 trials in 20 meta-analyses where blinding of participants was lacking. With regard to lack of blinding of healthcare providers or outcomes assessors, the RORs were 0.68 (95% CI: 0.53 to 0.87, P < 0.01 from 81 trials in 22 meta-analyses) and 1.00 (95% CI: 0.94 to 1.07, P = 0.94 from 858 trials among 155 meta-analyses) respectively. Sensitivity analyses indicate that these findings are applicable to both objective and subjective outcomes. CONCLUSIONS: Lack of blinding of participants and health care providers in randomized controlled trials may underestimate medication-related harms. Adequate blinding in randomized trials, when feasible, may help safeguard against potential bias in estimating the effects of harms.

Reporting of Harms in Randomized Controlled Trials Published in Urology Journals: An Updated Analysis.

PURPOSE: Harms are often overlooked, but important, outcomes of randomized controlled trial reporting. Our goal was to determine if harms reporting has improved in high-impact urology journals. MATERIALS AND METHODS: Randomized controlled trials published in The Journal of Urology®, Urology, European Urology, and BJU International in 2012 and 2020 were analyzed. Each randomized controlled trial was evaluated by 2 authors in a masked-duplicate fashion to evaluate for adherence to harms reporting guidelines recommended by the Consolidated Standards of Reporting Trials (CONSORT) group. RESULTS: One hundred and thirty-two published studies met inclusion criteria. Between 2012 and 2020, there was a statistically significant increase in the median number of harms criteria reported between 2012 and 2020 (5.3 vs 7.2; P = .01). Methods criteria demonstrating the greatest improvements included item #3 "which harms were assessed," item #4a "when harm information was collected," and item #4b "methods to attribute harm to intervention." Results sections with the most improvement in reporting include item #6 "reasons for patient withdrawal," item #8a "effect size for harms," and item #8b "stratified serious + minor harms." CONCLUSIONS: Reporting of adverse events in randomized trials published in several top urology journals has demonstrated marked improvement. Studies published in 2020 reported approximately 70% of CONSORT-Harms criteria-an increase of nearly 40% since 2004. While these improvements mark significant change, deficits remain present and should be addressed to provide clinicians with the most complete perspective possible.

A phase 2b double-blind placebo-controlled randomized clinical trial of SB-061, an aggrecan mimetic, in patients with symptomatic knee osteoarthritis.

OBJECTIVES: To evaluate the efficacy and safety of intra-articular injections of a novel aggrecan mimetic, SB-061, in subjects with knee osteoarthritis (OA). METHODS: This was a randomized, placebo-controlled, double-blind phase II study comparing intra-articular injections of SB-061 with placebo (isotonic saline) for 52 weeks, administered at baseline, Wk 16, and Wk 32. Eligible subjects had a KL grade of 2 or 3 on X-ray of the target knee and a Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) pain score ≥20 out of 50 at screening and baseline visits. Subjects having any other knee condition were excluded. Use of analgesics was prohibited, except for rescue medication. The primary endpoint was change from baseline (CFB) in WOMAC pain at Week 8. Secondary endpoints were CFB in WOMAC function and total, ICOAP, Patient Global Assessment, and 20-meter walk test. Exploratory endpoints included structural CFB in magnetic resonance imaging entities. RESULTS: A total of 288 subjects were randomized to SB-061 (n = 145) or placebo (n = 143), and 252 (87.5%) completed injections. The groups were comparable at baseline. The primary endpoint was not met, as no significant difference in the CFB of the WOMAC pain score at Week 8 between groups was observed, nor at any other time point during the study. Similarly, neither of the secondary or exploratory endpoints indicated any significant difference between groups. The frequency and type of adverse events were similar between groups. SB-061 was well-tolerated. CONCLUSION: Intra-articular injections of SB-061 administered at baseline, Week 16, and Week 32, over one year in subjects with knee OA, were safe but did not show any statistically significant effect on knee pain nor on other symptomatic or structural entities compared to placebo. TRIAL REGISTRATION NUMBER EUDRACT NO: 2019-004515-31.

Frailty as an Effect Modifier in Randomized Controlled Trials: A Systematic Review.

BACKGROUND: The effect of clinical interventions may vary by patients' frailty status. Understanding treatment effect heterogeneity by frailty could lead to frailty-guided treatment strategies and reduce overtreatment and undertreatment. This systematic review aimed to examine the effect modification by frailty in randomized controlled trials (RCTs) that evaluate pharmacological, non-pharmacological, and multicomponent interventions. METHODS: We searched PubMed, Web of Science, EMBASE, and ClinicalTrial.gov, from their inception to 8 December 2023. Two reviewers independently extracted trial data and examined the study quality with senior authors. RESULTS: Sixty-one RCTs that evaluated the interaction between frailty and treatment effects in older adults were included. Frailty was evaluated using different tools such as the deficit accumulation frailty index, frailty phenotype, and other methods. The effect of several pharmacological interventions (e.g., edoxaban, sacubitril/valsartan, prasugrel, and chemotherapy) varied according to the degree of frailty, whereas other treatments (e.g., antihypertensives, vaccinations, osteoporosis medications, and androgen medications) demonstrated consistent benefits across different frailty levels. Some non-pharmacological interventions had greater benefits in patients with higher (e.g., chair yoga, functional walking, physical rehabilitation, and higher dose exercise program) or lower (e.g., intensive lifestyle intervention, psychosocial intervention) levels of frailty, while others (e.g., resistance-type exercise training, moderate-intensive physical activity, walking and nutrition or walking) produced similar intervention effects. Specific combined interventions (e.g., hospital-based disease management programs) demonstrated inconsistent effects across different frailty levels. DISCUSSION: The efficacy of clinical interventions often varied by frailty levels, suggesting that frailty is an important factor to consider in recommending clinical interventions in older adults. REGISTRATION: PROSPERO registration number CRD42021283051.

Analyses of quality of life in cancer drug trials - a review of measurements and analytical choices in post-reimbursement studies.

OBJECTIVES: For drugs reimbursed with limited evidence of patient benefits, confirmatory evidence of overall survival (OS) and quality of life (QoL) benefits is important. For QoL data to serve as valuable input to patients and decision-makers, it must be measured and analyzed using appropriate methods. We aimed to assess the measurement and analyses of post-reimbursement QoL data for cancer drugs introduced in Swedish healthcare with limited evidence at the time of reimbursement. METHODS: We reviewed any published post-reimbursement trial data on QoL for cancer drugs reimbursed in Sweden between 2010 and 2020 with limited evidence of improvement in QoL and OS benefits at the time of reimbursement. We extracted information on the instruments used, frequency of measurement, extent of missing data, statistical approaches, and the use of pre-registration and study protocols. RESULTS: Out of 22 drugs satisfying our inclusion criteria, we identified published QoL data for 12 drugs in 22 studies covering multiple cancer types. The most frequently used QoL instruments were EORTC QLQ-C30 and EQ-5D-3/5L. We identified three areas needing improvement in QoL measurement and analysis: (i) motivation for the frequency of measurements, (ii) handling of the substantial missing data problem, and (iii) inclusion and adherence to QoL analyses in clinical trial pre-registration and study protocols. CONCLUSIONS: Our review shows that the measurements and analysis of QoL data in our sample of cancer trials covering drugs initially reimbursed without any confirmed QoL or OS evidence have significant room for improvement. The increasing use of QoL assessments must be accompanied by a stricter adherence to best-practice guidelines to provide valuable input to patients and decision-makers.

Dietary Interventions in Atopic Dermatitis: A Comprehensive Scoping Review and Analysis.

BACKGROUND: This scoping review aims to critically assess gaps in the current literature on atopic dermatitis (AD) by evaluating the overall effectiveness of dietary interventions. Through a comprehensive analysis that follows the Preferred Reporting Item for Systematic Review and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines, we conducted a thorough search on the Web of Science database in May 2023 using specific search strategies to identify all relevant studies on the research topic. SUMMARY: A total of 104 full-text articles were included for review. Our synthesis identified seven notable categories of dietary interventions for AD, showcasing the diversity of interventions utilized. This includes vitamin supplementation, probiotic and prebiotic supplementation, dietary fat, biological compounds, foods from natural sources, major nutrients, and diet-related approaches. Further analyses stratified by targeted populations revealed a predominant focus on pediatrics, particularly in probiotic supplementation, and on adults, with an emphasis on vitamin D and E supplementation. KEY MESSAGES: Despite most dietary interventions demonstrating overall effectiveness in improving AD severity and its subjective symptoms, several significant gaps were identified. There was a scarcity of studies on adults and whole-diet interventions, a prevalence of short-term interventions, heterogeneity in study outcomes, designs, and population, occasional disparity between statistical significance and clinical relevance, and a lack of a comprehensive multidisciplinary approach. Nonetheless, these findings offer valuable insights for future AD research, guiding additional evidence-driven dietary interventions and informing healthcare professionals, researchers, and individuals, advancing both understanding and management of AD.

Efficacy of TNF-α Inhibitors in the Treatment of nr-axSpA: A Systematic Review and Meta-Analysis Based on Randomized Controlled Trials.

INTRODUCTION: A growing number of randomized controlled trials (RCTs) have demonstrated the effectiveness of tumor necrosis factor-α (TNF-α) inhibitors in treating non-radiographic axial spondyloarthritis (nr-axSpA). This study aimed to evaluate the efficacy of TNF-α inhibitors in the treatment of nr-axSpA. METHODS: PubMed, EMBASE, Web of Science, and the Cochrane Library databases were systematically searched for relevant RCTs using specific keywords up to June 2023. The primary outcome was the proportion of patients who achieved Assessment in SpondyloArthritis international Society 40% (ASAS40). Secondary outcomes included ASAS20, Bath Ankylosing Spondylitis Disease Activity Index 50% (BASDAI50), ASAS partial remission, and ASAS5/6. RESULTS: A total of eight RCTs involving 1,376 patients were included. Patients receiving anti-TNF therapy exhibited a higher rate of ASAS40 (pooled RR = 2.36; 95% CI: 1.63-3.42; p < 0.001). In addition, the TNF-α inhibitor group showed higher BASDAI50 rates (pooled RR = 2.06; 95% CI: 1.48-2.89), ASAS20 rates (pooled RR = 1.48; 95% CI: 1.31-1.67), ASAS partial remission rates (pooled RR = 2.33; 95% CI: 1.58-3.43), and ASAS5/6 rates (RR = 3.46; 95% CI: 2.05-5.83) than the placebo group. CONCLUSION: The TNF-α inhibitors were effective in treating nr-axSpA.

Unpublished trials of alprazolam XR and their influence on its apparent efficacy for panic disorder.

OBJECTIVE: To test for publication bias with alprazolam, the most widely prescribed benzodiazepine, by comparing its efficacy for panic disorder using trial results from (1) the published literature and (2) the US Food and Drug Administration (FDA). METHODS: From FDA reviews, we included data from all phase 2/3 efficacy trials of alprazolam extended-release (Xanax XR) for the treatment of panic disorder. A search for matching publications was performed using PubMed and Google Scholar. Publication bias was examined by comparing: (1) overall trial results (positive or not) according to the FDA v. corresponding publications; (2) effect size (Hedges's g) based on FDA data v. published data. RESULTS: The FDA review showed that five trials were conducted, only one of which (20%) was positive. Of the four not-positive trials, two were published conveying a positive outcome; the other two were not published. Thus, according to the published literature, three trials were conducted and all (100%) were positive. Alprazolam's effect size calculated using FDA data was 0.33 (CI95% 0.07-0.60) v. 0.47 (CI95% 0.30-0.65) using published data, an increase of 0.14, or 42%. CONCLUSIONS: Publication bias substantially inflates the apparent efficacy of alprazolam XR.

The Effect of the Earned Income Tax Credit on Physical and Mental health-Results from the Atlanta Paycheck Plus Experiment.

Policy Points The Paycheck Plus randomized controlled trial tested a fourfold increase in the Earned Income Tax Credit (EITC) for single adults without dependent children over 3 years in New York and Atlanta. In New York, the intervention improved economic, mental, and physical health outcomes. In Atlanta, it had no economic benefit or impact on physical health and may have worsened mental health. In Atlanta, tax filing and bonus receipt were lower than in the New York arm of the trial, which may explain the lack of economic benefits. Lower mental health scores in the treatment group were driven by disadvantaged men, and the study sample was in good mental health. CONTEXT: The Paycheck Plus experiment examined the effects of an enhanced Earned Income Tax Credit (EITC) for single adults on economic and health outcomes in Atlanta, GA and New York City (NYC). The NYC study was completed two years prior to the Atlanta study and found mental and physical benefits for the subgroups that responded best to the economic incentives provided. In this article, we present the findings from the Atlanta study, in which the uptake of the treatment (tax filings and EITC bonus) were lower and economic and health benefits were not observed. METHODS: Paycheck Plus Atlanta was an unblinded randomized controlled trial that assigned n = 3,971 participants to either the standard federal EITC (control group) or an EITC supplement of up to $2,000 (treatment group) for three tax years (2017-2019). Administrative data on employment and earnings were obtained from the Georgia Department of Labor and survey data were used to examine validated measures of health and well-being. FINDINGS: In Atlanta, the treatment group had significantly higher earnings in the first project year but did not have significantly higher cumulative earnings than the control group overall (mean difference = $1,812, 95% CI = -150, 3,774, p = 0.07). The treatment group also had significantly lower scores on two measures of mental health after the intervention was complete: the Patient Health Questionnaire 8 (mean difference = 0.19, 95% CI = 0.06, 0.32, p = 0.005) and the Kessler 6 (mean difference = 0.15, 95% CI = 0.03, 0.27, p = 0.012). Secondary analyses suggested these results were driven by disadvantaged men, but the study sample was in good mental health. CONCLUSIONS: The EITC experiment in Atlanta was not associated with gains in earnings or improvements in physical or mental health.

High-impact journal publishing: the devil is in the detail!

Research in medicine is an indispensable tool to advance knowledge and improve patient care. This may be particularly true in the field of human reproduction as it is a relatively new field and treatment options are rapidly evolving. This is of particular importance in an emerging field like 'human reproduction', where treatment options evolve fast.The cornerstone of evidence-based knowledge, leading to evidence-based treatment decisions, is randomized controlled trials as they explore the benefits of new treatment approaches. The study design and performance are crucial and, if they are carried out correctly, solid conclusions can be drawn and be implemented in daily clinical routines. The dissemination of new findings throughout the scientific community occurs in the form of publications in scientific journals, and the importance of the journal is reflected in part by the impact factor. The peer review process before publication is fundamental in preventing flaws in the study design. Thus, readers of journals with a high impact factor usually rely on a thorough peer review process and therefore might not question the published data. However, even papers published in high-impact journals might not be free of flaws, so the aim of this paper is to encourage readers to be aware of this fact and critically read scientific papers as 'the devil lies in the details'.

Randomized controlled trials: not always the "gold standard" for evidence in obstetrics and gynecology.

Randomized controlled trials are considered the "gold standard" for therapeutic interventions, and it is not uncommon for sweeping changes in medical practice to follow positive results from such trials. However, randomized controlled trials are not without their limitations. Physicians frequently view randomized controlled trials as infallible, whereas they tend to dismiss evidence derived from sources other than randomized controlled trials as less credible or reliable. In several situations in obstetrics and gynecology, there are no randomized controlled trials to help guide the clinician. In these circumstances, it is important to evaluate the entire body of evidence including observational studies, rather than dismiss interventions altogether simply because no randomized controlled trials exist. Randomized controlled trials and observational studies should be viewed as complementary rather than at odds with each other. Some reversals in widely adopted clinical practice have recently been implemented following subsequent studies that contradicted the outcomes of major randomized controlled trials. The most notable of these was the withdrawal from the market of 17-hydroxyprogesterone caproate for preterm birth prevention. Such reversals could potentially have been averted if the inherent limitations of randomized controlled trials were carefully considered before implementing these universal practice changes. This Clinical Opinion underscores the limitations of an exclusive reliance on randomized controlled trials while disregarding other evidence in determining how best to care for patients. Solutions are proposed that advocate that clinicians adopt a more balanced perspective that considers the entirety of the available medical evidence and the individual patient characteristics, needs, and wishes.

Effect of sodium-glucose cotransporter-2 inhibitors on myocardial infarction incidence: A systematic review and meta-analysis of randomized controlled trials and cohort studies.

AIM: To assess whether sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce myocardial infarction (MI) incidence in patients with or without type 2 diabetes. METHODS: PubMed, Embase, Web of Science, the Cochrane library, and https://ClinicalTrials.gov were searched up to 7 May 2022. Randomized controlled trials (RCTs) and cohort studies reporting the effects of SGLT2 inhibitor treatment on MI incidence were included. Relative risks (RRs) with a 95% confidence interval (CI) for MI incidence were extracted and pooled. Subgroup analysis and meta-regression were performed to explore the heterogeneity. RESULTS: This meta-analysis included 54 RCTs and 32 cohort studies, with data from six SGLT2 inhibitors and 3 394 423 individuals. In the overall analysis, SGLT2 inhibitors significantly reduced MI incidence in RCTs (RR 0.9, 95% CI 0.84-0.96) and cohort studies (RR 0.89, 95% CI 0.83-0.94). In RCTs, the results of the subgroup analysis revealed no significant alterations in outcomes based on different SGLT2 inhibitor types, control drug types, cardiovascular disease (CVD) status and sources of outcome extraction (p for interaction >0.05). In cohort studies, the presence or absence of CVD led to similar effects of SGLT2 inhibitors on decreasing MI incidence (p for interaction = 0.179). However, variations in results were observed based on the type of control group in cohort studies (p for interaction = 0.036). Meta-regression results did not reveal an association between baseline cardiovascular risk factors, follow-up length, or MI incidence. CONCLUSIONS: In both RCTs and cohort studies, SGLT2 inhibitors reduced MI incidence. The cardioprotective effects of SGLT2 inhibitors were observed in patients with and without a history of CVD.

Efficacy and safety of once-weekly insulin icodec in type 2 diabetes: A meta-analysis of ONWARDS phase 3 randomized controlled trials.

AIM: Insulin icodec is a novel ultra-long action basal insulin analogue designed for once-weekly administration. With the merit of once-a-week administration, it promises better adherence and greater treatment satisfaction because of reduced injection frequency. The purpose of this study was to ascertain the efficacy and safety of once-weekly insulin icodec in comparison with other basal insulin analogues in the management of type 2 diabetes. MATERIALS AND METHODS: The PRISMA guidelines were followed during the conduct of this study. For the eligible studies, five databases and ClinicalTrials.gov were screened until July 2023. All randomized controlled trials comparing the efficacy and safety of insulin icodec in type 2 diabetes versus other insulin analogues were included. The extracted data were then analysed for meta-analysis using RevMan 5.3 software. RESULTS: Five clinical trials with 3764 participants were included. The meta-analysis showed that once-weekly insulin icodec had higher glycated haemoglobin (HbA1c) reduction [mean difference -0.17%, 95% confidence interval (CI; -0.28 to -0.06), p = .003], with no significant difference in fasting plasma glucose compared with other insulin analogues. HbA1c achievement <7% [odds ratio 1.51, 95% CI (1.14-1.99), p = .004] and HbA1c achievement <7% without hypoglycaemia [odds ratio 1.45, 95% CI (1.26-1.67), p < .00001] were observed in higher proportions with insulin icodec compared with the comparator group. The percentage of time spent in the target glycaemic range was comparatively similar between insulin icodec and the comparator [mean difference 2.42%, 95% CI (0.01-4.84), p = .05]. There was a significantly higher incidence of level 1 hypoglycaemia with insulin icodec but no significant difference was seen for the incidence of levels 2, 3 and combined 2/3 hypoglycaemia. Any adverse events and adverse events related to basal insulin were comparably similar in insulin icodec and comparators. The subgroup analysis of once-weekly insulin icodec with individual insulin analogues (glargine U100 and degludec) showed that insulin icodec had similar efficacy with insulin glargine U100 but superior efficacy with higher HbA1c reduction with insulin icodec compared with insulin degludec. The safety profile was comparable between insulin icodec and glargine U100, whereas insulin icodec reported higher incidence of hypoglycaemia events and any adverse events when compared with degludec. CONCLUSION: Once-weekly insulin icodec showed a better HbA1c reduction with a higher proportion of patients achieving HbA1c targets in comparison with once-daily basal insulin analogues. They were no major safety concerns with respect to hypoglycaemia or adverse events.

Frailty in clinical drug trials: Frailty assessments, subgroup analyses and outcomes.

With population ageing, drug trials are increasingly turning their attention to including older, frailer people. This review aimed to provide an overview of how frailty was assessed in published studies related to clinical pharmacological trials, and on the interaction of frailty on the efficacy of the treatments. We searched MEDLINE, EMBASE and Cochrane for clinical drug trials in older people. A total of 4031 abstracts were screened and 17 relevant studies were included in this review. We summarized the findings of these 17 trials into five main clinical areas: cardiovascular (eight studies), cognition (one study), vaccination (two studies), cancer (four studies) and other (two studies). Frailty was assessed retrospectively in most of the studies. Frailty was treated as an ordinal variable (with different levels of frailty) or binary variable (frail/non-frail) using cut-offs in some studies, and as a continuous in some other studies. The effect of frailty on the treatment efficacy was not consistent among the studies. While several trials, such as the Action in Diabetes and Vascular Disease-Preterax and Diamicron Modified Release Controlled Evaluation trials, the Systolic Blood Pressure Intervention Trial and the Aspirin in Reducing Events in the Elderly trial, showed some reduced effects of the treatment in frail patients, most of the trials showed that the benefits of the treatment are not affected by frailty. Some trials even showed that the benefits of the treatment were more significant in frailer patients (the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure and the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure trials). The results of this review suggest that routine measurement of frailty in participants in clinical drug trials would improve our knowledge of the effect of treatment in the frail and identify those who have more or least to gain from treatment.

Group sequential designs for pragmatic clinical trials with early outcomes: methods and guidance for planning and implementation.

BACKGROUND: Group sequential designs are one of the most widely used methodologies for adaptive design in randomized clinical trials. In settings where early outcomes are available, they offer large gains in efficiency compared to a fixed design. However, such designs are underused and used predominantly in therapeutic areas where there is expertise and experience in implementation. One barrier to their greater use is the requirement to undertake simulation studies at the planning stage that require considerable knowledge, coding experience and additional costs. Based on some modest assumptions about the likely patterns of recruitment and the covariance structure of the outcomes, some simple analytic expressions are presented that negate the need to undertake simulations. METHODS: A model for longitudinal outcomes with an assumed approximate multivariate normal distribution and three contrasting simple recruitment models are described, based on fixed, increasing and decreasing rates. For assumed uniform and exponential correlation models, analytic expressions for the variance of the treatment effect and the effects of the early outcomes on reducing this variance at the primary outcome time-point are presented. Expressions for the minimum and maximum values show how the correlations and timing of the early outcomes affect design efficiency. RESULTS: Simulations showed how patterns of information accrual varied between correlation and recruitment models, and consequentially to some general guidance for planning a trial. Using a previously reported group sequential trial as an exemplar, it is shown how the analytic expressions given here could have been used as a quick and flexible planning tool, avoiding the need for extensive simulation studies based on individual participant data. CONCLUSIONS: The analytic expressions described can be routinely used at the planning stage of a putative trial, based on some modest assumptions about the likely number of outcomes and when they might occur and the expected recruitment patterns. Numerical simulations showed that these models behaved sensibly and allowed a range of design options to be explored in a way that would have been difficult and time-consuming if the previously described method of simulating individual trial participant data had been used.