Utilization and Reporting of Patient-Reported Outcome Measures in Randomized Clinical Trials of Acute Stroke (2010-2020).

BACKGROUND: Patient-reported outcome measures (PROMs) describe health status from the perspective of the patient. There is growing interest in incorporating PROMs into clinical trials, but the extent that such measures are used in contemporary stroke trials is uncertain. We sought to determine how often acute stroke trials included PROMs as outcome measures and assessed the completeness of methodological reporting. METHODS: We searched MEDLINE for randomized controlled trials published in 9 high-impact journals between 2010 and 2020. Eligible studies were phase 2 or 3 trials that tested therapeutic interventions within 1 month of stroke onset. Using the trial's primary publication and protocol, we abstracted key study characteristics including all primary and secondary outcome measures. We defined PROMs as self-reported measures of quality of life, symptoms, or function collected without interpretation of an external party. RESULTS: Of 116 trials that met eligibility, 57 (49%) included at least 1 PROM. Of these, 41 trials (35%) included a PROM in its primary publication, while 16 (14%) identified a PROM in its protocol. Only 1 trial used a PROM as a primary outcome. Among the 57 total trials, the most commonly used measures were Euro-QOL (n=41, 72%), Stroke Impact Scale (n=10, 18%), and Short-Form 36 (n=6, 11%). Trials were more likely to include a PROM if they were published after 2016, were phase 3, or included only hemorrhagic stroke. Of the 41 trials that included a PROM in the primary publication, 40 (97%) provided PROM results, but only 9 (22%) found statistically significant differences between treatment groups. Quality of methodological reporting was generally poor. CONCLUSIONS: Half of contemporary acute stroke trials published in high-impact journals listed at least 1 PROM as a secondary outcome, but they played a minor role in the presentation of the final trial results. Inclusion of PROMs in acute stroke trials requires greater attention during both the design and reporting phases of the trial. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019128727.

Association between expectations and clinical outcomes in online v. face-to-face therapy - an individual participant data meta-analysis.

BACKGROUND: Online treatments are increasing in number and are currently available for a wide range of clinical problems. To date little is known about the role of treatment expectations and other placebo-like mechanisms in online settings compared to traditional face-to-face treatment. To address this knowledge gap, we analyzed individual participant data from randomized clinical trials that compared online and face-to-face psychological interventions. METHODS: MEDLINE (Ovid) and PsycINFO (Ovid) were last searched on 2 February 2021. Randomized clinical trials of therapist guided online v. face-to-face psychological interventions for psychiatric or somatic conditions using a randomized controlled design were included. Titles, abstracts, and full texts of studies were independently screened by multiple observers. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Authors of the matching trials were contacted for individual participant data. Ratings from the Credibility and Expectancy Questionnaire and the primary outcome measure from each trial were used to estimate the association between expectation ratings and treatment outcomes in online v. face-to-face interventions, using a mixed-effects model. RESULTS: Of 7045 screened studies, 62 full-text articles were retrieved whereof six studies fulfilled the criteria and provided individual participant data (n = 491). Overall, CEQ ratings predicted clinical outcomes (ß = 0.27) at end of treatment with no moderating effect of treatment modality (online v. face-to-face). CONCLUSIONS: Online treatment appears to be equally susceptible to expectancy effects as face-to-face therapy. This furthers our understanding of the importance of placebo-like factors in online treatment and may aid the improvement of healthcare in online settings.

Design of randomized clinical trials with a binary endpoint: Conditional versus unconditional analyses of a two-by-two table.

When designing a randomized clinical trial to compare two treatments, the sample size required to have desired power with a specified type 1 error depends on the hypothesis testing procedure. With a binary endpoint (e.g., response), the trial results can be displayed in a 2 × 2 table. If one does the analysis conditional on the number of positive responses, then using Fisher's exact test has an actual type 1 error less than or equal to the specified nominal type 1 error. Alternatively, one can use one of many unconditional "exact" tests that also preserve the type 1 error and are less conservative than Fisher's exact test. In particular, the unconditional test of Boschloo is always at least as powerful as Fisher's exact test, leading to smaller required sample sizes for clinical trials. However, many statisticians have argued over the years that the conditional analysis with Fisher's exact test is the only appropriate procedure. Since having smaller clinical trials is an extremely important consideration, we review the general arguments given for the conditional analysis of a 2 × 2 table in the context of a randomized clinical trial. We find the arguments not relevant in this context, or, if relevant, not completely convincing, suggesting the sample-size advantage of the unconditional tests should lead to their recommended use. We also briefly suggest that since designers of clinical trials practically always have target null and alternative response rates, there is the possibility of using this information to improve the power of the unconditional tests.

The Effectiveness of Dialectical Behavior Therapy Compared to Schema Therapy for Borderline Personality Disorder: A Randomized Clinical Trial.

INTRODUCTION: In the treatment of borderline personality disorder (BPD), there is empirical support for both dialectical behavior therapy (DBT) and schema therapy (ST); these treatments have never been compared directly. This study examines whether either of them is more effective than the other in treating patients with BPD. METHODS: In this randomized, parallel-group, rater-blind clinical trial, outpatients aged between 18 and 65 years with a primary diagnosis of BPD were recruited in a tertiary outpatient treatment center (Lübeck, Germany). Participants were randomized to DBT or ST with one individual and one group session per week over 1.5 years. The primary outcome was the BPD symptom severity assessed with the mean score of the Borderline Personality Disorder Severity Index at 1-year naturalistic follow-up. RESULTS: Between November 26, 2014, and December 14, 2018, we enrolled 164 patients (mean age = 33.7 [SD = 10.61] years). Of these, 81 (49.4%) were treated with ST and 83 (50.6%) with DBT, overall, 130 (79.3%) were female. Intention-to-treat analysis with generalized linear mixed models did not show a significant difference at 1-year naturalistic follow-up between DBT and ST for the BPDSI total score (mean difference 3.32 [95% CI: -0.58-7.22], p = 0.094, d = -24 [-0.69; 0.20]) with lower scores for DBT. Pre-to-follow-up effect sizes were large in both groups (DBT: d = 2.45 [1.88-3.02], ST: d = 1.78 [1.26-2.29]). CONCLUSION: Patients in both treatment groups showed substantial improvements indicating that even severely affected patients with BPD and various comorbid disorders can be treated successfully with DBT and ST. An additional non-inferiority trial is needed to show if both treatments are equally effective. The trial was retrospectively registered on the German Clinical Trials Register, DRKS00011534 without protocol changes.

genRCT: a statistical analysis framework for generalizing RCT findings to real-world population.

When evaluating the real-world treatment effect, the analysis based on randomized clinical trials (RCTs) often introduces generalizability bias due to the difference in risk factors between the trial participants and the real-world patient population. This problem of lack of generalizability associated with the RCT-only analysis can be addressed by leveraging observational studies with large sample sizes that are representative of the real-world population. A set of novel statistical methods, termed "genRCT", for improving the generalizability of the trial has been developed using calibration weighting, which enforces the covariates balance between the RCT and observational study. This paper aims to review statistical methods for generalizing the RCT findings by harnessing information from large observational studies that represent real-world patients. Specifically, we discuss the choices of data sources and variables to meet key theoretical assumptions and principles. We introduce and compare estimation methods for continuous, binary, and survival endpoints. We showcase the use of the R package genRCT through a case study that estimates the average treatment effect of adjuvant chemotherapy for the stage 1B non-small cell lung patients represented by a large cancer registry.

Patient-Reported Outcome Measures Used in Randomized Controlled Trials Following Surgical Intervention for Endometriosis: A Structured Review from the AAGL Practice Guidelines Group.

OBJECTIVE: No consensus currently exists regarding patient-reported outcome measure (PROM) instruments. This structured review was conducted to identify the PROMs used by randomized controlled trials (RCTs) that evaluated surgical treatment in patients with endometriosis. DATA SOURCES: Two parallel searches were conducted by a medical librarian using Ovid MEDLINE, Ovid Embase, and Cochrane Library for RCTs published from 2000 to July 2022. One search focused on studies reporting quality of life (QoL), and the second search focused on studies reporting pain and sexual, bowel, and bladder function. METHOD OF STUDY SELECTION: During the title and abstract screening and reference check, 600 results were identified on PROMs relating to QoL and 465 studies on PROMs relating to pain and sexual, bowel, and/or bladder function and an evaluation of 17 and 12 studies conducted, respectively. The inclusion criteria involved selecting RCTs that focused on surgical intervention and assessing QoL, pain, and sexual, bowel, and/or bladder function using PROMs. TABULATION, INTEGRATION, AND RESULTS: Covidence software was used to organize and identify duplicate articles through screening. We developed a data extraction form to collect key information about each included study, as well as the pertinent PROMs used in the study. Assessment of the risk of bias of each study was also performed. A total of 19 studies were identified involving 2089 participants and a total of 16 PROMs used across the studies; 9 of 19 studies (47%) were rated as having a low risk of bias. There were no high-risk studies identified in this review. CONCLUSION: This study identified a large number of RCTs in surgical treatment of endometriosis that used various PROMs to assess QoL, pain, and bladder, bowel, and sexual function. The PROMs used by high-quality RCTs for QoL include Endometriosis Health Profile-30, Endometriosis Health Profile-5, Short-Form 36, Short-Form 12, and EQ-5D; for bowel-related symptoms Knowles-Eccersley-Scott-Symptom Questionnaire, Gastrointestinal Quality of Life Index, and Cleveland Clinic Fecal Incontinence Severity Scoring System/Wexner; for bladder-related function Bristol Female Lower Urinary Tract Symptoms, International Prostate Symptom Score, Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire, and Urinary Symptom Profile; and finally for sexual function Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire and Sexual Activity Questionnaire. Unlike other domains, only one tool (visual analog scale) was the dominant PROM used for the assessment of pain. In addition, the use of more than one PROM in each study to assess different aspects of patient's health and pain symptoms did not become prevalent until after 2015.

Fermented Ophiocordyceps sinensis mycelium products for preventing contrast-associated acute kidney injury: a systematic review of randomized controlled trials.

BACKGROUND: To evaluate the efficacy, effectiveness and safety of fermented Ophiocordyceps sinensis mycelium (FOSM) products for preventing contrast-associated acute kidney injury (CA-AKI). METHODS: Randomized controlled trials were searched from four Chinese and four English electronic databases and three clinical trial registries up to July 2023. Methodological quality was assessed by using the Cochrane risk-of-bias tool 2.0. Risk difference (RD) or risk ratio (RR) and mean difference (MD) were calculated along with the 95% confidence intervals (CIs). RESULTS: Fourteen trials testing three types of FOSM products (Bailing, Zhiling, and Jinshuibao capsules) involving 1271 participants injected contrast agents were included. For the risk of bias, all trials were rated as some concerns. Compared with routine preventive procedure (RPP) (saline hydration and alprostadil), FOSM products plus RPP showed beneficial effects in reducing the incidence of CA-AKI (14.62% and 5.35%, respectively; RD -0.06, 95% CI -0.09 to -0.03). Subgroup analysis showed that Bailing/Jinshuibao plus RPP demonstrated lower incidence of CA-AKI compared to RPP. However, there was no statistically significant difference between Zhiling with RPP and RPP in the incidence of CA-AKI. Additionally, only when FOSM products were taken before injection of the contrast, it was superior to RPP in reducing the incidence of CA-AKI. There was no statistical difference in adverse events between these two groups. CONCLUSIONS: Low certainty evidence suggests that preventive oral use of FOSM products as an adjuvant agent was safe and might decrease the incidence of CA-AKI. However, high-quality placebo-controlled trials are needed to confirm its benefit.

Pharmacological evaluation of vitamin D in COVID-19 and long COVID-19: recent studies confirm clinical validation and highlight metformin to improve VDR sensitivity and efficacy.

Nearly four years after its first appearance, and having gone from pandemic to endemic, the SARS-CoV-2 remains out of control globally. The purpose of this study was to evaluate the clinical efficacy of vitamin D (VD) in COVID-19 and long COVID-19, explain the discrepancy in clinical outcomes and highlight the potential impact of metformin on VD efficacy in recent articles. Articles from January 2022 to August 2023 were selected for this review. The objective of this study was achieved by reviewing, analyzing, and discussing articles demonstrating (1) the mechanism of action of VD (2) observational or randomized clinical trials (RCTs) that support or not the beneficial clinical effects of VD in COVID-19 or long COVID. (3) genetic and non-genetic reasons for the variation in the effects of VD. Articles were collected from electronic databases such as PubMed, Scopus, MEDLINE, Google Scholar, Egyptian Knowledge Bank, Science Direct, and Cochrane Database of Systematic Reviews. Twenty three studies conducted in vitro or in animal models indicated that VD may act in COVID-19 through protecting the respiratory system by antimicrobial peptide cathelicidins, reducing lung inflammation, regulating innate and adaptive immune functions and up regulation of autophagy gene activity. Our review identified 58 clinical studies that met the criteria. The number of publications supporting a beneficial clinical activity of VD in treating COVID-19 was 49 (86%), including 12 meta-analyses. Although the total patients included in all articles was 14,071,273, patients included in publications supporting a beneficial role of VD in COVID-19 were 14,029,411 (99.7%). Collectively, extensive observational studies indicated a decisive relationship between low VD levels and the severity of COVID-19 and mortality outcomes. Importantly, evidence from intervention studies has demonstrated the effectiveness of VD supplements in treating COVID-19. Furthermore, the results of 4 observational studies supported the beneficial role of VD in alleviating symptoms of long COVID-19 disease. However, eight RCTs and one meta-analysis of RCTs may contain low-grade evidence against a beneficial role of VD in COVID-19. Twenty-five articles have addressed the association between VDR and DBP genetic polymorphisms and treatment failure of VD in COVID-19. Impaired VDR signaling may underlie the variability of VD effects as non-genetic mechanisms. Interestingly, in recent studies, metformin has a beneficial therapeutic role in COVID-19 and long COVID-19, possibly by improving AMPK signaling of the VDR and enhancing the efficacy of the VD. In conclusion, evidence has been significantly strengthened over the past 18 months, with several meta-analyses and RCTs reporting conclusive beneficial effects of VD supplementation against COVID-19 and highlighting metformin to improve VDR sensitivity and efficacy in treating COVID-19 and long COVID-19.

Ethical Problems of Observational Studies and Big Data Compared to Randomized Trials.

The temptation to use prospective observational studies (POS) instead of conducting difficult trials (RCTs) has always existed, but with the advent of powerful computers and large databases, it can become almost irresistible. We examine the potential consequences, were this to occur, by comparing two hypothetical studies of a new treatment: one RCT, and one POS. The POS inevitably submits more patients to inferior research methodology. In RCTs, patients are clearly informed of the research context, and 1:1 randomized allocation between experimental and validated treatment balances risks for each patient. In POS, for each patient, the risks of receiving inferior treatment are impossible to estimate. The research context and the uncertainty are down-played, and patients and clinicians are at risk of becoming passive research subjects in studies performed from an outsider's view, which potentially has extraneous objectives, and is conducted without their explicit, autonomous, and voluntary involvement and consent.

Effects of empathy training on psychological concerns and empathy in caregivers of older people: A randomized, double-blind, crossover, clinical trial with follow-up.

OBJECTIVES: To investigate the effects of empathy training on psychological concerns and empathy in caregivers of older people. METHODS: A randomized, double-blind, crossover, clinical trial with follow-up was conducted online. Thirty paid and unpaid caregivers of older people from different regions of Brazil participated in an empathy training program. The caregivers answered a sociodemographic questionnaire and measures for the evaluation of empathy (affective and cognitive domains), burden, the impact of providing care as well as depressive symptoms and psychiatric symptoms before and immediately after training. Empathy and its domains were also assessed at three post-intervention follow-ups. RESULTS: Empathy training diminished levels of psychological concerns. Moreover, an increase was found in levels of cognitive empathy 15, 30 and 60 days after the intervention. CONCLUSIONS: Empathy training with a focus on cognitive empathy diminished psychological concerns in caregivers of older people and increased the levels of this ability over time. This intervention can be considered a coping strategy for negative impacts related to providing care. CLINICA LTRIAL REGISTRATION: RBR-8kjtfx3.

Is "Less be More" Still a Valid Concept in Intensive Care? A Review of Critical Care Randomized Clinical Trials from the New England Journal of Medicine.

The concept of "Less is more" has been gaining increasing awareness and acceptance in Critical Care. In 2017, we attempted to systematically answer the question "Can less be more in intensive care" with empirical data. We reviewed all the critical care randomized clinical trials (RCTs) between 1 January 2008 and 5 October 2016 in the New England Journal of Medicine (NEJM). This article attempts to repeat the earlier exercise using data from 5 October 2016 to 31 December 2023. This analysis of critical care RCTs in the NEJM has shown three findings. Approximately three-quarter of RCTs in critical care in the NEJM between 2008 and 2023 failed to show benefit or harm. In the years 2008-2016, patients in the intervention cohort had a higher mortality compared to controls, but in the years 2016-2023, the difference in overall mortality in patients in the intervention and control arms was not statistically significant. Compared to the years 2008-2016, in the years from 2016 to 2023, the number of RCTs showing harm decreased and those showing benefit increased. How to cite this article: Kapadia F, Bharadwaj S, Sharma R. Is "Less be More" Still a Valid Concept in Intensive Care? A Review of Critical Care Randomized Clinical Trials from the New England Journal of Medicine. Indian J Crit Care Med 2024;28(6):533-551.

Generalizability of the Necrotizing Enterocolitis Surgery Trial to the Target Population of Eligible Infants.

OBJECTIVE: The objective of this study was to evaluate whether infants randomized in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Necrotizing Enterocolitis Surgery Trial differed from eligible infants and whether differences affected the generalizability of trial results. STUDY DESIGN: Secondary analysis of infants enrolled in Necrotizing Enterocolitis Surgery Trial (born 2010-2017, with follow-up through 2019) at 20 US academic medical centers and an observational data set of eligible infants through 2013. Infants born ≤1000 g and diagnosed with necrotizing enterocolitis or spontaneous intestinal perforation requiring surgical intervention at ≤8 weeks were eligible. The target population included trial-eligible infants (randomized and nonrandomized) born during the first half of the study with available detailed preoperative data. Using model-based weighting methods, we estimated the effect of initial laparotomy vs peritoneal drain had the target population been randomized. RESULTS: The trial included 308 randomized infants. The target population included 382 (156 randomized and 226 eligible, non-randomized) infants. Compared with the target population, fewer randomized infants had necrotizing enterocolitis (31% vs 47%) or died before discharge (27% vs 41%). However, incidence of the primary composite outcome, death or neurodevelopmental impairment, was similar (69% vs 72%). Effect estimates for initial laparotomy vs drain weighted to the target population were largely unchanged from the original trial after accounting for preoperative diagnosis of necrotizing enterocolitis (adjusted relative risk [95% CI]: 0.85 [0.71-1.03] in target population vs 0.81 [0.64-1.04] in trial) or spontaneous intestinal perforation (1.02 [0.79-1.30] vs 1.11 [0.95-1.31]). CONCLUSION: Despite differences between randomized and eligible infants, estimated treatment effects in the trial and target population were similar, supporting the generalizability of trial results. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01029353.

Improving Food and Drug Administration-Centers for Medicare and Medicaid Services Coordination for Drugs Granted Accelerated Approval.

Policy Points The increasing number of drugs granted accelerated approval by the Food and Drug Administration (FDA) has challenged the Medicare program, which often pays for expensive therapies despite substantial uncertainty about benefits and risks to Medicare beneficiaries. We recommend several administrative and legislative approaches for improving FDA-Centers for Medicare and Medicaid Services (CMS) coordination around accelerated-approval drugs, including promoting earlier discussions among the FDA, the CMS, and drug companies; strengthening Medicare's coverage with evidence development program; linking Medicare payment to evidence generation milestones; and ensuring that the CMS has adequate staffing and resources to evaluate new therapies. These activities can help improve the integrity; transparency; and efficiency of approval, coverage, and payment processes for drugs granted accelerated approval. CONTEXT: The Food and Drug Administration (FDA)'s accelerated-approval pathway expedites patient access to promising treatments. However, increasing use of this pathway has challenged the Medicare program, which often pays for expensive therapies despite substantial uncertainty about benefits and risks to Medicare beneficiaries. We examined approaches to improve coordination between the FDA and Centers for Medicare and Medicaid Services (CMS) for drugs granted accelerated approval. METHODS: We argue that policymakers have focused on expedited pathways at the FDA without sufficient attention to complementary policies at the CMS. Although differences between the FDA and CMS decisions are to be expected given the agencies' different missions and statutory obligations, procedural improvements can ensure that Medicare beneficiaries have timely access to novel therapies that are likely to improve health outcomes. To inform policy options and recommendations, we conducted semistructured interviews with stakeholders to capture diverse perspectives on the topic. FINDINGS: We recommend ten areas for consideration: clarifying the FDA's evidentiary standards; strengthening FDA authorities; promoting earlier discussions among the FDA, the CMS, and drug companies; improving Medicare's coverage with evidence development program; tying Medicare payment for accelerated-approval drugs to evidence generation milestones; issuing CMS guidance on real-world evidence; clarifying Medicare's "reasonable and necessary" criteria; adopting lessons from international regulatory-reimbursement harmonization efforts; ensuring that the CMS has adequate staffing and expertise; and emphasizing equity. CONCLUSIONS: Better coordination between the FDA and CMS could improve the transparency and predictability of drug approval and coverage around accelerated-approval drugs, with important implications for patient outcomes, health spending, and evidence generation processes. Improved coordination will require reforms at both the FDA and CMS, with special attention to honoring the agencies' distinct authorities. It will require administrative and legislative actions, new resources, and strong leadership at both agencies.

Age Gap between Stroke Patients Included in Randomized Clinical Trials of Acute Revascularization Therapy and Those in Population-Based Studies: A Review.

BACKGROUND: The ongoing aging population in high-income countries is responsible for a dramatic rise in the number of elderly stroke patients in whom many questions remain regarding the use of acute revascularization therapy. This review aimed to compare stroke patients from population-based studies to those included in RCTs in terms of age. SUMMARY: Population-based incidence studies conducted in high income that complied with the defined quality criteria were reviewed (period 1985-2020). RCTs of acute ischemic stroke therapy including intravenous thrombolysis (IVT) with either alteplase or tenecteplase and mechanical thrombectomy (MT) were retrieved from systematic reviews performed in recent guidelines from the European Stroke Organisation. When available, information on either mean and/or median age was extracted from each selected article. As a result, 36 population-based registries were included, 34 of which recorded patients with first-ever stroke over 63 distinct time periods with a total of 38,188 patients. Twenty-nine RCTs enrolling 11,666 patients were identified including 13 RCTs related to IVT with alteplase, 11 RCTs about MT, and 5 RCTs on IVT with tenecteplase. A gap in age between stroke patients in the RCTs and those in population-based studies was observed. With few exceptions, mean age of patients in the RCTs was about 4 years younger than in population-based studies, while the median age was approximately 7 years younger. Thirty-five (83%) population-based incidence studies and 8 RCTs (32%) reported a mean age of patients >70 years old. Mean age ≥75 years was observed in 9 (21%) population-based studies and in only 1 (4%) RCT. All population-based studies and half of the RCTs reported a median age >70 years. KEY MESSAGES: The gap in age between patients enrolled in acute stroke therapy RCTs and those from population-based studies highlights an under-representation of elderly stroke patients in RCTs. With the current aging of the population, this trend is likely to increase in the coming years, and there is a need to promote the inclusion of older patients, particularly those with disabilities, in future trials to reflect the true population of stroke patients and to help clinicians have evidence-based data to guide their decision-making.

Comparative effects of nutraceuticals on body weight in adults with overweight or obesity: A systematic review and network meta-analysis of 111 randomized clinical trials.

There is no research on the comparative effects of nutraceuticals on weight loss in adults with overweight or obesity. This study aimed at quantifying and ranking the effects of different nutraceuticals on weight loss. We searched PubMed, Scopus, and Web of Science to November 2022. We included randomized trials evaluating the comparative effects of two or more nutraceuticals, or compared a nutraceutical against a placebo for weight loss in adults with overweight or obesity. We conducted random-effects network meta-analysis with a Frequentist framework to estimate mean difference [MD] and 95% confidence interval [CI] of the effect of nutraceuticals on weight loss. One hundred and eleven RCTs with 6171 participants that investigated the effects of 18 nutraceuticals on body weight were eligible. In the main analysis incorporating all trials, there was high certainty of evidence for supplementation of spirulina (MD: -1.77 kg, 95% CI: -2.77, -0.78) and moderate certainty of evidence that supplementation of curcumin (MD: -0.82 kg, 95% CI: -1.33, -0.30), psyllium (MD: -3.70 kg, 95% CI: -5.18, -2.22), chitosan (MD: -1.70 kg, 95% CI: -2.62, -0.78), and Nigella sativa (MD: -2.09 kg, 95%CI: -2.92, -1.26) could result in a small improvement in body weight. Supplementations with green tea (MD: -1.25 kg, 95%CI: -1.68, -0.82) and glucomannan (MD: -1.36 kg, 95%CI: -2.17, -0.54) demonstrated small weight loss, also the certainty of evidence was rated low. Based on our findings, supplementations with nutraceuticals can result in a small weight loss in adults with overweight or obesity.

Sample size calculation for randomized trials via inverse probability of response weighting when outcome data are missing at random.

Randomized trials are an established method to evaluate the causal effects of interventions. Despite concerted efforts to retain all trial participants, some missing outcome data are often inevitable. It is unclear how best to account for missing outcome data in sample size calculations. A standard approach is to inflate the sample size by the inverse of one minus the anticipated dropout probability. However, the performance of this approach in the presence of informative outcome missingness has not been well-studied. We investigate sample size calculation when outcome data are missing at random given the randomized intervention group and fully observed baseline covariates under an inverse probability of response weighted (IPRW) estimating equations approach. Using M-estimation theory, we derive sample size formulas for both individually randomized and cluster randomized trials (CRTs). We illustrate the proposed method by calculating a sample size for a CRT designed to detect a difference in HIV testing strategies under an IPRW approach. We additionally develop an R shiny app to facilitate implementation of the sample size formulas.

Clinical evidence in ischemic stroke: Where we have gone so far and hopes for the future.

OBJECTIVE: Ischemic stroke is a significant cause of disability and death worldwide. Randomized clinical trials (RCTs) are important in changing guidelines and treatment strategies. This study aimed to analyze the progress of RCTs in ischemic stroke and to guide future research directions. METHODS: Ischemic stroke-related RCT articles were identified in six high-impact medical journals using the Web of Science Core Collection database. Google Scholar was used to check whether relevant articles were included in the guidelines. The characteristics of these articles were analyzed and future research hotspots were predicted. RESULTS: 389 relevant articles were included in the analysis. The number of articles increased rapidly from 1972 to 2022, from 5 (1.3%; 1972-1982) to 208 (53.5%; 2013-2022) articles. 338 (86.9%) articles were included in relevant guidelines. According to corresponding author location, Europe was the source of the highest number of publications (183; 47.0%), followed by the Americas (152; 39.1%) and the Western Pacific (54; 13.9%). The number of publications steadily increased over time in the USA, England, Canada, Australia, Germany, and France, and surged in China and Spain, especially in the last 5 years. In recent years, endovascular therapy has accounted for the majority of ischemic stroke-related RCT articles. CONCLUSIONS: Numerous RCTs related to ischemic stroke have been conducted in recent decades, and both the number of articles and their contribution to guideline updates are increasing. Also, a shift in research topics was observed. However, great regional imbalances in this research exist, calling for more research to be conducted in specific regions to promote the generalizability of trial conclusions.

Big data and RCT's in surgical oncology: Impact on improving hepatopancreatobiliary cancer surgical care on the global stage.

Randomized controlled clinical trials (RCTs) are at the heart of "evidence-based" medicine. Conducting well-designed RCTs for surgical procedures is often challenged by inadequate recruitment accrual, blinding, or standardization of the surgical procedure, as well as lack of funding and evolution of the treatment strategy during the many years over which such trials are conducted. In addition, most clinical trials are performed in academic high-volume centers with highly selected patients, which may not necessarily reflect a "real-world" practice setting. Large databases provide easy and inexpensive access to data on a large and diverse patient population at a variety of treatment centers. Furthermore, large database studies provide the opportunity to answer questions that would be impossible or very arduous to answer using RCTs, including questions regarding health policy efficacy, trends in surgical practice, access to health care, the impact of hospital volume, and adherence to practice guidelines, as well as research questions regarding rare disease, infrequent surgical outcomes, and specific subpopulations. Prospective data registries may also allow for quality benchmarking and auditing. There are several high-quality RCTs providing evidence to support current practices in hepatopancreatobiliary (HPB) oncology. Evidence from big data bridges the gap in several instances where RCTs are lacking. In this article, we review the evidence from RCTs and big data in HPB oncology identify the existing lacunae, and discuss the future directions of research in HPB oncology.

Utilization of anonymization techniques to create an external control arm for clinical trial data.

BACKGROUND: Subject-level real-world data (RWD) collected during daily healthcare practices are increasingly used in medical research to assess questions that cannot be addressed in the context of a randomized controlled trial (RCT). A novel application of RWD arises from the need to create external control arms (ECAs) for single-arm RCTs. In the analysis of ECAs against RCT data, there is an evident need to manage and analyze RCT data and RWD in the same technical environment. In the Nordic countries, legal requirements may require that the original subject-level data be anonymized, i.e., modified so that the risk to identify any individual is minimal. The aim of this study was to conduct initial exploration on how well pseudonymized and anonymized RWD perform in the creation of an ECA for an RCT. METHODS: This was a hybrid observational cohort study using clinical data from the control arm of the completed randomized phase II clinical trial (PACIFIC-AF) and RWD cohort from Finnish healthcare data sources. The initial pseudonymized RWD were anonymized within the (k, ε)-anonymity framework (a model for protecting individuals against identification). Propensity score matching and weighting methods were applied to the anonymized and pseudonymized RWD, to balance potential confounders against the RCT data. Descriptive statistics for the potential confounders and overall survival analyses were conducted prior to and after matching and weighting, using both the pseudonymized and anonymized RWD sets. RESULTS: Anonymization affected the baseline characteristics of potential confounders only marginally. The greatest difference was in the prevalence of chronic obstructive pulmonary disease (4.6% vs. 5.4% in the pseudonymized compared to the anonymized data, respectively). Moreover, the overall survival changed in anonymization by only 8% (95% CI 4-22%). Both the pseudonymized and anonymized RWD were able to produce matched ECAs for the RCT data. Anonymization after matching impacted overall survival analysis by 22% (95% CI -21-87%). CONCLUSIONS: Anonymization may be a viable technique for cases where flexible data transfer and sharing are required. As anonymization necessarily affects some aspects of the original data, further research and careful consideration of anonymization strategies are needed.

Sequential regression and simulation: a method for estimating causal effects from heterogeneous clinical trials without a common control group.

BACKGROUND: The advent of clinical trial data sharing platforms has created opportunities for making new discoveries and answering important questions using already collected data. However, existing methods for meta-analyzing these data require the presence of shared control groups across studies, significantly limiting the number of questions that can be confidently addressed. We sought to develop a method for meta-analyzing potentially heterogeneous clinical trials even in the absence of a common control group. METHODS: This work was conducted within the context of a broader effort to study comparative efficacy in Crohn's disease. Following a search of clnicaltrials.gov we obtained access to the individual participant data from nine trials of FDA-approved treatments in Crohn's Disease (N = 3392). We developed a method involving sequences of regression and simulation to separately model the placebo- and drug-attributable effects, and to simulate head-to-head trials against an appropriately normalized background. We validated this method by comparing the outcome of a simulated trial comparing the efficacies of adalimumab and ustekinumab against the recently published results of SEAVUE, an actual head-to-head trial of these drugs. This study was pre-registered on PROSPERO (#157,827) prior to the completion of SEAVUE. RESULTS: Using our method of sequential regression and simulation, we compared the week eight outcomes of two virtual cohorts subject to the same patient selection criteria as SEAVUE and treated with adalimumab or ustekinumab. Our primary analysis replicated the corresponding published results from SEAVUE (p = 0.9). This finding proved stable under multiple sensitivity analyses. CONCLUSIONS: This new method may help reduce the bias of individual participant data meta-analyses, expand the scope of what can be learned from these already-collected data, and reduce the costs of obtaining high-quality evidence to guide patient care.