Publication Of Clinical Trials Research Articles

Abdominal Organ Transplantation: Noteworthy Literature in 2023.

This review highlights noteworthy literature published in 2023 and pertinent to anesthesiologists and critical care physicians caring for patients undergoing abdominal organ transplantation. We feature 9 studies from 593 peer-reviewed papers on pancreatic transplantation, 3 from 194 on intestinal transplantation, and 28 from over 4513 on kidney transplantation. The liver transplantation section includes a special focus on 20 studies from 5666 clinical trial publications. We explore a broad range of topics, including donor management, perioperative recipient management, and innovative pharmacologic and mechanical interventions tested for the improvement of patient and graft outcomes and survival.

Delayed publication of clinical trials in gynecologic oncology

ObjectivesDelays in clinical trial publication can hinder timely implementation of evidence-based practices. We sought to determine publication rates and time to publication for clinical trials addressing gynecologic malignancies. MethodsAll clinical trials addressing gynecologic cancers in the ClinicalTrials.gov registry with a primary completion date between 1/1/2018 and 1/1/2020 were identified. The primary outcome was publication rate. All included studies had been completed for at least 3 years. Secondary outcomes were time to publication and associations between publication rate and sponsor, cancer type, and the number and location of primary study sites. ResultsOf the 290 trials included, 161 (55.5%) had a peer-reviewed publication for the primary outcome within at least 3 years after completion. Of these, 123 had positive results (76.4%) and 38 were negative (23.6%). The average duration from primary completion to manuscript publication was 23.6 months (SD 13.9; median 21.4, IQR 15.1–32.4). Only 73 had results posted on the ClinicalTrials.gov registry (25.2%). Studies with positive findings had a significantly faster time to publication than those with negative results (22.0 mo vs 29.0 mo, p = 0.009). There was no significant difference between publication rate and funding source, cancer type, or location and number of primary sites. ConclusionsTimely publication of clinical trials addressing gynecologic cancers remains an issue. Studies with positive findings were published faster than those with negative results, but the average publication time was still almost 2 years from trial completion. Further efforts should be made to identify and address barriers to clinical trial publication.

Publication Bias in Upper Gastrointestinal Oncology Clinical Trials.

Evidence-based medicine requires evaluation of the medical literature to guide clinical reasoning and treatment recommendations. The presence of publication bias towards exclusion of non-statistically significant clinical trials may be leading to an incomplete evaluation of the literature and cause potentially incomplete guidance for patients. We aimed to compare publication rates and impact of publications of positive and negative outcome clinical trials. We queried the US National Library of Medicine Clinical Trials database identifying clinical trials with reported results on the topics of pancreatic, liver, and gastric cancer. A "positive" trial was defined as having a statistically significant difference between the treatment arms, while a "negative" did not. Data collected included termination cause, intervention, funding type, publication rates, and journal characteristics. In total, 535 clinical trials were examined, across all pathologies clinical trials with significant findings for the primary outcome were published at a higher rate (99%) compared to those with non-significant findings (77%) (p < 0.01). Significantly, more studies with significant findings reached at least 80% of their estimated enrollment goal versus non-significant studies, 72% and 53% respectively (p < 0.01). Three of four metrics for impact of publication showed no difference between significant and non-significant studies once they reached publication. These findings suggest that clinical trials of three of the most common upper gastrointestinal malignancies have a publication bias towards studies with significant primary outcome findings. This study has implications to the way evidence-based medicine is practiced as the medical literature appears to be failing to capture important data for consideration of clinical decision making.

Cost-Effectiveness Analysis of Etranacogene Dezaparvovec Versus Extended Half-Life Prophylaxis for Moderate-to-Severe Haemophilia B in Germany.

Haemophilia B is a rare genetic disease that is caused by a deficiency of coagulation factor IX (FIX) in the blood and leads to internal and external bleeding. Under the current standard of care, haemophilia is treated either prophylactically or on-demand via intravenous infusions of FIX. These treatment strategies impose a high burden on patients and health care systems as haemophilia B requires lifelong treatment, and FIX is costly. Etranacogene dezaparvovec (ED) is a gene therapy for haemophilia B that has been recently approved by the United States Food and Drug Administration and has received a recommendation for conditional marketing authorization by the European Medicines Agency. We aimed to examine the cost-effectiveness of ED versus extended half-life FIX (EHL-FIX) prophylaxis for moderate-to-severe haemophilia B from a German health care payer perspective. A microsimulation model was implemented in R. The model used data from the ED phase 3 clinical trial publication and further secondary data sources to simulate and compare patients receiving ED or EHL-FIX prophylaxis over a lifetime horizon, with the potential for ED patients to switch treatment to EHL-FIX prophylaxis when the effectiveness of ED waned. Primary outcomes of this analysis included discounted total costs, discounted quality-adjusted life years (QALYs), incremental cost-effectiveness, and the incremental net monetary benefit. The annual discount rate for costs and effects was 3%. Uncertainty was examined via probabilistic analysis and additional univariate sensitivity analyses. Probabilistic analysis indicated that patients treated with ED instead of EHL-FIX prophylaxis gained 0.50 QALYs and experienced cost savings of EUR 1,179,829 at a price of EUR 1,500,000 per ED treatment. ED was the dominant treatment strategy. At a willingness to pay of EUR 50,000/QALY, the incremental net monetary benefit amounted to EUR 1,204,840. Depending on the price, ED can save costs and improve health outcomes of haemophilia patients compared with EHL-FIX prophylaxis, making it a potentially cost-effective alternative. These results are uncertain due to a lack of evidence regarding the long-term effectiveness of ED.

Efficacy and safety of neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy in locally advanced esophageal cancer: An updated meta-analysis.

Currently, the optimal treatment for neoadjuvant therapy for locally advanced esophageal cancer is not clear, and there is no evidence that neoadjuvant chemoradiotherapy (nCRT) is superior to neoadjuvant chemotherapy (nCT). Due to the publication of new clinical trials and defects in previous meta-analyses, we conducted an updated meta-analysis to evaluate the efficacy and safety of nCRT and nCT. The following databases were searched for studies: PubMed, EMBASE, and Cochrane library (updated to April 22, 2023). All randomized trials comparing nCRT with nCT in locally advanced esophageal cancer met the inclusion criteria. Data were analyzed using Review Manager 5.4.1 (Cochrane collaboration software). Primary outcomes assessed from the trials included overall survival (OS), progression-free survival (PFS), pathological complete response (pCR), R0 resection rate, postoperative complications, postoperative mortality, and grade 3 or higher adverse events (3 + AEs). This systematic review and meta-analysis included 7 randomized controlled studies involving 1372 patients (686 receiving nCRT and 686 receiving nCT). Compared with nCT, nCRT significantly improved OS (HR = 0.80; 95% CI: 0.68-0.94), PFS (HR = 0.78; 95% CI: 0.66-0.93), pCR (OR = 13.00; 95% CI: 7.82-21.61) and R0 resection (OR = 1.84; 95% CI: 1.32-2.57), but was associated with higher postoperative mortality (OR = 2.31; 95% CI: 1.26-4.25) and grade 3 + AEs (OR = 2.21; 95% CI: 1.36-3.58). There was no significant difference in postoperative complications between nCRT and nCT (OR = 1.15; 95% CI: 0.82-1.61). Subgroup analysis showed significant survival benefit in squamous cell carcinoma (HR = 0.80; 95% CI: 0.68-0.98), but not in adenocarcinoma (HR = 0.80; 95% CI: 0.63-1.08). Our meta-analysis found superior efficacy associated with nCRT compared with nCT in both tumor regression and prolonged survival, but increased the risk of postoperative mortality and grade 3 + AEs. Esophageal squamous cell carcinoma was more likely to benefit from nCRT than esophageal adenocarcinoma in the term of OS.

Global trends and research status in ankylosing spondylitis clinical trials: a bibliometric analysis of the last 20 years.

Ankylosing spondylitis (AS) is a rheumatic and autoimmune disease associated with a chronic inflammatory response, mainly characterized by pain, stiffness, or limited mobility of the spine and sacroiliac joints. Severe symptoms can lead to joint deformity, destruction, and even lifelong disability, causing a serious burden on families and society as a whole. A large number of clinical studies have been published on AS over the past 20 years. This study aimed to summarize the current research status and global trends relating to AS clinical trials through a bibliometric analysis. The Web of Science Core Collection database was searched for publications related to AS clinical trials published between January 2003 and June 2023. Bibliometric analysis and web visualization were performed using CiteSpace, VOSviewer, and a bibliometric online analysis platform (https://bibliometric.com), which included the number of publications, citations, countries, institutions, journals, authors, references, and keywords. 1,212 articles published in 201 journals from 65 countries were included in this study. The number of publications related to AS clinical trials is increasing annually. The United States and the Free University of Berlin, the countries and institutions, respectively, that have published the most articles on AS, have made outstanding contributions to this field. The author with the most published papers and co-citations over the period covered by the study was Desiree Van Der Heijde. The journal with the most published and cited articles was Annals of the Rheumatic Diseases. The keywords: "double-blind," "rheumatoid arthritis," "efficacy," "placebo-controlled trial," "infliximab," "etanercept," "psoriatic arthritis" and "therapy" represent the current research hotspots regarding AS. This is the first study to perform a bibliometric analysis and visualization of AS clinical trial publications, providing a reliable research focus and direction for clinicians. Future studies in the field of AS clinical trials should focus on placebo-controlled trials of targeted therapeutic drugs.

Approval, Evidence, and "Off-Label" Device Utilization: The Patent Foramen Ovale Closure Story.

Following regulatory approval, medical devices may be used "off-label." Patent foramen ovale (PFO) closure is indicated to reduce recurrent stroke but has been proposed for other indications, including migraine, transient ischemic attack, and diving decompression illness. We sought to evaluate PFO closure rates and indications relative to the timing of regulatory approval and publication of key randomized trials. We performed a retrospective cohort study using the OptumLabs Data Warehouse of US commercial insurance enrollees from 2006 to 2019. We quantified PFO closure among individuals with ≥2 years of preprocedure coverage to establish indications, classified hierarchically as stroke/systemic embolism, migraine, transient ischemia attack, or other. We identified 5315 patients undergoing PFO closure (51.8% female, 29.2%≥60 years old), which increased from 4.75 per 100 000 person-years in 2006 to 6.60 per 100 000 person-years in 2019. Patients aged ≥60 years accounted for 29.2% of closures. Procedure volumes corresponded weakly with supportive clinical publications and device approval. Among patients with PFO closure, 58.6% underwent closure for stroke/systemic embolism, 10.2% for transient ischemia attack, 8.8% for migraine, and 22.4% for other indications; 17.6% of patients had atrial fibrillation at baseline; and 11.9% developed atrial fibrillation postprocedure. Those aged ≥60 years and male were less likely to undergo closure for migraine than stroke/systemic embolism. From 2006 to 2019, PFO closure use was consistently low and corresponded weakly with clinical trial publications and regulatory status. Nearly half of patients underwent PFO closure for indications unapproved by the Food and Drug Administration. Regulators and payers should coordinate mechanisms to promote utilization for approved indications to ensure patient safety and should facilitate clinical trials for other possible indications.

Overview of systematic reviews comparing endovascular to best medical treatment for large-vessel occlusion acute ischaemic stroke: an umbrella review.

The literature on endovascular treatment (EVT) for large-vessel occlusion (LVO) acute ischaemic stroke (AIS) has been rapidly increasing after the publication of positive randomized-controlled clinical trials (RCTs) and a plethora of systematic reviews (SRs) showing benefit compared to best medical therapy (BMT) for LVO. An overview of SRs (umbrella review) and meta-analysis of primary RCTs were performed to summarize the literature and present efficacy and safety of EVT. MEDLINE via Pubmed, Embase and Epistemonikos databases were searched from January 2015 until 15 October 2023. All SRs of RCTs comparing EVT to BMT were included. Quality was assessed using Risk of Bias in Systematic Reviews scores and the RoB 2 Cochrane Collaboration tool, as appropriate. GRADE approach was used to evaluate the strength of evidence. Data were presented according to the Preferred Reporting Items for Overviews of Reviews statement. The primary outcome was 3-month good functional outcome [modified Rankin scale (mRS) score 0-2]. Three eligible SRs and 4 additional RCTs were included in the overview, comprising a total of 24 RCTs, corresponding to 5968 AIS patients with LVO (3044 randomized to EVT versus 2924 patients randomized to BMT). High-quality evidence shows that EVT is associated with an increased likelihood of good functional outcome [risk ratio (RR) 1.78 (95% confidence interval (CI): 1.54-2.06); 166 more per 1000 patients], independent ambulation [mRS-scores 0-3; RR 1.50 (95% CI: 1.37-1.64); 174 more per 1000 patients], excellent functional outcome [mRS-scores 0-1; RR 1.90 (95% CI: 1.62-2.22); 118 more per 1000 patients] at 3 months. EVT was associated with reduced 3-month mortality [RR 0.81 (95% CI: 0.74-0.88); 61 less per 1000 patients] despite an increase in symptomatic intracranial haemorrhage [sICH; RR 1.65 (95% CI: 1.23-2.21); 22 more per 1000 patients]. In patients with AIS due to LVO in the anterior or posterior circulation, within 24 h from symptom onset, EVT improves functional outcomes and increases the chance of survival despite increased sICH risk. PROSPERO Registration Number CRD42023461138.

Comparative Efficacy of Ciltacabtagene Autoleucel Versus Elotuzumab, Isatuximab, and Selinexor-Based Regimens in the Treatment of Patients with Relapsed or Refractory Multiple Myeloma with 1-3 Prior Lines of Therapy Using a Matching-Adjusted Indirect Comparison

Introduction: Ciltacabtagene autoleucel (cilta-cel; Carvykti) was assessed in the phase 3 randomized controlled trial CARTITUDE-4 for adult patients with relapsed and refractory multiple myeloma (RRMM) who have received 1-3 prior line(s) of therapy (LOT) that included an immunomodulatory agent (IMiD), and a proteasome inhibitor (PI) and are refractory to lenalidomide. Other therapies used to treat patients with multiple myeloma who have received at least one other therapy and are lenalidomide-refractory vary by country, but broadly include doublet and triplet regimens based on daratumumab, pomalidomide, bortezomib, and carfilzomib. This analysis aims to compare efficacy outcomes in patients randomized to the cilta-cel arm of CARTITUDE-4 versus relevant comparators based on their target trial populations. Methods: Comparators for the matching adjusted indirect comparisons (MAICs) were identified a priori based on regimens used in the target population including; SVd, EloPd, IsaKd, DKd, DVd, Kd, Vd, Pd, and Ide-cel. PVd and DPd were not of interest given their inclusion in the CARTITUDE-4 trial. Melflufen+d, PanVd, VenVd, PCd, IxaKd, D-monotherapy, V-monotherapy, CyVd, and DVCd were not of interest for the US, EU-5, the Netherlands, and Canada. A systematic literature review identified publications of relevant clinical trials for these treatments, which were assessed for feasibility of an indirect treatment comparison. Feasibility was determined based on study design and degree of overlap with the CARTITUDE-4 population (prior LOT, lenalidomide-refractoriness, and exclusion criteria around previous therapies, i.e., prior daratumumab). We report here on comparisons vs. EloPd (ELOQUENT-3), IsaPd (ICARIA-MM), and SVd (BOSTON). Due to differences in methods for the comparisons versus ide-cel (KarMMa-3) and versus DKd, Kd, DVd, Vd, and Pd, these are reported separately. Comparison to IsaKd was not feasible due to a lack of published data in the lenalidomide-refractory subgroup (baseline characteristics and efficacy data), and key differences in exclusion criteria. Given the lack of a common comparator between CARTITUDE-4 and the comparator trials, unanchored MAICs were performed utilizing individual patient-level data (IPD) from patients randomized to the cilta-cel arm of CARTITUDE-4 (N=208). The eligibility criteria from each of the comparator trials were applied to the cilta-cel IPD, and outcomes for the matched population were compared against published summary data for EloPd (N=60), IsaPd (N=154), and SVd (N=195) using reconstructed IPD for response endpoints and simulated IPD from published Kaplan-Meier (KM) curves for progression-free survival (PFS). Further imbalances in patient characteristics were adjusted by weighting the cilta-cel data to match the reported baseline characteristics of the comparator trials in terms of refractory status, cytogenetic risk, ISS stage, and presence of extramedullary disease. Comparative efficacy was estimated for overall response rate (ORR), very good partial response or better (≥VGPR) rate, complete response or better (≥CR) rate, and PFS. For binary endpoints, relative effects were quantified using relative response ratios (RRs) with 95% confidence intervals (CIs) derived from a weighted logistic regression analysis. For PFS, HRs including 95% CIs were estimated using a weighted Cox proportional hazards model. Results: After adjustment, patients in the cilta-cel arm were significantly more likely to achieve an overall response than patients in EloPd or IsaPd arms, and to achieve ≥VGPR and ≥CR versus patients in all other comparators arms ( Table 1). In addition, cilta-cel was associated with a significant reduction in the risk of disease progression or death (PFS) versus all comparators, ranging from 39% (versus SVd) to 68% (versus IsaPd) ( Table 2). Conclusions: Cilta-cel demonstrated clinical benefit over EloPd, IsaPd, and SVd for response outcomes and PFS, highlighting its potential as an effective treatment option for patients with RRMM who have received at least one other therapy and are lenalidomide-refractory. These comparisons provide valuable information to contextualize the efficacy of cilta-cel in countries where treatment for these patients may be different from DPd or PVd.

Reporting and impact of subsequent cycle toxicities in oncology phase I clinical trials.

As oncology treatments evolve, classic assumptions of toxicity associated with cytotoxic agents may be less relevant, requiring new design strategies for trials intended to inform dosing strategies for agents that may be administered beyond a set number of defined cycles. We describe the overall incidence of dose-limiting toxicities during and after cycle 1, frequency of reporting subsequent cycle toxicities, and the impact of post-cycle 1 dose-limiting toxicities on conclusions drawn from oncology phase 1 clinical trials. We conducted a systematic review of subsequent cycle toxicities in oncology phase I clinical trials published in the Journal of Clinical Oncology from 2000 to 2020. We used chi-square tests and multivariate logistic regression to describe predictors of reporting subsequent cycle toxicity data. From 2000 to 2020, we identified 489 articles reporting on therapeutic phase 1 clinical trials. Of these, 421 (86%) reported data regarding cycle 1 dose-limiting toxicities and 170 (35%) reported data on cycle 1 dose modifications. Of the trials that reported cycle 1 dose-limiting toxicities, the median percentage of patients that experienced cycle 1 dose-limiting toxicities was 8.89%. Only 47 (9.6%) publications reported on post-cycle 1 dose-limiting toxicities and only 92 (19%) reported on dose modifications beyond cycle 1. Of the trials that reported post-cycle 1 dose-limiting toxicities, the median percentage of patients that experienced post-cycle 1 dose-limiting toxicities was 14.8%. Among the 371 studies with a recommended phase 2 dose, 89% did not report whether post-cycle 1 toxicities impacted the recommended phase 2 dose. More recent year of publication was independently associated with reduced odds of reporting subsequent cycle toxicity. Reporting of subsequent cycle toxicity is uncommon in oncology phase I clinical trial publications and becoming less common over time. Guidelines for reporting of phase I oncology clinical trials should expand to include toxicity data beyond the first cycle.

Controversies in the microbiological diagnosis and treatment of bone and joint infections

Recently, bone and joint infections such as fracture-related infection (FRI) and prosthetic joint infections (PJI) have been defined for clinical and research purposes. National and international guidelines are being produced to guide clinicians towards what is considered best practice. However, much of what we do regarding the microbiological diagnosis and management of orthopaedic infection is based on expert opinion, rather than evidence-based medicine. This is largely because, prior to the publication of the clinical definitions of orthopaedic infection, studies included a heterogeneous population making comparisons between them difficult. More recently the publication of large clinical trials in the antimicrobial management of orthopaedic infection has demonstrated that such clinical research is possible, and can both challenge the existing dogma in this field and lead to universal changes in clinical practice. There is robust evidence for microbiological sampling techniques and their interpretation in diagnosis of orthopaedic infection, as well as the choice of empiric broad-spectrum antibiotics and the non-inferiority of oral versus intravenous systemic antibiotics. For other elements of the diagnosis and management of orthopaedic infection this is not the case. For example, there are limited or no data to support recommendations regarding time off antibiotics prior to microbiological sampling, systemic antibiotic duration, when to do a joint aspirate in PJI revisions or the timing of definitive joint implantation in the two-stage management of PJI. In summary, this review highlights what is currently considered best practice within the field of orthopaedic infection and discusses both the evidence behind it and where there is controversy or where further research is warranted.

Characteristics and Discrepancies in Publication of Clinical Trials Related to Foot and Ankle Surgery

Category: Other Introduction/Purpose: The significance of trial registration has grown rapidly as an increasing number of journals require NCT IDs prior to publication. Although various reports have been published in different medical fields, including several orthopaedic subspecialties, no study has examined the discrepancies between trial registries and publications in the area of foot and ankle surgery. Therefore, this study aimed to investigate (1) the characteristics of foot and ankle surgery-related clinical trials registered in the widely used Clinicaltrials.gov (CTG) clinical trials database, (2) the publication rates, (3) inconsistencies between the original trial plans and final publications, and (4) possible risk factors that could contribute to discrepancies. The hypothesis was that foot and ankle surgery-related trials would have a low publication rate, and discrepancies would exist between trial registries and final published results. Methods: The study used the CTG database to identify eligible trials based on the following inclusion criteria: (1) related to foot and ankle surgery, (2) interventional study, (3) randomized controlled, and (4) anticipated completion date before the end of 2018. Exclusion criteria consisted of (1) ongoing trials, (2) trials assessing vascular surgeries or anesthetic procedures, and (3) trials examining conservative treatment methods without any surgical intervention. The search was performed on January 1, 2021, allowing the authors at least 24 months from trial completion to publication. The corresponding publications of the included trials were searched using various databases, including Medline, Web of Science, Scopus, and Google Scholar. NCT ID, title, keywords, and the name of the principal investigator provided in CTG were used for literature search, and the title and abstract of the publications were reviewed to confirm the match with the trial. Results: Out of all the trials analyzed, 67.5% were registered either during the trial period or after completion. Industry funded 46.5% of trials. A reported 54.8% of trials were completed, and only 42% (66 trials) were published in a journal. Among the analyzed trials, 57.6% had a sample size discrepancy, 28.8% had a follow-up time discrepancy, 45.5% had a primary outcome discrepancy, and 89.4% had an inclusion/exclusion criteria discrepancy. Trials funded by industry exhibited significantly more sample size and inclusion/exclusion criteria discrepancies (p=0.024, 0.001, 0.037, respectively). Furthermore, industry-funded studies had a higher frequency of positive results (p=0.011). Conclusion: The findings of this study draw attention to the existing issues in clinical trials related to foot and ankle surgery. The results not only serve as a warning to researchers regarding potential inconsistencies but also support the need for stricter trial registry regulations. Registering a trial does not guarantee its publication or ensure that there will be no modifications to the methodology during the trial period. Therefore, it is crucial to register trials before enrolling the first patient to minimize the risk of bias.

Insufficient Reporting of Race and Ethnicity in Breast Cancer Clinical Trials.

Reporting race and ethnicity in clinical trial publications is critical for determining the generalizability and effectiveness of new treatments. This is particularly important for breast cancer, in which Black women have been shown to have between 40 and 100% higher mortality rate yet are underrepresented in trials. Our objective was to describe changes over time in the reporting of race/ethnicity in breast trial publications. We searched ClinicalTrials.gov to identify the primary publication linked to trials with results posted from May 2010-2022. Statistical analysis included summed frequencies and a linear regression model of the proportion of articles reporting race/ethnicity and the proportion of non-White enrollees over time. A proportion of 72 of the 98 (73.4%) studies that met inclusion criteria reported race/ethnicity. In a linear regression model of the proportion of studies reporting race/ethnicity as a function of time, there was no statistically significant change, although we detected a signal toward a decreasing trend (coefficient for quarter = -2.2, p = 0.2). Among all studies reporting race and ethnicity over the study period, the overall percentage of non-White enrollees during the study period was 21.9%, [standard error (s.e.) 1.8, 95% confidence interval (CI) 18.4, 25.5] with a signal towards a decreasing trend in Non-White enrollment [coefficient for year-quarter = -0.8 (p = 0.2)]. Our data demonstrate that both race reporting and overall representation of minority groups in breast cancer clinical trials did not improve over the last 12 years and may have, in fact, decreased. Increased reporting of race and ethnicity data forces the medical community to confront disparities in access to clinical trials. This may improve efforts to recruit and retain members of minority groups in clinical trials, and over time, reduce racial disparities in oncologic outcomes.

A practical approach to sequential nephron blockade in acute decompensated heart failure

Abstract Acute decompensated heart failure (ADHF) is a worldwide health problem, with poor prognosis and significant morbidity and mortality. Fluid overload is the primary reason for hospitalization in ADHF. The efficacy of diuretic monotherapy is suboptimal, with a substantial proportion of patients being discharged with residual congestion that portends a poor outcome. Accordingly, the loop diuretic monotherapy from the DOSE trial achieved a successful decongestion in less than 20% of patients. Although the concept of sequential nephron blockade has regained interest following the publication of several randomized clinical trials (RCTs), the optimal approach to combination diuretic therapy is still an area of uncertainty. The selection of an adequate approach remains difficult as comparisons between different trials cannot be made due to different diuretic doses used, timing of sequential blockade, differences in study cohorts or in definitions used to define decongestion. Moreover, a direct comparison of different combination therapies in large trials is lacking. Nonetheless, the approach to the combination diuretic therapy should rather take into account the patient phenotype, the suspected nephron segment responsible for diuretic resistance, and the anticipated electrolyte and acid–base disturbances in order to select diuretic agents with divergent effects. Herein, we review the molecular mechanisms of action of diuretic agents, highlight the most recent trials evaluating combined diuretic therapy in ADHF and identify clinical scenarios, apart from diuretic resistance, for optimal association of diuretics to counteract their anticipated adverse effects.

Global Association of the COVID-19 Pandemic With Pediatric Clinical Trial Publication

This cross-sectional study investigates the association of the COVID-19 pandemic with rates of pediatric clinical trial publication.

A Medical Writer’s Guide: Working on Clinical Research Manuscripts for Submission to Peer-Reviewed Medical Journals

Prompt publication of clinical trial results in peer-reviewed journals is essential to advance clinical practice and improve patient outcomes. The involvement of professional medical writers (PMWs) in the preparation of these clinical research manuscripts can enhance their quality and shorten publication timelines. For early-career PMWs, research manuscript projects can be daunting. In this guide, first I share my perspective on how PMWs contribute to such projects and the essential skills and competencies we should provide. Then, I describe my tactical approaches to initiating these projects, developing the first draft of a detailed outline or manuscript, and avoiding some common pitfalls that can undermine the quality of a manuscript. Finally, I share some tips for working with challenging personalities.

Integration of clinical trial development in hematology and oncology fellowship training: Washington university school of medicine experience.

11012 Background: Education in clinical trial design and development is highly variable among Hematology and Medical oncology fellowship programs. The Clinical Trial Development (CTD) program at Washington University in St. Louis (WUSM) is an experiential learning curriculum designed to provide a structured and personalized education to fellows about clinical investigation in Hematology and Oncology. We describe the results of the CTD program and its impact on subsequent academic faculty appointments. Methods: The CTD program was initiated at WUSM in 2002 as a hands-on learning experience for Hematology and Oncology fellows in the design, implementation, evaluation, and publication of clinical trials. Each fellow was required to identify a mentor in their first year of training and propose at least one CTD project, determined as a prospective investigator-initiated clinical trial involving human subjects or materials. Outcome data were collected from an internal registry of fellow CTD projects, Clinical Trials Management System (OnCore), PubMed, ClinicalTrials.gov and e-mail inquiries to fellows and mentors. Descriptive statistics were collected for the characteristics of CTD projects, including the phase of study, site (single center or multicenter), disease subtype, projects that received IRB approval, and projects that resulted in publication. Logistic regression and odds ratios (OR) were also used to assess the association between these characteristics and academic faculty appointments. Results: We included 118 fellows who began fellowship from 2002 to 2021 for this analysis with 16 still in training. Many trials were phase I/II (n = 53; 45%), phase I (n = 34; 29%) and phase II trials (n = 17; 14%) and most trials were single center studies (n = 93; 79%). Disease types of the investigations were evenly distributed between Oncology (n = 60, 51%) or Hematology (n = 58, 49%). Most fellows were successful in obtaining IRB approval for their CTD project (n = 93, 79%) and approximately two thirds of those with IRB approval went on to publish their results in peer-reviewed journals (n = 60, 65%). Forty-five percent of fellows who published their CTD projects were first authors (n = 27) and 38% published in journals with an impact factor of greater than 10. Among the graduating fellows, two-thirds (n = 67, 66%) secured an academic faculty appointment. Fellows with IRB approved CTD projects had significantly higher odds of obtaining an academic faculty appointment (OR 4.96, 95% CI 1.54-15.98, p &lt; 0.05). Conclusions: The CTD program is a well-established clinical investigation program for fellows with a track record of success and impact on subsequent academic faculty appointments. The CTD program is a model that other fellowship programs can emulate for education related to clinical trials.

Reporting and impact of subsequent cycle toxicities in oncology phase I clinical trials.

3149 Background: In recent years, the landscape of clinical trial development has evolved to include immunotherapy and targeted therapies, which have different lengths of administration and toxicity profiles compared to standard chemotherapy. As treatments have evolved, the classic assumptions of toxicity associated with cytotoxic agents may be less relevant, requiring new strategies for design of trials intended to inform dosing strategies for agents that may be administered beyond a set number of defined cycles. We aimed to describe the overall incidence of dose-limiting toxicities (DLTs) during and after cycle 1, the frequency of reporting subsequent cycle toxicities, and the impact of post-cycle 1 DLTs on conclusions drawn from oncology phase I clinical trials. Methods: We conducted a systematic review of subsequent cycle toxicities in oncology phase I clinical trials published in the Journal of Clinical Oncology from 2000 to 2020. Only trials that included more than one cycle of therapy were included. Data elements captured included: year of publication, study design, trial sponsor type, intervention type, number of anti-cancer therapies involved, primary diagnosis, incidence and type of cycle 1 DLT, incidence of dose modification in cycle 1, incidence and type of post-cycle 1 DLTs, incidence of dose modification in post-cycle 1, presence of a recommended phase 2 dose (RP2D) and impact of subsequent cycle toxicity on RP2D. Results: From 2000 to 2020, we identified 489 full-text articles reporting on therapeutic phase I clinical trials. Of these, 421 (86%) reported data regarding cycle 1 DLTs and 170 (35%) reported cycle 1 dose modifications. The overall median cycle 1 DLT rate was 8.89%. Only 47 (9.6%) publications reported whether or not there were post-cycle 1 DLTs and only 92 (19%) reported whether or not there were dose modifications beyond cycle 1. The overall median post-cycle 1 DLT rate among trials that reported post-cycle 1 data was 14.8%. A RP2D was reported in 76% (371 of 489) trials. Among these 371 studies, 89% did not report whether post-cycle 1 toxicities impacted the RP2D. Independent predictors of reporting toxicity data beyond cycle 1 included year of publication, investigational agent type, novelty, disease type, trial size, and sponsor. Conclusions: Reporting of subsequent cycle DLTs and dose modification is uncommon in oncology phase I clinical trial publications. As newer oncology treatments trend towards longer duration of treatment, there will be an increased need to understand toxicities occurring post-cycle 1. Guidelines for reporting of phase I clinical trials should expand to include toxicity data beyond the first cycle.

Ethnicity, Race and Skin Color: Challenges and Opportunities for Atopic Dermatitis Clinical Trials.

The number of clinical trials conducted in patients with atopic dermatitis is increasing steadily. These trials are conducted in several countries across all continents and include patients of different ethnicity, race and skin color. This diversity is desired, but it also brings challenges, including the diagnosis and evaluation of disease severity in patients with different skin colors; the influence of ethnicity on the perception of quality of life and patient reported outcomes; the inclusion of ethnicities that are only present in one country or that live far from clinical research sites; and the reporting of drug safety information. There is a need to better train physicians on the evaluation of atopic dermatitis in patients with different skin colors and a need to improve the systematic reporting of ethnicity, race and skin color in clinical trial publications.

Evolution of systemic therapy for advanced HCC patients: Did we make progress in 2022?

Great strides have been made in the systemic treatment of advanced HCC in the last 6 years. Approved tyrosine kinase inhibitors (TKIs) have been expanded to include lenvatinib (LEN), regorafenib, and cabozantinib (CABO). Meanwhile, immune checkpoint inhibitors (ICI) including nivolumab (NIVO) ± ipilimumab, pembrolizumab (PEMBRO), and atezolizumab (+ bevacizumab) (ATEZO+BEV) have revolutionized advanced HCC treatment. The past year saw the publication of important clinical trials, all of which evaluated ICIs but differed in ICI partners. They can be broadly categorized into single agents ICI, dual-ICIs, and ICI + antiangiogenic agent studies (Table 1). SINGLE-AGENT ICIS In the first-line setting (1 L), 2 phase 3 trials comparing anti-PD1 to sorafenib (SOR) released updates. The final analysis of CheckMate-459, which compared NIVO to SOR in a superiority design, reported a median overall survival (mOS) of 16.4 months for NIVO and 14.7 months for SOR (HR: 0.85, p = 0.075).1 The objective response rate (ORR) was 15% and 7%, respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 18% and 4% of NIVO, compared with 47% and 2% of SOR. Though overall survival (OS) improvement was not statistically significant with NIVO, there was a sustained separation of Kaplan-Meier curves and numerically higher OS at 12-, 18-, and 24-month landmarks. In addition, 20% of SOR patients received ICIs later, which potentially introduced confounding effects on the OS results. The second study, RATIONALE-301, compared tisleilizumab to SOR in a noninferiority design.2 mOS was 15.9 months for tisleilizumab and 14.1 months for SOR (HR: 0.85), meeting the cutoff for noninferiority but not superiority. ORR was 14.3% versus 5.4%, and grade ≥3 TRAE occurred in 22.2% and 53.4% of tisleilizumab and SOR arms, respectively. The results from these two studies are quite consistent, with NIVO and tisleilizumab demonstrating similar mOS and ORR, while both showed favorable safety profiles over SOR. Taken together, they suggest that single-agent ICI might be considered as an alternative to TKIs, or in patients for whom antiangiogenics carry substantial risks. In the second-line setting (2 L), KEYNOTE-394, evaluating PEMBRO versus placebo in Asian patients previously treated with SOR, was published.3 Notably, most patients were Chinese (85%) and HBV carriers (79%). mOS was significantly longer with PEMBRO (14.6 vs. 13.0 months, HR: 0.79, p = 0.018), with progression free survival (PFS) and ORR also favoring PEMBRO. These results are interesting as KEYNOTE-240, which was identically designed except with international enrollment, did not show statistically significant OS benefit for PEMBRO. Though one potential explanation of this difference is that most KEYNOTE-240 patients were non-Asian and not predominately HBV infected, it should be noted that the HR for OS (0.79 and 0.781) and PFS (0.74 and 0.775) were similar between the two studies. DUAL-ICIS Combined anti-CTLA-4 and anti-PD-1 ICIs have been approved in 2 L based on CheckMate-040 cohort 4 (NIVO + ipilimumab ). In 1 L, the HIMALAYA trial has, for the first time, demonstrated superior outcomes of dual-ICI compared with TKIs.4 In HIMALAYA, mOS was 16.4 months with the single tremelimumab regular interval durvalumab regimen (STRIDE), 16.6 months with single-agent durvalumab and 13.8 months with SOR, with STRIDE demonstrating statistically significant benefit over SOR (HR: 0.78, p = 0.0035) and durvalumab showing noninferiority (HR: 0.86). However, median PFS (mPFS) was not significantly different versus SOR (HR for STRIDE: 0.9, for durvalumab: 1.02). Grade 3–4 treatment-emergent adverse events occurred in 50.5% with STRIDE, 37.1% with durvalumab, and 52.4% with SOR. Based on these results, the US Food and Drug Administration has approved the STRIDE regimen for use in 1 L advanced HCC. COMBINED ANTI-PD-1/L1 ICIS AND ANTIANGIOGENIC AGENTS IMBrave150 established the new treatment standard in 1 L advanced HCC and demonstrated the potential synergy between ICIs and antiangiogenic agents, in this case, anti-VEGF-mAbs. Updated follow-up data were recently published, with mOS reaching 19.2 months for ATEZO-BEV and 13.4 months for SOR (HR: 0.66, p < 0.001).5 mPFS was 6.9 versus 4.3 months (HR: 0.65, p < 0.001); and grade 3–4 TRAEs occurred in 43% and 46% of patients, respectively. The results are broadly in line with those of the primary analysis. A wealth of phase 3 data on another approach of combining ICIs with antiangiogenic, this time multitargeted TKIs, was released recently. COSMIC-312 compared ATEZO + CABO to SOR in 1 L.6 mPFS was 6.8 months versus 4.2 months (HR: 0.63, p = 0.0012) significantly favoring ATEZO + CABO, but mOS was negative (15.4 vs. 15.5 months, HR: 0.9, p = 0.44). Grade 3 and 4 TRAEs occurred in 51% and 3% of ATEZO + CABO, compared with 30% and 2% of SOR. Based on these results, the authors concluded that additional studies are needed for ATEZO + CABO to be established in advanced HCC. In addition, results of LEAP-002 comparing PEMBRO + LEN to LEN + placebo, as well as the NCT03764293 trial comparing camrelizumab + rivoceranib (CAM + RIVO) to SOR, both for 1 L, were recently announced.7,8 In LEAP-002, mOS was 21.2 months for PEMBRO + LEN and 19.0 months for LEN + Placebo (HR: 0.84), whereas mPFS was 8.2 months and 8.0 months, respectively; neither result reached the superiority thresholds. Grade 3–4 TRAEs occurred in 61.5% and 56.7% of patients respectively. Finally, in the CAM + RIVO trial, mOS was 22.1 months for CAM + RIVO and 15.2 months for SOR, whereas mPFS was 5.6 months and 3.7 months, respectively, both significantly favoring CAM + RIVO. Grade 3–4 TRAEs occurred in 80.5% and 52% of CAM-RIVO and SOR patients, respectively. Overall, 2 observations can be made from these results. Firstly, current ICI-TKI combinations seem to have additional toxicity without efficacy benefit over ATEZO-BEV. Both COSMIC-312 and LEAP-002 failed to demonstrate OS benefit over their TKI control arms. Although the CAM + RIVO trial was positive, a considerable number of patients, especially in the SOR arm (18.8%), withdrew consent. In addition, most patients were Asian (82.7%) and HBV infected (74.5%), with the efficacy data of CAM + RIVO not obviously superior compared with the IMBrave150 Chinese cohort, which has comparable demographics.9 Meanwhile, higher incidences of grade ≥3 TRAEs were observed for all 3 studies, both compared with their control arms and to ATEZO-BEV in IMBrave150. Secondly, single-agent TKI, especially LEN, remains a viable option in 1 L. The OS of control-arm TKIs has improved continuously since their registration trials, most remarkably reaching a mOS of 19.0 months for LEN + placebo in LEAP-002, vastly exceeding that of LEN in the REFLECT trial (13.6 mo). DUAL-ICIS AND ANTIANGIOGENIC AGENTS Combining dual-ICIs and antiangiogenic agents has so far remained an investigational approach. The first such prospective trial was recently published: in the phase 1/2 CheckMate-040 cohort 6 study, NIVO + ipilimumab + CABO demonstrated a mOS of 22.1 months, mPFS of 4.3 months, and ORR of 29% in 1 L.10 The incidence of grade 3–4 TRAEs was 74%. Of note, the median duration of response was still not reached after 32.0 months of follow-up. Further trials in this direction, including the recently opened phase 1/2 RELATIVITY-106 investigating the combination of NIVO + BEV with the anti-LAG-3 ICI relatlimab in 1 L, are needed to determine the added value of this approach. In conclusion, 2022 was another fruitful year for advanced HCC therapeutics, with new treatment options being approved and ever more data published for greater treatment precision and novel drug development directions. We took another step forward toward defeating this deadly and ever-more-common condition (Table 1). TABLE 1 - List of advanced-HCC trial results released in 2022 Trials Phase Line Experimental arm Control arm mOS (mo) median PFS (mo) ORR (%) Grade 3–4 AEs (%) Single-agent ICI CheckMate-459 3 1 NIVO SOR 16.4 vs. 14.7 3.7 vs. 3.8 15 vs. 7 22 vs. 49 RATIONALE-301 3 1 TIS SOR 15.9 vs. 14.1 2.2 vs. 3.6 14.3 vs. 5.4 22.2 vs. 53.4 KEYNOTE-394 3 2 PEMBRO Placebo 14.6 vs. 13.0a 2.6 vs. 2.3a 12.7 vs. 1.3 13.3 vs. 5.9 Dual-ICIs HIMAYALA 3 1 STRIDE SOR 16.4 vs. 13.8a 3.78 vs. 4.07 20.1 vs. 5.1 50.5 vs. 52.4 ICI + antiangiogenic agents IMBrave150 3 1 ATEZO + BEV SOR 19.2 vs. 13.4a 6.9 vs. 4.3a 30 vs. 11 43 vs. 46 COSMIC-312 3 1 ATEZO + CABO SOR 15.4 vs. 15.5 6.8 vs. 4.2a 13 vs. 5 54 vs. 32 NCT03764293 3 1 CAM + RIVO SOR 22.1 vs. 15.2a 5.6 vs. 3.7a 25.4 vs. 5.9 80.5 vs. 52 LEAP-002 3 1 PEMBRO + LEN LEN + placebo 21.2 vs. 19.0 8.2 vs. 8.0 26.1 vs. 17.5 61.5 vs. 56.7 CheckMate-040 cohort 6 1/2 1 NIVO + IPI + CABO — 22.1 4.3 29 74 aStatistically significant results.Abbreviations: AEs, adverse events; ATEZO, atezolizumab; BEV, bevacizumab; CABO, cabozantinib; CAM, camrelizumab; ICI, immune checkpoint inhibitor; IPI, ipilimumab; LEN, lenvatinib; mOS, median overall survival; NIVO, nivolumab; ORR, objective response rate; PEMBRO, pembrolizumab; RIVO, rivoceranib; SOR, sorafenib; STRIDE, single tremelimumab regular interval durvalumab; TIS, tisleilizumab.