Biomedical applications of functional hydrogels: Innovative developments, relevant clinical trials and advanced products.

Functional hydrogels are used for numerous biomedical applications such as tissue engineering, wound dressings, lubricants, contact lenses and advanced drug delivery systems. Most of them are based on synthetic or natural polymers forming a three-dimensional network that contains aqueous media. Among synthetic polymers, poly(meth)acrylates, polyethyleneglycols, poly(vinylalcohols), poly(vinylpyrrolidones), PLGA and poly(urethanes) are of high relevance, whereas natural polymers are mainly polysaccharides such as hyaluronic acid, alginate or chitosan and proteins such as albumin, collagen or elastin. In contrast to most synthetic polymers, natural polymers are biodegradable. Both synthetic and natural polymers are often chemically modified in order to improve or induce favorable properties and functions like high mechanical strength, stiffness, elasticity, high porosity, adhesive properties, in situ gelling properties, high water binding capacity or drug release controlling properties. Within this review we provide an overview about the broad spectrum of biomedical applications of functional hydrogels, summarize innovative approaches, discuss the concept of relevant functional hydrogels that are in clinical trials and highlight advanced products as examples for successful developments.

Running the enrollment numbers on ophthalmic clinical trials in the United States.

SIGNIFICANCE: This is one of the first reports to summarize the enrollment metrics for ophthalmology trials completed in the United States (US). PURPOSE: This study aimed to describe US ophthalmology clinical trial enrollment metrics to facilitate planning and budgeting of US Food and Drug Administration-regulated ophthalmological drugs trials. METHODS: A GlobalData PLC search was conducted on or before February 27, 2024, to evaluate the clinical trial landscape for completed ophthalmology clinical trials conducted in the US. The primary search contained only the term "ophthalmology," which was restricted to trials that were completed and were conducted within the US. Trials were classified as multicenter when trials included three sites or more, and when the enrollment search resulted in ≥30 multicenter trials for an individual indication, enrollment data were further broken down by Food and Drug Administration trial phase. RESULT: The search yielded 2229 trials, which analyzed 980 different drugs produced by 854 different sponsors. The most common indications evaluated in US trials were macular degeneration, glaucoma, macular edema, allergies, and keratoconjunctivitis. Multicenter trials by indication had an overall median enrollment period range of 4.8 to 35.1 months; number of subjects enrollment, range of 36 to 518 subjects; number of sites utilized, range of 4 to 74 sites; and enrollment rate, range of 0.11 to 4.04 subjects/sites per month. There were 17 indications with ≥30 multicenter trials, which allowed for enrollment metric calculation by trial phase. CONCLUSIONS: This study provides sponsors with an understanding of the number of subjects and sites needed to complete a trial while also setting realistic enrollment timelines. Although this work represents the US market, more work is needed to better understand other countries given that country-specific guidelines and subject beliefs may impact enrollment metrics.

Design considerations for Factorial Adaptive Multi-Arm Multi-Stage (FAST) clinical trials.

BACKGROUND: Multi-Arm, Multi-Stage (MAMS) clinical trial designs allow for multiple therapies to be compared across a spectrum of clinical trial phases. MAMS designs fall under several overarching design groups, including adaptive designs (AD) and multi-arm (MA) designs. Factorial clinical trials designs represent a combination of factorial and MAMS trial designs and can provide increased efficiency relative to fixed, traditional designs. We explore design choices associated with Factorial Adaptive Multi-Arm Multi-Stage (FAST) designs, which represent the combination of factorial and MAMS designs. METHODS: Simulation studies were conducted to assess the impact of the type of analyses, the timing of analyses, and the effect size observed across multiple outcomes on trial operating characteristics for a FAST design. Given multiple outcomes types assessed within the hypothetical trial, the primary analysis approach for each assessment varied depending on data type. RESULTS: The simulation studies demonstrate that the proposed class of FAST trial designs can offer a framework to potentially provide improvements relative to other trial designs, such as a MAMS or factorial trial. Further, we note that the design implementation decisions, such as the timing and type of analyses conducted throughout trial, can have a great impact on trial operating characteristics. CONCLUSIONS: Motivated by a trial currently under design, our work shows that the FAST category of trial can potentially offer benefits similar to both MAMS and factorial designs; however, the chosen design aspects which can be included in a FAST trial need to be thoroughly explored during the planning phase.

SNMMI Clinical Trials Network Research Series for Technologists: An Introduction to Conducting Theranostic Clinical Trials.

This article is intended to introduce nuclear medicine technologists (NMTs) to the nuances of radiopharmaceutical therapy clinical trials. Here, we outline the potential roles and responsibilities of the NMT in clinical trials and provide context on different aspects of radionuclide therapy. The regulatory process involving investigational therapeutic radiopharmaceuticals is seldom taught to NMT students, nor is it included in the entry-level nuclear medicine certification examinations. Often, NMTs must spend significant time preparing for therapeutic clinical trials on their own, using multiple academic sources, seeking advice from various health care professionals, and reviewing numerous trial-specific manuals to recognize the detailed requirements. The emergence of theranostics has spurred an increase in the development of therapeutic radiopharmaceuticals. Investigators with a robust nuclear medicine background are required to help develop successful therapeutic clinical trials, and well-informed NMTs are crucial to the success of such trials. This article follows a series of previous publications from the Society of Nuclear Medicine and Molecular Imaging Clinical Trials Network research series for technologists and is intended to guide the investigational radiopharmaceutical landscape.

Comparative assessment of autologous and allogeneic iNKT cell transfer in iNKT cell-based immunotherapy.

Invariant natural killer T (iNKT) cells are a small subset of T lymphocytes that release large amounts of cytokines such as IFN-γ and exhibit cytotoxic activity upon activation, inducing strong anti-tumor effects. Harnessing the anti-tumor properties of iNKT cells, iNKT cell-based immunotherapy has been developed to treat cancer patients. In one of the iNKT cell-based immunotherapies, two approaches are utilized, namely, active immunotherapy or adoptive immunotherapy, the latter involving the ex vivo expansion and subsequent administration of iNKT cells. There are two sources of iNKT cells for adoptive transfer, autologous and allogeneic, each with its own advantages and disadvantages. Here, we assess clinical trials conducted over the last decade that have utilized iNKT cell adoptive transfer as iNKT cell-based immunotherapy, categorizing them into two groups based on the use of autologous iNKT cells or allogeneic iNKT cells.

The Digital Platform and Its Emerging Role in Decentralized Clinical Trials.

Decentralized clinical trials (DCTs) are becoming increasingly popular. Digital clinical trial platforms are software environments where users complete designated clinical trial tasks, providing investigators and trial participants with efficient tools to support trial activities and streamline trial processes. In particular, digital platforms with a modular architecture lend themselves to DCTs, where individual trial activities can correspond to specific platform modules. While design features can allow users to customize their platform experience, the real strengths of digital platforms for DCTs are enabling centralized data capture and remote monitoring of trial participants and in using digital technologies to streamline workflows and improve trial management. When selecting a platform for use in a DCT, sponsors and investigators must consider the specific trial requirements. All digital platforms are limited in their functionality and technical capabilities. Integrating additional functional modules into a central platform may solve these challenges, but few commercial platforms are open to integrating third-party components. The lack of common data standardization protocols for clinical trials will likely limit the development of one-size-fits-all digital platforms for DCTs. This viewpoint summarizes the current role of digital platforms in supporting decentralized trial activities, including a discussion of the potential benefits and challenges of digital platforms for investigators and participants. We will highlight the role of the digital platform in the development of DCTs and emphasize where existing technology is functionally limiting. Finally, we will discuss the concept of the ideal fully integrated and unified DCT and the obstacles developers must address before it can be realized.

Distinguishing Therapeutic Misconception from Religious Belief.

In the context of early-phase clinical trials, research subjects often confuse the differences between clinical research and personal treatment. This phenomenon, known as therapeutic misconception, potentially undermines the validity of informed consent. Several interventions have been proposed to help mitigate therapeutic misconception, although few have considered the role of religious belief. This is a notable omission, given that an association between therapeutic misconception and religious belief has been shown to exist. This perspective calls for more research into the nature of the association between therapeutic misconception and religious belief and suggests a framework that may help clinicians and researchers distinguish between the two, thereby bolstering the informed consent process.

Advancements in cell-based therapies for thermal burn wounds: a comprehensive systematic review of clinical trials outcomes.

BACKGROUND: Burn trauma is one of the major causes of morbidity and mortality worldwide. The standard management of burn wounds consists of early debridement, dressing changes, surgical management, and split-thickness skin autografts (STSGs). However, there are limitations for the standard management that inclines us to find alternative treatment approaches, such as innovative cell-based therapies. We aimed to systematically review the different aspects of cell-based treatment approaches for burn wounds in clinical trials. METHODS: A systematic search through PubMed, Medline, Embase, and Cochrane Library databases was carried out using a combination of keywords, including "Cell transplantation", "Fibroblast", "Keratinocyte", "Melanocyte", or "Stem Cell" with "Burn", "Burn wound", or "Burn injury". Firstly, titles and abstracts of the studies existing in these databases until "February 2024" were screened. Then, the selected studies were read thoroughly, and considering the inclusion and exclusion criteria, final articles were included in this systematic review. Moreover, a manual search was performed through the reference lists of the included studies to minimize the risk of missing reports. RESULTS: Overall, 30 clinical trials with 970 patients were included in our study. Considering the type of cells, six studies used keratinocytes, nine used fibroblasts, eight used combined keratinocytes and fibroblasts, one study used combined keratinocytes and melanocytes, five used combined keratinocytes and fibroblasts and melanocytes, and one study used mesenchymal stem cells (MSCs). Evaluation of the preparation type in these studies showed that cultured method was used in 25 trials, and non-cultured method in 5 trials. Also, the graft type of 17 trials was allogeneic, and of 13 other trials was autologous. CONCLUSIONS: Our study showed that employing cell-based therapies for the treatment of burn wounds have significant results in clinical studies and are promising approaches that can be considered as alternative treatments in many cases. However, choosing appropriate cell-based treatment for each burn wound is essential and depends on the situation of each patient.

Implementation of a rural emergency department-initiated buprenorphine program in the mountain west: a study protocol.

BACKGROUND: Opioid related overdose morbidity and mortality continue to significantly impact rural communities. Nationwide, emergency departments (EDs) have seen an increase in opioid use disorder (OUD)-related visits compared to other substance use disorders (SUD). ED-initiated buprenorphine is associated with increased treatment engagement at 30 days. However, few studies assess rural ED-initiated buprenorphine implementation, which has unique implementation barriers. This protocol outlines the rationale and methods of a rural ED-initiated buprenorphine program implementation study. METHODS: This is a two-year longitudinal implementation design with repeated qualitative and quantitative measures of an ED-initiated buprenorphine program in the rural Mountain West. The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework outlines intervention assessments. The primary outcome is implementation measured by ED-initiated buprenorphine protocol core components. Reach, adoption, and maintenance are secondary outcomes. External facilitators from an academic institution with addiction medicine and prior program implementation expertise partnered with community hospital internal facilitators to form an implementation team. External facilitators provide ongoing support, recommendations, education, and academic detailing. The implementation team designed and implemented the rural ED-initiated buprenorphine program. The program includes OUD screening, low-threshold buprenorphine initiation, naloxone distribution and administration training, and patient navigator incorporation to provide warm hand off referrals for outpatient OUD management. To address rural based implementation barriers, we organized implementation strategies based on Expert Recommendations for Implementing Change (ERIC). Implementation strategies include ED workflow redesign, local needs assessments, ED staff education, hospital leadership and clinical champion involvement, as well as patient and community resources engagement. DISCUSSION: Most ED-initiated buprenorphine implementation studies have been conducted in urban settings, with few involving rural areas and none have been done in the rural Mountain West. Rural EDs face unique barriers, but tailored implementation strategies with external facilitation support may help address these. This protocol could help identify effective rural ED-initiated buprenorphine implementation strategies to integrate more accessible OUD treatment within rural communities to prevent further morbidity and mortality. TRIAL REGISTRATION: ClinicalTrials.gov National Clinical Trials, NCT06087991. Registered 11 October 2023 - Retrospectively registered, https://clinicaltrials.gov/study/NCT06087991 .

The OHStat guidelines for reporting observational studies and clinical trials in oral health research: manuscript checklist.

Adequate and transparent reporting is necessary for critically appraising published research, yet ample evidence suggests that the design, conduct, analysis, interpretation, and reporting of oral health research could be greatly improved. Accordingly, the Task Force on Design and Analysis in Oral Health Research, statisticians and trialists from academia and industry, identified the minimum information needed to report and evaluate observational studies and clinical trials in oral health: the OHStat guidelines. Drafts were circulated to the editors of 85 oral health journals and to Task Force members and sponsors and discussed at a December 2020 workshop attended by 49 researchers. The guidelines were subsequently revised by the Task Force writing group. The guidelines draw heavily from the Consolidated Standards for Reporting Trials (CONSORT), Strengthening the Reporting of Observational Studies in Epidemiology, and CONSORT harms guidelines, and incorporate the SAMPL guidelines for reporting statistics, the CLIP principles for documenting images, and the GRADE indicating the quality of evidence. The guidelines also recommend reporting estimates in clinically meaningful units using confidence intervals, rather than relying on P values. In addition, OHStat introduces seven new guidelines that concern the text itself, such as checking the congruence between abstract and text, structuring the discussion, and listing conclusions to make them more specific. OHStat does not replace other reporting guidelines; it incorporates those most relevant to dental research into a single document. Manuscripts using the OHStat guidelines will provide more information specific to oral health research.

A call for clinical trials in glioblastoma multiforme for interleukin 4, interleukin 6, interleukin 13 and CD40.

Glioblastoma multiforme (GBM) is one of the most aggressive and deadly forms of brain cancer, which has a very complex tumor microenvironment (TME) promoting tumor growth, immune evasion, and resistance to therapy. The main players within this environment are represented by cytokines such as Interleukin-4, Interleukin-6, and Interleukin-13, along with the costimulatory molecule CD40. The paper draws back the curtain on the complex interactions played out by these molecules in contributing to the formation of a TME within GBM. IL-4 and IL-13 induce an immunosuppressive environment through the polarization of tumor-associated macrophages (TAMs) into a pro-tumoral M2 phenotype. In contrast, IL-6 takes part in the activation of the JAK-STAT3 pathway, enhancing survival and proliferation of tumor cells. In this context, CD40 either induces anti-tumor immunity through APC activation or facilitates tumors by angiogenesis and survival pathways. The synergistic actions of these molecules create feedback loops that keep up the malignancy of GBM and present a big problem for therapy. Knowledge of these interactions opens new ways for the development of multi-targeted therapeutic strategies at the other end. This may result in the interruption of the tumor-supportive environment in GBM, reducing tumor growth and improving patient outcomes by targeting IL-4, IL-6, IL-13, and CD40 simultaneously.

[Anti-amyloid Antibody Drugs as Disease-Modifying Therapies for Alzheimer's Disease].

Alzheimer's disease (AD) is a common dementia disorder in the elderly individuals, accounting for approximately 60-70% of all dementia cases. Recently, significant progress has been made in developing and approving anti-amyloid antibody drugs as one of the disease-modifying therapies (DMT) that aim to slow the progression of AD by targeting amyloid-beta accumulation in the brain. Notable drugs such as aducanumab, lecanemab, and donanemab have shown potential in clinical trials, leading to the approval of aducanumab and lecanemab, and approval is also expected for donanemab. Other anti-amyloid drugs such as remternetug and trontinemab are also under development. However, challenges remain, including adverse effects like amyloid-related imaging abnormalities (ARIA) and the need for addressing healthcare preparedness to support their use. This paper outlines the current status of DMT for AD, including the clinical trial results and current applications of these drugs. It also discusses the existing challenges to improve the safety and accessibility of DMTs.

Intersecting evidence: Bibliometric analysis and clinical trials illuminate immunotherapy in KRAS-mutation cancer: A review.

KRAS mutations play a critical role in the development and progression of several cancers, including non-small cell lung cancer and pancreatic cancer. Despite advancements in targeted therapies, the management of KRAS-mutant tumors remains challenging. This study leverages bibliometric analysis and a comprehensive review of clinical trials to identify emerging immunotherapies and potential treatments for KRAS-related cancers. Using the Web of Science Core Collection and Citespace, we analyzed publications from January 2008 to March 2023 alongside 52 clinical trials from ClinicalTrials.gov and WHO's registry, concentrating on immune checkpoint blockades (ICBs) and novel therapies. Our study highlights an increased focus on the tumor immune microenvironment and precision therapy. Clinical trials reveal the effectiveness of ICBs and the promising potential of T-cell receptor T-cell therapy and vaccines in treating KRAS-mutant cancers. ICBs, particularly in combination therapies, stand out in managing KRAS-mutant tumors. Identifying the tumor microenvironment and gene co-mutation profiles as key research areas, our findings advocate for multidisciplinary approaches to advance personalized cancer treatment. Future research should integrate genetic, immunological, and computational studies to unveil new therapeutic targets and refine treatment strategies for KRAS-mutant cancers.

Evaluating guideline and registration policies among neurology journals: a cross-sectional analysis.

BACKGROUND: Neurological disorders have had a substantial rise the last three decades, imposing substantial burdens on both patients and healthcare costs. Consequently, the demand for high-quality research has become crucial for exploring effective treatment options. However, current neurology research has some limitations in terms of transparency, reproducibility, and reporting bias. The adoption of reporting guidelines (RGs) and trial registration policies has been proven to address these issues and improve research quality in other medical disciplines. It is unclear the extent to which these policies are being endorsed by neurology journals. Therefore, our study aims to evaluate the publishing policies of top neurology journals regarding RGs and trial registration. METHODS: For this cross-sectional study, neurology journals were identified using the 2021 Scopus CiteScore Tool. The top 100 journals were listed and screened for eligibility for our study. In a masked, duplicate fashion, investigators extracted data on journal characteristics, policies on RGs, and policies on trial registration using information from each journal's Instruction for Authors webpage. Additionally, investigators contacted journal editors to ensure information was current and accurate. No human participants were involved in this study. Our data collection and analyses were performed from December 14, 2022, to January 9, 2023. RESULTS: Of the 356 neurology journals identified, the top 100 were included into our sample. The five-year impact of these journals ranged from 50.844 to 2.226 (mean [SD], 7.82 [7.01]). Twenty-five (25.0%) journals did not require or recommend a single RG within their Instructions for Authors webpage, and a third (33.0%) did not require or recommend clinical trial registration. The most frequently mentioned RGs were CONSORT (64.6%), PRISMA (52.5%), and ARRIVE (53.1%). The least mentioned RG was QUOROM (1.0%), followed by MOOSE (9.0%), and SQUIRE (17.9%). CONCLUSIONS: While many top neurology journals endorse the use of RGs and trial registries, there are still areas where their adoption can be improved. Addressing these shortcomings leads to further advancements in the field of neurology, resulting in higher-quality research and better outcomes for patients.

Anything is better than nothing': exploring attitudes towards novel therapies in leukodystrophy clinical trials.

BACKGROUND/AIM: Leukodystrophies comprise a group of genetic white matter disorders that lead to progressive motor and cognitive impairment. Recent development of novel therapies has led to an increase in clinical trials for leukodystrophies. To enable recruitment of individuals with a leukodystrophy into clinical trials, clinical trial acceptability should be ascertained. We sought therefore, to identify the motivations for and barriers to clinical trial participation in addition to clinical trial features that may be of concern to individuals with a leukodystrophy and/or their carers. METHODS: Adults with a leukodystrophy and parents/carers of individuals with a leukodystrophy were recruited through the Australian Leukodystrophy Registry and through online advertisements. Qualitative semi-structured interviews were used to explore participants views on what clinical trials involve, the perceived risks and benefits of clinical trials, their desire to participate in clinical trials and their personal experience with leukodystrophy. Thematic analysis of data was performed with co-coding of interview transcripts. RESULTS: 5 interviews were held with parents of children with leukodystrophy, 4 with parents of adults with leukodystrophy and 3 with adults diagnosed with leukodystrophy. Motivations for clinical trial enrolment include access to potentially lifesaving novel treatments and improved prognostic outcomes. Participants were concerned about adverse clinical trial outcomes, including side effects and exacerbation of illness. Despite this, majority of participants were willing to try anything in clinical trials, demonstrating a high tolerance for first in human trials and trials utilising invasive treatment options. CONCLUSIONS: Interviewees communicated a strong desire to participate in interventional clinical trials involving novel therapies. To support enrolment into future leukodystrophy clinical trials we suggest the provision of transparent information regarding clinical trial treatments, consideration of alternative trial control measures, and inclusion of treating clinicians in the trial recruitment process. Clinicians play an integral role in initiating transparent conversations regarding trial risks and adverse outcomes.

Ethical Considerations in the Design and Conduct of Clinical Trials of Artificial Intelligence.

Importance: Safe integration of artificial intelligence (AI) into clinical settings often requires randomized clinical trials (RCT) to compare AI efficacy with conventional care. Diabetic retinopathy (DR) screening is at the forefront of clinical AI applications, marked by the first US Food and Drug Administration (FDA) De Novo authorization for an autonomous AI for such use. Objective: To determine the generalizability of the 7 ethical research principles for clinical trials endorsed by the National Institute of Health (NIH), and identify ethical concerns unique to clinical trials of AI. Design, Setting, and Participants: This qualitative study included semistructured interviews conducted with 11 investigators engaged in the design and implementation of clinical trials of AI for DR screening from November 11, 2022, to February 20, 2023. The study was a collaboration with the ACCESS (AI for Children's Diabetic Eye Exams) trial, the first clinical trial of autonomous AI in pediatrics. Participant recruitment initially utilized purposeful sampling, and later expanded with snowball sampling. Study methodology for analysis combined a deductive approach to explore investigators' perspectives of the 7 ethical principles for clinical research endorsed by the NIH and an inductive approach to uncover the broader ethical considerations implementing clinical trials of AI within care delivery. Results: A total of 11 participants (mean [SD] age, 47.5 [12.0] years; 7 male [64%], 4 female [36%]; 3 Asian [27%], 8 White [73%]) were included, with diverse expertise in ethics, ophthalmology, translational medicine, biostatistics, and AI development. Key themes revealed several ethical challenges unique to clinical trials of AI. These themes included difficulties in measuring social value, establishing scientific validity, ensuring fair participant selection, evaluating risk-benefit ratios across various patient subgroups, and addressing the complexities inherent in the data use terms of informed consent. Conclusions and Relevance: This qualitative study identified practical ethical challenges that investigators need to consider and negotiate when conducting AI clinical trials, exemplified by the DR screening use-case. These considerations call for further guidance on where to focus empirical and normative ethical efforts to best support conduct clinical trials of AI and minimize unintended harm to trial participants.

Agreement Between Mega-Trials and Smaller Trials: A Systematic Review and Meta-Research Analysis.

Importance: Mega-trials can provide large-scale evidence on important questions. Objective: To explore how the results of mega-trials compare with the meta-analysis results of trials with smaller sample sizes. Data Sources: ClinicalTrials.gov was searched for mega-trials until January 2023. PubMed was searched until June 2023 for meta-analyses incorporating the results of the eligible mega-trials. Study Selection: Mega-trials were eligible if they were noncluster nonvaccine randomized clinical trials, had a sample size over 10 000, and had a peer-reviewed meta-analysis publication presenting results for the primary outcome of the mega-trials and/or all-cause mortality. Data Extraction and Synthesis: For each selected meta-analysis, we extracted results of smaller trials and mega-trials included in the summary effect estimate and combined them separately using random effects. These estimates were used to calculate the ratio of odds ratios (ROR) between mega-trials and smaller trials in each meta-analysis. Next, the RORs were combined using random effects. Risk of bias was extracted for each trial included in our analyses (or when not available, assessed only for mega-trials). Data analysis was conducted from January to June 2024. Main Outcomes and Measures: The main outcomes were the summary ROR for the primary outcome and all-cause mortality between mega-trials and smaller trials. Sensitivity analyses were performed with respect to the year of publication, masking, weight, type of intervention, and specialty. Results: Of 120 mega-trials identified, 41 showed a significant result for the primary outcome and 22 showed a significant result for all-cause mortality. In 35 comparisons of primary outcomes (including 85 point estimates from 69 unique mega-trials and 272 point estimates from smaller trials) and 26 comparisons of all-cause mortality (including 70 point estimates from 65 unique mega-trials and 267 point estimates from smaller trials), no difference existed between the outcomes of the mega-trials and smaller trials for primary outcome (ROR, 1.00; 95% CI, 0.97-1.04) nor for all-cause mortality (ROR, 1.00; 95% CI, 0.97-1.04). For the primary outcomes, smaller trials published before the mega-trials had more favorable results than the mega-trials (ROR, 1.05; 95% CI, 1.01-1.10) and subsequent smaller trials published after the mega-trials (ROR, 1.10; 95% CI, 1.04-1.18). Conclusions and Relevance: In this meta-research analysis, meta-analyses of smaller studies showed overall comparable results with mega-trials, but smaller trials published before the mega-trials gave more favorable results than mega-trials. These findings suggest that mega-trials need to be performed more often given the relative low number of mega-trials found, their low significant rates, and the fact that smaller trials published prior to mega-trial report more beneficial results than mega-trials and subsequent smaller trials.