Clinical trials involving rare gynaecological cancers.

Clinical trials that investigate therapies for rare gynaecological cancers (RGC) are essential to provide evidence-based data towards new effective and safe treatments, however, they present unique challenges. The main objective of this narrative review is to summarize completed phase III clinical trials investigating therapies for RGC and to discuss the outcomes of these trials. PRISMA guidelines were used to report the steps of the review. We searched the WHO's International Clinical Trials Registry Platform, clinicaltrials.gov and PubMed/Medline for publications reporting results from clinical trials on RGC including at least one medication. From 31 identified phase III clinical trials, 13 were still ongoing, four were terminated and just eight (25.8 %) had posted results and/or publications. The latter completed trials were mostly multi-center and located in at least two continents, participants were mainly adults, and the recruitment period varied from about 2.5 to 10.5 years. Allocation was randomized with parallel assignment in 7 out of 8 trials, while only one trial had double masking. The most common primary outcome measure was progression-free survival (PFS), followed by overall survival (OS). Patient-reported outcomes were secondary outcome measures in four completed trials, assessing quality of life by various questionnaires. Most of the trials did not meet their primary endpoints. By highlighting the scarcity of clinical trials on RGC, our findings further emphasize the need for designing, conducting and sustaining phase III clinical trials to investigate innovative therapies for these conditions and report meaningful outcome measures.

Incidence of aortic valve reintervention in patients with aortic stenosis undergoing transcatheter aortic valve implantation versus surgical aortic valve replacement: a systematic review and updated meta-analysis of randomized studies.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) are established interventions for alleviating symptoms and enhancing survival in individuals with severe aortic stenosis (AS). However, the long-term outcomes and incidence of reintervention associated with TAVI and SAVR remain uncertain. METHODS: We conducted a systematic review and meta-analysis to compare the incidence of reintervention in TAVI versus SAVR. PubMed, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs). Risk ratios (RR) and 95% confidence intervals (CI) were pooled with a random-effects model. A p-value < 0.05 was considered statistically significant. RESULTS: Nine RCTs were included, with 5144 (50.9%) patients randomized to TAVI. Compared with SAVR, TAVI increased reinterventions (RR 1.89; 95% CI 1.29-2.76; p < 0.01) and the need for pacemakers (RR 1.91; 95% CI 1.49-2.45; p < 0.01). In addition, TAVI significantly reduced the incidence of new-onset atrial fibrillation (RR 0.43; 95% CI 0.32- 0.59; p < 0.01). There were no significant differences in all-cause mortality (RR 1.04; 95% CI 0.92-1.16; p = 0.55), cardiovascular mortality (RR 1.04; 95% CI 0.94-1.17; p = 0.44), stroke (RR 0.97; 95% CI 0.80-1.17; p = 0.76), endocarditis (RR 0.96; 95% CI 0.70-1.33; p = 0.82), and myocardial infarction (RR 1.06; 95% CI 0.79-1.41; p = 0.72) between groups. CONCLUSIONS: In patients with severe AS, TAVI significantly increased the incidence of reinterventions and the need for pacemakers as compared with SAVR.

Efficacy and safety of chemoradiotherapy plus immune checkpoint inhibitors for the treatment of locally advanced cervical cancer: a systematic review and meta-analysis.

Background: Radiotherapy plus concurrent chemotherapy is a standard method for treating locally advanced cervical cancer (LACC). Immune checkpoint inhibitors (ICIs) are widely applied in the treatment of recurrent cervical cancer, metastatic cervical cancer or LACC. The efficacy and safety of radiotherapy plus immunotherapy for LACC require further investigation. The objective of this review and meta-analysis was to analyze the efficacy and safety of concurrent chemoradiotherapy (CCRT) combined with ICIs for treating LACC on the basis of the results of randomized controlled trials (RCTs). Methods: We comprehensively searched electronic databases to identify RCTs that focused on CCRT plus ICIs for LACC treatment. The outcomes included the objective response rate (ORR) and progression-free survival (PFS), overall survival (OS) and adverse events (AEs). A standard method for systematic review and meta-analysis was used. Review Manager 5.4 was used for data combination and analyses. Results: Three RCTs involving 1882 participants with LACC were identified and included in the systematic review and meta-analysis. CCRT plus ICIs improved the rates of PFS (hazard ratio [HR]: 0.76, 95% confidence interval [CI]: CI: 0.64, 0.91, P = 0.002) and OS (HR: 0.7695% CI (95% CI 0.58-0.99, P = 0.04) in patients with LACC. Compared with the control group, the CCRT plus immunotherapy group had an increased ORR (OR: 1.37, 95% CI: 1.02,1.85, P=0.04). The two methods had similar rates (HR=1.99, 95% CI: 0.99, 1.43; P=0.07) of treatment-related grade 3 or higher AEs. The CCRT plus immunotherapy group had a higher rate than did the control group (HR: 2.68, 95% CI: 1.38, 5.21; P=0.004) in terms of any grade immunotherapy-related AEs. Conclusions: CCRT plus ICIs is efficacious and safe for the management of LACC. The addition of ICIs to CCRT improved the rates of PFS and OS in patients with LACC. The adverse effects of immunotherapy-related AEs should be strictly examined and managed in a timely manner.

The evolution of small-molecule Akt inhibitors from hit to clinical candidate.

Akt, a key regulator of cell survival, proliferation, and metabolism, has become a prominent target for treatment of cancer and inflammatory diseases. The journey of small-molecule Akt inhibitors from discovery to the clinic has faced numerous challenges, with a significant emphasis on optimization throughout the development process. Early discovery efforts identified various classes of inhibitors, including ATP-competitive and allosteric modulators. However, during preclinical and clinical development, several issues arose, including poor specificity, limited bioavailability, and toxicity. Optimization efforts have been central to overcoming these hurdles. Researchers focused on enhancing the selectivity of inhibitors to target Akt isoforms more precisely, reducing off-target effects, and improving pharmacokinetic properties to ensure better bioavailability and distribution. Structural modifications and the design of prodrugs have played a crucial role in refining the efficacy and safety profile of these inhibitors. Additionally, efforts have been made to optimize the therapeutic window, balancing effective dosing with minimal adverse effects. The review highlights how these optimization strategies have been key in advancing small-molecule Akt inhibitors toward clinical success and underscores the importance of continued refinement in their development.

Treatment of the blood cancer polycythemia vera with ruxolitinib in the MAJIC-PV study: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article describing the main results of the MAJIC-PV study. This study looked at using the cancer drug ruxolitinib to treat a type of blood cancer called polycythemia vera. People with polycythemia vera make too many red blood cells in their body. This can make their blood thicker and can increase the chances of blood clots forming in their blood vessels.Researchers wanted to find out how well ruxolitinib worked compared with the best available therapy as a treatment for people with polycythemia vera who were at risk of developing blood clots that could lead to a heart attack or stroke. Specifically, the study looked at people who had already taken the chemotherapy hydroxycarbamide (also known as hydroxyurea) for their polycythemia vera, but it either didn't work for them or gave them side effects that they could not tolerate. WHAT WERE THE RESULTS?: In the study, researchers divided 180 adults with polycythemia vera who were at high risk of developing blood clots that could lead to a stroke into two groups: 93 people who took ruxolitinib twice a day, and 87 people who took the best available therapy. 43% of people who took ruxolitinib and 26% of people who had the best available therapy had normal blood counts and spleen size within 1 year of treatment. 84% of people who took ruxolitinib and 75% of people who had the best available therapy lived for at least 3 years without their polycythemia vera becoming a more advanced type of blood cancer. The most common side effects were disorders of the digestive system (stomach and gut), disorders of the blood vessels, and infections. This is similar to the side effects that doctors know about for ruxolitinib. WHAT DO THE RESULTS MEAN?: Compared with people who had the best available therapy for their polycythemia vera, people who took ruxolitinib were more likely to have normal blood counts and spleen size within 1 year of treatment, and were more likely to live longer without their polycythemia vera becoming a more advanced type of blood cancer.

Effect of add-on naldemedine treatment in patients with cancer and opioid-induced constipation insufficiently responding to magnesium oxide: a pooled, subgroup analysis of two randomized controlled trials.

OBJECTIVE: To evaluate the additive effect of naldemedine tosylate (naldemedine) on opioid-induced constipation in cancer patients insufficiently responding to magnesium oxide treatment. METHODS: We combined two randomized, double-blind, placebo-controlled, phase IIb and III trials of naldemedine and conducted a post hoc subgroup analysis. We evaluated the effect and safety of naldemedine in 116 patients who received naldemedine in addition to magnesium oxide (naldemedine group) and 117 patients who received placebo in addition to magnesium oxide (placebo group). Both groups included patients insufficiently responding to magnesium oxide for opioid-induced constipation. Effect was assessed using spontaneous bowel movement responder rate, complete spontaneous bowel movement responder rate, changes in spontaneous bowel movements and complete spontaneous bowel movements. Safety was also assessed. RESULTS: During the 2-week treatment period, the responder rates for spontaneous bowel movement and complete spontaneous bowel movement were 73.3 and 43.1% in naldemedine group, respectively, which were significantly higher (P < 0.0001) than 41.9 and 14.5% in placebo group, respectively. Median time to first spontaneous bowel movement and first complete spontaneous bowel movement was significantly shorter (P < 0.0001) in the naldemedine group (4.0 and 21.3 h, respectively) than in the placebo group (27.7 and 211.7 h, respectively). The incidence of adverse events and diarrhoea was significantly higher (P < 0.05) in the naldemedine group than in the placebo group, while the incidence of serious adverse events and severe diarrhoea was not significantly different between the naldemedine and placebo groups. CONCLUSION: The study suggested the addition of naldemedine as an effective treatment option for opioid-induced constipation in cancer patients insufficiently responding to magnesium oxide treatment.

Traditional Chinese medicine for the treatment of cancers of hepatobiliary system: from clinical evidence to drug discovery.

Hepatic, biliary, and pancreatic cancer pose significant challenges in the field of digestive system diseases due to their highly malignant nature. Traditional Chinese medicine (TCM) has gained attention as a potential therapeutic approach with long-standing use in China and well-recognized clinical benefits. In this review, we systematically summarized the clinical applications of TCM that have shown promising results in clinical trials in treating hepatic, biliary, and pancreatic cancer. We highlighted several commonly used TCM therapeutics with validated efficacy through rigorous clinical trials, including Huaier Granule, Huachansu, and Icaritin. The active compounds and their potential targets have been thoroughly elucidated to offer valuable insights into the potential of TCM for anti-cancer drug discovery. We emphasized the importance of further research to bridge the gap between TCM and modern oncology, facilitating the development of evidence-based TCM treatment for these challenging malignancies.

Efficacy of vitamin D supplementation in the treatment of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials.

Context: COVID-19 has substantial effects on respiratory health and overall well-being. Recent studies suggest vitamin D as a potential treatment, but the results are inconclusive. Objective: The authors conducted a systematic review of randomized controlled trials (RCTs) to examine the link between vitamin D and patients with COVID-19. Data sources: The authors searched electronic databases PubMed, Cochrane, CINAHL, EMBASE and Google Scholar from their inception till August 2023. Study selection: Inclusion criteria used in our systematic review include: (1) patients who tested positive for COVID-19, (2) intervention was vitamin D supplementation, (3) the comparator was either a placebo, standard care of treatment, or, no treatment, (4) at least one of the clinical outcomes of interest were investigated, (5) study design being RCTs. Data extraction: Two independent reviewers manually extracted information from selected articles, including study characteristics, patient characteristics, and the primary outcomes: all-cause mortality, ICU and hospital stay length and secondary outcomes: mechanical ventilation, supplemental oxygen, ICU admission, and adverse events. Risk ratios or mean differences and 95% CIs were calculated using a random-effects model. Data synthesis: The authors' analysis included 14 RCTs with 2165 patients. Vitamin D significantly reduced ICU admissions and lowered the need for mechanical ventilation compared to placebo. However, it did not significantly affect hospital stay length, ICU stay length, mechanical ventilation duration, mortality, or the need for supplemental oxygen. Conclusion: Vitamin D does not significantly improve certain clinical outcomes, such as hospital and ICU stay length, for patients with COVID-19. However, it still may be significantly beneficial in decreasing the burden on intensive care services.

Exploring the clinical effectiveness of glucagon-like peptide-1 receptor agonists in managing cardiovascular complications: an updated comprehensive review and future directives.

The possible cardiovascular advantages of glucagon-like peptide-1 receptor agonists (GLP-1RAs), a class of drugs predominantly used to treat type 2 diabetes (T2D), have garnered increasing attention in recent years. Clinical trials have looked into the possibility that GLP-1RAs have extra cardioprotective benefits in addition to their ability to manage T2D, demonstrating significant major adverse cardiovascular events (MACE) reduction and a favorable safety profile. GLP-1 RAs improve cardiovascular outcomes, especially in those with existing cardiovascular disease. MACE has been steadily declining with this class of drugs, which results in a noticeable rise in cardiovascular outcome trials (CVOTs). GLP-1 RAs have a variety of impacts on the cardiovascular system beyond their function in glycemic control. They offer direct cardioprotection, vasodilation, promotion of salt excretion, reduction of weight, improved lipid profile, and anti-inflammatory qualities through a variety of mechanisms. Thus, this review focuses on GLP-1RAs, its mechanism of action, its clinical effectiveness in CVOTs, the mechanism behind its cardiovascular benefits, its potential role in heart failure, cardiovascular outcomes, its underutilization, and future directives. In conclusion, GLP-1 RAs shows potential in controlling T2D while also lowering cardiovascular risk, but warrants further study into long-term results and real-world data to optimize treatment regimens, ultimately increasing patient outcomes and lowering the burden of cardiovascular disease in T2D populations.

Glucagon-like peptide-1 receptor agonists and kidney outcomes.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained increasing attention for their potential benefits in people with type 2 diabetes mellitus (T2DM) with chronic kidney disease (CKD). Most supportive evidence of a kidney-protective effect of the GLP-1RA class of medications has been derived from kidney-related outcomes reported from cardiovascular outcome trials (CVOTs). GLP-1RAs have been shown to reduce albuminuria, mitigate cardiovascular risk, and possibly attenuate estimated glomerular filtration rate (eGFR) decline. The kidney-protective effects of GLP-1RAs are thought to be attributed to their anti-inflammatory, antioxidant, and vasodilatory properties. Despite these promising findings, the use of GLP-RAs has yet to be definitively shown to slow progression to chronic kidney failure in people with T2DM. The Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW trial) is the first major trial assessing the potential of a GLP-1RA to slow progression of kidney disease in people with established CKD to clinically important kidney end points. On March 5, 2024, the top line result from FLOW was announced with semaglutide 1.0 mg being reported to reduce the primary end point of the trial by a significant 24% compared with placebo. Here, we summarize the kidney outcomes reported from CVOTs for the GLP-1RA class of medication and briefly describe kidney outcomes from other major GLP-1RAs trials. We also discuss a potential role of the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, tirzepatide, as a kidney-protective agent.

Efficacy and safety in early-phase clinical trials for refractory colorectal cancer: A meta-analysis.

BACKGROUND: Despite recent metastatic colorectal cancer (mCRC) therapeutic innovations a comprehensive synthesis of patient outcome and risk-benefit assessment of phase 1/2 trials is missing. The aim of this meta-analysis is to assess efficacy, safety, and trends over time for phase 1 and 2 mCRC trials by examining clinical benefit rate (CBR), overall response rate (ORR), grade 3 or higher adverse events (AE), and discontinuation due to AE. METHODS: The PRISMA guidelines were followed. We searched PubMed and Embase for publications of phase 1/2 trials between 2010-2021. Trials reporting on new therapies for treatment-refractory mCRC were included. RESULTS: The search strategy yielded 4175 unique reports, of which 258 publications were eligible. These publications report data of 277 unique treatment arms. Overall ORR was 6 %, CBR was 27 % in phase 1 % and 36 % in phase 2 trials. CBR increased from 23 % in 2010-2012 to 42 % in 2019-2021. Compared to 2010-2012, trials in 2019-2021 more often tested immunomodulators (4 % vs 23 %), included molecularly preselected populations (4 % vs 38 %) and younger patients (median age<60 44 % vs 66 %). Grade 3 + AE occurred in 35 % of patients, most frequently in trials investigating targeted treatments. CONCLUSIONS: Treatment efficacy in phase 1/2 trials is modest but improved from 2010 to 2021. This improvement is accompanied by a shift towards testing in a younger, fitter, and more strictly molecularly preselected population, as well as an increased focus on targeted and immunotherapies.

Adaptive designs in clinical trials: a systematic review-part I.

BACKGROUND: Adaptive designs (ADs) are intended to make clinical trials more flexible, offering efficiency and potentially cost-saving benefits. Despite a large number of statistical methods in the literature on different adaptations to trials, the characteristics, advantages and limitations of such designs remain unfamiliar to large parts of the clinical and research community. This systematic review provides an overview of the use of ADs in published clinical trials (Part I). A follow-up (Part II) will compare the application of AD in trials in adult and pediatric studies, to provide real-world examples and recommendations for the child health community. METHODS: Published studies from 2010 to April 2020 were searched in the following databases: MEDLINE (Ovid), Embase (Ovid), and International Pharmaceutical Abstracts (Ovid). Clinical trial protocols, reports, and a secondary analyses using AD were included. We excluded trial registrations and interventions other than drugs or vaccines to align with regulatory guidance. Data from the published literature on study characteristics, types of adaptations, statistical analysis, stopping boundaries, logistical challenges, operational considerations and ethical considerations were extracted and summarized herein. RESULTS: Out of 23,886 retrieved studies, 317 publications of adaptive trials, 267 (84.2%) trial reports, and 50 (15.8%) study protocols), were included. The most frequent disease was oncology (168/317, 53%). Most trials included only adult participants (265, 83.9%),16 trials (5.4%) were limited to only children and 28 (8.9%) were for both children and adults, 8 trials did not report the ages of the included populations. Some studies reported using more than one adaptation (there were 390 reported adaptations in 317 clinical trial reports). Most trials were early in drug development (phase I, II (276/317, 87%). Dose-finding designs were used in the highest proportion of the included trials (121/317, 38.2 %). Adaptive randomization (53/317, 16.7%), with drop-the-losers (or pick-the-winner) designs specifically reported in 29 trials (9.1%) and seamless phase 2-3 design was reported in 27 trials (8.5%). Continual reassessment methods (60/317, 18.9%) and group sequential design (47/317, 14.8%) were also reported. Approximately two-thirds of trials used frequentist statistical methods (203/309, 64%), while Bayesian methods were reported in 24% (75/309) of included trials. CONCLUSION: This review provides a comprehensive report of methodological features in adaptive clinical trials reported between 2010 and 2020. Adaptation details were not uniformly reported, creating limitations in interpretation and generalizability. Nevertheless, implementation of existing reporting guidelines on ADs and the development of novel educational strategies that address the scientific, operational challenges and ethical considerations can help in the clinical trial community to decide on when and how to implement ADs in clinical trials. STUDY PROTOCOL REGISTRATION: https://doi.org/10.1186/s13063-018-2934-7 .

Personalized mRNA vaccines in glioblastoma therapy: from rational design to clinical trials.

Glioblastomas (GBMs) are the most common and aggressive malignant brain tumors, presenting significant challenges for treatment due to their invasive nature and localization in critical brain regions. Standard treatment includes surgical resection followed by radiation and adjuvant chemotherapy with temozolomide (TMZ). Recent advances in immunotherapy, including the use of mRNA vaccines, offer promising alternatives. This review focuses on the emerging use of mRNA vaccines for GBM treatment. We summarize recent advancements, evaluate current obstacles, and discuss notable successes in this field. Our analysis highlights that while mRNA vaccines have shown potential, their use in GBM treatment is still experimental. Ongoing research and clinical trials are essential to fully understand their therapeutic potential. Future developments in mRNA vaccine technology and insights into GBM-specific immune responses may lead to more targeted and effective treatments. Despite the promise, further research is crucial to validate and optimize the effectiveness of mRNA vaccines in combating GBM.

Antidepressants for pain management in adults with chronic pain: a network meta-analysis.

Background: Chronic pain is common and costly. Antidepressants are prescribed to reduce pain. However, there has not been a network meta-analysis examining all antidepressants across all chronic pain conditions, so effectiveness and safety for most antidepressants for pain conditions remain unknown. Objective: To assess the efficacy and safety of antidepressants for chronic pain (except headache) in adults. Our primary outcomes were as follows: substantial pain relief (50%), pain intensity, mood and adverse events. Our secondary outcomes were as follows: moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change, serious adverse events and withdrawal. Design: This was a systematic review with a network meta-analysis. We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials of antidepressants for chronic pain conditions up until 4 January 2022. The review was registered in PROSPERO (CRD42020171855), and the protocol was published in the Cochrane Library (https://doi.org/10.1002/14651858.CD014682). Setting: We analysed trials from all settings. Participants: We included trials in which participants had chronic pain, defined as longer than 3 months, from any condition excluding headache. Interventions: We included all antidepressants. Main outcome measures: Our primary outcome was substantial pain relief, defined as a reduction ˃ 50%. We also measured pain intensity, mood and adverse events. Secondary measures included moderate pain relief (above 30% reduction), physical function, sleep, quality of life, Global Impression of Change, serious adverse events, and withdrawal from trial. Results: We identified 176 studies with a total of 28,664 participants. Most studies were placebo-controlled (n = 83) and parallel armed (n = 141). The most common pain conditions examined were fibromyalgia (59 studies), neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of randomised controlled trials was 10 weeks. Most studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. Standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that for duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Limitations: The evidence for antidepressants other than duloxetine is poor. For duloxetine, it is not clear whether the effect applies to groups with both pain and low mood, since these groups were excluded from trials. There is also insufficient evidence on long-term outcomes and on adverse effects. Conclusions: There is only reliable evidence for duloxetine in the treatment of chronic pain. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Data for all other antidepressants were of low certainty. However, the findings should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. Future work: There is a need for large, methodologically sound trials testing the effectiveness of antidepressants for chronic pain. These trials should examine long-term outcomes (> 6 months) and include people with low mood. There should also be better reporting of adverse events, tolerance of drugs, and long-term compliance. Study registration: This study is registered as PROSPERO CRD42020171855. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128782) and is published in full in Health Technology Assessment; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information.

Chronic pain is pain that lasts for more than 3 months. Over one-third of people across the world experience chronic pain. This often has a detrimental impact on people's mood, disability and well-being. Antidepressants are often prescribed to reduce pain, but we are not sure which antidepressants work best for different types of pain, or whether they are safe. We wanted to find out whether antidepressants were effective and safe for management of chronic pain. We searched for studies that had compared any antidepressant with any other treatment for any type of chronic pain (except headache). We compared all the treatments against each other using a statistical method called network meta-analysis. This method allows us to rank the treatments in order of best to worst for each outcome. We found 176 studies that included a total of 28,664 people with chronic pain. Most of the studies (83/176) compared an antidepressant with a placebo (which looks like the real medicine but does not have any medicine in it). The evidence from our analysis suggests that: Duloxetine is the antidepressant that we have the most confidence in. It was the best antidepressant for reducing pain and improving physical function. A standard dose of duloxetine was equally as effective for reducing pain as a high dose of duloxetine. Milnacipran was also effective at reducing pain, but we are not as confident in this result as in the one for duloxetine because there were fewer studies with fewer people involved. Aside from duloxetine and milnacipran, we do not have confidence in the results from any other antidepressant included in this review, and even for duloxetine and milnacipran, we do not know the long-term effects. It is important to recognise that the lack of evidence for the majority of antidepressants in this review does not necessarily equal a lack of benefit. Rather, this means that the large, high-quality trials required for us to be certain of an antidepressant's effectiveness have not been undertaken. Altogether, although duloxetine and milnacipran are effective, the results of this review should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. These conclusions were informed by our patient and public involvement group.

Reporting of patient-reported outcomes amongst randomized clinical trials in plastic surgery: a systematic review using CONSORT-PRO.

BACKGROUND: Patient-reported outcomes (PROs) are key to investigating patient perspectives in randomized controlled trials (RCTs). Standardization of PRO reporting is critical for trial generalizability and the application of findings to clinical practice. This systematic review aimed to evaluate the reporting quality of RCTs published in the top plastic surgery journals according to the consolidated standards of reporting trials (CONSORT)-PRO extension. METHODS: We completed a comprehensive search of MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. All RCTs with a validated PRO endpoint published in the top 10 plastic surgery journals (based on the 2021 Web of Science Impact Factor) from 2014 to 2023 were included. Two reviewers independently extracted data and scored the included studies using the CONSORT-PRO checklist. Univariate regression was applied to assess factors associated with reporting adherence. Studies were assessed for their risk of bias using the Cochrane Risk of Bias 2.0 tool. RESULTS: A total of 88 RCTs were included. PROs were the primary endpoint in 50 (57%) and the secondary endpoint of 38 (43%) studies. Mean overall reporting adherence was poor (39% (±12) and 36% (±13) in studies with PRO as primary and secondary endpoints, respectively). The presence of industry support was significantly associated with greater adherence. CONCLUSIONS: There is low adherence to the CONSORT-PRO extension among plastic surgery RCTs published in the top 10 plastic surgery journals. We encourage journals and authors to endorse and apply the CONSORT-PRO extension. This may optimize the dissemination of clinical findings from RCTs and assist patient-centered care.

Gender, Racial, and Academic Authorship Diversity in the Otolaryngology Clinical Trial Literature.

OBJECTIVE: To investigate the state and trajectory of gender, racial, and academic authorship diversity in the otolaryngology clinical trial literature over the past 2 decades. STUDY DESIGN: Bibliometric analysis. SETTING: Otolaryngology clinical trial literature. METHODS: Clinical trials published in the 9 major otolaryngology journals between 2000 and 2020 were included. The gender, race, and academic seniority of the first, senior, and corresponding authors were recorded for each trial. Multivariable regression models assessed the temporal trajectory of authorship diversity over time and the disparity in citations across author characteristics. Models adjusted for relevant confounders pertaining to publication environment and study design. RESULTS: Among 2117 trials, first, senior, and corresponding authors have been predominantly White (60%-64%), male (76%-80%), and attending physicians (63%-69%). Trials led by Black (<1%) and Hispanic (<5%) authors were severely underrepresented. Over time, the representation of female (adj. ß 0.8%, 95% CI [0.5%, 1.1%] per year), Asian (1.0% [0.7%, 1.3%] per year), and MD resident (0.4% [0.1%, 0.7%] per year) first authorship increased, but representation of female (0.2% [-0.1%, 0.5%] per year), Black (0% [-0.03%, 0.02%] per year), Hispanic (-0.2% [-0.33%, -0.02%] per year) senior authorship remained persistently low. Asian-led trials were cited significantly less compared to White-led trials even after adjusting for study design and publication year (aIRR 0.82 [0.73, 0.92]). CONCLUSIONS: Despite promising signs of improving authorship diversity over time, persistent underrepresentation of female, Black, Hispanic senior authorship underscore the need for additional efforts to diversify the otolaryngology clinical science workforce.

Do prospective randomized controlled trials comply with filed protocols? Spin study of 206 trials from 2010 to 2023.

INTRODUCTION: Prospective randomized controlled trials (RCT) have a robust methodology, but some distortions may occur during the course of study. Some protocols may not be available at the time an article is reading. Some authors may change the methodology between the time the protocol was submitted and when the trial results are actually published. Others may distort results to favor more attractive findings and draw conclusions that support prior hypotheses. This has rarely been investigated and none explored the RCTs published in the Journal of Bone and Joint Surgery (JBJS). Therefore, we did a retrospective investigation aiming to determine: (1) the proportion of trials with a protocol deposited and accessible to the reader, (2) whether the trials scrupulously followed the filed protocols. HYPOTHESIS: Protocols were available in over 80% of cases, and these protocols were followed in over 80% of trials for the primary endpoint. PATIENTS AND METHODS: This was a retrospective study of articles published in the JBJS between January 2010 and November 2023. Differences in primary and secondary endpoints between protocols and articles were sought. RESULTS: Of the 206 RCT articles studied, 113 (54.9%) described clear and identifiable endpoints, and 93 (45.1%) were not identifiable and were inferred in the results; 184 (89.3%) articles identified a trial protocol. For the 184 articles (89.3%) declaring a trial protocol in the text, 23 (11.1%) protocols were not accessible. In all, 45 articles (21.8%) thus had no protocol available on the Internet (i.e., not available to the reader either because it was not cited in the text or because it was not accessible) so we analyzed 161 articles. The primary endpoint remained unchanged in 97 articles (60.2%) out of the 161 studied, was changed in 64 articles (39.8%), and was lacking (protocol not accessible) in 45 articles (21.8% of all articles). The secondary endpoints of the articles were unchanged in 61 articles (37.9%) out of the 161 studied. DISCUSSION: Like other leading journals, JBJS publishes RCT articles containing a significant proportion of inconsistencies between preoperative trial protocols and the methods actually used in the research. LEVEL OF EVIDENCE: III; retrospective comparative study non randomized.

Impact of DNA Repair Deficiency in the Evolving Treatment Landscape of Bladder Cancer.

PURPOSE OF REVIEW: This review explores the current landscape of treatments which target the DNA damage response (DDR) in metastatic and muscle-invasive bladder cancer. It emphasizes recent clinical trials which integrate DDR inhibitors with standard chemotherapy and immunotherapy. RECENT FINDINGS: Noteworthy findings include the ATLANTIS trial, which demonstrated prolonged progression-free survival (PFS) in DDR biomarker-selected patients using PARP inhibitors as maintenance after standard chemotherapy. Trials such as BAYOU, which combined immunotherapy with PARP inhibition, similarly suggested a potential therapeutic benefit in DDR biomarker-selected patients with bladder cancer. Efforts to develop bladder-sparing treatment regimens based on DDR-associated mutational profiles, such as the RETAIN and HCRN 16-257 trials, have had mixed outcomes to date. There are now ongoing efforts to combine DDR inhibitors with the newest bladder cancer therapies, such as antibody-drug conjugates. This review highlights the most recent advances in targeting DNA repair deficiency in the evolving treatment landscape of bladder cancer.

Joint Models Inform the Longitudinal Assessment of Patient-Reported Outcomes in Clinical Trials: A Simulation Study and Secondary Analysis of the Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery (RELIEF) Randomized Controlled Trial.

OBJECTIVE: Evaluate the utility of a joint model when analysing a patient-reported endpoint as part of a randomized controlled trial in which censoring occurs when patients die during follow-up. STUDY DESIGN AND SETTING: The present study comprises two parts: first we re-analyzed data from a previously published randomized controlled trial comparing two fluid regimens in the first 24 hours of major abdomino-pelvic surgery ('RELIEF' trial). In this trial, patient-reported disability was measured at multiple timepoints before and after surgery. Next, we conducted a simulation study to jointly emulate patient-reported disability and survival, similar to the RELIEF trial, under nine treatment-outcome scenarios. In both parts, we compared a joint model analysis to a linear mixed effect model combined with one of several traditional methods of handling longitudinal missingness: available data analysis, complete case analysis, last observation carried forward, and worst-case assumption. RESULTS: In part one, the joint model revealed no between-group differences in patient-reported disability at one, three, six, and 12 months after surgery. The worst-case approach consistently resulted in the largest deviation from the joint model estimates, although in this particular setting none of the approaches materially changed the study's conclusions. In part two, the simulations revealed that across all treatment-outcome scenarios, the joint model expectedly produced unbiased estimates of patient-reported disability. Similarly, employing an approach based on all available data (i.e., relying on the maximum likelihood estimator for handling missingness) yielded disability estimates close to the simulated values, albeit with slight bias across some scenarios. The last observation carried forward approach mirrored the joint model's estimates except when the treatment had a non-null effect on patient-reported disability. The worst case analysis resulted in high bias, which was particularly evident when the treatment had a large effect on survival. The complete case analysis resulted in high bias across all scenarios. CONCLUSIONS: In randomized trials that employ a patient-reported outcome as one of their endpoints, a joint model can address bias arising from informative missingness related to death. Methods for handling missingness based on all available data appear to be a reasonable alternative to joint models, with only slight bias across some simulated scenarios.

Most common symptomatic adverse reactions of cancer treatments from US drug labels (2015-2021) to inform selection of patient-reported outcomes.

OBJECTIVES: Incorporating patient-reported outcomes (PROs) to assess symptomatic adverse events (AEs) in cancer clinical trials (CTs) is important to characterize treatment tolerability. Cancer therapies approved over the past decade have expanded the types of expected toxicities. To inform future symptomatic AE PRO item selection, we identified the most common symptomatic adverse reactions from recently approved products. METHODS: We reviewed approvals from 2015-2021 for lung, breast, and hematologic cancer indications. Using United States Prescribing Information safety data, we recorded symptomatic adverse reactions reported in ≥20% of patients in the experimental arm of CTs supporting approvals. We calculated the proportion of arms reporting each symptomatic adverse reaction. RESULTS: In total, 130 experimental arms were included (lung=30, breast=10, hematologic=90). For all cancer types, fatigue and diarrhea were reported in >50% of the arms. Nausea was reported in ≥50% of the arms for all except lung. Vomiting, decreased appetite, and alopecia, were reported in ≥50% of breast cancer arms. Rash, musculoskeletal pain, and cough were reported in >50% of leukemia/lymphoma arms. Cough was common (50%) in multiple myeloma arms. CONCLUSIONS: Heterogeneity in symptomatic adverse reactions across CTs supports the use of item libraries when building a PRO strategy to assess tolerability. Fatigue, diarrhea, and nausea were the most frequent symptomatic adverse reactions reported in contemporary cancer CTs and could provide a starting point when selecting PRO symptomatic AE items. Additional symptomatic AE PRO items should be selected based on the mechanism of action, early clinical data, published literature, and patient and clinician input.