Pivotal Clinical Trials Research Articles

Disseminated intravascular coagulation is an underestimated but fatal adverse event associated with blinatumomab therapy: A pharmacovigilance analysis of FAERS

AbstractHematologic adverse events (AEs) are common and serious toxicities in patients with hematologic malignancies undergoing blinatumomab therapy. However, restrictive selection criteria in pivotal clinical trials can lead to an underestimation of rare but fatal toxicities. In this study, we systematically analyzed hematologic AEs associated with blinatumomab using the Food and Drug Administration Adverse Event Reporting System (FAERS) from October 2014 to December 2023. Disproportionate analysis was performed to identify overreported AEs, with a reporting odds ratio (ROR), and a lower bound of the 95% confidence interval (ROR025) exceeding one considered significant. Additionally, adjusted mortality rates and risk ratios (RR) of the top 10 reported hematologic AEs were calculated using a logistic regression model. Among 4745 blinatumomab‐related cases, 418 (8.81%) involved hematologic AEs. We identified 22 significantly overreporting hematologic AEs compared to the full database, with myelosuppression (n = 39 [9.33%], ROR025 = 8.04), disseminated intravascular coagulation (DIC, n = 31 [7.42%], ROR025 = 15.14), and bone marrow failure (n = 14 [3.35%], ROR025 = 3.41) notably underestimated in clinical trials. DIC resulted in a substantial mortality rate of 45.16%. Finally, DIC was found to be independently associated with death in a multivariable logistic regression analysis (RR = 2.47 [95% CI: 1.11–3.83]). These findings could aid clinicians in the early detection of these rarely reported but fatal hematologic AEs, thereby reducing the risk of severe toxicities in blinatumomab recipients.

Measles–Rubella Microarray Patches Phase III Clinical Trial Framework: Proposal and Considerations

Background: The Measles–Rubella Microarray Patch (MR-MAP) is an important technology that is expected to reduce coverage and equity gaps for measles-containing vaccines (MCVs), reach zero-dose children, and contribute to elimination of measles and rubella. MR-MAPs are anticipated to be easier to deploy programmatically and could be delivered by lesser-trained health workers, thereby increasing immunization coverage. The most advanced MR-MAP has reached clinical proof-of-concept through a Phase I/II trial in the target population of infants and young children. The World Health Organization (WHO) and partners have developed the Phase III clinical trial framework for MR-MAPs presented in this article. Objectives and Methods: The purpose of such framework is to inform the considerations, design and approach for the pivotal clinical trial design, while considering the anticipated data requirements to inform regulatory approval, WHO prequalification, and policy decision. Results: The proposed Phase III trial would compare the immunogenicity and safety of an MR-MAP with MR vaccine delivered subcutaneously in 9- to 10-month-old infants. An analysis of non-inferiority (NI) of immunogenicity would occur six weeks after the first dose. Should regulatory agencies or policy makers require, a proportion of infants could receive a second dose of either the same or alternate MR vaccine presentation six months after the first dose, with those children returning six weeks after the second dose for a descriptive assessment of immunogenicity, and then followed up six months after the second dose for evaluation of safety and immunogenicity. It is anticipated that this proposed pivotal Phase III trial framework would generate the required clinical data for regulatory licensure and WHO prequalification (PQ) of MR-MAPs. However, the trial design would need to be reviewed and confirmed by a national regulatory authority (NRA) that will assess the product for regulatory licensure and the WHO PQ team. Additional research will likely be required to generate data on concomitant vaccine delivery, the safety and immunogenicity of MR-MAPs in other age groups such as children 1–5 years and infants younger than 9 months of age, and the impact of MR-MAPs on coverage and equity. Such studies could be conducted during or after clinical MR-MAP development.

Perfluorohexyloctane ophthalmic solution for dry eye disease: pooled analysis of two phase 3 clinical trials

BackgroundDry eye disease (DED) is commonly caused by excessive tear film evaporation due to Meibomian gland dysfunction (MGD). There is a need for DED treatment options that address tear evaporation and benefit patients across a broad range of demographic and disease characteristics. This study evaluated treatment effects of perfluorohexyloctane ophthalmic drop (formerly NOV03) in the pooled dataset from 2 pivotal clinical trials in patients with DED associated with MGD, both in the overall population and in patient subgroups based on sex, age, and baseline severity of eye dryness.MethodsPooled data from 2 similarly designed, phase 3, randomized controlled trials (GOBI, MOJAVE) were analyzed. Patients aged ≥18 years with DED administered perfluorohexyloctane (n=614) or hypotonic (0.6% solution) saline control (n=603) four times daily for 8 weeks. Primary endpoints were total corneal fluorescein staining (tCFS) score (National Eye Institute scale, 0-15) and eye dryness visual analog scale (VAS) score (0-100). Efficacy was evaluated using analysis of covariance among patient subgroups (male and female, older [≥65 years] and younger [18 to <65 years], tCFS score <7 and ≥7, VAS eye dryness score <70 and ≥70, MGD score <7 and ≥7, Schirmer I test <10 mm and ≥10 mm).ResultsReductions in tCFS and VAS eye dryness scores were greater for perfluorohexyloctane versus control. In the overall patient population, least-squares mean treatment difference was −1.1 (95% CI: −1.41 to −0.79; p<0.0001) for tCFS and −9.0 (95% CI: −11.90 to −6.00; p<0.0001) for VAS eye dryness. Treatment favored perfluorohexyloctane over control in all patient subgroup analyses of tCFS and VAS eye dryness. Overall, the most common adverse event with perfluorohexyloctane was blurred vision (2.1% of patients), which was mild and transient.ConclusionsCompared with a hypotonic saline control, perfluorohexyloctane improved both the signs and symptoms of DED, including in patients with greater self-reported severity of eye dryness.Clinical trial registrationThis study represents an integrated analysis of 2 previous clinical trials: GOBI (ClinicalTrials.gov, NCT04139798) and MOJAVE (ClinicalTrials.gov, NCT04567329).

Current and future strategies for the prevention and treatment of cytomegalovirus infections in transplantation.

Successful prevention and treatment of cytomegalovirus (CMV) infection remains a central focus of clinical care in solid organ and allogeneic hematopoietic cell transplantation. Over the past 5 years, pivotal clinical trials have created new paradigms in CMV prevention, including diverging approaches in HCT and SOT. We review recent advances in CMV risk assessment and progress in antiviral and immune-based strategies for CMV prevention and treatment. We highlight approaches to optimize CMV-specific immunity through vaccination, monoclonal antibodies, and virus-specific T-cells. Observational studies and interventional trials of commercially-available CMV cell-mediated immunity assays for refining preventive and treatment strategies are summarized. Finally, we discuss the importance of enhancing CMV-specific immunity to mitigate the negative impacts of CMV in different transplant settings. CMV infections in recipients of chimeric antigen receptor-T (CAR-T) cell therapies and other immunocompromised populations are growing areas of importance that are beyond the scope of this review.

12206 The Minitouch 3.8 Era Office Endometrial Ablation Procedure: 36-Month Outcomes from a Prospective, Multicenter, Pivotal Clinical Trial

12206 The Minitouch 3.8 Era Office Endometrial Ablation Procedure: 36-Month Outcomes from a Prospective, Multicenter, Pivotal Clinical Trial

Comparative Efficacy of Adagrasib and Sotorasib in KRAS G12C-Mutant NSCLC: Insights from Pivotal Trials

Background: The KRAS G12C mutation, prevalent in various malignancies, including non-small cell lung cancer (NSCLC), represents a unique therapeutic target. Adagrasib and sotorasib, two FDA-approved agents specifically targeting this mutation, have shown promise in clinical trials. This study aims to compare their efficacy in treating KRAS G12C-mutated NSCLC, drawing insights from pivotal clinical trials. Methods: We analyzed data from three key clinical trials: KRYSTAL-1, CodeBreak100, and CodeBreak200. Our methodology involved reconstructing individual patient data from published Kaplan–Meier curves using the IPDfromKM tool (Version 0.1.10). The primary endpoints were progression-free survival (PFS) and overall survival (OS), evaluated through hazard ratios (HRs) and the restricted mean survival time (RMST) method. Results: The HR for PFS favored adagrasib (HR: 0.90 [95% CI: 0.69, 1.19], p = 0.473), suggesting a non-significant trend toward better disease control compared to sotorasib. For OS, the HR was 0.99 [95% CI: 0.75, 1.33] (p = 0.969), indicating no significant difference between the two drugs. RMST analysis supported these findings, with adagrasib showing a consistently higher RMST in PFS at 6, 12, and 18 months. However, OS benefits converged over time, with adagrasib marginally surpassing sotorasib by the 18-month mark. Conclusions: This comprehensive analysis reveals that while adagrasib may offer a slight advantage in PFS, both drugs demonstrate comparable efficacy in OS for KRAS G12C-mutated NSCLC. The subtle differences observed, particularly in PFS, could inform clinical decision-making, emphasizing the need for personalized treatment strategies. Future research should focus on long-term effects and identifying patient subgroups that may benefit more from one drug over the other.

Single‑center, retrospective, evaluator‑blinded, pilot and pivotal clinical trials: Assessing the mirCaP Kit (hsv2‑miR‑H9/hsa‑miR‑3659) as a diagnostic marker for prostate cancer in patients with PSA levels in the gray zone.

Prostate-specific antigen (PSA) remains a key biomarker for the diagnosis and monitoring of prostate cancer (PCa). For patients within the 'PSA gray zone', the positive predictive value (PPV) of PSA for PCa detection by biopsy is estimated to be between 30 and 42%. In the present study, a single-center, retrospective, evaluator-blinded, pilot and pivotal clinical trial was performed to assess the clinical performance of the mirCaP kit (Urotech, Inc.), which measures the herpes simplex virus 2-microRNA (miR)-H9/hsa-miR-3659 ratio, with respect to helping physicians make appropriate decisions regarding further assessment of patients with PSA levels within this gray zone. For the patients in the initial clinical trial group who were in the PSA gray zone, the sensitivity, specificity, accuracy, PPV and negative predictive value (NPV) of the mirCaP kit were 94.29, 77.50, 85.33, 78.57 and 93.94%, respectively. For those in the pivotal clinical trial, these values were 94.50, 82.73, 87.90, 81.10 and 95.04%, respectively. These results suggest that the mirCaP kit may be an effective non-invasive diagnostic marker for PCa in patients with PSA levels in the gray zone. Thus, the mirCaP kit is a promising tool that can help physicians make a decision regarding the need for prostate biopsy in these patients. Of note, the NPV of >90% indicates that the mirCaP kit could prevent unnecessary prostate biopsies in >90% of these cases.

Real-World Persistence with Ocrelizumab in Multiple Sclerosis: a Systematic Review.

In clinical trials, the percentage of patients discontinuing treatment with ocrelizumab due to adverse events was low. However, real-world populations are often more diverse than randomized controlled trials (RCTs), therefore it is important to assess discontinuation rates in real-world studies. This systematic literature review (SLR) was conducted to identify real-world discontinuation and persistence data for ocrelizumab in studies of patients with relapsing remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). Searches were conducted in MEDLINE and Embase to identify relevant real-world studies that met pre-determined Population, Intervention, Comparison, Outcomes, and Study (PICOS) criteria. Only articles published in English were included, but the study country was not restricted. A total of 30 studies were included, with the majority reporting real-world persistence data that appear to be similar to or better than in the pivotal clinical trials, with only 1 study reporting higher discontinuation rates due to adverse events compared with the clinical trials. Other studies identified reported that the risk of discontinuation was higher for other disease-modifying therapies (DMTs) compared with ocrelizumab, and adherence was also higher for ocrelizumab versus other DMTs. These findings have clinical relevance, as other studies have reported improved clinical outcomes and lower care costs for patients that are persistent or adherent to other DMTs.

Navigating therapeutic sequencing in the metastatic castration-resistant prostate cancer patient journey.

Novel therapies for metastatic castration-resistant prostate cancer (mCRPC) have improved patient outcomes. However, there is uncertainty on the optimal selection of therapeutic agents for subsequent lines of therapy. We conducted a comprehensive review of published evidence from pivotal clinical trials and recent guidelines for the treatment of mCRPC. We further identify gaps in knowledge and areas for future research. Key considerations to help guide treatment selection for patients with mCRPC include personal treatment history, individual clinical characteristics, symptoms, prognosis, availability of clinical trials, and other patient-specific factors. Genetic testing and prostate-specific membrane antigen-targeted imaging are important tools to evaluate candidacy for newer therapeutic options such as poly (ADP-ribose) polymerase inhibitors, alone or in combination with androgen receptor pathway inhibitors, and [177Lu]Lu-PSMA-617. This article provides an overview of the evolving treatment landscape of mCRPC, discussing guideline-recommended treatment options and data from key clinical trials, while highlighting ongoing trials that may impact the future treatment landscape. Recommendations for optimal treatment sequencing based on individual patient factors are provided.

Clinical Benefit, Price, and Regulatory Approval of Cancer Drugs Granted Breakthrough Therapy Designation in China, 2020-2024

The China National Drug Administration (NMPA) established the breakthrough therapy designation (BTD) in 2020 to encourage the accelerated development of drugs for the prevention and treatment of diseases that are life-threatening. However, the differences between BTD and non-BTD cancer drugs regarding clinical benefit, regulatory approval, and price are unclear. To compare BTD and non-BTD cancer drugs in clinical benefit (defined as efficacy and safety), novelty, time to approval, and average monthly treatment price. This cross-sectional study analyzes the original indication of BTD and non-BTD novel cancer drugs approved by the NMPA between July 8, 2020, and July 8, 2024. Data on efficacy, safety, regulatory approval, and price of cancer drugs were extracted from pivotal clinical trials based on review reports published by the NMPA, peer-reviewed articles or meeting reports, and winning bid prices for cancer drugs in the Chinese provincial-level centralized procurement process. The main outcome was the efficacy and safety associated with BTD vs non-BTD cancer drugs, including progression-free survival (PFS), response rate (RR), duration of response, serious adverse events, grade 3 or higher adverse events, and treatment-related deaths. In addition, the time to approval, novelty, and initial and latest average monthly treatment prices were evaluated, as well as the average annual reduction rate (AARR; the sum of the reduction rates divided by the number of years for the monthly treatment price) for these cancer drugs. Between July 2020 and July 2024, 18 BTD (36%) and 32 non-BTD (64%) cancer drugs were approved by the NMPA. The median (IQR) clinical development time for BTD drugs was significantly shorter than for non-BTD drugs (5.6 [95% CI, 4.3-7.3] vs 6.6 [95% CI, 6.0-8.5] years; P = .02). No significant differences were observed in PFS (HR, 0.44 [95% CI, 0.38-0.52] vs HR, 0.51 [95% CI, 0.40-0.65]; P = .20), PFS gained (median [IQR], 5.4 [3.9-7.0] vs 2.7 [2.6-5.9] months; P = .77), RR (58% [95% CI, 45%-74%] vs 59% [95% CI, 51%-69%]; P = .85), and duration of response (median [IQR], 18.0 [15.0-21.6] vs 11.1 [7.4-17.4] months; P = .09) between BTD and non-BTD drugs. The rates of serious adverse events (37% [95% CI, 26%-52%] vs 32% [95% CI, 27%-36%]; P = .45), adverse events grade 3 or higher (64% [95% CI, 53%-77%] vs 55% [95% CI, 45%-68%]; P = .31), and treatment-related deaths (2% [95% CI, 1%-4%] vs 1% [95% CI, 1%-2%]; P = .10) were similar between BTD and non-BTD drugs. BTD drugs are more likely to be first-in-class drugs (5 of 18 [28%] vs 1 of 32 [3%]; P = .02). Differences in the median (IQR) initial ($5665 [$3542-$9321] vs $3361 [$2604-$5474]; P = .06) and latest ($5665 [$1553-$9321] vs $2145 [$1318-$4276]; P = .18) average monthly treatment prices for BTD drugs and non-BTD drugs were not significant. The median (IQR) AARRs for BTD drugs and non-BTD drugs were 15.2% (0%-46.9%) and 19.8% (1.0%-42.9%), respectively. The findings of this cross-sectional study suggest that BTD has facilitated faster time to market for cancer drugs and improved novelty, but the price of treatment is relatively higher. There was no significant difference on comparative efficacy and safety.

Trastuzumab Deruxtecan in Human Epidermal Growth Factor Receptor 2-Positive Metastatic Gastric Cancer in a Real-World Setting: A Nationwide Cohort Study.

Trastuzumab deruxtecan (T-DXd) has been approved for human epidermal growth factor receptor 2-positive locally advanced or metastatic gastric and gastroesophageal junction (HER2+ mG/GEJ) cancer since July 2022 in France, through an accelerated approval. The aim of this study was to evaluate its real-world use. We characterized T-DXd users treated for HER2+ mG/GEJ cancer using data from the French National Health Insurance database. The cohort included 196 patients, mostly men (78.1%), with a median age of 65 years. Median overall survival reached 7.7 months (95% CI: 6.2-9.0). Patients treated with T-DXd for HER2+ mG/GEJ cancer in the real world showed lower outcomes than those in pivotal clinical trials, consistent with previous reports on accelerated approvals.

Long-Term Clinical Outcomes Following the WATCHMAN Device Use in Medicare Beneficiaries.

Long-term outcomes following left atrial appendage occlusion outside clinical trials and small registries are largely unknown. Collecting these data was a condition of US market authorization of the WATCHMAN device. The aim of this analysis was to evaluate the rates of stroke, bleeding, and death among Medicare beneficiaries following left atrial appendage occlusion implantation during initial commercial availability of the WATCHMAN left atrial appendage occlusion device overall and in important subgroups. All Medicare fee-for-service beneficiaries ≥65 years of age who underwent left atrial appendage occlusion from April 1, 2016, to August 31, 2020, were included based on the International Classification of Diseases, Tenth Revision, and Current Procedural Terminology codes. Over a 5-year follow-up period, the cumulative incidence over time of mortality, ischemic stroke, and major bleeding were calculated using the International Classification of Diseases, Tenth Revision, diagnosis codes for the full study cohort and within important prespecified subgroups. WATCHMAN recipients (n=48 763) were a median of 77 (interquartile range, 72-82) years of age, 42% female, and mostly White (93%). The median CHA2DS2VASc score was 4 (interquartile range, 3-5) with prior major bleeding in 42% and prior stroke in 12%. At 5 years, death occurred in 44%, bleeding in 15% (with higher risk early following implantation), and ischemic stroke in 7%. Each of these end points was more common with greater baseline age. Male patients had greater 5-year mortality than female patients (46.9% versus 40.6%), but there was no difference between sexes in the rates of ischemic stroke (6.6% versus 7.5%) or major bleeding (14.9% for both). WATCHMAN recipients with prior ischemic stroke or a major bleeding event were older and frailer; these groups had higher rates of ischemic stroke, major bleeding, and death. Compared with patients enrolled in the pivotal clinical trials, Medicare beneficiaries undergoing WATCHMAN implantation were older, more female, and had more comorbid conditions. Substantial long-term mortality and major bleeding following WATCHMAN reflect the high-risk nature of the patient population, while the ischemic stroke rate was relatively low (<1.5% per year).

Enfortumab Vedotin Following Platinum Chemotherapy and Avelumab Maintenance in Patients with Metastatic Urothelial Carcinoma: A Retrospective Data from the ARON-2EV Study.

Enfortumab vedotin (EV) has been approved for the treatment of patients with locally advanced/metastatic urothelial carcinoma (la/mUC) who previously received platinum-based chemotherapy followed by immune checkpoint inhibitors. However, the pivotal clinical trials did not include patients previously treated with avelumab maintenance therapy. The aim of the present retrospective analysis was to assess the effectiveness of EV following avelumab in patients with mUC enrolled in the ARON-2EV study. The study included 182 patients with mUC treated with EV following avelumab maintenance. The primary objective was to assess clinical outcomes, including progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and duration of response (DoR). Statistical analysis involved Fisher exact test, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. Median OS and PFS were 12.7 (95% CI 10.2-14.1) and 7.9 (95% CI 6.4-9.9) months, respectively. Complete response (CR) was achieved in 5% and partial response (PR) in 34% of patients, with an ORR of 39%. The DoR in patients who achieved CR/PR was 10.9 months (95% CI 8.1-11.4). The incidence of grade ≥ 3 peripheral neuropathy and skin rash was 9%, followed by 8% of grade ≥ 3 diarrhea and 4% of grade ≥ 3 hyperglycemia. The results of our large international retrospective study confirm the effectiveness of EV and endorse its use in the population of patients with mUC treated with EV following the frontline platinum-based chemotherapy and subsequent maintenance treatment with avelumab.

TNF-α inhibitors for type 1 diabetes: exploring the path to a pivotal clinical trial.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreas. This destruction leads to chronic hyperglycemia, necessitating lifelong insulin therapy to manage blood glucose levels. Typically diagnosed in children and young adults, T1D can, however, occur at any age. Ongoing research aims to uncover the precise mechanisms underlying T1D and to develop potential interventions. These include efforts to modulate the immune system, regenerate β-cells, and create advanced insulin delivery systems. Emerging therapies, such as closed-loop insulin pumps, stem cell-derived β-cell replacement and disease-modifying therapies (DMTs), offer hope for improving the quality of life for individuals with T1D and potentially moving towards a cure. Currently, there are no disease-modifying therapies approved for stage 3 T1D. Preserving β-cell function in stage 3 T1D is associated with better clinical outcomes, including lower HbA1c and decreased risk of hypoglycemia, neuropathy, and retinopathy. Tumor Necrosis Factor alpha (TNF-α) inhibitors have demonstrated efficacy at preserving β-cell function by measurement of C-peptide in two clinical trials in people with stage 3 T1D. However, TNF-α inhibitors have yet to be evaluated in a pivotal trial for T1D. To address the promising clinical findings of TNF-α inhibitors in T1D, Breakthrough T1D convened a panel of key opinion leaders (KOLs) in the field. The workshop aimed to outline an optimal clinical path for moving TNF-α inhibitors to a pivotal clinical trial in T1D. Here, we summarize the evidence for the beneficial use of TNF-α inhibitors in T1D and considerations for strategies collectively identified to advance TNF-α inhibitors beyond phase 2 clinical studies for stage 3 T1D.

The Role of CAR T-Cell Therapy in Relapsed/Refractory Adult B-ALL.

CAR T-cell therapy is a recent therapeutic advancement that has transformed the management of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). To date, there are 2 FDA-approved CAR-T products for R/R B-ALL: tisagenlecleucel in patients aged <26 years and brexucabtagene autoleucel in those aged ≥18 years. This review summarizes the pivotal clinical trials that led to FDA approval of these 2 products and highlight emerging data addressing key questions pertinent to CAR-T utilization in the rapidly evolving landscape of R/R ALL management. These include optimal sequencing of CAR-T among other novel immunotherapeutic agents, the role of consolidation and maintenance following CAR-T, novel CAR-T constructs currently under clinical development, and strategies to optimize use of commercially available CAR-T products to improve patient outcomes.

Insights from Clinical Trials: Evidence-Based Recommendations for Induction Treatment of Newly Diagnosed Transplant-Eligible Multiple Myeloma.

Multiple myeloma (MM) is a hematological malignancy and poses significant therapeutic challenges. This review synthesizes evidence from pivotal clinical trials to guide induction treatment for transplant-eligible (TE), newly diagnosed MM (NDMM) patients. Emphasizing the evolution from three-drug to four-drug induction therapies, we highlight the integration of monoclonal antibodies, particularly CD38 recombinant monoclonal antibody agents, into treatment regimens. This analysis includes a comprehensive literature review of research from major databases and conferences conducted between 2010 and 2023, culminating in the detailed evaluation of 47 studies. The findings underscore the superiority of quadruple regimens in TE NDMM, notably those incorporating daratumumab, in achieving superior responses including progression-free survival (PFS), minimal residual disease (MRD) negativity, objective response rate (ORR), and overall survival (OS) when compared to triple-drug regimens. As treatment regimens evolve with additional agents, the improved outcomes with treatment-related adverse events should be carefully balanced. This review advocates for a paradigm shift towards quadruple induction therapies for TE NDMM, offers a detailed insight into the current landscape of MM treatment, and reinforces a new standard of care.

The Evolution of Carotid Surgery

This review traces the evolution of carotid surgery from its ancient roots to modern practice. The first significant appreciation of the carotid arteries’ role in cerebral ischemia was made by Johann Jakob Wepfer in his 1658 book on apoplexy, which described the separate blood supply to each cerebral hemisphere by the carotid arteries. The 16th-19th centuries saw initial attempts at carotid ligation, while the 20th century marked significant advancements. The first carotid endarterectomy (CEA) by DeBakey, Cooley, and Eastcott in the 1950s paved the way for a new technique in carotid surgery and many subsequent refinements in surgical techniques related to CEA. The latter half of the 20th century brought innovations such as patch angioplasty, microsurgical techniques, and intraoperative shunting, significantly improving outcomes. Pivotal clinical trials established CEA as the standard treatment for symptomatic carotid stenosis. The emergence of carotid artery stenting (CAS) in the 1980s introduced a less invasive alternative, sparking ongoing debates about optimal treatment strategies. Recent developments include transcarotid artery revascularization (TCAR) and transfemoral CAS, with studies comparing their efficacy to traditional CEA. Current research focuses on plaque morphology and novel diagnostic factors to further personalize treatment strategies for carotid artery stenosis.

Fulvestrant en la práctica clínica: análisis de efectividad en pacientes uruguayas con cáncer de mama HR+/HER2.

Fulvestrant demonstrated benefits in overall survival and progression-free survival in patients with advanced breast cancer, who are hormone receptor-positive and human epidermal growth factor receptor 2 negative. The characteristics, evolution, and survival of patients with hormone receptor-positive, HER2-negative breast cancer treated with fulvestrant were evaluated according to the national treatment coverage protocols of the National Resources Fund, with the aim of understanding the efficacy of fulvestrant in patients treated in usual clinical practice and comparing our results with those from pivotal studies. A database from the National Resources Fund covering the period from 2009 to 2022 was used. Survival curves were assessed using the Kaplan-Meier method, and differences were analyzed using the Log-Rank test. A total of 1085 patients with an average age of 63,66 years were included. Following a follow-up of 14 months, the median overall survival was 16 months, and the median progression-free survival was 6 months. The presence of liver and bone metastases was associated with a shorter overall survival. Patients from the public sector and those with a better performance status experienced longer overall survival. Our findings provide a valuable perspective for treatment management in a context of limited resources. Overall survival and progression-free survival were somewhat lower than those reported in pivotal clinical trials. The presence of liver and bone metastases was associated with worse prognosis and survival; additionally, patients with worse performance status had shorter overall survival. These findings underscore the need for personalized therapies, opening new lines of future research.

Comparison of Product Features and Clinical Trial Designs for the DTx Products with the Indication of Insomnia Authorized by Regulatory Authorities

BackgroundDigital therapeutics (DTx) have attracted attention as the substitutes or add-ons to conventional pharmacotherapy and the number of DTx products authorized with the regulatory reviews of the clinical evidence is increasing. Insomnia is one of the major targets of the DTx due to the benefit from cognitive behavioral interventions and several products have been launched in the market with regulatory reviews. However, common features of the products and the clinical evidence required by each regulatory agency have not been investigated.MethodsIn this study, we identified the DTx products with the primary indication of insomnia authorized with regulatory reviews of clinical evidence by literature and website searches, and investigated the common features of the products and of the study designs for the pivotal clinical trials.ResultsThe total of 6 DTx products were identified. The components of cognitive behavioral therapy for insomnia (CBT-I) were identified as common features of the products. All the pivotal clinical trials were randomized, parallel-group, blind studies against insomnia patients. No products have been authorized in multiple countries regardless of the similarity of the features of the products and of the study designs for the pivotal clinical trials.ConclusionsOur study revealed that the components of CBT-I and gold standard design in pivotal clinical trials were adopted in all the DTx products for insomnia authorized with reviews of clinical evidence. At the same time, our findings suggest the needs of internationally harmonized regulatory review and authorization system to facilitate the early patient access to the promising DTx products.

Psychosocial outcomes with the Omnipod® 5 Automated Insulin Delivery System in caregivers of very young children with type 1 diabetes.

Automated insulin delivery (AID) systems have demonstrated improved glycaemic outcomes in people with type 1 diabetes (T1D), yet limited data exist on these systems in very young children and their impact on caregivers. We evaluated psychosocial outcomes following use of the tubeless Omnipod® 5 AID System in caregivers of very young children. This 3-month single-arm, multicentre, pivotal clinical trial enrolled 80 children aged 2.0-5.9 years with T1D to use the Omnipod 5 AID System. Caregivers completed questionnaires assessing psychosocial outcomes-diabetes distress (Problem Areas in Diabetes), hypoglycaemia confidence (Hypoglycemia Confidence Scale), well-being (World Health Organization 5 Well-Being Index), sleep quality (Pittsburgh Sleep Quality Index), insulin delivery satisfaction (Insulin Delivery Satisfaction Survey) and system usability (System Usability Scale) at baseline with standard therapy and after 3 months of AID use. Following 3 months of Omnipod 5 use, caregivers experienced significant improvements across all measures, including diabetes-related psychosocial outcomes (Problem Areas in Diabetes; p < 0.0001, Hypoglycemia Confidence Scale; p < 0.01), well-being (World Health Organization 5 Well-Being Index; p < 0.0001) and perceived system usability (System Usability Scale; p < 0.0001). Significant improvements were seen in the Pittsburgh Sleep Quality Index total score and the overall sleep quality, sleep duration and efficiency subscales (all p < 0.05). Insulin Delivery Satisfaction Survey scores improved on all subscales (greater satisfaction, reduced burden and reduced inconvenience; all p < 0.0001). Caregivers face unique challenges when managing T1D in very young children. While glycaemic metrics have unquestioned importance, these results evaluating psychosocial outcomes reveal additional meaningful benefits and suggest that the Omnipod 5 AID System alleviates some of the burdens caregivers face with diabetes management.