Clinical Trial Data Research Articles

Faricimab versus bevacizumab for neovascular age-related macular degeneration: Cost analysis based on real-world data from the Swedish Macula Registry.

To analyse the impact on cost if faricimab is used as the first-line treatment for neovascular age-related macular degeneration (nAMD) compared to standard treatment with bevacizumab. Retrospective registry study including real-world data from the Swedish Macula Registry between 2017 and 2022. The observed number of injections and visits for bevacizumab during the first two years of treatment was used (n = 437 patients). Number of faricimab injections was obtained from published clinical trial data and unit costs mostly from publicly available Swedish sources. The provider cost included medication and visit cost and societal cost included additionally patient travel cost. Costs are presented in 2023 EUR. The incremental societal cost of faricimab was 277 EUR per patient compared to bevacizumab in the base case. Medication cost was higher (1516 EUR) while visit cost (-1183 EUR) and patient travel cost (-56 EUR) were lower due to longer injection intervals. Faricimab was of similar cost as bevacizumab for patients residing far from the clinic. The faricimab injection interval and the number of bevacizumab injections were major drivers of uncertainty in the results. Faricimab represents a cost-effective alternative to bevacizumab for patients with nAMD in Sweden. Its extended treatment interval is particularly beneficial for patients living far from clinics, and if the real-life faricimab injection interval extends beyond 12 weeks. Our findings emphasize faricimab's potential to free up healthcare staff to treat a larger patient population with existing clinic resources.

Advances in systemic treatment for recurrent metastatic cervical cancer.

Cervical cancer remains a leading cause of cancer-related mortality among women worldwide, particularly in underdeveloped nations. Despite advances in standard therapies, patients with recurrent metastatic cervical cancer face a poor prognosis and limited treatment options. This study aims to evaluate the efficacy and safety of emerging therapeutic approaches in managing this challenging condition, including immunotherapy, targeted medicines, and chemotherapy. Our review of recent literature and clinical trials highlights the significant progress made in the systematic treatment of metastatic cervical cancer. While each treatment modality has its strengths and limitations, the collective data suggest a trend towards improved patient outcomes with the adoption of these novel therapies. However, the heterogeneity of patient responses underscores the need for personalised treatment strategies. In conclusion, improvements in medical technology and the adoption of tailored treatment approaches have led to promising advancements in the management of recurrent metastatic cervical cancer. To further enhance patient care, there is an urgent need for more extensive clinical trial data and the development of more efficient personalised treatment plans. This study aims to contribute to this effort by comprehensively analysing current therapeutic strategies and identifying areas for future research.

Stroke-heart syndrome and early mortality in patients with acute ischaemic stroke using hierarchical cluster analysis: An individual patient data pooled analysis from the VISTA database.

The patient clinical phenotypes at particularly high risk for early cardiac complications after a recent acute ischaemic stroke (AIS), that is, stroke-heart syndrome (SHS), remain poorly defined. We utilised hierarchical cluster analysis to identify specific phenotypic profiles associated with this risk. We gathered data on patients with AIS from the Virtual International Stroke Trials Archive, a global repository of clinical trial data. We examined cardiac complications within 30 days post-stroke, including acute coronary syndrome, heart failure, arrhythmias and cardiorespiratory arrest. We employed hierarchical cluster analysis to define distinct phenotypic risk profiles. The incidence/risk of SHS and 90-day mortality were compared across these profiles. We included 12,482 patients (mean age 69 ± 12 years; 55% male), yielding five phenotypes: Profile 1 ('elderly and AF'), Profile 2 ('young and smoker'), Profile 3 ('young'), Profile 4 ('cardiac comorbidities') and Profile 5 ('hypertension with atherosclerotic comorbidities'). Profiles 4 and 1 exhibited the highest risk for SHS (adjusted HR (95% CI): 2.01 (1.70-2.38) and 1.26 (1.05-1.51), respectively, compared to Profile 3), while Profiles 5 and 2 showed moderate risk and Profile 3 had the lowest risk. Although Profiles 1 and 4 were at the highest risk for most SHS presentations, Profile 5 had the highest risk for cardiorespiratory arrest (adjusted HR (95% CI): 2.99 (1.22-7.34)). The 90-day mortality risk was stratified by phenotype, with the highest risk observed in Profiles 5, and 4. Hierarchical cluster analysis effectively identified phenotypes with the highest risk of SHS and early mortality in patients with AIS.

Etiology, Recent Advances, and Clinical Trials Data for the Treatment of Angioedema: A Review.

Angioedema is a health issue that affects parts of the body like the upper pulmonary and gastric pathways and is identified by abrupt, nonpitting enlargement of the skin, mucous membranes, or both. The swelling usually lasts a few hours to 72 hours and may appear as non-puritic, subcutaneous, or submucosal organ edema. It is characterized by localized swelling brought on by the release of histamine. Itching is rare, and usual areas of appearance include the hands, feet, face, and genitalia, with periorbital swelling being the most often. The main objective of this review article is to study in brief the classifications, etiology, pathophysiology, and clinical trial data by describing the recent advancement in the treatment of angioedema. Various research articles obtained from different journals indexed under Scopus and SCI were used to prepare the review article and for illustrative work software such as Biorender and Microsoft Word was used. Histamine-- mediated angioedema, linked to allergic reactions, coexists with urticaria. Bradykinin-mediated angioedema, exemplified by hereditary angioedema and acquired forms, lacks urticaria. Idiopathic angioedema, with uncertain etiology. Imitated angioedema results from non-IgE-mediated reactions, often induced by medications. It is a complicated medical condition with a variety of causes and mechanisms. Over time, outcomes for patients have been greatly improved by a growing understanding of its etiology, pathophysiology, and available treatments. The field of medical treatment for this difficult problem is always changing, and this is partly due to clinical trials.

Real World Outcomes in Patients With Recurrent, Advanced, or Metastatic Endometrial Cancer Treated With Lenvatinib Plus Pembrolizumab

AimsPatients with endometrial cancer who progress following first line therapy have improved survival outcomes with pembrolizumab and lenvatinib (pem/len) compared with standard of care chemotherapy, as demonstrated in KEYNOTE-775. This was in a group of trial patients with good performance status and excluded those with carcinosarcoma histology. In KEYNOTE-775 pem/len was associated with significant toxicity, leading to dose reductions, treatment cessation, and patient morbidity. We set out to assess the tolerability, toxicity and outcomes following pem/len for patients with recurrent, advanced or metastatic endometrial cancer in a real-world setting. Materials and methodsUK centres treating patients with pem/len for advanced endometrial cancer within the compassionate access programme were approached. Retrospective data were analysed for those treated between May 2022 and June 2023. Data on patient demographics, treatment, toxicity and outcomes were extracted from medical records. Toxicity and tolerability were compared in those over and under the age of 70. ResultsSeven centres returned data for 70 patients. Median age of patients was 68.5 years (range 45–85) with a performance status of 0–1 in 77.1% and of 2 in 22.9%. Histological subtypes included serous (34.3%), endometrioid (32.9%), carcinosarcoma (14.3%), clear cell (7.1%), mixed (2.9%) and other (8.6%). Grade ≥3 toxicity was reported in 55.7% with any-grade toxicity observed in 85.7%. In those aged ≥70 years (n = 30) the rate of grade ≥3 toxicity was 60.0%. Rates of dose reduction of lenvatinib were 64.3%, and toxicity-related treatment interruption was 45.7%. The 6-month progression-free and overall survival rates were 54.0% (95%CI: 39.0–66.8) and 70.1% (95%CI:56.5–80.1) respectively. ConclusionThis real-world, observational study of pem/len showed comparable tolerability, toxicity, and outcomes to previously reported clinical trial data. Our cohort included patients with a poorer PS and a broader range of histological subtypes including carcinosarcoma.

MMFP-Tableau: enabling precision mitochondrial medicine through integration, visualization, and analytics of clinical and research health system electronic data.

To describe a novel data integration workflow developed to automate clinical and research electronic health system data integration and harmonization from siloed sources for centralized access, visualization and analysis by clinicians and researchers in an end user-friendly customized analytic platform. A centralized, semi-automated framework provides data provenance and user access to integrated data sources. Data models are implemented leveraging a centralized server (Alteryx) for high-level analytics including scheduling, integration, and modeling. Data are then sent to a secure Tableau instance for end-user visualization and interaction, with minimal software development required. MMFP-Tableau, named for its origin in the Mitochondrial Medicine Frontier Program (MMFP) at the Children's Hospital of Philadelphia (CHOP), has advanced efforts to realize precision medicine by facilitating expert clinician and researcher end-user direct access to integrated, highly robust health system datasets. This scalable data solution enables translational researchers to link subject and cohort clinical and research parameters with research samples; enhances external biopharma collaborations for clinical trial design, subject recruitment, and data tracking; accelerates retrospective clinical cohort data analysis; and improves complex data visualization for clinicians and researchers. MMFP-Tableau promotes complex data integration, visibility, and advanced analytic capabilities to facilitate seamless multidisciplinary research, benefitting clinical care and research in rare disease patients and cohorts. The MMFP-Tableau data platform integrates multiple data sources across various siloed data platforms to transform complex data into readily accessible datasets. This approach represents a generalizable workflow concept readily adaptable to implement across diverse fields of medicine.

Changes in the Treatment and Prevention of Heart Failure Based on the 2023 Focused Update of the 2021 European Society of Cardiology Guidelines

Introduction and Objective:The 2023 update to the 2021 ESC Guidelines for diagnosing and treating acute and chronic heart failure introduces significant changes in pharmacotherapy and prevention. Staying informed about these updates is crucial given the evolving landscape of heart failure management. This review provides an overview of the latest recommendations and supporting evidence. Review Methods:A comprehensive review of scientific publications and guidelines from PubMed, Google Scholar, Clinical Key, Via Medica Journals, and relevant clinical guidelines was conducted to ensure the most recent evidence is considered. Brief Description of the State of Knowledge:Heart failure is a growing global concern. The 2023 update highlights key management changes. Recent trials, including EMPEROR-Preserved and DELIVER, show empagliflozin and dapagliflozin reduce heart failure hospitalization and cardiovascular death in patients with mildly reduced and preserved ejection fraction. The guidelines now recommend intravenous iron for patients with reduced or mildly reduced ejection fraction and iron deficiency. For those with type 2 diabetes and chronic kidney disease, SGLT2 inhibitors and finerenone, a non-steroidal mineralocorticoid antagonist, are recommended to reduce heart failure hospitalization and prevent renal function decline. Summary:The 2023 ESC Guidelines update offers revised recommendations for heart failure management and prevention, integrating the latest clinical trial data and meta-analyses. Key areas include the use of SGLT2 inhibitors, iron deficiency management, and preventive strategies for high-risk populations. Implementing these guidelines can significantly improve preventive and therapeutic outcomes for heart failure patients.

Streamlining Clinical Trial Data from Raw to Regulatory Submission with R Shiny and Pharmaverse

In recent years, the pharmaceutical and biotech industries have increasingly adopted open-source tools to enhance the efficiency, transparency, and reproducibility of clinical trial data analysis. R Shiny, a web application framework for R, has become a key component in creating interactive dashboards and visualizations that support real-time data exploration and decision-making. As part of the Pharmaverse ecosystem, R Shiny plays a vital role in regulatory submissions, data analysis, and reporting, offering dynamic, user-friendly interfaces for clinical trial monitoring, patient safety reporting, and efficacy analysis. This abstract explores the application of R Shiny within the Pharmaverse, emphasizing its seamless integration with tools such as Tplyr and admiral for generating CDISC-compliant SDTM and ADaM datasets. Metadata management and validation are facilitated through OAK, ensuring consistency and traceability. The automated creation of Define.xml using tools like defineR further enhances transparency and regulatory compliance. Through case studies and practical examples, this abstract highlights how R Shiny and related tools improve data transparency, accelerate decision-making, and support regulatory compliance in clinical trials. By leveraging these open-source technologies, clinical trial teams can streamline data workflows, enhance collaboration, and improve outcomes, ultimately driving innovation within the pharmaceutical industry. The integration of these tools into a cohesive framework significantly enhances the submission process to regulatory bodies like the FDA and EMA, ensuring that clinical data meets both industry and regulatory standards.

Improvement in coping skills from culturally-adapted digital CBT for Spanish-speaking Hispanics with substance use disorder: Secondary analysis of a randomized clinical trial

IntroductionDeveloping adaptive coping skills for avoiding substance use is a proposed treatment mechanism of cognitive behavioral therapy (CBT) for substance use disorder (SUD). However, the generalizability of research on treatment mechanisms of CBT for SUD is limited by the underrepresentation of racial/ethnic minorities in clinical trials. In a secondary analysis of clinical trial data, we tested whether a culturally-adapted digital CBT program for Hispanics (“Spanish CBT4CBT”) improved the quality of coping skills for avoiding substance use. We also tested whether coping skills' quality was associated with reductions in primary substance use. MethodsParticipants were Spanish-speaking Hispanic adults seeking outpatient treatment for SUD (n = 85; 68 % male; primary substance type: 36 % cannabis, 33 % alcohol, 26 % cocaine, 5 % other). They were randomized to 8 weeks of outpatient treatment as usual (TAU) or TAU + Spanish CBT4CBT and assessed for 6 months after treatment. The study conducted separate analyses for the full sample (n = 85) and for those who engaged in at least 5 treatment sessions (“treatment exposed”; n = 64). Daily substance use and coping skills' quality were assessed repeatedly during the treatment and follow-up periods. Bayesian mixed models for repeated measures tested hypotheses. ResultsAmong treatment-exposed participants, those receiving TAU + Spanish CBT4CBT improved the quality of coping skills more than TAU alone during the treatment period (b = 0.77; 95 % CI[0.08, 1.47]), but this difference was not detected during the follow-up period. In the full sample and treatment exposed subsample, participants with higher quality coping skills during the study reported less primary substance use (b = −0.67; 95 % CI[−1.08, −0.26]). Among treatment-exposed participants only, within-person increases in the quality of coping skills were associated with reductions in future primary substance use (b = −0.18; 95 % CI[−0.36, −0.01]). ConclusionsSpanish-speaking Hispanics with SUD may improve the quality of their coping skills more when they are sufficiently exposed to a culturally-adapted digital CBT program during outpatient treatment. Coping skills' quality may be a mechanism of CBT for SUD among Hispanic populations. Spanish-speaking Hispanics' access to treatments that target mechanisms of behavior change may be expanded by digital therapeutics.

6814 Durability of Teprotumumab for the Treatment of Thyroid Eye Disease (TED) in Clinical Trials

Abstract Disclosure: G.J. Kahaly: Consulting Fee; Self; Amgen Inc. Research Investigator; Self; Amgen Inc. P.S. Subramanian: Consulting Fee; Self; Amgen Inc. Research Investigator; Self; Amgen Inc. E. Conrad: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. R.J. Holt: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. T.J. Smith: Consulting Fee; Self; Amgen Inc, Viridian, Minghui, Lassen, Lundbeck. Other; Self; US patents covering the use of IGF-1 receptor inhibitors in TED which are held by UCLA and the Lundquist Institute. Introduction: Teprotumumab has demonstrated efficacy for the treatment of thyroid eye disease (TED). To assess durability of responses to teprotumumab over the longer term, pooled clinical trial data were assessed beyond the 24-week treatment period for patients in phase 2, OPTIC, and OPTIC-X studies who received a full course of teprotumumab. Methods: Observed rates for clinical activity score (CAS, ≥2 point improvement), EUGOGO-recommended composite response, diplopia (≥1 Gorman grade improvement), proptosis (≥2 mm improvement), and Overall responder status (≥2 mm improvement proptosis and ≥2 point improvement CAS) were assessed and pooled from study baseline to Week 24 (formal study) and up to Week 72 (51 weeks post-final teprotumumab infusion). Graves’ ophthalmopathy quality-of-life (GO-QOL) scores were also examined. Additional therapies for TED administered up to Week 120 (i.e., 99 weeks post-therapy) were assessed for evidence of persistent benefit from Week 24 through Week 120. Studies differed in the timing of follow-up visits. Data were not available at every time point for all patients. Results: Response rates among patients receiving a full (8-infusion) course of teprotumumab (N=112) were largely maintained 51 weeks after the final teprotumumab infusion at study Week 72: CAS 52/57 (91.2%); composite 51/57 (89.5%); diplopia 35/48 (72.9%); proptosis 38/56 (67.9%); and Overall 37/56 (66.1%). The mean reduction in proptosis was 2.68 (SD 1.92) mm (N=56), mean GO-QOL reduction was 15.22 (SE 2.82, N=56), and disease inactivation (CAS ≤1) was detected in 40/57 (70.2%). Post-teprotumumab treatment, 17.9% (19/106) of reporting patients received additional TED treatment (systemic steroids or teprotumumab) and/or remedial periocular surgery as of 99 weeks after the last dose (to study Week 120). Conclusions: At Week 72, nearly one-year posttherapy, responses to teprotumumab were similar to those at Week 24 formal study end. Both CAS and ophthalmic composite responses were observed in 90% of observed patients. Diplopia and proptosis responses were seen in almost 70%. Additionally, 82% of patients did not require additional treatment for TED nearly two years after therapy completion. Public Presentation: 6/2/2024

Biopharmaceutical pipeline funded by venture capital firms, 2014 to 2024.

Venture capital (VC) firms fund biopharmaceutical research and development (R&D) while incurring substantial financial risk. VC firms seek to invest in clinical areas with the greatest potential for financial return. Using a combination of data for clinical trials and VC investment deals between January 2014 and March 2024, we found that approximately 75% of VC investments were allocated to clinical trials studying small-molecule drugs compared to biologics or gene therapies, without substantial changes over the study period. Most of VC firms' investment in biopharmaceutical R&D was concentrated in phase 1 and phase 2 clinical trials. This trend has increased in recent years, with phase 1 trials accounting for nearly half of total deals and capital investments in 2023. VC investments were concentrated in several therapeutic areas, including cancer.

Pharmacoeconomic Analysis of the Use of C1-inhibitor in Treatment of Hereditary Angioedema: Clinical Trial Data in Belarus

Pharmacoeconomic Analysis of the Use of C1-inhibitor in Treatment of Hereditary Angioedema: Clinical Trial Data in Belarus

Neoadjuvant Pembrolizumab Plus Chemotherapy in Early-Stage Triple-Negative Breast Cancer: A Nationwide Retrospective Turkish Oncology Group Study

Background/Objectives: Following the results of the phase 3 KEYNOTE-522 trial, the U.S. Food and Drug Administration approved pembrolizumab, a humanized IgG4 kappa monoclonal antibody, in combination with neoadjuvant chemotherapy as a new standard of care for high-risk early-stage triple-negative breast cancer (TNBC). This retrospective, multicenter study in Türkiye assessed the real-world efficacy and safety of neoadjuvant pembrolizumab combined with chemotherapy in early-stage TNBC. Methods: The study included 108 patients treated between 2021 and 2023 across 14 oncology centers. Three distinct neoadjuvant regimens incorporating pembrolizumab were administered at the discretion of the treating physicians. The primary outcomes were the pathological complete response (pCR) rate after neoadjuvant therapy and the 2-year event-free survival (EFS) and overall survival (OS) rates. Results: The observed pCR rate was 63.9%, closely mirroring the 64.8% reported in the KEYNOTE-522 trial. At the two-year mark, the EFS rate was 87.2% and the OS rate was 92.3%. Multivariable analysis identified pCR as the sole independent predictor of both EFS and OS. The safety profile was consistent with previous clinical trial data, with most adverse events being of grade 1–2 in severity. Conclusions: These findings provide valuable real-world confirmation of the efficacy and safety of neoadjuvant pembrolizumab–chemotherapy in early-stage TNBC, complementing evidence from randomized trials.

New Drug Development Strategy in Japan: Flexibility in Guideline Adherence.

Recently, a new type of drug lag, known as "drug loss" has emerged in Japan. It is a condition where the development of a drug approved in other countries has not been initiated in Japan. For 265 new drugs approved in the United States or Europe during 2010-2020, only 31% had commenced development in Japan as of December 31, 2020. A characteristic feature of Japanese guidelines on new drug development is that, in principle, clinical trial data in Japanese participants are required in each study phase. Given key players in new drug development are shifting from large pharmaceutical companies to emerging biopharma companies, primarily based outside Japan, the necessity for Japanese data may contribute to the drug lag. This study aimed to clarify the guideline adherence to new drug applications in Japan. Of the 159 new drugs approved in Japan between April 2019 and March 2024, the clinical data packages for almost all drugs included both pharmacokinetic (PK) data and efficacy and safety data in Japanese participants, irrespective of the study phase or design. We identified three flexible development approaches: the absence of Japanese dose-response data (39.6%), absence of Japanese confirmatory data generated from phase III randomized controlled trials (35.2%), and post-hoc Japanese PK data (43.0%, 34/79). Biologics, orphan drug designation, antineoplastic agents, and same applicant and originator were identified as factors significantly associated with these flexibilities. The results will help foreign companies, including emerging biopharmas, in formulating effective new drug development strategies, potentially alleviating the drug lag in Japan.

Incidence and Outcomes of Patients With Early Cardiac Complications After Intracerebral Hemorrhage: A Report From VISTA.

The incidence and outcomes of early cardiac complications in patients with intracerebral hemorrhage (ICH) are poorly understood. These cardiac complications may be part of the so-called stroke-heart syndrome in patients with ICH. We investigated this issue in an individual patient data pooled analysis from an international repository of clinical trial data. We used the Virtual International Stroke Trials Archive to investigate the incidence of cardiac complications within 30 days post-ICH or acute ischemic stroke (AIS). These complications included acute coronary syndrome encompassing myocardial injury, heart failure/left ventricular dysfunction, atrial fibrillation/atrial flutter, other arrhythmia/ECG abnormalities, and cardiorespiratory arrest. We used propensity score matching to compare the incidence of patients with stroke-heart syndrome in patients with ICH with those following AIS. Factors associated with 90-day mortality were evaluated using multivariate logistic regression analysis in the ICH cohort. We pooled data from 8698 participants recruited in acute stroke trials (mean age, 68±12 years; 56% male), of whom 914 (11%) were patients with ICH. Among the patients with ICH, 123 (13%) had stroke-heart syndrome in patients with ICH. Following propensity score matching, a total of 1828 patients (914 for each of the cohorts) were analyzed. While the overall incidence of cardiac events tended to be lower in the ICH group compared with the AIS group (the cumulative incidence freedom from the event, 86.3% [95% CI, 84.1-88.6] versus 83.6% [95% CI, 81.2-86.0]; P=0.100), the incidences cardiac events other than atrial fibrillation/atrial flutter were comparable between the 2 matched groups. The incidence of atrial fibrillation/atrial flutter was significantly lower in the ICH group than in the AIS group (P<0.001). The multivariate-adjusted analysis found that stroke-heart syndrome in patients with ICH was associated with 90-day mortality (adjusted odds ratio, 1.12 [95% CI, 1.06-1.19]; P<0.001). Cardiac events are common and negatively affect prognosis in patients with ICH, just as seen in AIS.

Knowledge-guided Deep Temporal Clustering for Alzheimer's Disease Subtypes in Completed Clinical Trials.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder with varied patient progression. We aim to test the hypothesis that AD patients can be categorized into subgroups based on differences in progression. We leveraged data from three randomized clinical trials (RCTs) to develop a knowledge-guided, deep temporal clustering (KG-DTC) framework for AD subtyping. This model combined autoencoders for contextual information capture, k-means clustering for representation formation, and clinical outcome classification for clinical knowledge integration. The derived representations, encompassing demographics, APOE genotype, cognitive assessments, brain volumes, and biomarkers, were clustered using the Gaussian Mixture Model to identify AD subtypes. Our novel KG-DTC framework was developed using placebo data from 2,087 AD patients across three solanezumab clinical trials (EXPEDITION, EXPEDITION2, and EXPEDITION3), achieving high performance in outcome prediction and clustering. The KG-DTC model demonstrated superior clustering structures, especially when combined with k-means clustering loss. External validation with independent clinical trial data showed consistent clustering results, with a 0.33 silhouette score for three clusters. The model's stability was confirmed through a leave-one-out approach, with an average adjusted Rand Index around 0.945. Three distinct AD subtypes were identified, each exhibiting unique patterns of cognitive function, neurodegeneration, and amyloid beta levels. Notably, Subtype 3 (S3) showed rapid cognitive decline across multiple clinical measures (e.g., 0.64 in S1 vs. -1.06 in S2 vs. 15.09 in S3 of average ADAS total change score, p<.001). This innovative approach offers promising insights for understanding variability in treatment outcomes and personalizing AD treatment strategies.

Real-world safety and effectiveness of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

Multiple randomized controlled studies have shown that pirfenidone and nintedanib are effective and safe for treating idiopathic pulmonary fibrosis. This study aimed to evaluate their efficacy, safety, and tolerability in a real-world setting. We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases for real-world studies published up to March 3, 2023, on pirfenidone and nintedanib for idiopathic pulmonary fibrosis. A total of 74 studies with 23,119 participants were included. After 12months of treatment, the change from baseline in percent predicted FVC (%FVC) was - 0.75% for pirfenidone and - 1.43% for nintedanib. The change from baseline in percent predicted DLCO (%DCLO) was - 2.32% for pirfenidone and - 3.95% for nintedanib. The incidence of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) was 12.5% for pirfenidone and 14.4% for nintedanib. The IPF-related mortality rates of pirfenidone and nintedanib were 13.4% and 7.2%, respectively. The all-cause mortality was 20.1% for pirfenidone and 16.6% for nintedanib. In the pirfenidone group, 16.6% of patients discontinued treatment because of adverse events, and in the nintedanib group, 16.2% of patients discontinued treatment because of adverse events. The incidence of adverse events was 56.4% and 69.7% for pirfenidone and nintedanib, respectively. The results of this study indicate that pirfenidone and nintedanib are both effective in slowing down the decline of lung function in IPF patients in real-world settings. The incidence of adverse events with pirfenidone is lower than that with nintedanib, but both are below the clinical trial data, and no new major adverse events have been observed. The discontinuation rates due to adverse reactions of the two drugs are consistent with clinical trial data, indicating good tolerability. However, the mortality rates and AE-IPF incidence rates of these two drugs in real-world settings are higher than those in previous clinical trials, with pirfenidone patients showing a higher mortality rate. Further large-sample studies are needed to investigate the risks of these drugs in these aspects. Additionally, we recommend that future real-world studies pay more attention to patients' subjective symptoms and conduct stratified analyses of the efficacy and safety of pirfenidone and nintedanib based on factors such as patients' baseline lung function, comorbidities, and age, in order to provide more personalized medication advice for IPF patients in clinical practice.

Clinical Trial Data Review of the Combination FTD/TPI + Bevacizumab in the Treatment Landscape of Unresectable Metastatic Colorectal Cancer.

Recommended first and second line treatments for unresectable metastatic colorectal cancer (mCRC) include fluorouracil-based chemotherapy, anti-vascular endothelial growth factor (VEGF)-based therapy, and anti-epidermal growth factor receptor-targeted therapies. In third line, the SUNLIGHT trial showed that trifluridine/tipiracil + bevacizumab (FTD/TPI + BEV) provided significant survival benefits and as such is now a recommended third line regimen in patients with refractory mCRC, irrespective of RAS mutational status and previous anti-VEGF treatment. Some patients are not candidates for intensive combination chemotherapy as first-line therapy due to age, low tumor burden, performance status and/or comorbidities. Capecitabine (CAP) + BEV is recommended in these patients. In the SOLSTICE trial, FTD/TPI + BEV as a first line regimen in patients not eligible for intensive therapy was not superior to CAP + BEV in terms of progression-free survival (PFS). However, in SOLSTICE, FTD/TPI + BEV resulted in similar PFS, overall survival, and maintenance of quality of life as CAP + BEV, with a different safety profile. FTD/TPI + BEV offers a possible first line alternative in patients for whom CAP + BEV is an unsuitable treatment. This narrative review explores and summarizes the clinical trial data on FTD/TPI + BEV.

Progression to type 1 diabetes in the DPT-1 and TN07 clinical trials is critically associated with specific residues in HLA-DQA1-B1 heterodimers.

The aim of this work was to explore molecular amino acids (AAs) and related structures of HLA-DQA1-DQB1 that underlie its contribution to the progression from stages 1 or 2 to stage 3 type 1 diabetes. Using high-resolution DQA1 and DQB1 genotypes from 1216 participants in the Diabetes Prevention Trial-Type 1 and the Diabetes Prevention Trial, we applied hierarchically organised haplotype association analysis (HOH) to decipher which AAs contributed to the associations of DQ with disease and their structural properties. HOH relied on the Cox regression to quantify the association of DQ with time-to-onset of type 1 diabetes. By numerating all possible DQ heterodimers of α- and β-chains, we showed that the heterodimerisation increases genetic diversity at the cellular level from 43 empirically observed haplotypes to 186 possible heterodimers. Heterodimerisation turned several neutral haplotypes (DQ2.2, DQ2.3 and DQ4.4) to risk haplotypes (DQ2.2/2.3-DQ4.4 and DQ4.4-DQ2.2). HOH uncovered eight AAs on the α-chain (-16α, -13α, -6α, α22, α23, α44, α72, α157) and six AAs on the β-chain (-18β, β9, β13, β26, β57, β135) that contributed to the association of DQ with progression of type 1 diabetes. The specific AAs concerned the signal peptide (minus sign, possible linkage to expression levels), pockets 1, 4 and 9 in the antigen-binding groove of the α1β1 domain, and the putative homodimerisation of the αβ heterodimers. These results unveil the contribution made by DQ to type 1 diabetes progression at individual residues and related protein structures, shedding light on its immunological mechanisms and providing new leads for developing treatment strategies. Clinical trial data and biospecimen samples are available through the National Institute of Diabetes and Digestive and Kidney Diseases Central Repository portal ( https://repository.niddk.nih.gov/studies ).

Establishing Consensus for Mohs Micrographic Surgical Techniques in the Treatment of Melanoma in Situ for Future Clinical Trials: A Modified Delphi Study.

Mohs micrographic surgery (MMS) is a promising treatment modality for melanoma in situ (MIS). However, variations in surgical technique limit the generalizability of existing data and may impede future study of MMS in clinical trials. A modified Delphi method was selected to establish consensus on optimal MMS techniques for treating MIS in future clinical trials. The Delphi method was selected due to the limited current data, the wide range of techniques used in the field, and the intention to establish a standardized technique for future clinical trials. A literature review and interviews with experienced MMS surgeons were performed to identify dimensions of the MMS technique for MIS that (1) likely impacted costs or outcomes of the procedure, and (2) showed significant variability between surgeons. A total of 8 dimensions of technical variation were selected. The Delphi process consisted of 2 rounds of voting and commentary, during which 44 expert Mohs surgeons across the United States rated their agreement with specific recommendations using a Likert scale. Five of eight recommendations achieved consensus in Round 1. All 3 of the remaining recommendations achieved consensus in Round 2. Techniques achieving consensus in Round 1 included the use of a starting peripheral margin of ≤5 mm, application of immunohistochemistry, frozen tissue processing, and resecting to the depth of subcutaneous fat. Consensus on the use of Wood's lamp, dermatoscope, and negative tissue controls was established in Round 2. This study generated 8 consensus recommendations intended to offer guidance for Mohs surgeons treating MIS. The adoption of these recommendations will promote standardization to facilitate comparisons of aggregate data in multicenter clinical trials.