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{"title":"More than just another IDH inhibitor: Insights from the HMPL-306 phase 1 trial.","authors":"Ted M Getz, Jan Philipp Bewersdorf","doi":"10.1016/j.medj.2025.100600","DOIUrl":"10.1016/j.medj.2025.100600","url":null,"abstract":"<p><p>Resistance to isocitrate dehydrogenase (IDH) inhibitors poses a significant challenge in acute myeloid leukemia (AML), indicating a need for novel IDH inhibitors. Hu et al. report the results of a phase 1 study of the dual IDH1/2 inhibitor HMPL-306 in relapsed/refractory IDH-mutant AML.¹ The study highlights its manageable safety profile and robust preliminary efficacy, suggesting that it may be a valuable AML therapy.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 6","pages":"100600"},"PeriodicalIF":12.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical trials reimagined: Integrating community engagement and artificial intelligence.","authors":"Isla S Mackenzie, LaPrincess C Brewer, Alex Zhavoronkov","doi":"10.1016/j.medj.2025.100743","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100743","url":null,"abstract":"<p><p>In celebration of Clinical Trials Day, May 20, this collection of Voices highlights visionary perspectives on the evolving landscape of clinical research. It explores decentralized clinical trials, which bring research into participants' homes, enhancing diversity and convenience. It also emphasizes the imperative of community engagement to address health disparities and build trust. Finally, it showcases how generative AI promises to revolutionize drug discovery and clinical development through end-to-end automation and precision. Together, these insights underscore transformative shifts where innovation, inclusivity, and technology converge to accelerate the delivery of effective therapies for all.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 6","pages":"100743"},"PeriodicalIF":12.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WAYPOINT: Are we there yet for patients with nasal polyposis?","authors":"Jack L Birkenbeuel, Vinay K Rathi","doi":"10.1016/j.medj.2025.100701","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100701","url":null,"abstract":"<p><p>The WAYPOINT trial demonstrated that tezepelumab treatment for chronic sinusitis with nasal polyposis was associated with statistically significant and clinically meaningful reductions vs. placebo in both objective (nasal polyp score and rates of rescue steroids or surgery) and subjective (nasal congestion, loss of smell, and sinonasal outcomes test scores) measures of disease burden at 52 weeks.¹.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 6","pages":"100701"},"PeriodicalIF":12.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of low- versus high-dose-LSD-assisted therapy in patients with major depression: A randomized trial.","authors":"Felix Müller, Hannes Zaczek, Anna M Becker, Laura Ley, Stefan Borgwardt, Joyce Santos de Jesus, Nico Loh, Jan Kohut, Mathias Auernig, Christopher Boehlke, Matthias E Liechti","doi":"10.1016/j.medj.2025.100725","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100725","url":null,"abstract":"<p><strong>Background: </strong>This trial aimed to assess the efficacy of lysergic acid diethylamide (LSD)-assisted therapy in patients with moderate-to-severe major depressive disorder.</p><p><strong>Methods: </strong>This was a randomized, parallel, double-blind, low-dose controlled trial (Clinicaltrials.gov: NCT03866252). Patients were randomly assigned in a 1:1 ratio to receive supportive psychotherapy and either 100 μg + 200 μg LSD or 25 μg + 25 μg LSD in two dosing sessions. The primary endpoints were the changes in scores on the Inventory of Depressive Symptomatology, in the Clinician-Rated (IDS-C) version (assessed by the treating therapist) and the Self-Rated (IDS-SR) version, from baseline to 2 weeks after the second administration. The IDS scores were also assessed 6 and 12 weeks after the second administration.</p><p><strong>Findings: </strong>Thirty-one patients were randomized to the low-dose group, and 30 were randomized to the high-dose group. At the primary endpoint, least-squares mean change (LSM) in IDS-SR scores was -3.9 in the low-dose and -11.8 in the high-dose group (difference: -7.9; 95% CI, -16.0 to 0.3; effect size: -0.5; p = 0.059). LSM in IDS-C scores was -3.6 in the low-dose and -12.9 in the high-dose group (difference: -9.2; CI, -17.1 to -1.3; effect size: -0.6; p = 0.023; corrected <0.05). However, significance was not reached after adjusting for baseline depression scores (p = 0.086). Both outcomes remained numerically consistent up to the final follow-up at 12 weeks. Adverse events were comparable between groups.</p><p><strong>Conclusions: </strong>The findings of this exploratory study support further investigation of LSD-assisted therapy in depression in a larger phase 3 trial.</p><p><strong>Funding: </strong>Gertrud Thalmann Fund for depression research.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100725"},"PeriodicalIF":12.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of adjuvant TTFields plus pembrolizumab and temozolomide in newly diagnosed glioblastoma: A phase 2 study.","authors":"Dongjiang Chen, Son B Le, Ashley P Ghiaseddin, Harshit Manektalia, Ming Li, Adam O'Dell, Maryam Rahman, David D Tran","doi":"10.1016/j.medj.2025.100708","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100708","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) have shown limited success in glioblastoma due to the tumor's profoundly immunosuppressive microenvironment. Tumor treating fields (TTFields), a non-invasive electric field therapy, activate the type I interferon (T1IFN) pathway via DNA sensor-dependent inflammasomes, promoting in situ immunization against glioblastoma.</p><p><strong>Methods: </strong>In this phase 2 study (this study was registered at ClinicalTrials.gov: NCT03405792), 31 newly diagnosed glioblastoma patients were enrolled post-chemoradiation to evaluate synergy between TTFields, pembrolizumab, and temozolomide. The primary endpoint was progression-free survival (PFS) compared to case-matched controls treated with TTFields and temozolomide alone. Secondary endpoints included overall survival (OS), response rate, safety, and immune correlates assessed through single-cell transcriptomics and T cell clonotyping of blood and tumor samples.</p><p><strong>Findings: </strong>Among 26 patients treated per protocol, the median PFS was 12.0 vs. 5.8 months in controls (HR 0.377, 95% CI 0.217-0.653; p = 0.0026), and the median OS was 24.8 vs. 14.6 months (HR 0.522, 95% CI 0.301-0.905; p = 0.0477). Patients undergoing biopsy had longer PFS (27.2 vs. 9.6 months; HR 0.37, 95% CI 0.16-0.85; p = 0.014) and OS (31.6 vs. 18.8 months; HR 0.4, 95% CI 0.17-0.92; p = 0.023) compared to maximal resection. Severe adverse events constituted 7.5% of treatment-related toxicities. TTFields promoted clonal T cell expansion via a T1IFN-driven trajectory, while pembrolizumab supported adaptive replacement of these clones, sustaining T cell activation and memory formation, especially in biopsy-only patients.</p><p><strong>Conclusions: </strong>These findings demonstrate synergy between TTFields and ICIs, particularly in patients with high tumor burden, and support further study in larger trials.</p><p><strong>Funding: </strong>This work was supported by a grant from Novocure.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100708"},"PeriodicalIF":12.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal progression of blood biomarkers reveals a key role of reactive astrocytosis in preclinical Alzheimer's disease.","authors":"Vijay R Varma, Yang An, Przemek R Kac, Murat Bilgel, Abhay Moghekar, Tina Loeffler, David Amschl, Magdalena Daurer, Manuela Prokesch, Juan Troncoso, Kaj Blennow, Henrik Zetterberg, Nicholas J Ashton, Luigi Ferrucci, Susan M Resnick, Madhav Thambisetty","doi":"10.1016/j.medj.2025.100724","DOIUrl":"10.1016/j.medj.2025.100724","url":null,"abstract":"<p><strong>Background: </strong>Defining the progression of blood biomarkers in Alzheimer's disease (AD) is essential for targeting treatments in patients most likely to benefit from early intervention. We delineated the temporal ordering of blood biomarkers a decade prior to the onset of AD, explored associations with AD brain pathology, and examined the relationship between reactive astrocytosis in the brain and plasma in a transgenic mouse model.</p><p><strong>Methods: </strong>We analyzed plasma blood biomarkers using the Quanterix HD-X instrument in case-control and postmortem cohorts from the Baltimore Longitudinal Study on Aging (BLSA). We assessed plasma and cortical reactive astrocytosis, measured by glial fibrillary acidic protein (GFAP), in 5xFAD transgenic and wild-type mice.</p><p><strong>Findings: </strong>In AD-converters (N = 158, 377 samples), higher plasma GFAP levels are observed 10 years prior to the onset of cognitive impairment due to AD compared with individuals who remain cognitively unimpaired (N = 160, 379 samples). Plasma GFAP levels are highest in neuropathologically confirmed AD, intermediate in asymptomatic AD, and lowest in cognitively unimpaired and associated with severity of neuritic plaques and neurofibrillary tangles. GFAP-labeled immunoreactive astrocytes in the cortex of 3- and 7-month-old 5xFAD transgenic mice increased relative to wild-type mice and higher blood GFAP concentration was associated with more GFAP-expressing astrocytes.</p><p><strong>Conclusions: </strong>Reactive astrocytosis, assessed by elevated GFAP levels, is an early event in the progression of blood biomarker changes in preclinical AD, may be an early marker of AD pathogenesis, and a promising therapeutic target.</p><p><strong>Funding: </strong>Intramural Research Program, NIA.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100724"},"PeriodicalIF":12.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Allogeneic CD19-targeted CAR-T therapy in refractory systemic lupus erythematosus achieved durable remission.","authors":"Dandan Wang, Xiaobing Wang, Binghe Tan, Xin Wen, Songying Ye, Yingyi Wu, Xuan Cao, Xin Zhang, Chun Wang, Linyu Geng, Huayong Zhang, Xuebing Feng, Biao Zheng, Yanran He, Mingyao Liu, Xin Wu, Bing Du, Lingyun Sun, Huji Xu","doi":"10.1016/j.medj.2025.100749","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100749","url":null,"abstract":"<p><strong>Background: </strong>Autoreactive B cells play a key role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study is to assess the safety of allogeneic chimeric antigen receptor (CAR)-T cells for patients with lupus. This study was registered at ClinicalTrials.gov (NCT05859997).</p><p><strong>Methods: </strong>In this study, 3 patients with refractory and severe SLE with multi-organ involvement were enrolled. Genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells were infused intravenously at a dose of 1 million cells per kilogram of body weight. The safety indices, including the occurrence of graft-versus-host disease (GvHD), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS), were evaluated. The proliferation of CAR+ T cells and the number of peripheral B cells were assessed. The clinical efficacy was also assessed based on the SELENA-SLEDAI, SLEDAI-2K, BILAG, clinical SLE responder index-4 (SRI-4), and DORIS remission index.</p><p><strong>Findings: </strong>Between August 2023 and October 2023, 3 patients with SLE were enrolled and completed a 12-month follow-up. No patient underwent GvHD, CRS, or ICANS, and no severe adverse events were recorded. CAR+ T cells expanded in vivo, peaking at day 14, and then declined. The percentage of B cells in lymphocytes and the absolute circulating B cell counts were profoundly decreased. Patient 1 withdrew from the study at month 1 due to unresolved and severe thrombocytopenia and the need for the addition of an immunosuppressive drug. SELENA-SLEDAI and SLEDAI-2K scores declined, and all the patients reached SRI-4 remission at the last visit.</p><p><strong>Conclusions: </strong>In patients with severe and refractory SLE, allogeneic CAR-T cell therapy showed profound safety and clinical efficacy for disease remission.</p><p><strong>Funding: </strong>82320108010, 31821003, 81930043, 82330055, and U24A20380.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100749"},"PeriodicalIF":12.8,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Donor composition and fiber promote strain engraftment in a randomized controlled trial of fecal microbiota transplant for ulcerative colitis.","authors":"Lasha Gogokhia, Nancy Tran, Alex Grier, Manabu Nagayama, Grace Xiang, Gabriela Funez-dePagnier, Alexa Lavergne, Caroline Ericsson, Sarah Ben Maamar, Mengrui Zhang, Robert Battat, Ellen Scherl, Dana J Lukin, Randy S Longman","doi":"10.1016/j.medj.2025.100707","DOIUrl":"10.1016/j.medj.2025.100707","url":null,"abstract":"<p><strong>Background: </strong>Fecal microbiota transplantation (FMT) is an emerging treatment for ulcerative colitis (UC), but the impact of prebiotic fiber on FMT efficacy for UC is unclear. We performed a randomized, double-blind, placebo-controlled clinical trial to examine the efficacy of FMT with and without dietary fiber supplementation in patients with UC.</p><p><strong>Methods: </strong>27 patients with mild to moderate UC were randomized to receive a single FMT or placebo with or without psyllium fiber supplementation for 8 weeks. The primary outcome was clinical response at week 8, and secondary outcomes included endoscopic improvement and clinical remission. Metagenomic sequencing of fecal DNA was analyzed to determine taxonomic profiles and donor strain engraftment.</p><p><strong>Findings: </strong>The trial was terminated early due to manufacturer discontinuation of FMT product. FMT induced clinical response, remission, and endoscopic improvement in UC patients compared to placebo (p < 0.05), but fiber did not improve clinical outcomes of FMT. Recipient microbiome composition post-FMT shifted toward donor composition in responders and non-responders, but the durability of this change was stronger in responders. Clinical response and durable change in microbiome composition following FMT was donor dependent. Strain tracking analysis also demonstrated a donor-dependent variability in the rate of successful engraftment and identified a consortium of engrafted bacteria associated with treatment response or fiber supplementation.</p><p><strong>Conclusions: </strong>Single-dose FMT demonstrated clinical efficacy for mild to moderate UC compared to placebo but revealed no benefit of fiber supplementation. These results highlight proof of concept that donor selection and prebiotic fiber can shape strain-level engraftment. This study was registered at ClinicalTrials.gov: NCT03998488.</p><p><strong>Funding: </strong>National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK128257, to R.S.L.).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100707"},"PeriodicalIF":12.8,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-treatment untargeted cerebrospinal fluid metabolomic profiling in tuberculous meningitis uncovers pathways associated with mortality.","authors":"Thanh Hoang Nhat Le, Kirsten C J van Abeelen, Edwin Ardiansyah, Julian Avila-Pacheco, Sofiati Dian, Gesa Carstens, Lara Schramke, Hoang Thanh Hai, Tran Binh Minh Nguyen, Thai Minh Triet, Amy Deik, Jesse Krejci, Jeff Pruyne, Lucas Dailey, Bachti Alisjahbana, Mihai G Netea, Riwanti Estiasari, Trinh Thi Bich Tram, Joseph Donovan, Dorothee Heemskerk, Thi Hong Chau Tran, Nguyen Duc Bang, Ahmad Rizal Ganiem, Raph L Hamers, Rovina Ruslami, Darma Imran, Kartika Maharani, Vinod Kumar, Reinout van Crevel, Guy Thwaites, Clary B Clish, Nguyen Thuy Thuong Thuong, Arjan van Laarhoven","doi":"10.1016/j.medj.2025.100703","DOIUrl":"10.1016/j.medj.2025.100703","url":null,"abstract":"<p><strong>Background: </strong>Dysregulation of cerebrospinal fluid (CSF) tryptophan metabolism contributes to the high mortality of tuberculous meningitis (TBM). We aimed to identify novel metabolic pathways associated with TBM mortality through untargeted metabolome-wide analysis.</p><p><strong>Methods: </strong>We measured 619 metabolites using untargeted liquid chromatography-mass spectrometry in pre-treatment CSF from adults with TBM from Indonesia (n = 388, 34 HIV positive) and Vietnam (n = 679, 250 HIV positive). Sixty-day mortality was modeled using Cox regression, adjusting for age and HIV status. Metabolites were ranked in a screening subset (n = 194, Indonesia) and validated in the same cohort (n = 194) and externally (n = 679, Vietnam). Secondary analysis included variable selection, clustering to classify associated metabolites into subgroups, comparison with non-infectious controls, and correlation with patient characteristics, CSF cytokines, CSF protein, and serum metabolite concentrations.</p><p><strong>Findings: </strong>Sixty-day mortality was 21.6% and was associated with the concentration of 10 CSF metabolites, including tryptophan. The strongest association was with 3-hydroxyoctanoate (FA 8:0;3OH), part of a cluster of hydroxylated fatty acids also including hydroxy-isocaproate (FA 6:0;OH), hydroxyisobutyrate (FA 4:0;OH), and C4-OH-carnitine. These fatty acids correlated weakly with CSF tumor necrosis factor alpha, interleukin-6 (IL-6), leukocyte counts, bacterial load, and CSF protein. Mediation analysis showed that the variation in fatty acids was linked directly to mortality rather than through disease severity.</p><p><strong>Conclusion: </strong>We identified and validated nine new metabolites associated with TBM mortality, independent of HIV status, disease severity, and tryptophan. These metabolites suggest that altered fatty acid β-oxidation is linked to TBM-associated mortality. Interventions targeting cerebral fatty acid metabolism may improve survival of TBM.</p><p><strong>Funding: </strong>National Institute of Health; Wellcome Trust, UK.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100703"},"PeriodicalIF":12.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral lamivudine in diabetic macular edema: A randomized, double-blind, placebo-controlled clinical trial.","authors":"Felipe Pereira, Joseph Magagnoli, Meenakshi Ambati, Talita Fernandes de Oliveira, Juliana Angélica Estevão de Oliveira, Vinicius Oliveira Pesquero, Lucas Zago Ribeiro, Dante Akira Kondo Kuroiwa, Fernando Korn Malerbi, Sergio Atala Dib, Nilva Bueno Moraes, Michel Eid Farah, Eduardo Buchele Rodrigues, Jayakrishna Ambati","doi":"10.1016/j.medj.2025.100747","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100747","url":null,"abstract":"<p><strong>Background: </strong>Diabetic macular edema (DME) affects millions worldwide. Intraocular injections of expensive anti-vascular endothelial growth factor (VEGF) inhibitors associated with complications are standard therapy. Lamivudine, an inexpensive oral drug, inhibits inflammasome activation, which is implicated in DME. This randomized, double-blind, placebo-controlled trial compared oral lamivudine to placebo for improving visual acuity in center-involved DME (CI-DME).</p><p><strong>Methods: </strong>Twenty-four adults enrolled between February 2022 and September 2023 with 1 or 2 eyes with CI-DME and a best-corrected visual acuity (BCVA) of less than 69 letters (Brazilian Registry of Clinical Trials RBR-87b6r5s) were randomized to lamivudine (150 mg twice daily; 10 participants; 16 eyes) or placebo (14 participants; 21 eyes) for 8 weeks. Participants were assigned intravitreous bevacizumab (1.25 mg) at week 4. Co-primary outcomes were mean changes in BCVA from baseline to weeks 4 and 8. Comparisons to anti-VEGF drugs used synthetic controls from DRCR.net Protocol T. Secondary outcomes included retinal thickness and adverse events.</p><p><strong>Findings: </strong>At 4 weeks, BCVA improved 9.8 letters with lamivudine and decreased 1.8 letters with placebo (p < 0.001). At 8 weeks, BCVA improved 16.9 letters with lamivudine and bevacizumab and 5.3 letters with placebo and bevacizumab (p < 0.001). Lamivudine was associated with greater BCVA improvement than bevacizumab or ranibizumab (p < 0.05) and was not different from aflibercept (p = 0.5). There was no significant difference in retinal thickness or adverse events between groups.</p><p><strong>Conclusions: </strong>Lamivudine, an oral inflammasome inhibitor, significantly improved vision in patients with CI-DME.</p><p><strong>Funding: </strong>This work was supported by Universidade Federal de São Paulo, Latinofarma, UVA SIF, and NIH.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100747"},"PeriodicalIF":12.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144175068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}