Background Optimal treatment for patients with both type 2 diabetes mellitus and stable ischemic heart disease has not been established. Methods We randomly assigned 2368 patients with both type 2 diabetes and heart disease to undergo either prompt revascularization with intensive medical therapy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy. Primary end points were the rate of death and a composite of death, myocardial infarction, or stroke (major cardiovascular events). Randomization was stratified according to the choice of percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) as the more appropriate intervention. Results At 5 years, rates of survival did not differ significantly between the revascularization group (88.3%) and the medical-therapy group (87.8%, P=0.97) or between the insulin-sensitization group (88.2%) and the insulin-provision group (87.9%, P=0.89). The rates of freedom from major cardiovascular events also did not differ significantly among the groups: 77.2% in the revascularization group and 75.9% in the medical-treatment group (P=0.70) and 77.7% in the insulin-sensitization group and 75.4% in the insulin-provision group (P=0.13). In the PCI stratum, there was no significant difference in primary end points between the revascularization group and the medical-therapy group. In the CABG stratum, the rate of major cardiovascular events was significantly lower in the revascularization group (22.4%) than in the medical-therapy group (30.5%, P=0.01; P=0.002 for interaction between stratum and study group). Adverse events and serious adverse events were generally similar among the groups, although severe hypoglycemia was more frequent in the insulin-provision group (9.2%) than in the insulin-sensitization group (5.9%, P=0.003). Conclusions Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision. (ClinicalTrials.gov number, NCT00006305.)

Background We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. Methods In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov , NCT04501978 . Findings Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50–72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74–1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67–1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74–1·58]; BRII-196 plus BRII-198 1·00 [0·68–1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91–...

No abstract

7116 Background: P and G have well demonstrated, single-agent activity in pts with locally advanced or metastatic NSCLC. This phase II study was designed to determine the activity of the combination of PG when G was administered immediately prior to P on day 8 of a 21-day cycle. Methods: Pts with Stage IIIB/IV NSCLC were enrolled. Treatment was G 1250 mg/m2 on D 1 and 8, with P 500 mg/m2 on D 8, immediately following G. Treatment was repeated every 21 days for 6 cycles. Pts received folic acid, vitamin B12 and steroid prophylaxis. Results: 54 pts (32 M/22 F) were enrolled in the study. Median age was 65.0 (range = 43 - 87) years, ECOG PS 0: 1 = 35.2%: 57.4%; Stage IIIB (9.3%), Stage IV (90.7%); Histology: adeno (61.1%) squamous (18.5%), and large cell (5.6%). Median dose intensity was 83.2% for P and 82.2% for G. Grade 3 toxicities were neutropenia (12.0%), thrombocytopenia (8.0%), dyspnea (16.0%), febrile neutropenia (10.0%), anemia (4.0%), fatigue (18.0%), nausea (10.0%), vomiting (8.0%), and rash (2.0%). Grade 4 toxicities were neutropenia (28%), thrombocytopenia (4%), dyspnea (6%), anemia (0%), fatigue (4%), nausea (0%), vomiting (0%), rash (0%). Five patients (10%) experienced Grade 1 alopecia. Median TTPD was 4.4 months and survival was 10.6 months. There were 0 CR, 16 PR (35.6%), 16 SD (35.6%), and 12 PD (26.7%), for an overall best response rate of 35.6%. Conclusions: In this study, PG had a disease control rate (ORR + SD) of 71.1% in the front-line treatment of NSCLC, suggesting that this is an active doublet. Administering P on D 8 rather than D 1 did not seem to negatively impact the therapeutic index. [Table: see text]