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Background. High-dose inactivated influenza vaccine has been shown to provide protection against influenza that is superior to that with the standard dose. However, data from individually randomized trials on the effectiveness of the high-dose vaccine against severe outcomes are limited.
Methods. In this pragmatic, open-label, randomized, controlled trial conducted in Denmark during the 2022-2023, 2023-2024, and 2024-2025 influenza seasons, we assigned older adults (≥65 years of age) to receive the high dose of the inactivated influenza vaccine or the standard dose. Data collection relied on nationwide administrative health registries. The primary end point was hospitalization for influenza or pneumonia that occurred from 14 days after vaccination through May 31 of the following year.
Results. Of the 332,438 participants who underwent randomization, 166,218 were assigned to receive the high-dose vaccine and 166,220 to receive the standard-dose vaccine. The mean (±SD) age of the participants was 73.7±5.8 years, and 161,538 participants (48.6%) were women. A primary end-point event occurred in 1138 participants (0.68%) in the high-dose group and in 1210 (0.73%) in the standard-dose group (relative vaccine effectiveness, 5.9%; 95.2% confidence interval [CI], -2.1 to 13.4; P = 0.14). Hospitalization for influenza occurred in 0.06% of the participants in the high-dose group and in 0.11% of those in the standard-dose group (relative vaccine effectiveness, 43.6%; 95.2% CI, 27.5 to 56.3); hospitalization for pneumonia occurred in 0.63% and 0.63%, respectively (relative effectiveness, 0.5%; 95.2% CI, -8.6 to 8.8); hospitalization for cardiorespiratory disease in 2.25% and 2.38% (relative effectiveness, 5.7%; 95.2% CI, 1.4 to 9.9); hospitalization for any cause in 9.38% and 9.58% (relative effectiveness, 2.1%; 95.2% CI, -0.1 to 4.3), and death from any cause in 0.67% and 0.66% (relative effectiveness, -2.5%; 95.2% CI, -11.6 to 5.9). The incidence of serious adverse events was similar in the two groups.
Conclusions. In this trial, a high-dose inactivated influenza vaccine did not result in a significantly lower incidence of hospitalization for influenza or pneumonia than a standard dose among older adults. (Funded by Sanofi; DANFLU-2 ClinicalTrials.gov number, NCT05517174; EU Clinical Trials Register number, 2022-500657-17-00.).
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Background. Superior protection against laboratory-confirmed influenza has been proved for high-dose inactivated influenza vaccine, as compared with the standard dose, among adults 65 years of age or older. However, data on the relative effectiveness of the high-dose vaccine against severe clinical outcomes, including hospitalizations, are limited.
Methods. We conducted a pragmatic, registry-based, open-label, randomized, active-controlled trial to evaluate the relative effectiveness of high-dose inactivated influenza vaccine, as compared with the standard dose, against severe clinical outcomes among community-dwelling adults 65 to 79 years of age. The trial was performed during two influenza seasons (2023-2024 and 2024-2025) with regional health registry data in Galicia, Spain. In each influenza season, the participants were randomly assigned in a 1:1 ratio to receive high-dose inactivated influenza vaccine or the standard dose. The primary end point was a composite of hospitalization for influenza or pneumonia from 14 days after vaccination to May 31 of the following year.
Results. A total of 103,169 unique participants underwent randomization; 31,307 participants were enrolled in both seasons and were counted for each. During the 2023-2024 and 2024-2025 seasons, 59,490 and 74,986 participants, respectively, underwent randomization. Among the participants, the mean (±SD) age was 72.3±4.3 years, and 53.6% were men. A primary end-point event occurred in 174 of 67,093 participants (absolute risk, 0.26%) in the high-dose group and in 227 of 66,789 (absolute risk, 0.34%) in the standard-dose group (relative vaccine effectiveness, 23.7%; 95% confidence interval [CI], 6.6 to 37.7). Hospitalization for influenza occurred in 63 of 67,093 participants (absolute risk, 0.09%) in the high-dose group and in 92 of 66,789 (absolute risk, 0.14%) in the standard-dose group (relative vaccine effectiveness, 31.8%; 95% CI, 5.0 to 51.3). The incidence of serious adverse events appeared to be similar in the two trial groups.
Conclusions. Among community-dwelling adults 65 to 79 years of age, there appeared to be fewer hospitalizations for influenza or pneumonia with high-dose inactivated influenza vaccine than with the standard dose. (Funded by Sanofi; GALFLU ClinicalTrials.gov number NCT06141655; EudraCT number, 2023-506977-36-00.).
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Background. Patients benefit from antiplatelet therapy after coronary-artery bypass grafting (CABG) for an acute coronary syndrome. Whether the addition of ticagrelor to aspirin, as compared with aspirin alone, further reduces the risk of adverse cardiovascular outcomes is unclear.
Methods. In this open-label, registry-based, clinical trial conducted at 22 Nordic cardiothoracic surgery centers, we randomly assigned patients in a 1:1 ratio to receive either ticagrelor plus aspirin or aspirin alone for 1 year after CABG for an acute coronary syndrome. The primary outcome was a composite of death, myocardial infarction, stroke, or repeat revascularization, evaluated at 1 year. A key secondary outcome was net adverse clinical events, defined as a primary-outcome event or major bleeding.
Results. A total of 2201 patients were randomly assigned to receive ticagrelor plus aspirin (1104 patients) or aspirin alone (1097 patients). The mean age of the patients was 66 years, and 14.4% were women. A primary-outcome event occurred in 53 patients (4.8%) in the ticagrelor-plus-aspirin group and 50 (4.6%) in the aspirin-alone group (hazard ratio, 1.06; 95% confidence interval [CI], 0.72 to 1.56; P = 0.77). Net adverse clinical events occurred in 9.1% of patients in the ticagrelor-plus-aspirin group and 6.4% in the aspirin-alone group (hazard ratio, 1.45; 95% CI, 1.07 to 1.97). Major bleeding occurred in 4.9% of patients in the ticagrelor-plus-aspirin group and 2.0% in the aspirin-alone group (hazard ratio, 2.50; 95% CI, 1.52 to 4.11).
Conclusions. Among patients who underwent CABG for an acute coronary syndrome, ticagrelor plus aspirin did not result in a lower incidence of death, myocardial infarction, stroke, or repeat coronary revascularization than aspirin alone at 1 year. (Funded by the Swedish Research Council and others; TACSI ClinicalTrials.gov number, NCT03560310; EudraCT number, 2017-001499-43; EU Clinical Trials number, 2023-508551-40-00.).
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Background. Human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate monotherapy has shown preliminary clinical efficacy in patients with chemotherapy-refractory HER2-positive locally advanced or metastatic urothelial cancer. Previous data showed promising antitumor activity and safety of HER2-specific disitamab vedotin as monotherapy and when combined with programmed cell death protein 1 (PD-1)-directed immunotherapy in this cancer.
Methods. In this phase 3, multicenter, open-label, randomized trial, we assigned patients with previously untreated HER2-expressing (immunohistochemical score of 1+, 2+, or 3+) locally advanced or metastatic urothelial cancer in a 1:1 ratio to receive either disitamab vedotin plus PD-1-specific toripalimab every 2 weeks or chemotherapy (gemcitabine plus cisplatin or carboplatin) every 3 weeks. The dual primary end points were progression-free survival (assessed by blinded independent review) and overall survival. Secondary end points included objective response and safety. Here we report the prespecified progression-free survival analysis and interim overall survival analysis.
Results. A total of 484 patients underwent randomization. The median follow-up was 18.2 months. Progression-free survival was significantly longer in the disitamab vedotin-toripalimab group than in the chemotherapy group (median, 13.1 vs. 6.5 months; hazard ratio for progression or death, 0.36; 95% confidence interval [CI], 0.28 to 0.46; P<0.001). Overall survival was also significantly longer in the disitamab vedotin-toripalimab group than in the chemotherapy group (median, 31.5 vs. 16.9 months; hazard ratio for death, 0.54; 95% CI, 0.41 to 0.73; P<0.001). The percentage of patients with an objective response was 76.1% (95% CI, 70.3 to 81.3) in the disitamab vedotin-toripalimab group and 50.2% (95% CI, 43.7 to 56.7) in the chemotherapy group. The safety profile of disitamab vedotin plus toripalimab was more favorable than that of chemotherapy; grade 3 or higher treatment-related adverse events occurred in 55.1% of patients who received disitamab vedotin plus toripalimab and 86.9% of those who received chemotherapy.
Conclusions. Disitamab vedotin-toripalimab led to a significantly greater improvement in outcomes than chemotherapy among patients with untreated HER2-expressing locally advanced or metastatic urothelial cancer. (Funded by RemeGen and others; RC48-C016 ClinicalTrials.gov number, NCT05302284; ChinaDrugTrials.org.cn number, CTR20220348.).
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