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Background. An appropriate duration of dual antiplatelet therapy after percutaneous coronary intervention for acute myocardial infarction that has been treated with guideline-recommended complete revascularization and a contemporary drug-eluting stent remains unclear.
Methods. We conducted a multicenter, open-label, randomized trial at 40 European sites. Adults with acute myocardial infarction who had undergone successful complete revascularization within 7 days after the infarction and had subsequently completed 1 month of dual antiplatelet therapy with no ischemic or major bleeding events were randomly assigned to transition to a P2Y12 inhibitor as monotherapy or to continue dual antiplatelet therapy for an additional 11 months. The primary outcome was a composite of death from any cause, myocardial infarction, stent thrombosis, stroke, or major bleeding (defined by the Bleeding Academic Research Consortium [BARC] as a bleeding event of type 3 or 5) at 11 months after randomization (tested for noninferiority with a margin of 1.25 percentage points). The main secondary outcome was BARC type 2, 3, or 5 bleeding (clinically relevant bleeding) at 11 months after randomization (tested for superiority).
Results. Among the 2246 enrolled patients, 1942 underwent randomization: 961 to receive P2Y12-inhibitor monotherapy and 981 to continue dual antiplatelet therapy. A primary-outcome event occurred in 20 patients (2.1%) in the P2Y12-inhibitor monotherapy group and in 21 patients (2.2%) in the dual antiplatelet therapy group (difference, -0.09 percentage points; 95% confidence interval [CI], -1.39 to 1.20; P = 0.02 for noninferiority). BARC type 2, 3, or 5 bleeding occurred in 2.6% of the patients in the P2Y12-inhibitor monotherapy group and in 5.6% of those in the dual antiplatelet therapy group (hazard ratio, 0.46; 95% CI, 0.29 to 0.75; P = 0.002 for superiority). Stent thrombosis was infrequent, and the incidence was similar in the two groups. The incidence of serious adverse events appeared to be similar in the two groups.
Conclusions. Among low-risk patients with acute myocardial infarction who had undergone early complete revascularization and had completed 1 month of dual antiplatelet therapy without complications, P2Y12-inhibitor monotherapy was noninferior to continued dual antiplatelet therapy with respect to the occurrence of adverse cardiovascular and cerebrovascular events and resulted in a lower incidence of bleeding events. (Funded by MicroPort [France]; TARGET-FIRST ClinicalTrials.gov number, NCT04753749.).
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Background. Whether potent P2Y12 inhibitor monotherapy without aspirin initiated shortly after successful percutaneous coronary intervention (PCI) is effective and safe for patients with acute coronary syndromes is unclear.
Methods. We conducted a multicenter, open-label, randomized trial in Brazil involving patients with acute coronary syndromes who had undergone successful PCI. Patients were assigned in a 1:1 ratio within the first 4 days of hospitalization to stop treatment with aspirin and receive potent P2Y12 inhibitor monotherapy (ticagrelor or prasugrel) or to receive dual antiplatelet therapy (aspirin and a potent P2Y12 inhibitor) for 12 months. The two ranked primary outcomes, assessed through 12 months, were a composite of death from any cause, myocardial infarction, stroke, or urgent target-vessel revascularization (tested for noninferiority, with a noninferiority margin of 2.5 percentage points) and major or clinically relevant nonmajor bleeding (tested for superiority).
Results. A total of 3410 patients were included in the intention-to-treat population (1712 in the monotherapy group and 1698 in the dual antiplatelet therapy group). At 12 months, death from any cause, myocardial infarction, stroke, or urgent revascularization had occurred in 119 patients (Kaplan-Meier estimate, 7.0%) in the monotherapy group and in 93 patients (Kaplan-Meier estimate, 5.5%) in the dual antiplatelet therapy group (absolute risk difference, 1.47 percentage points; 95% confidence interval [CI], -0.16 to 3.10; P = 0.11 for noninferiority). Major or clinically relevant nonmajor bleeding had occurred in 33 patients (Kaplan-Meier estimate, 2.0%) in the monotherapy group and in 82 patients (Kaplan-Meier estimate, 4.9%) in the dual antiplatelet therapy group (absolute risk difference, -2.97 percentage points; 95% CI, -4.20 to -1.73). Stent thrombosis occurred in 12 patients in the monotherapy group and in 4 in the dual antiplatelet therapy group.
Conclusions. Among patients who had undergone successful PCI for acute coronary syndromes, potent P2Y12 inhibitor monotherapy was not found to be noninferior to dual antiplatelet therapy with respect to a composite of death or ischemic events at 12 months. (Funded by the Brazilian Ministry of Health; NEO-MINDSET ClinicalTrials.gov number, NCT04360720.).
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Background. Approximately half the worldwide population is at risk for dengue. No antiviral prophylaxis or treatment options are available.
Methods. In a phase 2a, double-blind, randomized trial, we assigned healthy adults to receive oral mosnodenvir once daily as a low dose (40-mg loading dose followed by 10-mg maintenance dose), medium dose (200 mg followed by 50 mg), or high dose (600 mg followed by 200 mg) or matched placebo. Loading doses were given for 5 days and maintenance doses for 21 days. In a controlled human infection model, participants received subcutaneous inoculation of an underattenuated dengue virus serotype 3 (DENV-3) strain (rDEN3Δ30) on the day of the first maintenance dose (day 1). The primary efficacy end point was the DENV-3 RNA load, assessed as the log10 area under the concentration-time curve from day 1 (immediately before inoculation) through day 29 (AUCD1-29). The high-dose and placebo groups were compared in the primary end-point analysis. Safety, pharmacokinetic features, and virologic and serologic features were evaluated through day 85.
Results. The percentage of participants without signs of DENV-3 infection was 0% (0 of 6 participants) with the low dose of mosnodenvir, 17% (1 of 6) with the medium dose, and 60% (6 of 10) with the high dose, as compared with 0% (0 of 7) with placebo. High-dose mosnodenvir led to a significantly lower DENV-3 RNA load, assessed as the log10 AUCD1-29, than placebo (two-sided P<0.001 by tobit analysis of variance). In this small trial, mosnodenvir did not result in any serious adverse events. Plasma concentrations of mosnodenvir increased from day -5 to day 1 and were maintained through day 21. Among participants with available NS4B sequencing data, emerging amino acid variations in the NS4B region of the rDEN3Δ30 genome were detected in 14 of 14 mosnodenvir recipients and none of 7 placebo recipients.
Conclusions. In a controlled human infection model, a high daily dose of oral mosnodenvir led to a significantly lower DENV-3 RNA load than placebo. Mosnodenvir did not result in any serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and Johnson & Johnson; ClinicalTrials.gov number, NCT05048875.).
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Background. Angiopoietin-like protein 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases. ANGPTL3 loss-of-function genetic variants are associated with decreased levels of low-density lipoprotein cholesterol and triglycerides and a decreased lifetime risk of atherosclerotic cardiovascular disease.
Methods. We conducted an ascending-dose phase 1 trial to assess the safety and efficacy of CTX310, a lipid-nanoparticle-encapsulated clustered regularly interspaced short palindromic repeats-Cas9 endonuclease (CRISPR-Cas9) messenger RNA (mRNA) and guide RNA targeting hepatic ANGPTL3 to induce a loss-of-function mutation. Adults who had uncontrolled hypercholesterolemia, hypertriglyceridemia, or mixed dyslipidemia and were receiving maximally tolerated lipid-lowering therapy received a single intravenous dose of CTX310 (0.1, 0.3, 0.6, 0.7, or 0.8 mg per kilogram of body weight). The primary end point was adverse events, including dose-limiting toxic effects.
Results. A total of 15 participants received CTX310 and had at least 60 days of follow-up. No dose-limiting toxic effects related to CTX310 occurred. Serious adverse events occurred in two participants (13%): one participant had a spinal disk herniation, and the other died suddenly 179 days after treatment with the 0.1-mg-per-kilogram dose. Infusion-related reactions were reported in three participants (20%), and one participant (7%) who had elevated levels of aminotransferases at baseline had a transient elevation in aminotransferases to between three times and five times as high as those at baseline, peaking on day 4 and returning to baseline by day 14. The mean percent change in ANGPTL3 level was 9.6% (range, -21.8 to 71.2) with the dose of 0.1 mg per kilogram, 9.4% (range, -25.0 to 63.9) with 0.3 mg per kilogram, -32.7% (range, -51.4 to -19.4) with 0.6 mg per kilogram, -79.7% (range, -86.8 to -72.5) with 0.7 mg per kilogram, and -73.2% (range, -89.0 to -66.9) with 0.8 mg per kilogram.
Conclusions. Editing of ANGPTL3 was associated with few adverse events and resulted in reductions from baseline in ANGPTL3 levels. (Funded by CRISPR Therapeutics; Australia New Zealand Clinical Trials Registry number, ACTRN12623000809639.).
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Background. Hereditary hemorrhagic telangiectasia (HHT) can cause recurrent, severe epistaxis, as well as anemia and reduced quality of life. The disease remains without licensed therapies worldwide.
Methods. In this proof-of-concept, multicenter, double-blind, placebo-controlled trial, we evaluated the safety and efficacy of oral engasertib, a new, allosteric, selective AKT inhibitor, in patients with HHT. Patients were randomly assigned in a 1:1:1 ratio to receive engasertib at a dose of 30 mg, engasertib at a dose of 40 mg, or placebo once daily for 12 weeks. The primary outcomes were the frequency and severity of adverse events. Key secondary outcomes included the frequency and duration of epistaxis. An open-label extension is ongoing.
Results. A total of 75 patients were assigned to 30-mg engasertib (24 patients), 40-mg engasertib (25 patients), or placebo (26 patients). Among the patients who received at least one dose of the trial regimen, the most common on-target adverse events associated with engasertib included mild-to-moderate rash (5 patients [21%] in the 30-mg engasertib group, 10 [42%] in the 40-mg engasertib group, and 2 [8%] in the placebo group) and mild-to-moderate hyperglycemia (3 patients [12%] in the 40-mg engasertib group and no patients in the other two groups), which were reversible. The incidence of serious adverse events in each of the two engasertib groups was similar to that in the placebo group. From baseline to week 12, the mean (±SD) decrease in epistaxis frequency was 26.5±26.5% with 30-mg engasertib, 27.8±35.1% with 40-mg engasertib, and 18.0±36.0% with placebo; the mean decrease in epistaxis duration was 29.9±53.2%, 41.4±41.0%, and 23.8±53.4%, respectively.
Conclusions. The safety profile of engasertib was similar to that of placebo except for mild-to-moderate rash, which resolved in most patients who continued to receive the drug. Engasertib treatment was associated with decreases in epistaxis frequency and duration. (Funded by Vaderis Therapeutics; ClinicalTrials.gov number, NCT05406362.).
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