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Among over 1100 patients with pulmonary arterial hypertension who received selexipag, an oral selective IP prostacyclin-receptor agonist, or placebo, the risk of the composite end point of death or complication was lower with selexipag than with placebo at 1.3 years of follow-up. Pulmonary arterial hypertension is a severe disease with a poor prognosis despite available treatment options. 1 Current recommendations support the use of a combination of therapies that target the endothelin, nitric-oxide, and prostacyclin pathways. 2 , 3 Despite the benefits of intravenous prostacyclin therapy, 2 , 4 many patients with pulmonary arterial hypertension die without ever receiving this treatment. 5 , 6 The burden and risks related to the administration of prostacyclin therapy are probably contributing factors. 7 Selexipag is an oral selective IP prostacyclin-receptor agonist that is structurally distinct from prostacyclin. 8 – 11 In a placebo-controlled, phase 2 trial involving patients who were already receiving treatment for pulmonary . . .

Despite important advances in treatment, the risk of recurrent ischaemic events is high both early and late after an acute coronary syndrome. We aimed to assess the effectiveness of ximelagatran and acetylsalicylic acid for prevention of death, non-fatal myocardial infarction, and severe recurrent ischaemia after a recent myocardial infarction. In this placebo-controlled, double-blind, multicentre, multinational dose-guiding study we assessed 1883 patients who had had recent ST-elevation or non-ST-elevation myocardial infarction. Within 14 days after the index event we randomised the participants in the proportions 1/1/1/1/2 to oral ximelagatran at doses of 24 mg, 36 mg, 48 mg, or 60 mg twice daily, or placebo, respectively for 6 months. All patients received acetylsalicylic acid 160 mg once daily. The primary efficacy outcome was the dose response of ximelagatran by comparison with placebo for the occurrence of all-cause death, non-fatal myocardial infarction, and severe recurrent ischaemia. Analysis was by intention to treat. Oral ximelagatran significantly reduced the risk for the primary endpoint compared with placebo from 16·3% (102 of 638) to 12·7% (154 of 1245) (hazard ratio 0·76, 95% Cl 0·59–0·98, p=0·036) for the combined ximelagatran groups versus placebo. There was no indication of a dose response between the ximelagatran groups. Major bleeding events were rare, 1·8 % (23 of 1245) and 0·9 % (six of 638) (hazard ratio 1·97, 95% Cl 0·80–4·84) in the combined ximelagatran and placebo groups, respectively. We recorded no serious clinically adverse outcomes judged related to the investigational drug. Oral direct thrombin inhibition with ximelagatran and acetylsalicylic acid is more effective than acetylsalicylic acid alone in preventing major cardiovascular events during 6 months of treatment in patients who have had a recent myocardial infarction. Published online Sept 1, 2003 http://image.thelancet.com/extras/03art6477web.pdf

In this international trial involving 371 patients with highly drug-resistant HIV-1 infection, fostemsavir reduced the HIV-1 RNA level by 0.79 log 10 copies per milliliter during the first 8 days of treatment. At week 48, more than half the patients treated with fostemsavir and an optimized background regimen had a virologic response.

Antiplatelet therapy with aspirin and a thienopyridine is a key component in the management of acute coronary syndromes. This trial compared a novel, potent thienopyridine (prasugrel) with the standard thienopyridine (clopidogrel) in patients with acute coronary syndromes scheduled to have a coronary intervention. Prasugrel led to better cardiovascular outcomes, but at the expense of more bleeding, including fatal bleeding. This trial compared a novel thienopyridine (prasugrel) with clopidogrel in patients with acute coronary syndromes. Prasugrel led to better cardiovascular outcomes, but at the expense of more bleeding, including fatal bleeding. The short-term and long-term benefits of dual-antiplatelet therapy with aspirin and clopidogrel have been established for patients with acute coronary syndromes 1 – 3 and those undergoing percutaneous coronary intervention (PCI). 4 , 5 Despite these benefits, many patients continue to have recurrent atherothrombotic events while receiving standard dual antiplatelet therapy. 1 In addition, important limitations of clopidogrel remain, such as only a modest antiplatelet effect, with substantial interpatient variability 6 , 7 and a delayed onset of action. 5 Small clinical studies have suggested that patients with a reduced pharmacologic response to clopidogrel may be at increased risk for adverse clinical events, including myocardial infarction and coronary-stent . . .

Background Metformin is the first-line treatment for type 2 diabetes mellitus (T2DM), but many patients either cannot tolerate it or cannot achieve glycemic control with metformin alone, so treatment with other glucose-lowering agents in combination with metformin is frequently required. Remogliflozin etabonate, a novel agent, is an orally bioavailable prodrug of remogliflozin, which is a potent and selective sodium-glucose co-transporter-2 inhibitor. Objective Our objective was to evaluate the efficacy and safety of remogliflozin etabonate compared with dapagliflozin in subjects with T2DM in whom a stable dose of metformin as monotherapy was providing inadequate glycemic control. Methods A 24-week randomized, double-blind, double-dummy, active-controlled, three-arm, parallel-group, multicenter, phase III study was conducted in India. Patients aged ≥ 18 and ≤ 65 years diagnosed with T2DM, receiving metformin ≥ 1500 mg/day, and with glycated hemoglobin (HbA1c) levels ≥ 7 to ≤ 10% at screening were randomized into three groups. Every patient received metformin ≥ 1500 mg and either remogliflozin etabonate 100 mg twice daily (BID) (group 1, n  = 225) or remogliflozin etabonate 250 mg BID (group 2, n  = 241) or dapagliflozin 10 mg once daily (QD) in the morning and placebo QD in the evening (group 3, n  = 146). The patients were followed-up at weeks 1 and 4 and at 4-week intervals thereafter until week 24. The endpoints included mean change in HbA1c (primary endpoint, noninferiority margin = 0.35), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), bodyweight, blood pressure, and fasting lipids. Treatment-emergent adverse events (TEAEs), safety laboratory values, electrocardiogram, and vital signs were evaluated. Results Of 612 randomized patients, 167 (group 1), 175 (group 2), and 103 (group 3) patients with comparable baseline characteristics completed the study. Mean change ± standard error (SE) in HbA1c from baseline to week 24 was − 0.72 ± 0.09, − 0.77 ± 0.09, and − 0.58 ± 0.12% in groups 1, 2, and 3, respectively. The difference in mean HbA1c of group 1 versus group 3 (− 0.14%, 90% confidence interval [CI] − 0.38 to 0.10) and group 2 versus group 3 (− 0.19%; 90% CI − 0.42 to 0.05) was noninferior to that in group 3 ( p  < 0.001). No significant difference was found between group 1 or group 2 and group 3 in change in FPG, PPG, and bodyweight. The overall incidence of TEAEs was comparable across study groups (group 1 = 32.6%, group 2 = 34.4%, group 3 = 29.5%), including adverse events (AEs) of special interest (hypoglycemic events, urinary tract infection, genital fungal infection). Most TEAEs were mild to moderate in intensity, and no severe AEs were reported. Conclusion This study demonstrated the noninferiority of remogliflozin etabonate 100 and 250 mg compared with dapagliflozin, from the first analysis of an initial 612 patients. Remogliflozin etabonate therefore may be considered an effective and well-tolerated alternative treatment option for glycemic control in T2DM. Trial Registration CTRI/2017/07/009121.

In a large, randomized trial, two doses of the direct thrombin inhibitor dabigatran were compared with warfarin in patients who had atrial fibrillation and were at risk for stroke. At 2 years, the 110-mg dose of dabigatran was found to be noninferior, and the 150-mg dose superior, to warfarin with respect to the primary outcome of stroke or systemic embolism. At 2 years, the 110-mg dose of dabigatran was found to be noninferior, and the 150-mg dose superior, to warfarin with respect to the primary outcome of stroke or systemic embolism. Atrial fibrillation increases the risks of stroke and death. Vitamin K antagonists, such as warfarin, reduce the risks of stroke and death but increase the risk of hemorrhage as compared with control therapy. 1 Therefore, warfarin is recommended for patients who have atrial fibrillation and are at risk for stroke. 2 Vitamin K antagonists are cumbersome to use, because of their multiple interactions with food and drugs, and they require frequent laboratory monitoring. Therefore, they are often not used, and when they are, rates of discontinuation are high. 3 , 4 Many patients receiving warfarin still have inadequate anticoagulation. 5 Thus, there is a need . . .

Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

Ximelagatran, a direct inhibitor of thrombin, is administered orally, and its use does not necessitate monitoring of coagulation. In this study, patients treated for venous thromboembolism with warfarin for six months were randomly assigned to receive ximelagatran or placebo. During the subsequent 18 months, the patients in the ximelagatran group had many fewer episodes of recurrent thromboembolism than those in the placebo group, without an increase in the frequency of bleeding. Ximelagatran to prevent recurrent thromboembolism. Despite progress in diagnosis and treatment, venous thromboembolism continues to be associated with high morbidity and mortality. 1 Previous studies have shown a risk of recurrence after six months of anticoagulant therapy of 5 to 7 percent per year. 2 , 3 The rate of recurrence can be reduced with the use of vitamin K antagonists such as warfarin, 4 – 7 but such therapy is associated with an annual risk of major hemorrhage of 3 to 4 percent. 4 – 6 Treatment with lower-intensity anticoagulants for a longer period may reduce the risk of hemorrhage, 7 although this hypothesis is controversial. 8 Routine monitoring of coagulation and frequent . . .

Warfarin prevents ischaemic stroke in patients with non-valvular atrial fibrillation, but dose adjustment, coagulation monitoring, and bleeding risk limit its use. The oral direct thrombin inhibitor ximelagatran represents a potential alternative. We aimed to establish whether ximelagatran is non-inferior to warfarin, within a margin of 2% per year, for prevention of stroke and systemic embolism. We randomised 3410 patients with atrial fibrillation and one or more stroke risk factors to open-label warfarin (adjusted-dose, international normalised ratio [INR] 2·0-3·0) or ximelagatran (fixed-dose, 36 mg twice daily); patients were recruited from 259 hospitals, doctor's offices, or health-care clinics. Primary analysis was based on masked event assessment and was by intention to treat. Primary endpoint was stroke or systemic embolism. During 4941 patient-years of exposure (mean 17·4 months, SD 4·1), 96 patients had primary events (56 in the warfarin group vs 40 in the ximelagatran group). The primary event rate by intention to treat was 2·3% per year with warfarin and 1·6% per year with ximelagatran (absolute risk reduction 0·7% [95% Cl -0·1 to 1·4], p=0·10; relative risk reduction 29% [95% Cl -6·5 to 52]). Rates of disabling or fatal stroke, mortality, and major bleeding were similar between groups, but combined minor and major haemorrhages were lower with ximelagatran than with warfarin (29·8%vs 25·8% per year; relative risk reduction 14% [4 to 22]; p=0·007). Raised serum alanine amino-transferase was more common with ximelagatran. In high-risk patients with atrial fibrillation, fixed-dose oral ximelagatran was at least as effective as well-controlled warfarin for prevention of stroke and systemic embolism.

Heparins substantially reduce the risk of thromboembolic complications after total hip or knee replacement. However, they can be given only by injection and have several other drawbacks. We did a multicentre, randomised, double-blind study to examine the dose-response relation of subcutaneous melagatran, a direct thrombin inhibitor, followed by oral ximelagatran as thromboprophylaxis after total hip or knee replacement. We aimed to compare the efficacy and safety with that of dalteparin. Of 1900 patients, 1495 were assigned to four dose categories of subcutaneous melagatran from just before surgery (1·00 mg, 1·50 mg, 2·25 mg, or 3·00 mg twice daily) followed from the day after surgery by oral ximelagatran (8 mg, 12 mg, 18 mg, or 24 mg twice daily). 381 patients were assigned subcutaneous dalteparin 5000 IU once daily, from the evening before surgery. Bilateral venography was done at 7–10 days, and clinically suspected venous thromboembolism (VTE) was confirmed radiologically. The primary endpoint was the rate of deep-vein thrombosis and pulmonary embolism (PE). Analyses were by intention to treat. 1876 patients underwent total replacement of hip (n=1270) or knee (n=606); evaluable venograms were obtained in 1473 (79%). Four patients without evaluable venograms had PE. Overall, a significant dose-dependent decrease in VTE was seen with melagatran/ximelagatran (lowest to highest group: 111 [37·8%] 70 [24·1%], 71 [23·7%], and 43 [15·1%]; p=0·0001); there were also significant relations for both total hip and total knee replacement individually. The frequency of VTE was significantly lower with the highest dose of melagatran/ ximelagatran than with dalteparin (15·1% vs 28·2%, p<0·0001). There were no reoperations due to bleeding and no critical organ bleeding. Excessive surgical bleeding was uncommon but more frequent in the highest dose group. This sequential therapy was effective and safe in patients undergoing major joint replacement surgery. The findings should be confirmed in a large phase III trial.