Anticoagulant Effects of Dabigatran on Coagulation Laboratory Parameters in Pediatric Patients: Combined Data from Five Pediatric Clinical Trials.

Background:  Dabigatran etexilate, a direct oral thrombin inhibitor, is approved to treat venous thromboembolism (VTE) in both adults and children.

Objectives:  This population analysis characterized relationships between dabigatran total plasma concentrations and coagulation laboratory parameters (activated partial thromboplastin time [aPTT]; diluted thrombin time [dTT]; ecarin clotting time [ECT]).

Methods:  Data from three phase 2a and one single-arm and one randomized, comparative phase 2b/3 pediatric studies (measurements: aPTT 2,925 [ = 358]; dTT 2,348 [ = 324]; ECT 2,929 [ = 357]) were compared with adult data (5,740 aPTT, 3,472 dTT, 3,817 ECT measurements;  = 1,978).

Safety and tolerability of spesolimab in patients with ulcerative colitis.

Background: Interleukin (IL)-36 signaling has been shown to be increased in ulcerative colitis (UC). Spesolimab, a novel humanized monoclonal antibody, targets the IL-36 pathway.

Research Design And Methods: We report safety, immunogenicity, and efficacy data of intravenous (IV) spesolimab in UC.

Pharmacokinetic modeling and simulation support for age- and weight-adjusted dosing of dabigatran etexilate in children with venous thromboembolism.

Background: Dabigatran etexilate (DE), a direct oral thrombin inhibitor, has been evaluated in children with venous thromboembolism (VTE) using oral solution, pellets, or capsules.

Objectives: This study evaluated DE pharmacokinetics (PK) in children with VTE and the appropriateness of a DE pediatric age- and weight-based dosing algorithm.

Patients/methods: A population PK model was fitted to data from four single-arm and one randomized, comparative pediatric VTE studies (358 children aged birth to <18 years; 2748 PK observations) and one healthy-adult study (32 males aged <40 years; 1523 PK observations) using nonlinear mixed-effects modeling.

Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial.

Background: Dabigatran etexilate is a direct oral anticoagulant with potential to overcome the limitations of standard of care in children with venous thromboembolism. The aims of this clinical trial were to study the appropriateness of a paediatric dabigatran dosing algorithm, and the efficacy and safety of dabigatran dosed according to that algorithm versus standard of care in treating children with venous thromboembolism.

Methods: DIVERSITY is a randomised, controlled, open-label, parallel-group, phase 2b/3 non-inferiority trial done in 65 centres in 26 countries.

Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children.

This open-label, single-arm, prospective cohort trial is the first phase 3 safety study to describe outcomes in children treated with dabigatran etexilate for secondary venous thromboembolism (VTE) prevention. Eligible children aged 12 to <18 years (age stratum 1), 2 to <12 years (stratum 2), and >3 months to <2 years (stratum 3) had an objectively confirmed diagnosis of VTE treated with standard of care (SOC) for ≥3 months, or had completed dabigatran or SOC treatment in the DIVERSITY trial (NCT01895777) and had an unresolved clinical thrombosis risk factor requiring further anticoagulation. Children received dabigatran for up to 12 months, or less if the identified VTE clinical risk factor resolved.

Anticoagulant Effects of Dabigatran in Paediatric Patients Compared with Adults: Combined Data from Three Paediatric Clinical Trials.

Background:  Physiological age-related changes in the haemostatic and coagulation systems result in differing anticoagulant assay responses to standard anticoagulants. Therefore, we investigated the response of anticoagulant assays to dabigatran etexilate (DE) in children compared with adults.

Objective:  This article assesses the relationship between plasma dabigatran concentration and coagulation assay results across age groups in children and adults.

Phase 3, single-arm, multicenter study of dabigatran etexilate for secondary prevention of venous thromboembolism in children: Rationale and design.

Background: Anticoagulant therapy for venous thromboembolism (VTE) in children is largely based on treatment recommendations for adults. However, differences in both physiology (ie, renal maturation and drug excretion) and developmental hemostasis must be considered when treating children, as such differences could affect dose appropriateness, safety and efficacy.

Objectives: To address these concerns, a study was designed to evaluate the safety of dabigatran etexilate in children requiring secondary thrombus prevention in whom an initial VTE was associated with an identified risk factor that persisted after the acute VTE treatment period.

Design and rationale for the DIVERSITY study: An open-label, randomized study of dabigatran etexilate for pediatric venous thromboembolism.

Background: The current standard of care (SOC) for pediatric venous thromboembolism (VTE) comprises unfractionated heparin (UFH), or low-molecular-weight heparin (LMWH) followed by LMWH or vitamin K antagonists, all of which have limitations. Dabigatran etexilate (DE) has demonstrated efficacy and safety for adult VTE and has the potential to overcome some of the limitations of the current SOC. Pediatric trials are needed to establish dosing in children and to confirm that results obtained in adults are applicable in the pediatric setting.

Rationale and design of a phase III safety trial of idarucizumab in children receiving dabigatran etexilate for venous thromboembolism.

Background: The incidence of venous thromboembolism (VTE) in children has been increasing. Anticoagulants are the mainstay of treatment but are associated with bleeding events that may be life-threatening. Idarucizumab is a fragment antigen-binding (fab) that provides immediate, complete, and sustained reversal of dabigatran's anticoagulant effects in adults.

Comparison of Oral Anticoagulants for Stroke Prevention in Nonvalvular Atrial Fibrillation: A Multicriteria Decision Analysis.

Background: Decision on the most appropriate oral anticoagulation therapy for stroke prevention in patients with nonvalvular atrial fibrillation is difficult because multiple treatment options are available, and these vary in their clinical effects and relevant nonclinical characteristics.

Objectives: To use a multicriteria decision analysis (MCDA) to compare the oral anticoagulants apixaban, dabigatran, edoxaban, rivaroxaban, and vitamin K antagonist (VKAs; specifically warfarin) in patients with nonvalvular atrial fibrillation.

Methods: We identified the evaluation criteria through a targeted literature review and clinical judgment.

Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Dabigatran Etexilate Oral Liquid Formulation in Infants with Venous Thromboembolism.

Venous thromboembolism (VTE) is more frequent in infants than in older children. Treatment guidelines in children are adapted from adult VTE data, but do not currently include direct oral anticoagulant use. Dabigatran etexilate (DE) use in the paediatric population with VTE therefore requires verification.

Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation.

Background: Triple antithrombotic therapy with warfarin plus two antiplatelet agents is the standard of care after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, but this therapy is associated with a high risk of bleeding.

Methods: In this multicenter trial, we randomly assigned 2725 patients with atrial fibrillation who had undergone PCI to triple therapy with warfarin plus a P2Y inhibitor (clopidogrel or ticagrelor) and aspirin (for 1 to 3 months) (triple-therapy group) or dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y inhibitor (clopidogrel or ticagrelor) and no aspirin (110-mg and 150-mg dual-therapy groups). Outside the United States, elderly patients (≥80 years of age; ≥70 years of age in Japan) were randomly assigned to the 110-mg dual-therapy group or the triple-therapy group.

Design and Rationale of the RE-DUAL PCI Trial: A Prospective, Randomized, Phase 3b Study Comparing the Safety and Efficacy of Dual Antithrombotic Therapy With Dabigatran Etexilate Versus Warfarin Triple Therapy in Patients With Nonvalvular Atrial Fibrillation Who Have Undergone Percutaneous Coronary Intervention With Stenting.

Antithrombotic management of patients with atrial fibrillation (AF) undergoing coronary stenting is complicated by the need for anticoagulant therapy for stroke prevention and dual antiplatelet therapy for prevention of stent thrombosis and coronary events. Triple antithrombotic therapy, typically comprising warfarin, aspirin, and clopidogrel, is associated with a high risk of bleeding. A modest-sized trial of oral anticoagulation with warfarin and clopidogrel without aspirin showed improvements in both bleeding and thrombotic events compared with triple therapy, but large trials are lacking.

Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency.

Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patient's burden of disease.

Ozenoxacin 1% cream in the treatment of impetigo: a multicenter, randomized, placebo- and retapamulin-controlled clinical trial.

Aim: We compared the efficacy and safety of ozenoxacin (a new nonfluorinated quinolone) 1% cream with placebo in the treatment of impetigo.

Patients & Methods: In a randomized, double-blind, multicenter study, patients received ozenoxacin cream or placebo cream twice daily for 5 days (a third group received retapamulin 1% ointment as a control). Clinical, microbiological and laboratory evaluations were performed during follow-up (over 2 weeks).

Systemic bioavailability and safety of twice-daily topical ozenoxacin 1% cream in adults and children with impetigo.

In this Phase I open-label study, the systemic absorption, clinical response, safety and tolerability of multiple-dose ozenoxacin 1% cream were evaluated in children (≥ 2 months of age) and adults with impetigo. A single (evening) dose of ozenoxacin 1% cream on day 1 was followed by twice-daily application for 4 days (every 12 h), and then a final single (morning) dose on day 6. A total of 46 patients were enrolled in the study.

In vitro percutaneous absorption and metabolism of ozenoxacin in excised human skin.

In vitro studies using excised human skin samples were conducted to evaluate the percutaneous absorption and skin metabolism of ozenoxacin. The formulations studied were 1% ointment, 1% cream and 2% cream. Permeation assays met the conditions for infinite dose experiments.

Cumulative irritation, sensitizing potential, phototoxicity and photoallergy of ozenoxacin in healthy adult volunteers.

In this series of Phase I, randomized, placebo-controlled studies in healthy volunteers, the potential for ozenoxacin 1 and 2% cream formulations to cause irritation, sensitization, phototoxicity and photoallergy under occlusive patch conditions was evaluated. Both ozenoxacin formulations showed excellent dermal tolerability; in the vast majority of cases, only minimal signs of erythema were observed, with no evidence of edema or a papular response. No subject met the criteria for a phototoxic reaction with the ozenoxacin 1 or 2% cream formulations.

Skin tissue exposure of once- versus twice-daily topical ozenoxacin 2% cream: a Phase I study in healthy volunteers.

In this Phase I study, healthy volunteers (n = 24) were randomly allocated to receive either one or two 0.2-g applications per day (12 h apart) of ozenoxacin 2% cream on three different areas of the back for 3 consecutive days. Ozenoxacin concentrations were measured in tape stripping samples (from the stratum corneum) and in skin punch biopsy samples (from the epidermis and dermis) taken predose from selected dosing areas on study days 2, 3 and 4.

Systemic bioavailability, safety and tolerability of topical ozenoxacin in healthy adult volunteers.

A series of Phase I studies was conducted in healthy volunteers to examine the systemic bioavailability and safety of topical ozenoxacin. Study 1 examined increasing single doses (relating to quantity and body surface area) of ozenoxacin 1% ointment. Study 2 compared multiple doses of ozenoxacin 1% ointment and placebo applied for 7 days.

A single-dose, randomized, double-blind, double dummy, placebo and positive-controlled, five-way cross-over study to assess the pharmacodynamic effects of lorediplon in a phase advance model of insomnia in healthy Caucasian adult male subjects.

Objective: A 5-h phase advance model of insomnia was used to evaluate the efficacy of lorediplon, a new non-benzodiazepine hypnotic.

Methods: Thirty-five male, healthy subjects were included in a five-way randomized cross-over study. During each of the periods, sleep was recorded, and residual effects were measured.

Clinical effects of torasemide prolonged release in mild-to-moderate hypertension: a randomized noninferiority trial versus torasemide immediate release.

The efficacy of a new torasemide prolonged release (PR) formulation to torasemide immediate release (IR) was compared in a randomized noninferiority double-blind trial. Patients with newly diagnosed mild-to-moderate hypertension or unresponsive or poor tolerability to previous antihypertensive monotherapy received 5 mg/day of torasemide-PR (n = 219) or torasemide-IR (n = 223) for 12 weeks (uptitration to 10 mg/day if no response at 4 or 8 weeks). Mean diastolic blood pressure (DBP) reduction in the torasemide-PR group (11.