Efficacy and safety of ozanimod in multiple sclerosis: Dose-blinded extension of a randomized phase II study.

Background: Ozanimod, an oral immunomodulator, selectively targets sphingosine 1-phosphate receptors 1 and 5.

Objective: Evaluate efficacy, safety, and tolerability of ozanimod in relapsing multiple sclerosis.

Methods: In the RADIANCE Part A phase II study (NCT01628393), participants with relapsing multiple sclerosis were randomized (1:1:1) to once-daily ozanimod hydrochloride (0.

The role of carbon monoxide and heme oxygenase in the prevention of sickle cell disease vaso-occlusive crises.

Sickle Cell Disease (SCD) is a painful, lifelong hemoglobinopathy inherited as a missense point mutation in the hemoglobin (Hb) beta-globin gene. This disease has significant impact on quality of life and mortality, thus a substantial medical need exists to reduce the vaso-occlusive crises which underlie the pathophysiology of the disease. The concept that a gaseous molecule may exert biological function has been well known for over one hundred years.

Anti-NKG2D monoclonal antibody (NNC0142-0002) in active Crohn's disease: a randomised controlled trial.

Objective: Anti-NKG2D (NNC0142-0002) is an antagonising human immunoglobulin G4 monoclonal antibody that binds to natural killer group 2 member D (NKG2D) receptors, which are expressed by T cells and innate lymphoid cells, and may be linked to mucosal damage in Crohn's disease (CD).

Design: Seventy-eight patients (aged ≥18 and ≤75 years) with CD for ≥3 months, Crohn's Disease Activity Index (CDAI) ≥220 and ≤450 and either C-reactive protein ≥10 mg/L or endoscopic evidence of inflammation, were randomised 1:1 to a single subcutaneous (SC) dose of 2 mg/kg anti-NKG2D or placebo. Primary endpoint was change in CDAI (ΔCDAI) from baseline to week 4.

Neuroprotection Trials in Traumatic Brain Injury.

Traumatic brain injury (TBI) is a significant cause of mortality and morbidity worldwide. Current treatment of acute TBI includes surgical intervention when needed, followed by supportive critical care such as optimizing cerebral perfusion, preventing pyrexia, and treating raised intracranial pressure. While effective in managing the primary injury to the brain and skull, these treatment modalities do not address the complex secondary cascades that occur at a cellular level following initial injury and greatly affect the ultimate neurologic outcome.

First-In-Human, Phase 1, Randomized, Dose-Escalation Trial with Recombinant Anti-IL-20 Monoclonal Antibody in Patients with Psoriasis.

Background: The current trial was a first-in-human clinical trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the recombinant monoclonal anti-interleukin-20 (IL-20) antibody, NNC0109-0012, which targets the inflammatory cytokine IL-20.

Methods: In total, 48 patients aged 18 to 75 years with moderate to severe stable chronic plaque psoriasis with affected body surface area ≥15% and physician global assessment score ≥3 were enrolled in this randomized, double-blind, multicenter, placebo-controlled, phase 1 dose-escalation trial. Patients were randomized within each single dose cohort (0.

A clinical trial of progesterone for severe traumatic brain injury.

Background: Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized, controlled trials. We investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized clinical trial.

Methods: We conducted a multinational placebo-controlled trial, in which 1195 patients, 16 to 70 years of age, with severe TBI (Glasgow Coma Scale score, ≤8 [on a scale of 3 to 15, with lower scores indicating a reduced level of consciousness] and at least one reactive pupil) were randomly assigned to receive progesterone or placebo.

Quantitative CT densitometry for predicting intracerebral hemorrhage growth.

Background And Purpose: Intracerebral hemorrhage growth independently predicts disability and death. We hypothesized that noncontrast quantitative CT densitometry reflects active bleeding and improves predictive models of growth.

Materials And Methods: We analyzed 81 of the 96 available baseline CT scans obtained <3 hours post-ICH from the placebo arm of the phase IIb trial of recombinant factor VIIa.

Reversal of clopidogrel-induced bleeding with rFVIIa in healthy subjects: a randomized, placebo-controlled, double-blind, exploratory study.

Background: Clopidogrel (Plavix®) therapy, although effective for minimizing risk of thrombotic events, is also associated with potential bleeding risk. Recombinant activated FVII (rFVIIa, NovoSeven®) induces hemostasis in hemophilia patients with inhibitors (alloantibodies) and has been proposed as potential treatment for mitigating clopidogrel therapy-mediated bleeding.

Methods: In this single-center, randomized, placebo-controlled, double-blind, dose-escalation, exploratory phase I trial, we assessed the safety and effects of rFVIIa in reversing clopidogrel-enhanced bleeding in an experimentally induced punch biopsy in healthy subjects.

Stroke: working toward a prioritized world agenda.

Background And Purpose: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.

Methods: Preliminary work was performed by seven working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.

Stroke: working toward a prioritized world agenda.

Background And Purpose: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.

Methods: Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.

Stroke: working toward a prioritized world agenda.

Background And Purpose: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.

Methods: Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.

Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects.

The use of warfarin has a well-known bleeding risk. Recombinant activated factor VII (rFVIIa) is a non-plasma-derived, rapid-acting, and rapidly infused potential treatment. This randomized, single-center, placebo-controlled, double-blinded, dose-escalation, exploratory phase 1 trial assessed safety and effects of rFVIIa in reversing warfarin-induced changes in bleeding and coagulation parameters, using a punch biopsy-induced bleeding model in healthy subjects.

Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial.

Background And Purpose: Patients with intracerebral hemorrhage have a high risk of thromboembolic events (TEs) due to advanced age, hypertension, atherosclerosis, diabetes, and immobility. Use of recombinant activated factor VII (rFVIIa) could increase TEs in high-risk patients. Factor Seven for Acute Hemorrhagic Stroke (FAST) trial data were reviewed to define the frequency of and risk factors for TE with rFVIIa.

Density and shape as CT predictors of intracerebral hemorrhage growth.

Background And Purpose: Intracerebral hemorrhage (ICH) growth predicts mortality and functional outcome. We hypothesized that irregular hematoma shape and density heterogeneity, reflecting active, multifocal bleeding or a variable bleeding time course, would predict ICH growth.

Methods: Three raters examined baseline sub-3-hour CT brain scans of 90 patients in the placebo arm of a Phase IIb trial of recombinant activated Factor VII in ICH.

Can a subset of intracerebral hemorrhage patients benefit from hemostatic therapy with recombinant activated factor VII?

Background And Purpose: In the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial, 80 microg/kg of recombinant activated factor VII (rFVIIa) significantly reduced intracerebral hemorrhage (ICH) expansion when given within 4 hours of onset. However, in contrast to an earlier Phase 2b study, rFVIIa did not improve survival or functional outcome. In this exploratory analysis, we hypothesized that earlier treatment and exclusion of patients with a poor prognosis at baseline might enhance the benefit of rFVIIa treatment.

Recombinant factor VIIA in traumatic intracerebral hemorrhage: results of a dose-escalation clinical trial.

Objective: Intracerebral hemorrhages, whether spontaneous or traumatic (tICH), often expand, and an association has been described between hemorrhage expansion and worse clinical outcomes. Recombinant factor VIIa (rFVIIa) is a hemostatic agent that has been shown to limit hemorrhage expansion and which, therefore, could potentially reduce morbidity and mortality in tICH. This first prospective, randomized, placebo-controlled, dose-escalation study evaluated the safety and preliminary effectiveness of rFVIIa to limit tICH progression.

Progression of traumatic intracerebral hemorrhage: a prospective observational study.

ABSTRACT Preliminary evidence has shown that intracerebral hemorrhages, either spontaneous (sICH) or traumatic (tICH) often expand over time. An association between hemorrhage expansion and clinical outcomes has been described for sICH. The intent of this prospective, observational study was to characterize the temporal profile of hemorrhage progression, as measured by serial computed tomography (CT) scanning, with the aim of better understanding the natural course of hemorrhage progression in tICH.

Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage.

Background: Intracerebral hemorrhage is the least treatable form of stroke. We performed this phase 3 trial to confirm a previous study in which recombinant activated factor VII (rFVIIa) reduced growth of the hematoma and improved survival and functional outcomes.

Methods: We randomly assigned 841 patients with intracerebral hemorrhage to receive placebo (268 patients), 20 microg of rFVIIa per kilogram of body weight (276 patients), or 80 microg of rFVIIa per kilogram (297 patients) within 4 hours after the onset of stroke.

Risk of thromboembolic events in controlled trials of rFVIIa in spontaneous intracerebral hemorrhage.

Background And Purpose: Recombinant activated factor VII (rFVIIa) reduces hematoma expansion and improves outcome after intracerebral hemorrhage (ICH), with an apparent increase in nonfatal thromboembolic events (TEs) with higher doses. Despite low incidences of such events in rFVIIa-treated hemophiliacs, the frequency in older patients with more atherosclerosis and immobility has yet to be defined.

Methods: Data were pooled from 3 randomized placebo-controlled studies in patients diagnosed within 3 hours of spontaneous ICH who received a single dose of rFVIIa (5 to 160 microg/kg; n=371) or placebo (n=115).

Impact of recombinant activated factor VII on health-related quality of life after intracerebral hemorrhage.

Background: We recently demonstrated that recombinant activated factor VII (rFVIIa) given to patients presenting within 3 h of acute spontaneous intracerebral hemorrhage (ICH) reduces mortality (18% vs. 29%) and poor outcome (modified Rankin Scale, mRS, 4-6, 53 vs. 69%).

Determinants of intracerebral hemorrhage growth: an exploratory analysis.

Background And Purpose: We report an exploratory analysis from a randomized study of recombinant activated factor VII (rFVIIa) in patients with intracerebral hemorrhage (ICH) examining potential factors associated with hemorrhage growth.

Methods: We explored the relationship between 5 different measures of change in hemorrhage volume between baseline and 24-hour CTs (absolute and percent change in ICH volume, ICH growth-categoric [no growth if change <33% and <12.5 mL], absolute and percent change in ICH plus intraventricular hemorrhage [IVH] volume) and 31 demographic, clinical, imaging, historic, and baseline laboratory variables.

Dynamics of intraventricular hemorrhage in patients with spontaneous intracerebral hemorrhage: risk factors, clinical impact, and effect of hemostatic therapy with recombinant activated factor VII.

Objective: To evaluate predictors of intraventricular hemorrhage (IVH) and IVH growth, impact of IVH growth on outcome, and impact of recombinant activated factor VII (rFVIIa) in patients with intracerebral hemorrhage (ICH).

Methods: We analyzed 374 patients out of 399 who were randomized to rFVIIa (40, 80, or 160 mug/kg) or placebo for ICH (diagnosed within 3 h of symptoms). Risk factors for IVH growth (>2 ml increase in IVH volume at 24 h), and death or severe disability (modified Rankin scale score 4-6) at 3 months were identified (logistic regression).