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 (0.5 or 1 mg) or placebo. After 24 weeks, participants could enter a 2-year, dose-blinded extension. Ozanimod-treated participants continued their assigned dose; placebo participants were re-randomized (1:1) to ozanimod hydrochloride 0.5 or 1 mg (equivalent to ozanimod 0.46 and 0.92 mg). RESULTS: A total of 223 (89.6%) of the 249 participants completed the blinded extension. At 2 years of the extension, the percentage of participants who were gadolinium-enhancing lesion-free ranged from 86.5% to 94.6%. Unadjusted annualized relapse rate during the blinded extension (week 24-end of treatment) was 0.32 for ozanimod hydrochloride 0.5 mg → ozanimod hydrochloride 0.5 mg, 0.18 for ozanimod hydrochloride 1 mg → ozanimod hydrochloride 1 mg, 0.30 for placebo → ozanimod hydrochloride 0.5 mg, and 0.18 for placebo → ozanimod hydrochloride 1 mg. No second-degree or higher atrioventricular block or serious opportunistic infection was reported. CONCLUSION: Ozanimod demonstrated sustained efficacy in participants continuing treatment up to 2 years and reached similar efficacy in participants who switched from placebo; no unexpected safety signals emerged.

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. Carbon monoxide (CO), although studied in SCD for over 50 years, has recently emerged as a powerful cytoprotective biological response modifier capable of regulating a host of physiologic and therapeutic processes that, at low concentrations, exerts key physiological functions in various models of tissue inflammation and injury. CO is physiologically generated by the metabolism of heme by the heme oxygenase enzymes and is measurable in blood. A substantial amount of preclinical and clinical data with CO have been generated, which provide compelling support for CO as a potential therapeutic in a number of pathological conditions. Data underlying the therapeutic mechanisms of CO, including in SCD, have been generated by a plethora of in vitro and preclinical studies including multiple SCD mouse models. These data show CO to have key signaling impacts on a host of metallo-enzymes as well as key modulating genes that in sum, result in significant anti-inflammatory, anti-oxidant and anti-apoptotic effects as well as vasodilation and anti-adhesion of cells to the endothelium resulting in preservation of vascular flow. CO may also have a role as an anti-polymerization HbS agent. In addition, considerable scientific data in the non-SCD literature provide evidence for a beneficial impact of CO on cerebrovascular complications, suggesting that in SCD, CO could potentially limit these highly problematic neurologic outcomes. Research is needed and hopefully forthcoming, to carefully elucidate the safety and benefits of this potential therapy across the age spectrum of patients impacted by the host of pathophysiological complications of this devastating disease.

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. Prespecified significance level was 10% for CDAI endpoints. A futility analysis was instituted due to slow recruitment. RESULTS: Primary endpoint was not significantly different between anti-NKG2D and placebo (week 4 ΔCDAI=-16); however, there was a significant difference by week 12 (ΔCDAI=-55; p≤0.10). Significant improvements were noted in the non-failure to biologics subgroup (treated with anti-NKG2D (n=28)) from week 1 onward. Greater effects of anti-NKG2D were also observed in patients with baseline CDAI ≥330. Frequencies of adverse events (AEs) were comparable between anti-NKG2D and placebo. Most AEs were mild (49%) or moderate (43%). No antidrug antibodies were observed. CONCLUSIONS: A single SC dose of 2 mg/kg anti-NKG2D did not reduce disease activity at week 4 versus placebo, but the difference was significant at week 12, and effects were evident in key subgroups. These data support further development of anti-NKG2D in IBD. TRIAL REGISTRATION NUMBER: NCT01203631.

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 (0.01, 0.05, 0.2, 0.6, 1.5, or 3.0 mg/kg) or multiple dose cohort (0.05, 0.2, 0.5, 1.0, or 2.0 mg/kg; 1 dose every other week for 7 weeks) of NNC0109-0012 or placebo in a 3:1 ratio. In the expansion phase, 7 patients were randomized to weekly doses of 2.0 mg/kg NNC0109-0012 or placebo for 7 weeks. The primary objective, safety and tolerability, was assessed by evaluating adverse events (AEs). Additional endpoints included pharmacokinetics, pharmacodynamics, and clinical response (assessed using the Psoriasis Area and Severity Index [PASI] score). RESULTS: AEs were reported in 85% of patients (n = 40) in the initial study phases (NNC0109-0012, 83%; placebo, 92%) and in 4 of 7 patients in the multiple-dose expansion phase. One serious AE was reported but was judged not to be causally related to NNC0109-0012. No dose-limiting toxicities were reported. NNC0109-0012 pharmacokinetics was similar to other monoclonal antibodies, with an average half-life of approximately 3 weeks. There was a dose-proportional increase in area under the curve and maximum concentration after single dosing. No substantial changes in pharmacodynamic parameters were observed. The expansion phase was terminated early due to apparent lack of PASI improvement. CONCLUSION: Single and multiple doses of NNC0109-0012, ranging from 0.05 to 3.0 mg/kg, were well tolerated in patients with psoriasis and exhibited pharmacokinetics similar to that of other monoclonal antibodies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01261767.

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. Dosing began within 8 hours after injury and continued for 120 hours. The primary efficacy end point was the Glasgow Outcome Scale score at 6 months after the injury. RESULTS: Proportional-odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18). The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo. CONCLUSIONS: Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials. (Funded by BHR Pharma; SYNAPSE ClinicalTrials.gov number, NCT01143064.).

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. Efficacy assessments included the reversal of bleeding characteristics (bleed duration [BD], the primary end point and blood loss volume [BV] induced by punch biopsy, and thromboelastograph [TEG®] parameters) with rFVIIa or placebo after clopidogrel treatment. RESULTS: A significant number of subjects (56%) had limited response to clopidogrel (defined as ≤30% platelet aggregation inhibition) and were discontinued from study. The remaining subjects continued and had 4 biopsies. Of 40 subjects randomized, 37 were evaluated for efficacy. Clopidogrel treatment increased BD and BV compared with the baseline biopsy. Recombinant FVIIa (10 and 20 µg/kg) significantly mitigated the clopidogrel-induced effects on BV (P = 0.007 and P = 0.001, respectively). Early trial termination limited the evaluation of effects of higher rFVIIa doses. Subgroup analyses of subjects biopsied by the same physician demonstrated significant reduction of clopidogrel-induced BD with 20 µg/kg rFVIIa (P = 0.048). Ex vivo analysis of rFVIIa demonstrated clotting dynamics presented by parameters time to clot onset (TEG®-R) and clot angle (TEG®-A) (P < 0.005). CONCLUSIONS: In this clinical study, rFVIIa (10 and 20 µg/kg) reversed the effect of clopidogrel on blood loss.

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. RESULTS: Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent 'silo' mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a 'Brain Health' concept that enables promotion of preventive measures. CONCLUSIONS: To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.

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. RESULTS: Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent 'silo' mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (e.g., social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a 'Brain Health' concept that enables promotion of preventive measures. CONCLUSIONS: To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.

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. RESULTS: Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent "silo" mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a "Brain Health" concept that enables promotion of preventive measures. CONCLUSIONS: To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.

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. The effects of warfarin (experiment 1) and rFVIIa (5-80 microg/kg; experiment 2) were evaluated. Outcomes were bleeding duration, blood loss, coagulation parameters, and safety. Warfarin treatment significantly increased bleeding duration and blood loss from pretreatment (experiment 1, 12 subjects). However, these parameters after rFVIIa treatment were not significantly different from placebo (experiment 2, 85 subjects). Mean activated partial thromboplastin time, prothrombin time, and international normalized ratio were reduced from warfarin-elevated levels. rFVIIa (80 microg/kg) significantly reversed warfarin effects on all thromboelastography parameters, compared with placebo (P < .05), and returned the thrombin generation speed to baseline. There were no thromboembolic or serious adverse events. In this exploratory trial, the reversal of warfarin effects was observed in the thromboelastography, thrombin generation, and clotting assays. However, this reversal did not translate to improvements in the bleeding model parameters evaluated in the punch biopsy model. Trial registration is exempt (phase 1).

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. METHODS: Eight hundred forty-one patients presenting <3 hours after spontaneous intracerebral hemorrhage were randomized to 20 or 80 microg/kg of rFVIIa or placebo. Those with Glasgow Coma Scale score <5, planned early surgery, coagulopathy, or recent TE were excluded. Myocardial, cerebral, or venous TEs were subject to detailed reporting and expedited local review. Additionally, a blinded Data Monitoring Committee reviewed all electrocardiograms, centrally analyzed troponin I values, and CT scans. RESULTS: There were 178 arterial and 47 venous TEs. Venous events were similar across groups. There were 49 (27%) arterial events in the placebo group, 47 (26%) in the 20-microg/kg group, and 82 (46%) in the 80 microg/kg group (P=0.04). Of the myocardial events, 38 were investigator-reported and 103 identified by the Data Monitoring Committee. They occurred in 17 (6.3%) placebo and 57 (9.9%) rFVIIa patients (P=0.09). Arterial TEs were associated with: receiving 80 microg/kg rFVIIa (OR=2.14; P=0.031), signs of cardiac or cerebral ischemia at presentation (OR=4.19; P=0.010), age (OR=1.14/5 years; P=0.0123), and prior use of antiplatelet agents (OR=1.83; P=0.035). Ischemic strokes possibly related to study drug occurred in 7, 5, and 8 patients in the placebo, 20 microg/kg, and 80-microg/kg groups, respectively. CONCLUSIONS: Higher doses of rFVIIa in a high-risk population are associated with a small increased risk of what are usually minor cardiac events. Demonstration of the ability of rFVIIa to improve outcome in future studies should be driven by its effectiveness in slowing bleeding outweighting the risk of a small increase in arterial TEs.

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. Each rater, blinded to growth data, independently applied novel 5-point categorical scales of density and shape to randomly presented baseline CT images of ICH. Density and shape were defined as either homogeneous/regular (Category 1 to 2) or heterogeneous/irregular (Category 3 to 5). Within- and between-rater reliability was determined for these scales. Growth was assessed as a continuous variable and using 3 binary definitions: (1) any ICH growth; (2) >or=33% or >or=12.5 mL ICH growth; and (3) radial growth >1 mm between baseline and 24-hour CT scan. Patients were divided into tertiles of baseline ICH volume: "small" (0 to 10 mL), "medium" (10 to 25 mL), and "large" (25 to 106 mL). RESULTS: Inter- and intrarater agreements for the novel scales exceeded 85% (+/-1 category). Median growth was significantly higher in the large-volume group compared with the small group (P<0.001) and in heterogeneous compared with homogeneous ICH (P=0.008). Median growth trended higher in irregular ICHs compared with regular ICHs (P=0.084). Small ICHs were more regularly shaped (43%) than medium (17%) and large (3%) ICHs (P<0.001). Small ICHs were more homogeneous (73%) compared with medium (37%) and large (17%) ICHs (P<0.001). Adjusting for baseline ICH volume and time to scan, density heterogeneity, but not shape irregularity, independently predicted ICH growth (P=0.046) on a continuous growth scale. CONCLUSIONS: Large ICHs were significantly more irregular in shape, heterogeneous in density, and had greater growth. Density heterogeneity independently predicted ICH growth using some definitions.

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. METHODS: Using the FAST data set, the impact of rFVIIa (80 microg/kg) on poor outcome at 3 months (modified Rankin Score of 5 or 6) was systematically evaluated within subgroups using clinically meaningful cut points in onset-to-treatment time, age, and baseline ICH and intraventricular hemorrhage volume. The effect of treatment on outcome was analyzed using logistic regression, and ICH volume was analyzed with linear mixed models. RESULTS: A subgroup (n=160, 19% of the FAST population) was identified comprising patients

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. The primary end point was poor outcome, defined as severe disability or death according to the modified Rankin scale 90 days after the stroke. RESULTS: Treatment with 80 microg of rFVIIa per kilogram resulted in a significant reduction in growth in volume of the hemorrhage. The mean estimated increase in volume of the intracerebral hemorrhage at 24 hours was 26% in the placebo group, as compared with 18% in the group receiving 20 microg of rFVIIa per kilogram (P=0.09) and 11% in the group receiving 80 microg (P<0.001). The growth in volume of intracerebral hemorrhage was reduced by 2.6 ml (95% confidence interval [CI], -0.3 to 5.5; P=0.08) in the group receiving 20 microg of rFVIIa per kilogram and by 3.8 ml (95% CI, 0.9 to 6.7; P=0.009) in the group receiving 80 microg, as compared with the placebo group. Despite this reduction in bleeding, there was no significant difference among the three groups in the proportion of patients with poor clinical outcome (24% in the placebo group, 26% in the group receiving 20 microg of rFVIIa per kilogram, and 29% in the group receiving 80 microg). The overall frequency of thromboembolic serious adverse events was similar in the three groups; however, arterial events were more frequent in the group receiving 80 microg of rFVIIa than in the placebo group (9% vs. 4%, P=0.04). CONCLUSIONS: Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage. (ClinicalTrials.gov number, NCT00127283 [ClinicalTrials.gov].).

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. METHODS: Patients were enrolled if they had tICH lesions of at least 2 ml on a baseline computed tomographic scan obtained within 6 hours of injury. rFVIIa or placebo was administered within 2.5 hours of the baseline computed tomographic scan but no later than 7 hours after injury. Computed tomographic scans were repeated at 24 and 72 hours. Five escalating dose tiers were evaluated (40, 80, 120, 160, and 200 microg/kg rFVIIa). Clinical evaluations and adverse events were recorded until Day 15. RESULTS: No significant differences were detected in mortality rate or number and type of adverse events among treatment groups. Asymptomatic deep vein thrombosis, detected on routinely performed ultrasound at Day 3, was observed more frequently in the combined rFVIIa treatment group (placebo, 3%; rFVIIa, 8%; not significant). A nonsignificant trend for rFVIIa dose-response to limit tICH volume increase was observed (placebo, 21.0 ml; rFVIIa, 10.1 ml). CONCLUSION: In this first prospective study of rFVIIa in tICH, there appeared to be less hematoma progression in rFVIIa-treated patients (80-200 microg/kg) compared with that seen in placebo treated patients. The potential significance of this biological effect on clinical outcomes and the significance of the somewhat higher incidence of ultrasound-detected deep vein thromboses in the rFVIIa-treated group need to be examined in a larger prospective randomized clinical trial.

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. There was also a desire to document the baseline adverse event (AE) profile in this patient group. An important motive for performing this study was to set the stage for subsequent studies that will examine the role of a new systemic hemostatic agent in tICH. Subjects were enrolled if they had tICH lesions of at least 2 mL on a baseline CT scan obtained within 6 h of a head injury. CT scans were repeated at 24 and 72 h. Clinical outcomes and pre-defined AEs were documented. The data showed that 51% of the subjects demonstrated an increase in tICH volume, and that most of the increase occurred early. In addition, larger hematomas exhibited the greatest expansion. Thromboembolic complications were identified in 13% of subjects. This study demonstrates that tICH expansion between the baseline and 24-h CT scans occurred in approximately half of the subjects. The earlier after injury that the initial CT scan is obtained, the greater is the likelihood that the hematoma will expand on subsequent scans. The time frame during which hemorrhagic expansion occurs provides an opportunity for early intervention to limit a process with adverse prognostic implications.

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). Clinical/laboratory evaluations, lower extremity Doppler studies, and 72-hour CT scans were used to monitor for TEs. Adverse events occurring while hospitalized and serious events occurring through day 90 were carefully reviewed. RESULTS: There was no overall increase in risk of total TEs in rFVIIa-treated patents; however, there were more arterial, but not venous, TEs in the high dose group (120 to 160 microg/kg) compared with placebo (5.4% versus 1.7%; P=0.13). Arterial events occurring within 7 days of drug administration classified as possibly or probably associated with study drug included myocardial ischemia (n=9, 8 were non-ST-segment elevation and non-Q-wave events; 2 of the 9 had sequelae) and ischemic stroke (n=9, 4 of which had likely causes other than rFVIIa). Regression analysis identified high doses (120 to 160 microg/kg) of rFVIIa as the only factor associated with arterial TEs (odds ratio=6.75; P=0.02). CONCLUSIONS: There appears to be a increased risk of arterial TEs associated with higher doses of rFVIIa in ICH patients as compared with placebo. Further studies are underway to identify specific factors associated with these events and to define the dose that maximizes benefit and minimizes risk.

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%). This analysis was performed to determine the impact of rFVIIa on health-related quality of life (HRQoL) in those patients. METHODS: In a prospective, randomized controlled trial, 399 patients (mean age, 66 years) received placebo, 40, 80 or 160 microg/kg of rFVIIa within 4 h of acute ICH. At 90 days, HRQoL was assessed with the EuroQoL (EQ-5D), a 5-dimensional measure of health which also includes the Visual Analogue Scale. Additionally, each level of the 90-day mRS was adjusted, using 4 different previously published utility values, to obtain a clearer picture of perceived HRQoL. RESULTS: Among the 5 dimensions of EQ-5D, only mobility rating was significantly better for rFVIIa-treated patients (serious problems, 34 vs. 54%; p = 0.01). Yet, the utility value (scaled 1.0 = perfect health and 0.0 = dead) associated with the composite EQ-5D demonstrated significantly better HRQoL (0.48 vs. 0.36; p = 0.01). This was also true for the EQ-5D Visual Analogue Scale score (44 vs. 36; p = 0.04). Finally, all 4 algorithms for applying utility scores to the mRS indicated that rFVIIa was associated with significantly better perceived HRQoL (all p < 0.006). CONCLUSIONS: Treatment with rFVIIa within 4 h of acute spontaneous ICH improves HRQoL.