Izokibep for the treatment of moderate-to-severe plaque psoriasis: a phase II, randomized, placebo-controlled, double-blind, dose-finding multicentre study including long-term treatment.

BACKGROUND: Monoclonal antibodies to interleukin (IL)-17 have shown strong efficacy in patients with psoriasis. Izokibep is a unique IL-17A inhibitor with a small molecular size and favourable distribution to sites of inflammation. OBJECTIVES: To evaluate the dose response, efficacy and safety of izokibep in patients with plaque psoriasis. METHODS: In this double-blind, randomized, phase II dose-finding study (AFFIRM-35) in adults with moderate-to-severe plaque psoriasis and inadequate response to two or more standard therapies, patients were randomized (1:1:1:1:1) to placebo or izokibep 2, 20, 80 or 160 mg every 2 weeks for 12 weeks. During the remainder of the 52-week core study, patients given placebo were switched to izokibep 80 mg, and dosing intervals were adapted based on Psoriasis Area and Severity Index (PASI) scores for all patients. The core study was followed by two optional consecutive 1-year extension periods for a total duration of 3 years. The primary endpoint was a 90% reduction in PASI score (PASI 90) at week 12. Additional efficacy outcomes and adverse event (AE) rates were evaluated. RESULTS: In total, 109 patients were randomized [safety set, n = 108 (one exclusion criteria failure); full analysis set, n = 106]. At week 12, PASI 90 response rates were 0%, 5%, 19%, 71% and 59% for the placebo, 2-, 20-, 80- and 160-mg izokibep groups, respectively. Rapid dose-dependent improvements were also observed across other efficacy outcomes. During the placebo-controlled period, AEs in the izokibep groups were similar to placebo except for mild injection site reactions. AEs were generally mild to moderate and the drug was well tolerated. Izokibep maintained efficacy at the higher dosage groups for up to 3 years, with no new safety signals. CONCLUSIONS: Data from this phase II study indicate that izokibep is well tolerated and efficacious in the treatment of plaque psoriasis. Higher doses or more frequent dosing could be explored to further enhance response rates.

Existing Data Sources in Clinical Epidemiology: The Danish COVID-19 Cohort.

BACKGROUND: To facilitate research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a prospective cohort of all Danish residents tested for SARS-CoV-2 in Denmark is established. DATA STRUCTURE: All Danish residents tested by reverse transcriptase polymerase chain reactions (RT-PCR) for SARS-CoV-2 in Denmark are included. The cohort is identified using the Danish Microbiology Database. Individual-level record linkage between administrative and health-care registries is facilitated by the Danish Civil Registration System. Information on outcomes related to SARS-CoV-2 infection includes hospital admission, intensive care unit admission, mechanical ventilation, and death and is retrieved from the five administrative Danish regions, the Danish National Patient Registry, and the Danish Register of Causes of Death. The Patient Registry further provides a complete hospital contact history of somatic and psychiatric conditions and procedures. Data on all prescriptions filled at community pharmacies are available from the Danish National Prescription Registry. Health-care authorization status is obtained from the Danish Register of Healthcare Professionals. Finally, selected laboratory values are obtained from the Register of Laboratory Results for Research. The cohort is governed by a steering committee with representatives from the Danish Medicines Agency, Statens Serum Institut, the Danish Health Authority, the Danish Health Data Authority, Danish Patients, the Faculties of Health Sciences at the Danish universities, and Danish regions. The steering committee welcomes suggestions for research studies and collaborations. Research proposals will be prioritized based on timeliness and potential clinical and public health implications. All research protocols assessing specific hypotheses for medicines will be made publicly available using the European Union electronic Register of Post-Authorisation Studies. CONCLUSION: The Danish COVID-19 cohort includes all Danish residents with an RT-PCR test for SARS-CoV-2. Through individual-level linkage with existing Danish health and administrative registries, this is a valuable data source for epidemiological research on SARS-CoV-2.

Big Data - How to Realize the Promise.

The increasing volume and complexity of data now being captured across multiple settings and devices offers the opportunity to deliver a better characterization of diseases, treatments, and the performance of medicinal products in individual healthcare systems. Such data sources, commonly labeled as big data, are generally large, accumulating rapidly, and incorporate multiple data types and forms. Determining the acceptability of these data to support regulatory decisions demands an understanding of data provenance and quality in addition to confirming the validity of new approaches and methods for processing and analyzing these data. The Heads of Agencies and the European Medicines Agency Joint Big Data Taskforce was established to consider these issues from the regulatory perspective. This review reflects the thinking from its first phase and describes the big data landscape from a regulatory perspective and the challenges to be addressed in order that regulators can know when and how to have confidence in the evidence generated from big datasets.

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.

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].).

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.

Recombinant factor VIIa (rFVIIa): its potential role as a hemostatic agent.

Recombinant activated coagulation factor VII (rFVIIa) was developed for the treatment of patients with hemophilia who have developed inhibitors against the factor they are missing. Hemophilia is a serious bleeding disorder and patients with hemophilia develop repeated spontaneous CNS, joint and muscle bleeding. Any trauma, even mild events, may cause life-threatening bleeding, and without treatment, these patients have a life expectancy of about 16 years. Thus, hemophilia can be regarded as a model of severe bleeding, and an agent capable of inducing hemostasis in severe hemophilia independent of the hemophilia proteins (FVIII or FIX) may also be effective in patients without hemophilia who experience serious bleeds. The availability of rFVIIa stimulated research on the role of FVII and tissue factor (TF) in the hemostatic process. As a result, a picture partly different from the one suggested by previous models has emerged. These previous models basically neglected the role of cells and cell membranes. The importance of platelets and platelet membrane phospholipids in hemostasis has been demonstrated, and the new concept of the hemostatic process, focusing on cell surfaces, has been outlined.

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. Variables with a probability value of < or =0.10 were included in the final multivariable models. RESULTS: Treatment with rFVIIa and a longer time-from-onset-to-baseline CT were related to a decrease in hemorrhage growth in all 5 models. ICH volume on baseline CT was consistently associated with ICH growth in the various models. Other variables significantly related to growth of ICH or ICH+IVH in at least 1 of the 5 models include serum glucose (increased levels associated with increased growth), body mass index (heavier people have less growth), prior use of antiplatelet agent (prior use associated with increased growth), serum cholesterol (higher level associated with less hemorrhage growth), and serum creatinine (higher level associated with more hemorrhage growth). CONCLUSIONS: Our exploratory analyses confirm that treatment with rFVIIa limits ICH growth in subjects with spontaneous ICH who met the criteria for this study. Most hematoma growth occurs early after onset of ICH. Larger hematomas on the baseline CT were associated with increased absolute ICH growth. The relationship of other factors to hemorrhage growth warrants further study.

Recombinant activated factor VII for acute intracerebral hemorrhage: US phase IIA trial.

BACKGROUND AND PURPOSE: Ultra-early hemostatic therapy may improve outcome after intracerebral hemorrhage (ICH) by preventing rebleeding and hematoma expansion. We conducted this trial to evaluate the safety of activated recombinant factor VII (rFVIIa; NovoSeven) for preventing early hematoma growth in acute ICH. METHODS: In this multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial, 40 patients diagnosed with ICH by computed tomography within 3 hours of onset were treated with placebo or 5, 20, 40, or 80 microg/kg of rFVIIa ( n = 8 per group). Patients with any history of thromboembolic or vaso-occlusive disease were excluded. The primary endpoint was the frequency of adverse events (AEs). RESULTS: Mean age was 65 years (range 34 - 91) and the median admission Glasgow Coma Scale score was 14.5 (range 6 to 15). Mean ICH volume was 17 +/- 19 mL; nearly three-quarters were located in the basal ganglia ( n = 29). The mean interval from onset to treatment was 178 +/- 41 minutes. Thirty-three patients experienced 186 AEs, which occurred with similar frequency in the five groups. There were 10 thromboembolic AEs, including one case of deep vein thrombosis (20 microg g/kg group); one case of cerebral infarction (placebo); two cases of pulmonary embolism (20 and 40 microg g/kg groups); and six instances of ischemic ECG changes or cardiac enzyme elevation (placebo [ n = 2], 20 microg g/kg [ n = 1], 40 microg g/kg [ n = 1], and 80 microg g/kg [ n = 2] groups). No consumption coagulopathy or dose-related increase in edema-to-ICH volume ratio occurred. CONCLUSIONS: Ultra-early rFVIIa treatment for ICH was associated with a reasonable safety profile in this preliminary study across a wide range of dosages. Further research is warranted to investigate the safety and potential efficacy of rFVIIa for minimizing ICH growth.

Recombinant activated factor VII for acute intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage is the least treatable form of stroke and is associated with high mortality. Among patients who undergo computed tomography (CT) within three hours after the onset of intracerebral hemorrhage, one third have an increase in the volume of the hematoma related to subsequent bleeding. We sought to determine whether recombinant activated factor VII (rFVIIa) can reduce hematoma growth after intracerebral hemorrhage. METHODS: We randomly assigned 399 patients with intracerebral hemorrhage diagnosed by CT within three hours after onset to receive placebo (96 patients) or 40 microg of rFVIIa per kilogram of body weight (108 patients), 80 microg per kilogram (92 patients), or 160 microg per kilogram (103 patients) within one hour after the baseline scan. The primary outcome measure was the percent change in the volume of the intracerebral hemorrhage at 24 hours. Clinical outcomes were assessed at 90 days. RESULTS: Hematoma volume increased more in the placebo group than in the rFVIIa groups. The mean increase was 29 percent in the placebo group, as compared with 16 percent, 14 percent, and 11 percent in the groups given 40 microg, 80 microg, and 160 microg of rFVIIa per kilogram, respectively (P=0.01 for the comparison of the three rFVIIa groups with the placebo group). Growth in the volume of intracerebral hemorrhage was reduced by 3.3 ml, 4.5 ml, and 5.8 ml in the three treatment groups, as compared with that in the placebo group (P=0.01). Sixty-nine percent of placebo-treated patients died or were severely disabled (as defined by a modified Rankin Scale score of 4 to 6), as compared with 55 percent, 49 percent, and 54 percent of the patients who were given 40, 80, and 160 microg of rFVIIa, respectively (P=0.004 for the comparison of the three rFVIIa groups with the placebo group). Mortality at 90 days was 29 percent for patients who received placebo, as compared with 18 percent in the three rFVIIa groups combined (P=0.02). Serious thromboembolic adverse events, mainly myocardial or cerebral infarction, occurred in 7 percent of rFVIIa-treated patients, as compared with 2 percent of those given placebo (P=0.12). CONCLUSIONS: Treatment with rFVIIa within four hours after the onset of intracerebral hemorrhage limits the growth of the hematoma, reduces mortality, and improves functional outcomes at 90 days, despite a small increase in the frequency of thromboembolic adverse events.

Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Hematoma growth occurs in 38% of intracerebral hemorrhage (ICH) patients scanned by computed tomography (CT) within 3 hours of onset. Activated recombinant factor VII (rFVIIa) promotes hemostasis at sites of vascular injury and may minimize hematoma growth after ICH. METHODS: In this randomized, double-blind, placebo-controlled, dose-escalation trial, 48 subjects with ICH diagnosed within 3 hours of onset were treated with placebo (n=12) or rFVIIa (10, 20, 40, 80, 120, or 160 microg/kg; n=6 per group). The primary endpoint was the frequency of adverse events (AEs). Safety assessments included serial electrocardiography (ECG), troponin I and coagulation testing, lower extremity Doppler ultrasonography, and calculation of edema:ICH volume ratios. RESULTS: Mean age was 61 years (range, 30 to 93) and 57% were male. At admission, mean National Institutes of Health Stroke Scale (NIHSS) score was 14 (range, 1 to 26), median Glasgow Coma Scale score was 14 (range, 6 to 15), and mean ICH volume was 21 mL (range, 1 to 151). Mean time from onset to treatment was 181 minutes (range, 120 to 265). Twelve serious AEs occurred, including 5 deaths (mortality 11%). Six AEs were considered possibly treatment-related, including rash, vomiting, fever, ECG T-wave inversion, and 2 cases of deep vein thrombosis (placebo and 20-microg/kg groups). No myocardial ischemia, consumption coagulopathy, or dose-related increase in edema:ICH volume occurred. CONCLUSIONS: This small phase II trial evaluated a wide range of rFVIIa doses in acute ICH and raised no major safety concerns. Larger studies are justified to determine whether rFVIIa can safely and effectively limit ICH growth.