Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease.

Crizanlizumab is an anti-P-selectin monoclonal antibody indicated to reduce the frequency/prevent recurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) aged ≥16 years. This analysis of an ongoing phase 2, nonrandomized, open-label study reports the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of crizanlizumab 5.0 mg/kg (N = 45) and 7.5 mg/kg (N = 12) in patients with SCD with a history of VOCs. The median treatment duration was 104.7 and 85.7 weeks in the 5.0 and 7.5 mg/kg groups, respectively. For both doses, serum crizanlizumab concentrations rose to near maximum levels shortly after infusion, and near complete and sustained ex vivo P-selectin inhibition was observed. Grade ≥3 adverse events (AEs) occurred in 48.9% and 33.3% of patients in the 5.0 and 7.5 mg/kg groups, respectively; only 1 event was deemed treatment-related (7.5 mg/kg group). No treatment-related serious AEs occurred. One infusion-related reaction was recorded (5.0 mg/kg, grade 2 "pain during infusion"), which resolved without treatment withdrawal. Infections occurred in 57.8% and 41.7% of patients in the 5.0 and 7.5 mg/kg groups, respectively; none were drug-related. No treatment-related bleeding events were reported. No patients developed immunogenicity. The median (range) absolute reduction from baseline in the annualized rate of VOCs leading to a health care visit was -0.88 (-14.7 to 13.3) and -0.93 (-2.0 to 0.4) in the 5.0 and 7.5 mg/kg groups, respectively. Results here demonstrate the PK/PD properties of crizanlizumab in patients with SCD and the potential sustained efficacy and long-term safety of the drug after >12 months' treatment. This trial was registered at www.clinicaltrials.gov as #NCT03264989.

Influence of age on thrombolysis outcome in wake-up stroke.

BACKGROUND AND PURPOSE: Thrombolysis in patients >80 years remains controversial; we hypothesized that >80-year-old patients with wake-up ischemic stroke (WUIS) will benefit from thrombolysis despite risks because of poor outcomes with no treatment. METHODS: The study included 68 thrombolysed patients with WUIS (33 [48%] >80 years), 54 nonthrombolysed patients with WUIS (21 [39%] >80 years), and 117 patients (>80 years old) thrombolysed within 4.5 hours of symptom onset (reference group). Mortality and modified Rankin Scale (mRS) were assessed at 90 days. RESULTS: Baseline characteristics of thrombolysed and nonthrombolysed >80 and ≤80-year-old patients with WUIS were comparable. Thrombolysis outcomes in >80-year-old patients with WUIS were better than in nonthrombolysed >80-year-old patients with WUIS (90-day mortality: 24% versus 47%, P=0.034; mRS 0-2: 30% versus 5%, P=0.023; mRS 0-1: 15% versus 5%, P=0.24) and comparable with thrombolysed ≤80-year-old patients with WUIS. Thrombolysis was associated with odds ratio 0.27 (95% confidence interval, 0.05-0.97) for mortality and odds ratio 28.6 (95% confidence interval, 1.8-448) for mRS 0 to 2 at 90 days in >80-year-old patients with WUIS after adjusting for stroke severity and risk factors. CONCLUSIONS: Thrombolysis may be associated with greater benefit in >80-year-old patients with WUIS but a selection bias favoring thrombolysis in those most likely to benefit may significantly reduce interpretability of these findings.

A case-controlled comparison of thrombolysis outcomes between wake-up and known time of onset ischemic stroke patients.

BACKGROUND AND PURPOSE: Wake-up ischemic stroke (WUIS) patients are not thrombolysed even if they meet other criteria for treatment. We hypothesized that patients with WUIS showing no or early ischemic changes on brain imaging will have thrombolysis outcomes comparable with those with known time of symptom onset. METHODS: Consecutive sampling of a prospective registry of patients with stroke between January 2009 and December 2010 identified 394 thrombolysed patients meeting predefined inclusion criteria, 326 presenting within 0 to 4.5 hours of symptom onset (Reference Group) and 68 WUIS patients. Inclusion criteria were last seen normal<12 hours or >4.5 hours (WUIS) or presented <4.5 hours (Reference Group), had National Institutes of Health Stroke Scale score ≥5, and no or early ischemic changes on imaging at presentation. The primary outcome measure was the modified Rankin Scale of 0 to 2 at 90 days measured by trained assessors blinded to patient grouping. Other outcome measures were symptomatic intracerebral hemorrhage, modified Rankin Scale 0 to 1, and mortality at 90 days. RESULTS: The groups were comparable for mean age (72.8 versus 73.9 years; P=0.58) and baseline median National Institutes of Health Stroke Scale score (median 13 versus 12; P=0.34). The proportions of patients with modified Rankin Scale 0 to 2 (38% versus 37%; P=0.89) and modified Rankin Scale 0 to 1 (24% versus 16%; P=0.18) at 90 days, any ICH (20% versus 22%; P=0.42) and symptomatic intracerebral hemorrhage (3.4% versus 2.9%; P=1.0) were comparable after adjusting for age, stroke severity, and imaging changes. Only 9/394 (2%) patients were lost to follow-up. CONCLUSIONS: Thrombolysis in selected patients with WUIS is feasible, and its outcomes are comparable with those thrombolysed with 0 to 4.5 hours.

An observational study of thrombolysis outcomes in wake-up ischemic stroke patients.

BACKGROUND AND PURPOSE: Wake-up ischemic stroke (WUIS) patients are not eligible for thrombolysis; the a priori hypothesis was that thrombolysis of selected WUIS patients who meet clinical and imaging criteria for treatment is associated with better outcomes. METHODS: The sample consisted of consecutive WUIS patients who fulfilled predefined criteria: (1) were last seen normal >4.5 hours and <12 hours before presentation; (2) National Institute of Health Stroke Scale score ≥ 5; (3) No or early ischemic changes <1/3 middle cerebral artery territory on computed tomography imaging; (4) No absolute contraindications to thrombolysis. The primary outcome measure was the modified Rankin Scale of 0 to 2 at 90 days. Other outcome measures were mortality and symptomatic intracerebral hemorrhage. RESULTS: WUIS patients constituted 10.5% (193/1836) of all stroke admissions. Inclusion criteria were fulfilled by 122 (63%) patients, of whom 68 (56%) were thrombolysed. Thrombolysed and nonthrombolysed patients were comparable for baseline characteristics, but the median baseline National Institute of Health Stroke Scale score was higher in thrombolysed patients (9 versus 11.5; P=0.034). There was no difference in modified Rankin Scale 0 to 2 (25 [37%] versus 14 [26%]; P=0.346), death (10 [15%] versus 14 [26%]; P=0.122), and symptomatic intracerebral hemorrhage (2 versus 0; P=0.204) between thrombolysed and nonthrombolysed patients. After adjusting for age, sex, and baseline National Institute of Health Stroke Scale score thrombolysis was associated with odds ratio of 5.2 (95% confidence interval 1.3-20.3), P=0.017 for modified Rankin Scale 0 to 2 at 90 days and odds ratio of 0.09 (95% confidence interval 0.02-0.44), P=0.003 for death. CONCLUSIONS: Thrombolysis in selected WUIS patients is feasible and may have potential of benefit.