Long-Term Efficacy and Safety of Risankizumab in Patients with Active Psoriatic Arthritis: Results from a 76-Week Phase 2 Randomized Trial.

INTRODUCTION: The objective of this work was to assess the efficacy and safety of risankizumab in psoriatic arthritis (PsA) over 76 weeks. METHODS: In this double-blind, dose-ranging phase 2 study, adults with active PsA were randomized 2:2:2:1:2 to risankizumab 150 mg at weeks 0, 4, 8, 12, and 16 (arm 1), 150 mg at weeks 0, 4, and 16 (arm 2), 150 mg at weeks 0 and 12 (arm 3), 75 mg at week 0 (arm 4), or placebo (arm 5). Patients completing week 24 could receive risankizumab 150 mg in a 52-week open-label extension study. Efficacy assessments included American College of Rheumatology (ACR) responses, Psoriasis Area Severity Index (PASI) responses, minimal disease activity (MDA), and 28-joint Disease Activity Score based on C-reactive protein (DAS28[CRP]). RESULTS: Of 185 randomized patients, 173 (93.5%) completed week 16 and 145 (78.4%) entered the open-label extension. Significantly more patients in each risankizumab arm achieved ACR20 at week 16 versus placebo (primary endpoint: pooled arms 1 + 2 [59.5%] versus placebo [35.7%]; treatment difference [90% CI] 24.0 [9.3, 38.7]; P = 0.007). Similarly, significantly more patients in most risankizumab arms achieved ACR20/50/70, PASI75/90/100, MDA, and greater improvements in DAS28(CRP) versus placebo at week 16. These benefits of risankizumab were maintained long term. Treatment-emergent adverse events were comparable across treatment arms. Risankizumab 150 mg was well tolerated over 76 weeks. CONCLUSIONS: Risankizumab improved joint and skin symptoms versus placebo in patients with active PsA over 16 weeks; improvements were sustained long term. Risankizumab was well tolerated over the long term with no new safety findings. TRIAL REGISTRATION NUMBERS: NCT02719171 and NCT02986373.

Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study.

OBJECTIVES: To evaluate the efficacy and safety of risankizumab, a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), in patients with active ankylosing spondylitis (AS). METHODS: A total of 159 patients with biological-naïve AS, with active disease (Bath Ankylosing Spondylitis Disease Activity Index score of ≥4), were randomised (1:1:1:1) to risankizumab (18 mg single dose, 90 mg or 180 mg at day 1 and weeks 8, 16 and 24) or placebo over a 24-week blinded period. The primary outcome was a 40% improvement in Assessment in Spondylo Arthritis International Society (ASAS40) at week 12. Safety was assessed in patients who received at least one dose of study drug. RESULTS: At week 12, ASAS40 response rates were 25.5%, 20.5% and 15.0% in the 18 mg, 90 mg and 180 mg risankizumab groups, respectively, compared with 17.5% in the placebo group. The estimated difference in proportion between the 180 mg risankizumab and placebo groups (primary endpoint) was -2.5% (95% CI -21.8 to 17.0; p=0.42). Rates of adverse events were similar in all treatment groups. CONCLUSIONS: Treatment with risankizumab did not meet the study primary endpoint and showed no evidence of clinically meaningful improvements compared with placebo in patients with active AS, suggesting that IL-23 may not be a relevant driver of disease pathogenesis and symptoms in AS. TRIAL REGISTRATION NUMBER: NCT02047110; Pre-results.

HCVerso1 and 2: faldaprevir with deleobuvir (BI 207127) and ribavirin for treatment-naïve patients with chronic hepatitis C virus genotype-1b infection.

The interferon-free combination of once-daily faldaprevir 120 mg, twice-daily deleobuvir 600 mg, and weight-based ribavirin was evaluated in two Phase III studies (HCVerso1, HCVerso2) in hepatitis C virus genotype-1b-infected, treatment-naïve patients, including those ineligible for peginterferon (HCVerso2). Patients without cirrhosis were randomized to 16 weeks (Arm 1; n=208 HCVerso1, n=213 HCVerso2) or 24 weeks (Arm 2; n=211 in both studies) of faldaprevir + deleobuvir + ribavirin. Patients with compensated cirrhosis received open-label faldaprevir + deleobuvir + ribavirin for 24 weeks (Arm 3; n=51, n=72). Primary endpoints were comparisons of adjusted sustained virologic response (SVR) rates with historical rates: 71% (HCVerso1) and 68% (HCVerso2). Adjusted SVR12 rates were significantly greater than historical controls for Arms 1 and 2 in HCVerso2 (76%, 95% confidence interval [CI] 71-81, P=0.002; 81%, 95% CI 76-86, P<0.0001) and Arm 2 in HCVerso1 (81%, 95% CI 77-86, P<0.0001), but not for Arm 1 of HCVerso1 (72%, 95% CI 66-77, P=0.3989). Unadjusted SVR12 rates in Arms 1, 2, and 3 were 71.6%, 82.5%, and 72.5%, respectively, in HCVerso1 and 75.6%, 82.0%, and 73.6%, respectively, in HCVerso2. Virologic breakthrough and relapse occurred in 24-week arms in 8%-9% and 1% of patients, respectively, and in 16-week arms in 7%-8% and 9%-11% of patients, respectively. The most common adverse events were nausea (46%-61%) and vomiting (29%-35%). Adverse events resulted in discontinuation of all medications in 6%-8% of patients. In treatment-naïve patients with hepatitis C virus genotype-1b infection, with or without cirrhosis, faldaprevir + deleobuvir + ribavirin treatment for 24 weeks resulted in adjusted SVR12 rates significantly higher than historical controls. Both studies were registered in ClinicalTrials.gov (NCT01732796, NCT01728324).

Nevirapine extended-release formulation tablets in HIV-1-infected children--long-term follow-up.

In the optional extension of clinical trial 1100.1518 39/40, human immunodeficiency virus-infected patients (aged 3 to <18 years) received ≥48 weeks of treatment with extended-release nevirapine. By last visit, all patients had undetectable viral loads and no new safety signals, demonstrating the safety and efficacy of a once-daily antiretroviral regimen.

Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial.

BACKGROUND: IL-23 is associated with plaque psoriasis susceptibility and pathogenesis. BI 655066 is a fully human IgG1 mAb specific for the IL-23 p19 subunit. OBJECTIVE: This first-in-human proof-of-concept study evaluated the clinical and biological effects of BI 655066 in patients with moderate-to-severe plaque psoriasis. METHODS: We performed a single-rising-dose, multicenter, randomized, double-blind, placebo-controlled, within-dose cohort phase I trial. Patients received 0.01, 0.05, 0.25, 1, 3, or 5 mg/kg BI 655066 intravenously, 0.25 or 1 mg/kg BI 655066 subcutaneously, or matched placebo. The primary objective was safety evaluation. RESULTS: Thirty-nine patients received single-dose BI 655066 intravenously (n = 18) or subcutaneously (n = 13) or placebo (n = 8). Adverse events were reported with similar frequency in the BI 655066 and placebo groups. Four serious adverse events (not considered treatment related) were reported among BI 655066-treated patients. BI 655066 was associated with clinical improvement from week 2 and maintained for up to 66 weeks after treatment. At week 12, 75%, 90%, and 100% decreases in the Psoriasis Area and Severity Index were achieved by 87%, 58%, and 16% of BI 655066-treated patients (any dose), respectively, versus none receiving placebo. BI 655066 treatment resulted in reduced expression of lesional skin genes associated with IL-23/IL-17 signaling pathways and normalization of psoriatic lesion gene expression profiles to a profile approaching that of nonlesional skin. Significant correlation between treatment-associated molecular changes and psoriasis area and severity index improvement was observed (r = 0.73, P = 2 × 10(-6)). CONCLUSIONS: BI 655066 was well tolerated and associated with rapid, substantial, and durable clinical improvement in patients with moderate-to-severe psoriasis, supporting a central role for IL-23 in psoriasis pathogenesis.

Effects of tipranavir, darunavir, and ritonavir on platelet function, coagulation, and fibrinolysis in healthy volunteers.

The use of HIV protease inhibitors (PIs) as part of antiretroviral therapy in the treatment of HIV-1 infection may be associated with an increased risk of bleeding. This prospective, randomized, open-label trial in healthy volunteers compared the effects of tipranavir/ritonavir (TPV/r), darunavir/ ritonavir (DRV/r), and ritonavir (RTV) alone on platelet aggregation after a single dose and at steady-state concentrations. Subjects were selected on the basis of normal platelet aggregation and arachidonic acid (AA)-induced platelet aggregation inhibition after administration of a single 325-mg dose of aspirin. All 3 PI therapies were administered twice daily for 10 days. In some but not all subjects, TPV/r inhibited AA-induced platelet aggregation and prolonged PFA-100® closure time with collagen-epinephrine cartridge, which was of lesser magnitude and consistency compared with aspirin, but greater when compared to DRV/r and RTV. At least 2 subjects in each treatment arm showed complete inhibition of AA-induced platelet aggregation on treatment, and the magnitude of change in all platelet-function tests did not correlate with PI plasma concentrations. Effects of TPV/r on platelet aggregation were reversed 24 hours after the last TPV/r dose. None of the PI treatments tested were associated with increases in bleeding time, decreases in plasma coagulation factors, or increase in fibrinolysis. There was large inter-patient variability in antiplatelet effect for all PI treatments, ranging from no effect to complete inhibition of AA-induced platelet aggregation.

Magnesium for treatment of acute lacunar stroke syndromes: further analysis of the IMAGES trial.

BACKGROUND AND PURPOSE: A prespecified interaction analysis of the neutral Intravenous Magnesium Efficacy in Stroke (IMAGES) trial revealed significant benefit from magnesium (Mg) in patients with noncortical stroke. Post hoc analysis indicated that this effect was seen in lacunar clinical syndromes (LACS), interaction P=0.005. We have now examined whether this interaction could be explained by confounding baseline factors. METHODS: LACS was defined on the basis of neurological signs and did not include imaging. We investigated the interaction between baseline variables and Mg treatment on global outcome. We used logistic-regression models to test whether the Mg-LACS interaction remained significant after adjusting for stratification variables, sex, a novel stroke severity score, and baseline variables that had an interaction with treatment (P<0.1). RESULTS: The Mg (n=383) and placebo (n=382) groups of LACS patients were well matched on baseline factors. In addition to LACS, we found an interaction between beneficial Mg treatment effect and younger age (P=0.003), higher baseline diastolic blood pressure (P=0.02), higher mean blood pressure (P=0.02), and absence of ischemic heart disease (P=0.07). Even so, the adjusted Mg-LACS interaction remained significant (odds ratio [OR] 0.57; 95% CI, 0.39 to 0.83; P=0.003). In the LACS subgroup, Mg improved Barthel Index <95 (OR 0.73; 95% CI, 0.55 to 0.98), modified Rankin Scale >1 (OR 0.67; 95% CI, 0.50 to 0.91), and global outcome (OR 0.70; 95% CI, 0.53 to 0.92) but not Barthel Index <60 or mortality. CONCLUSIONS: The positive treatment effect of Mg in LACS cannot be ascribed to general issues of severity, time to treatment, blood pressure, or other baseline factors; equally, this finding may be due to chance. A large trial of Mg treatment in LACS appears justified.

Poststroke neurological improvement within 7 days is associated with subsequent deterioration.

BACKGROUND AND PURPOSE: Improvement in the National Institutes of Health Stroke Scale (NIHSS) 24 hours after stroke has been associated with subsequent neurological deterioration. We hypothesized that a similar association would be apparent for events occurring after 7 days, when acute changes from edema and herniation are less common. We evaluated the degree of NIHSS improvement at 7 days (recovery) as a predictor of subsequent neurological deterioration from day 7 to day 90. METHODS: We studied all patients of the Glycine Antagonist (gavestinel) In Neuroprotection (GAIN) International Trial with ischemic stroke alive at day 7, excluding patients with hemorrhagic events and deaths from nonstroke-related causes. The GAIN International Trial was a randomized, double-blind, placebo-controlled, and parallel-group trial; because the study drug had no effect on stroke outcome, treatment groups were combined for this analysis. Neurological deterioration was assessed by the combined measure, including: (1) stroke-related events recorded as "serious adverse events," (2) recurrent stroke recorded on a separate case report form, and (3) any NIHSS worsening. RESULTS: Among 1187 patients included, 25% had >65% recovery. Deterioration was more prevalent in the group with >65% early recovery (15.5% versus 10.3%; P=0.01). Logistic regression modeling indicated that recovery was associated with subsequent neurological deterioration (odds ratio, 1.2; 95% CI, 1.1 to 1.3, per 10% recovery) after adjusting for age, NIHSS at 7 days, and stroke subtype. CONCLUSIONS: Substantial neurological recovery at 7 days is associated with subsequent neurological deterioration.

Elevated pulse pressure during the acute period of ischemic stroke is associated with poor stroke outcome.

BACKGROUND: It is controversial which component of blood pressure (BP) during acute period of stroke best predicts outcome. We hypothesized that elevated pulse pressure (PP), the difference between systolic BP (SBP) and diastolic BP (DBP), is independently associated with poor stroke outcome at 3 months. METHODS: We analyzed both treatment groups from the Glycine Antagonist (Gavestinel) in Neuroprotection (GAIN) International trial (1455 ischemic stroke cases of mostly moderate severity). Cox proportional hazards and logistic regression modeling corrected for demography, medical history, heart rate, stroke severity, and clinical subtype. RESULTS: Elevated weighted average PP during the first 60 hours was associated with poor outcome by mortality, Barthel index, National Institutes of Health Stroke Score (NIHSS) and Rankin scores. Elevated baseline PP was associated with Barthel index and Rankin score. CONCLUSIONS: Elevated PP is associated with poor stroke outcome at 3 months.

Effect of area-based deprivation on the severity, subtype, and outcome of ischemic stroke.

BACKGROUND AND PURPOSE: Markers of low socioeconomic status (deprivation) are associated with stroke and its causes. In the United Kingdom, area-based deprivation measures are available routinely through links with postal codes. We hypothesized that deprivation is associated with ischemic stroke risk factors, severity, subtype, and outcome. METHODS: We studied 2026 patients, each with at least 2 years of outcome follow-up by record linkage after first admission with ischemic stroke to an acute stroke unit. Baseline factors recorded routinely were age, sex, medical history, blood pressure, and stroke severity and subtype. Deprivation was assessed by the Womersley score (WS) and Murray score (MS). RESULTS: Higher WS and MS were associated with stroke at younger age (eg, WS linear regression coefficient (r)=-0.26; 95% confidence interval [CI], -0.51 to -0.01 per additional point), smoking (odds ratio [OR], 1.12; 95% CI, 1.08 to 1.17), and claudication (OR, 1.09; 95% CI, 1.01 to 1.17); WS was associated with higher systolic blood pressure (r=0.13; 95% CI, 0.02 to 0.24); and MS was associated with severe stroke. Deprivation was not associated with case fatality in univariate analysis or after correction for all baseline factors. Deprivation was associated with readmission to hospital as a result of any vascular event in univariate analysis (hazard ratio [HR], 1.05; 95% CI, 1.02 to 1.09) and after correction for all baseline factors (HR, 1.06; 95% CI, 1.02 to 1.10). CONCLUSIONS: Tackling health inequalities in stroke should focus on stroke primary prevention by tackling deprivation, including promoting changes in lifestyle.

Effect of blood pressure during the acute period of ischemic stroke on stroke outcome: a tertiary analysis of the GAIN International Trial.

BACKGROUND AND PURPOSE: The effects of blood pressure (BP) and its fluctuations during the acute phase on the clinical course of ischemic stroke are incompletely understood. We tested the hypotheses that baseline mean arterial BP [MAP=(2xdiastolic BP+systolic BP)/3], weighted average MAP, and an increase or decrease of >30% from baseline MAP are independently associated with stroke outcome. METHODS: We studied the 1455 patients with ischemic stroke in the Glycine Antagonist (Gavestinel) in Neuroprotection (GAIN) International Trial. BP management was at the discretion of investigators and was measured at 0, 0.5, 4, 12, 12.25, 60, and 60.25 hours. Outcome was assessed by mortality, Barthel Index (dead or 0 to 55 versus 60 to 90 versus > or =95), National Institutes of Health Stroke Scale (NIHSS) score (dead or > or =2), and Rankin Scale (dead or > or =2). Cox proportional-hazards and stepwise logistic regression modeling corrected for demography, medical history, stroke severity, and clinical subtype. RESULTS: Elevated weighted average MAP was associated with poor outcome assessed by mortality at 3 months (hazard ratio, 1.16; 1.06 to 1.27 per 10 mm Hg), NIHSS score (odds ratio [OR] 1.14; 95% confidence interval [CI], 1.01 to 1.28), and Barthel Index at 1 month (OR, 1.12; 95% CI, 1.03 to 1.23). A 30% increase from baseline MAP was associated with poor outcome assessed by NIHSS score and Barthel Index at 1 and 3 months and by Rankin score at 1 month (OR, 2.01; 95% CI, 1.16 to 3.49 to OR, 3.03; 95% CI, 1.30 to 7.02). CONCLUSIONS: Baseline MAP was not associated with poor ischemic stroke outcome. However, variables describing the course of BP over the first 2.5 days have a marked and independent relationship with 1- and 3-month outcome.