Efficacy of belimumab in two serologically distinct high disease activity subgroups of patients with systemic lupus erythematosus: post-hoc analysis of data from the phase III programme.

OBJECTIVE: To assess the appropriateness of expanded serological activity eligibility criteria for belimumab use in the UK systemic lupus erythematosus (SLE) population (and possibly other countries), which includes patients with either anti-double-stranded DNA (anti-dsDNA) positivity or hypocomplementaemia rather than both criteria. METHODS: This post-hoc analysis used data from three randomised, double-blind, placebo-controlled phase III belimumab trials: BLISS-52 (BEL110752; NCT00424476), BLISS-76 (BEL110751; NCT00410384) and BLISS-SC (BEL112341; NCT01484496). Patients with SLE were stratified by high disease activity (HDA): HDA1, Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score ≥10, low complement and positive anti-dsDNA; and HDA2, SELENA-SLEDAI ≥10 and either low complement or positive anti-dsDNA. RESULTS: This analysis included 660 HDA1 patients (n=396 on intravenous treatment; n=264 on subcutaneous treatment) and 969 HDA2 patients (n=532 on intravenous treatment; n=437 on subcutaneous treatment). Significant improvements were observed at week 52 with belimumab versus placebo, irrespective of subgroups or drug formulations, in SLE Responder Index (SRI) 4 response (OR (95% CI): HDA1 intravenous 2.7 (1.8 to 4.1); HDA2 intravenous 2.3 (1.61 to 3.26); HDA1 subcutaneous 2.2 (1.22 to 3.85); HDA2 subcutaneous 1.8 (1.17 to 2.74)); proportion of patients achieving ≥4-point reduction in SELENA-SLEDAI score (OR (95% CI): HDA1 intravenous 2.6 (1.7 to 3.9); HDA2 intravenous 2.1 (1.49 to 3.03); HDA1 subcutaneous 2.3 (1.30 to 4.14); HDA2 subcutaneous 1.9 (1.21 to 2.84)); patients with no worsening in Physician Global Assessment (OR (95% CI): HDA1 intravenous 2.0 (1.3 to 3.1); HDA2 intravenous 1.7 (1.17 to 2.45); HDA1 subcutaneous 2.3 (1.18 to 4.40); HDA2 subcutaneous 1.8 (1.11 to 2.92)); and risk of severe flares (HR (95% CI): HDA1 intravenous 0.6 (0.37 to 0.81); HDA2 intravenous 0.6 (0.43 to 0.86); HDA1 subcutaneous 0.52 (0.30 to 0.92); HDA2 subcutaneous 0.59 (0.37 to 0.94)). CONCLUSION: Broadening the HDA population to include either low complement or positive anti-dsDNA, rather than both, would enable more UK patients to receive SLE treatment and experience improved clinical outcomes.

The role of baseline BLyS levels and type 1 interferon-inducible gene signature status in determining belimumab response in systemic lupus erythematosus: a post hoc meta-analysis.

BACKGROUND: Elevated B lymphocyte stimulator (BLyS) levels in patients with systemic lupus erythematosus (SLE) correlate positively with disease activity; BLyS expression is directly linked to interferon (IFN) pathway activation. This post hoc meta-analysis of BLISS-52 and BLISS-76 explored the relationship between baseline BLyS mRNA/protein levels and/or type 1 IFN-inducible gene signature (IFN-1) and responses to the BLyS-targeting monoclonal antibody belimumab in SLE. METHODS: In BLISS-52 and BLISS-76, patients with autoantibody-positive SLE and a SELENA-SLEDAI score ≥ 6 and receiving stable standard SLE therapy were randomised to intravenous belimumab 10 mg/kg or placebo, plus standard of care (SoC), for 52 or 76 weeks. For this post hoc meta-analysis, patients with an appropriate mRNA sample were stratified by BLyS mRNA expression (tertiles: high/medium/low; revised quantiles: high/low), IFN-1 mRNA expression (high/low) and BLyS protein level (high/low). Co-primary endpoints were correlation between baseline BLyS and IFN-1 mRNA levels and SLE Responder Index (SRI)4 response at week 52 within BLyS/IFN-1 subgroups. Secondary endpoints included time to first severe SELENA-SLEDAI Flare Index (SFI) flare. RESULTS: Of 554 patients included in this analysis, 281 had received belimumab and 273 had received placebo. Baseline BLyS and IFN-1 mRNA levels were highly correlated (Spearman's rank correlation coefficient 0.7799; 95% confidence interval [CI] 0.7451, 0.8106; p < 0.0001). The proportion of SRI4 responders was higher with belimumab versus placebo in all subgroups, but the difference reached statistical significance in the medium BLyS mRNA tertile (odds ratio [OR] 2.17; 95% CI 1.16, 4.04; p = 0.0153), high BLyS mRNA quantile (OR 1.58; 95% CI 1.02, 2.44; p = 0.0402), high IFN-1 mRNA (OR 1.58; 95% CI: 1.08, 2.31; p = 0.0186) and high BLyS protein (OR 3.57; 95% CI 1.63, 7.83; p = 0.0015) subgroups only. The risk of severe SFI flare was significantly lower with belimumab than placebo in the high BLyS mRNA quantile (hazard ratio [HR] 0.59; 95% CI 0.36, 0.97; p = 0.0371) and high BLyS protein (HR 0.39; 95% CI 0.19, 0.79; p = 0.0090) subgroups. CONCLUSIONS: This post hoc meta-analysis demonstrated a tendency towards improved response to add-on intravenous belimumab 10 mg/kg versus SoC alone in patients with high baseline BLyS protein and IFN-1 mRNA levels and medium/high BLyS mRNA levels.

Paroxetine treatment in children and adolescents with major depressive disorder: a randomized, multicenter, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the efficacy and tolerability of paroxetine in pediatric major depressive disorder. METHOD: Subjects 7 to 17 years old with major depressive disorder received paroxetine (10-50 mg/day) or placebo for 8 weeks from 2000 to 2001. The primary efficacy measure was change from baseline in the Children's Depression Rating Scale-Revised total score at week 8 last observation carried forward). Safety was primarily assessed by spontaneous reporting of adverse events. RESULTS: A total of 206 patients (intent to treat) were randomized to paroxetine (n = 104) or placebo (n = 102). Week 8 Children's Depression Rating Scale-Revised total score adjusted mean changes from baseline for patients receiving paroxetine and placebo were -22.58 (SE 1.47) and -23.38 points (SE 1.60), respectively (0.80, 95% confidence interval -3.09 to 4.69, p = 0.684). Increased cough (5.9% versus 2.9%), dyspepsia (5.9% versus 2.9%), vomiting (5.9% versus 2.0%), and dizziness (5.0% versus 1.0%) occurred in >or=5% of the paroxetine group and at least twice that of the placebo group. Six of 104 (5.8%) paroxetine patients reported serious adverse events compared to 1 placebo patient (1.0%). The incidence of adverse events of suicidal behavior and/or ideation while taking study medication (excluding taper) was 1.92% (2/104) for paroxetine versus 0.98% (1/102) for placebo. CONCLUSIONS: Paroxetine was not shown to be more efficacious than placebo for treating pediatric major depressive disorder.

An international, multicenter, placebo-controlled trial of paroxetine in adolescents with major depressive disorder.

OBJECTIVE: The aim of this study was to examine the efficacy, safety, and tolerability of paroxetine in adolescents with unipolar major depression. METHOD: Two hundred eighty-six (286) adolescents with unipolar major depression were randomly assigned to receive either paroxetine or placebo for 12 weeks. RESULTS: The proportion of Montgomery-Asberg Depression Rating Scale (MADRS) responders (at least 50% reduction from baseline) for paroxetine and placebo were similar and not statistically different at endpoint (p = 0.702). A similar result was obtained for change from baseline on the Kiddie-Schedule for Affective Disorders and Schizophrenia for School- Age Children (K-SADS-L) depression subscale. Among secondary endpoints, only a significantly higher Clinical Global Impression-Improvement (CGI-I) response rate was reported in paroxetine-treated patients versus placebo (69.2% versus 57.3%; p = 0.045). In general, results differed by age, with patients older than 16 years demonstrating a greater response to active treatment. This age group also reported more adverse experiences (AEs) relative to placebo than younger adolescents. Overall, paroxetine was generally well tolerated (11% discontinued owing to an AE versus 7% of placebo-treated patients). A post hoc analysis of AEs related to suicidal behavior suggested a greater incidence of these events for paroxetine than for placebo (4.4% versus 2.1%); however, this difference was not statistically significant (odds ratio, 2.15, 95% Confidence Interval 0.45, 10.33; p = 0.502). CONCLUSIONS: No statistically significant differences were observed for paroxetine compared with placebo on the two prospectively defined primary efficacy variables. Paroxetine at 20-40 mg/day administered over a period of up to 12 weeks was generally well tolerated.

Evaluation of suicidal thoughts and behaviors in children and adolescents taking paroxetine.

OBJECTIVE: The aim of this study was to summarize results of a blinded review of potential suicidal events and analyses comparing incidence rates between paroxetine- and placebo-treated pediatric patients. METHOD: One thousand one hundred ninety-one (1191) children and adolescents received paroxetine (n = 642) or placebo (n = 549) during placebo-controlled portions of all acute double-blind trials of paroxetine (n = 5). An expert panel blindly reviewed and categorized all identified cases detected by electronic and manual search of adverse events (AEs), serious AEs, and selected cases as suicidal or non-suicidal behavior. Incidence rates were calculated for suicide-related events and for rating scale items assessing suicidality. RESULTS: Suicide-related events occurred more often in paroxetine (22 of 642, 3.4%) than placebo groups (5 of 549, 0.9%); odds ratio (OR) 3.86 (95% CI 1.45, 10.26; p = 0.003). All suicide-related events occurred in adolescents of at least 12 years, except for 1 of 156 paroxetine-treated children. All suicide attempts occurred in major depressive disorder (MDD); few suicide-related events occurred in patients with a primary anxiety disorder. Suicide item analyses did not reveal significant differences between paroxetine and placebo. CONCLUSIONS: Adolescents treated with paroxetine showed an increased risk of suicide-related events. Suicidality rating scales did not show this risk difference. The presence of uncontrolled suicide risk factors, the relatively low incidence of these events, and their predominance in adolescents with MDD make it difficult to identify a single cause for suicidality in these pediatric patients.