Karla Alaka

Duloxetine Versus Placebo in Patients With Chronic Low Back Pain: A 12-Week, Fixed-Dose, Randomized, Double-Blind Trial

UNLABELLED This randomized, double-blind, placebo-controlled study assessed efficacy and safety of duloxetine in patients with chronic low back pain (CLBP). Adults (n = 401) with a nonneuropathic CLBP and average pain intensity of ≥ 4 on an 11-point numerical scale (Brief Pain Inventory [BPI]) were treated with either duloxetine 60 mg once daily or placebo for 12 weeks. The primary measure was BPI average pain. Secondary endpoints included Patients Global Impressions of Improvement (PGI-I), Roland Morris Disability Questionnaire (RMDQ-24), BPI-Severity (BPI-S), BPI-Interference (BPI-I), and response rates (either ≥ 30% or ≥ 50% BPI average pain reduction at endpoint). Health outcomes included Short Form-36, European Quality of Life-5 Dimensions, and the Work Productivity and Activity Impairment questionnaire. Safety and tolerability were assessed. Compared with placebo-treated patients, duloxetine-treated patients reported a significantly greater reduction in BPI average pain (P ≤ .001). Similarly, duloxetine-treated patients reported significantly greater improvements in PGI-I, BPI-S, BPI-I, 50% response rates, and some health outcomes. The RMDQ and 30% response rate showed numerical improvements with duloxetine treatment. Significantly more patients in the duloxetine group (15.2%) than patients in the placebo group (5.4%) discontinued because of adverse events (P = .002). Nausea and dry mouth were the most common treatment-emergent adverse events with rates significantly higher in duloxetine-treated patients. PERSPECTIVE This study provides clinical evidence of the efficacy and safety of duloxetine at a fixed dose of 60 mg once daily in the treatment of chronic low back pain (CLBP). As of December 2009, duloxetine has not received regulatory approval for the treatment of CLBP.

Calming versus sedative effects of intramuscular olanzapine in agitated patients

Distinct calming rather than nonspecific sedation is desirable for the treatment of acute agitation. In 3 double-blind studies, acutely agitated patients with schizophrenia (N = 311), bipolar mania (N = 201), or dementia (N = 206) were treated with intramuscular (1-3 injections/24 hrs) olanzapine (2.5-10.0 mg), haloperidol (7.5 mg), lorazepam (2.0 mg), or placebo. The Agitation-Calmness Evaluation Scale (ACES; Eli Lilly and Co.) and treatment-emergent adverse events assessed sedation. Across all studies, 1 patient (lorazepam-treated, bipolar) became unarousable. There were no significant between-group differences in ACES scores of deep sleep or unarousable at any time across. Excluding asleep patients, agitation remained significantly more reduced with olanzapine than placebo (P <.05). The incidences of adverse events indicative of sedation were not significantly different with olanzapine versus comparators. For the treatment of acute agitation associated with schizophrenia, bipolar mania, or dementia, intramuscular olanzapine-treated patients experienced no more sedation than haloperidol- or lorazepam-treated patients and experienced distinct calming rather than nonspecific sedation.

A double-blind, randomized, placebo-controlled trial of olanzapine in the prevention of psychotic relapse

Sustained response to antipsychotic therapy is an important outcome measure for patients with psychotic disorders. Placebo control in studies of relapse prevention contributes valuable information yet provokes much debate. This study, using placebo as a control, evaluated olanzapine’s efficacy in preventing a psychotic relapse. Participants were stable minimally symptomatic outpatients with schizophrenia or schizoaffective disorder. The study included 4 phases: (1) 4-day to 9-day screening/evaluation (N = 583), (2) 6-week conversion to open-label olanzapine (N = 493; 10-20 mg/d), (3) 8-week stabilization on olanzapine (N = 458; 10-20 mg/d), and (4) 52-week randomized (2:1), double-blind maintenance with olanzapine (N = 224; 10–20 mg/d) or placebo (N = 102). Primary relapse criteria were clinically significant changes in the Brief Psychiatric Rating Scale (BPRS) positive item cluster or rehospitalization due to positive symptoms. Statistical methodology allowed sequential real-time estimation of efficacy across blinded treatment groups and multiple interim analyses, which permitted study termination when efficacy was significantly different between treatments. A significant between-treatment difference emerged 210 days after first patient randomization to double-blind treatment. Thus, 151 (46.3%) of the randomized patients were discontinued early and 34 (10.4%) of the planned patient enrollment were not required. The olanzapine group had a significantly longer time to relapse (P < 0.0001) than the placebo group. The 6-month cumulative estimated relapse rate (Kaplan-Meier) was 5.5% for olanzapine-treated patients versus 55.2% for placebo-treated patients. The design of this study enabled appropriate statistical testing of the primary hypothesis while minimizing exposure of patients to a less effective treatment than olanzapine. In remitted stabilized patients with schizophrenia or schizoaffective disorder, olanzapine demonstrated a positive benefit-to-risk profile in relapse prevention.

Intramuscular olanzapine and intramuscular haloperidol in acute schizophrenia: Antipsychotic efficacy and extrapyramidal safety during the first 24 hours of treatment

Objective: To determine the antipsychotic efficacy and extrapyramidal safety of intramuscular (IM) olanzapine and IM haloperidol during the first 24 hours of treatment of acute schizophrenia. Method: Patients (n = 311) with acute schizophrenia were randomly allocated (2:2:1) to receive IM olanzapine (10.0 mg, n = 131), IM haloperidol (7.5 mg, n = 126), or IM placebo (n = 54). Results: After the first injection, IM olanzapine was comparable to IM haloperidol and superior to IM placebo for reducing mean change scores from baseline on the Brief Psychiatric Rating Scale (BRPS) Positive at 2 hours (–2.9 olanzapine, −2.7 haloperidol, and −1.5 placebo) and 24 hours (–2.8 olanzapine, −3.2 haloperidol, and −1.3 placebo); the BPRS Total at 2 hours (–14.2 olanzapine, −13.1 haloperidol, and −7.1 placebo) and 24 hours (–12.8 olanzapine, −12.9 haloperidol, and −6.2 placebo); and the Clinical Global Impressions (CGI) scale at 24 hours (–0.5 olanzapine, −0.5 haloperidol, and −0.1 placebo). Patients treated with IM olanzapine had significantly fewer incidences of treatment-emergent parkinsonism (4.3% olanzapine vs 13.3% haloperidol, P = 0.036), but not akathisia (1.1% olanzapine vs 6.5% haloperidol, P = 0.065), than did patients treated with IM haloperidol; they also required significantly less anticholinergic treatment (4.6% olanzapine vs 20.6% haloperidol, P < 0.001). Mean extrapyramidal symptoms (EPS) safety scores improved significantly from baseline during IM olanzapine treatment, compared with a general worsening during IM haloperidol treatment (Simpson–Angus Scale total score mean change: −0.61 olanzapine vs 0.70 haloperidol; P < 0.001; Barnes Akathisia Scale global score mean change:−0.27 olanzapine vs 0.01 haloperidol; P < 0.05). Conclusion: IM olanzapine was comparable to IM haloperidol for reducing the symptoms of acute schizophrenia during the first 24 hours of treatment, the efficacy of both being evident within 2 hours after the first injection. In general, more EPS were observed during treatment with IM haloperidol than with IM olanzapine.

Effects of intramuscular olanzapine vs. haloperidol and placebo on QTc intervals in acutely agitated patients

Prolongation of the QTc interval has been reported during treatment with oral antipsychotic agents and may be more pronounced during parenteral administration. Pooled QTc interval data from acutely agitated patients across four double-blind trials were compared. Databases included: placebo-controlled [two schizophrenia, one bipolar mania trials (n=565)]; haloperidol-controlled [two schizophrenia trials (n=482)]; geriatric placebo-controlled [1 dementia trial (n=204)]. Patients received 1-3 injections of intramuscular (IM) olanzapine (2.5-10 mg/injection), IM haloperidol (7.5 mg/injection), or IM placebo. At 2 and 24 h after IM olanzapine treatment, the mean QTc interval decreased approximately 3 ms from baseline in the placebo- and haloperidol-controlled databases. When there was a statistically significant difference between IM olanzapine and IM placebo, QTc intervals decreased during treatment with IM olanzapine and increased with IM placebo. The incidences of prolonged (endpoint >/=99th percentile of healthy adults or >/=500 ms) or lengthened (increase >/=60 ms) QTc intervals during treatment with IM olanzapine (<3% placebo- and haloperidol-controlled databases, <12% geriatric placebo-controlled database) were never significantly greater than with comparators. These data suggest that IM olanzapine has a favorable QTc interval profile in acutely agitated patients with schizophrenia, bipolar mania, or dementia.

Efficacy and safety of duloxetine in the treatment of older adult patients with generalized anxiety disorder: a randomized, double-blind, placebo-controlled trial.

This was a flexible‐dosed study to evaluate the efficacy and safety of duloxetine 30–120 mg once daily in the treatment of generalized anxiety disorder (GAD) in older adult patients.

Quantile regression to characterize solanezumab effects in Alzheimer's disease trials

In two solanezumab trials for mild‐to‐moderate Alzheimers disease (AD) dementia, 27% of patients had biomarker confirmation of amyloid status. Of these, approximately 25% of mild patients and approximately 10% of moderate patients were amyloid negative and, as a group, did not exhibit clinical progression typical of AD. This post‐hoc analysis describes a statistical surrogate for amyloid status.

USE OF QUANTILE REGRESSION TO CHARACTERIZE SOLANEZUMAB EFFECTS ACROSS PERCENTILES OF DISEASE PROGRESSION IN EXPEDITION ALZHEIMER'S DISEASE TRIALS

OBJECTIVE: Use quantile regression to characterize solanezumab effects in Alzheimer’s disease (AD) patients based on degree of disease progression. BACKGROUND: Twenty-seven percent of patients with clinically defined mild-to-moderate AD enrolled in 2 solanezumab trials had baseline assessments of amyloid status. Of those, 17[percnt] were negative and did not exhibit progressive decline typical of AD. Because comparison of solanezumab- and placebo-treatment effects on clinical progression in amyloid positive versus negative patients in the full cohort was precluded, we developed a novel statistical strategy to examine treatment effects in patients who did and did not show typical disease progression. DESIGN/METHODS: Quantile regression was used to examine solanezumab- and placebo-treatment differences in a pooled dataset. Patients demonstrating clinical decline typical of AD were represented in upper clinical-change percentiles; patients with a clinical course atypical of AD were represented in lower percentiles. This approach modeled change from baseline on 2 primary measures: Alzheimer9s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) and Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory Instrumental domain (ADCS iADL). RESULTS: ADAS-Cog14 at Week 80: In patients with mild AD, solanezumab treatment effect was greater in the upper percentiles (AD-typical). Compared with placebo, solanezumab slowed disease progression by 1.27, 1.98, 2.55, and 3.07 points in the 30th, 40th, 60th, and 80th percentiles. In lower percentiles (AD-atypical), solanezumab showed less effect. ADCS-iADL at Week 80: In patients with mild AD, compared with placebo, solanezumab slowed disease progression by 0.47, 0.99, 1.79, and 1.69 points in the 30th, 40th, 60th, and 80th percentiles. In patients with moderate AD, solanezumab did not show effects across most percentiles on either measure. Conclusions: Results support design of current/future solanezumab trials to be limited to mild AD patients with evidence of amyloid pathology. Further, quantile regression is useful for retrospectively analyzing data when amyloid status was not uniformly determined. Disclosure: Dr. Chen has received personal compensation for activities with Eli Lilly & Company. Dr. Ma has received personal compensation for activities with Eli Lilly & Company as an employee. Dr. Sundell has received personal compensation for activities with Eli Lilly & Company as an employee. Dr. Alaka has received personal compensation for activities with Eli Lilly and Company as an employee. Dr. Alaka holds stock and/or stock options in Eli Lilly and Company. Dr. Schuh has received personal compensation for activities with Eli Lilly & Company as an employee. Dr. Raskin has received personal compensation for activities with Eli Lilly & Company as an employee. Dr. Dean has received personal compensation for activities with Eli Lilly & Company. Dr. Dean holds stock and/or stock options in Eli Lilly & Company.