Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial.

Background: Biological disease-modifying anti-rheumatic drugs (bDMARDs) are recommended for radiographic axial spondyloarthritis, otherwise known as ankylosing spondylitis, when conventional therapies are not effective. We report efficacy and safety data on ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A (IL-17A), in patients with radiographic axial spondyloarthritis who have not previously been treated with bDMARDs.

Methods: In this phase 3, randomised, double-blind, placebo-controlled superiority study of ixekizumab, adult patients with inadequate response or intolerance to non-steroidal anti-inflammatory drugs, an established diagnosis of radiographic axial spondyloarthritis, radiographic sacroiliitis centrally defined by modified New York criteria, and at least one spondyloarthritis feature according to the Assessment of SpondyloArthritis international Society (ASAS) criteria, were recruited from 84 sites (12 countries) in Europe, Asia, and North America.

Long-term safety profile of ixekizumab in patients with moderate-to-severe plaque psoriasis: an integrated analysis from 11 clinical trials.

Background: Psoriasis in many patients is a chronic and recalcitrant disease that requires long-term treatment, reinforcing the importance of long-term safety data. Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A, is approved for treating patients with moderate-to-severe plaque psoriasis.

Objective: To determine long-term safety of ixekizumab in psoriasis.

Usability of a novel disposable autoinjector device for ixekizumab: results from a qualitative study and an open-label clinical trial, including patient-reported experience.

Background: Most biologic therapies for psoriasis are delivered via subcutaneous injection. Ixekizumab, an anti-interleukin 17A monoclonal antibody approved for patients with moderate-to-severe plaque psoriasis, is delivered subcutaneously via prefilled syringe or autoinjector. Here we report the results of an ixekizumab autoinjector usability study as well as the patient-reported experience with the autoinjector in a clinical trial.

Phase 3, open-label, randomized study of the pharmacokinetics, efficacy and safety of ixekizumab following subcutaneous administration using a prefilled syringe or an autoinjector in patients with moderate-to-severe plaque psoriasis (UNCOVER-A).

Background: The efficacy of ixekizumab, an anti-interleukin-17A (anti-IL-17A) monoclonal IgG4 antibody, was demonstrated in moderate-to-severe psoriasis patients when administered via prefilled syringe (PFS).

Objective: To evaluate the effect of two drug delivery devices on the pharmacokinetics (PK) of ixekizumab as well as efficacy and safety with both devices.

Methods: In the first 12 weeks of an open-label, phase 3 study, moderate-to-severe psoriasis patients were randomized to ixekizumab delivery via PFS or autoinjector device.

Efficacy outcomes from 3 clinical trials of edivoxetine as adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment.

Objective: Three studies examined whether edivoxetine (a highly selective norepinephrine reuptake inhibitor) had efficacy as adjunctive therapy for patients with major depressive disorder (DSM-IV-TR) who were partial responders to selective serotonin reuptake inhibitor (SSRI) treatment of at least 6 weeks' duration.

Method: Studies were 8-week randomized, placebo-controlled trials with a 3-week double-blind placebo lead-in phase, conducted from December 16, 2010, to October 21, 2013. Patients entered the double-blind adjunctive treatment phase if they met randomization criteria (< 25% improvement on Montgomery-Asberg Depression Rating Scale [MADRS] and MADRS total score ≥ 14); patients not randomized remained on adjunctive placebo.

Safety and tolerability of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor antidepressants for patients with major depressive disorder.

Objective: The aim of this analysis was to assess the safety profile of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor (SSRI) antidepressants.

Methods: A pooled analysis was conducted on data obtained from the integrated safety database of edivoxetine as adjunctive treatment to SSRIs. Safety and tolerability assessments included discontinuation rates, spontaneously reported treatment-emergent adverse events (TEAEs), clinical laboratory tests, blood pressure (BP) and pulse, and electrocardiograms (ECGs).

Acute and longer-term safety results from a pooled analysis of duloxetine studies for the treatment of children and adolescents with major depressive disorder.

Objective: To assess acute and longer-term safety of duloxetine in the treatment of children and adolescents with major depressive disorder (MDD), a pooled analysis of data from two completed randomized, double-blind, multicenter, phase 3, placebo- and active-controlled trials was undertaken. In these studies, neither duloxetine (investigational drug) nor fluoxetine (active control) demonstrated a statistically significant improvement compared with placebo on the primary efficacy measure.

Methods: Patients ages 7-17 years with MDD as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed.

A randomized, placebo-controlled study of duloxetine for the treatment of children and adolescents with generalized anxiety disorder.

Objective: To evaluate the efficacy, safety, and tolerability of the selective serotonin norepinephrine inhibitor duloxetine in children and adolescents with generalized anxiety disorder (GAD).

Method: Youth aged 7 through 17 years with a primary diagnosis of GAD were treated with flexibly dosed duloxetine (30-120 mg daily, n = 135) or placebo (n = 137) for 10 weeks, followed by open-label duloxetine (30-120mg daily) for 18 weeks. Efficacy measures included the Pediatric Anxiety Rating Scale (PARS), Clinical Global Impression-Severity (CGI-Severity) scale, and Children's Global Assessment Scale (CGAS).

Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects.

Duloxetine selectively inhibits the serotonin (5-HT) and norepinephrine (NE) transporters (5-HTT and NET, respectively), as demonstrated in vitro and in preclinical studies; however, transporter inhibition has not been fully assessed in vivo at the approved dose of 60 mg/d. Here, the in vivo effects of dosing with duloxetine 60 mg once daily for 11 days in healthy subjects were assessed in 2 studies: (1) centrally (n = 11), by measuring concentrations of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylglycol (DHPG), and NE in cerebrospinal fluid, and (2) versus escitalopram 20 mg/d (n = 32) in a 2-period crossover study by assessing the ΔDHPG/ΔNE ratio in plasma during orthostatic testing and by pharmacokinetic/pharmacodynamic modeling of reuptake inhibition using subjects' serum in cell lines expressing cloned human 5-HTT or NET. At steady state, duloxetine significantly reduced concentrations of DHPG and 5-hydroxyindoleacetic acid (P < 0.

Evaluation of the effects of duloxetine and escitalopram on 24-hour heart rate variability: a mechanistic study using heart rate variability as a pharmacodynamic measure.

A decrease in heart rate variability (HRV) can indicate increased sympathetic nervous system activity and possibly increased norepinephrine levels. In this randomized, placebo- and escitalopram (ESC)-controlled, subject-blind, 2-period, crossover study, 26 healthy subjects 50 to 65 years old received duloxetine (DLX) 60 mg once daily or ESC 20 mg once daily for 11 days, each in sequential study periods separated by a 10-day or more washout period. Continuous electrocardiogram recordings were obtained by Holter monitoring (baseline, day 9, and day 10 of treatment).

Efficacy and safety of duloxetine 30 mg/d in patients with fibromyalgia: a randomized, double-blind, placebo-controlled study.

Objectives: To evaluate the efficacy and safety of duloxetine 30 mg/d in adults with fibromyalgia.

Methods: This 12-week, randomized, double-blind, placebo-controlled study was conducted in the United States, Mexico, Argentina, and Israel and enrolled patients meeting the criteria for primary fibromyalgia as defined by the American College of Rheumatology. The primary endpoint was the average pain severity item from the Brief Pain Inventory (BPI)-Modified Short Form, assessed by an analysis of covariance model using change from baseline to the modified baseline-observation-carried-forward endpoint.

An open-label safety and pharmacokinetics study of duloxetine in pediatric patients with major depression.

Objective: This preliminary, 32-week study assessed the safety, tolerability, and pharmacokinetics of duloxetine in pediatric patients (aged 7-17 years) with major depressive disorder.

Methods: Patients received flexible duloxetine doses of 20-120 mg once daily, with dose changes made based on clinical improvement and tolerability. Pharmacokinetic samples were collected across all duloxetine doses, and data were analyzed using population modeling.

A randomized, double-blind study comparing LY2216684 and placebo in the treatment of major depressive disorder.

The efficacy, tolerability, and safety of LY2216684, a highly selective norepinephrine reuptake inhibitor, were studied in adult patients with major depressive disorder (MDD). This randomized, double-blind study compared flexible-dose LY2216684 6-18 mg once daily (N = 250) with placebo (N = 245) for 10 weeks acute therapy followed by 1 year LY2216684 treatment (results not reported here). Primary inclusion criteria consisted of GRID 17-item Hamilton Rating Scale for Depression total score ≥18 and Clinical Global Impressions-Severity score ≥4.

Long-term safety of duloxetine during open-label compassionate use treatment of patients who completed previous duloxetine clinical trials.

Purpose: To provide duloxetine for the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), fibromyalgia (FM) and diabetic peripheral neuropathic pain (DPNP) to patients who had previously completed a duloxetine clinical study and for whom, in the opinion of the investigator, no effective alternative therapy was available.

Methods: Adult outpatients who had previously completed a duloxetine study for the treatment of MDD, GAD, DPNP, or FM received duloxetine 30 mg to 120 mg daily up until its local commercial availability. Safety analyses included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), AEs reported as reason for discontinuation, and vital signs.

Hepatic effects of duloxetine-I: non-clinical and clinical trial data.

Objective: Review nonclinical and clinical trial data for hepatic effects of duloxetine.

Methods: Review studies of toxicology, metabolism, mitochondrial effects, and clinical trials.

Results: Nonclinical studies revealed no treatment-related transaminase elevations and no effects of duloxetine on mitochondrial beta-oxidation in rat hepatocytes.

Effects of the antidepressant duloxetine on body weight: analyses of 10 clinical studies.

Objective: To assess the effect of duloxetine, an inhibitor of serotonin and norepinephrine reup-take, on body weight of patients with major depressive disorder (MDD).

Method: Body weight data were obtained from all 10 phase II and III registration studies of duloxetine in the treatment of MDD, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), performed by Eli Lilly and Company between February 1999 and July 2003. Both acute (8-9 weeks) and long-term (26, 34, and 52 weeks) studies were analyzed.

Cardiovascular profile of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine.

This analysis assessed the effects of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, on indices of cardiovascular safety, including heart rate, blood pressure (BP), and electrocardiograms (ECGs), in a large group of clinical trial patients with depression. Data were available from 8 double-blind, randomized, placebo-controlled (n = 777), and active comparator-controlled depression trials. Duloxetine (n = 1139) doses ranged from 40 to 120 mg/d, and fluoxetine (n = 70) and paroxetine (n = 359) were administered at a dose of 20 mg/d.

Urinary Side Effects of Duloxetine in the Treatment of Depression and Stress Urinary Incontinence.

BACKGROUND: The efficacy and safety of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine at the recommended starting dose, have been demonstrated in the treatment of major depressive disorder (MDD) in men and women and in the treatment of stress urinary incontinence (SUI) in women. Since the mechanism of action of duloxetine in the treatment of SUI is believed to be related to enhanced urethral closure forces, it is important to clarify the risk of acute urinary retention. METHOD: The relationship between duloxetine and obstructive voiding symptoms was examined in 8 double-blind, 8- to 9-week, placebo-controlled studies and 1 open-label study in men and women treated for MDD with duloxetine 40 to 120 mg/day and in 4 double-blind, 12-week, placebo-controlled studies and 4 ongoing open-label studies in women treated for SUI with duloxetine 80 mg/day.