An Analysis of Patient-reported Outcomes in IXORA-S: Comparing Ixekizumab and Ustekinumab over 52 Weeks in Moderate-to-severe Psoriasis.

Patient-reported outcomes are valuable for assessing new psoriasis therapies. This study investigated patient-reported outcomes in patients with moderate-to-severe plaque psoriasis treated with ixekizumab or ustekinumab, dosed according to their respective labels, for 52 weeks (IXORA-S-NCT02561806). Patient-reported outcomes investigated included patient global assessment, pruritus, skin pain, health-related quality of life, and work productivity. Ixekizumab-treated patients reported greater improvements in patient-reported outcomes sooner after treatment compared with ustekinumab-treated patients, and maintained greater improvements in patient global assessment scores (ixekizumab 0.72, ustekinumab 1.19; p < 0.001), rates of Dermatology Life Quality Index (0, 1) (ixekizumab 71.3%, ustekinumab 56.6%, p < 0.01), and 36-item Short-form Health survey physical component summary score change from baseline (ixekizumab 5.53, ustekinumab 3.28; p < 0.05) at week 52. While clinically meaningful improvements in patient-reported outcomes resulted with either treatment, ixekizumab provided more rapid improvements in patient-reported outcomes and superior outcomes for some assessments through one year of treatment, while maintaining statistically superior improvements in skin severity, as assessed by either physicians or patients.

Ixekizumab and Ustekinumab Efficacy in Nail Psoriasis in Patients with Moderate-to-Severe Psoriasis: 52-Week Results from a Phase 3, Head-to-Head Study (IXORA-S).

INTRODUCTION: Patients with plaque psoriasis often have nail psoriasis, which is difficult to treat. Ixekizumab (IXE) and ustekinumab (UST) are biologics with established efficacy in nail psoriasis. We present post hoc data from a head-to-head trial of IXE and UST (IXORA-S) to examine the efficacy in nail psoriasis in patients with moderate-to-severe plaque psoriasis over 52 weeks. METHODS: In IXORA-S, randomised patients received IXE (N = 136) or UST (N = 166) per label for 52 weeks. Eighty-four (61.8%) and 105 (63.3%) of the patients treated with IXE or UST, respectively, had baseline fingernail psoriasis (Nail Psoriasis Severity Index [NAPSI] > 0); of these, 54 (64.3%) and 63 (60.0%) patients, respectively, had significant baseline fingernail psoriasis (defined as NAPSI ≥ 16 with ≥ 4 fingernails involved). The proportion of patients achieving NAPSI = 0, a NAPSI score change from baseline and correlations in Psoriasis Area of Severity Index (PASI) and NAPSI improvement over 52 weeks were examined. RESULTS: Progressive improvement occurred in both treatment groups over 52 weeks. Statistically significantly more patients achieved NAPSI = 0 with IXE versus UST by week 16-20, and the proportions continued to increase through week 52 among patients with baseline nail psoriasis (61.9 vs. 28.6%, respectively; P < 0.001), including those with significant nail psoriasis (57.4 vs. 17.5%, respectively; P < 0.001). Similar results were observed for NAPSI score improvement from baseline to week 52. Interestingly, the presence of nail psoriasis was associated with lower skin response with UST but not with IXE. CONCLUSIONS: Ixekizumab was superior to UST in the clearance of nail psoriasis, with earlier improvement continued through 52 weeks regardless of baseline nail severity. TRIAL REGISTRATION: ClinicalTrials.gov identifier; NCT02561806.

Absolute and Relative Psoriasis Area and Severity Indices (PASI) for Comparison of the Efficacy of Ixekizumab to Etanercept and Placebo in Patients with Moderate-to-severe Plaque Psoriasis: An Integrated Analysis of UNCOVER-2 and UNCOVER-3 Outcomes.

Treatment goals defined by the absolute Psoriasis Area and Severity Index (PASI) scores offer certain advantages in the clinical setting. In order to investigate potential treatment targets, this study evaluated absolute PASI outcomes relative to other measures of response using data from two randomized clinical trials of patients with moderate-to-severe psoriasis treated with ixekizumab, etanercept, or placebo (n=2,567). Response was assessed throughout 12 weeks as the proportion of patients achieving absolute PASI band cut-offs who also reached established response criteria. Most PASI band ≤2 responders also achieved PASI 90 (70.1-100%), static Physician's Global Assessment (0,1) (91.3-96.1%), Dermatology Life Quality Index (0,1) (63.0-67.7%), Patient Global Assessment of Disease Severity (0,1) (80.3-86.7%), and Itch Numeric Rating Scale improvement ≥4 (87.2-87.6%). Agreement sharply decreased for less stringent PASI criteria. These data indicate that PASI ≤2 represents significantly meaningful clinical and health-related quality of life improvements and may be a suitable treatment target for moderate-to-severe plaque psoriasis.

Efficacy and safety of ixekizumab in patients with plaque psoriasis across different degrees of disease severity: results from UNCOVER-2 and UNCOVER-3.

PURPOSE: To evaluate short- and long-term efficacy and safety of ixekizumab in patients according to psoriasis severity. MATERIALS AND METHODS: Data were integrated from clinical trials (UNCOVER-2, UNCOVER-3). Patients received placebo, 80-mg ixekizumab every 2 weeks (IXEQ2W), every 4 weeks (IXEQ4W), or 50 mg etanercept (ETN) biweekly for 12 weeks, then open-label IXEQ4W (UNCOVER-3). Psoriasis severity was categorized by baseline Psoriasis Area and Severity Index (PASI <20 and ≥20). Efficacy was evaluated by percentage reaching PASI 75, 90, 100, and absolute PASI ≤5, ≤2, and ≤1. RESULTS: Significantly more patients with PASI ≥20 (vs. PASI <20) were male and had higher body weight. After 12 weeks, both severity groups had significantly more IXEQ2W- than ETN-treated patients reach PASI 75, 90, 100, and absolute PASI ≤5, ≤2, ≤1. Fewer PASI ≥20 vs. PASI <20 patients across treatments reached PASI ≤5, ≤2, and ≤1 at week 12. Efficacy was maintained during 156 weeks of ixekizumab treatment with no differences between groups. The IXEQ2W safety profile was similar between groups except for injection-site reactions (significantly higher in PASI <20). CONCLUSIONS: Ixekizumab demonstrated a high level of efficacy and had a consistent safety profile in patients with different baseline psoriasis severity levels.

Impact of Ixekizumab Treatment on Itch and Psoriasis Area and Severity Index in Patients with Moderate-to-Severe Plaque Psoriasis: An Integrated Analysis of Two Phase III Randomized Studies.

INTRODUCTION: We evaluated baseline itch and its impact on the efficacy of ixekizumab (IXE) in clearing psoriasis and improving quality-of-life measures, and we explored the relationship between itch and psoriatic skin improvement. METHODS: Data were analyzed from two double-blind, randomized, controlled phase III studies (UNCOVER-2/3) comparing etanercept (ETN), IXE, and placebo (PBO) in patients with moderate-to-severe plaque psoriasis. Long-term analysis included UNCOVER-3 data from week 0 to week 156. RESULTS: At week 12, a clinically meaningful improvement in itch [Itch Numeric Rating Scale (NRS) reduction ≥ 4] was seen in 70.0%, 88.6%, and 90.8% of the IXE-treated patients in the baseline Itch NRS 4-6, 7-8, and 9-10 groups, respectively (all itch severity groups p < 0.001 versus ETN and PBO). Also, 68.9%, 67.1%, and 73.6% of the IXE-treated patients in the baseline Itch NRS 4-6, 7-8, and 9-10 groups, respectively, showed an improvement of ≥ 90.0% in the Psoriatic Area and Severity Index (PASI) at week 12 as compared to the baseline (PASI 90) (all itch severity groups p < 0.001 versus ETN and PBO). For most patients, itch reduction preceded psoriatic plaque improvement. Sustained effects of IXE on itch and PASI were observed during 3 years of treatment. CONCLUSIONS: Regardless of baseline itch severity, IXE treatment provided a rapid improvement in itch followed by clinically meaningful improvements in psoriasis. FUNDING: Eli Lilly and Company. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT01597245 and NCT01646177.

Growth hormone in combination with leuprorelin in pubertal children with idiopathic short stature.

OBJECTIVE: There is a scarcity of data from randomised controlled trials on the association of growth hormone (GH) with gonadotrophin-releasing hormone agonists in idiopathic short stature (ISS), although this off-label use is common. We aimed to test whether delaying pubertal progression could increase near-adult height (NAH) in GH-treated patients with ISS. METHODS: Patients with ISS at puberty onset were randomised to GH with leuprorelin (combination, n = 46) or GH alone (n = 45). NAH standard deviation score (SDS) was the primary outcome measure. The French regulatory authority requested premature discontinuation of study treatments after approximately 2.4 years; patients from France were followed for safety. RESULTS: Mean (s.d.) baseline height SDS was -2.5 (0.5) in both groups, increasing at 2 years to -2.3 (0.6) with combination and -1.8 (0.7) with GH alone. NAH SDS was -1.8 (0.5) with combination (n = 19) and -1.9 (0.8) with GH alone (n = 16). Treatment-emergent adverse events and bone fractures occurred more frequently with combination than GH alone. CONCLUSION: Due to premature discontinuation of treatments, statistical comparison of NAH SDS between the two cohorts was not possible. During the first 2-3 years of treatment, patients treated with the combination grew more slowly than those receiving GH alone. However, mean NAH SDS was similar in the two groups. No new GH-related safety concerns were revealed. A potentially deleterious effect of combined treatment on bone fracture incidence was identified.

Clinical outcomes with olanzapine long-acting injection: impact of the 3-hour observation period on patient satisfaction and well-being.

BACKGROUND: The objective of the present analysis is to determine the impact of the 3-hour observation period for olanzapine long-acting injection (LAI) on patient satisfaction and well-being by comparing data collected before and after its implementation. METHODS: This is a post hoc analysis of patients treated with olanzapine LAI in 1) a 6-month fixed-dose randomized controlled trial and/or 2) a 6-year open-label safety study. This analysis was limited to patients with schizophrenia who were treated with olanzapine LAI consistent with the approved indication and dosing recommendations of the European Union Summary of Product Characteristics (N=966). Of the 966 patients, the analysis further focused only on those patients who received both 1) at least one injection before the implementation of the 3-hour observation period and 2) at least one injection after implementation of the 3-hour observation period (N=487). Patient satisfaction was assessed with the three-item Patient Satisfaction with Medication Questionnaire-Modified. Responses were averaged across all postbaseline visits occurring before (ie, without) the implementation of the 3-hour observation period and across all postbaseline visits occurring after (ie, with) the implementation of the 3-hour observation period. In addition, the rate of postinjection delirium/sedation syndrome events was calculated. RESULTS: There was no meaningful change after implementation of the 3-hour observation period in satisfaction (before: mean [SD] =4.0 [1.02] and after: mean [SD] =4.1 [0.82]), preference for olanzapine LAI over oral medication (before: mean [SD] =4.0 [0.90] and after: mean [SD] =4.1 [0.77]), or ratings of satisfaction regarding side effects (before: mean [SD] =1.9 [0.79] and after: mean [SD] =1.8 [0.60]). For the total population (N=966), postinjection delirium/sedation syndrome occurred in 26 (0.07%) of 38,010 injections. CONCLUSION: For patients with schizophrenia receiving treatment with olanzapine LAI, the 3-hour observation period had no impact on their satisfaction with the medication or on their subjective well-being.

Relationships Between Functional Outcomes and Symptomatic Improvement in Atomoxetine-Treated Adult Patients with Attention-Deficit/Hyperactivity Disorder: Post Hoc Analysis of an Integrated Database.

BACKGROUND: Atomoxetine treatment is associated with improvements in functional outcomes in patients with attention-deficit/hyperactivity disorder (ADHD), although relationships between improvements in these outcomes and reductions in ADHD symptoms have not been comprehensively investigated in adults. OBJECTIVES: The aim of this study was to assess relationships between functional outcomes and ADHD symptoms (primary objective), and to assess time courses of changes in functional outcomes from baseline to weeks 10 and 24 (secondary objective). METHODS: We analyzed data pooled from seven Eli Lilly-sponsored placebo-controlled trials of atomoxetine in adults with ADHD that had Conners' Adult ADHD Rating Scales-Investigator Rated: Screening Version (CAARS-Inv:SV) total scores and functional outcome data at baseline and at week 10. Two trials also had these data at week 24. Patients were included in these pooled analyses if they had a CAARS-Inv:SV total score at baseline and at one or more post-baseline visits at weeks 10 or 24, or had post-baseline scores that would allow missing scores at weeks 10 or 24 to be imputed. To address the primary objective, changes in functional outcomes during treatment with atomoxetine versus placebo were assessed using last observation carried forward (LOCF) analysis of covariance (ANCOVA) and mixed-effects model repeated measures (MMRM) analysis, and correlations between score changes in CAARS-Inv:SV total and functional outcomes were assessed using Spearman's rank correlation coefficient (r) at weeks 10 and 24. The secondary objective was addressed using MMRM. RESULTS: At baseline, patients generally had moderately severe or worse ADHD symptoms (based on CAARS-Inv:SV total scores) and impaired functional outcomes (based on Adult ADHD Quality-of-Life [AAQoL], Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A], Sheehan Disability Scale [SDS], and 36-item Short-Form Health Survey [SF-36] scores). These baseline characteristics were comparable in the atomoxetine and placebo groups. For atomoxetine versus placebo, statistically significant improvements were detected in AAQoL total and subscores at weeks 10 and 24, and in BRIEF-A Self-Report scores at week 10, but not in BRIEF-A Informant Report or SDS scores at week 10 (no BRIEF-A or SDS data were available at week 24), and not in SF-36 at weeks 10 or 24. All functional improvements were gradual. During treatment with atomoxetine, there were moderate correlations between reductions in CAARS-Inv:SV total scores and increases in AAQoL total and subscores at weeks 10 and 24 (r range -0.58 to -0.39; n = 394-545), and also with reductions in BRIEF-A Self-Report at week 10 (r = 0.49; n = 256). With placebo, moderate correlations were also found between reductions in CAARS-Inv:SV total scores and increases in AAQoL total and subscores at weeks 10 and 24 (r range -0.56 to -0.28; n = 321-542), and with reductions in BRIEF-A Self-Report at week 10 (r = 0.49; n = 271). However, correlations between changes in CAARS-Inv:SV and BRIEF-A Informant at week 10 were low for atomoxetine-treated patients (r = 0.25; n = 65), moderate with placebo (r = 0.42; n = 72), and there were low/no correlations between changes in CAARS-Inv:SV and functional outcome rating scales that are not specific to ADHD; that is, for atomoxetine-treated patients, SDS total r = 0.19 (n = 32 at week 10) and SF-36 r range - 0.20 to -0.01 (n = 51 at week 10, n = 183 at week 24). CONCLUSIONS: Atomoxetine-treated adult patients experienced improvements in functional outcomes (AAQoL and BRIEF-A Self-Report) that correlated with reductions in ADHD symptoms. Although atomoxetine improved both the ADHD symptoms and functional outcomes, the correlation between symptoms and functional outcomes was low to moderate, suggesting that they measure overlapping but different aspects of the disorder. Hence, clinicians should assess not just ADHD symptoms, but also the functional impairments.

Post Hoc Analysis of Potential Predictors of Response to Atomoxetine for the Treatment of Adults with Attention-Deficit/Hyperactivity Disorder using an Integrated Database.

BACKGROUND: Responses to atomoxetine vary for individual patients with attention-deficit/hyperactivity disorder (ADHD). However, we do not know whether any factors can be used to reliably predict how individuals with ADHD will respond to treatment. OBJECTIVE: Our objective was to evaluate background variables that facilitate early identification of those adults with ADHD who are likely to respond to treatment with atomoxetine. METHODS: We pooled data for atomoxetine-treated adults with ADHD from 12 clinical trials for a short-term (10-week) analysis, and from 11 clinical trials for a long-term (24-week) analysis. Patients not meeting a response definition [≥30 % reduction in Conners' Adult ADHD Rating Scales-Investigator Rated: Screening Version (CAARS-Inv:SV) total score and Clinical Global Impressions of ADHD Severity Scale (CGI-S) score ≤3 at endpoint], or who discontinued, were defined as non-responders. Another definition of response (≥30 % reduction in CAARS-Inv:SV total score at endpoint) was also used in these analyses; only the results with the former definition are shown in this abstract, as the same conclusions were gained with both definitions. A treatment-specified subgroup detection tool (a resampling-based ensemble tree method) was used to identify predictors of response. RESULTS: Of 1945 adults in the long-term analysis, 548 (28.2 %) were responders to atomoxetine at week 24; 65.2 % of 1397 non-responders had discontinued. Of 4524 adults in the short-term analysis, 1490 (32.9 %) were responders at week 10; 33.2 % of 1006 non-responders had discontinued. No analyzed baseline parameters (age, sex, prior stimulant use, ADHD subtype, CAARS-Inv:SV, CGI-S) were statistically significant predictors of response. Reductions in CAARS-Inv:SV total, CAARS-Inv:SV subscores, and CGI-S at week 4 in the short-term analysis, and at weeks 4 or 10 in the long-term analysis, were statistically significant predictors of response, i.e., patients with versus without these reductions early in treatment were more likely to be clinical responders at later time points. Sensitivity ranged from 28.6 to 85.9 %, and specificity ranged from 23.8 to 86.7 %. Predictors with higher sensitivity had lower specificity, and vice versa. CONCLUSIONS: Reductions in CAARS-Inv:SV and CGI-S scores at weeks 4 and 10 are statistically significant predictors of response to atomoxetine at later time points in adults with ADHD. However, the predictors identified by these analyses are not reliable enough for use in clinical practice. The only currently available method to judge whether individuals with ADHD will respond to atomoxetine is to start treatment and assess the response over an extended period, sometimes longer than 10 weeks.

A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients.

The lack of head-to-head clinical studies powered to compare atomoxetine and osmotic release oral system (OROS) methylphenidate necessitates treatment comparison by methods that include indirect evidence such as network meta-analysis (NMA). A NMA assessing the relative treatment effects of atomoxetine and OROS methylphenidate in adults with attention-deficit/hyperactivity disorder (ADHD) was conducted. Studies were identified by systematic literature review. Analyses summarised improvements in efficacy, measured by ADHD-specific scales, using Cohen'sdto calculate the standardised mean difference (SMD), and all cause discontinuations. Results showed effect sizes (SMD, 95% credible interval (CrI)) relative to placebo that did not differ significantly between atomoxetine (0.46, 0.36-0.56) and OROS methylphenidate (0.51, 0.40-0.63) in clinical studies of up to 12 weeks' duration (SMD, 95% CrI for atomoxetine versus OROS methylphenidate: -0.05, -0.18-0.08). Patients treated with these medications responded better than those given placebo across all analyses. There was also no significant difference in discontinuation rates between atomoxetine and OROS methylphenidate (odds ratio, 95% CrI: 0.85, 0.53-1.35). Between-study heterogeneity was low overall. Results of this NMA suggest that the efficacy of atomoxetine and OROS methylphenidate in adults does not differ significantly. Clinical guidelines may require amendment to reflect these recent data.

Assessment of functional outcomes by Sheehan Disability Scale in patients with major depressive disorder treated with duloxetine versus selective serotonin reuptake inhibitors.

OBJECTIVE: We compared functional impairment outcomes assessed with Sheehan Disability Scale (SDS) after treatment with duloxetine versus selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder. METHODS: Data were pooled from four randomized studies comparing treatment with duloxetine and SSRIs (three double blind and one open label). Analysis of covariance, with last-observation-carried-forward approach for missing data, explored treatment differences between duloxetine and SSRIs on SDS changes during 8 to 12 weeks of acute treatment for the intent-to-treat population. Logistic regression analysis examined the predictive capacity of baseline patient characteristics for remission in functional impairment (SDS total score ≤ 6 and SDS item scores ≤ 2) at endpoint. RESULTS: Included were 2193 patients (duloxetine n = 1029; SSRIs n = 835; placebo n = 329). Treatment with duloxetine and SSRIs resulted in significantly (p < 0.01) greater improvements in the SDS total score versus treatment with placebo. Higher SDS (p < 0.0001) or 17-item Hamilton Depression Rating Scale baseline scores (p < 0.01) predicted lower probability of functional improvement after treatment with duloxetine or SSRIs. Female gender (p ≤ 0.05) predicted higher probability of functional improvement after treatment with duloxetine or SSRIs. CONCLUSIONS: Treatment with SSRIs and duloxetine improved functional impairment in patients with major depressive disorder. Higher SDS or 17-item Hamilton Depression Rating Scale baseline scores predicted less probability of SDS improvement; female gender predicted better improvement in functional impairment at endpoint.

A 6-year open-label study of the efficacy and safety of olanzapine long-acting injection in patients with schizophrenia: a post hoc analysis based on the European label recommendation.

PURPOSE: To assess the long-term efficacy and safety of olanzapine long-acting injection (LAI) in the treatment of schizophrenia, focusing on clinical trial data consistent with the approved indication and dosing recommendations in the European label and which forms the basis for treatment decisions made by clinicians in daily clinical practice. PATIENTS AND METHODS: This was a post hoc analysis of a 6-year open-label study of olanzapine LAI in patients (male or female, 18-75 years old) with schizophrenia entering this study following feeder studies of olanzapine LAI. Patients were flexibly dosed (45-405 mg, 2- to 4-week intervals), but those receiving oral olanzapine supplementation whose total olanzapine dose was >20 mg/day equivalent were excluded from this post hoc analysis. RESULTS: Data from 669 patients were analyzed (44.5% completed). Positive and Negative Syndrome Scale total scores did not change significantly from baseline to endpoint; Clinical Global Impression-Severity scores improved significantly. Mean weight change was +2.19 kg (P<0.001), with 40.8% of patients experiencing ≥7% weight gain. There were 24 occurrences of post-injection delirium/sedation syndrome (PDSS). CONCLUSION: Olanzapine LAI appeared to be effective in the long-term maintenance of schizophrenia, and the safety profile was consistent with that of oral olanzapine, except for injection-related events and PDSS events.

Individual residual symptoms and functional impairment in patients with depression.

The aim of treatment of depression is remission of symptoms and functioning. Although there is a relationship between remission of symptoms and remission of functioning, it is not known how individual residual symptoms are related to functioning. Here we report a post-hoc analysis of two studies which treated depressed patients with duloxetine in an open fashion for 10-12 weeks. We evaluated the association of individual residual symptoms and functional impairment in patients who remitted or partially remitted after acute treatment. Logistic regression was used to investigate residual symptoms associated with functional impairment at endpoint. Our results suggest that in partial remitters, the only residual symptom associated with a reduction in the risk of having impaired function was the resolution of painful physical symptoms (PPS). In patients who remitted, the presence of residual core mood symptoms (CMS), particularly in patients without any anxiety, predicted impaired functioning. The resolution of PPS in the presence of residual CMS was associated with less risk of impaired functioning. Our results contribute to understand better the role of specific residual symptoms on functional impairment. To achieve normal functioning, intervention on specific residual symptoms is recommended.

Impact of comorbidities on pharmacotherapy of painful diabetic neuropathy in clinical practice.

AIMS: We evaluated the impact of baseline comorbidities on the effectiveness of duloxetine and anticonvulsants (pregabalin/gabapentin) in patients with painful diabetic neuropathy in clinical care. METHODS: Outcomes from a 6-month, observational study with 2575 patients initiating/switching DPNP treatment were analyzed post-hoc. Propensity scoring was used to adjust for baseline factors influencing treatment choice in 1523 patients receiving duloxetine or anticonvulsants. Analysis of covariance models with fixed effects for baseline pain, treatment, propensity score, baseline characteristics or comorbidities, and their interaction with treatment were used to estimate LSmean effects on Brief Pain Inventory (BPI) average pain and interference scores. RESULTS: 89.5% of patients reported comorbidities, including hypertension (70.5%), hyperlipidemia (39.2%), and depression (24.8%). Macrovascular complications (37.0%) and 'other chronic pain' (41.5%), particularly joint pain had an impact on both pain treatments, i.e. less improvement of average pain and interference of pain. Better treatment responses with duloxetine vs. anticonvulsants were observed in patients with depression, those with high baseline BPI total interference score, especially general activity, and in patients with joint pain. CONCLUSIONS: Comorbidities such as macroangiopathy and depression as well as pain characteristics should be considered in the treatment of DPNP as they may predict the effectiveness of duloxetine and anticonvulsants.

Impact of pretreatment with antidepressants on the efficacy of duloxetine in terms of mood symptoms and functioning: an analysis of 15 pooled major depressive disorder studies.

OBJECTIVE: This post hoc analysis aimed to determine whether patients with major depressive disorder (MDD) in duloxetine trials who were antidepressant naive or who were previously exposed to antidepressants exhibited differences in efficacy and functioning. METHOD: Data were pooled from 15 double-blind, placebo- and/or active-controlled duloxetine trials of adult patients with MDD conducted by Eli Lilly and Company. The individual studies took place between March 2000 and November 2009. Data were analyzed using 4 pretreatment subgroups: first-episode never treated, multiple-episode never treated, treated previously only with selective serotonin reuptake inhibitors (SSRIs), and previously treated with antidepressants other than just SSRIs. Measures included the 17-item Hamilton Depression Rating Scale (HDRS-17) total and somatic symptom subscale scores, Montgomery-Asberg Depression Rating Scale (MADRS) total score, and Sheehan Disability Scale total score. Response rates (50% and 30%) were based on the HDRS-17 total score and remission rates on either the HDRS-17 or MADRS total score. RESULTS: Response and remission rates were significantly greater (P < .05 in 11 of 12 comparisons) for duloxetine versus placebo in the 4 subgroups. A trend of greater response and remission occurred for first-episode versus multiple-episode patients; both groups were generally higher than the antidepressant-treated groups. Mean changes in efficacy measures were mostly significantly greater (P < .05 in 13 of 16 comparisons) for duloxetine versus placebo within each pretreatment subgroup, with some (P < .05 in 2 of 24 comparisons) significant interaction effects between subgroups on HDRS-17 total and somatic symptoms scores. CONCLUSIONS: Duloxetine was generally superior to placebo on response and remission rates and in mean change on efficacy measures. Response and remission rates were numerically greater for first-episode versus multiple-episode and drug-treated patients. Mean change differences on efficacy measures among the 4 subgroups were inconsistent. Duloxetine showed a similar therapeutic effect independent of episode frequency and antidepressant pretreatment.

Switching to olanzapine long-acting injection from either oral olanzapine or any other antipsychotic: comparative post hoc analyses.

BACKGROUND: A considerable proportion of patients suffering from schizophrenia show suboptimal responses to oral antipsychotics due to inadequate adherence. Hence, they are likely to benefit from switching to a long-acting injectable formulation. These post hoc analyses assessed the clinical effects of switching to olanzapine long-acting injection (OLAI) from either oral olanzapine (OLZ) or other antipsychotics (non-OLZ). METHODS: Post hoc analyses were done based on two randomized studies (one short-term, one long-term) conducted in patients suffering from schizophrenia and treated with OLAI. The short-term study was an 8-week placebo-controlled, double-blind trial in acute patients, and the long-term study was a 2-year, oral olanzapine-controlled, open-label, follow-up of stabilized outpatients. RESULTS: These analyses used data from 62 OLAI-treated patients (12 switched from OLZ, 50 from non-OLZ) from the short-term study and 190 OLAI-treated patients (56 switched from OLZ, 134 from non-OLZ) from the long-term study. Kaplan-Meier survival analyses of time to all-cause discontinuation of OLAI treatment did not differ significantly between OLZ and non-OLZ patients in the short-term study (P=0.209) or long-term study (P=0.448). Similarly, the proportions of OLZ and non-OLZ patients that discontinued OLAI were not statistically different in the short-term (16.7% versus 36.0%, respectively; P=0.198) or long-term (57.1% versus 47.8% respectively; P=0.238) studies. In the short-term study, no significant differences were detected between the patient groups in mean change in Positive and Negative Syndrome Scale (PANSS) total score (-13.4 OLZ versus -20.8 non-OLZ; P=0.166). In the long-term study, mean change in PANSS total score (3.9 OLZ versus -3.6 non-OLZ; P=0.008) was significantly different between the non-OLZ and OLZ groups. Rates of treatment-emergent adverse events were similar in OLZ and non-OLZ groups per study. CONCLUSION: These post hoc analyses suggest that no significant differences in clinical effectiveness were seen after switching from non-OLZ or OLZ to OLAI. However, these findings should be interpreted with care, due to small sample sizes and differences in patients' clinical profiles.

Randomized, double-blind study of the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder.

OBJECTIVES: This study assessed the efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder (MDD). DESIGN: An 11-week (9-week randomized; 2-week posttreatment phase), double-blind, placebo-controlled, Phase III study (D1448C00014). SETTING: A total of 53 centers in Argentina, Estonia, Finland, Russia, Ukraine, and the United States. PARTICIPANTS: A total of 338 patients (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of MDD, age ≥66 years, Hamilton Rating Scale for Depression [HAM-D] total score ≥22, HAM-D Item 1 [depressed mood] score ≥2) were randomized (mean age: 71.3 years). INTERVENTION: Patients were randomized to quetiapine XR (n = 166; flexible-dosing 50-300 mg/day) or placebo (n = 172). MEASUREMENTS: Primary outcome was Montgomery Åsberg Depression Rating Scale (MADRS) total score change from randomization at Week 9. RESULTS: At Week 9, quetiapine XR (least squares [LS] means: -16.33, standard error [SE]: 0.95; mean change: -16.0, standard deviation [SD]: 9.3) significantly reduced MADRS total score from randomization versus placebo (LS means [SE]: -8.79 [0.94]; mean [SD]: -9.0 [9.9]); significant improvements were also seen at Week 1 (LS means [SE]: -4.65 [0.53] versus -2.56 [0.53], respectively; mean [SD]: -4.3 [5.1] versus -2.4 [3.7], respectively). At Week 9, secondary outcome variables significantly improved with quetiapine XR versus placebo, including MADRS response (≥50% reduction in total score); MADRS remission (total score ≤8); HAM-D total, HAM-A total, HAM-A psychic and somatic cluster, and Clinical Global Impressions-Severity of Illness (CGI-S) total scores; proportion of patients with CGI-Improvement score of 2 or less; Q-LES-Q-SF% maximum total, Pittsburgh Sleep Quality Index global, and pain Visual Analog Scale scores. Common adverse events (>10% patients with quetiapine XR) were somnolence, headache, dry mouth, and dizziness. CONCLUSION: In elderly patients with MDD, quetiapine XR monotherapy (50-300 mg/day, flexibly dosed) is effective at improving depressive symptoms, with symptom improvement observed as early as Week 1. Overall tolerability and safety were consistent with the known profile of quetiapine.

Self-reported sedation profile of immediate-release quetiapine fumarate compared with extended-release quetiapine fumarate during dose initiation: a randomized, double-blind, crossover study in healthy adult subjects.

OBJECTIVES: The primary study objective was to assess the time course and intensity of sedation after administration of immediate-release (IR) and extended-release (XR) quetiapine fumarate in healthy subjects during dose initiation. The tolerability of the 2 formulations was also evaluated. METHODS: This was a randomized, double-blind, double-dummy, 2-period crossover study in healthy adult (age 18-50 years) subjects. It employed the dose-initiation schedule used in studies of the 2 quetiapine formulations in patients with bipolar depression: 50 mg on day 1, 100 mg on day 2, 200 mg on day 3, and 300 mg on days 4 and 5. Doses were administered in the morning. The primary end point was the level of sedation 1 hour after dosing on day 1, as rated by subjects using a visual analog scale (VAS) ranging from 0 = alert to 100 = drowsy. Secondary VAS end points included sedation over a 14-hour period on day 1, and on days 2 through 5. Blood was drawn on day 5 of both periods for determination of plasma drug concentrations by a liquid chromatography method with tandem mass-spectrometric detection. Adverse events (AEs) were recorded throughout the study. RESULTS: Sixty-three subjects were enrolled in the study, comprising the safety population. The perprotocol population consisted of 58 subjects (79.0% male, 21.0% female; 67.2% black, 24.1% white; mean age, 31.8 years; mean weight, 80.7 kg). One hour after dosing on day 1, sedation was significantly greater with quetiapine IR than with quetiapine XR (mean VAS score, 33.2 vs 11.3, respectively; P < 0.001). There were no significant differences in sedation between formulations at 7 hours after dosing (64.5 and 53.6), 8 hours after dosing (46.9 and 50.8), or 14 hours after dosing (both, 12.7). On day 1, numerically more subjects had a VAS score>75 (substantial sedation) 1 hour after dosing in the quetiapine IR group than in the quetiapine XR group (14 vs 4 subjects). On day 5, the mean (95% CI) quetiapine C(max) for the IR and XR formulations was 689.19 (605.83-784.02) and 381.70 (341.40-426.76) ng/mL; the mean was AUC(0-11) was 2835.89 (2517.92-3194.02) and 2515.21 (2281.76--2772.55) ng . h/mL; and the median T(max) was 2.0 and 5.0 hours. The incidence of any AEs was 21.7% with quetiapine IR and 9.8% with quetiapine XR. CONCLUSION: In these healthy subjects, quetiapine XR was associated with a lower intensity of self-reported sedation compared with quetiapine IR. ClinicalTrials.gov Identifier: NCT00702676; Astra Zenecaclinicaltrials.com Identifier: D1443C00033.