Weeks Of Double-blind Treatment Research Articles

Vilazodone in patients with generalized anxiety disorder: a double-blind, randomized, placebo-controlled, flexible-dose study.

Vilazodone is a selective serotonin reuptake inhibitor and a 5-HT1A receptor partial agonist that is approved for treatment of major depressive disorder in adults in the USA and Mexico. The efficacy, safety, and tolerability of vilazodone for generalized anxiety disorder (GAD) were investigated in a clinical trial (NCT01766401 ClinicalTrials.gov). Participants (18–70 years, inclusive) who met Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision, criteria for GAD were randomized (1 : 1) to placebo or flexible-dose vilazodone (20–40 mg/day) for 8 weeks of double-blind treatment. Primary and secondary efficacy parameters were changes from baseline to week 8 in Hamilton Rating Scale for Anxiety and Sheehan Disability Scale total scores, respectively. Analysis was based on a mixed-effects model for repeated measures approach on the intent-to-treat population. The intent-to-treat population comprised 395 patients (placebo=197, vilazodone=198); 77% completed the study. The least squares mean difference in change from baseline to week 8 in the Hamilton Rating Scale for Anxiety total score was statistically significant for vilazodone versus placebo [−1.50 (−2.96, −0.04), P=0.0438]. The mean change from baseline to week 8 in the Sheehan Disability Scale total score for vilazodone versus placebo was not statistically significant. Adverse events were reported in 60% of placebo-treated and 83% of vilazodone-treated patients. This was a positive clinical trial of 20–40 mg/day vilazodone versus placebo in the treatment of GAD.

COMBINED MIRTAZAPINE AND SSRI TREATMENT OF PTSD: A PLACEBO-CONTROLLED TRIAL.

Combined treatment with a selective serotonin reuptake inhibitor (SSRI) plus mirtazapine has shown superior efficacy in some studies of depression, but has not been studied in posttraumatic stress disorder (PTSD). This study aimed to assess acceptability of combined sertraline plus mirtazapine treatment for PTSD and to estimate its effect size relative to sertraline plus placebo. Thirty-six adults with PTSD were randomized to 24 weeks of double-blind treatment with sertraline plus mirtazapine or sertraline plus placebo. Outcomes were analyzed with mixed effects models. The combined treatment group showed a significantly greater remission rate (P = .042) and improvement in depressive symptoms (P = .023) than the sertraline plus placebo group. There were no significant group differences in the two primary outcomes of treatment retention and PTSD severity, or in other secondary outcomes (sleep impairment, sexual functioning, quality of life, and physical and mental functioning), but the combined treatment group showed numerical advantages on all of these outcomes, and effect sizes relative to sertraline plus placebo ranged from small to moderate (d = .26-.63). Both treatments were well-tolerated, with significantly increased appetite but not weight gain in the combined treatment group. Findings suggest that combined treatment of PTSD with sertraline plus mirtazapine may have clinically meaningful advantages in symptomatic improvement, relative to SSRI treatment alone, and acceptable tolerability. Combined treatment with an SSRI plus mirtazapine in PTSD deserves additional study as initial treatment or as an augmentation strategy for nonresponders to an SSRI.

Longterm Safety and Efficacy of Subcutaneous Tocilizumab Monotherapy: Results from the 2-year Open-label Extension of the MUSASHI Study.

To evaluate the longterm safety and efficacy of subcutaneous tocilizumab (TCZ-SC) as monotherapy in patients with rheumatoid arthritis (RA). Of 346 patients who received 24 weeks of double-blind treatment with either TCZ-SC monotherapy, 162 mg every 2 weeks (q2w); or intravenous TCZ (TCZ-IV) monotherapy, 8 mg/kg every 4 weeks; 319 patients continued to receive TCZ-SC q2w in the 84-week open-label extension (OLE) of the MUSASHI study (JAPICCTI-101117). Efficacy, safety, and immunogenicity were evaluated for all patients treated with TCZ during 108 weeks. The proportions of patients who achieved American College of Rheumatology 20/50/70 responses, low disease activity [28-joint Disease Activity Score (DAS28) ≤ 3.2], or remission (DAS28 < 2.6) at Week 24 were maintained until Week 108. The incidences of adverse events and serious adverse events were 498.3 and 16.9 per 100 patient-years (PY), respectively. The overall safety of TCZ-SC monotherapy was similar to that of TCZ-IV monotherapy. Rates of injection site reactions (ISR) through 108 weeks remained similar to rates through 24 weeks. ISR were mild and did not cause any patient withdrawals. No serious hypersensitivity events (including anaphylactic reactions) occurred. Anti-TCZ antibodies were present in 2.1% of patients treated with TCZ-SC monotherapy. TCZ-SC monotherapy maintained a favorable safety profile and consistent efficacy throughout the 108-week study. Like TCZ-IV, TCZ-SC could provide an additional treatment option for patients with RA.

Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study.

This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with Major Depressive Disorder (MDD). 155 subjects with DSM-IV MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ≥ 15 and baseline biomarker data (IL-1ra, IL-6, hs-CRP, leptin, adiponectin), were randomized between 05/18/06 and 06/30/11, to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg/day, docosahexaenoic acid (DHA)-enriched n-3 900 mg/day, or placebo. Outcomes were determined using mixed model repeated measures (MMRM) analysis for “high” and “low” inflammation groups based on individual and combined biomarkers. Results are presented in terms of standardized treatment effect size (ES) for change in HAM-D-17 from baseline to treatment week 8. While overall treatment group differences were negligible (ES=−0.13 to +0.04), subjects with any “high” inflammation improved more on EPA than placebo (ES=−0.39) or DHA (ES=−0.60) and less on DHA than placebo (ES=+0.21); furthermore, EPA-placebo separation increased with increasing numbers of markers of high inflammation. Subjects randomized to EPA with “high” IL-1ra or hs-CRP or low adiponectin (“high” inflammation) had medium ES decreases in HAM-D-17 scores versus subjects “low” on these biomarkers. Subjects with “high” hs-CRP, IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers (medium to large ES differences). Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA versus placebo in our cohort. Studies are needed to replicate and extend this proof of concept work.

Responder analysis of a randomized comparison of the 13.3 mg/24 h and 9.5 mg/24 h rivastigmine patch.

IntroductionOPtimizing Transdermal Exelon In Mild-to-moderate Alzheimer’s disease (OPTIMA) was a randomized, double-blind comparison of 13.3 mg/24 h versus 9.5 mg/24 h rivastigmine patch in patients with mild-to-moderate Alzheimer’s disease who declined despite open-label treatment with 9.5 mg/24 h patch. Over 48 weeks of double-blind treatment, high-dose patch produced greater functional and cognitive benefits compared with 9.5 mg/24 h patch.MethodsUsing OPTIMA data, a post-hoc responder analysis was performed to firstly, compare the proportion of patients demonstrating improvement or absence of decline with 13.3 mg/24 h versus 9.5 mg/24 h patch; and secondly, identify predictors of improvement or absence of decline. ‘Improvers’ were patients who improved on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) by ≥4 points from baseline, and did not decline on the instrumental domain of the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale (ADCS-IADL). ‘Non-decliners’ were patients who did not decline on either scale.ResultsOverall, 265 patients randomized to 13.3 mg/24 h and 271 to 9.5 mg/24 h patch met the criteria for inclusion in the intention-to-treat population and were included in the analyses. Significantly more patients were ‘improvers’ with 13.3 mg/24 h compared with 9.5 mg/24 h patch at Weeks 24 (44 (16.6%) versus 19 (7.0%); P < 0.001) and 48 (21 (7.9%) versus 10 (3.7%); P = 0.023). A significantly greater proportion of patients were ‘non-decliners’ with 13.3 mg/24 h compared with 9.5 mg/24 h patch at Week 24 (71 (26.8%) versus 44 (16.2%); P = 0.002). At Week 48, there was a trend in favor of 13.3 mg/24 h patch. Functional and cognitive assessment scores at double-blind baseline did not consistently predict effects at Weeks 24 or 48.ConclusionMore patients with mild-to-moderate Alzheimer’s disease who are titrated to 13.3 mg/24 h rivastigmine patch at time of decline are ‘improvers’ or ‘non-decliners’ i.e. show responses on cognition and activities of daily living compared with patients remaining on 9.5 mg/24 h patch.Trial registrationClinicaltrials.gov identifier: NCT00506415; registered July 20, 2007.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-014-0088-8) contains supplementary material, which is available to authorized users.

The Efficacy and Safety of Evekeo, Racemic Amphetamine Sulfate, for Treatment of Attention-Deficit/Hyperactivity Disorder Symptoms: A Multicenter, Dose-Optimized, Double-Blind, Randomized, Placebo-Controlled Crossover Laboratory Classroom Study.

Objective: The study goal was to determine the efficacy and safety of an optimal dose of Evekeo, racemic amphetamine sulfate, 1:1 d-amphetamine and l-amphetamine (R-AMPH), compared to placebo in treating children with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting.Methods: A total of 107 children ages 6–12 years were enrolled in this multicenter, dose-optimized, randomized, double-blind, placebo-controlled crossover study. After 8 weeks of open-label dose optimization, 97 subjects were randomized to 2 weeks of double-blind treatment in the sequence of R-AMPH followed by placebo (n=47) or placebo followed by R-AMPH (n=50). Efficacy measures included the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale and Permanent Product Measure of Performance (PERMP) administered predose and at 0.75, 2, 4, 6, 8, and 10 hours postdose on 2 laboratory classroom days. Safety assessments included physical examination, chemistry, hematology, vital signs, and treatment-emergent adverse events (TEAEs).Results: Compared to placebo, a single daily dose of R-AMPH significantly improved SKAMP-Combined scores (p<0.0001) at each time point tested throughout the laboratory classroom days, with effect onset 45 minutes postdose and extending through 10 hours. R-AMPH significantly improved PERMP number of problems attempted and correct (p<0.0001) throughout the laboratory classroom days. During the twice-daily dose-optimization open-label phase, improvements were observed with R-AMPH in scores of the ADHD-Rating Scale IV and Clinical Global Impressions Severity and Improvement Scales. TEAEs and changes in vital signs associated with R-AMPH were generally mild and not unexpected. The most common TEAEs in the open-label phase were decreased appetite (27.6%), upper abdominal pain (14.3%), irritability (14.3%), and headache (13.3%).Conclusions: Compared to placebo, R-AMPH was effective in treating children aged 6–12 years with ADHD, beginning at 45 minutes and continuing through 10 hours postdose, and was well tolerated.Trial registration: ClinicalTrials.gov identifier: NCT01986062. https://clinicaltrials.gov/ct2/show/NCT01986062

Olanzapine/Fluoxetine Combination in Children and Adolescents With Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Trial

To assess the efficacy and safety of olanzapine/fluoxetine combination (OFC) for the acute treatment of bipolar depression in children and adolescents. Patients 10 to 17 years of age with bipolar I disorder (BP-I), depressed episode, baseline Children's Depression Rating Scale-Revised (CDRS-R) total score≥40, Young Mania Rating Scale (YMRS) total score≤15, and YMRS-item 1≤2 were randomized to OFC (6/25-12/50 mg/day olanzapine/fluoxetine; n= 170) or placebo (n= 85) for up to 8 weeks of double-blind treatment. The primary efficacy measure was mean change in CDRS-R using mixed-model repeated-measures methodology. Baseline-to-week-8 least-squares mean change in CDRS-R total score was greater for OFC-treated patients than for placebo-treated patients (-28.4 versus-23.4, p = .003; effect size= .46), with between-group differences statistically significant at week 1 (p= .02) and all subsequent visits (all p< .01). Rates of and times to response and remission were statistically significantly greater for OFC- than for placebo-treated patients. The most frequent treatment-emergent adverse events in the OFC group were weight gain, increased appetite, and somnolence. Mean weight gain at patient's endpoint was significantly greater for OFC- than for placebo-treated patients (4.4 kg versus 0.5 kg, p< .001). Treatment-emergent hyperlipidemia was very common among OFC-treated patients. Abnormal increases in hepatic analytes, prolactin, and corrected QT interval (QTc) were also common or very common but generally not clinically significant. In this study, OFC was superior to placebo, and has been approved by the US Food and Drug Administration (FDA) for the acute treatment of bipolar I depression in patients 10 to 17 years of age. Benefits should be weighed against the risk of adverse events, particularly weight gain and hyperlipidemia. Clinical trial registration information-A Study for Assessing Treatment of Patients Ages 10-17 with Bipolar Depression; http://clinicaltrials.gov; NCT00844857.

1565Identifying Optimal HIV Viral Load (VL) Thresholds for Predicting Antiretroviral Treatment Failure (TF) Using ROC Curve Analysis

Background: Guidelines on HIV treatment differ globally in recommended viral load (VL) thresholds indicative of treatment failure (TF). Improvements in VL assay sensitivity and worldwide scale-up of VL monitoring make it increasingly important to determine optimal VLs thresholds for guiding treatment changes. Receiver operating characteristic (ROC) curves can identify optimal VL thresholds which maximize sensitivity and specifi city for predicting TF. The BRAVO study was a retrospective study, using the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, v2.0, to explore thresholds of VL that might predict subsequent TF. Methods: Longitudinal patient specimens were collected through the VERxVE study, a randomized, double-blind (DB) study in treatment-naive patients treated with nevirapine immediate-release or extended-release (VIRAMUNE IR or XR), plus emtricitabine and tenofovir DF. Stored plasma samples from up to 24 timepoints (pre-treatment through 144 weeks of DB treatment), were tested with the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, v2.0. The BRAVO patient endpoints of TF (which differed from the primary VERxVE endpoints) were determined by two independent HIV physicians based on VL trajectories. Guideline-based defi nitions of TF were also examined. A simple logistic regression model and ROC curves were created to determine the optimal VL thresholds for predicting TF at key study timepoints. Results: Of 563 evaluable patient-series, 74 patients (13%) had TF. By ROC curve analysis, a VL threshold of 95 copies/ml at week 24 and 33 copies/ml at week 48 maximized sensitivity and specifi city of predicting eventual TF [Area Under Curve: 0.75 and 0.73, respectively]. Overall sensitivity and specifi city were similar when compared to guidelines-based VL thresholds of 50 or 200 copies/ml and when using thresholds from an endpoint-based TF defi nition. Conclusions: ROC curve analysis identifi ed a VL threshold that maximized sensitivity and specifi city in predicting TF. Viral load thresholds of 50 or 200 copies/ml can also be used without a signifi cant decrease in overall sensitivity and specifi city. As VL assays may differ in sensitivity, ROC curve analysis can help optimize the clinical utility of VL monitoring.

Cariprazine in the treatment of acute mania in bipolar I disorder: A double-blind, placebo-controlled, Phase III trial

BackgroundThis Phase III, randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of flexibly-dosed cariprazine in patients with acute manic or mixed episodes associated with bipolar I disorder. MethodsPatients were randomized to 3 weeks of double-blind treatment with cariprazine 3–12mg/day (n=158) or placebo (n=154). The primary efficacy parameter was change from baseline to Week 3 in Young Mania Rating Scale (YMRS) total score. The secondary efficacy parameter was change from baseline to Week 3 in Clinical Global Impressions-Severity (CGI-S) score. ResultsMean change from baseline to Week 3 in YMRS total score was significantly greater for patients receiving cariprazine 3–12mg/day versus placebo (P=0.0004). Significant differences between groups in YMRS total score mean change were observed by Day 4 (first postbaseline assessment) and maintained throughout double-blind treatment (all assessments, P<0.01). Cariprazine also demonstrated statistically significant superiority over placebo on YMRS response (≥50% improvement: cariprazine, 58.9%; placebo, 44.1%; P=0.0097) and remission (YMRS total score≤12: cariprazine, 51.9%; placebo, 34.9%; P=0.0025) and mean change in CGI-S (P=0.0027) score and Positive and Negative Syndrome Scale (PANSS) (P=0.0035) total score. The most common cariprazine-related (≥10% and twice placebo) treatment emergent adverse events (TEAEs) were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Mean change from baseline in metabolic parameters were generally small and similar between groups. LimitationsLack of active comparator arm; short duration of study. ConclusionIn this study, cariprazine 3–12mg/day was effective and generally well tolerated in the treatment of manic and mixed episodes associated with bipolar I disorder.

Atomoxetine in Autism Spectrum Disorder: No Effects on Social Functioning; Some Beneficial Effects on Stereotyped Behaviors, Inappropriate Speech, and Fear of Change

Abstract Objective: The objective of this study was to investigate the short-term treatment effects of atomoxetine on autism spectrum disorder (ASD) symptoms in children and adolescents with both ASD and attention-deficit/hyperactivity disorder (ADHD). A total of 97 patients 6-17 years of age, with ASD and ADHD, were treated with 1.2 mg/kg/day of atomoxetine during an 8 week double-blind placebo-controlled period. Here, we investigated effects on two parent-based secondary outcome measures, the Aberrant Behavior Checklist (ABC) and the Children's Social Behavior Questionnaire (CSBQ). After 8 weeks of double-blind treatment, atomoxetine administration was associated with significant treatment effects on the ABC subscales Hyperactivity, Inappropriate Speech, and Stereotypic Behavior, and on the CSBQ subscale Fear for Changes. Our study results indicate no beneficial effects of atomoxetine on social functioning. However, atomoxetine may ameliorate restricted and stereotyped behaviors and communication. This study has been registered in ClinicalTrials.gov ( www.clinicaltrials.gov ) under registration number NCT00380692.

Quality of Life (Qol) Associated with Lanreotide Autogel (Lan) Treatment for Carcinoid Syndrome (Cs) in Gastroenteropancreatic Neuroendocrine Tumour (Gepnet) Patients: Results of the Elect Study

ABSTRACT Aim: QoL is an important consideration for CS treatment. This analysis evaluated QoL in GEP-NET patients treated for CS in the ELECT study. Methods: ELECT was a 16-week, randomised, double-blind (DB) phase III study (NCT00774930). Patients with GEP-NETs and a history of CS were treated with LAN 120 mg (n = 59) or placebo (n = 56) every 4 weeks. It was followed by 32-week and ≥2-year open-label extensions (OLEs). The primary endpoint was % of days of rescue medication use (SC octreotide) during DB study. Safety evaluations focused on adverse events (AEs). QoL was assessed using the EORTC QLQ-C30 and the EORTC QLQ-GI.NET21. Scores for global health status score (QLQ-C30) and endocrine and gastrointestinal subscales (QLQ-GI.NET21) were secondary endpoints; other scores were exploratory. Results: Mean [95% CI] % of days of rescue medication use was significantly lower with LAN (34% [25, 42%]) than placebo (49% [40, 57%]); difference –15% [–27, –3%], p = 0.02. Treatment-related AEs occurred in 15 (26%) LAN vs. 11 (19%) placebo patients: most common AEs were gastrointestinal. The global health status score (QLQ-C30) remained similar after 12 weeks of DB treatment with LAN and placebo. Treatment differences in endocrine and gastrointestinal subscale scores are shown in the table. For all functional scales of the QLQ-C30, scores remained stable/slightly improved in the LAN group, while there were small deteriorations in the placebo group; however CIs were wide. For the other subscales of the QLQ-GI.NET21, changes in scores were similar in both treatment groups. Conclusions: LAN 120 mg treatment for CS symptoms was not associated with a deterioration in QoL in GEP-NET patients. In fact, despite the relatively short duration of the study, there was evidence of initial improvements in some aspects of QoL. Results of QoL scores in OLE may provides more information. Table: Effect of LAN on QoL secondary endpoints. Values are mean (SD) unless otherwise stated. P-value tested at a significance level of 0.05. A hierarchical testing procedure was applied for secondary endpoints. Data shown are for the transformed scores, which can range from 0 to 100. A higher transformed score for global health status represents a better QoL. A higher transformed score for Endocrine and GI symptoms represents a higher level of symptomatology/problems Lanreotide Autogel Placebo LS mean treatment difference in change from baseline [95% CI] p-value QLQ-C30 Global health status/QoL Baseline 59.89 (20.15) [n = 59] 62.58 (20.28) [n = 55] 4.05 [–2.09, 10.20] 0.1931 Week 12 64.93 (19.37) [n = 48] 61.19 (18.07) [n = 35] 4.05 [–2.09, 10.20] 0.1931 QLQ-GI.NET21 Endocrine symptoms Baseline 25.89 (22.83) [n = 59] 33.54 (23.92) [n = 53] –7.04 [–14.80, 0.73] 0.0750 Week 12 18.06 (20.06) [n = 48] 29.84 (22.51) [n = 35] –7.04 [–14.80, 0.73] 0.0750 QLQ-GI.NET21 Gastrointestinal symptoms Baseline 22.40 (16.95) [n = 59] 24.84 (20.09) [n = 53] –4.68 [–9.63, 0.26] 0.0632 Week 12 17.64 (14.32) [n = 48] 23.62 (15.45) [n = 35] –4.68 [–9.63, 0.26] 0.0632 Disclosure: E. Gomez-Panzani: Ipsen: employee; A.I. Vinik: Ipsen: Research grant, advisory board member; E.M. Wolin: Research grant from Ipsen. Advisory board member for Ipsen, Novartis and Celgene; H. Audry: Received consulting fee (contract statistician) from Ipsen.

The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial.

Cariprazine, an orally active and potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors, is being developed for the treatment of schizophrenia and bipolar mania. This Phase II trial evaluated the efficacy, safety, and tolerability of cariprazine versus placebo in the treatment of acute manic or mixed episodes associated with bipolar I disorder. This was a multinational, randomized, double-blind, placebo-controlled, flexible-dose study of cariprazine 3-12mg/day in patients with acute manic or mixed episodes associated with bipolar I disorder. Following washout, patients received three weeks of double-blind treatment. The primary and secondary efficacy parameters were change from baseline to Week 3 in Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity (CGI-S) scores, respectively. Post-hoc analysis evaluated changes on YMRS single items. In each group, 118 patients received double-blind treatment; 61.9% of placebo and 63.6% of cariprazine patients completed the study. The overall mean daily dose of cariprazine was 8.8mg/day. At Week 3, cariprazine significantly reduced YMRS and CGI-S scores versus placebo, with least square mean differences of -6.1 (p<0.001) and -0.6 (p<0.001), respectively. On each YMRS item, change from baseline to Week 3 was significantly greater for cariprazine versus placebo (all, p<0.05). A significantly greater percentage of cariprazine patients than placebo patients met YMRS response (48% versus 25%; p<0.001) and remission (42% versus 23%; p=0.002) criteria at Week 3. Adverse events (AEs) led to discontinuation of 12 (10%) placebo and 17 (14%) cariprazine patients. The most common AEs (> 10% for cariprazine) were extrapyramidal disorder, headache, akathisia, constipation, nausea, and dyspepsia. Changes in metabolic parameters were similar between groups, with the exception of fasting glucose; increases in glucose were significantly greater for cariprazine versus placebo (p<0.05). Based on Barnes Akathisia Rating Scale and Simpson-Angus Scale scores, more cariprazine than placebo patients experienced treatment-emergent akathisia (cariprazine: 22%; placebo: 6%) or extrapyramidal symptoms (parkinsonism) (cariprazine: 16%; placebo: 1%). Cariprazine demonstrated superior efficacy versus placebo and was generally well tolerated in patients experiencing acute manic or mixed episodes associated with bipolar I disorder.

SAT0339 Asas40 and ASDAS Responses Are Associated with Improved Physical Function, Hrqol, and Work Productivity in Patients with Non-Radiographic Axial Spondyloarthritis

BackgroundASAS40 response has been used as a primary endpoint in clinical trials of patients (pts) with axial spondyloarthritis (axSpA), and ASDAS inactive disease is recommended as a treatment target. However,...

Efficacy and safety of nebivolol and valsartan as fixed-dose combination in hypertension: a randomised, multicentre study

The fixed-dose combination of any two antihypertensive drugs from different drug classes is typically more effective in reducing blood pressure than a dose increase of component monotherapy. We assessed the efficacy and safety of a fixed-dose combination of a vasodilating β blocker (nebivolol) and an angiotensin II receptor blocker (valsartan) in adults with hypertension. We did an 8-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial at 401 US sites. Participants (age ≥18 years) with hypertension but with blood pressure less than 180/110 mm Hg were randomly assigned (2:2:2:2:2:2:2:1) by a 24-h interactive web response system in blocks of 15 to 4 weeks of double-blind treatment with nebivolol and valsartan fixed-dose combination (5 and 80 mg/day, 5 and 160 mg/day, or 10 and 160 mg/day), nebivolol (5 mg/day or 20 mg/day), valsartan (80 mg/day or 160 mg/day), or placebo. Doses were doubled in weeks 5-8; results are reported according to the final dose. Participants and research staff were masked to treatment allocation. The primary and key secondary endpoints were changes from baseline to week 8 in diastolic and systolic blood pressure, respectively. The primary statistical comparison was between the highest fixed-dose combination dose and the highest monotherapy doses; lower doses were then compared if this comparison was positive (Hochberg method for multiple testing). Efficacy analyses were by intention to treat. Safety assessments included monitoring of adverse events. Continuous efficacy parameters were analysed using an ANCOVA model; binary outcomes were analysed using a logistic regression model. This study is registered with ClinicalTrials.gov, NCT01508026. Between Jan 6, 2012, and March 15, 2013, 4161 patients were randomly assigned (277 to placebo and 554-555 to each active comparator group), 4118 of whom were included in the primary analysis. At week 8, the fixed-dose combination 20 and 320 mg/day group had significantly greater reductions in diastolic blood pressure from baseline than both nebivolol 40 mg/day (least-squares mean difference -1·2 mm Hg, 95% CI -2·3 to -0·1; p=0·030) and valsartan 320 mg/day (-4·4 mm Hg, -5·4 to -3·3; p<0·0001); all other comparisons were also significant, favouring the fixed-dose combinations (all p<0·0001). All systolic blood pressure comparisons were also significant (all p<0·01). At least one treatment-emergent adverse event was experienced by 30-36% of participants in each group. Nebivolol and valsartan fixed-dose combination is an effective and well-tolerated treatment option for patients with hypertension. Forest Research Institute.

S-adenosyl methionine (SAMe) versus escitalopram and placebo in major depression RCT: Efficacy and effects of histamine and carnitine as moderators of response

ObjectiveTo assess the antidepressant efficacy of S-adenosyl methionine (SAMe), a naturally occurring methyl donor, versus the selective serotonin reuptake inhibitor (SSRI) escitalopram and a placebo control; and to determine whether serum histamine or carnitine levels modified treatment response. MethodsWe examined a subsample (n=144) from one site of a two-site study of adults with diagnosed Major Depressive Disorder (MDD), recruited from 4/13/05 to 12/22/09, who consented to the additional blood draw for serum histamine and carnitine levels. After washout, eligible subjects were randomized to SAMe (1600–3200mg/daily), escitalopram (10–20mg/daily), or matching placebo for 12 weeks of double-blind treatment (titration at week 6 in non-response). ResultsOn the primary outcome of the Hamilton Depression Rating Scale (HAMD-17), a significant difference in improvement was observed between groups from baseline to week 12 (p=0.039). The effect size from baseline to endpoint was moderate to large for SAMe versus placebo (d=0.74). SAMe was superior to placebo from week 1, and to escitalopram during weeks 2, 4, and 6. No significant effect was found between escitalopram and placebo or SAMe. Response rates (HAMD-17≥50% reduction) at endpoint were 45%, 31%, and 26% for SAMe, escitalopram, and placebo, respectively; while remission rates (HAM-D≤7) were 34% for SAMe (p=0.003), 23% for escitalopram (p=0.023), and 6% for placebo. No correlation between baseline histamine level and reduction of HAMD-17 score was found for either the SAMe or escitalopram groups. Baseline carnitine levels were also not found to moderate response to either treatment. LimitationsWhile SAMe appears to be an effective antidepressant agent, the overall findings from the parent study (which showed no significant difference between groups due to site differences) must be taken into consideration. ConclusionsThese preliminary results provide encouraging evidence for the use of SAMe in the treatment of MDD. Histamine and carnitine serum level may not necessarily moderate response to SAMe.

Factors predicting relapse in elderly patients with major depressive disorder treated with escitalopram in an outpatient setting

Objective:We investigated which factors can best predict relapse in older patients with major depressive disorder (MDD) who have achieved remission with escitalopram.Methods:A total of 405 patients who were 65 years or older with a primary diagnosis of MDD received 12 week, open-label escitalopram 10 or 20 mg/day. Patients in remission (MADRS ≤12) at Week 12 were randomized to 24 weeks of double-blind treatment with either placebo or escitalopram (fixed dose from Week 6).Results:After randomization of 312 patients in remission, patients whose dose had been increased to 20 mg escitalopram after 2 weeks of open-label treatment had a high escitalopram relapse rate (16.7%) and a placebo relapse rate of 32.5% with a hazard ratio (HR) of 2.2, whereas patients titrated to 20 mg escitalopram at Weeks 4 or 6 had a high placebo relapse rate (41.2%) and an escitalopram relapse rate of 5.7% with a HR = 8.9. A high placebo relapse rate was also observed for patients with a baseline MADRS below median, while low escitalopram relapse rates were characteristic of patients who had achieved remission by Week 6 or 8 (HR = 8.9), had a current depressive episode length below median, baseline MADRS below median (HR = 11.8), or received 10 mg for 12 weeks (HR = 6.3). A key limitation of the study was that some analyses were post-hoc and that none of the comparisons between complementary subgroups had nominal p-values <0.05.Conclusions:In this post-hoc analysis of elderly patients with MDD, several factors, including female gender, early remission, low baseline MADRS score, major depressive episode (MDE) duration, and escitalopram dosage, significantly affected the relapse rate after randomization to escitalopram or placebo.

Pregabalin monotherapy in patients with partial-onset seizures

To assess pregabalin monotherapy for partial-onset seizures using a historical-controlled conversion-to-monotherapy design. Adults with inadequately controlled partial-onset seizures while receiving 1 or 2 antiepileptic drugs during an 8-week prospective baseline were randomized to double-blind monotherapy with pregabalin 600 or 150 mg/d (4:1) for 20 weeks (8-week conversion and 12-week monotherapy period). The primary endpoint was the seizure-related exit rate for pregabalin 600 mg/d, based on discontinuations due to predefined criteria. Efficacy was declared if the upper limit of the 95% confidence interval for the exit rate was below a historical-control threshold of 74%, with stepwise evaluation using a threshold of 68%. The trial was stopped early for positive efficacy after an interim analysis in 125 patients. The full study population included 161 patients, with 148 evaluable for efficacy. The mean time since epilepsy diagnosis was 14 years. Overall, 54.3% (600 mg/d) and 46.9% (150 mg/d) of patients completed 20 weeks of double-blind treatment. Seizure-related exit rate in the 600 mg/d group (27.5%; 95% confidence interval, 17.8%-37.2%) was significantly below the 74% and 68% thresholds (p < 0.001 for both). Eight patients on 600 mg/d and 2 on 150 mg/d were seizure-free throughout pregabalin monotherapy. Pregabalin's overall safety profile was consistent with prior trials. Pregabalin monotherapy was safe and efficacious for patients with inadequately controlled partial-onset seizures. This study provides Class III evidence that patients with inadequately controlled partial-onset seizures switched to pregabalin monotherapy have fewer seizure-related exit events compared with historical controls switched to pseudo-placebo monotherapy.

Randomized clinical trial of disulfiram for cocaine dependence or abuse during buprenorphine treatment

BackgroundDisulfiram may be efficacious for treating cocaine dependence or abuse, possibly through inhibiting dopamine β-hydroxylase (DβH). Consequently, this randomized, placebo-controlled clinical trial of disulfiram during buprenorphine maintenance treatment evaluated the study hypothesis that disulfiram is superior to placebo and explored whether disulfiram response is greatest for participants with a single nucleotide polymorphism coding for genetically low DβH (T-allele carriers). MethodsWe randomized 177 buprenorphine-treated opioid dependent participants with cocaine dependence or abuse to 12 weeks of double-blind treatment with disulfiram 250mg daily (n=91) or placebo (n=86). Of 155 participants genotyped, 84 were CC-homozygous, and 71 CT or TT genotypes. Primary outcomes included days per week cocaine use, number of cocaine-negative urine tests, and maximum consecutive weeks of cocaine abstinence. We analyzed an intention-to-treat comparison between disulfiram and placebo. We also explored potential pharmacogenetic interactions and examined treatment responses of four participant groups based on medication (disulfiram or placebo) by genotype (CC-homozygous or T-allele carrier) classification. ResultsDisulfiram participants reported significantly less frequent cocaine use; the differences in cocaine-negative urine tests or consecutive weeks abstinence were not significant. Frequency of cocaine use was lowest in disulfiram-treated T-allele carriers; differences in cocaine-negative urine tests or consecutive weeks abstinence were not significant among the four medication-genotype groups. ConclusionsThe findings provide limited support for the efficacy of disulfiram for reducing cocaine use and suggest that its mechanism of action may involve inhibition of DβH. Further studies of its efficacy, mechanism of action, and pharmacogenetics of response are warranted.

P.3.d.008 Reproductive side effects of antipsychotic-induced hyperprolactinemia; a cross-sectional study – preliminary results

Cariprazine is an orally active and potent D3 and D2 partial agonist with preferential binding to D3 receptors in development for the treatment of schizophrenia and bipolar mania. This study (NCT00694707) evaluated the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia.This study was a multinational, double-blind, randomized, placebo- and active-controlled, fixed-dose trial. Patients were randomized to receive placebo, cariprazine 1.5 mg/d, cariprazine 3.0 mg/d, cariprazine 4.5 mg/d, or risperidone 4.0 mg/d (for assay sensitivity) for 6 weeks of double-blind treatment and 2 weeks of safety follow-up. Primary and secondary efficacy parameters were change from baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total and Global Impressions-Severity of Illness (CGI-S) scores, respectively. Safety parameters included adverse events (AEs), vital signs, laboratory measures, and extrapyramidal symptom (EPS) scales.Of 732 randomized patients, 64% completed the study. PANSS total score improvement at Week 6 was statistically significant versus placebo for cariprazine 1.5 mg/d, 3.0 mg/d, and 4.5 mg/d (least squares mean difference [LSMD]: − 7.6, − 8.8, − 10.4, respectively; p < 0.001; LOCF) and risperidone (− 15.1, p < 0.001; LOCF); significant improvement on CGI-S was demonstrated for all active treatments (p < 0.05). The most frequent cariprazine AEs (≥ 5% and at least twice the rate of the placebo group) were insomnia, extrapyramidal disorder, akathisia, sedation, nausea, dizziness, and constipation. Mean changes in metabolic parameters were small and similar between groups.The results of this study support the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia.

P.2.b.018 Post hoc analyses of levomilnacipran SR 40, 80, and 120 mg on functional outcomes in major depressive disorder

Cariprazine is an orally active and potent D3 and D2 partial agonist with preferential binding to D3 receptors in development for the treatment of schizophrenia and bipolar mania. This study (NCT00694707) evaluated the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia.This study was a multinational, double-blind, randomized, placebo- and active-controlled, fixed-dose trial. Patients were randomized to receive placebo, cariprazine 1.5 mg/d, cariprazine 3.0 mg/d, cariprazine 4.5 mg/d, or risperidone 4.0 mg/d (for assay sensitivity) for 6 weeks of double-blind treatment and 2 weeks of safety follow-up. Primary and secondary efficacy parameters were change from baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total and Global Impressions-Severity of Illness (CGI-S) scores, respectively. Safety parameters included adverse events (AEs), vital signs, laboratory measures, and extrapyramidal symptom (EPS) scales.Of 732 randomized patients, 64% completed the study. PANSS total score improvement at Week 6 was statistically significant versus placebo for cariprazine 1.5 mg/d, 3.0 mg/d, and 4.5 mg/d (least squares mean difference [LSMD]: − 7.6, − 8.8, − 10.4, respectively; p < 0.001; LOCF) and risperidone (− 15.1, p < 0.001; LOCF); significant improvement on CGI-S was demonstrated for all active treatments (p < 0.05). The most frequent cariprazine AEs (≥ 5% and at least twice the rate of the placebo group) were insomnia, extrapyramidal disorder, akathisia, sedation, nausea, dizziness, and constipation. Mean changes in metabolic parameters were small and similar between groups.The results of this study support the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia.