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The endogenous opioid system is thought to play an important role in the regulation of mood. Buprenorphine/samidorphan (BUP/SAM) combination is an investigational opioid system modulator for adjunctive treatment of major depressive disorder (MDD). To confirm results from early studies, we report the efficacy and safety of BUP/SAM as adjunctive treatment in patients with MDD and an inadequate response to antidepressant therapy (ADT) in FORWARD-4 and FORWARD-5: two phase 3, randomized, double-blind, placebo-controlled studies that utilized the same sequential parallel-comparison design. Efficacy was measured using the Montgomery–Åsberg Depression Rating Scale (MADRS). FORWARD-5 achieved the primary endpoint and demonstrated that adjunctive BUP/SAM 2 mg/2 mg was superior to placebo (average difference change from baseline to week 3 through end of treatment [EOT] in MADRS-6 and −10 versus placebo: −1.5, P = 0.018; −1.9, P = 0.026, respectively). FORWARD-4 did not achieve the primary endpoint (change from baseline in MADRS-10 at week 5 versus placebo: –1.8, P = 0.109), although separate analyses showed significant treatment differences at other timepoints using traditional, regulatory-accepted endpoints such as reduction in MADRS-10 at EOT. The pooled analysis of the two studies demonstrated consistently greater reduction in MADRS-10 scores from baseline for BUP/SAM 2 mg/2 mg versus placebo at multiple timepoints including EOT and average change from baseline to week 3 through EOT (–1.8, P = 0.010; –1.8, P = 0.004, respectively). The overall effect size (Hedges’ g) in the pooled analyses for MADRS-10 change from baseline to EOT was 0.22. Overall, BUP/SAM was generally well tolerated, with most adverse events (AEs) being mild or moderate in severity. The most common AEs, occurring in ≥5% of patients in the BUP/SAM 2 mg/2 mg treatment group, which was more frequently than the placebo group, included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, and no evidence of dependence or opioid withdrawal by AEs or objective measures. This report describes adjunctive BUP/SAM 2 mg/2 mg combination, a therapy with a novel opioidergic mechanism of action, as a potential new treatment option for patients with MDD who have an inadequate response to currently available ADT.

Valdecoxib, a cyclooxygenase (COX)-2 specific inhibitor, is indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis, and primary dysmenorrhea. Therapeutic doses of COX-2 specific inhibitors are as effective as nonspecific nonsteroidal anti-inflammatory drugs in reducing inflammatory pain while sparing the gastrointestinal and platelet toxicity associated with nonspecific COX-1 inhibition. The aim of this study was to assess the analgesic efficacy and tolerability of valdecoxib 40 mg/d compared with placebo in the treatment of chronic low back pain. This 4-week, prospective, randomized, double-blind placebo-controlled, parallel-group study was conducted at 37 centers across the United States and 5 centers in Canada. Patients aged ≥18 years with chronic low back pain in flare were enrolled. Patients were randomized to receive valdecoxib 40-mg/d or placebo tablets, once daily for 4 weeks. Patients rated low back pain intensity on a visual analog scale and completed the Roland-Morris Disability Questionnaire and the modified Brief Pain Inventory—Short Form (mBPI-SF) at each visit. Two hundred ninety-three patients were enrolled. The valdecoxib group comprised 148 patients (81 women, 67 men; mean [SD] age, 48.6 [13.3] years; mean [SD] body weight, 86.6 [20.9] kg), and the placebo group included 145 patients (85 women, 60 men; mean [SD] age, 48.7 [12.6] years; mean [SD] body weight, 85.6 [19.9] kg). Of the enrolled patients, 249 completed the study: 134 patients (91%) who received valdecoxib and 115 patients (79%) who received placebo. No statistically significant differences in patient baseline characteristics were noted between treatment groups, except in response to 1 mBPI-SF question; patients in the valdecoxib group reported significantly greater interference in relations with other people due to pain than did those in the placebo group (P = 0.048). Changes from baseline in low back pain intensity were significantly greater in valdecoxib-treated patients at each assessment (all, P < 0.001 vs placebo). Pain scores on the mBPI-SF indicated significantly greater pain relief with valdecoxib at each assessment (all, P ≤ 0.014 vs placebo). Improvements in mean Roland-Morris Disability Questionnaire score with valdecoxib were significantly greater than with placebo at each assessment (all, P ≤ 0.003). Although the overall incidence of adverse events (AEs) was significantly higher among patients receiving valdecoxib than those receiving placebo (35.1% vs 24.1%, respectively; P = 0.042), no significant differences were found between groups for the incidence of any individual AE. Most AEs (89% [77/87 total events]) were mild or moderate in severity. In this study of patients with chronic low back pain, valdecoxib 40 mg/d provided rapid relief (within 1 week) and consistent relief (over 4 weeks). In addition, significant improvement in function and decreased disability were found with valdecoxib compared with placebo.

ALKS 3831, a combination of olanzapine and samidorphan (OLZ/SAM) in development for schizophrenia, is intended to mitigate olanzapine-associated weight gain. This thorough QT (tQT) study evaluated OLZ/SAM effects on electrocardiogram parameters. In this randomized, double-blind, parallel-group study, 100 patients with stable schizophrenia were randomized 3:2 to either receive OLZ/SAM 10/10 mg (therapeutic dose) on days 2-4, 20/20 mg on days 5-8, and 30/30 mg (supratherapeutic dose) on days 9-13 with moxifloxacin-matching placebo on days 1 and 14, or a single dose of moxifloxacin 400 mg and matching placebo on days 1 and 14 (nested crossover design). Drug concentration relation to change from baseline in Fridericia-corrected QTc (ΔQTcF) was evaluated using a linear mixed-effect concentration-QTc (C-QTc) model. Adverse events were assessed. The slope (90% CI) of the C-QTc was not significant for olanzapine or samidorphan (0.03 [-0.01, 0.08] and 0.01 [-0.01, 0.04] msec per ng/mL, respectively). Predicted placebo-corrected ΔQTcF (90% CI) was 2.33 (-2.72, 7.38) and 1.38 (-3.37, 6.12) msec at the observed geometric mean maximal concentration of olanzapine (62.6 ng/mL) and samidorphan (75.1 ng/mL), respectively, on day 13. A clinically relevant QT effect (ie, placebo-corrected ΔQTcF ≥10 msec) can be excluded for olanzapine and samidorphan concentrations up to ≈110 and ≈160 ng/mL, respectively. Assay sensitivity was confirmed by the C-QTc relationship of moxifloxacin. OLZ/SAM was well tolerated. OLZ/SAM, in doses and plasma concentrations up to supratherapeutic levels, was well tolerated and had no clinically relevant effects on electrocardiogram parameters, including QT interval, in patients with schizophrenia. This study was funded by Alkermes, Inc.

IntroductionBuprenorphine (BUP)/samidorphan (SAM) combination is an opioid system modulator being investigated as an adjunctive treatment for major depressive disorder (MDD). BUP/SAM is a fixed-dose combination of BUP, a partial µ-opioid receptor agonist and κ-opioid receptor antagonist, and SAM, a µ-opioid receptor antagonist added to address the abuse and dependence potential of BUP.1,2Study ObjectiveWe assessed the effects of SAM on the abuse potential of BUP in the BUP/SAM combination in two ways: (1) a human abuse potential (HAP) study in volunteers; and (2) an evaluation of the clinical experience across studies of patients with MDD. Study 212 (ClinicalTrials.gov ID: NCT02413281) was a HAP study in nondependent, recreational, adult opioid users. Following a qualification period, participants were randomized to 6 treatments in a blinded, crossover design: placebo (PBO), BUP/SAM at the target therapeutic dose (BUP/SAM 2mg/2mg), at 8mg/8mg and 16mg/16mg , and BUP alone (8mg and 16mg). The primary endpoint was maximum effect (Emax) for \"At The Moment\" Drug Liking Visual Analog Scale (VAS).The clinical program for BUP/SAM included 4 PBO-controlled studies of patients with MDD (n=961). Pooled safety data were evaluated for adverse events (AEs) that may be associated with abuse, dependence, or withdrawal, as well as for objective signs of withdrawal with the Clinical Opioid Withdrawal Scale (COWS). In Study 212 (n=38), Emax Drug Liking VAS scores for the BUP/SAM 2mg/2mg dose were similar to those for PBO (median within-subject difference [90% CI]: 2.5 [0.0-9.0]). Emax Drug Liking VAS scores for all BUP/SAM dose groups, including supratherapeutic doses, were significantly lower than those observed for either of the BUP doses. The supratherapeutic doses of BUP/SAM (8mg/8mg and 16mg/16mg) had higher Emax Drug Liking VAS scores than PBO, but the differences were small.In the MDD controlled studies, the incidence of euphoria-related AEs was low for BUP/SAM 2mg/2mg and PBO (1.6% vs 0.2%, respectively) and there was no evidence of abuse or dependence behavior. Euphoria-related events typically occurred with treatment initiation and resolved with continued treatment. There was minimal evidence of withdrawal by reported AEs or COWS assessment. These findings indicate that SAM mitigates the abuse potential of BUP in the BUP/SAM combination.Funding Acknowledgements: Alkermes, Inc.

This article develops a general methodology for small domain estimation based on data from repeated surveys. The results are directly applied to the estimation of median income of four-person families for the 50 states and the District of Columbia. These estimates are needed by the U.S. Department of Health and Human Services (HHS) to formulate its energy assistance program for low income families. The U.S. Bureau of the Census, by an informal agreement, has provided such estimates to HHS through a linear regression methodology since the latter part of the 1970s. The current method is an empirical Bayes method (EB) that uses the Current Population Survey (CPS) estimates as well as the most recent decennial census estimates updated by the per capita income estimates of the Bureau of Economic Analysis. However, with the existing methodology, standard errors associated with these estimates are not easy to obtain. The EB estimates, when used naively, can lead to underestimation of standard errors. Moreover, because the sample estimates are collected through the CPS every year, there is a very natural time series aspect of the data that is currently ignored. We have performed a full Bayesian analysis using a hierarchical Bayes (HB) time series model. In addition to providing the median income estimates as the posterior means, we have provided also the posterior standard deviations. Included in our model is the information on the median incomes of three- and five-person families as well. In this way a multivariate HB procedure is used. The Bayesian analysis requires evaluation of high-dimensional integrals. We have overcome this problem by using the Gibbs sampling technique, which has turned out to be a very convenient tool for Monte Carlo integration. Also, we have validated our results by comparing them against the 1989 four-person median income figures obtained from the 1990 census. We used four different criteria for such comparisons. It turns out that the estimates obtained by using a bivariate time-series model are the best overall. We use a criterion based on deviances for model selection and also provide a sensitivity analysis of the proposed hierarchical model.

We consider in this dissertation estimation and prediction of local area means based on repeated surveys over time. A general hierarchical Bayes model is used for this purpose. The resulting HB estimators for a small area \"borrow strength\" over time in addition to borrowing strength from other local areas. The Bayesian procedure provides current as well as retrospective estimates simultaneous for all the small areas. The HB methodology, in infinite as well as finite population sampling situations, has been implemented by adopting a Monto Carlo integration technique--the Gibbs Sampler. A multivariate HB model is considered to exploit the inter-relationship among the parameters in improving the small area estimators. Both the univariate and multivariate methodologies have been implemented on median income estimation problem. The results show that the estimators borrowing strength over time and from other local areas are substantially better than the estimators which borrow strength only from other local areas. In finite population sampling, the predictive distribution of a characteristic of interest for the unsampled population units is found given the observations on the sampled units and is used to draw inference. In particular, we have provided HB predictors and the associated standard errors of the local area means over time. In a special case of this HB analysis, when the vector of the ratios of the variance components is known, the HB predictor of the vector of local area means is shown to possess some frequentist optimality properties. For example, among other properties, we have shown that the HB predictors are best unbiased, best equivariant predictor under a suitable group of transformations.