18-Month efficacy and safety analysis of monthly subcutaneous buprenorphine injection for opioid use disorder: Integrated analysis of phase 3 studies.

BACKGROUND: Few studies investigate the natural history of patients on long-term treatment for opioid use disorder (OUD). We evaluated the long-term efficacy, safety, and tolerability experience of monthly extended-release buprenorphine (BUP-XR) in participants seeking treatment for OUD, via integrated analysis of phase 3 studies. METHODS: Study 1 was a 24-week randomized, double-blind, placebo-controlled trial of participants receiving monthly injections of BUP-XR (300 mg × 2, 100 mg × 4 [n = 203] or 300 mg × 6 [n = 201]) or placebo (n = 100). Study 2 was a 48-week, open-label trial enrolling 257 participants who completed study 1 and 412 de novo participants, to receive 6 and 12 BUP-XR injections, respectively. Study 3 was a 24-week, open-label extension enrolling 208 participants who completed study 2 for 6 additional injections. We assessed opioid abstinence as the proportion of urine opioid negative participants by visit and the percentage of each participant's negative opioid assessments during the first 6 months. RESULTS: In total, 916 participants were treated with BUP-XR or placebo. By the end of 18 months, 92.7 % of the de novo cohort and 81.8 % of the study 1 cohort were urine negative for opioids. Among early nonresponders (percentage of abstinence ≤20 %), 73.1 % were urine negative after 18 months. The longer treatment period was well tolerated, with no new safety concerns, and a low incidence of opioid withdrawal signs and symptoms, and hepatic disorder. CONCLUSIONS: Extending BUP-XR treatment beyond 6 months sustained improvement in opioid abstinence and was well tolerated, supporting clinical benefit up to 18 months. TRIAL REGISTRATION: NCT02357901 (study 1); NCT02510014 (study 2); NCT02896296 (study 3).

Assessment of craving in opioid use disorder: Psychometric evaluation and predictive validity of the opioid craving VAS.

BACKGROUND: This work evaluated the psychometric properties of the single-item Opioid Craving Visual Analog Scale (OC-VAS) for opioid use disorder (OUD). METHODS: Psychometric evaluation of the OC-VAS (range: 0-100 mm) was supported by Subjective Opiate Withdrawal Scale (SOWS) item 16 and total score, Clinical Opiate Withdrawal Scale (COWS) scores, and the 36-Item Short-Form Health Survey, using data from phase 3 study (NCT02357901; N = 487) participants who received randomized treatment and completed the OC-VAS at screening. Descriptive properties, test-retest reliability, construct validity, known-groups validity, and responsiveness were assessed. Interpretation of meaningful change and predictive validity were also explored. RESULTS: Descriptive properties for the OC-VAS at screening did not provide evidence of problematic floor/ceiling effects or missingness. The test-retest reliability was established by weekly intraclass correlations >0.70. At the screening and end of the study, the strong positive correlations between OC-VAS and SOWS Total/Item 16 score and the significant OC-VAS differences among COWS severity groups supported construct validity and known-groups (discriminating ability) validity, respectively. The associations between the changes in OC-VAS and in supporting measures/opioid use from screening to the end of the study demonstrated responsiveness and the ability to detect change in clinical status. During the induction and randomization treatment periods, significant relationships were identified between OC-VAS score and subsequent opioid use. CONCLUSIONS: This psychometric evaluation of the OC-VAS performed on a large OUD patient population provides evidence to support its use to measure the severity of opioid craving and its ability to predict opioid use.

Folate metabolism biomarkers from two randomised placebo-controlled clinical studies with paroxetine and venlafaxine.

OBJECTIVES: Based on the hypothesis of a role for folate and vitamin B12 in major depressive disorders (MDD), we aimed at validating the association between folate pathway biomarkers and depression or antidepressant response in clinical trial populations. METHODS: We investigated serum levels erythrocyte folate and serum levels of homocysteine, vitamin B12, and folate as disease and response biomarkers for MDD in two independent randomised, placebo-controlled clinical trials, where paroxetine or venlafaxine were used as active controls, for a total of 881 patients. RESULTS: Significant but weak correlations between depression severity and biomarker levels could be detected in the paroxetine study for serum folate and vitamin B12, with no correlations for any biomarker in the venlafaxine study. Besides a weak association for erythrocyte folate in the venlafaxine study, no significant associations were observed between treatment response and pre-treatment levels of any of the biomarkers tested. CONCLUSIONS: Notwithstanding the relatively large number of patients tested, we did not find consistent associations between folate biomarkers and MDD severity, or response to paroxetine and venlafaxine. Our results may be related to the particular study design or clinical population; however, our findings do not support the hypothesis of a dysfunction of one-carbon metabolism in MDD.

Treating Opioid Use Disorder With a Monthly Subcutaneous Buprenorphine Depot Injection: 12-Month Safety, Tolerability, and Efficacy Analysis.

BACKGROUND: BUP-XR (RBP-6000 or SUBLOCADE) is the first Food and Drug Administration-approved subcutaneously administered monthly extended-release buprenorphine medication for the treatment of moderate or severe opioid use disorder. The primary objective of this phase III study was to assess the long-term safety, tolerability, and efficacy of BUP-XR. METHODS: This open-label multicenter study in adults with moderate or severe opioid use disorder enrolled 257 participants from a previously conducted placebo-controlled, double-blind phase III study (rollover group) and 412 de novo participants not previously treated with BUP-XR. Participants received an initial injection of BUP-XR 300 mg and subsequent monthly 300 mg or 100 mg flexible doses. By study end, participants received up to 12 injections. RESULTS: Overall, 66.8% of participants reported more than 1 treatment-emergent adverse event (TEAE). Injection-site TEAEs (13.2% of participants) were mostly mild or moderate in severity. There were no clinically meaningful changes in safety assessments. An integrated analysis of the double-blind and open-label study participants showed that the incidence of TEAEs, including injection-site TEAEs, was lower in the second 6 months of treatment versus the first 6 months. After 12 months of treatment, 61.5% of the rollover participants and 75.8% of the de novo participants were abstinent. Retention rates after 12 months were 50.6% for the participants who initiated BUP-XR in the double-blind study and 50.5% for de novo participants. CONCLUSIONS: This study demonstrates that the clinical benefits and acceptable safety profile of BUP-XR demonstrated in the 6-month double-blind study are sustained over a 12-month open-label study, with lower incidence of TEAEs in the second 6 months of treatment.

Recovery From Opioid Use Disorder (OUD) After Monthly Long-acting Buprenorphine Treatment: 12-Month Longitudinal Outcomes From RECOVER, an Observational Study.

OBJECTIVES: While evidence has mounted regarding the short-term effectiveness of pharmacotherapy for opioid use disorder (OUD), little is known about longer-term psychosocial, economic, and health outcomes. We report herein 12-month outcomes for an observational study enrolling participants who had previously taken part in a long-acting buprenorphine subcutaneous injection (BUP-XR) trial for moderate to severe OUD. METHODS: The RECOVER (Remission from Chronic Opioid Use: Studying Environmental and SocioEconomic Factors on Recovery; NCT03604861) study enrolled participants from 35 US community-based sites. Self-reported sustained opioid abstinence over 12 months and self-reported past-week abstinence at 3-, 6-, 9-, and 12-month visits were assessed. Multiple regression models assessed the association of BUP-XR duration with abstinence, controlling for potential confounders. Withdrawal, pain, health-related quality of life, depression, and employment at RECOVER baseline and 12-month visits were also compared to values collected before treatment in the BUP-XR trial. RESULTS: Of 533 RECOVER participants, 425 completed the 12-month visit (average age 42 years; 66% male); 50.8% self-reported sustained 12-month and 68.0% past-week opioid abstinence. In multiple regressions, participants receiving 12-month versus ≤2-month BUP-XR treatment duration had significantly higher likelihood of sustained opioid abstinence (75.3% vs 24.1%; P = 0.001), with similar results for past-week self-reported abstinence over time. During RECOVER, participants had fewer withdrawal symptoms, lower pain, positive health-related quality of life, minimal depression, and higher employment versus pre-trial visit. CONCLUSIONS: RECOVER participants reported positive outcomes over the 12-month observational period, including high opioid abstinence and stable or improved humanistic outcomes. These findings provide insights into the long-term impact of pharmacotherapy in OUD recovery.

Effects of monthly buprenorphine extended-release injections on patient-centered outcomes: A long-term study.

INTRODUCTION: The physical, social, psychological, and economic burden of opioid use disorder (OUD) is substantial. As of the year 2019, the predominant focus of OUD research was outcomes such as retention and abstinence. We report herein the effects of extended-release buprenorphine (BUP-XR), the first FDA-approved subcutaneously injected, monthly treatment for OUD, on patient-centered outcomes. MATERIALS AND METHODS: Patient-centered outcomes were collected during an open-label safety study of participants with OUD (NCT# 02510014) evaluating BUP-XR. Measures collected during the study included the EQ-5D-5L, SF-36v2, Treatment Effectiveness Assessment (TEA), Addiction Severity Index-Lite (ASI-Lite), employment/insurance status questionnaire, and Medication Satisfaction Questionnaire (MSQ). Changes from baseline to end of study week 49 were analyzed using mixed models for repeated measures. "Baseline" was defined as the value collected prior to the first BUP-XR injection. Results presented are for those participants who initiated treatment on BUP-XR during the open-label study and were eligible to receive up to 12 injections. RESULTS: Four hundred twelve participants were included in analyses; 206 participants discontinued BUP-XR prematurely. Mean EQ-5D-5L scores remained stable from baseline to end of study. Statistically significant improvements from baseline to end of study were noted for the SF-36v2 mental component summary score (difference = 5.0, 95%CI: 3.5-6.5) and 7 of 8 domain scores (P < .05 for all comparisons); the SF-36v2 physical component summary remained stable from baseline to end of study. The TEA total score (difference = 9.3 points, 95%CI: 8.0-10.5) and 4 of 4 domain scores (difference = 2-3 points per domain) significantly improved from baseline to end of study. Significant improvements (P < .05 for all comparisons) on the ASI-Lite were seen for all problem areas except alcohol use from baseline to end of study. Employment rate increased 7% whereas health insurance status remained stable from baseline to end of study. Medication satisfaction measured using the MSQ was >88% at end of study. CONCLUSIONS: Treatment with BUP-XR monthly injections for up to 12 months in this cohort of treatment-seeking individuals with OUD led to positive PCOs and high treatment satisfaction, which correspond to personal recovery.

Biomarkers for response in major depression: comparing paroxetine and venlafaxine from two randomised placebo-controlled clinical studies.

The identification of biomarkers of response might speed drug development and set the premises to assist clinical practice in psychiatry. In this work, we evaluated a panel of peripheral biomarkers (including IL-6, IL-10, TNF-α, TNFRII, BDNF, CRP, MMP9 and PAI1) in depressed patients receiving paroxetine, venlafaxine, or placebo. Samples were obtained from two randomised placebo-controlled studies evaluating the efficacy and tolerability of a novel drug candidate, using either paroxetine or venlafaxine as active comparators. In both studies, the biomarker candidates were analysed in plasma collected at randomization and after 10 weeks of treatment with either placebo or active comparator (for a total of 106 and 108 subjects in the paroxetine and venlafaxine study, respectively). Data were obtained by multiplexing sandwich-ELISA system. Data were subjected to statistical analysis to assess their correlation with baseline severity and with response outcome. Increases in biomarker levels were correlated with reduction in depression severity for TNF-α, IL-6 IL-10 and CRP. Response to paroxetine treatment correlated with baseline IL-10, IL-6 and TNF-α levels, with the strongest signal being observed in males. In the venlafaxine study, a correlation was observed only between CRP level at randomisation and response, suggesting differences between the two active treatments and the two studies. Our investigations suggest that a combination of pro- and anti-inflammatory cytokines may predict response outcome in patients treated with paroxetine. The potential for IL-10, IL-6 and TNF-α as response biomarkers for a wider range of antidepressants warrants further investigations in clinical trials with other monoamine reuptake inhibitors.

Patient-reported outcomes in schizophrenia patients treated with once-monthly extended-release risperidone in a long-term clinical study.

PURPOSE: RBP-7000 (PERSERIS™) is a once-monthly subcutaneous extended-release risperidone formulation approved by the United States Food and Drug Administration for the treatment of schizophrenia in adults. The objective of this study was to describe the long-term impact of RBP-7000 on health-related quality of life (HRQoL), subjective well-being, treatment satisfaction and medication preference in patients with schizophrenia. PATIENTS AND METHODS: HRQoL was derived from a 52-week multicentre Phase III single-arm open-label outpatient study that assessed the safety and efficacy of RBP-7000 (120 mg) in patients with schizophrenia. HRQoL was measured using the EuroQol EQ-5D-5L and Short-Form Survey SF-36 version 2; well-being using the Subjective Well-being Under Neuroleptic Treatment - Short Version (SWN-S); satisfaction using the Medication Satisfaction Questionnaire and medication preference using the Preference of Medication questionnaire. RESULTS: Of 482 participants at baseline, 234 remained through the end of study (EOS; week 52). Mean HRQoL and well-being scores remained stable between baseline (EQ-5D-5L index: 0.83; SF-36v2 Physical Component Score: 50; SF-36v2 Mental Component Score: 46; total SWN-S score: 89) and EOS (EQ-5D-5L index: 0.86; SF-36v2 Physical Component Score: 49; SF-36v2 Mental Component Score: 47; total SWN-S score: 90). The proportion of participants reporting satisfaction increased between week 4 (66%) and EOS (81%), with a similar trend for the preference of RBP-7000 over previous treatment (week 4: 66%; EOS: 72%). Sensitivity analyses suggested a minor effect of dropout on characterization of change over time in patient-reported outcomes (PRO) measures. CONCLUSION: Study participants attained mean HRQoL scores near that of the general US population. Over two-thirds reported high satisfaction with and preference for RBP-7000 across the study period. Additional research is needed to confirm whether these PRO translate into improved outcomes such as adherence and ultimately fewer relapses in patients with schizophrenia.

Measuring recovery in opioid use disorder: clinical utility and psychometric properties of the Treatment Effectiveness Assessment.

Purpose: The Treatment Effectiveness Assessment (TEA) is a patient-centered instrument for evaluating treatment progress and recovery from substance use disorders, including opioid use disorder (OUD). We assessed the TEA's reliability and validity and determined minimal clinically important differences (MIDs) in participants with moderate to severe OUD. Patients and methods: The TEA measures change in four single-item domains (substance use, health, lifestyle, community involvement) from treatment initiation across the duration of a treatment program. Self-reported responses range from 1 ("none or not much") to 10 ("much better") with items summed to a total score ranging from 4-40. We assessed floor and ceiling effects, internal consistency, test-retest reliability, known-groups validity (ANOVA stratified by current health status [36-Item Short Form Health Survey item 1]), convergent/divergent validity, and MIDs using data from a phase 3, open-label clinical trial of buprenorphine extended-release monthly injection for subcutaneous use (BUP-XR). Participants with OUD completed the TEA at screening and before monthly injections for up to 12 months. Results: Among 410 participants (mean age 38 years; 64% male), the mean baseline (pre-injection 1) TEA total score was 25.4 (SD 9.7), with <10% of participants at the measure floor and 10%-20% at the ceiling across domains. Internal consistency was high (Cronbach's α=0.90), with marginal test-retest reliability (intraclass correlation coefficient =0.69). Mean TEA total score consistently increased from baseline (n=410; mean 25.4 [SD 9.7]) to end of study (n=337; 35.0 [6.7]) and differentiated between current health status groups (P<0.001); it was weakly correlated with other measures of health-related quality of life/severity. MIDs ranged from 5-8 for the TEA total score across anchor- and distribution-based approaches. Conclusion: The TEA exhibited acceptable reliability and validity in a cohort of participants with moderate to severe OUD treated with BUP-XR. Given its brevity and psychometric properties, the TEA is a promising tool for use in clinical practice and research.

Pharmacokinetics of Sublingual Buprenorphine Tablets Following Single and Multiple Doses in Chinese Participants With and Without Opioid Use Disorder.

BACKGROUND: Two phase I studies assessed the pharmacokinetics of buprenorphine, its metabolite norbuprenorphine, and naloxone following administration of buprenorphine/naloxone sublingual tablets in Chinese participants. METHODS: In the first phase I, open-label, single ascending-dose (SAD) study, 82 opioid-naïve volunteers received a single buprenorphine/naloxone dose ranging from 2 mg/0.5 mg to 24 mg/6 mg while under naltrexone block. In a second phase I, open-label, multiple ascending-dose (MAD) study, 27 patients with opioid dependence in withdrawal received buprenorphine/naloxone doses of either 16 mg/4 mg or 24 mg/6 mg for 9 consecutive days. Serial blood samples were collected after a single dose (SAD study) and at steady-state (MAD study). Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety assessments included adverse events monitoring and laboratory tests. RESULTS: The pharmacokinetic profiles of buprenorphine and naloxone were consistent between single- and multiple-dose studies. Peak plasma concentrations (Cmax) were reached early for buprenorphine (0.75-1.0 h) and naloxone (0.5 h), supporting rapid absorption. In the SAD study, increases in plasma exposures to buprenorphine and naloxone were less than dose proportional, in line with previous observations in Western populations. Buprenorphine-to-naloxone ratios for Cmax and area under the curve (AUC) were constant over the dose range investigated and also consistent with Western populations data. Steady state was reached within 7 days of daily dosing, with slight accumulation over repeated doses. No serious adverse events were observed. CONCLUSIONS: The present data suggest that buprenorphine/naloxone pharmacokinetic profiles in Chinese participants are consistent, overall, with those in Western populations, supporting no differences in dosing. CLINICAL TRIAL REGISTRATION: The protocols were registered on the official website of the China Food and Drug Administration (CFDA): http://www.chinadrugtrials.org.cn/ ; Registration numbers CTR20132963 (RB-CN-10-0012), CTR20140153 (RB-CN-10-0015).

Patient-centered Outcomes in Participants of a Buprenorphine Monthly Depot (BUP-XR) Double-blind, Placebo-controlled, Multicenter, Phase 3 Study.

OBJECTIVE: Opioid use disorder (OUD) is associated with physical, social, psychological, and economic burden. This analysis assessed the effects of RBP-6000, referred to as BUP-XR (extended-release buprenorphine), a subcutaneously injected, monthly buprenorphine treatment for OUD compared with placebo on patient-centered outcomes measuring meaningful life changes. METHODS: Patient-centered outcomes were collected in a 24-week, phase 3, placebo-controlled study assessing the efficacy, safety, and tolerability of BUP-XR 300/300 mg (6 × 300 mg) and 300/100 mg (2 × 300 mg followed by 4 × 100 mg) injections in treatment-seeking participants with moderate-to-severe OUD. Measures included the EQ-5D-5L, SF-36v2, Medication Satisfaction Questionnaire, employment/insurance status, and healthcare resource utilization (HCRU). Changes from baseline to end of study were compared across treatment arms, using mixed models for repeated measures. RESULTS: Participants receiving BUP-XR (n = 389) versus placebo (n = 98) had significantly greater changes from baseline on the EQ-5D-5L index (300/300 mg: difference = 0.0636, P = 0.003), EQ-5D-5L visual analog scale (300/300 mg: difference = 5.9, P = 0.017; 300/100 mg: difference = 7.7, P = 0.002), and SF-36v2 physical component summary score (300/300 mg: difference = 3.8, P < 0.001; 300/100 mg: difference = 3.2, P = 0.002). Satisfaction was significantly higher for participants receiving BUP-XR 300/300 mg (88%, P < 0.001) and 300/100 mg (88%, P < 0.001) than placebo (46%). Employment and percentage of insured participants increased by 10.8% and 4.1% with BUP-XR 300/300 mg and 10.0% and 4.7% with 300/100 mg but decreased by 12.6% and 8.4% with placebo. Participants receiving BUP-XR compared with placebo had significantly fewer hospital days per person-year observed. CONCLUSIONS: These results show the feasibility of measuring patient-centered life changes in substance use disorder clinical studies. Participants receiving up to 6 monthly injections of BUP-XR, compared with placebo, reported better health, increased medication satisfaction, increased employment, and decreased healthcare utilization.

Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: RBP-6000, referred to as BUP-XR (extended-release buprenorphine), is a subcutaneously injected, monthly buprenorphine treatment for opioid use disorder. BUP-XR provides sustained buprenorphine plasma concentrations to block drug-liking of abused opioids over the entire monthly dosing period, while controlling withdrawal and craving symptoms. Administration of BUP-XR in a health-care setting also mitigates abuse, misuse, diversion, and unintentional exposure. We aimed to investigate the efficacy of different BUP-XR dosing regimens in participants with opioid use disorder. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done at 36 treatment centres in the USA. Treatment-seeking adults aged 18-65 years who had moderate or severe opioid use disorder (as defined by the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders) entered an open-label run-in phase of up to 2 weeks' treatment with buprenorphine-naloxone sublingual film. Eligible participants were then randomly assigned (4:4:1:1) with an interactive voice/web-response system to receive BUP-XR 300 mg/300 mg (six injections of 300 mg), BUP-XR 300 mg/100 mg (two injections of 300 mg plus four injections of 100 mg), or volume-matched placebo every 28 days, and received weekly individual drug counselling. No supplemental buprenorphine was allowed. The primary efficacy endpoint was participants' percentage abstinence from opioid use, defined as the percentage of each participant's negative urine samples and self-reports of illicit opioid use from week 5 to week 24, analysed in the full analysis set. Safety was assessed in all participants who received at least one dose of BUP-XR or placebo. This study is registered with ClinicalTrials.gov, number NCT02357901. FINDINGS: From Jan 28, 2015, to Nov 12, 2015, 1187 potential participants were screened, 665 entered run-in, and 504 received BUP-XR 300 mg/300 mg (n=201), BUP-XR 300 mg/100 mg (n=203), or placebo (n=100). Mean participants' percentage abstinence was 41·3% (SD 39·7) for BUP-XR 300 mg/300 mg and 42·7% (38·5) for 300 mg/100 mg, compared with 5·0% (17·0) for placebo (p<0·0001 for both BUP-XR regimens). No compensatory non-opioid drug use was observed during BUP-XR treatment. The most common adverse events were headache (17 [8%] participants in the BUP-XR 300 mg/300 mg group vs 19 [9%] participants in the BUP-XR 300 mg/100 mg group vs six [6%] participants in the placebo group), constipation (16 [8%] vs 19 [9%] vs 0), nausea (16 [8%] vs 18 [9%] vs five [5%]), and injection-site pruritis (19 [9%] vs 13 [6%] vs four [4%]). The BUP-XR safety profile was consistent with other buprenorphine products for treatment of opioid use disorder, except for injection-site reactions, which were reported in more than 5% of all participants who received BUP-XR, but were mostly mild and not treatment-limiting. INTERPRETATION: Participants' percentage abstinence was significantly higher in both BUP-XR groups than in the placebo group. Treatment with BUP-XR was also well tolerated. The availability of this monthly formulation, delivered by health-care providers, represents an advance in treatment for opioid use disorder that enhances the benefits of buprenorphine by delivering sustained, optimal exposure, while reducing risks of current buprenorphine products. FUNDING: Indivior.

Remission from chronic opioid use-Studying environmental and socio-economic factors on recovery (RECOVER): Study design and participant characteristics.

Few opioid use disorder (OUD) treatment studies measure meaningful life changes during long-term recovery, focusing instead on retention and abstinence. Here, we report on the design and participant characteristics of the RECOVER study, a study exploring life changes in persons with OUD for up to 24 months following participation in a Phase III trial evaluating buprenorphine extended-release monthly injection for subcutaneous use (known as RBP-6000 during development). This multisite, observational, cohort study tracks clinical, environmental, and socio-economic changes using self-administered assessments, urine drug screens (UDS), and public databases. Outcomes include demographics (e.g., patient characteristics, employment history, criminal history), lifetime and recent OUD drug use and treatment, and current health and resource use. Demographic and psychosocial characteristics are compared to a national, population-based study. RECOVER participants (N = 533) tend to be single, white, males aged 26 years or older. Mean age at first opioid use was 21.7 years; lifetime substance-related overdose was 24.2%. At first assessment, 334 (62.7%) participants reported past 7-day and 296 (55.5%) reported past 28-day opioid abstinence. Five hundred UDS were collected at the first assessment; buprenorphine (90.6%), marijuana (45.2%), and opiates (34.4%) were most commonly identified. Two hundred forty-nine (47.2%) participants reported full- or part-time employment. Participants were like a national sample with differences found for age, race/ethnicity, employment, education, and health-related quality of life. We hope that further research using this approach can provide data supporting the patient-centered development of OUD treatments and be adopted by substance use disorder studies to incorporate recovery-related, life-activity outcomes.

Evaluation of antidepressant properties of the p38 MAP kinase inhibitor losmapimod (GW856553) in Major Depressive Disorder: Results from two randomised, placebo-controlled, double-blind, multicentre studies using a Bayesian approach.

Pro-inflammatory cytokines (PICs) may play important pathophysiological roles in some forms of Major Depressive Disorder (MDD). The p38 MAPK inhibitor losmapimod (GW856553) attenuates the pro-inflammatory response in humans by reducing PIC production. Losmapimod (7.5 mg BD) was administered for 6 weeks in two randomised, placebo-controlled trials in subjects with MDD enriched with symptoms of loss of energy/interest and psychomotor retardation (Studies 574 and 009). Primary efficacy endpoints were the Bech 6-item depression subscale of the HAMD-17 (the 'Bech,') for Study 009; and the Bech, Inventory of Depressive Symptomatology-Clinician Rated (IDS-C), HAMD-17, and Quick Inventory of Depressive Symptomatology (self-rated) (QIDS-SR) for Study 574. Key cytokine biomarker levels were also measured. Study 574 (n=24) was terminated prematurely in light of emerging data from an internal study in rheumatoid arthritis. Efficacy results available at termination favoured losmapimod (Bech, 6 weeks: endpoint drug vs. placebo difference = -4.10; 95% CI, -7.36, -0.83; p=0.017). A subsequent study, Study 009 (n=128), designed using a Bayesian approach based on a prior derived from Study 574, showed no advantage for losmapimod (Bech, 6 weeks: endpoint drug vs. placebo difference = 1.11; 95% credible interval, -0.22, 2.50). Biomarker data showed no significant changes. In conclusion 7.5 mg BID losmapimod was not effective in MDD.

Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials.

GSK372475 is a triple reuptake inhibitor with approximately equipotent inhibition of serotonin, norepinephrine, and dopamine transporters. Two randomized, placebo- and active-controlled, double-blind studies examined the efficacy and safety of GSK372475 in outpatients (aged 18-64 years) with a diagnosis of major depressive episode associated with major depressive disorder (MDD). Patients were randomized 1:1:1 to placebo, GSK372475 (1-2 mg/d), or active control (Study 1: venlafaxine XR 150-225 mg/d; Study 2: paroxetine 20-30 mg/d). GSK372475 did not significantly differ from placebo on any of the key efficacy endpoints (six-item Bech scale, IDS-Clinician Rated, MADRS) in either study. Both active controls demonstrated significant antidepressant activity compared with placebo on both primary and secondary endpoints. The most common adverse effects (AEs) with GSK372475 were dry mouth, headache, insomnia, and nausea. AEs were more frequent for GSK372475 versus placebo for sleep, anxiety-related, gastrointestinal, and tachycardia events. Increases in mean change from baseline in heart rate and sitting blood pressure were greater for GSK372475 than observed for either placebo or active control groups. Completion rates were lower for GSK372475 (49%, 58%) compared with placebo (67%, 74%), venlafaxine XR (63%), or paroxetine (77%). GSK372475 was neither efficacious nor well tolerated in patients with MDD in two 10-week studies.