Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies.

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.

Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study.

BACKGROUND: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing-remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. OBJECTIVE: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. METHODS: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. RESULTS: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1-98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%; p < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13-0.20). CONCLUSION: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.

Transition of Patients with Opioid Use Disorder from Buprenorphine to Extended-Release Naltrexone: A Randomized Clinical Trial Assessing Two Transition Regimens.

BACKGROUND AND OBJECTIVE: When patients seek to discontinue buprenorphine (BUP) treatment, monthly injectable extended-release naltrexone (XR-NTX) may help them avoid relapse. The efficacy of low ascending doses of oral NTX vs placebo for patients transitioning from BUP to XR-NTX is evaluated in this study. METHODS: In a phase 3, hybrid residential/outpatient study, clinically stable participants with opioid use disorder (N = 101), receiving BUP for more than or equal to 3 months and seeking antagonist treatment, were randomized (1:1) to 7 residential days of descending doses of BUP and low ascending doses of oral NTX (NTX/BUP, n = 50) or placebo (PBO-N/BUP, n = 51). Both groups received standing ancillary medications and psychoeducational counseling. Following negative naloxone challenge, participants received XR-NTX (day 8). The primary endpoint was the proportion of participants who received and tolerated XR-NTX. RESULTS: There was no statistical difference between groups for participants receiving a first dose of XR-NTX: 68.6% (NTX/BUP) vs 76.0% (PBO-N/BUP; P = .407). The mean number of days with peak Clinical Opiate Withdrawal Scale (COWS) score less than or equal to 12 during the treatment period (days 1-7) was similar for NTX/BUP and PBO-N/BUP groups (5.8 vs 6.3; P = .511). Opioid withdrawal symptoms during XR-NTX induction and post-XR-NTX observation period (days 8-11) were mild and similar between groups (mean peak COWS score: NTX/BUP, 5.1 vs PBO-N/BUP, 5.4; P = .464). Adverse events were mostly mild/moderate. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Low ascending doses of oral NTX did not increase induction rates onto XR-NTX compared with placebo. The overall rate of successful induction across treatment groups supports a brief BUP taper with standing ancillary medications as a well-tolerated approach for patients seeking transition from BUP to XR-NTX. (Am J Addict 2020;00:00-00).

Narsoplimab, a Mannan-Binding Lectin-Associated Serine Protease-2 Inhibitor, for the Treatment of Adult Hematopoietic Stem-Cell Transplantation-Associated Thrombotic Microangiopathy.

PURPOSE: Hematopoietic stem-cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with significant mortality and no approved therapy. HSCT-TMA results from endothelial injury, which activates the lectin pathway of complement. Narsoplimab (OMS721), an inhibitor of mannan-binding lectin-associated serine protease-2 (MASP-2), was evaluated for safety and efficacy in adults with HSCT-TMA. METHODS: In this single-arm open-label pivotal trial (NCT02222545), patients received intravenous narsoplimab once weekly for 4-8 weeks. The primary end point (response rate) required clinical improvement in two categories: (1) laboratory TMA markers (both platelet count and lactate dehydrogenase) and (2) organ function or freedom from transfusion. Patients receiving at least one dose (full analysis set [FAS]; N = 28) were analyzed. RESULTS: The response rate was 61% in the FAS population. Similar responses were observed across all patient subgroups defined by baseline features, HSCT characteristics, and HSCT complications. Improvement in organ function occurred in 74% of patients in the FAS population. One-hundred-day survival after HSCT-TMA diagnosis was 68% and 94% in FAS population and responders, respectively, whereas median overall survival was 274 days in the FAS population. Narsoplimab was well tolerated, and adverse events were typical of this population, with no apparent safety signal of concern. CONCLUSION: In this study, narsoplimab treatment was safe, significantly improved laboratory TMA markers, and resulted in clinical response and favorable overall survival.

Opioid use and dropout from extended-release naltrexone in a controlled trial: implications for mechanism.

BACKGROUND AND AIMS: Extended-release formulations of naltrexone have emerged as effective treatment options for opioid use disorder. This post-hoc analysis examined the temporal relationship between episodes of opioid use and subsequent dropout in a placebo-controlled trial of extended-release injection naltrexone (XR-NTX) to draw inferences about the mechanism by which extended blockade of opioid receptors translates into clinical effectiveness. DESIGN: This was a 24-week multiple-site, double-blind, randomized trial of monthly XR-NTX versus placebo injections. We analyzed time to dropout from treatment using survival analysis with an extended Cox model as a function of treatment (XR-NTX versus placebo) and with weekly urine drug test (UDT) results for opioids at each week as a time-dependent covariate. SETTING: Thirteen addiction treatment programs in Russia, 2008-09. PARTICIPANTS: A total of 250 adults with opioid use disorder who had completed in-patient detoxification. INTERVENTION: XR-NTX injection or placebo injection every 4 weeks with weekly clinic visits and biweekly counseling. MEASUREMENTS: Urine toxicology for opioids measured weekly and week of dropout from treatment. FINDINGS: The Cox model yielded a significant interaction of time-dependent urine toxicology by treatment (P = 0.024). Among patients receiving placebo, a positive UDT in a given week increased the risk for dropout from treatment in the subsequent week [hazard ratio (HR) = 6.25; 95% confidence interval (CI) = 3.6-10.0], whereas among patients receiving XR-NTX, a positive UDT result showed no significant effect on risk for dropout (HR = 1.67; 95% CI = 0.6-4.5). The proportion of patients who completed all 24 weeks without any positive UDT result was 31% on XR-NTX compared with 20% on placebo (P = 0.051). CONCLUSIONS: Extended-release injection naltrexone was effective at reducing the risk of dropout from opioid use disorder treatment after an episode of opioid use. Just under a third of patients (31%) on XR-NTX had no opioid-positive urine tests across the trial, but the hypothesis that this would differ from placebo (20%) was not confirmed.

Cognitive performance of patients with opioid use disorder transitioned to extended-release injectable naltrexone from buprenorphine: Post hoc analysis of exploratory results of a phase 3 randomized controlled trial.

BACKGROUND: Opioid use disorder (OUD) is associated with cognitive dysfunction. Understanding how pharmacotherapy may affect cognition is an important treatment consideration. METHODS: This was a hybrid residential-outpatient, randomized trial assessing transition regimens (naltrexone/buprenorphine [NTX/BUP] vs placebo-NTX/buprenorphine [PBO-N]/BUP) to extended-release naltrexone (XR-NTX) in patients with OUD seeking BUP discontinuation. Cognition was assessed at baseline, Day 22 (XR-NTX Day 14), and Day 36 (XR-NTX Day 28) using a range of measures (Brief Assessment of Cognition Symbol Coding test, Controlled Oral Word Association Task, Wechsler Memory Scale-III Spatial Span test, Continuous Performance Test, and Test of Attentional Performance). Pre-specified exploratory analyses compared treatment groups. Post hoc analyses were treatment-arm-independent analyses overall and by baseline BUP dose (<8 mg/day [low-dose] or 8 mg/day [higher-dose]). RESULTS: Baseline cognitive measures were similar between NTX/BUP and PBO-N/BUP groups and between BUP low-dose and higher-dose groups. There were improvements in several cognitive outcomes at Day 22 and Day 36 relative to baseline for the overall population, but no differences between NTX/BUP and PBO-N/BUP treatment groups were observed. Participants entering the study on low-dose BUP showed improvements at Day 36 relative to baseline in 5 of 7 cognitive outcomes; participants entering the study on higher-dose BUP generally did not show improvements in cognitive outcomes. CONCLUSIONS: Improvements in most cognitive domains were associated with the transition from BUP to XR-NTX, particularly in participants entering the study on low-dose (<8 mg/day) BUP. These improvements may be due to the discontinuation of BUP, the treatment with XR-NTX, or both.

Combination of olanzapine and samidorphan has no clinically relevant effects on ECG parameters, including the QTc interval: Results from a phase 1 QT/QTc study.

BACKGROUND: OLZ/SAM is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist, and is in development for the treatment of schizophrenia and bipolar I disorder. OLZ/SAM is under development with the intent to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. This thorough QT study assessed the effects of therapeutic and supratherapeutic doses of OLZ/SAM on cardiac repolarization in patients with schizophrenia. METHODS: In this randomized, double-blind, placebo- and positive (moxifloxacin)-controlled, parallel-group study, 100 patients aged 18 to 60 years with stable schizophrenia were randomized 3:2 to the active arm and control arm. Subjects in the active arm received a therapeutic dose of 10/10 mg (10 mg olanzapine/10 mg samidorphan) on days 2-4, 20/20 mg on days 5-8, and a supratherapeutic dose of 30/30 mg (1.5 times and 3 times the maximum recommended daily dose of olanzapine and samidorphan, respectively) on days 9-13, and moxifloxacin-matched placebo on days 1 and 14. Subjects in the control arm received a single oral dose of moxifloxacin 400 mg and moxifloxacin-matched placebo on days 1 and 14 in a nested crossover fashion, along with OLZ/SAM-matched placebo on days 2-13. Serial electrocardiograms (ECGs) and simultaneous plasma drug concentrations were determined pre- and post-dose. The effects of OLZ/SAM on heart rate and ECG parameters (QT interval with Fridericia's correction [QTcF], PR and QRS interval, and T-wave morphology) were evaluated, and the primary endpoint was change from baseline in QTcF (ΔQTcF). The relationship between drug concentration and ΔQTcF (C-QTc) was evaluated using a linear mixed-effects model. Safety monitoring included adverse events reporting and clinical laboratory assessments. RESULTS: Based on primary analysis using C-QTc modeling, no clinically concerning QTc effect (ie, placebo-corrected ΔQTcF [ΔΔQTcF] ≥10 msec) was observed across the OLZ/SAM dose range tested (10/10 to 30/30 mg), up to olanzapine and samidorphan concentrations of approximately 110 and 160 ng/mL, respectively. The slope (90% confidence interval [CI]) of the C-QTc relationship was shallow and not significant for either olanzapine or samidorphan (0.03 [-0.01, 0.08] and 0.01 [-0.01, 0.04] msec per ng/mL, respectively). The predicted ΔΔQTcF (90% CI) was 2.33 (-2.72, 7.38) and 1.38 (-3.37, 6.12) msec at the observed geometric mean maximal concentration (Cmax) of olanzapine (62.6 ng/mL) and samidorphan (75.1 ng/mL) on day 13, respectively. The study's assay sensitivity was confirmed by the C-QTc relationship of moxifloxacin. OLZ/SAM was well tolerated at all doses; adverse events occurring in >5% of subjects treated with OLZ/SAM were somnolence, weight increased, nausea, and dizziness. CONCLUSIONS: This thorough QT study in patients with stable schizophrenia demonstrated that OLZ/SAM, in doses and plasma concentrations up to supratherapeutic levels, does not have a clinically relevant effect on ECG parameters, including QT/QTc prolongation.

Abuse Potential of Buprenorphine/Samidorphan Combination Compared to Buprenorphine and Placebo: A Phase 1 Randomized Controlled Trial.

Buprenorphine/samidorphan combination (BUP/SAM) is an opioid system modulator being investigated as adjunctive treatment for major depressive disorder. BUP/SAM is a fixed-dose combination of buprenorphine, a partial µ-opioid receptor agonist and κ-opioid receptor antagonist, and samidorphan, a µ-opioid receptor antagonist added to address the abuse and dependence potential of buprenorphine. In this study, we assessed the effect of samidorphan on the abuse potential of buprenorphine in the BUP/SAM combination in nondependent, recreational, adult opioid users (ClinicalTrials.gov ID: NCT02413281). Participants were randomized to 6 treatments in a blinded, Williams crossover design: placebo, BUP/SAM at the intended therapeutic dose (2 mg/2 mg), at 4-fold (8 mg/8 mg) and 8-fold (16 mg/16 mg) the therapeutic dose, and buprenorphine alone (8 mg and 16 mg). The primary end point was maximum effect (Emax ) on the visual analog scale for "at the moment" Drug Liking. Emax of Drug Liking for the BUP/SAM 2 mg/2 mg dose was similar to that for placebo (median within-subject difference [90% confidence interval]: 2.5 [0.0-9.0]). The supratherapeutic doses of BUP/SAM showed differences of small magnitude on Drug Liking Emax compared to placebo. Drug Liking Emax for all BUP/SAM doses were significantly lower than those observed for either buprenorphine dose alone. Fewer participants reported adverse events associated with abuse potential with BUP/SAM than with buprenorphine alone, and the overall safety profile of BUP/SAM was consistent with prior reports in healthy volunteers. These findings indicate that samidorphan substantially reduces the abuse potential of buprenorphine in the BUP/SAM combination.

Abuse Potential of Samidorphan: A Phase I, Oxycodone-, Pentazocine-, Naltrexone-, and Placebo-Controlled Study.

Samidorphan is a µ-opioid receptor antagonist in development for the treatment of schizophrenia, in combination with olanzapine, and major depressive disorder, in combination with buprenorphine, at proposed therapeutic doses of samidorphan 10 mg and 2 mg, respectively. A double-blind, double-dummy, active- and placebo-controlled, crossover study evaluated the abuse potential of samidorphan in healthy, nondependent, recreational opioid users. Following a qualification phase, participants were randomized to 1 of 6 treatment sequences of study drugs: placebo, samidorphan (10 or 30 mg), oxycodone (40 mg), pentazocine (30 mg), and naltrexone (100 mg) in a 6 × 6 Williams design. The primary end point was maximum effect (Emax ) for "at-the-moment" Drug Liking visual analog scale scores. Secondary end points included Emax visual analog scale scores for Take Drug Again and Overall Drug Liking and safety assessments. Among 47 participants, at-the-moment Emax Drug Liking scores for positive study controls oxycodone and pentazocine were significantly higher than placebo (P < .001) and samidorphan (both doses; P < .001). Both samidorphan doses had Emax Drug Liking scores similar to placebo and naltrexone (median within-subject differences of 0.0). Emax Take Drug Again scores for samidorphan (both doses) were higher than placebo, but similar to naltrexone, an unscheduled µ-opioid receptor antagonist. Adverse events to evaluate abuse potential occurred less frequently with samidorphan, naltrexone, and placebo than with oxycodone and pentazocine. Findings from this study support a lack of abuse potential with samidorphan at doses up to 30 mg and a safety profile consistent with previous samidorphan clinical studies.

Outpatient transition to extended-release injectable naltrexone for patients with opioid use disorder: A phase 3 randomized trial.

BACKGROUND: Injectable extended-release naltrexone (XR-NTX), approved to prevent relapse to opioid dependence, requires initial abstinence. This multisite outpatient clinical trial examined the efficacy and safety of low-dose oral naltrexone (NTX), combined with a brief buprenorphine (BUP) taper and standing ancillary medications, for detoxification and induction onto XR-NTX. METHODS: Patients (N = 378) were randomized, stratified by primary short-acting opioid-of-use, to one of three regimens: NTX + BUP; NTX + placebo BUP (PBO-B); placebo NTX (PBO-N) + PBO-B. Patients received 7 days of ascending NTX or placebo, concurrent with a 3-day BUP or placebo taper, and ancillary medications in an outpatient setting. Daily psychoeducational counseling was provided. On Day 8, patients passing a naloxone challenge received XR-NTX. RESULTS: Rates of transition to XR-NTX were comparable across groups: NTX/BUP (46.0%) vs. NTX/PBO-B (40.5%) vs. PBO-N/PBO-B (46.0%). Thus, the study did not meet its primary endpoint. Adverse events, reported by 32.5% of all patients, were mild to moderate in severity and consistent with opioid withdrawal. A first, second, and third XR-NTX injection was received by 44.4%, 29.9%, and 22.5% of patients, respectively. Compared with the PBO-N/PBO-B group, the NTX/BUP group demonstrated higher opioid abstinence during the transition and lower post-XR-NTX subjective opioid withdrawal scores. CONCLUSIONS: A 7-day detoxification protocol with NTX alone or NTX + BUP provided similar rates of induction to XR-NTX as placebo. For those inducted onto XR-NTX, management of opioid withdrawal symptoms prior to induction was achieved in a structured outpatient setting using a well-tolerated, fixed-dose ancillary medication regimen common to all three groups.

Optimizing adaptive design for Phase 2 dose-finding trials incorporating long-term success and financial considerations: A case study for neuropathic pain.

In this paper, we propose an adaptive randomization design for Phase 2 dose-finding trials to optimize Net Present Value (NPV) for an experimental drug. We replace the traditional fixed sample size design (Patel, et al., 2012) by this new design to see if NPV from the original paper can be improved. Comparison of the proposed design to the previous design is made via simulations using a hypothetical example based on a Diabetic Neuropathic Pain Study.

Effects of valdecoxib in the treatment of chronic low back pain: results of a randomized, placebo-controlled trial.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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 > or =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. RESULTS: 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 < or = 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 < or = 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. CONCLUSIONS: 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.