Model-based comparison of subcutaneous versus sublingual apomorphine administration in the treatment of motor fluctuations in Parkinson's disease.

The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson's disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment. Apomorphine concentrations and UPDRS motor scores were simulated from the PK/PD models using 500 hypothetical subjects. UPDRS motor score change from baseline was evaluated using time to clinically relevant response, response duration, area under the curve, maximal response, and time to maximal response. Higher doses of each apomorphine formulation were associated with shorter time to response, longer response duration, and greater maximal response. Although the mean maximal responses to SC and SL apomorphine were comparable, the time to response was four times shorter (7 vs. 31 min) and time to maximal response was two times shorter (27 vs. 61 min) for 4 mg SC vs. 50 mg SL. Thus, faster onset of action was observed for the SC formulation compared to SL. These data may be useful for physicians when selecting "on demand" therapy for patients with Parkinson's disease experiencing motor fluctuations.

Complex Metabolism of the Novel Neurosteroid, Ganaxolone, in Humans: A Unique Challenge for Metabolites in Safety Testing Assessment.

The human pharmacokinetics, metabolism, and excretion of [14C]-ganaxolone (GNX) were characterized in healthy male subjects (n = 8) following a single 300-mg (150 µCi) oral dose. GNX exhibited a short half-life of 4 hours in plasma, whereas total radioactivity had a half-life of 413 hours indicating extensive metabolism to long-lived metabolites. Identification of the major GNX circulating metabolites required extensive isolation and purification for liquid chromatography-tandem mass spectrometry analysis, together with in vitro studies, NMR spectroscopy, and synthetic chemistry support. This revealed that the major routes of GNX metabolism involved hydroxylation at the 16α-hydroxy position, stereoselective reduction of the 20-ketone to afford the corresponding 20α-hydroxysterol, and sulfation of the 3α-hydroxy group. This latter reaction yielded an unstable tertiary sulfate, which eliminated the elements of H2SO4 to introduce a double bond in the A ring. A combination of these pathways, together with oxidation of the 3ß-methyl substituent to a carboxylic acid and sulfation at the 20α position, led to the major circulating metabolites in plasma, termed M2 and M17. These studies, which led to the complete or partial identification of no less than 59 metabolites of GNX, demonstrated the high complexity of the metabolic fate of this drug in humans and demonstrated that the major circulating products in plasma can result from multiple sequential processes that may not be easily replicated in animals or with animal or human in vitro systems. SIGNIFICANCE STATEMENT: Studies on the metabolism of [14C]-ganaxolone in humans revealed a complex array of products that circulated in plasma, the two major components of which were formed via an unexpected multi-step pathway. Complete structural characterization of these (disproportionate) human metabolites required extensive in vitro studies, along with contemporary mass spectrometry, NMR spectroscopy, and synthetic chemistry efforts, which served to underscore the limitations of traditional animal studies in predicting major circulating metabolites in man.

A post hoc analysis of the effect of viloxazine extended-release capsules on learning and school problems in children and adolescents with attention-deficit/hyperactivity disorder.

Improvement in attention-deficit/hyperactivity disorder (ADHD) symptoms vs. placebo was reported in a series of pediatric clinical trials of viloxazine extended-release capsules (viloxazine ER; Qelbree™). This post hoc analysis of those studies evaluated the effect of viloxazine ER on learning and school problems (LSPs). We used data from four Phase 3 placebo-controlled trials of 100-600 mg/day viloxazine ER (N = 1354; 6-17 years of age). LSPs were evaluated using the School domain of the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P-S) and the Learning Problems content scale of the Conners 3rd Edition-Parent Short Form (C3PS-LP) at baseline and end of study (≥ Week 6). ADHD symptoms were assessed weekly using the ADHD Rating Scale 5th Edition. The analyses were performed using the general linear mixed model with participant as a random effect. The responder analyses were performed using the Chi-square test. Viloxazine ER demonstrated significantly greater improvements in WFIRS-P-S (p < 0.0001) and C3PS-LP (p = 0.0113) scores vs. placebo. The response rate for the WFIRS-P-S was significantly greater for viloxazine ER vs. placebo (p = 0.001), and the number needed to treat (NNT) was 10.3 (effect size 0.7). Conversely, response rates for C3PS-LP did not differ between groups (p = 0.9069). In addition to ADHD symptoms improvement demonstrated in previous studies, viloxazine ER significantly reduced LSPs in pediatric subjects with ADHD. The responder analyses and NNT estimates indicate that a substantial number of children and adolescents with ADHD treated with viloxazine ER improved in clinically assessed LSPs.

The role of placebo response in the efficacy outcome assessment in viloxazine extended-release pivotal trials in paediatric subjects with attention-deficit/hyperactivity disorder.

AIMS: Four Phase 3 studies evaluated efficacy and safety of viloxazine extended-release in the treatment of attention-deficit/hyperactivity disorder (ADHD). The primary efficacy objective-change from baseline in ADHD Rating Scale-5 (ADHD-RS-5) Total score at end of study (EOS)-was not met in one of the studies (812P304). A band-pass analysis was performed to evaluate the impact of placebo response on the results. METHODS: The distribution of placebo response at EOS of each trial was evaluated. The 2.5th and 97.5th percentiles of the distribution of ADHD-RS-5 Total score were used as boundaries for the band-pass analysis. An independent mixed model for repeated measures analysis was conducted for each trial using all eligible data (active and placebo) from the total and band-pass filtered populations. RESULTS: The 2.5th and 97.5th percentiles at EOS were 3.5 and 53.5, respectively. Application of the band-pass filter (filtering out all subjects [active, n = 305 (32.1%) and placebo, n = 134 (33.5%)] of clinical sites with placebo scores <3.5 or >53.5) revealed statistically significant improvement at the primary endpoint (600-mg/d viloxazine ER vs. placebo) in Study 812P304 (mean [confidence interval] = 4.9537 [0.5405-9.3669]), previously masked by a high placebo response (mean [confidence interval] = 3.5756 [-0.3332-7.4844]). The outcome of the analysis indicated that the impact of the band-pass adjustment is greater when placebo response is higher. CONCLUSION: This analysis indicated that a higher placebo response in Study 812P304 confounded the assessment of treatment effect. Application of the band-pass methodology confirmed the positive results of the 3 prior studies and the signal detection confounder in the fourth study.

A Phase 3, Placebo-Controlled Trial of Once-Daily Viloxazine Extended-Release Capsules in Adolescents With Attention-Deficit/Hyperactivity Disorder.

PURPOSE: This phase 3 clinical trial evaluated the efficacy and safety of viloxazine extended-release capsules (VLX-ER) as a monotherapy for attention-deficit/hyperactivity disorder (ADHD) in adolescents (12-17 years). METHODS: Eligible subjects (n = 310) were randomized to receive once-daily 200 and 400 mg VLX-ER, or placebo for 6 weeks. The primary efficacy end point was change from baseline (CFB) at the end of study (EOS) in ADHD Rating Scale-5 Total score. Key secondary end points were Clinical Global Impression-Improvement score at EOS, CFB at EOS in Conners 3-Parent Short Form Composite T-score, and CFB at EOS in Weiss Functional Impairment Rating Scale-Parent Total average score. RESULTS: In the 200-mg/d and 400-mg/d VLX-ER treatment groups, a significant improvement was found in the CFB at EOS in ADHD Rating Scale-5 Total (P = 0.0232, P = 0.0091) and Inattention (P = 0.0424, P = 0.0390) and Hyperactivity/Impulsivity (P = 0.0069, P = 0.0005) subscale scores versus placebo. The Clinical Global Impression-Improvement score was significantly improved at EOS in the 200-mg/d and 400-mg/d VLX-ER groups versus placebo (P = 0.0042, P = 0.0003). The Conners 3-Parent Short Form composite T-score and Weiss Functional Impairment Rating Scale-Parent Total average score exhibited improvement in both VLX-ER groups; however, the difference versus placebo was not statistically significant. The most common treatment-related adverse events were somnolence, headache, decreased appetite, nausea, and fatigue. The adverse event-related discontinuation rates were <5% in all groups. CONCLUSIONS: Viloxazine extended-release demonstrated statistically significant and clinically meaningful improvement in ADHD symptoms in adolescents and was generally well tolerated.

Evaluating the likelihood to be helped or harmed after treatment with viloxazine extended-release in children and adolescents with attention-deficit/hyperactivity disorder.

AIMS: When clinicians evaluate potential medications for their patients, they must weigh the probability of a treatment's benefits against the possible risks. To this end, the present analyses evaluate the novel nonstimulant viloxazine extended-release (viloxazine ER) using measures of effect size to describe the potential benefits of its treatment in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) as well as the risk of discontinuation because of intolerable adverse events. METHODS: These post hoc analyses use pooled data from four pivotal Phase 3 trials in paediatric patients treated with viloxazine ER. The Likelihood to be Helped or Harmed (LHH) effect size measure was calculated to describe the probability of patients benefiting from treatment vs discontinuing. The Number Needed to Treat (NNT) was calculated from frequently used thresholds of response. The Number Needed to Harm (NNH) was calculated using discontinuations because of adverse events. RESULTS: LHH values for viloxazine ER ranged from 5 to 13, suggesting that subjects were 5-13 times more likely to benefit from, rather than discontinue, viloxazine ER treatment. Specifically, NNT values for viloxazine ER treatment ranged from 6 to 7. NNH values for viloxazine ER treatment ranged from 31 to 74. By convention, single-digit NNTs (<10) suggest the intervention is potentially useful, while NNH values ≥10 for adverse events suggest it is potentially safe or tolerable. CONCLUSIONS: These results indicate that patients with ADHD are likely to benefit from treatment with viloxazine ER, and are unlikely to discontinue, as viloxazine ER treatment was associated with favourable LHH, NNT, and NNH values. Clinicaltrials.gov: NCT03247530, NCT03247543, NCT03247517, NCT03247556.

Response of peer relations and social activities to treatment with viloxazine extended-release capsules (Qelbree® ): A post hoc analysis of four randomized clinical trials of children and adolescents with attention-deficit/hyperactivity disorder.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is associated with impairments related to peer relations (PR) and social activities (SA). The objective of this post hoc analysis was to assess the degree to which viloxazine extended-release (viloxazine ER; viloxazine extended-release capsules; Qelbree® ) improves clinical assessments of PR and SA in children and adolescents with ADHD. METHODS: Data were used from four Phase III placebo-controlled trials of 100 to 600 mg/day of viloxazine ER (N = 1354; 6-17 years of age). PR and SA were measured with the Peer Relations content scale of the Conners 3rd Edition Parent Short Form's Peer Relation content scale (C3PS-PR) and the Social Activities domain of the Weiss Functional Impairment Rating Scale-Parent Report's (WFIRS-P-SA) at baseline and end of study. ADHD symptoms were assessed weekly with the ADHD Rating Scale, 5th Edition. The analyses relied on the general linear mixed model with the subject as a random effect. RESULTS: Improvement in C3PS-PR (p = .0035) and WFIRS-P-SA (p = .0029) scores were significantly greater in subjects treated with viloxazine ER compared with placebo. When using measures of clinically meaningful response, the C3PS-PR responder rate was significantly higher for viloxazine ER (19.2%) compared with placebo (14.1%) and the difference was statistically significant (p = .0311); the Number Needed to Treat (NNT) was 19.6. The WFIRS-P-SA responder rate was significantly higher for viloxazine ER (43.2%) compared with placebo (28.5%) and the difference was statistically significant (p < .0001); the NNT was 6.8. The standardized mean difference effect size for both PR and SA was 0.09. CONCLUSIONS: Viloxazine ER significantly reduces the impairment of PR and SA in children and adolescents with ADHD. Although its effects on PR and SA are modest, many ADHD patients can be expected to achieve clinically meaningful improvements in PR and SA with viloxazine ER treatment for longer than 6 weeks.

Predicting efficacy of viloxazine extended-release treatment in adults with ADHD using an early change in ADHD symptoms: Machine learning Post Hoc analysis of a phase 3 clinical trial.

Early response to viloxazine extended-release (viloxazine ER, Qelbree®) treatment predicted efficacy outcome in pediatric subjects with attention-deficit/hyperactivity disorder (ADHD). This study sought to determine whether the machine learning lasso model used in the pediatric study would predict response to viloxazine ER in an adult population based on early improvements in ADHD symptoms. We used data from a double-blind, placebo-controlled, flexible-dose (200-600 mg) study of viloxazine ER (N = 354; 18 to 60 years old). Area under the Receiver Operating Characteristic Curve (ROC AUC) statistics were computed using the lasso model from pediatric data to predict responder status in adults. Response was defined as ≥50% reduction from baseline in the Adult ADHD Investigator Symptoms Rating Scale (AISRS) Total score at Week 6. The adult study sample included 127 viloxazine ER-treated subjects with Week 6 data. Fifty-one subjects (40.2%) were categorized as responders. The ROC curves indicated that data collected up to Week 2 were sufficient to accurately predict treatment response at Week 6 with 68% positive predictive power, 80% sensitivity, and 74% specificity. This analysis demonstrated that the predictive model estimated from the child data generalizes to adults with ADHD, further supporting the consistency of viloxazine ER treatment across age groups.

The Effect of Viloxazine Extended-Release Capsules on Functional Impairments Associated with Attention-Deficit/Hyperactivity Disorder (ADHD) in Children and Adolescents in Four Phase 3 Placebo-Controlled Trials.

PURPOSE: The ADHD Rating Scale (ADHD-RS) assesses 18 symptoms of inattention and hyperactivity/impulsivity and has been used in many clinical trials to evaluate the treatment effect of drugs on ADHD. The fifth edition of this scale (ADHD-RS-5) also assesses the impact of inattention and hyperactivity/impulsivity symptoms on six domains of functional impairment (FI): family relationships, peer relationships, completing/returning homework, academic performance at school, controlling behavior at school, and self-esteem. Here, we report the effect of viloxazine extended-release capsules (viloxazine ER), a novel nonstimulant treatment for ADHD in children and adolescents (ages 6-17 years), on FI from a post hoc analysis of four randomized, double-blind, placebo-controlled Phase 3 clinical trials (N=1354). PATIENTS AND METHODS: ADHD-RS-5 investigator ratings of ADHD symptoms and FIs were conducted at baseline and weekly post-baseline for 6-8 weeks in the four trials. Change from baseline (CFB) in ADHD-RS-5 FI scores (Total score [sum of 12 FI items] and Inattention and Hyperactivity/Impulsivity subscale scores [sum of 6 corresponding FI items]) and the 30% and 50% Responder Rates (ADHD-RS-5 FI Total score) were compared between viloxazine ER and placebo. RESULTS: The reduction (improvement) in ADHD-RS-5 FI scores (Total and subscale scores) and the percentage of responders (30% and 50%) at Week 6 were significantly greater in each viloxazine ER dose group vs placebo. In the 100-400 mg/day viloxazine ER groups, improvements were found as early as Week 1 (100-mg/day) or Week 2 (200-, 400-mg/day) of treatment. Analysis of individual items of ADHD-related FIs demonstrated that the effect of viloxazine ER was observed across all domains of impairment. CONCLUSION: Significant improvements observed in ADHD-related FIs are consistent with the reduction in inattention and hyperactivity/impulsivity symptoms demonstrated in the viloxazine ER Phase 3 pediatric trials. Therefore, viloxazine ER provides clinically meaningful improvement of ADHD symptoms and functioning in children and adolescents with ADHD, starting as early as Week 1-2 of treatment.

Executive Function Outcome of Treatment with Viloxazine Extended-Release Capsules in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Post-Hoc Analysis of Four Randomized Clinical Trials.

AIM: The aim of this study was to evaluate the effect of viloxazine extended-release capsules (viloxazine ER; Qelbree™) on executive function deficits (EFDs) in pediatric subjects (6-17 years of age) with attention-deficit/hyperactivity disorder (ADHD). METHODS: Data from four phase III placebo-controlled trials of 100-600 mg/day viloxazine ER (6-8 weeks of treatment) were used to evaluate the change from baseline (CFB) in the Conners 3rd Edition Parent Short Form-Executive Function (C3PS-EF) content scale T-score. Subjects were defined as EFD responders if they had C3PS-EF T-score > 70 at baseline and < 65 at end of study. ADHD symptoms were assessed with ADHD Rating Scale 5th Edition (ADHD-RS-5). Subjects were defined as ADHD symptom responders if they had a ≥ 50% reduction in CFB ADHD-RS-5 Total score at Week 6. The number needed to treat (NNT) and Cohen's d effect sizes were estimated for EFD and ADHD symptoms. RESULTS: A total of 1154 subjects were included in the analysis. Statistically significant improvements in EFDs were observed with viloxazine ER versus placebo (p = 0.0002). There were 52.5% of EFD or ADHD symptom responders in the viloxazine ER treatment group and 35.4% in the placebo group (p < 0.0001). The NNT was 5.8. The Cohen's d effect size for EFD and ADHD symptoms was 0.31. CONCLUSION: Consistent with the efficacy of viloxazine ER demonstrated in pivotal trials, viloxazine ER significantly reduced EFDs in subjects with ADHD. Moreover, a substantial proportion of subjects treated with viloxazine ER had large improvements in EFDs, ADHD symptoms, or both. CLINICAL TRIAL REGISTRATION NUMBERS: NCT03247530, NCT03247517, NCT03247543, NCT03247556.

Early response to SPN-812 (viloxazine extended-release) can predict efficacy outcome in pediatric subjects with ADHD: a machine learning post-hoc analysis of four randomized clinical trials.

Machine learning (ML) was used to determine whether early response can predict efficacy outcome in pediatric subjects with ADHD treated with SPN-812. We used data from four Phase 3 placebo-controlled trials of 100- to 600-mg/day SPN-812 (N=1397; 6-17 years of age). The treatment response was defined as having a ≥50% reduction in change from baseline (CFB) in ADHD Rating Scale-5 (ADHD-RS-5) Total score at Week 6. The variables used were: ADHD-RS-5 Total score, age, body weight, and body mass index at baseline; CFB ADHD-RS-5 Total score at Week 1, cumulative change in ADHD-RS-5 Total score at Week 2, and cumulative change in ADHD-RS-5 Total score at Week 3; Clinical Global Impressions-Improvement (CGI-I) score at Week 1, 2, and 3; and target dose. Using the best selected model, lasso regression, to generate importance scores, we found that change in ADHD-RS-5 Total score and CGI-I score were the best predictors of efficacy outcome. Change in ADHD-RS-5 Total score at Week 2 could predict treatment response at Week 6 (75% positive predictive power, 75% sensitivity, 74% specificity). Therefore, early response after two weeks of treatment with once-daily SPN-812 in pediatric patients with ADHD can predict efficacy outcome at Week 6.

Once-Daily SPN-812 200 and 400 mg in the treatment of ADHD in School-aged Children: A Phase III Randomized, Controlled Trial.

PURPOSE: SPN-812 (viloxazine extended-release) is under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This Phase III study evaluated the efficacy and tolerability of SPN-812 200 and 400 mg once daily in children 6-11 years of age with ADHD. METHODS: Patients were randomly assigned to receive SPN-812 200 mg, SPN-812 400 mg, or placebo, once daily for 8 weeks (including ≤3 weeks titration period). The primary efficacy endpoint was the change from baseline (CFB) in ADHD Rating Scale (RS)-5 Total score at end of study (EOS). Key secondary endpoints included Clinical Global Impression-Improvement (CGI-I) score at EOS, CFB in Conners 3-Parent Short Form (PS) composite T-score at EOS, and CFB in Weiss Functional Impairment Rating Scale-Parent (WFIRS-P) Total average score at EOS. FINDINGS: A total of 313 patients were enrolled, with 301 in the intent-to-treat population (194 boys, 107 girls; mean age [SD], 8.4 [1.7] years). At EOS, the CFBs in ADHD-RS-5 Total score and CGI-I score were significantly improved with both 200- and 400-mg/d SPN-812 versus placebo (ADHD-RS-5, P = 0.0038 and 0.0063, respectively; CGI-I, P = 0.0028 and 0.0099). At EOS, the CFB in Conners 3-PS composite T-score was significantly improved with 200- (P = 0.0064), but not 400-mg/d (P = 0.0917), SPN-812 compared to placebo. No significant difference between the groups was found in WFIRS-P Total average score. The rate of discontinuations due to adverse events in both SPN-812 treatment groups combined was <5%. IMPLICATIONS: SPN-812 200 and 400 mg once daily was associated with improvements in ADHD symptoms in school-aged children and was generally well tolerated. ClinicalTrials.gov identifier: NCT03247543.

A Phase 3 Placebo-Controlled Trial of Once-Daily 400-mg and 600-mg SPN-812 (Viloxazine Extended-Release) in Adolescents with ADHD.

Objectives: Three Phase 3 trials have demonstrated the efficacy and safety of SPN-812 in pediatric subjects with ADHD. Here, we report the results of a fourth trial. Methods: Eligible adolescent subjects (N = 297) were randomized to SPN-812 (400- or 600-mg/day) or placebo. The primary efficacy endpoint was change from baseline (CFB) at end of study (EOS) in the ADHD Rating Scale-5 (ADHD-RS-5) Total score. Statistical analyses included sequential testing for multiple treatment comparisons. Key secondary endpoints included: Clinical Global Impression-Improvement (CGI-I) score at EOS and CFB at EOS in the Conners 3-Parent Short Form (Conners 3-PS) Composite T-score and Weiss Functional Impairment Rating Scale-Parent (WFIRS-P) Total average score. Results: The CFB at EOS ADHD-RS-5 Total score (least square [LS] means ± SE) for 400-mg/day, 600-mg/day SPN-812, and placebo was -18.3 ± 1.36, -16.7 ± 1.39, and -13.2 ± 1.38, respectively. The difference vs. placebo was statistically significant only for the 400-mg/day SPN-812 treatment group (600 mg/day: p = 0.0712; 400 mg/day: p = 0.0082). Neither dose could be considered superior to placebo due to the use of statistical method of sequential testing. Significant improvements were observed on a number of secondary endpoints. SPN-812 was well tolerated at both doses, with <5% discontinuation rate due to adverse events. Conclusions: Treatment with 400- but not 600-mg/day SPN-812 resulted in statistically significant improvement in the primary endpoint. The negative result seen in the 600-mg/day SPN-812 group was likely due to an unusually high placebo response. Safety data were consistent across all doses in the SPN-812 trials.

Translating Attention-Deficit/Hyperactivity Disorder Rating Scale-5 and Weiss Functional Impairment Rating Scale-Parent Effectiveness Scores into Clinical Global Impressions Clinical Significance Levels in Four Randomized Clinical Trials of SPN-812 (Viloxazine Extended-Release) in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

Objectives: Clinical trials in psychiatry frequently report results from lengthy, comprehensive assessments to characterize a subject emotionally, cognitively, and behaviorally before and after treatment. However, the potential treatment implications of these results and how they translate into clinical practice remain unclear. Conversely, the Clinical Global Impressions (CGI) scales are quick, intuitive assessments used to assess the functional impact of a treatment in clinically relevant terms. The objectives of the present analyses are to translate scores from comprehensive assessments of symptom severity and functional impairment into clinically meaningful CGI levels. Methods: These post-hoc analyses use data integrated from four pivotal Phase 3 trials in attention-deficit/hyperactivity disorder (ADHD) in children and adolescents treated with the novel nonstimulant SPN-812 (Viloxazine Extended-Release). In this study, we evaluated the ADHD Rating Scale-5 (ADHD-RS-5) and Weiss Functional Impairment Rating Scale-Parent (WFIRS-P), assessments of symptom severity and functional impairment, respectively, by linking these scales with the CGI scales at baseline and end of study. Results: For participants that improved, a one-level change on the CGI-Improvement (CGI-I) was associated with a 10-15-point change on the ADHD-RS-5, and a 0.2-0.5-point change on the WFIRS-P. On the CGI-I, ratings of much improved and very much improved were associated with a percent score decrease (i.e., improvement) of ∼55% and 80% on the ADHD-RS-5 and ∼40% and 70% on the WFIRS-P, respectively. Differences between children and adolescents were minor and are unlikely to be clinically meaningful. Conclusion: These post-hoc analyses provide clinically meaningful benchmarks for the interpretation of scores on the ADHD-RS-5 and WFIRS-P in terms of CGI evaluations in subjects with ADHD. These results may be useful for physicians seeking to understand a treatment's potential impact on their ADHD patients or for researchers looking to define their study results within a clinically relevant context. Data are from clinical trials NCT03247530, NCT03247543, NCT03247517, and NCT03247556.

Evaluation of the Effect of SPN-812 (Viloxazine Extended-Release) on QTc Interval in Healthy Adults.

OBJECTIVE: To assess the effects of a supratherapeutic dose of SPN-812, a drug currently under investigation as a treatment for attention-deficit/hyperactivity disorder, on cardiac repolarization (QTc) in healthy adults. METHODS: The study was conducted from June 27, 2018, to July 10, 2018. It had a double-blind, randomized, crossover design in which subjects received a 3-treatment sequence-placebo, 400 mg moxifloxacin, and 1,800 mg SPN-812 for 2 consecutive days (separated by at least a 3-day washout). The primary endpoint was the correlation between the change from baseline (CFB) in individual heart rate corrected QT interval (QTcI) (ΔQTcI) and viloxazine and 5-hydroxyviloxazine glucuronide (5-OH-VLX-gluc) plasma concentrations (Cps). The secondary endpoint was the time point placebo-adjusted CFB in QTcI (ΔΔQTcI) for viloxazine. For assay sensitivity, the correlations between moxifloxacin Cp and the ΔQTcI, and moxifloxacin and time point ΔΔQTcI were evaluated. Additional evaluations included Fridericia's formula QT correction, heart rate, and the PR and QRS intervals. Changes in electrocardiogram (ECG) morphology along with other safety parameters were also analyzed and reported. RESULTS: The correlation between ΔQTcI and viloxazine Cp demonstrated a statistically significant negative slope (P = .0012). 5-OH-VLX-gluc Cp and ΔQTcI also demonstrated a statistically significant negative slope (P = .0007). Secondary time point analyses showed no effect of SPN-812 on QTcI. Assay sensitivity with moxifloxacin was confirmed. Safety parameters were acceptable. CONCLUSIONS: This study demonstrated that SPN-812 had no effect on cardiac repolarization or other ECG parameters in healthy adults, suggesting that it is not associated with a risk for cardiac arrhythmias or other electrocardiographic parameters.

A Phase III, Randomized, Placebo-controlled Trial to Assess the Efficacy and Safety of Once-daily SPN-812 (Viloxazine Extended-release) in the Treatment of Attention-deficit/Hyperactivity Disorder in School-age Children.

PURPOSE: The limitations of current US Food and Drug Administration (FDA)-approved medications for the treatment of attention-deficit/hyperactivity disorder (ADHD) set the need for the development of novel, effective, and tolerable medications to treat this disorder. The purpose of this study was to evaluate whether treatment with SPN-812 (viloxazine extended-release) significantly reduces symptoms of ADHD in children. METHODS: This study was a randomized, double-blind, placebo-controlled 6-week trial to assess the efficacy and safety of once-daily 100- and 200-mg SPN-812 in the treatment of ADHD in male and female children 6-11 years of age. Inclusion criteria required subjects to have a confirmed Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, ADHD diagnosis, an ADHD-Rating Scale-5 (ADHD-RS-5) score ≥28, a Clinical Global Impression-Severity score ≥4, and for subjects to be free of ADHD medication ≥1 week before randomization. The primary efficacy endpoint was the change from baseline (CFB) at end of study (EOS) in ADHD-RS-5 Total score. Key secondary endpoints included Clinical Global Impression-Improvement (CGI-I) scores at EOS and CFB at EOS in the Conners 3-Parent Short Form (Conners 3-PS) Composite T-score and the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P) Total average score. Safety assessments included adverse events (AEs), laboratory tests, vital signs, physical examinations, ECGs, and the Columbia-Suicide Severity Rating Scale. The primary efficacy endpoint was analyzed by using a mixed model for repeated measures; all secondary measures were analyzed by using an ANCOVA model. RESULTS: A total of 477 subjects were randomized to treatment (intent-to-treat population, n = 460). The majority of subjects were male (63%) and either White (51.3%) or African American (43.7%). The demographic and baseline characteristics between the groups were similar. Statistically significant improvements in ADHD-RS-5 Total score were observed in both the 100- and 200-mg/day SPN-812 treatment groups compared to placebo at week 1 of treatment (P = 0.0004 and P = 0.0244, respectively), which was maintained through EOS (P = 0.0004 and P < 0.0001). Significant improvements were also observed at EOS in the CGI-I scale (P = 0.0020 and P < 0.0001), Conners 3-PS Composite T-score (P = 0.0003 and P = 0.0002), and WFIRS-P Total average score (P = 0.0019 and P = 0.0002) versus placebo. Treatment-related AEs reported in ≥5% of subjects included somnolence, decreased appetite, and headache. The discontinuation rate due to AEs was <5%. IMPLICATIONS: SPN-812 significantly reduced ADHD symptoms in children and was well tolerated. SPN-812 may prove to be an effective treatment for children with ADHD. ClinicalTrials.gov identifier: NCT03247530.

The effects of nicotine on ethanol-induced conditioned taste aversions in Long-Evans rats.

RATIONALE: Overall drug acceptability is thought to be a function of the balance between its rewarding and aversive effects, the latter of which is reportedly affected by polydrug use. OBJECTIVES: Given that nicotine and alcohol are commonly co-used, the present experiments sought to assess nicotine's impact on ethanol's aversive effects within a conditioned taste aversion design. MATERIALS AND METHODS: Experiment 1 examined various doses of nicotine (0, 0.4, 0.8, 1.2 mg/kg) to determine a behaviorally active dose, and experiment 2 examined various doses of ethanol (0, 0.5, 1.0, 1.5 g/kg) to determine a dose that produced intermediate aversions. Experiment 3 then examined the aversive effects of nicotine (0.8 mg/kg) and ethanol (1.0 g/kg) alone and in combination. Additionally, nicotine's effects on blood alcohol concentrations (BAC) and ethanol-induced hypothermia were examined. RESULTS: Nicotine and ethanol combined produced aversions significantly greater than those produced by either drug alone or the summed aversive effects of the individual compounds. These effects were unrelated to changes in BAC, but nicotine and ethanol combined produced a prolonged hypothermic effect which may contribute to the increased aversions induced by the combination. CONCLUSIONS: These data demonstrate that nicotine may interact with ethanol, increasing ethanol's aversive effects. Although the rewarding effects of concurrently administered nicotine and ethanol were not assessed, these data do indicate that the reported high incidence of nicotine and ethanol co-use is unlikely due to reductions in the aversiveness of ethanol with concurrently administered nicotine. It is more likely attributable to nicotine-related changes in ethanol's rewarding effects.

An assessment of sex differences in nicotine-induced conditioned taste aversions.

Sex differences in taste aversion learning have been reported for a number of different compounds. It is unknown, however, to what degree, if any, such differences exist when nicotine is the aversion-inducing agent. To address this issue, in the present experiment male and female rats were given limited access to saccharin followed by an intraperitoneal (i.p.) injection of either vehicle or nicotine (0.4, 0.8 or 1.2 mg/kg). Although nicotine induced significant taste aversions in both males and females, the aversions were generally weak at all doses tested. There were no sex differences in the acquisition or strength of the aversions induced by nicotine. The vulnerability to drug abuse has been suggested to be a function of the balance of the rewarding and aversive effects of a drug. Given the relatively weak aversions induced in both sexes and the absence of differences between males and females, it is unlikely that the reported sex difference in the self-administration of nicotine is a function of differences in nicotine's aversive effects. The reported difference in the self-administration of nicotine by males and females is more likely a function of differences in the sensitivity to the rewarding effects of the drug.

Strain-dependent sex differences in the effects of alcohol on cocaine-induced taste aversions.

Research using the conditioned taste aversion procedure has reported that a cocaine/alcohol combination induces a significantly stronger taste aversion than either cocaine or alcohol alone. These findings suggest that the co-administration of alcohol intensifies the aversive effects of cocaine. Although the behavioral interaction of cocaine and alcohol is well established, little is known about how the effects of this drug combination might be modulated by a variety of subject variables. The current investigation addressed this by assessing if the ability of alcohol to potentiate cocaine-induced taste aversions is dependent upon the strain and/or sex of the subject. In this series of studies, male and female rats of Long-Evans (Experiment 1) and Sprague-Dawley (Experiment 2) descent were given limited access to a novel saccharin solution to drink and were then injected with either vehicle, cocaine (20 mg/kg), alcohol (0.56 g/kg) or the alcohol/cocaine combination. This procedure was repeated every fourth day for a total of four conditioning trials. All subjects were then compared on an Aversion Test that followed the fourth conditioning cycle. In three of the groups tested (male Long-Evans; male and female Sprague-Dawley), cocaine induced a significant taste aversion that was unaffected by the co-administration of alcohol. However, in female Long-Evans subjects, the addition of alcohol significantly strengthened the avoidance of the saccharin solution. Although the effects of alcohol on cocaine-induced taste aversions are dependent upon an interaction of sex and strain, the basis for this SexxStrain interaction is not known. That such an interaction is evident suggests that attention to such factors in assessing the effects of drug combinations is important to understanding the likelihood of the use and abuse of such drugs.