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.

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.

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.

Sleep Restriction and Recurrent Circadian Disruption Differentially Affects Blood Pressure, Sodium Retention, and Aldosterone Secretion.

Prolonged exposure to chronic sleep restriction (CSR) and shiftwork are both associated with incident hypertension and cardiovascular disease. We hypothesized that the combination of CSR and shiftwork's rotating sleep schedule (causing recurrent circadian disruption, RCD) would increase blood pressure, renal sodium retention, potassium excretion, and aldosterone excretion. Seventeen healthy participants were studied during a 32-day inpatient protocol that included 20-h "days" with associated scheduled sleep/wake and eating behaviors. Participants were randomly assigned to restricted (1:3.3 sleep:wake, CSR group) or standard (1:2 sleep:wake, Control group) ratios of sleep:wake duration. Systolic blood pressure during circadian misalignment was ∼6% higher in CSR conditions. Renal sodium and potassium excretion showed robust circadian patterns; potassium excretion also displayed some influence of the scheduled behaviors (sleep/wake, fasting during sleep so made parallel fasting/feeding). In contrast, the timing of renal aldosterone excretion was affected predominately by scheduled behaviors. Per 20-h "day," total sodium excretion increased, and total potassium excretion decreased during RCD without a change in total aldosterone excretion. Lastly, a reduced total renal sodium excretion was found despite constant oral sodium consumption and total aldosterone excretion, suggesting a positive total body sodium balance independent of aldosterone excretion. These findings may provide mechanistic insight into the observed adverse cardiovascular and renal effects of shiftwork.

A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial Assessing the Efficacy and Safety of Viloxazine Extended-Release Capsules in Adults with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND AND OBJECTIVE: Attention-deficit/hyperactivity disorder is a neurodevelopmental disorder that typically begins in childhood and often persists into adulthood. Recent phase III trials have demonstrated the efficacy and safety of viloxazine extended-release capsules (viloxazine ER; Qelbree®) in pediatrics (6-17 years of age). The aim of this study was to evaluate the efficacy and safety of viloxazine ER in adults with attention-deficit/hyperactivity disorder. METHODS: This was a phase III, randomized, double-blind, placebo-controlled, two-arm trial in adults (18-65 years of age) with attention-deficit/hyperactivity disorder. Eligible subjects were randomized 1:1 to viloxazine ER (flexible dose of 200-600 mg/day) or matched placebo. The primary efficacy endpoint was the change from baseline at end of study (week 6) in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score. The key secondary endpoint was the change from baseline at end of study in the Clinical Global Impressions-Severity of Illness (CGI-S) score. Additional secondary outcome measures included the AISRS Inattention and Hyperactivity/Impulsivity subscales, the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A), the Generalized Anxiety Disorder-7 Item (GAD-7), and the Clinical Global Impressions-Improvement (CGI-I); each was analyzed at end of study. Responder rates on CGI scales and the AISRS were also assessed. RESULTS: A total of 374 subjects were randomized. At end of study, the mean viloxazine ER dose was 504 mg. The reduction in the change from baseline at end of study AISRS total score (least-square means ± standard error) was significantly greater in subjects treated with viloxazine ER (-15.5 ± 0.91) compared with placebo (-11.7 ± 0.90), p = 0.0040. The reduction in the CGI-S score was also significantly greater in subjects treated with viloxazine ER (-1.4 ± 0.10) compared with placebo (-1.0 ± 0.10), p = 0.0023. The viloxazine ER group demonstrated significantly greater improvements in the AISRS Inattention (p = 0.0015) and Hyperactivity/Impulsivity (p = 0.0380) subscales, the CGI-I (p = 0.0076), and the BRIEF-A Global Executive Composite (p = 0.0468) and Metacognition Index (p = 0.0100). Analysis of categorical secondary endpoints revealed that the viloxazine ER group had a significantly higher AISRS 30% response rate compared with placebo (p = 0.0395); all other comparisons were not significant. Many treatment effects (including the primary and key secondary endpoints) were significant by week 2. The most common treatment-related adverse events that occurred in ≥5% of subjects receiving viloxazine ER were insomnia (14.8%), fatigue (11.6%), nausea (10.1%), decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). Viloxazine ER was well tolerated, with a 9.0% discontinuation rate due to adverse events compared with 4.9% in the placebo group. CONCLUSIONS: Treatment with viloxazine ER resulted in a statistically significant improvement in primary and key secondary endpoints, indicating improvements in attention-deficit/hyperactivity disorder symptomology, executive function, and overall clinical illness severity in adults. Viloxazine ER was well tolerated at the tested doses in adults with attention-deficit/hyperactivity disorder. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04016779.

Attention-deficit/hyperactivity disorder (ADHD) is a condition characterized by inattention (difficulty maintaining focus), and/or impulsiveness/hyperactivity. In 2021, a nonstimulant medication called viloxazine ER (brand name: Qelbree^®) received US FDA-approval for ADHD in children and adolescents (aged 6 to 17 years), based on efficacy and safety demonstrated in clinical trials. Here we present results of a phase 3, randomized, double-blind, placebo-controlled, clinical trial that enrolled 374 adults with ADHD. In this trial, half the patients received viloxazine ER, and half received placebo (identical capsule without active ingredient). Medication doses ranged from 200­600 mg/day, based on symptom response and presence of side effects. To reduce bias, patients and investigators did not know which medication the patient was receiving. The primary measure of efficacy was the Adult ADHD Investigator Symptom Rating Scale (AISRS), a standardized questionnaire rating presence and severity of patient-reported ADHD symptoms. At the end of the 6-week trial, participants receiving viloxazine ER showed greater improvement in ADHD symptoms according to AISRS than those receiving placebo. Improvement was seen in both the Inattentive and Impulsive/Hyperactive components of ADHD and in other study measures, including a measure of behaviors called Executive Function. Viloxazine ER was generally safe and well-tolerated in the trial. The most common side effects were insomnia (14.8%), fatigue (11.6%), and nausea (10.1%). Overall, 9.0% of patients receiving viloxazine and 5% receiving placebo left the trial because of side effects. Due to these positive results, the US FDA recently approved viloxazine ER to treat adults with ADHD.

Chronic Circadian Disruption and Sleep Restriction Influence Subjective Hunger, Appetite, and Food Preference.

Chronic circadian disruption (CCD), such as occurs during rotating shiftwork, and insufficient sleep are each independently associated with poor health outcomes, including obesity and glucose intolerance. A potential mechanism for poor health is increased energy intake (i.e., eating), particularly during the circadian night, when the physiological response to energy intake is altered. However, the contributions of CCD and insufficient sleep to subjective hunger, appetite, food preference, and appetitive hormones are not clear. To disentangle the influences of these factors, we studied seventeen healthy young adults in a 32-day in-laboratory study designed to distribute sleep, wakefulness, and energy intake equally across all phases of the circadian cycle, thereby imposing CCD. Participants were randomized to the Control (1:2 sleep:wake ratio, n = 8) or chronic sleep restriction (CSR, 1:3.3 sleep:wake ratio, n = 9) conditions. Throughout each waking episode the participants completed visual analog scales pertaining to hunger, appetite, and food preference. A fasting blood sample was collected to assess appetitive hormones. CCD was associated with a significant decrease in hunger and appetite in a multitude of domains in both the Control and CSR groups. This change in hunger was significantly correlated with changes in the ghrelin/leptin ratio. These findings further our understanding of the contributions of CCD and insufficient sleep on subjective hunger and appetite as well as of their possible contributions to adverse health behaviors.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Chronic sleep restriction greatly magnifies performance decrements immediately after awakening.

STUDY OBJECTIVES: Sleep inertia, subjectively experienced as grogginess felt upon awakening, causes cognitive performance impairments that can require up to 1.5 hr to dissipate. It is unknown, however, how chronic sleep restriction (CSR) influences the magnitude and duration of sleep inertia-related performance deficits. METHODS: Twenty-six healthy participants were enrolled in one of two in-laboratory sleep restriction protocols (one 32 day randomized control and one 38 day protocol) that separated the influence of sleep and circadian effects on performance using different "day"-lengths (20 and 42.85 hr day-lengths, respectively). The sleep opportunity per 24 hr day was the equivalent of 5.6 hr for each CSR condition and 8 hr for the Control condition. Participant's performance and subjective sleepiness were assessed within ~2 min after electroencephalogram-verified awakening and every 10 min thereafter for 70 min to evaluate performance and subjective sleepiness during sleep inertia. RESULTS: Performance within 2 min of awakening was ~10% worse in CSR conditions compared with Control and remained impaired across the dissipation of sleep inertia in the CSR conditions when compared with Control. These impairments in performance during sleep inertia occurred after only chronic exposure to sleep restriction and were even worse after awakenings during the biological nighttime. Interestingly, despite differences in objective performance, there were no significant differences between groups in subjective levels of sleepiness during sleep inertia. CONCLUSIONS: CSR worsens sleep inertia, especially for awakenings during the biological night. These findings are important for individuals needing to perform tasks quickly upon awakening, particularly those who obtain less than 6 hr of sleep on a nightly basis. CLINICAL TRIAL: The study "Sleep Duration Required to Restore Performance During Chronic Sleep Restriction" was registered as a clinical trial (#NCT01581125) at clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT01581125?term=NCT01581125.&rank=1).

Light modulates oscillatory alpha activity in the occipital cortex of totally visually blind individuals with intact non-image-forming photoreception.

The discovery of intrinsically photosensitive retinal ganglion cells (ipRGCs) marked a major shift in our understanding of how light information is processed by the mammalian brain. These ipRGCs influence multiple functions not directly related to image formation such as circadian resetting and entrainment, pupil constriction, enhancement of alertness, as well as the modulation of cognition. More recently, it was demonstrated that ipRGCs may also contribute to basic visual functions. The impact of ipRGCs on visual function, independently of image forming photoreceptors, remains difficult to isolate, however, particularly in humans. We previously showed that exposure to intense monochromatic blue light (465 nm) induced non-conscious light perception in a forced choice task in three rare totally visually blind individuals without detectable rod and cone function, but who retained non-image-forming responses to light, very likely via ipRGCs. The neural foundation of such light perception in the absence of conscious vision is unknown, however. In this study, we characterized the brain activity of these three participants using electroencephalography (EEG), and demonstrate that unconsciously perceived light triggers an early and reliable transient desynchronization (i.e. decreased power) of the alpha EEG rhythm (8-14 Hz) over the occipital cortex. These results provide compelling insight into how ipRGC may contribute to transient changes in ongoing brain activity. They suggest that occipital alpha rhythm synchrony, which is typically linked to the visual system, is modulated by ipRGCs photoreception; a process that may contribute to the non-conscious light perception in those blind individuals.

Chronic Insufficient Sleep Has a Limited Impact on Circadian Rhythmicity of Subjective Hunger and Awakening Fasted Metabolic Hormones.

Weight gain and obesity have reached epidemic proportions in modern society. Insufficient sleep-which is also prevalent in modern society-and eating at inappropriate circadian times have been identified as risk factors for weight gain, yet the impact of chronic insufficient sleep on the circadian timing of subjective hunger and physiologic metabolic outcomes are not well understood. We investigated how chronic insufficient sleep impacts the circadian timing of subjective hunger and fasting metabolic hormones in a 32-day in-laboratory randomized single-blind control study, with healthy younger participants (range, 20-34 years) randomized to either Control (1:2 sleep:wake ratio, 6.67 h sleep:13.33 h wake, n = 7, equivalent to 8 h of sleep per 24 h) or chronic sleep restriction (CSR, 1:3.3 sleep:wake ratio, 4.67 h sleep:15.33 h wake, n = 8, equivalent to 5.6 h of sleep per 24 h) conditions. Participants lived on a "20 h day" designed to distribute all behaviors and food intake equally across all phases of the circadian cycle over every six consecutive 20 h protocol days. During each 20 h day, participants were provided a nutritionist-designed, isocaloric diet consisting of 45-50% carbohydrate, 30-35% fat, and 15-20% protein adjusted for sex, weight, and age. Subjective non-numeric ratings of hunger were recorded before and after meals and fasting blood samples were taken within 5 min of awakening. Subjective levels of hunger and fasting concentrations of leptin, ghrelin, insulin, glucose, adiponectin, and cortisol all demonstrated circadian patterns; there were no differences, however, between CSR and Control conditions in subjective hunger ratings or any fasting hormone concentrations. These findings suggest that chronic insufficient sleep may have a limited role in altering the robust circadian profile of subjective hunger and fasted metabolic hormones. CLINICAL TRIAL REGISTRATION: The study was registered as clinical trial #NCT01581125.