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.

Impact of Paroxetine, a Strong CYP2D6 Inhibitor, on SPN-812 (Viloxazine Extended-Release) Pharmacokinetics in Healthy Adults.

SPN-812 (viloxazine extended-release) is a novel nonstimulant recently approved as a treatment for attention-deficit/hyperactivity disorder in children and adolescents. Given that SPN-812 is metabolized by CYP2D6 and may be coadministered with CYP2D6 inhibitors, this trial investigated the pharmacokinetics and safety of SPN-812 coadministered with the potent CYP2D6 inhibitor paroxetine. In this single-sequence, 3-treatment period study in healthy volunteers, subjects received a single oral dose of 700 mg SPN-812 alone (period 1), 20 mg daily paroxetine (10 days, period 2), followed by concurrent administration of SPN-812 and paroxetine (period 3). Blood samples were collected for 72 hours post-SPN-812 dosing and analyzed for viloxazine and its primary metabolite, 5-HVLX-gluc. Twenty-two healthy adults were enrolled; all completed the trial. The potential for drug interaction between SPN-812 and paroxetine was assessed using analysis of variance on the log-transformed pharmacokinetic parameters Cmax , AUC0-t , and AUCinf . The least-squares geometric mean ratios for viloxazine were (reported as the ratio of combination/SPN-812 alone) Cmax , 116.04%; 90%CI, 109.49%-122.99%; AUC0-t , 134.65%; 90%CI, 127.65-142.03; and AUCinf , 134.80%; 90%CI, 127.94%-142.03%. CYP2D6 inhibition resulted in a modest change (<35%) on viloxazine AUCs with no change in Cmax . All adverse events were mild in severity.

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.

Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Lisdexamfetamine in Healthy Adults.

BACKGROUND: Viloxazine extended-release is a novel nonstimulant under investigation as a potential treatment for attention-deficit/hyperactivity disorder (ADHD). Given the potential for viloxazine extended-release to be co-administered with stimulant ADHD pharmacotherapies, this trial investigated the pharmacokinetics and safety of combination viloxazine extended-release + lisdexamfetamine dimesylate (lisdexamfetamine) versus viloxazine extended-release and lisdexamfetamine alone. METHODS: In this single-center, cross-over, open-label trial, healthy, non-ADHD adults received single oral doses of 700 mg viloxazine extended-release alone, 50 mg lisdexamfetamine alone, and a combination of viloxazine extended-release (700 mg) + lisdexamfetamine (50 mg), with blood samples collected over 4 days postadministration. The active drug in viloxazine extended-release (viloxazine) and primary metabolite of lisdexamfetamine (d-amphetamine) were measured using chromatographic tandem mass spectrometry. Safety assessments included adverse events, vital signs, echocardiograms, and clinical laboratory evaluations. RESULTS: Thirty-six adults were enrolled, and 34 completed the trial. The least squares geometric mean ratios are reported as [combination / single drug (90% confidence intervals)]. Viloxazine extended-release: Cmax = 95.96% (91.33-100.82), area under the concentration-time curve from 0 to the last measurable time (AUC0-t) = 99.19% (96.53-101.91), and area under the concentration-time curve from 0 to infinity (AUCinf) = 99.23% (96.61-101.93). Lisdexamfetamine: Cmax = 112.78% (109.93-115.71), AUC0-t = 109.64% (105.25-114.22), and AUCinf = 109.52% (105.19-114.03). All reported adverse events, except 1 (moderate vomiting), were mild in severity. CONCLUSIONS: Co-administration of viloxazine extended-release and lisdexamfetamine did not impact the pharmacokinetics of viloxazine or d-amphetamine relative to administration of either drug alone. After single dose administration, the combination appeared to be safe and well tolerated.

Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Methylphenidate in Healthy Adults.

BACKGROUND AND OBJECTIVES: Viloxazine extended-release (viloxazine ER, SPN-812) is a novel non-stimulant with activity at serotonin receptors and the norepinephrine transporter, which is under investigation as a potential treatment for attention-deficit/hyperactivity disorder. Given the potential for viloxazine ER to be coadministered with other pharmacotherapies, this trial investigated the pharmacokinetics and safety of combination viloxazine ER + methylphenidate versus viloxazine ER or methylphenidate alone. METHODS: In this single-center, crossover, open-label trial, healthy adult participants received oral administration of 700 mg viloxazine ER alone, 36 mg methylphenidate alone, and combination viloxazine ER (700 mg) + methylphenidate (36 mg), with blood samples collected over 4 days post-administration. The active drug in viloxazine ER (viloxazine) and methylphenidate was measured using chromatographic tandem mass spectrometry. Safety assessments included adverse events (AEs), vital signs, echocardiograms, and clinical laboratory evaluations. RESULTS: Of 36 healthy adults who were enrolled, 34 completed the trial. The geometric least squares mean ratios are reported as [combination/single drug (90% confidence intervals)]. For viloxazine ER, maximum measured plasma concentration (Cmax) = 100.98% (96.21-105.99), area under the concentration-time curve from time zero to the last measurable time (AUCt) = 98.62% (96.21-101.08), and area under the concentration-time curve from time zero to infinity (AUC∞) = 98.96% (96.55-101.44). For methylphenidate, Cmax = 103.55% (97.42-110.07), AUCt = 106.67% (101.01-112.64), and AUC∞ = 106.61% (100.99-112.54). All reported AEs were mild in severity. CONCLUSIONS: Coadministration of viloxazine ER and methylphenidate did not impact the pharmacokinetics of viloxazine or methylphenidate relative to administration of either drug alone. The combination appeared to be safe and well tolerated.

A Double-Blind, Randomized Study of Extended-Release Molindone for Impulsive Aggression in ADHD.

Objective: To evaluate efficacy and safety of SPN-810 (extended-release molindone) in a Phase-2b, randomized, double-blind, placebo-controlled, dose-ranging study of children (6-12 years) with ADHD and persistent impulsive aggression (IA). Method: After lead-in, children were randomized to (a) placebo (N = 31); (b) low-dose (N = 29, 12/18 mg/day); (c) medium-dose (N = 30, 24/36 mg/day); and (4) high-dose (N = 31, 36/54 mg/day) groups. Treatment included ~2.5-week titration, 3-week maintenance, and 1-week tapering/conversion, alongside existing monotherapy (stimulants/nonstimulants) and behavioral therapy. The primary endpoint was change in Retrospective-Modified Overt Aggression Scale (R-MOAS) score at end of study, with safety monitored. Results: A total of 95 (78.5%) children completed the study. Aggression (R-MOAS) improved with low and medium doses (low dose: p = .031; medium dose: p = .024; high dose: p = .740). The most common adverse events were headache (10.0%), sedation (8.9%), and increased appetite (7.8%). Conclusion: These results suggest SPN-810 may be effective in reducing residual IA behaviors in children with ADHD. Research is still needed to support the benefit-risk profile of SPN-810 in pediatric populations.

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.

A Phase II Double-Blind, Placebo-Controlled, Efficacy and Safety Study of SPN-812 (Extended-Release Viloxazine) in Children With ADHD.

Objective: The objective of this study is to evaluate efficacy and safety of SPN-812 (extended-release viloxazine) for ADHD in children aged 6 to 12 years. Method: In an 8-week study, 222 participants were randomized to placebo or SPN-812 100, 200, 300, or 400 mg/day. Measurements included ADHD Rating Scale (RS)-IV total score and Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scores. Safety assessments included laboratory and electrocardiogram (ECG) measurements, suicidality monitoring (Columbia-Suicide Severity Rating Scale), and adverse event (AE) reporting. Results: Significant improvements in ADHD-RS-IV total score were observed for 200, 300, and 400 mg dose groups versus placebo (p < .05; effect size [ES] = 0.547, 0.596, and 0.623). CGI-I score for the 300 mg group and CGI-S score for all SPN-812 groups except for 100 mg improved significantly (p < .05) versus placebo. The most frequent AEs (≥15%) were somnolence, headache, and decreased appetite. Conclusion: SPN-812 significantly reduced the severity of ADHD symptoms and was well tolerated. The efficacy and safety of SPN-812 are being investigated in Phase III trials.