Author (Year)	Groups Studied and Intervention	Results and Findings	Conclusions
Nasser et al. (2021)[@146286]	Four hundred seventy-seven children between ages of 6-11 were randomized to three treatment arms: SPN-812 100 mg/day, SPN-812 200 mg/day, or placebo. Primary outcomes measured by ADHD-RS-5 Total scores from CFB to EOS. Secondary outcomes measured by CGI-I, Conners 3-PS Composite T-score, and WFIRS-P Total average scores compared to placebo.	After 1 week of therapy the ADHD-RS-5 scores were improved in the 100 mg (p = 0.0004) and 200 mg/day (p = 0.0244) SPN-812 arms and present through EOS (p = 0.0020 and p < 0.0001, respectively). when compared to placebo. Somnolence, headache, decreased appetite were adverse events seen in ≥ 5% of participants related to treatment.	Viloxazine ER demonstrated a statistically significant reduction in ADHD symptoms in school aged children from both SPN-812 groups. Less than 5% of subjects discontinued the treatment due to AEs suggesting its tolerability and safety.
Nasser et al. (2021)[@146287]	Three hundred thirteen children ages 6-11 years old were enrolled in a phase III randomized control and administered 200 mg/day SPN-812, 400mg SPN-812, or placebo. The efficacy of the treatment arms were analyzed via ADHD-RS-5, CBI-I, Conners 3-PS, and WFIRS-P scales.	The CFB to EOS in the 200 mg/day and 400 mg/day showed significant improvements in ADHD-RS-5 (p = 0.0038, p = 0.0063, respectively) and CGI-I scores (p = 0.0028, p = 0.0099, respectively). Conners 3-PS scale only demonstrated an improvement in the 200 mg/day group, while the WFIRS-P observed no difference between either treatment arm.	Similar to the trial above, both doses of the SPN-812 were efficacious in reducing ADHD symptoms making it a promising novel therapy.
Johnson et al. (2020)[@146288]	Two hundred twenty-two children (ages 6-12) were administered placebo or 100, 200, 300, or 400 mg/day SPN-812 over an 8-week study period. The efficacy of the treatments were evaluated through ADHD-RS-4, CGI-S, CGI-I scales. Safety of the procedures were assessed through ECG, laboratory, and suicide severity rating scale.	All 4 treatment groups saw a significant reduction in the ADHD-RS-IV scale versus placebo. CGI-I scores were only improved in the 300 mg/day (p = 0.009). All SPN-812 treatment arms saw an improvement in CGI-S scores, while the 100 mg/day saw no statistically significant difference to placebo.	The 4 treatment arms demonstrated an overall safety and efficacy of SPN-812 on ADHD symptoms in children.
Nasser et al. (2021)[@146289]	Three hundred ten adolescents (aged 12-17) were randomized to three groups placebo or SPN-812 (200 mg/day or 400 mg/day). The trial was conducted over a 6-week period.	When compared to placebo, the 200 mg/day and 400 mg/day viloxazine groups had a significant reduction of ADHD symptoms in the ADHD-RS-5 scale (p = 0.0232, p = 0.0091). There were no statistically significant improvements in the Conners 3-PS and WFIRS-P scores versus placebo.	Viloxazine ER provided significantly improved clinical outcomes for adolescents diagnosed with ADHD.
Nasser et al. (2021)[@146290]	Two hundred ninety-seven adolescents (aged 12-17) were randomized to receive placebo or viloxazine ER (400 mg/daily or 600 mg/daily).	The ADHD-RS-5 total scores for the 400 mg/day (p = 0.0082) group had a statistically significant reduction in ADHD symptoms, whereas the 600 mg/day (p = 0.0712) did not.	Though the 400 mg/day SPN-812 resulted in ADHD symptom reductions, the 600 mg/day did not have the same statistical difference. This result was elaborated by the researchers as an abnormal placebo response.
Nasser et al. (2020)[@146291]	Fifty-six adults (aged 18-45) were randomized to receive placebo, 400 mg moxifloxacin, and 1800 mg SPN-812 in different sequences to observe effects on cardiac repolarization. The primary outcome measured was the relationship between the CFB in heart rate corrected QT interval (QTcI) versus SPN-812 and 5-hydroxyviloxazine glucuronide (SPN-812 metabolite) plasma concentrations. Secondary outcomes evaluated were heart rate, PR and QRS intervals, and ECG morphology.	The change in QTcI when compared to SPN-812 and metabolite concentrations demonstrated statistically negative correlations (p = 0.0012 and p = 0.0007, respectively).	There were no correlations between the supratherapeutic doses of SPN-812 and cardiac repolarization. No significant changes in heart rate and abnormal ECG morphologies observed were clinically relevant to the SPN-812 treatment.
Faison et al. (2021)[@146294]	Thirty-four healthy adults completed the open-label trial to receive single dose methylphenidate (36 mg), SPN-812 (700 mg), or combination of both drugs (36 mg and 700 mg). Blood samples were collected and measured using mass spectrometry to assess the pharmacokinetics of the two drugs in tandem.	The LSM ratios for the maximum plasma concentration for SPN-812 and methylphenidate with a 90% CI were 100.98% (96.21-105.99) and 103.55% (97.42- 110.07) respectively. The AUC concentration from time zero and infinity for both therapies fell within the 90% CI.	Administering SPN-812 in conjunction with methylphenidate did not negatively impact the pharmacokinetics of either drug.
Fasion et al. (2021)[@146295]	As above, thirty-four healthy adults completed the open-label trial to receive single dose lisdexamfetamine (50 mg), SPN-812 (700 mg), or combination of both drugs (50 mg and 700 mg). Blood samples were collected and measured using mass spectrometry to assess the pharmacokinetics of the two drugs in tandem.	The LSM ratios for the maximum plasma concentration for SPN-812 and lisdexamfetamine with a 90% CI were 95.96% (91.33–100.82) and 112.78% (109.93–115.71) respectively. The AUC concentration from time zero and infinity for both therapies fell within the 90% CI.	Administering SPN-812 in conjunction with lisdexamfetamine did not negatively impact the pharmacokinetics of either drug.