Open-label Long-Term Safety and Efficacy of SPN-812 (Viloxazine Extended-release Capsule) in Adults With ADHD

Study Overview
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Brief Summary
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Open label, flexible dose, long-term multicenter study of safety and efficacy of SPN-812 in adult ADHD patients

Detailed Description
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This is a multicenter, open-label extension study aimed to assess long-term safety and efficacy of SPN-812 when administered alone or in conjunction with an Food and Drug Administration (FDA)-approved Attention-Deficit Hyperactivity Disorder (ADHD) medication in the treatment of ADHD in adult subjects who completed a blinded study of SPN-812 (812P306). Subjects initiate SPN-812 dosing at 200 mg/day once daily (QD) during first 2 weeks. At or after Visit 2 (Week 2), per the Investigator's discretion and based on Investigator's assessment of subject's clinical response and tolerability, the dose of SPN-812 can be titrated up or tapered down in increments of 50 mg/day, 100 mg/day, 150 mg/day, or 200 mg/day per week to a target dose within the ranges between 200 and 600 mg/day. Additionally, after 12 weeks of dosing (after Visit 4), at the discretion of the Investigator and based on subject's clinical response, the optimized dose of SPN-812 may be supplemented with an adjunctive FDA-approved stimulant treatment. Total treatment duration per subject from Visit 1 to Visit 22 (end of study) is approximately 3 years (156 weeks ± 1 week) or until SPN-812 becomes commercially available.

Official Title
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An Open-Label Extension Study to Evaluate the Long-Term Safety and Efficacy of SPN-812 (Viloxazine Extended-release Capsule) in Adults With Attention-Deficit/Hyperactivity Disorder

Conditions
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Attention-Deficit/Hyperactivity Disorder

Intervention / Treatment
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* Drug: SPN-812


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Is a male or female who completed Study 812P306 and opts/consents to participate in the study if approved by PI. Continues to be medically healthy and with clinically normal laboratory profiles, vital signs, and electrocardiograms (ECGs), in the opinion of the Investigator, assessed at Visit 1. Is able to read and understand the Informed Consent Form (ICF). Has signed the ICF. Is willing and able to attend study appointments within specified time windows. Is a female of childbearing potential (FOCP) who is either sexually inactive (abstinent) or, if sexually active, agrees to use one of the following acceptable birth control methods beginning at least 30 days prior to the first dose of SM and throughout the study: Simultaneous use of male condom and intra-uterine contraceptive device placed at least 4 weeks prior to first SM administration Surgically sterile male partner Simultaneous use of male condom and diaphragm with spermicide Established hormonal contraceptive Females are considered not to be of childbearing potential if they are either post-menopausal (amenorrhea for at least 2 years and serum follicle stimulating hormone [FSH] level of >40 IU/L) or permanently sterilized (e.g., bilateral tubal ligation, hysterectomy, bilateral oophorectomy for 6 months minimum prior to their Visit 1). Is a male who: Agrees to use 2 methods of contraception in combination if his female partner is of childbearing potential; this combination of contraceptive methods must be used from Visit 1 to ≥ 1 month after the last dose of SM, OR Has been surgically sterilized prior to Visit 1. Exclusion Criteria Is currently participating in another clinical trial other than Study 812P306. Has any current psychiatric disorder per Diagnostic and Statistical Manual of Mental Disorders - 5th Edition (DSM-5) criteria other than ADHD with the following exceptions: ADHD is primary diagnoses with comorbidity/secondary diagnoses of major depression disorder (MDD), nicotine dependence, social anxiety disorder, generalized anxiety disorder, or phobias. Current diagnosis of significant systemic disease and/or of a major psychiatric or neurological disorder, including history or family history of seizures or seizure-like disorders. Current evidence of suicidality (suicidal thoughts or behaviors). Female subjects who are pregnant, lactating and/or sexually active and not agreeing to use one of the acceptable birth control methods throughout the study. Has a positive result on urine drug screen at Visit 1. Use of prohibited concomitant medications including known CYP1A2 substrates (e.g., theophylline, melatonin) at the Visit 1 for the duration of the study. Has a clinical laboratory value, vital sign value or ECG result at Visit 1 that is considered to be clinically significant in the opinion of the Investigator. Has one or more clinical laboratory test values outside the reference range at Visit 1 that, in the opinion of the Investigator, are clinically significant, or any of the following (see Note below): Serum creatinine > 1.5 times the upper limit of normal (ULN); Serum total bilirubin > 1.5 times ULN; Serum alanine aminotransferase or aspartate aminotransferase > 2 times ULN. Has any of the following cardiology findings at Visit 1 (see Note below): Abnormal ECG that is, in the Investigator's opinion, clinically significant; PR interval > 220 ms; QRS interval > 130 ms; QTcF interval > 450 ms (for men) or > 470 ms (for women) (QT corrected using Fridericia's method); Second- or third-degree atrioventricular block; Any rhythm, other than sinus rhythm, that is interpreted by the Investigator to be clinically significant. Any reason that, in the opinion of the Investigator, would prevent the subject from participating in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-Label Treatment<br>SPN-812 Open-Label Treatment 200mg to 600mg SPN-812 once daily for up to 156 weeks | Drug: SPN-812<br>* SPN-812 200 to 600 mg/day<br>* Other names: SPN-812 ER;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Change from baseline | Weeks 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ADHD symptoms as measured by the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score | Change from baseline in Adult ADHD Investigator Symptom Rating Scale (AISRS) total score by visit | Weeks 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Global assessment of severity as measured by the Clinical Global Impression - Severity of Illness (CGI-S) scale for ADHD | Change from baseline in CGI-S by visit | Weeks 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Clinical response rate of severity of illness as measured by the categorical CGI-S Responder Rate (CGI-S score of 1 or 2) | Percentage of subjects with a CGI-S score of 1 (Normal, not at all ill) or 2 (Borderline ill) by visit | Weeks 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Global assessment of improvement as measured by the Clinical Global Impression - Improvement scale (CGI-I) for ADHD | CGI-I score by visit | Weeks 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Clinical response rate of improvement as measured by the categorical CGI-I Responder Rate (CGI-I score of 1 or 2) | Percentage of subjects with CGI-I score of 1 (Very much improved) or 2 (Much improved) by visit | Weeks 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Anxiety symptoms as measured by the Generalized Anxiety Disorder 7-Item scale (GAD-7) | Change from baseline in the GAD-7 total score by visit | Weeks 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Clinician-rated ADHD symptoms as measured by the AISRS Inattention subscale and AISRS Hyperactivity/Impulsivity subscale | Change from baseline in the AISRS Inattention subscale score by visit and AISRS Hyperactivity/Impulsivity subscale score by visit | Weeks 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Clinician response rate of ADHD symptom reduction as measured by the 50% responder rate in Adult ADHD Investigator Symptom Rating Scale (AISRS total score) | Percentage of ≥50%AISRS responders (responder defined as the percentage of subjects with a ≥ 50% reduction in the CFB AISRS total score) by visit | Weeks 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Clinician response rate of ADHD symptom reduction as measured by the 30% responder rate in Adult ADHD Investigator Symptom Rating Scale (AISRS) total score | Percentage of ≥30% AISRS responders (responder defined as the percentage of subjects with a ≥ 30% reduction in the CFB AISRS total score) by visit | Weeks 2, 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Executive functioning as measured by the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A; Self Report) | Change from Baseline in the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Global Executive Composite (GEC) T-score by visit | Weeks 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Aspects of executive function and problems of self-regulation as measured by the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A; Self Report) Summary Index Scales and subscales | Change from baseline in the BRIEF-A T-score by each Summary Index Scale and subscale by visit | Weeks 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Depressive symptoms as measured by the Symptoms of Depression Questionnaire (SDQ) | Change from baseline in the Symptoms of Depression Questionnaire (SDQ) Total score by visit | Weeks 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Depressive-related symptom features as measured by the Symptoms of Depression Questionnaire (SDQ) | Change from baseline in the Symptoms of Depression Questionnaire (SDQ) subscale scores by visit | Weeks 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Overall Quality of Life as assessed by the Adult ADHD Quality of Life Scale (AAQoL) | Change from baseline in the Adult ADHD Quality of Life Scale (AAQoL) Total score by visit | Weeks 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 | 
| Aspects of Quality of Life as assessed by the Adult ADHD Quality of Life Scale (AAQoL) | Change from baseline in the Adult ADHD Quality of Life Scale (AAQoL) subscale scores by visit | Weeks 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148 and 156 |