Evaluation of SPN-812 (Viloxazine Extended-release Capsule) in Adults With ADHD

This study will evaluate the efficacy and safety of SPN-812 (Viloxazine extended-release capsules; 200-600 mg) in adults 18-65 years of age with Attention-Deficit/Hyperactivity Disorder (ADHD).

This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, 2-arm, parallel-group, flexible dose trial assessing the efficacy and safety of SPN-812 (Viloxazine extended-release capsules; 200-600 mg) as monotherapy for the treatment of adults 18-65 years old with Attention-Deficit/Hyperactivity Disorder (ADHD).

Eligibility Criteria:
Inclusion Criteria:

1. Is male or female, aged 18 to ≤ 65 years at screening.
2. Is able to read and understand the Informed Consent Form (ICF).
3. Written informed consent obtained from the subject (a signed ICF).
4. Weight within the normal or overweight ranges according to accepted values of the Body Mass Index Chart (18.0 to 35 kg/m2).
5. Is able to swallow capsules whole, without crushing, chewing or cutting.
6. Is willing and able to attend study appointments within the specified time windows.
7. Has a primary diagnosis of ADHD according to the DSM-5 classification, with diagnosis made at least 6 months prior to screening and confirmed with Structured Clinical Interview for DSM-5 Clinical Trials version (SCID-5-CT).
8. Has an AISRS Adult ADHD (Attention-Deficit/Hyperactivity Disorder) Investigator Symptom Rating Scale total score of ≥ 26 at the Screening Visit and at the Baseline Visit (V2, Day 1).
9. Has a CGI-S score of ≥ 4 (moderately ill or worse) at the Screening Visit (V1) and Baseline Visit (V2, Day 1).
10. Females of childbearing potential (FOCP) must be either sexually inactive (abstinent) or, if sexually active, must agree to use one of the following acceptable birth control methods beginning 30 days prior to the first dose of SM and throughout the study:

    1. Simultaneous use of male condom and intra-uterine contraceptive device placed at least 4 weeks prior to first SM administration
    2. Surgically sterile male partner
    3. Simultaneous use of male condom and diaphragm with spermicide
    4. 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 screening).
11. Males must:

    1. Use 2 methods of contraception in combination if his female partner is of childbearing potential; this combination of contraceptive methods must be used from the Baseline Visit to ≥ 1 month after the last dose of SM, or
    2. Have been surgically sterilized prior to the Screening Visit.

Exclusion Criteria:

1. Has previously enrolled in a SPN-812 study.
2. Is currently participating in another clinical trial or has participated in a clinical trial within 60 days prior to the first Screening Visit.
3. Is a member of the study personnel or of their immediate families, or is a subordinate (or immediate family member of a subordinate) to any of the study personnel.
4. 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.
5. Has history of severe drug allergy or hypersensitivity, or known hypersensitivity, to the study medication or excipients.
6. Has history of moderate or severe head trauma or other neurological disorder or systemic medical disease that, in the Investigator's opinion, is likely to affect central nervous system functioning. This would include subjects with:

   1. A current diagnosis of a major neurological disorder; or
   2. Seizures, seizure disorder or seizure-like events; or a history of seizure disorder within the immediate family (siblings, parents); or
   3. Encephalopathy
7. Has any history of schizophrenia, schizoaffective disorder, bipolar disorder, borderline personality disorder, antisocial personality disorder, narcissistic personality disorder, autism, post-traumatic stress disorder or obsessive-compulsive disorder.
8. Has any current psychiatric disorder (per DSM-5 criteria) other than ADHD with the following exceptions: ADHD is primary diagnosis with comorbidity/secondary diagnoses of major depression disorder (MDD), nicotine dependence, social anxiety disorder, generalized anxiety disorder, or phobias, and subject is not receiving pharmacological treatment for the comorbidity/secondary diagnoses (e.g., antidepressant for MDD) at time of screening nor for the duration of study.
9. Has a Symptoms of Depression Questionnaire (SDQ) mean score \>3.0 at screening.
10. Has a Hamilton Anxiety Rating Scale (HAM-A) score of \> 21 at screening.
11. Has organic mental disorders, or mental disorders due to a general medical condition (per DSM-5 criteria).
12. Has a current diagnosis or history of substance use disorder including alcohol use disorder (excluding nicotine and caffeine) (per DSM-5 criteria) within the 12 months prior to screening; or is assessed by the Investigator as having regularly consumed alcohol exceeding 21 units for males and 14 units for females per week (1 unit equals 340 mL of beer, 115 mL of wine, or 43 mL of spirits) within the 12 months prior to screening.
13. Is currently using, or has a positive result on the drug screening at the Screening Visit for drugs of abuse (alcohol, opiates, methadone, cocaine, methamphetamine \[including ecstasy\], phencyclidine, propoxyphene, methylphenidate, barbiturates, and benzodiazepines). If subject's serum drug screen for ethanol is positive at Screening (V1) and the investigator determines subject does not have alcohol use disorder, then the subject may have a repeat serum drug screen for ethanol performed before baseline within the allotted screening period (results must be received prior to V2 baseline). If second serum drug screen for ethanol is positive, subject is excluded from participating in the study, however, if second serum drug screen for ethanol is negative, subject may proceed to V2.
14. Is a (known or self-identified) current habitual/chronic cannabis user (medicinal or recreational); or

    * Has a positive urine drug screen for cannabis at the Screening Visit and is considered, per the Investigator's judgement, to be a habitual/chronic cannabis user; or
    * Has a positive urine drug screen for cannabis at both the screening and follow-up drug screen at the Baseline Visit, even though the subject is not considered, per the Investigator's judgement, to be a habitual/chronic cannabis user.

    Note: Subjects who have a positive urine drug screen for cannabis at the Screening Visit but who are not considered to be a habitual/chronic cannabis user per the Investigator's judgement may, with Sponsor approval, undergo an additional urine drug screen at least 4 weeks after the original urine drug screen at Baseline Visit, prior to randomization. Subjects must agree to refrain from cannabis use throughout study.
15. Has treatment-resistant ADHD based on a history of receipt of \>2 approved ADHD medications that failed to adequately improve the subject's symptoms. A subject who is naïve to ADHD treatment is not excluded from study participation.
16. Has any other disorder for which its treatment takes priority over treatment of ADHD or is likely to interfere with study treatment, impair treatment compliance, or interfere with interpretation of study results.
17. Has history of cancer, other than basal cell or Stage 1 squamous cell carcinoma of the skin that has not been in remission for \> 5 years prior to the first dose of SM.
18. Has or has had one or more of the following conditions considered clinically significant/relevant by the Investigator in the context of the study:

    * cardiovascular disease
    * congestive heart failure
    * cardiac hypertrophy
    * arrhythmia
    * bradycardia (pulse \< 50 bpm)
    * tachycardia (pulse \> 100 bpm)
    * respiratory disease
    * hepatic impairment or renal insufficiency
    * metabolic disorder
    * endocrine disorder
    * gastrointestinal disorder
    * hematological disorder
    * infectious disorder
    * any clinically significant immunological condition
    * dermatological disorder
19. Exhibits clinically significant abnormal vital signs at screening.
20. Has one or more screening clinical laboratory test values outside the reference range that, in the opinion of the Investigator, are clinically significant, or any of the following:

    * 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.
21. Has any of the following cardiology findings at screening:

    * 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.
22. Has any disease or medication that could, in the Investigator's opinion, interfere with the assessments of safety, tolerability, or efficacy, or interfere with study conduct or interpretation of results.
23. Evidence of infection with hepatitis B or C, or human immunodeficiency virus (HIV)-1 or HIV-2, as determined by results of testing at screening.
24. Lost or donated more than 450 mL of blood during the 30 days prior to screening.
25. Use of any investigational drug or prohibited concomitant medications including known CYP1A2 substrates (e.g., theophylline, melatonin) within 30 days or 5 half-lives prior to Baseline Visit (Day 1) (whichever is longer) during the screening period or anticipated for the duration of the study.
26. History of unexplained loss of consciousness, unexplained syncope, unexplained irregular heartbeats or palpitations or near drowning with hospital admission.
27. Has attempted suicide within the 6 months prior to screening, or is at significant risk of suicide, either in the opinion of the Investigator or defined as a "yes" to suicidal ideation questions 4 or 5 or answering "yes" to suicidal behavior on the Columbia Suicide Severity Rating Scale (C-SSRS) within the 6 months prior to screening.
28. In the Investigator's opinion, is unlikely to comply with the protocol or is unsuitable for any other reason.