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

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

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.

Eligibility Criteria:
\*Please note, Inclusion/Exclusion Criterion "A" applies to subjects who completed Study 812P306 and enrolled in Study 812P311 on either the same day or up to 7 days after the end of Study 812P306. Inclusion/Exclusion Criterion "B" applies to subjects who completed Study 812P306, but enrolled in study 812P311 greater than 7 days after the end of study 812P306\*

Inclusion Criteria "A"

1. Is a male or female who completed Study 812P306 and opts/consents to participate in the study if approved by PI.
2. 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.
3. Is able to read and understand the Informed Consent Form (ICF).
4. Has signed the ICF.
5. Is willing and able to attend study appointments within specified time windows.
6. 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:

   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 their Visit 1).
7. Is a male who:

   1. 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
   2. Has been surgically sterilized prior to Visit 1.

Exclusion Criteria "A"

1. Is currently participating in another clinical trial other than Study 812P306.
2. 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 diagnosis with comorbidity/secondary diagnoses of major depression disorder (MDD), nicotine dependence, social anxiety disorder, generalized anxiety disorder, or phobias.
3. 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.
4. Current evidence of suicidality (suicidal thoughts or behaviors).
5. 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.
6. Has a positive result on urine drug screen at Visit 1.
7. Use of prohibited concomitant medications including known CYP1A2 substrates (e.g., theophylline, melatonin) at the Visit 1 for the duration of the study.
8. 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.
9. 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.
10. 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.
11. Any reason that, in the opinion of the Investigator, would prevent the subject from participating in the study.

Inclusion Criteria "B"

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 (BMI) Chart (18.0 to 35.0 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; de novo subjects).
8. Has an AISRS total score of ≥ 24 at the screening (Visit 'S').
9. Has a CGI-S score of ≥ 4 (mildly ill or worse) at the screening (Visit 'S').
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 at least 28 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 postmenopausal (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 Visit 1 (baseline) to ≥ 1 month after the last dose of SM; or
    2. Have been surgically sterilized prior to the Screening Visit.

Exclusion Criteria "B"

1. Is currently participating in another clinical trial or has participated in a clinical trial within 60 days prior screening, with the exception of Study 812P306.
2. 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.
3. 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.
4. Has a history of severe drug allergy or hypersensitivity, or known hypersensitivity, to the study medication.
5. Has a 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 Encephalopathy
6. 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.
7. Has any current psychiatric disorder (per 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, 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.
8. Has organic mental disorders, or mental disorders due to a general medical condition (per DSM-5 criteria).
9. 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.
10. 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 (Visit 'S') 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 Visit 1 within the allotted screening period (results must be received prior to Visit 1). 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 Visit 1.
11. Is a (known or self-identified) current habitual/chronic cannabis user (medicinal or recreational); or

    * Has a positive urine drug screen for cannabis at screening (Visit 'S') 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 (Visit 'S') and follow-up drug screen (Visit 1), 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 screening (Visit 'S') but who are not considered, per the Investigator's judgement, to be a habitual/chronic cannabis user may, with Sponsor approval, undergo an additional urine drug screen at least 4 weeks after the initial urine drug screen at Visit 1 prior to randomization. Subjects must agree to refrain from cannabis use throughout study.
12. Has treatment-resistant ADHD based on a history of receipt of \>2 approved ADHD medications that failed to adequately improve the subject's symptoms, with the exception of subjects who completed Study 812P306. A subject who is naïve to ADHD treatment is not excluded from study participation.
13. 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.
14. Has a 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.
15. 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
16. Exhibits clinically significant abnormal vital signs at screening (see Note below).
17. 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 (see Note below):

    * Serum creatinine \> 1.5 × the upper limit of normal (ULN);
    * Serum total bilirubin \> 1.5 × ULN;
    * Serum alanine aminotransferase or aspartate aminotransferase \> 2 × ULN.
18. Has any of the following cardiology findings at screening (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.
19. 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.
20. 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.
21. Lost or donated more than 450 mL of blood during the 30 days prior to screening.
22. Use of any investigational drug or prohibited concomitant medications including known CYP1A2 substrates (e.g., theophylline, melatonin) within 30 days or 5 halflives prior to Visit 1 (baseline) (whichever is longer) during the screening period or anticipated for the duration of the study.
23. History of unexplained loss of consciousness, unexplained syncope, unexplained irregular heartbeats or palpitations or near drowning with hospital admission.
24. 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.
25. In the Investigator's opinion, is unlikely to comply with the protocol or is unsuitable for any other reason.