Open-label Long-Term Safety and Efficacy of SPN-812 (Viloxazine Extended-release Capsule) in Adults With ADHD
Condition: Attention-Deficit/Hyperactivity Disorder
MeSH terms: Hyperkinesis; Attention Deficit Disorder with Hyperactivity
Intervention: SPN-812
Intervention description: SPN-812 200 to 600 mg/day
Intervention MeSH terms: Viloxazine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: Single Group Assignment
Masking: None (Open Label)
Masking description: None (Open Label)
Enrollment: 159.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

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

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.