Open-Label Study of SPN-812 Administered With Psychostimulants in Children and Adolescents With ADHD

This open label, flexible-dose study evaluating the safety and efficacy of SPN-812 administered with psychostimulants in children and adolescents (6 to 17 years of age) with Attention-Deficit/Hyperactivity Disorder (ADHD).

This is an open-label, multicenter, flexible-dose, safety study of SPN-812 in pediatric patients (6-17 years of age) diagnosed with ADHD, when administered with a FDA-approved medication (psychostimulant) in the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in pediatric subjects. Participants will be screened for eligibility for up to 4 weeks, and he/she will continue to take their prescribed psychostimulant ADHD medication during that time. Following the screening period, eligible subjects will receive SPN-812 with their current psychostimulant treatment for ADHD for 8 weeks. For the first 4 weeks of treatment subjects will take SPN-812 dose in the morning (AM dosing), and for the last 4 weeks of treatment, subjects will take SPN-812 dose in the evening (PM dosing). The total duration of the study between the screening visit and the end of the treatment period/end of study (EOS) visit is up to 12 weeks.

Eligibility Criteria:
Inclusion Criteria:

1. Is male or female, 6 to ≤17 years and 9 months of age at screening.
2. Parent(s)/legal guardian(s) is able to read and understand the Informed Consent Form (ICF).
3. Written informed consent obtained by parent(s)/legal guardian(s) and informed assent obtained from the subject, if applicable.
4. Subject and parent(s)/legal guardian(s) are willing and able to comply with all of the procedures and requirements defined in the protocol, including parents(s)/legal guardian(s) oversight of morning and evening dosing of the SPN-812 and recording a daily medication/dosing diary for psychostimulant and/or SPN-812 during the study.
5. Has lived with the same parent(s)/legal guardian(s) at same residence for at least the last 6 months prior to screening.
6. Has a primary diagnosis of ADHD (inattentive, hyperactive, or combined presentation) confirmed with the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) at screening.
7. Is currently on a single, stable psychostimulant regimen (see Inclusion Criterion 8 for definition) for treatment of ADHD with a partial, but inadequate efficacy response to at least 2 weeks of treatment with a psychostimulant (methylphenidate or amphetamine) prior to screening. An inadequate response is defined as an investigator-rated ADHD-RS-5 Total score ≥24 and a CGI-S score ≥3 (mildly ill or worse) at Screening and Baseline. Subjects taking additional medication for ADHD (e.g., nonstimulant) are excluded.
8. Is currently and expecting to continue and remain on a stable psychostimulant regimen throughout the study. A stable stimulant regimen is defined as taking dose at least 5 days per week (morning), no significant change in dose or dosing frequency at least 2 weeks prior to baseline (Visit 2), and the investigator believes the subject's psychostimulant dose is optimized.
9. Is functioning at an age-appropriate level intellectually, as judged by the Investigator.
10. Is a child (6-11 years of age) with a body weight of at least 20 kg at screening or is an adolescent (12-17 years of age) with a body weight of at least 35 kg at screening.
11. Has a resting (sitting) blood pressure (BP) and resting pulse rate measurement within the 95th percentile for age, sex, and height.
12. Is considered medically healthy by the Investigator via assessment of physical examination, medical and psychiatric histories, clinical laboratory tests, vital signs, and electrocardiogram (ECG).
13. Females of childbearing potential (FOCP) must be either sexually inactive (abstinent) or, if sexually active, must agree to use/practice one of the following acceptable, highly effective contraceptive methods beginning/during the screening period prior to the first dose of SM and throughout the study:

    1. Simultaneous use of male condom and intra-uterine contraceptive device placed during screening period prior to first dose of SM
    2. Surgically sterile male partner (e.g., vasectomized partner is sole partner)
    3. Barrier method: condom with spermicidal foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
    4. Established use of oral, injected, or implanted hormonal methods of contraception

    With approval by the Investigator, subjects' parents or legal guardians may select abstinence as a form of birth control if deemed more appropriate. For the purposes of this study, all females are considered to be of childbearing potential unless they are confirmed by the Investigator to be premenarchal, biologically sterile, or surgically sterile (e.g., hysterectomy with bilateral oophorectomy, tubal ligation).
14. Adolescent males, if sexually active, 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. Is currently participating in another clinical trial or has participated in a clinical trial within 60 days prior to screening.
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. Is a female subject who is pregnant, lactating and/or sexually active and not agreeing to use one of the acceptable contraceptive methods throughout the study.
4. Has history of severe drug allergy or hypersensitivity, or known hypersensitivity, to the study medication (SPN-812).
5. 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;
   2. seizures, seizure disorder or seizure-like events;
   3. history of seizure disorder within the immediate family (siblings, parents); or
   4. encephalopathy

   Note: Febrile seizures are not exclusionary and will be assessed on a case-by-case basis. If for any reason the subject received medication for a febrile seizure or has a history of complex febrile seizures, this will be exclusionary.
6. Has current diagnosis or history of major psychiatric disorders or intellectual disabilities other than ADHD per DSM-5 criteria (including schizophrenia, schizoaffective disorder, bipolar disorder, borderline personality disorder, antisocial personality disorder, narcissistic personality disorder, post-traumatic stress disorder, obsessive-compulsive disorder, severe oppositional defiant disorder (ODD), conduct disorder, and disruptive mood dysregulation disorder, and autism spectrum disorders). The following is not exclusionary:

   1. a history of mild social anxiety disorder or generalized anxiety disorder according to DSM-5 criteria;
   2. a history of mild to moderate ODD according to DSM-5 criteria;
   3. a history of Major Depressive Disorder, if he/she has not experienced a major depressive disorder episode or required psychiatric counselling; or pharmacotherapy within the 6 months prior to screening
7. Has a known history of physical, sexual, or emotional abuse in the last year prior to screening.
8. 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.
9. Has a current diagnosis of drug abuse or dependence disorder within the 12 months prior to screening, has a history of drug abuse or dependence disorder or has an immediate family member living at study participant's' home who has current diagnosis drug abuse or dependence disorder (per DSM-5 criteria).
10. Evidence of suicidality (defined as either active suicidal plan/intent or active suicidal thoughts, or more than one lifetime suicide attempt) within the six months before Screening or at Screening.
11. Has positive findings on C-SSRS for suicidal ideation or behaviors at screening. 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 C-SSRS within the 6 months prior to screening.
12. Is currently using, or has a positive result on the urine drug screening for, drugs of abuse (alcohol, amphetamine, barbiturates, benzodiazepines, cannabis \[THC\], cocaine, cotinine, methadone, methamphetamine \[including ecstasy\], methylphenidate, phencyclidine, propoxyphene, and opiates) with the exception of the psychostimulant prescribed for the treatment of ADHD.
13. Is unable to discontinue all prohibited medication at least 7 days prior to baseline.
14. Has body mass index (BMI) greater than 95th percentile for her/his appropriate age and gender (per CDC's gender specific "BMI-for-age percentiles" charts).
15. Has a current diagnosis of significant systemic disease.
16. Has uncontrolled thyroid disorder defined as thyroid stimulating hormone ≤ 0.8 x the lower limit of normal or ≥ 1.25 x the upper limit of normal for the reference laboratory range.
17. Has resting (sitting) blood pressure and pulse rate greater than the 95th percentile for age and gender.
18. Has a known personal history, or presence, of structural cardiac abnormalities, cardiovascular or cerebrovascular disease, serious heart rhythm abnormalities, syncope, tachycardia, cardiac conduction problems (e.g., clinically significant heart block or QT interval prolongation: QTc \>0.44 seconds), exercise-related cardiac events including syncope and pre-syncope, or clinically significant bradycardia.
19. Has any clinically significant abnormal clinical laboratory test, urine test, electrocardiogram (ECG) result, vital signs or physical examination finding at screening that, in the opinion of the Investigator, would interfere with the safety of the subject
20. Has a concurrent chronic or acute illness (such as severe allergic rhinitis or an infectious process requiring antibiotics), disability, or other condition that might confound the results of safety assessments.
21. Has or has had one or more medical conditions considered clinically significant/relevant by the Investigator in the context of the study (e.g., cardiovascular disease, congestive heart failure, cardiac hypertrophy, arrhythmia, bradycardia \[pulse \< 70 bpm (6-11 years), pulse \< 60 bpm (12-17 years)\], tachycardia \[pulse \> 120 bpm (6-11 years); pulse \> 100 bpm (12-17 years)\], respiratory disease, hepatic impairment or renal insufficiency, metabolic disorder, endocrine disorder, gastrointestinal disorder, hematological disorder, infectious disorder, any clinically significant immunological condition, dermatological disorder.
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. Lost or donated more than 450 mL of blood during the 30 days prior to screening.
24. Use of any investigational drug or prohibited concomitant medications including known CYP1A2 substrates (e.g., theophylline, melatonin) within 28 days or 5 half-lives prior to Baseline Visit (Day 1) (whichever is longer) or anticipated for the duration of the study.
25. History of unexplained loss of consciousness, unexplained syncope, unexplained irregular heartbeats or palpitations or near drowning with hospital admission.
26. Has an allergy to applesauce and cannot swallow capsules whole.
27. In the Investigator's opinion, is unlikely to comply with the protocol or is unsuitable for any other reason.