Evaluation of Viloxazine and Its Metabolite 5-Hydroxy-viloxazine Glucuronide Into Breast Milk in Healthy Lactating Women

This is an open label, single treatment, multiple doses lactation study of SPN-812 in healthy lactating women. The study is designed to assess the excretion of viloxazine and its major metabolite 5-HVLX-gluc into breast milk following repeated administration of SPN-812 600 mg, QD.

This study is comprised of Screening, Inpatient Admission, Treatment Period and End of Study (EOS). The total duration of the study is up to 32 days including Screening up to 28 days and 4 days of Treatment Period. Subjects will remain in the inpatient unit for 5 days, including the day of admission to the inpatient unit (Day -1), 3 days of dosing SM (Days 1-3), and the day of discharge (Day 4).

This is an open label, single treatment, multiple doses, lactation study of SPN-812 at steady state in healthy lactating women. The study is designed to assess the excretion of viloxazine and its major metabolite 5-HVLX-gluc into breast milk following repeated administration of SPN-812 600 mg daily for 3 days. The study is designed to assess the excretion of viloxazine and its major metabolite 5-HVLX-gluc into breast milk following repeated administration of SPN-812 600 mg, QD.

This study is comprised of Screening, Inpatient Admission, Treatment Period, End of Study (EOS) with FU phone call. The total duration of the study is up to 32 days including Screening up to 28 days and 4 days of Treatment Period. Subjects will remain in the inpatient unit for 5 days, including the day of admission to the inpatient unit (Day -1), 3 days of dosing SM (Days 1-3), and the day of discharge (Day 4).

Subjects will complete the screening visit, after informed consent is obtained, within 28 days prior to dose initiation. Inclusion/exclusion criteria will be reviewed to determine the subject's eligibility at Screening. A lactation consultant will be available to provide lactation support to subjects once they are enrolled.

Since the mother's infant cannot receive breast milk for 7 consecutive days (Day-1 to Day 6), the mother will be reminded at Screening to make plans to have their infant fed 7 consecutive days with either (a) formula or (b) stored breast milk (e.g., breast milk pumped and stored in the freezer during the screening period between the screening visit and the day of admission to inpatient unit).

Subjects will be admitted to the inpatient unit on Day -1 to confirm eligibility. Subjects will receive 600 mg SPN-812 in the morning of Days 1, 2 and 3 after completion of safety assessments. SM should be administered at the same time in the morning (±30 min) of dosing days. Breast milk and blood sample for PK analysis will then be collected on Day 3 per schedule. Non-PK breast milk expressed on Days -1, 1, and 2 will be collected over the time intervals and these samples will not be analyzed for drug concentrations. The volume and the start and end times of the collection of each non-PK and PK breast milk sample will be recorded. The end of study (EOS) procedures will be conducted prior to discharge on Day 4 following the last breast milk and blood sample collection. If subject discontinues early, all EOS procedures will be conducted.

Eligibility Criteria:
Inclusion Criteria:

1. Healthy lactating females, 18 to 45 years of age, who are actively breastfeeding (including baby to breast, bottle feeding mother's expressed breast milk) and are at least 12 weeks postpartum of a healthy term newborn infant (no medical complications) and not more than 2 years postpartum. Lactation must be well established and the mother is exclusively breast feeding her baby (not providing supplemental formula) prior to the day of admission to inpatient unit.
2. Has a body mass index between 18 to 35 kg/m2, included.
3. Is considered medically healthy by the Investigator via assessment of physical examination (neurological examinations included), medical history, clinical laboratory tests, vital signs, Columbia-Suicide Severity Rating Scale (C-SSRS) and electrocardiogram (ECG).
4. Is willing to temporarily discontinue breastfeeding their infant and discard all their breast milk for 7 consecutive days, including day of admission to inpatient unit (Day -1), 3 consecutive days of dosing SM while in the inpatient unit (Days 1 to 3), and 3 consecutive days after last dose of SM (including day of discharge from the inpatient unit and 2 days at home; Days 4 to 6); and willing to store sufficient amount of breast milk (e.g., breast milk pumped and stored in freezer before the day of admission), and/or infant formula to feed infant during these 7 consecutive days.
5. Is either sexually inactive (abstinent) or, if sexually active, must agree to use/practice one of the following acceptable birth control methods beginning during the screening period prior to the first dose of SM, throughout the inpatient study, and for 3 days following the last dose of SM (Day 3):

   * intra-uterine contraceptive device;
   * 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;
   * is surgically sterile or male partner is surgically sterile;
   * established use of a patch, vaginal ring, oral, injected or implanted hormonal methods of contraception that can be used in lactating women;
   * Essure® procedure performed at least 6 months prior to Screening and had hysterosalpingogram after the Essure procedure to document tubal occlusion prior to screening.
6. Must not be in the process of weaning before admission and have maintained an adequate breast milk supply with regularly pumping or routine breastfeeding (e.g., pumping or feeding 3-4 times a day) at admission.
7. Is currently a non-smoker who has not used tobacco or nicotine-containing products (chewed or smoked) or replacement products, including electronic cigarettes, within 3 months prior to screening and a negative cotinine test result at Screening.
8. Agrees to use only the emollient or nipple cream recommended by the investigator for use during the sampling period, if needed.
9. Able to voluntarily provide written informed consent to participate in the study.
10. Able to understand and willing to comply with all study requirements.
11. Able and willing to swallow capsules whole, without crushing, chewing, or cutting.

Exclusion Criteria:

1. Participation in any other investigational study drug trial in which receipt of an investigational study drug within 30 days or 5 half-lives before Screening, whichever is longer.
2. Is unwilling or unable to comply with the Lifestyle guidelines presented in the protocol during the study period.
3. Has history or presence of clinically significant systemic disease (including psychological and psychiatric disorders).
4. Is currently using, or tests positive at Screening for cotinine, alcohol, or drugs (opiates, methadone, cocaine, amphetamines \[including ecstasy\], barbiturates, PCP, benzodiazepines, and THC/cannabis).
5. Is pregnant (has positive serum pregnancy test at Screening) or becomes pregnant during study (has positive urine pregnancy test).
6. Has history of breast implants, breast augmentation, or breast reduction surgery.
7. Has history of mastitis within 30 days, breast cancer and/or has had a mastectomy or lumpectomy with the exception of a benign fibroma or lipoma removal at the investigator's discretion; and/or a clinically significant abnormality observed in either breast during a clinical breast exam at Screening or Admission (Day -1).
8. Has a history of alcohol use disorder within 1 year of Screening; or assessed by the PI as having regularly consumed alcohol exceeding 14 units per week (1 unit equals 340 mL of beer, 115 mL of wine, or 43 mL of spirits) within 1 year of Screening.
9. Is using recreational or illicit drug(s) (e.g., cannabis /tetrahydrocannabinol (THC), opiates, methadone, cocaine, amphetamines \[including ecstasy\], barbiturates, and benzodiazepines) within 1 year of Screening.
10. Has clinically significant vital signs abnormalities (systolic blood pressure less than 90 or greater than 140 mmHg, diastolic blood pressure less than 60 or greater than 90 mmHg, or pulse rate (PR) less than 50 or greater than 100 bpm at Screening.
11. Has a clinical laboratory test values outside the reference range at Screening 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 (ALT) or aspartate aminotransferase (AST) \>2 times ULN
12. Has clinically significant ECG abnormalities at Screening, including:

    * PR interval \>220 ms
    * QRS interval \>130 ms
    * QTcF interval \>470 ms
13. Has any disease or medication that could, in the investigator's opinion, interfere with the assessments of safety, tolerability, or interfere with the conduct or interpretation of the study.
14. Has evidence of infection with hepatitis B and C, and human immunodeficiency virus HIV-1 and HIV-2, as determined by results of testing at Screening.
15. Has a condition or planned procedure that may interfere with the absorption, metabolism, or elimination of the study drug (e.g., cholecystectomy).
16. Is using prescription medication within 14 days prior to administration of SM or 5 half-lives, whichever is longer, with the exception of hormonal contraceptives.
17. Is using over-the-counter products (including vitamins, herbal products and natural food supplements) within 14 days prior to administration of SM or 5 half-lives, whichever is longer. Exceptions include postnatal vitamins, topical products without systemic absorption and acetaminophen (\< 2 g/day).
18. Has an allergy to viloxazine.
19. Has an Edinburgh Postnatal Depression Scale score \>13.
20. 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 12 months prior to screening).
21. In the investigator's opinion, is unlikely to comply with the protocol or is unsuitable for any other reason.