A Study to Investigate Lithium Brain/Plasma Pharmacokinetics and Safety of an AL001 Oral Capsule Compared to a Marketed Immediate-release Lithium Carbonate Capsule in Subjects With Bipolar I Disorder

Exclusion Criteria

• •1. Clinically significant abnormalities detected by medical history, physical examination, vital sign measurements, ECG findings (including prolonged QT interval), or clinical laboratory findings (as determined by the Investigator) that may affect the safety or successful participation of the subject. Specifically, evidence of clinically significant hematological, renal, endocrine, pulmonary, cardiovascular, dermatologic, muscular, or allergic disease or disorder (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) that may affect the safety or successful participation of the subject.
• •2. Any history of drug hypersensitivity or asthma (with the exception of childhood asthma), urticaria or other severe allergic diathesis.
• •3. Presence or history of any disorder other than the diagnosis under study that may prevent the successful completion of the study.
• •4. Other severe acute, chronic, or historical medical or psychiatric condition or laboratory abnormality or social circumstance that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.
• •5. History of seizure disorder and/or severe head trauma (other than a single childhood febrile seizure).
• •6. History or presence of gastrointestinal disease including chronic gastritis, peptic ulcers, inflammatory bowel disease, hemorrhagic gastritis, or duodenitis.
• •7. History or presence of acute or chronic liver disease as determined by the Investigator.
• •8. Any surgical or medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the study treatments.
• •9. Any history of frequent headache or migraine.
• •10. Kidney disease (eGFR \< 60 mL/minute/1.73 m2).
• •11. Uncontrolled tachy/brady arrhythmias, atrial fibrillation, or coronary heart failure.
• •12. Systemic related exclusions:
• •1. Active cancer (except squamous cell and basal skin cancers) requiring chemo- or radiation therapy.
• •2. Positive test results for HIV, HBV, or HCV (unless quantitative PCR negative for HCV) at Screening.
• •3. Severe hepatic impairment (Child-Pugh Class C).
• •4. Uncontrolled hypertension with a sustained blood pressure \> 160/100 mmHg at Screening, or at check-in on Day -1 (P1).
• •5. Fever (body temperature \> 101.4°F \[38.5°C\]), acute upper respiratory, or any other infections at Screening, or at check-in on Day -1 (P1).
• •13. Psychiatric or neurological illnesses other than-and not associated with-bipolar I disorder (e.g., bipolar II disorder exclusively, schizophrenia or other psychotic syndromes, Parkinson's disease and related movement disorders, seizure disorder, and myasthenia gravis).
• •14. Treatment with haloperidol, antipsychotics (except stable regimens), monoamine oxidase inhibitors, neuromuscular blocking agents. Subjects who have ever received chronic immunosuppressant treatment (excluding topical or oral corticosteroids taken 1 year and 5 years before Screening, respectively).
• •15. Current and during lithium treatment hyponatremia, defined as serum sodium laboratory value outside the standard reference range.
• •16. The regular and long-term use of any medication, supplement, or OTC medication within 14 days prior to the Screening visit or at least 6 times the respective elimination half-life, whichever is longer, through the completion of the study on Day 42 (P2). EXCEPTIONS to this are as follows:
• •1. Hormonal contraceptives for females of childbearing potential.
• •2. Acetaminophen (up to 1000 mg TID) at the discretion of the Investigator.
• •3. Low-Dose aspirin for cardio protection.
• •4. Non-medicated ophthalmic products (for lubrication and comfort).
• •5. Clinically acceptable, stably dosed mood stabilizing medication regimen for \> 30 days prior to Screening visit, with no medication changes planned over the entire study period. See Section 6.3 for list of medications not allowed for mood stabilization purposes. Exceptions to this may be made on a case-by-case basis following agreement by the Investigator and the Sponsor.
• •6. PRN medications needed for treatment of AE's during the study at the joint discretion of the Investigator and the Sponsor, reviewed on a case-by-case basis.
• •17. Subjects treated with electroconvulsive therapy within 6 months prior to Screening visit.
• •18. Unwilling to refrain from consumption of poppy seeds or quinine (tonic water) 48 hours prior to check-in on Day -1 (P1) and throughout the course of the study.
• •19. Aspirin/nasal polyposis/asthma syndrome.
• •20. Female who is breastfeeding.
• •21. Female who is pregnant according to the pregnancy test at Screening or on Day -1 (P1); female planning to become pregnant during the study.
• •22. History of adverse or hypersensitivity reaction to lithium, aspirin, salicylate, L-proline, or any investigational or reference article excipient.
• •23. Drug/alcohol abuse:
• •1. History of drug abuse (barbiturate, amphetamine, benzodiazepine, cocaine, opiates and cannabis) within the last 12 months or a positive urine drug screen at Screening or Day -1 (P1).
• •2. Admitted alcohol abuse or history of alcohol use that may interfere with the subject's ability to comply with the protocol requirements or positive ethanol (alcohol) test at Screening or Day -1 (P1).
• •3. More than moderate current alcohol consumption. Subjects will be advised to consume no more than 2 units of alcohol per day and completely abstain from 72 hours prior to any study visit (1 unit is equal to approximately 10 g of pure alcohol, \[250 mL\] of beer \[5%\], 1 small glass \[100 mL\] of wine \[12%\], or 35 mL of spirits \[35%\]).
• •24. Demonstrating excess xanthine consumption (e.g., ingests more than 5 cups of coffee or equivalent per day). Also, subject is not willing to refrain from xanthine products for 48 hours prior to check-in on Day -1 (P1) until discharge from Period 2 treatment on Day 15 (P2). The subject is not willing to refrain from grapefruit, pomelo, Seville orange products or juice within 14 days prior to check-in on Day -1 (P1) until discharge from Period 2 treatment on Day 15 (P2). Exceptions may be made on a case-by-case basis following agreement by the Principal Investigator and the Sponsor.
• •25. Participation in a clinical trial and receipt of an investigational medication within 30 days or 5 half-lives (if known), whichever is greater, prior to the first dose of the current study drug.
• •26. History of untreated thyroid dysfunction (due to potential lithium drug-disease interaction).
• •28. Subjects with any past apparent suicide attempt or suicidal behavior, including those with a lifetime history of suicide attempt(s) or a past year level 4 or higher SI/B (C-SSRS) or past month SI/B (C-SSRS) of any kind.
• •29. Suspected of having or at risk for Brugada Syndrome.
• •30. Central nervous system-related exclusions: Any medical condition that in the Investigator's judgement could affect subject safety and scientific integrity of the study, e.g., untreated hypothyroidism (TSH \>10 mIU/L) or vitamin B12 deficiency (vitamin B12 \<300 pg/mL) which may contribute to cognitive impairment, delirium, dementia and other encephalopathies.