A Randomized, Balanced, Phase 1, Multiple-dose, Open-label, Two-treatment, Two-period, Two-sequence, Crossover, Relative Bioavailability Study to Investigate Lithium Brain/Plasma Pharmacokinetics and Safety of an AL001 Oral Capsule Compared to a Marketed Immediate-release Lithium Carbonate Capsule in Healthy Adult Subjects
A Randomized, Balanced, Phase 1, Multiple-dose, Open-label, Two-treatment, Two-period, Two-sequence, Crossover, Relative Bioavailability Study to Investigate Lithium Brain/Plasma Pharmacokinetics and Safety of an AL001 Oral Capsule Compared to a Marketed Immediate-release Lithium Carbonate Capsule in Healthy Adult Subjects
The goal of this clinical trial is to assess the safety and effects of a crystalized form of lithium, AL001, when compared to commonly used Lithium Carbonate in healthy volunteers. The main questions this study aims to answer are:
How safe and effective is AL001 when compared to Lithium Carbonate? How is AL001 broken down in the brain and body compared to Lithium Carbonate?
Participants will be asked to:
This study is researching the effects of a new type of crystalized lithium, AL001, on it's ability to reach the brain and have an effect. The investigators will be comparing this to a commonly used type of lithium, lithium carbonate. Investigators want to see if the crystalized lithium can have the same or better effect when compared to lithium carbonate. Past research has shown a greater effect within the body with crystalized lithium when compared to commonly used lithium.
This past research suggests that crystallized lithium may be more effective, potentially allowing for lower doses and fewer side effects. If successful, this new form of lithium could offer a new and safe treatment option for psychiatric and neurological disorders.
This study involves two, 2-week long overnight stays at the main campus of Massachusetts General Hospital. During these stays participants will receive lithium carbonate for one stay and the crystalized lithium for the other. There are frequent blood draws and brain MRI scans during two periods of the study to look at how the crystalized lithium is broken down in the body and to see how it reaches the brain. This study will compare AL001 to a study reference treatment of lithium carbonate. The majority of the blood draws and MRIs will occur over a 24 hour period during each 2-week long overnight stay at MGH.
Inclusion Criteria:
Healthy subjects ≥18 and <65 years old in reasonably good physical and psychological health as determined by the Investigator's review of medical and surgical history, physical examination (including neurological examination), 12-lead ECG, vital signs, and clinical laboratory tests.
Assessment of subject's mental health status will be conducted to avoid enrolling subjects who are on the verge of a manic or depressive episode. Affective stability, defined by a Young Mania Rating Scale (YMRS) rating of <8 and a Hamilton Depression Rating Scale (HRSD-17) rating of ≤7 at screening and baseline. Assessment of subject's suicidal ideation and behavior (SI/B) using the Columbia-Suicide Severity Rating Scale (C SSRS) will be conducted to avoid enrolling subjects with concerning results, defined as a lifetime history of a suicide attempt, past year level 4 or higher suicidal ideation on the C-SSRS, or past month suicidal ideation of any kind. The "Lifetime/Recent" version will be used at screening and the "Since Last Visit" version will be used subsequently.
Able to understand and follow instructions during the study as determined by the Investigator.
Willing to follow study procedures.
Willing and able to adhere to study restrictions and to be confined at the clinical research center per protocol requirements.
Any gender, race, or ethnicity.
Able to understand and provide written informed consent.
Males (non-vasectomized and vasectomized) must agree to use barrier contraception during the study until after Treatment Period 2 in-clinic follow-up visit on Day 23 (P2).
Females must meet one the of the following criteria:
Is of childbearing potential and agrees to use an acceptable contraceptive method. Acceptable contraceptive methods include:
Abstinence from heterosexual intercourse from the Screening visit through to at least 30 days after the last dose of the second study drug on Day 14 (P2).
One of the following highly-effective contraceptive methods, used from at least 28 days prior to the Screening visit through to at least 30 days after the last dose of the second study drug on Day 14 (P2).
One of the following double-barrier contraceptive methods, used from the Screening visit through to at least 30 days after the last dose of the second study drug on Day 14 (P2):
Or
Is of non-childbearing potential, defined as surgically sterile (i.e., has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation), or is in a postmenopausal state (i.e., at least 1 year without menses prior to the Screening visit).
Able to communicate in English, including speaking, reading, and writing.
Body mass index (BMI) within 18.0 to 30.0 kg/m2, inclusive, and body weight of at least 50 kg at the time of Screening.
ECG recording, after at least 5 minutes of rest in a supine position without clinically significant abnormalities as determined by the Investigator.
Exclusion Criteria:
Clinically significant abnormalities detected by medical history, physical examination, vital sign measurements, ECG findings, 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. Any history of drug hypersensitivity, asthma (with the exception of childhood asthma), urticaria or other severe allergic diathesis.
Presence or history of any disorder that may prevent the successful completion of the study.
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.
History of seizure disorder and/or severe head trauma (other than a single childhood febrile seizure).
History or presence of gastrointestinal disease including chronic gastritis, peptic ulcers, inflammatory bowel disease, hemorrhagic gastritis, or duodenitis.
History or presence of acute or chronic liver disease as determined by the Investigator.
Any surgical or medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the study treatments.
Any history of frequent headache or migraine.
Kidney disease (eGFR <60 mL/minute/1.73 m2).
Uncontrolled tachy/brady arrhythmias, atrial fibrillation, or coronary heart failure.
Systemic related exclusions:
Psychiatric or neurological illnesses (e.g., depression, schizophrenia or other psychotic syndromes, Parkinson's disease and related movement disorders, seizure disorder, and myasthenia gravis).
Treatment with haloperidol, antipsychotics, monoamine oxidase inhibitors, neuromuscular blocking agents. Subjects who have ever received immunosuppressant treatment (excluding topical or oral corticosteroids taken 1 and 5 years before Screening, respectively).
Current and during Lithium treatment hyponatremia, defined as serum sodium laboratory value outside the standard reference range.
The use of any medication on a chronic basis with the exception of hormonal contraceptives for females of childbearing potential. An appropriate drug free period will be required for prescription or over the counter (OTC) drugs to washout, particularly of any especially long half-life drugs (see exclusion criteria 16 and 17 below for relevant details).
The use of any medication (OTC, prescription medication, vitamins, and herbal supplements) within 14 days prior to the Screening visit and 14 days prior to Day -1 (P1) - or at least 6 times the respective elimination half-life rather than 14 days, whichever is longer - through the completion of the second study drug treatment on Day 14 (P2). Contraception may be continued. Acetaminophen may be concomitantly used at the discretion of the Investigator (up to 1000 mg TID). Non-medicated opthalmic products (for lubrication and comfort) may also be permitted at the discretion of the Investigator.
Prescribed or OTC use of a salicylate-containing product other than low dose aspirin for cardioprotection (e.g., aspirin, magnesium salicylate, bismuth sub-salicylate, salicylazosulfapyridine [sulfasalazine]) from 1 week before first dose of the first study drug on Day 1 (P1) to 1 week after last dosing of the second study drug on Day 14 (P2); any other prescribed anticoagulant medication. (Section 5.7.10).
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.
Aspirin/nasal polyposis/asthma syndrome.
Female who is breastfeeding.
Female who is pregnant according to the pregnancy test at Screening or prior to the first dosing of the first study drug on Day 1 (P1); female planning to become pregnant during the study.
History of adverse or hypersensitivity reaction to lithium, aspirin, salicylate, L-proline, or any investigational or reference article excipient.
Drug/alcohol abuse:
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-base basis following agreement by the Principal Investigator and the Sponsor.
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.
History of untreated thyroid dysfunction (due to potential lithium drug-disease interaction).
Screening MRI-related exclusion criteria: intracranial mass, evidence of other anatomical findings that might affect safety or causes of cognitive/behavioral impairment as assessed by a qualified neurologist. Subjects must not have any implantable medical device (e.g., aneurysm clip, vagus nerve stimulator, cardiac pacemaker) or be reliant on a non-removable medical device (e.g., insulin pump) unless that device is certified as MRI compatible. Known intolerability to MRI neuroimaging procedures.
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 or past month SI/B (C-SSRS) of any kind.