Multiple Ascending Dose Safety, Tolerability, PK Study of AL001 in Alzheimer's Disease Patients & Healthy Adult Subjects

Study Overview
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Brief Summary
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This is a Phase 1/2a, multi-center, placebo-controlled, double-blinded, randomized, multiple ascending dose (MAD) clinical trial to determine the safety and maximum tolerated dose of AL001. Up to 72 participants will be randomly assigned to receive study drug (active AL001) or placebo. The study consists of a 4-week screening period, a 14-day treatment period, and a 42-day follow-up period.

Detailed Description
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This is a Phase 1/2a, multi-center, placebo-controlled, double-blind, randomized, multiple ascending dose (MAD) clinical trial to determine the safety and maximum tolerated dose (MTD) of AL001, a crystal engineered lithium-salicylate-proline lithium delivery product that in nonclinical studies was shown to enhance and prolong the pharmacokinetic (PK) profile of lithium in the brain with enhanced efficacy potential in Alzheimer's models compared to lithium carbonate. A maximum of approximately 72 participants will be enrolled. Participants will be randomly assigned to receive study drug (active AL001) or placebo in a ratio of 6:2, respectively, with 8 patients in each dosing cohort. Cohorts 2a, 3a, 4a and 5a will involve 1:1 healthy non-elderly and elderly subjects; cohorts 1, 2b, 3b, 4b and 5b will involve Alzheimer's subjects. The study will consist of a screening period (Days -28 to -2), a 14-day treatment period, and a 42-day follow-up period.

Official Title
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A Multiple-dose, Steady-state, Double-blind, Ascending Dose, Safety, Tolerability, Pharmacokinetic Study of AL001 in Patients With Mild to Moderate Alzheimer's Disease and Healthy Adult Subjects (MAD Study)

Conditions
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Alzheimer's Disease, Healthy Non-elderly and Elderly Adults

Intervention / Treatment
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* Drug: AL 001
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Alzheimer's Patients): Mild to moderate Alzheimer's disease (reasonably good physical health per Investigator's review of medical & surgical history, physical examination incl. neurological examination, 12-lead ECG, vital signs, and clinical laboratory tests) Able to understand and provide written informed consent and able to understand and follow instructions during study as determined by Investigator Subject and caregiver (if accompanying subject on site) willing to follow study procedures, willing & able to adhere to study restrictions and to be confined at the clinical research center for 16 days Fluent in English speaking, reading, and writing (for cognitive testing) Availability of medical history to provide information about the cognitive and functional level of the participant and of a qualified source such as the caregiver willing and able to provide information about the cognitive and functional level of the participant Males (non-vasectomized and vasectomized) must agree to use barrier contraception during the study until after Study Day 42 Females must meet criteria if childbearing for contraception or be non-childbearing Clinical diagnosis of dementia (neurocognitive disorder) by a qualified clinician based on the DSM-V criteria Considered AD Stage 2, 3, or 4 based on the FDA classification Mini-Mental State Examination (MMSE) score between 16 and 26, inclusive, at Screening Negative result to COVID-19 test at Screening and admission (performed on Day -1) Exclusion Criteria (Alzheimer's Patients): Clinically significant abnormalities (as determined by investigator based on medical history, physical examination, vital sign measurements, ECG findings, or clinical laboratory findings) that may affect subject safety or successful study participation 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 judgment of the Investigator, would make the subject inappropriate for entry into this study 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 participant of the subject Any history or presence of gastrointestinal disease including chronic gastritis, hemorrhagic gastritis, peptic ulcers, duodenitis, diarrhea, or inflammatory bowel disease Any presence or history of acute or chronic liver diseases Any post-surgical or medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the study treatment 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 Psychiatric or neurological illnesses (other than Alzheimer's disease), e.g., schizophrenia or other psychotic syndromes, Parkinson's disease and related movement disorders, myasthenia gravis, and seizure disorder/history of seizure disorder and/or severe head trauma (other than a single childhood febrile seizure) Presence of depression, except for mild depression with no acute episodes and stable condition, as determined by the Investigator History of untreated thyroid dysfunction that may be independently associated with cognitive impairment Central nervous system-related exclusions: any medical condition that (per investigator's judgement) would affect subject safety and scientific integrity of the study, e.g., untreated hypothyroidism (TSH >10 mIU/L) or vitamin B12 deficiency (<300 pg/mL) which may contribute to cognitive impairment, delirium, non-AD dementia and other encephalopathies Hachinski scale score >4 or evidence of stroke within the past 5 years Systemic related exclusions: Active cancer (except squamous cell and basal skin cancers) requiring chemo- or radiation therapy Positive test results for HIV, HBV, and HCV (unless quantitative PCR negative for HCV) at Screening Uncontrolled hypertension with a sustained blood pressure >160/100 mmHg at Screening, check-in (Day -1), and prior to the first study drug administration Fever (body temperature >101.4°F [38.5°C]), acute upper respiratory, or any other infections at Screening, check-in (Day -1), and prior to the first study drug administration Any history of drug hypersensitivity, asthma (with the exception of childhood asthma), urticaria or other severe allergic diathesis History of adverse - or hypersensitivity reaction to lithium, aspirin, salicylate, L-proline, or any test article excipient Female who is breastfeeding, pregnant according to the pregnancy test at Screening or prior to the first study drug administration, or planning to become pregnant during the study Magnetic resonance imaging (MRI)-related exclusion criteria (such as intracranial mass, evidence or other anatomical findings that might affect safety or causes of cognitive impairment as assessed by a qualified neurologist) 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 Admitted alcohol abuse or history of alcohol use that may interfere with the subject's ability to comply with the protocol requirements or positive alcohol test at Screening or Day -1. More than moderate current alcohol consumption (subjects will be advised to consume no more than 2 units of alcohol/d and completely abstain from 72 hours prior to any visit. Treatment with haloperidol, antipsychotics, monoamine oxidase inhibitors, or neuromuscular blocking agents. An appropriate drug-free period will be required for washout, particularly for any especially long half-life drugs. Hyponatremia, defined as serum sodium laboratory value outside the standard reference range Suspected of having or at risk for Brugada Syndrome Prescribed or OTC use of a salicylate-containing product other than low-dose aspirin for cardioprotection (e.g., aspirin, bismuth sub-salicylate, salicylazosulfapyridine [sulfasalazine]) from 1 week before first dose to 1 week after last dosing; any other prescribed anticoagulant medication Consumption of poppy seeds or quinine (tonic water) 48 hours prior to Day 1 Aspirin/nasal polyposis/asthma syndrome 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. Inclusion criteria (Healthy Subjects): Non-elderly (≥18 and <65 years) and elderly (≥65 and ≤80 years) male and/or female adult subjects of any gender, race or ethnicity, determined to be generally in good physical health Willingness to use contraceptive methods as appropriate Exclusion criteria (Healthy Subjects) Clinically significant abnormalities detected by medical history, physical examination, vital sign measurements, ECG findings, or clinical laboratory findings or any historical or present condition/ treatment that may prevent successful or safe study completion, including substance abuse, kidney disease (estimated glomerular filtration rate [eGFR] <60 mL/minute/1.73 m2) or hyponatremia Use of any medication on a chronic basis except an oral contraceptive, with appropriate washout of prescription, OTC, vitamins and herbal supplements Female pregnant or planning to be pregnant, or breastfeeding

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multi-center, placebo-controlled, double-blind, randomized, multiple ascending dose clinical trial to determine the safety and maximum tolerated dose of AL001.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multiple Ascending Doses of AL001 vs. Placebo - Cohort 1<br>Participants will be randomized to receive AL001. When adequate safety data are available, a review will be done for all participants to make a dose-escalation or dose and/or regimen modification decision. This will be repeated for each cohort. A total of 9 cohorts will receive 5 different dose levels of AL001 in multiple ascending doses under fasted conditions up to tolerability/safety limits. Cohort 1 will include 8 AD subjects. In this cohort, 6 active and 2 placebo AD subjects (as per randomization code) will receive the following treatment or placebo: • Cohort 1: 60% of 450 mg lithium carbonate equivalent of AL001 (1890 mg AL001 daily ×14 days, given as 3 × 210 mg AL001 capsules TID) | Drug: AL 001<br>* a crystal engineered lithium-salicylate-proline lithium delivery product<br>Drug: Placebo<br>* matching placebo formulation<br>|
| Experimental: Multiple Ascending Doses of AL001 vs. Placebo - Cohort 2<br>The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated. Cohort 2 will be sub-divided into 2 cohorts: Cohort 2a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults) and Cohort 2b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort: • Cohort 2a and 2b: 100% 450 mg lithium carbonate equivalent of AL001 (3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID). | Drug: AL 001<br>* a crystal engineered lithium-salicylate-proline lithium delivery product<br>Drug: Placebo<br>* matching placebo formulation<br>|
| Experimental: Multiple Ascending Doses of AL001 vs. Placebo - Cohort 3<br>The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated. Cohort 3 will be sub-divided into 2 cohorts: Cohort 3a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults) and Cohort 3b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort: • Cohort 3a and 3b: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID) | Drug: AL 001<br>* a crystal engineered lithium-salicylate-proline lithium delivery product<br>Drug: Placebo<br>* matching placebo formulation<br>|
| Experimental: Multiple Ascending Doses of AL001 vs. Placebo - Cohort 4<br>The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated. Cohort 4 will be sub-divided into 2 cohorts: Cohort 4a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults) and Cohort 4b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort: • Cohort 4a and 4b: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID) | Drug: AL 001<br>* a crystal engineered lithium-salicylate-proline lithium delivery product<br>Drug: Placebo<br>* matching placebo formulation<br>|
| Experimental: Multiple Ascending Doses of AL001 vs. Placebo - Cohort 5<br>The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated. Cohort 5 will be sub-divided into 2 cohorts: Cohort 5a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults) and Cohort 5b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort: • Cohort 5a and 5b: 200% of 450 mg lithium carbonate equivalent of AL001 (6300 mg AL001 daily × 14 days - lithium dose equivalent to that used for bipolar/affective disorders, given as 10 × 210 mg AL001 capsules TID) | Drug: AL 001<br>* a crystal engineered lithium-salicylate-proline lithium delivery product<br>Drug: Placebo<br>* matching placebo formulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with serious AEs, TEAEs that lead to premature discontinuation, abnormal laboratory test results, abnormal ECG readings. | To evaluate the safety and tolerability of AL001 in healthy subjects and patients with adverse event(s), AD, descriptive statistics will be presented by treatment group for each cohort and overall, for the following: Proportion of participants with treatment-emergent adverse events (TEAEs) Proportion of participants with serious AEs Proportion of participants with TEAEs that lead to premature discontinuation Proportion of participants with abnormal values for each safety laboratory test (change from baseline) Proportion of participants with abnormal values for each Electrocardiogram (ECG) parameter (change from baseline in standard 12-lead ECG parameters) | a 14-day treatment period | 
| Number of participants with serious AEs, TEAEs that lead to premature discontinuation, abnormal laboratory test results, abnormal ECG readings. | To evaluate the safety and tolerability of AL001 in participants with adverse event(s), AD, descriptive statistics will be presented by treatment group for each cohort and overall, for the following: Proportion of participants with treatment-emergent adverse events (TEAEs) Proportion of participants with serious AEs Proportion of participants with TEAEs that lead to premature discontinuation Proportion of participants with abnormal values for each safety laboratory test (change from baseline) Proportion of participants with abnormal values for each ECG parameter (change from baseline in standard 12-lead ECG parameters) | a 42-day follow-up period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of AL001 in healthy subjects and patients with Alzheimers Disease | To characterize the MTD of AL001 in healthy subjects and in patients with AD, descriptive statistics will be presented by treatment group for each cohort and overall, for the following: Proportion of healthy non-elderly adult subjects and healthy elderly subjects/patients with plasma trough measurements of lithium > 1.0 and >1.2 mEq/L, respectively Proportion of healthy subjects and patients with plasma maximum concentration (Cmax) measurements for salicylate > 30 mg/dL | a 14-day treatment period |