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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.
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. Placebos will be pooled and regarded as a comparative cohort for safety.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Multiple Ascending Doses of AL001 vs. Placebo - Cohort 1 | Experimental | 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) |
|
| Multiple Ascending Doses of AL001 vs. Placebo - Cohorts 2a | Experimental | The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated. Cohort 2a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults). Per randomization, there will be 6 active and 2 placebo subjects in each cohort: • Cohort 2a: 100% 450 mg lithium carbonate equivalent of AL001 (3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID). |
|
| Multiple Ascending Doses of AL001 vs. Placebo - Cohort 3a | Experimental | 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) |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| AL001 | Drug | a crystal engineered lithium-salicylate-proline lithium delivery product |
|
| 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)
For all analyses, placebo-treated subjects from each Cohort were combined (pooled) to provide a composite placebo group for all comparisons. Adverse event profiles for all treated subjects were benign as were placebo-treated subjects. No further statistical analyses were therefore appropriate. | 42 days with a 14-day treatment period |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Tolerated Dose of AL001 (Lithium Component) in All Subjects Treated With AL001 | To characterize the MTD of AL001 in all subjects treated with AL001: • Proportion of subjects in each Cohort with plasma trough measurements of lithium > 1.0 mEq/L. Subjects above these values invoke stopping rules for subsequent cohort enrollment. | 42 days with a 14-day treatment period |
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Inclusion Criteria (Alzheimer's Patients):
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:
Systemic related exclusions:
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):
Exclusion criteria (Healthy Subjects)
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| Name | Affiliation | Role |
|---|---|---|
| Eric Sicard, MD | Alzamend | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CenExel iResearch, LLC | Decatur | Georgia | 30030 | United States | ||
| Altasciences |
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There were no pre-specified comparisons between healthy controls and AD patients.
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| ID | Title | Description |
|---|---|---|
| FG000 | Multiple Ascending Doses of AL001 - Cohort 1 | AD-only participants (no normal healthy subjects) were randomized to receive AL001. When adequate safety data were available, a review was done for all participants to make a dose-escalation or dose and/or regimen modification decision. This was repeated for each cohort. A total of 8 cohorts received 5 different dose levels of AL001 in multiple ascending doses under fasted conditions up to tolerability/safety limits. Cohort 1 included 6 AD subjects only (7 were randomized because 1 subject voluntarily withdrew before dosing); 6 active AD subjects (as per randomization code) received 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) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Nov 28, 2022 | Jan 6, 2025 |
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Multi-center, placebo-controlled, double-blind, randomized, multiple ascending dose clinical trial to determine the safety and maximum tolerated dose of AL001.
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double-blind
|
| Multiple Ascending Doses of AL001 vs. Placebo - Cohort 4a | Experimental | The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated. Cohort 4a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults). Per randomization, there will be 6 active and 2 placebo subjects in each cohort: • Cohort 4a: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID) |
|
| Multiple Ascending Doses of AL001 vs. Placebo - Cohort 5a | Experimental | The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated. Cohort 5a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults). Per randomization, there will be 6 active and 2 placebo subjects in each cohort: • Cohort 5a: 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) |
|
| Multiple Ascending Doses of AL001 vs. Placebo - Cohorts 2b | Experimental | The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated. Cohort 2b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort: • Cohort 2b: 100% 450 mg lithium carbonate equivalent of AL001 (3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID). |
|
| Multiple Ascending Doses of AL001 vs. Placebo - Cohort 3b | Experimental | The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated. Cohort 3b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort: • Cohort 3b: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID) |
|
| Multiple Ascending Doses of AL001 vs. Placebo - Cohort 4b | Experimental | The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated. Cohort 4b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort: • Cohort 4b: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID) |
|
| Multiple Ascending Doses of AL001 vs. Placebo - Cohort 5b | Experimental | The data from the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated. Cohort 5b (8 AD subjects). Per randomization, there will be 6 active and 2 placebo subjects in each cohort: • Cohort 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). |
|
|
| Placebo | Other | matching placebo formulation |
|
| Maximum Tolerated Dose of AL001 (Salicylate Component) in All AL001-treated Subjects | To characterize the MTD of AL001 in all subjects: • Proportion of all subjects with plasma maximum concentration (Cmax) measurements for salicylate > 30 mg/dL | 42 days with a 14-day treatment period |
| Mount Royal |
| Quebec |
| H3P 3P1 |
| Canada |
| FG001 | Multiple Ascending Doses of AL001 - Cohort 2a | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 2a (6 healthy subjects - 3 non-elderly adults and 3 elderly adults). Blinded results from Cohort 2a were reviewed by the safety review committee before Cohort 2b was randomized. Per randomization, there were 6 active subjects in each cohort: • Cohort 2a: 100% 450 mg lithium carbonate equivalent of AL001 (3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID). AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| FG002 | Multiple Ascending Doses of AL001 - Cohort 2b | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 2b (6 AD subjects). Blinded results from Cohort 2a were reviewed by the safety review committee before Cohort 2b was randomized. Per randomization, there were 6 active subjects in each cohort: • Cohort 2b: 100% 450 mg lithium carbonate equivalent of AL001 (3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID). AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| FG003 | Multiple Ascending Doses of AL001 - Cohort 3a | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 3a (6 healthy subjects - 3 non-elderly adults and 3 elderly adults). Blinded results from Cohort 3a were reviewed by the safety review committee before Cohort 3b was randomized. Per randomization, there were 6 active subjects in each cohort: • Cohort 3a: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| FG004 | Multiple Ascending Doses of AL001 - Cohort 3b | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 3b (6 AD subjects). Blinded results from Cohort 3a were reviewed by the safety review committee before Cohort 3b was randomized. Per randomization, there were 6 active subjects in each cohort: • Cohort 3b: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| FG005 | Multiple Ascending Doses of AL001 - Cohort 4a | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 4a (6 healthy subjects - 3 non-elderly adults and 3 elderly adults). Blinded results from Cohort 4a were reviewed by the safety review committee before Cohort 4b was randomized. Per randomization, there were 6 active subjects in each cohort: • Cohort 4a: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| FG006 | Multiple Ascending Doses of AL001 - Cohort 4b | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 4b (6 AD subjects). Blinded results from Cohort 4a were reviewed by the safety review committee before Cohort 4b was randomized. Per randomization, there were 6 active subjects in each cohort: • Cohort 4b: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| FG007 | Multiple Ascending Doses of AL001 - Cohort 5a | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 5 was planned to be divided into 2 sub-cohorts: Cohort 5a (6 healthy subjects - 3 non-elderly adults and 3 elderly adults) and Cohort 5b (8 AD subjects). Per randomization, there were 6 active normal healthy subjects in cohort 5a. Stopping rules were invoked by the Safety Committee due to the pharmacokinetic results of Cohort 5a. The Stopping Rules were not invoked due to any adverse event. The stopping criteria were modest increases in plasma levels of lithium and salicylate above what is reported in the literature as the maximum therapeutic range concentrations. • Cohort 5a: 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) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| FG008 | Multiple Ascending Doses of AL001 - Cohort 5b | Subjects for Cohort 5b (6 AD subjects) were not enrolled because the Safety Committee invoked study stopping rules. Per randomization, there were 6 active normal healthy subjects in cohort 5a. Stopping rules were invoked by the Safety Committee due to the pharmacokinetic results of Cohort 5a. The Stopping Rules were not invoked due to any adverse event. The stopping criteria were modest increases in plasma levels of lithium and salicylate above what is reported in the literature as the maximum therapeutic range concentrations. • Cohort 5b was not dosed. Subjects would have been dosed at 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) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| FG009 | Combined Placebo Group | 2 subjects were randomized to receive matching placebo (no active drug) concurrently with each of the 8 treatment cohorts. A total of 16 subjects receiving placebo were combined in 1 group. |
| COMPLETED |
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| NOT COMPLETED |
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Cohort 1 (AD subject), n=6 randomized to AL001(1 withdrawal before dosing). Cohort 2a (healthy volunteers [HV]): n=6 rand. to AL001. Cohort 2b (AD): n=6 rand. to AL001.
Cohort 3a (HV): n=6 rand. to AL001. Cohort 3b (AD): n=6 rand. to AL001. Cohort 4a (HV): n=6 rand. to AL001. Cohort 4b (AD): n=6 rand. to AL001. Cohort 5 (HV), n=6 rand. to AL001. Combined Placebo Group, n=16.
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| ID | Title | Description |
|---|---|---|
| BG000 | Multiple Ascending Doses of AL001- Cohort 1 (1890 mg AL001/d, 630mg TID ×14 Days) | AD-only participants (no normal healthy subjects) were randomized to receive AL001. When adequate safety data were available, a review was done for all participants to make a dose-escalation or dose and/or regimen modification decision. This was repeated for each cohort. A total of 8 cohorts received 5 different dose levels of AL001 in multiple ascending doses under fasted conditions up to tolerability/safety limits. Cohort 1 included 6 AD subjects only (7 were randomized because 1 subject voluntarily withdrew before dosing); 6 active AD subjects (as per randomization code) received the following treatment: • 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) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| BG001 | Multiple Ascending Doses of AL001 - Cohort 2a (3150 mg AL001/d, 1050mg TID × 14 Days) | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 2 was divided into 2 sub-cohorts: Cohort 2a (6 healthy subjects - 3 non-elderly adults and 3 elderly adults) and Cohort 2b (6 AD subjects). Blinded results from Cohort 2a were reviewed by the safety review committee before Cohort 2b was randomized. Per randomization, there were 6 active subjects in each cohort: • Cohort 2a: 100% 450 mg lithium carbonate equivalent of AL001 (3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID). AL001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| BG002 | Multiple Ascending Doses of AL001 - Cohort 2b (3150 mg AL001/d, 1050mg TID × 14 Days) | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 2 was divided into 2 sub-cohorts: Cohort 2a (6 healthy subjects - 3 non-elderly adults and 3 elderly adults) and Cohort 2b (8 AD subjects). Blinded results from Cohort 2a were reviewed by the safety review committee before Cohort 2b was randomized. Per randomization, there were 6 active subjects in each cohort: • Cohort 2b: 100% 450 mg lithium carbonate equivalent of AL001 (3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID). AL001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| BG003 | Multiple Ascending Doses of AL001 - Cohort 3a (4410 mg AL001/d, 1470mg TID × 14 Days) | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 3 was divided into 2 sub-cohorts: Cohort 3a (6 healthy subjects - 3 non-elderly adults and 3 elderly adults) and Cohort 3b (6 AD subjects). Blinded results from Cohort 3a were reviewed by the safety review committee before Cohort 3b was randomized. Per randomization, there were 6 active subjects in each cohort: • Cohort 3a: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| BG004 | Multiple Ascending Doses of AL001 - Cohort 3b (4410 mg AL001/d, 1470mg TID × 14 Days) | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 3 was divided into 2 sub-cohorts: Cohort 3a (6 healthy subjects - 3 non-elderly adults and 3 elderly adults) and Cohort 3b (6 AD subjects). Blinded results from Cohort 3a were reviewed by the safety review committee before Cohort 3b was randomized. Per randomization, there were 6 active subjects in each cohort: • Cohort 3b: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| BG005 | Multiple Ascending Doses of AL001 - Cohort 4a (5040 mg AL001/d, 1680mg TID × 14 Days) | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 4 was divided into 2 sub-cohorts: Cohort 4a (6 healthy subjects - 3 non-elderly adults and 3 elderly adults) and Cohort 4b (6 AD subjects). Blinded results from Cohort 4a were reviewed by the safety review committee before Cohort 4b was randomized. Per randomization, there were 6 active subjects in each cohort: • Cohort 4a: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| BG006 | Multiple Ascending Doses of AL001 - Cohort 4b (5040 mg AL001/d, 1680mg TID × 14 Days) | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 4 was divided into 2 sub-cohorts: Cohort 4a (6 healthy subjects - 3 non-elderly adults and 3 elderly adults) and Cohort 4b (6 AD subjects). Blinded results from Cohort 4a were reviewed by the safety review committee before Cohort 4b was randomized. Per randomization, there were 6 active subjects in each cohort: • Cohort 4b: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| BG007 | Multiple Ascending Doses of AL001 - Cohort 5a (6300 mg AL001/d, 2100mg TID × 14 Days) | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 5 was planned to be divided into 2 sub-cohorts: Cohort 5a (6 healthy subjects - 3 non-elderly adults and 3 elderly adults) and Cohort 5b (6 AD subjects). Per randomization, there were 6 active normal healthy subjects in cohort 5a. Stopping rules were invoked by the Safety Committee due to the pharmacokinetic results of Cohort 5a. The Stopping Rules were not invoked due to any adverse event. The stopping criteria were modest increases in plasma levels of lithium and salicylate above what is reported in the literature as the maximum therapeutic range concentrations. • Cohort 5a: 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) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| BG008 | Multiple Ascending Doses of AL001 - Cohort 5b (6300 mg AL001/d, 2100mg TID × 14 Days) | Subjects for Cohort 5b (6 AD subjects) were not enrolled because the Safety Committee invoked study stopping rules due to the pharmacokinetic results of Cohort 5a. The Stopping Rules were not invoked due to any adverse event. The stopping criteria were modest increases in plasma levels of lithium and salicylate above what is reported in the literature as the maximum therapeutic range concentrations. • Cohort 5b was not dosed. Subjects would have been dosed at 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) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product. |
| BG009 | Combined Placebo Group | 2 subjects were randomized to receive matching placebo (no active drug) concurrently with each of the 8 treatment cohorts. A total of 16 subjects receiving placebo were combined in 1 group. |
| BG010 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Mean | Full Range | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Ratio of Plasma Lithium trough >1.0mEq/L or plasma salicylate peak concentrations >30mg/dL | Number | ratio |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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)
For all analyses, placebo-treated subjects from each Cohort were combined (pooled) to provide a composite placebo group for all comparisons. Adverse event profiles for all treated subjects were benign as were placebo-treated subjects. No further statistical analyses were therefore appropriate. | All subjects in the Randomized Analysis Set who received any dose of the study drug. This analysis set was used for all safety analyses. | Posted | Count of Participants | Participants | 42 days with a 14-day treatment period |
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| Secondary | Maximum Tolerated Dose of AL001 (Lithium Component) in All Subjects Treated With AL001 | To characterize the MTD of AL001 in all subjects treated with AL001: • Proportion of subjects in each Cohort with plasma trough measurements of lithium > 1.0 mEq/L. Subjects above these values invoke stopping rules for subsequent cohort enrollment. | All subjects in the Safety Analysis Set who received AL001 and had a trough measurement for lithium. | Posted | Number | Proportion of Subjects | 42 days with a 14-day treatment period |
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| Secondary | Maximum Tolerated Dose of AL001 (Salicylate Component) in All AL001-treated Subjects | To characterize the MTD of AL001 in all subjects: • Proportion of all subjects with plasma maximum concentration (Cmax) measurements for salicylate > 30 mg/dL | All subjects in the Safety Analysis Set who received AL001 and had a Cmax measurement for salicylate. | Posted | Number | Proportion of Subjects | 42 days with a 14-day treatment period |
|
42 days with a 14 day treatment period per cohort (phone call follow-up on day 42 to confirm safety)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | AD in Cohort 1 | Subject w/AD randomized to 1890 mg AL001 daily ×14 days, given as 3 × 210 mg AL001 capsules TID. | 0 | 6 | 0 | 6 | 0 | 6 |
| EG001 | AD on Cohort 2 | Subject w/AD randomized to 3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID. | 0 | 6 | 0 | 6 | 0 | 6 |
| EG002 | AD in Cohort 3 | Subject w/AD randomized to 4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID. | 0 | 6 | 0 | 6 | 5 | 6 |
| EG003 | AD in Cohort 4 | Subject w/AD randomized to 5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID. | 0 | 6 | 0 | 6 | 5 | 6 |
| EG004 | Healthy Subjects in Cohort 2 | Healthy Subject randomized to 3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID. | 0 | 6 | 0 | 6 | 3 | 6 |
| EG005 | Healthy Subjects in Cohort 3 | Healthy Subject randomized to 4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID. | 0 | 6 | 0 | 6 | 5 | 6 |
| EG006 | Healthy Subjects in Cohort 4 | Healthy Subject randomized to 5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID. | 0 | 6 | 0 | 6 | 3 | 6 |
| EG007 | Healthy Subjects in Cohort 5 | Healthy Subject randomized to 6300 mg AL001 daily × 14 days - lithium dose equivalent to that used for bipolar/affective disorders, given as 10 × 210 mg AL001 capsules TID. | 0 | 6 | 0 | 6 | 5 | 6 |
| EG008 | AD Subjects on Placebo | Subjects w/AD randomized to Placebo across all Cohorts | 0 | 8 | 0 | 8 | 4 | 8 |
| EG009 | Healthy Subjects on Placebo | Healthy Subjects randomized to Placebo in all Cohorts | 0 | 8 | 0 | 8 | 5 | 8 |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal | Gastrointestinal disorders | MedDRA 25.0 | Systematic Assessment | Constipation, Abdominal discomfort/distention/pain, nausea, dyspepsia. |
|
| Nervous System | Nervous system disorders | MedDRA 25.0 | Systematic Assessment | Headache |
|
| Investigations | Investigations | MedDRA 25.0 | Systematic Assessment | Hepatic enzyme increased |
|
| Renal and Urinary | Renal and urinary disorders | MedDRA 25.0 | Systematic Assessment | Pollakisuria |
|
| Skin | Skin and subcutaneous tissue disorders | MedDRA 25.0 | Systematic Assessment | Hypopigmentation, Erythema |
|
| Procedural complications | Injury, poisoning and procedural complications | MedDRA 25.0 | Systematic Assessment | Procedural dizziness |
|
| Respiratory | Respiratory, thoracic and mediastinal disorders | MedDRA 25.0 | Systematic Assessment | Rhinorrhea |
|
| Psychiatric | Psychiatric disorders | MedDRA 25.0 | Systematic Assessment | Insomnia |
|
| Musculoskeletal | Musculoskeletal and connective tissue disorders | MedDRA 25.0 | Systematic Assessment | Myalgia |
|
| Ear Labyrinth | Ear and labyrinth disorders | MedDRA 25.0 | Systematic Assessment | Tinnitus |
|
| Endocrine | Endocrine disorders | MedDRA 25.0 | Systematic Assessment | Hypothyroidism |
|
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Eve Del Rio, MD, PhD | Alzamend Inc. | 9736993847 | Eve@RioPharma.com |
| Prot_002.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 5, 2023 | Jan 6, 2025 | SAP_003.pdf |
Not provided
| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D024801 | Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
Not provided
Not provided
| Male |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| OG003 | Multiple Ascending Doses of AL001 vs. Placebo - Cohort 3a | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 3 was divided into 2 sub-cohorts: Cohort 3a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults) and Cohort 3b (8 AD subjects). Blinded results from Cohort 3a were reviewed by the safety review committee before Cohort 3b was randomized. Per randomization, there were 6 active and 2 placebo subjects in each cohort: • Cohort 3a: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product Placebo: matching placebo formulation |
| OG004 | Multiple Ascending Doses of AL001 vs. Placebo - Cohort 3b | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 3 was divided into 2 sub-cohorts: Cohort 3a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults) and Cohort 3b (8 AD subjects). Blinded results from Cohort 3a were reviewed by the safety review committee before Cohort 3b was randomized. Per randomization, there were 6 active and 2 placebo subjects in each cohort: • Cohort 3b: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product Placebo: matching placebo formulation |
| OG005 | Multiple Ascending Doses of AL001 vs. Placebo - Cohort 4a | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 4 was divided into 2 sub-cohorts: Cohort 4a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults) and Cohort 4b (8 AD subjects). Blinded results from Cohort 4a were reviewed by the safety review committee before Cohort 4b was randomized. Per randomization, there were 6 active and 2 placebo subjects in each cohort: • Cohort 4a: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product Placebo: matching placebo formulation |
| OG006 | Multiple Ascending Doses of AL001 vs. Placebo - Cohort 4b | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 4 was divided into 2 sub-cohorts: Cohort 4a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults) and Cohort 4b (8 AD subjects). Blinded results from Cohort 4a were reviewed by the safety review committee before Cohort 4b was randomized. Per randomization, there were 6 active and 2 placebo subjects in each cohort: • Cohort 4b: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product Placebo: matching placebo formulation |
| OG007 | Multiple Ascending Doses of AL001 vs. Placebo - Cohort 5a | The data from the previous cohort were deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 5 was planned to be divided into 2 sub-cohorts: Cohort 5a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults) and Cohort 5b (8 AD subjects). Per randomization, there were 6 active and 2 placebo normal healthy subjects in cohort 5a. Stopping rules were invoked by the Safety Committee due to the pharmacokinetic results of Cohort 5a. The Stopping Rules were not invoked due to any adverse event. The stopping criteria were modest increases in plasma levels of lithium and salicylate above what is reported in the literature as the maximum therapeutic range concentrations. • Cohort 5a: 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). AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product Placebo: matching placebo formulation |
| OG008 | Multiple Ascending Doses of AL001 vs. Placebo - Cohort 5b | Subjects for Cohort 5b (8 AD subjects) were not enrolled because the Safety Committee invoked study stopping rules due to the pharmacokinetic results of Cohort 5a. The Stopping Rules were not invoked due to any adverse event. The stopping criteria were modest increases in plasma levels of lithium and salicylate above what is reported in the literature as the maximum therapeutic range concentrations. • Cohort 5b was not dosed. Subjects would have been dosed at 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) AL 001: a crystal engineered lithium-salicylate-proline lithium delivery product Placebo: matching placebo formulation. |
| OG009 | Multiple Ascending Doses of AL001 - Pooled Placebo Group | This is a Cohort which is a composite of all 16 placebo-treated participants derived from all recruited Cohorts. Placebo: matching placebo formulation |
| TEAEs that lead to premature discontinuation |
|
| Abnormal values for safety laboratory tests (change from baseline) |
|
| abnormal ECG parameters (change from baseline) |
|
| No Adverse Events observed |
|
| Multiple Ascending Doses of AL001 in AD Subjects - Cohort 2b |
Steady State Assessment for Trough Plasma Lithium Concentrations • Cohort 2b: 100% 450 mg lithium carbonate equivalent of AL001 (3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID). |
| OG003 | Multiple Ascending Doses of AL001 in Healthy Subjects - Cohort 3a | Steady State Assessment for Trough Plasma Lithium Concentrations • Cohort 3a: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID) |
| OG004 | Multiple Ascending Doses of AL001 in AD Subjects - Cohort 3b | Steady State Assessment for Trough Plasma Lithium Concentrations • Cohort 3b: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID) |
| OG005 | Multiple Ascending Doses of AL001 in Healthy Subjects - Cohort 4a | Steady State Assessment for Trough Plasma Lithium Concentrations • Cohort 4a: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID) |
| OG006 | Multiple Ascending Doses of AL001 in AD Subjects - Cohort 4b | Steady State Assessment for Trough Plasma Lithium Concentrations • Cohort 4b: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID) |
| OG007 | Multiple Ascending Doses of AL001 in Healthy Subjects - Cohort 5a | The data from the previous cohort had to be deemed safe before the next sequential cohort was enrolled and dosing initiated. Cohort 5 was planned to be divided into 2 sub-cohorts: Cohort 5a (8 healthy subjects - 4 non-elderly adults and 4 elderly adults) and Cohort 5b (8 AD subjects). Modestly higher than threshold lithium plasma concentrations were observed in Cohort 5a and can be expected to occur in AD subjects. It was decided to not run Cohort 5b. • Cohort 5a: 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) |
| OG008 | Multiple Ascending Doses of AL001 in AD Subjects - Cohort 5b | Cohort 5b was not dosed, because the Safety Committee invoked study stopping rules that were not due to AEs. It was decided to not run Cohort 5b. |
| OG009 | Multiple Ascending Doses of AL001 - Pooled Placebo Group | This is a Cohort which is a composite of all 16 placebo-treated participants derived from all recruited Cohorts. Placebo: matching placebo formulation |
|
|
| OG002 |
| Multiple Ascending Doses of AL001 in AD Subjects - Cohort 2b |
Steady State Assessment for Peak Plasma Salicylate Concentrations • Cohort 2b: 100% 450 mg lithium carbonate equivalent of AL001 (3150 mg AL001 daily × 14 days, given as 5 × 210 mg AL001 capsules TID). |
| OG003 | Multiple Ascending Doses of AL001 in Healthy Subjects - Cohort 3a | Steady State Assessment for Peak Plasma Salicylate Concentrations • Cohort 3a: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID) |
| OG004 | Multiple Ascending Doses of AL001 in AD Subjects - Cohort 3b | Steady State Assessment for Peak Plasma Salicylate Concentrations • Cohort 3b: 140% of 450 mg lithium carbonate equivalent of AL001 (4410 mg AL001 daily × 14 days, given as 7 × 210 mg AL001 capsules TID) |
| OG005 | Multiple Ascending Doses of AL001 in Healthy Subjects - Cohort 4a | Steady State Assessment for Peak Plasma Salicylate Concentrations • Cohort 4a: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID) |
| OG006 | Multiple Ascending Doses of AL001 in AD Subjects - Cohort 4b | Steady State Assessment for Peak Plasma Salicylate Concentrations • Cohort 4b: 160% of 450 mg lithium carbonate equivalent of AL001 (5040 mg AL001 daily × 14 days, given as 8 × 210 mg AL001 capsules TID) |
| OG007 | Multiple Ascending Doses of AL001 in Healthy Subjects - Cohort 5a | Steady State Assessment for Peak Plasma Salicylate Concentrations. Based on the data from Cohort 5a suggested the previous cohort must be deemed safe before the next sequential cohort may be enrolled and dosing initiated. It was decided by the safety committee based on stopping rules to not run Cohort 5b. • Cohort 5a: 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) |
| OG008 | Multiple Ascending Doses of AL001 - Pooled Placebo Group | This is a Cohort which is a composite of all 16 placebo-treated participants derived from all recruited Cohorts. Placebo: matching placebo formulation |
|
|