Multiple Ascending Dose Study of ALZ-801

Study Overview
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Brief Summary
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Phase I, single-center, double-blind, randomized, placebo-controlled, parallel-group study of the safety, tolerability, and pharmacokinetics (PK) in plasma and urine, of multiple ascending doses of ALZ-801 (capsule, Part 1; prototype tablet Part 2) and the primary metabolite in healthy male or female subjects.

Detailed Description
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The study was conducted in two parts: Part 1 Primary objective: To evaluate the safety, tolerability, and pharmacokinetics, of multiple doses of ALZ-801 capsule formulation in healthy elderly subjects. Methodology: Phase I, single center, in-patient and out-patient, double-blind, randomized, placebo-controlled, parallel-group study of the safety, tolerability and pharmacokinetics (PK) in plasma and urine of multiple ascending doses of ALZ-801 in healthy male or female subjects aged 50 to 75 years, inclusive. A total of 36 subjects were enrolled into 3 successive cohorts (A, B, C with 12 subjects per cohort) and randomized in a 3:1 ratio to receive treatment with ALZ-801 capsules (9 subjects) or placebo capsules (3 subjects) for 2 weeks. Progression to the next cohort was permitted after review of safety and available PK data suggested that it was safe to do so. Subjects were confined to the clinical unit for the first day of dosing (Day 1 and for Days 7 through 14). Subjects took investigational drug at home for Days 2 through 6). Cohorts A was dosed in the fasted state and evaluated 171 mg ALZ-801 or placebo QD for 1 day, followed by 171 mg ALZ-801 or placebo BID for 6 days and 256.5 mg or placebo QD for 7 days. Cohort B was dosed in the fasted state and evaluated 256.5 mg ALZ-801 or placebo QD for 1 day, followed by 256.5 mg ALZ-801 or placebo BID for 6 days and 340 mg or placebo QD for 7 days. Cohort C was dosed in the fed state and evaluated 256.5 mg ALZ-801 or placebo QD for 1 day, followed by 256.5 mg ALZ-801 or placebo BID for 6 days, then 340 mg or placebo BID for 6 days and 340 mg or placebo QD for 1 day. Part 2 Primary objective: To evaluate the safety, tolerability, and pharmacokinetics, of multiple doses of prototype ALZ-801 tablet formulation in healthy elderly subjects. Methodology: Phase I, single center, in-patient and out-patient, double-blind, randomized, placebo-controlled, parallel-group study of the safety, tolerability and pharmacokinetics (PK) in plasma and urine of multiple ascending doses of ALZ-801 in healthy male or female subjects aged 60 to 75 years, inclusive. A total of 12 subjects were enrolled into one cohort (D) and randomized in a 3:1 ratio to receive treatment with ALZ-801 tablets (9 subjects) or placebo capsules (3 subjects) for 1 week. Cohort D was dosed in the fed state and evaluated 265 mg ALZ-801 or placebo QD for 1 day, followed by 265 mg ALZ-801 prototype tablet or placebo BID for 5 days, 265 mg or placebo QD for 1 day. For all subjects in the study blood and urine samples for the determination of concentrations of ALZ-801, and its metabolites, were collected for up to 24 h after the first dose of medication on Day1; and for up to 48 hours after the last dose of medication on Day 7 (Cohort D) or Day 14 (Cohorts A, B and C). All subjects had blood samples and safety assessment at 72 and 96 hours after the final dose of medication. All subjects returned for a post treatment follow-up 7-10 days after the last dose of study medication.

Official Title
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A Phase I, Single Centre, Double-Blind, Placebo-Controlled Study of the Safety, Tolerability and Pharmacokinetics in Plasma and Urine of Multiple Ascending Doses of ALZ-801 in Healthy Elderly Subjects

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: ALZ-801 or matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males, and females Age: 50-75 years, Part 1; 60-75 years Part 2 Females must be of non-childbearing potential Body Mass Index 18-35 kg/m squared; Vital signs normal for age: BP 90-160/40-90 mmHg; HR 50 to 90 bpm) No clinically significant electrocardiogram readings Exclusion Criteria: Body weight < 50 kg History of any drug or alcohol abuse in the past 2 years Subjects known to have a creatinine clearance of <60 mL/min Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results History of clinically significant cardiovascular, pulmonary, chronic respiratory, renal, hepatic, GI, immunologic, endocrine, neurologic, psychiatric or thromboembolic disease History of metabolic disturbances;

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 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: Sequential Assignment
Interventional Model Description: double blind, placebo controlled, matching placebo
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A Capsule - Fasted<br>ALZ-801 171 mg or matching placebo once daily Day 1, ALZ-801 171 mg or matching placebo twice daily Days 2-7, ALZ-801 256.5 mg or matching placebo once daily Days 8-14 | Drug: ALZ-801 or matching placebo<br> <br> |
| Experimental: Cohort B Capsule - Fasted<br>ALZ-801 256.5 mg or matching placebo once daily Day 1, ALZ-801 256.5 or matching placebo mg twice daily Days 2-7, ALZ-801 340 mg or matching placebo once daily Days 8-14 | Drug: ALZ-801 or matching placebo<br> <br> |
| Experimental: Cohort C Capsule - Fed<br>ALZ-801 256.5 mg or matching placebo once daily Day 1, ALZ-801 256.5 mg or matching placebo twice daily Days 2-7, ALZ-801 340 mg or matching placebo twice daily Days 8-13, ALZ-801 340 mg or matching placebo once daily Day 14 | Drug: ALZ-801 or matching placebo<br> <br> |
| Experimental: Cohort D Tablet - Fed<br>ALZ-801 265 mg or matching placebo once daily Day 1, ALZ-801 265 mg or matching placebo twice daily Days 2-6, ALZ-801 265 mg or matching placebo once daily Day 7 | Drug: ALZ-801 or matching placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events as a measure of safety and tolerability | Incidence and nature of adverse events (AEs) and serious adverse events (SAEs). Assessments reported as AEs or SAEs include physical examination, clinical laboratory tests, and 12-lead electrocardiogram (ECG) findings | Duration of dosing: 14 days for Part 1; 7 days for Part 2 | 
| Cmax for ALZ-801 and tramiprosate | Maximum concentration after dosing [Cmax] measured as ng/ml | Days 1, 7 and 14 | 
| Tmax for ALZ-801 and tramiprosate | Time to reach Cmax [Tmax] measured in hours (h) after dosing | Days 1, 7 and 14 | 
| AUC for ALZ-801 and tramiprosate | AUC from time zero to time t (AUCt) | Days 1, 7 and 14 | 
| t1/2 for ALZ-801 and tramiprosate | Elimination half-life (t1/2) measured in hours after dosing | Days 1, 7, 14 | 
| Renal clearance of ALZ-801 and tramiprosate | Clearance (CLr) measured in mL/min | Days 1, 7 and 14 |