Safety, Tolerability, and Pharmacokinetic Study of EVP-6124 in Patients With Alzheimer's Disease

Study Overview
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Brief Summary
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This study is being conducted to determine the safety, tolerability, and pharmacokinetics (PK) of three different doses of an investigational medication, EVP-6124, in individuals with mild to moderate Alzheimer's disease who are also taking an Alzheimer's medication (AChEI [acetylcholinesterase inhibitor]: either donepezil or rivastigmine). In addition, PK of AChEI medications will be assessed. Cognitive function will be evaluated on an exploratory basis.

Detailed Description
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This is a randomized, double-blind, placebo-controlled, Phase 1b safety study of three dose levels of EVP-6124 in subjects with mild or moderate Alzheimer's disease and who are taking an AChEI medication (donepezil or rivastigmine). Study drug will be supplied as capsules and will be orally administered once daily for a total of 28 days. Eligible subjects will be admitted to an inpatient study unit on Day -2 (two days before the first dose of study drug is administered) and will remain confined to the inpatient study unit for a total of five days. Starting on Day 4, subjects will continue the study in the outpatient setting, with study visits on Days 7, 14, 21, and 28. Safety assessments, PK sampling, and cognitive testing will be performed inpatient and at each study visit.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Phase 1b Safety Study of Three Different Doses of an Alpha-7 Nicotinic Acetylcholine Receptor Agonist (EVP-6124) or Placebo in Patients With Mild to Moderate Probable Alzheimer's Disease

Conditions
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Alzheimer's Disease, Central Nervous System Diseases

Intervention / Treatment
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* Drug: EVP-6124 (0.1 mg/day)
* Drug: EVP-6124 (0.3 mg/day)
* Drug: EVP-6124 (1.0 mg/day)
* Drug: Comparator: Placebo
* Drug: Donepezil
* Drug: Rivastigmine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: male and post-menopausal or surgically sterile female pts 50-90 yrs old, who meet clinical criteria for probable Alzheimer's disease (Mini-Mental State Examination of 18-26; Hachinski Ischemic Score ≤4) must be taking donepezil or rivastigmine for at least 3 mos. Exclusion Criteria: Unstable medical condition that is clinically significant in the judgment of the investigator; major organ system dysfunction Untreated hypothyroidism Insufficiently controlled diabetes mellitus Diagnosis of major depression requiring antidepressant medications within the last 5 years Stroke within 6 months before screening, or concomitant with onset of dementia Certain concomitant medications

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EVP-6124 (0.1 mg/day)<br> | Drug: EVP-6124 (0.1 mg/day)<br>* EVP-6124 was administered as one 0.1 mg capsule per day for 28 days.<br>Drug: Donepezil<br>* Concomitant therapy with donepezil at a stable dose, taken daily at the same time or immediately after the assigned EVP-6124 dose. Patients must have been taking concomitant therapy for at least 3 months prior to enrollment to be eligible for the study.<br>Drug: Rivastigmine<br>* Concomitant therapy with rivastigmine at a stable dose, taken daily at the same time or immediately after the assigned EVP-6124 dose. Patients must have been taking concomitant therapy for at least 3 months prior to enrollment to be eligible for the study.<br>|
| Experimental: EVP-6124 (0.3 mg/day)<br> | Drug: EVP-6124 (0.3 mg/day)<br>* EVP-6124 was administered as one 0.3 mg capsule every day for 28 days.<br>Drug: Donepezil<br>* Concomitant therapy with donepezil at a stable dose, taken daily at the same time or immediately after the assigned EVP-6124 dose. Patients must have been taking concomitant therapy for at least 3 months prior to enrollment to be eligible for the study.<br>Drug: Rivastigmine<br>* Concomitant therapy with rivastigmine at a stable dose, taken daily at the same time or immediately after the assigned EVP-6124 dose. Patients must have been taking concomitant therapy for at least 3 months prior to enrollment to be eligible for the study.<br>|
| Experimental: EVP-6124 (1.0 mg/day)<br> | Drug: EVP-6124 (1.0 mg/day)<br>* EVP-6124 was administered as one 1.0 mg capsule every day for 28 days.<br>Drug: Donepezil<br>* Concomitant therapy with donepezil at a stable dose, taken daily at the same time or immediately after the assigned EVP-6124 dose. Patients must have been taking concomitant therapy for at least 3 months prior to enrollment to be eligible for the study.<br>Drug: Rivastigmine<br>* Concomitant therapy with rivastigmine at a stable dose, taken daily at the same time or immediately after the assigned EVP-6124 dose. Patients must have been taking concomitant therapy for at least 3 months prior to enrollment to be eligible for the study.<br>|
| Placebo Comparator: Placebo<br> | Drug: Comparator: Placebo<br>* Matching placebo was administered as one capsule per day for 28 days.<br>Drug: Donepezil<br>* Concomitant therapy with donepezil at a stable dose, taken daily at the same time or immediately after the assigned EVP-6124 dose. Patients must have been taking concomitant therapy for at least 3 months prior to enrollment to be eligible for the study.<br>Drug: Rivastigmine<br>* Concomitant therapy with rivastigmine at a stable dose, taken daily at the same time or immediately after the assigned EVP-6124 dose. Patients must have been taking concomitant therapy for at least 3 months prior to enrollment to be eligible for the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | All adverse experiences spontaneously reported by subject and/or observed by investigator and repeated clinical evaluation of physical examinations, vital signs, 12-lead ECG (electrocardiogram), ambulatory ECG, and laboratory tests (hematology/blood chemistry/urinalysis) | Pre-treatment (Day -2) [or screening for physical examination] to Day 28 [or Day 35, for AEs only] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EVP-6124 PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | EVP-6124 PK data; Maximum Concentration (Cmax); i.e, highest concentration of drug in plasma | 24 hours | 
| EVP-6124 PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | EVP-6124 PK data; Time to Maximum Concentration (Tmax); i.e, amount of time required to reach highest concentration of drug in plasma | 24 hours | 
| EVP-6124 PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | EVP-6124 PK data; Area Under the Curve (AUC[0-24 h]); i.e, area under the concentration-time plot | 24 hours | 
| Donepezil PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | Donepezil PK data; Maximum Concentration (Cmax); i.e, highest concentration of donepezil (parent compound only) in plasma after dosing with EVP-6124 | 24 hours | 
| Donepezil PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | Donepezil PK data; Time to Maximum Concentration (Tmax); i.e, amount of time required to reach highest concentration of donepezil (parent compound only) in plasma after dosing with EVP-6124 | 24 hours | 
| Donepezil PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | Donepezil PK data; Area Under the Curve (AUC[0-24 h]); i.e, area under the concentration-time plot for donepezil (parent compound only) after dosing with EVP-6124 | 24 hours | 
| Rivastigmine PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | Rivastigmine PK data; Maximum Concentration (Cmax); i.e, highest concentration of rivastigmine in plasma after dosing with EVP-6124 | 24 hours | 
| Rivastigmine PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | Rivastigmine PK data; Time to Maximum Concentration (Tmax); i.e, amount of time required to reach highest concentration of rivastigmine in plasma after dosing with EVP-6124 | 24 hours | 
| Rivastigmine PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | Rivastigmine PK data; Area Under the Curve (AUC[0-24 h]); i.e, area under the concentration-time plot for rivastigmine after dosing with EVP-6124 | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, Central Nervous System Diseases, Pharmacokinetics, Cognition