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

• ClinicalTrials.gov Identifier: NCT00766363
• Recruitment Status: Completed
• First Posted: October 3, 2008
• Results First Posted: July 14, 2011
• Last Update Posted: April 20, 2012
• Sponsor: FORUM Pharmaceuticals Inc
• Collaborator: Syneos Health
• Information provided by (Responsible Party): FORUM Pharmaceuticals Inc

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Alzheimer's Disease; Central Nervous System Diseases	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	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: October 2008
• Actual Primary Completion Date: March 2009
• Actual Study Completion Date: March 2009

Arms and Interventions

Arm	Intervention/treatment
Experimental: EVP-6124 (0.1 mg/day)	Drug: EVP-6124 (0.1 mg/day); EVP-6124 was administered as one 0.1 mg capsule per day for 28 days.; Drug: Donepezil; 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.; Drug: Rivastigmine; 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.
Experimental: EVP-6124 (0.3 mg/day)	Drug: EVP-6124 (0.3 mg/day); EVP-6124 was administered as one 0.3 mg capsule every day for 28 days.; Drug: Donepezil; 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.; Drug: Rivastigmine; 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.
Experimental: EVP-6124 (1.0 mg/day)	Drug: EVP-6124 (1.0 mg/day); EVP-6124 was administered as one 1.0 mg capsule every day for 28 days.; Drug: Donepezil; 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.; Drug: Rivastigmine; 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.
Placebo Comparator: Placebo	Drug: Comparator: Placebo; Matching placebo was administered as one capsule per day for 28 days.; Drug: Donepezil; 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.; Drug: Rivastigmine; 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.

Outcome Measures

Primary Outcome Measures :

1. Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease [ Time Frame: Pre-treatment (Day -2) [or screening for physical examination] to Day 28 [or Day 35, for AEs only] ]
   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)

Secondary Outcome Measures :

1. EVP-6124 PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) [ Time Frame: 24 hours ]
   EVP-6124 PK data; Maximum Concentration (Cmax); i.e, highest concentration of drug in plasma
2. EVP-6124 PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) [ Time Frame: 24 hours ]
   EVP-6124 PK data; Time to Maximum Concentration (Tmax); i.e, amount of time required to reach highest concentration of drug in plasma
3. EVP-6124 PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) [ Time Frame: 24 hours ]
   EVP-6124 PK data; Area Under the Curve (AUC[0-24 h]); i.e, area under the concentration-time plot
4. Donepezil PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) [ Time Frame: 24 hours ]
   Donepezil PK data; Maximum Concentration (Cmax); i.e, highest concentration of donepezil (parent compound only) in plasma after dosing with EVP-6124
5. Donepezil PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) [ Time Frame: 24 hours ]
   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
6. Donepezil PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) [ Time Frame: 24 hours ]
   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
7. Rivastigmine PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) [ Time Frame: 24 hours ]
   Rivastigmine PK data; Maximum Concentration (Cmax); i.e, highest concentration of rivastigmine in plasma after dosing with EVP-6124
8. Rivastigmine PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) [ Time Frame: 24 hours ]
   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
9. Rivastigmine PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) [ Time Frame: 24 hours ]
   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

Eligibility Criteria

• Ages Eligible for Study: 50 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Pacific Research Network, Inc.

San Diego, California, United States, 92103

United States, Florida

MD Clinical

Hallandale Beach, Florida, United States, 33009

United States, New Jersey

Comprehensive Clinical Research

Berlin, New Jersey, United States, 08009

Global Medical Institutes, LLC

Princeton, New Jersey, United States, 08540

Sponsors and Collaborators

FORUM Pharmaceuticals Inc

Syneos Health

Investigators

• Principal Investigator: David R. Hassmann, D.O.; Comprehensive Clinical Research
• Principal Investigator: Beth Safirstein, M.D.; MD Clinical
• Principal Investigator: Stephen Thein, Ph.D.; Pacific Research Network, Inc.
• Principal Investigator: Jeffrey Apter, M.D.; Global Medical Institutes

More Information

• Responsible Party: FORUM Pharmaceuticals Inc
• ClinicalTrials.gov Identifier: NCT00766363
• Other Study ID Numbers: EVP-6124-007
• First Posted: October 3, 2008
• Results First Posted: July 14, 2011
• Last Update Posted: April 20, 2012
• Last Verified: April 2012

Keywords provided by FORUM Pharmaceuticals Inc:

Alzheimer's Disease; Central Nervous System Diseases; Pharmacokinetics; Cognition

Additional relevant MeSH terms:

Alzheimer Disease; Nervous System Diseases; Central Nervous System Diseases; Dementia; Brain Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Rivastigmine; Donepezil; Cholinesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Nootropic Agents; Neuroprotective Agents; Protective Agents