Alzheimer's Disease, Central Nervous System Diseases
Conditions
Keywords
Alzheimer's Disease, Central Nervous System Diseases, Pharmacokinetics, Cognition
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.
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.
Interventions
DRUGEVP-6124 (0.1 mg/day)
EVP-6124 was administered as one 0.1 mg capsule per day for 28 days.
EVP-6124 was administered as one 0.3 mg capsule every day for 28 days.
EVP-6124 was administered as one 1.0 mg capsule every day for 28 days.
DRUGComparator: Placebo
Matching placebo was administered as one capsule per day for 28 days.
DRUGDonepezil
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.
DRUGRivastigmine
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.
Sponsors
Syneos Health
FORUM Pharmaceuticals Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | 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
| Measure | Time frame | Description |
|---|---|---|
| EVP-6124 PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | 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 |
| EVP-6124 PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | 24 hours | EVP-6124 PK data; Area Under the Curve (AUC\[0-24 h\]); i.e, area under the concentration-time plot |
| Donepezil PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | 24 hours | Donepezil PK data; Maximum Concentration (Cmax); i.e, highest concentration of donepezil (parent compound only) in plasma after dosing with EVP-6124 |
| Donepezil PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | 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 |
| EVP-6124 PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | 24 hours | EVP-6124 PK data; Maximum Concentration (Cmax); i.e, highest concentration of drug in plasma |
| Rivastigmine PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | 24 hours | Rivastigmine PK data; Maximum Concentration (Cmax); i.e, highest concentration of rivastigmine in plasma after dosing with EVP-6124 |
| Rivastigmine PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | 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 |
| Rivastigmine PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | 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 |
| Donepezil PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | 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 |
Countries
United States
Participant flow
Recruitment details
The recruitment period was from September 2008 to February 2009 at 4 study centers in the US (CA, FL, and 2 in NJ).
Pre-assignment details
61 subjects were screened and 49 subjects were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| EVP-6124 (0.1 mg/Day) 1 capsule per day for 28 days. | 12 |
| EVP-6124 (0.3 mg/Day) 1 capsule per day for 28 days. | 13 |
| EVP-6124 (1.0 mg/Day) 1 capsule per day for 28 days. | 11 |
| Placebo 1 capsule per day for 28 days. | 13 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event Prior to Randomization | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | EVP-6124 (0.3 mg/Day) | EVP-6124 (1.0 mg/Day) | EVP-6124 (0.1 mg/Day) | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 7 Participants | 7 Participants | 9 Participants | 31 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 4 Participants | 5 Participants | 4 Participants | 18 Participants |
| Age Continuous | 68.3 years STANDARD_DEVIATION 11.1 | 70.2 years STANDARD_DEVIATION 12.3 | 68.6 years STANDARD_DEVIATION 8.5 | 72.0 years STANDARD_DEVIATION 10.5 | 69.8 years STANDARD_DEVIATION 10.4 |
| Region of Enrollment United States | 13 participants | 11 participants | 12 participants | 13 participants | 49 participants |
| Sex: Female, Male Female | 7 Participants | 6 Participants | 8 Participants | 8 Participants | 29 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 4 Participants | 5 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 12 | 3 / 13 | 4 / 11 | 4 / 13 |
| serious Total, serious adverse events | 0 / 12 | 0 / 13 | 0 / 11 | 0 / 13 |
Outcome results
Primary
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)
Time frame: Pre-treatment (Day -2) [or screening for physical examination] to Day 28 [or Day 35, for AEs only]
Population: Safety Population: All randomized subjects who ingested at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EVP-6124 (0.1 mg/Day) | Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | Serious Adverse Events | 0 Participants |
| EVP-6124 (0.1 mg/Day) | Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | No Adverse Events Reported | 10 Participants |
| EVP-6124 (0.1 mg/Day) | Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | Non-Serious Adverse Events | 2 Participants |
| EVP-6124 (0.3 mg/Day) | Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | Serious Adverse Events | 0 Participants |
| EVP-6124 (0.3 mg/Day) | Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | No Adverse Events Reported | 10 Participants |
| EVP-6124 (0.3 mg/Day) | Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | Non-Serious Adverse Events | 3 Participants |
| EVP-6124 (1.0 mg/Day) | Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | Non-Serious Adverse Events | 4 Participants |
| EVP-6124 (1.0 mg/Day) | Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | Serious Adverse Events | 0 Participants |
| EVP-6124 (1.0 mg/Day) | Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | No Adverse Events Reported | 7 Participants |
| Placebo | Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | Serious Adverse Events | 0 Participants |
| Placebo | Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | No Adverse Events Reported | 9 Participants |
| Placebo | Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer's Disease | Non-Serious Adverse Events | 4 Participants |
Secondary
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
Time frame: 24 hours
Population: PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EVP-6124 (0.1 mg/Day) | Donepezil PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | 299 h*ng/mL | Standard Deviation 179 |
| EVP-6124 (0.3 mg/Day) | Donepezil PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | 240 h*ng/mL | Standard Deviation 194 |
| EVP-6124 (1.0 mg/Day) | Donepezil PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | 345 h*ng/mL | Standard Deviation 225 |
| Placebo | Donepezil PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | 427 h*ng/mL | Standard Deviation 233 |
Secondary
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
Time frame: 24 hours
Population: PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EVP-6124 (0.1 mg/Day) | Donepezil PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | 29.5 ng/mL | Standard Deviation 15.8 |
| EVP-6124 (0.3 mg/Day) | Donepezil PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | 24.7 ng/mL | Standard Deviation 19.8 |
| EVP-6124 (1.0 mg/Day) | Donepezil PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | 39.2 ng/mL | Standard Deviation 26.7 |
| Placebo | Donepezil PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | 41.9 ng/mL | Standard Deviation 19.7 |
Secondary
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
Time frame: 24 hours
Population: PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EVP-6124 (0.1 mg/Day) | Donepezil PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | 2.30 hours | Standard Deviation 2.65 |
| EVP-6124 (0.3 mg/Day) | Donepezil PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | 1.85 hours | Standard Deviation 2.15 |
| EVP-6124 (1.0 mg/Day) | Donepezil PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | 3.31 hours | Standard Deviation 3.01 |
| Placebo | Donepezil PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | 3.56 hours | Standard Deviation 4.02 |
Secondary
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
Time frame: 24 hours
Population: PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EVP-6124 (0.1 mg/Day) | EVP-6124 PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | 1.31 h*ng/mL | Standard Deviation 0.23 |
| EVP-6124 (0.3 mg/Day) | EVP-6124 PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | 3.89 h*ng/mL | Standard Deviation 0.84 |
| EVP-6124 (1.0 mg/Day) | EVP-6124 PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | 11.44 h*ng/mL | Standard Deviation 2.24 |
Secondary
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
Time frame: 24 hours
Population: PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EVP-6124 (0.1 mg/Day) | EVP-6124 PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | 0.0715 ng/mL | Standard Deviation 0.0121 |
| EVP-6124 (0.3 mg/Day) | EVP-6124 PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | 0.1911 ng/mL | Standard Deviation 0.074 |
| EVP-6124 (1.0 mg/Day) | EVP-6124 PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | 0.6122 ng/mL | Standard Deviation 0.1235 |
Secondary
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
Time frame: 24 hours
Population: PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EVP-6124 (0.1 mg/Day) | EVP-6124 PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | 7.70 hours | Standard Deviation 3.31 |
| EVP-6124 (0.3 mg/Day) | EVP-6124 PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | 7.94 hours | Standard Deviation 3.61 |
| EVP-6124 (1.0 mg/Day) | EVP-6124 PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | 10.72 hours | Standard Deviation 6.69 |
Secondary
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
Time frame: 24 hours
Population: PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters. Only 4 subjects took rivastigmine concomitantly.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EVP-6124 (0.1 mg/Day) | Rivastigmine PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | 143.55 h*ng/mL | Standard Deviation 85.52 |
| EVP-6124 (0.3 mg/Day) | Rivastigmine PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) | 54.60 h*ng/mL | Standard Deviation 6.28 |
Secondary
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
Time frame: 24 hours
Population: PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters. Only 4 subjects took rivastigmine concomitantly.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EVP-6124 (0.1 mg/Day) | Rivastigmine PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | 23.35 ng/mL | Standard Deviation 5.16 |
| EVP-6124 (0.3 mg/Day) | Rivastigmine PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) | 3.51 ng/mL | Standard Deviation 0.37 |
Secondary
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
Time frame: 24 hours
Population: PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters. Only 4 subjects took rivastigmine concomitantly.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EVP-6124 (0.1 mg/Day) | Rivastigmine PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | 1.00 hours | Standard Deviation 0.02 |
| EVP-6124 (0.3 mg/Day) | Rivastigmine PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) | 12.12 hours | Standard Deviation 15.72 |