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

This study has been completed.

Sponsor:

Collaborator:

INC Research

Information provided by (Responsible Party):

EnVivo Pharmaceuticals, Inc.

ClinicalTrials.gov Identifier:

NCT00766363

First received: October 1, 2008

Last updated: April 18, 2012

Last verified: April 2012

History of Changes

Results First Received: June 16, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Conditions:	Alzheimer's Disease Central Nervous System Diseases
Interventions:	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

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
61 subjects were screened and 49 subjects were enrolled.

Reporting Groups

	Description
EVP-6124 (0.1 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (0.3 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (1.0 mg/Day)	1 capsule per day for 28 days.
Placebo	1 capsule per day for 28 days.

Participant Flow: Overall Study

	EVP-6124 (0.1 mg/Day)	EVP-6124 (0.3 mg/Day)	EVP-6124 (1.0 mg/Day)	Placebo
STARTED	12	13	12 ^[1]	12 ^[1]
SAFETY POPULATION	12	13	11 ^[2]	13 ^[3]
PK POPULATION	12	13	10	13
COMPLETED	11	12	12	12
NOT COMPLETED	1	1	0	0
Withdrawal by Subject	1	0	0	0
Adverse Event Prior to Randomization	0	1	0	0

[1]	Number randomized.
[2]	Decreased by one subject who took placebo instead due to treatment assignment error.
[3]	Increased by one subject who took placebo due to treatment assignment error.

Baseline Characteristics

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Reporting Groups

	Description
EVP-6124 (0.1 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (0.3 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (1.0 mg/Day)	1 capsule per day for 28 days.
Placebo	1 capsule per day for 28 days.
Total	Total of all reporting groups

Baseline Measures

	EVP-6124 (0.1 mg/Day)	EVP-6124 (0.3 mg/Day)	EVP-6124 (1.0 mg/Day)	Placebo	Total
Number of Participants [units: participants]	12	13	11	13	49
Age [units: participants]
<=18 years	0	0	0	0	0
Between 18 and 65 years	5	5	4	4	18
>=65 years	7	8	7	9	31
Age [units: years] Mean ± Standard Deviation	68.6 ± 8.5	68.3 ± 11.1	70.2 ± 12.3	72.0 ± 10.5	69.8 ± 10.4
Gender [units: participants]
Female	8	7	6	8	29
Male	4	6	5	5	20
Region of Enrollment [units: participants]
United States	12	13	11	13	49

Outcome Measures

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1. Primary:

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] ]

Measure Type	Primary
Measure Title	Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer’s Disease
Measure Description	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]
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population: All randomized subjects who ingested at least 1 dose of study drug.

Reporting Groups

	Description
EVP-6124 (0.1 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (0.3 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (1.0 mg/Day)	1 capsule per day for 28 days.
Placebo	1 capsule per day for 28 days.

Measured Values

	EVP-6124 (0.1 mg/Day)	EVP-6124 (0.3 mg/Day)	EVP-6124 (1.0 mg/Day)	Placebo
Number of Participants Analyzed [units: participants]	12	13	11	13
Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer’s Disease [units: Participants]
Serious Adverse Events	0	0	0	0
Non-Serious Adverse Events	2	3	4	4
No Adverse Events Reported	10	10	7	9

No statistical analysis provided for Safety and Tolerability of Multiple Doses of EVP-6124 or Placebo in Subjects With Alzheimer’s Disease

2. Secondary:

EVP-6124 PK Data Following the First Dose of EVP-6124 – Maximum Concentration (Cmax) [ Time Frame: 24 hours ]

Measure Type	Secondary
Measure Title	EVP-6124 PK Data Following the First Dose of EVP-6124 – Maximum Concentration (Cmax)
Measure Description	EVP-6124 PK data; Maximum Concentration (Cmax); i.e, highest concentration of drug in plasma
Time Frame	24 hours
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters.

Reporting Groups

	Description
EVP-6124 (0.1 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (0.3 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (1.0 mg/Day)	1 capsule per day for 28 days.

Measured Values

	EVP-6124 (0.1 mg/Day)	EVP-6124 (0.3 mg/Day)	EVP-6124 (1.0 mg/Day)
Number of Participants Analyzed [units: participants]	12	13	10
EVP-6124 PK Data Following the First Dose of EVP-6124 – Maximum Concentration (Cmax) [units: ng/mL] Mean ± Standard Deviation	0.0715 ± 0.0121	0.1911 ± 0.0740	0.6122 ± 0.1235

No statistical analysis provided for EVP-6124 PK Data Following the First Dose of EVP-6124 – Maximum Concentration (Cmax)

3. Secondary:

EVP-6124 PK Data Following the First Dose of EVP-6124 – Time to Maximum Concentration (Tmax) [ Time Frame: 24 hours ]

Measure Type	Secondary
Measure Title	EVP-6124 PK Data Following the First Dose of EVP-6124 – Time to Maximum Concentration (Tmax)
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters.

Reporting Groups

	Description
EVP-6124 (0.1 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (0.3 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (1.0 mg/Day)	1 capsule per day for 28 days.

Measured Values

	EVP-6124 (0.1 mg/Day)	EVP-6124 (0.3 mg/Day)	EVP-6124 (1.0 mg/Day)
Number of Participants Analyzed [units: participants]	12	13	10
EVP-6124 PK Data Following the First Dose of EVP-6124 – Time to Maximum Concentration (Tmax) [units: hours] Mean ± Standard Deviation	7.70 ± 3.31	7.94 ± 3.61	10.72 ± 6.69

No statistical analysis provided for EVP-6124 PK Data Following the First Dose of EVP-6124 – Time to Maximum Concentration (Tmax)

4. Secondary:

EVP-6124 PK Data Following the First Dose of EVP-6124 – Area Under the Curve (AUC[0-24 h]) [ Time Frame: 24 hours ]

Measure Type	Secondary
Measure Title	EVP-6124 PK Data Following the First Dose of EVP-6124 – Area Under the Curve (AUC[0-24 h])
Measure Description	EVP-6124 PK data; Area Under the Curve (AUC[0-24 h]); i.e, area under the concentration-time plot
Time Frame	24 hours
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters.

Reporting Groups

	Description
EVP-6124 (0.1 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (0.3 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (1.0 mg/Day)	1 capsule per day for 28 days.

Measured Values

	EVP-6124 (0.1 mg/Day)	EVP-6124 (0.3 mg/Day)	EVP-6124 (1.0 mg/Day)
Number of Participants Analyzed [units: participants]	12	11	7
EVP-6124 PK Data Following the First Dose of EVP-6124 – Area Under the Curve (AUC[0-24 h]) [units: h*ng/mL] Mean ± Standard Deviation	1.31 ± 0.23	3.89 ± 0.84	11.44 ± 2.24

No statistical analysis provided for EVP-6124 PK Data Following the First Dose of EVP-6124 – Area Under the Curve (AUC[0-24 h])

5. Secondary:

Donepezil PK Data Following the First Dose of EVP-6124 – Maximum Concentration (Cmax) [ Time Frame: 24 hours ]

Measure Type	Secondary
Measure Title	Donepezil PK Data Following the First Dose of EVP-6124 – Maximum Concentration (Cmax)
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters.

Reporting Groups

	Description
EVP-6124 (0.1 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (0.3 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (1.0 mg/Day)	1 capsule per day for 28 days.
Placebo	1 capsule per day for 28 days.

Measured Values

	EVP-6124 (0.1 mg/Day)	EVP-6124 (0.3 mg/Day)	EVP-6124 (1.0 mg/Day)	Placebo
Number of Participants Analyzed [units: participants]	10	13	7	13
Donepezil PK Data Following the First Dose of EVP-6124 – Maximum Concentration (Cmax) [units: ng/mL] Mean ± Standard Deviation	29.5 ± 15.8	24.7 ± 19.8	39.2 ± 26.7	41.9 ± 19.7

No statistical analysis provided for Donepezil PK Data Following the First Dose of EVP-6124 – Maximum Concentration (Cmax)

6. Secondary:

Donepezil PK Data Following the First Dose of EVP-6124 – Time to Maximum Concentration (Tmax) [ Time Frame: 24 hours ]

Measure Type	Secondary
Measure Title	Donepezil PK Data Following the First Dose of EVP-6124 – Time to Maximum Concentration (Tmax)
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters.

Reporting Groups

	Description
EVP-6124 (0.1 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (0.3 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (1.0 mg/Day)	1 capsule per day for 28 days.
Placebo	1 capsule per day for 28 days.

Measured Values

	EVP-6124 (0.1 mg/Day)	EVP-6124 (0.3 mg/Day)	EVP-6124 (1.0 mg/Day)	Placebo
Number of Participants Analyzed [units: participants]	10	12	7	13
Donepezil PK Data Following the First Dose of EVP-6124 – Time to Maximum Concentration (Tmax) [units: hours] Mean ± Standard Deviation	2.30 ± 2.65	1.85 ± 2.15	3.31 ± 3.01	3.56 ± 4.02

No statistical analysis provided for Donepezil PK Data Following the First Dose of EVP-6124 – Time to Maximum Concentration (Tmax)

7. Secondary:

Donepezil PK Data Following the First Dose of EVP-6124 – Area Under the Curve (AUC[0-24 h]) [ Time Frame: 24 hours ]

Measure Type	Secondary
Measure Title	Donepezil PK Data Following the First Dose of EVP-6124 – Area Under the Curve (AUC[0-24 h])
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters.

Reporting Groups

	Description
EVP-6124 (0.1 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (0.3 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (1.0 mg/Day)	1 capsule per day for 28 days.
Placebo	1 capsule per day for 28 days.

Measured Values

	EVP-6124 (0.1 mg/Day)	EVP-6124 (0.3 mg/Day)	EVP-6124 (1.0 mg/Day)	Placebo
Number of Participants Analyzed [units: participants]	10	13	7	13
Donepezil PK Data Following the First Dose of EVP-6124 – Area Under the Curve (AUC[0-24 h]) [units: h*ng/mL] Mean ± Standard Deviation	299 ± 179	240 ± 194	345 ± 225	427 ± 233

No statistical analysis provided for Donepezil PK Data Following the First Dose of EVP-6124 – Area Under the Curve (AUC[0-24 h])

8. Secondary:

Rivastigmine PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) [ Time Frame: 24 hours ]

Measure Type	Secondary
Measure Title	Rivastigmine PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax)
Measure Description	Rivastigmine PK data; Maximum Concentration (Cmax); i.e, highest concentration of rivastigmine in plasma after dosing with EVP-6124
Time Frame	24 hours
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters. Only 4 subjects took rivastigmine concomitantly.

Reporting Groups

	Description
EVP-6124 (0.1 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (1.0 mg/Day)	1 capsule per day for 28 days.

Measured Values

	EVP-6124 (0.1 mg/Day)	EVP-6124 (1.0 mg/Day)
Number of Participants Analyzed [units: participants]	2	2
Rivastigmine PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax) [units: ng/mL] Mean ± Standard Deviation	23.35 ± 5.16	3.51 ± 0.37

No statistical analysis provided for Rivastigmine PK Data Following the First Dose of EVP-6124 - Maximum Concentration (Cmax)

9. Secondary:

Rivastigmine PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) [ Time Frame: 24 hours ]

Measure Type	Secondary
Measure Title	Rivastigmine PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax)
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters. Only 4 subjects took rivastigmine concomitantly.

Reporting Groups

	Description
EVP-6124 (0.1 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (1.0 mg/Day)	1 capsule per day for 28 days.

Measured Values

	EVP-6124 (0.1 mg/Day)	EVP-6124 (1.0 mg/Day)
Number of Participants Analyzed [units: participants]	2	2
Rivastigmine PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax) [units: hours] Mean ± Standard Deviation	1.00 ± 0.02	12.12 ± 15.72

No statistical analysis provided for Rivastigmine PK Data Following the First Dose of EVP-6124 - Time to Maximum Concentration (Tmax)

10. Secondary:

Rivastigmine PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) [ Time Frame: 24 hours ]

Measure Type	Secondary
Measure Title	Rivastigmine PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h])
Measure Description	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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population: All safety population subjects who had sufficient plasma concentration data to facilitate calculation of PK parameters. Only 4 subjects took rivastigmine concomitantly.

Reporting Groups

	Description
EVP-6124 (0.1 mg/Day)	1 capsule per day for 28 days.
EVP-6124 (1.0 mg/Day)	1 capsule per day for 28 days.

Measured Values

	EVP-6124 (0.1 mg/Day)	EVP-6124 (1.0 mg/Day)
Number of Participants Analyzed [units: participants]	2	2
Rivastigmine PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h]) [units: h*ng/mL] Mean ± Standard Deviation	143.55 ± 85.52	54.60 ± 6.28

No statistical analysis provided for Rivastigmine PK Data Following the First Dose of EVP-6124 - Area Under the Curve (AUC[0-24 h])

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days from the time submitted for review. At the sponsor’s request, the PI will delete confidential information other than trial data and will delay publication or disclosure for up to 90 days to allow patent filings. The PI agrees that the first publication shall be a joint publication.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Maria Gawryl, Ph.D., Vice President, Regulatory Affairs & Drug Development
Organization: EnVivo Pharmaceuticals, Inc.
phone: 617-225-4264
e-mail: mgawryl@envivopharma.com

No publications provided

Responsible Party:	EnVivo Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT00766363 History of Changes
Other Study ID Numbers:	EVP-6124-007
Study First Received:	October 1, 2008
Results First Received:	June 16, 2011
Last Updated:	April 18, 2012
Health Authority:	United States: Food and Drug Administration

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