ELND005 in Patients With Mild to Moderate Alzheimer's Disease

This study has been completed.

Sponsor:

Collaborator:

Transition Therapeutics

Information provided by (Responsible Party):

Transition Therapeutics Ireland Limited

ClinicalTrials.gov Identifier:

NCT00568776

First received: December 4, 2007

Last updated: April 11, 2016

Last verified: April 2016

History of Changes

Results First Received: September 27, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Alzheimer Disease
Interventions:	Drug: Placebo Control Drug: ELND005

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
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Placebo BID	oral administration for 78 weeks
ELND005 250 mg BID	oral administration for 78 weeks
ELND005 1000 mg BID	oral administration for 78 weeks
ELND005 2000 mg BID	oral administration for 78 weeks

Participant Flow: Overall Study

	Placebo BID	ELND005 250 mg BID	ELND005 1000 mg BID	ELND005 2000 mg BID
STARTED	83 ^[1]	88 ^[2]	89 ^[3]	91 ^[4]
COMPLETED	53	52	15	19
NOT COMPLETED	30	36	74	72
Adverse Event	8	8	10	8
Death	0	1	4	3
Physician Decision	0	2	0	0
Lack of Efficacy	2	2	2	4
Lost to Follow-up	1	1	1	1
Protocol Violation	1	0	1	1
Withdrawal by Subject	13	15	13	7
Loss of Caregiver	0	2	1	2
Sponsor Decision	2	2	41	42
Miscellaeneous	3	3	1	4

^[1]	One randomized patient withdrew consent and did not receive placebo
^[2]	One randomized patient withdrew consent and did not receive ELND005 250 mg BID
^[3]	41 patients withdrawn per interim safety review (sponsors decision); excluded in efficacy analysis.
^[4]	42 patients withdrawn per interim safety review (sponsors decision); excluded in efficacy analysis.

Baseline Characteristics

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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.
No text entered.

Reporting Groups

	Description
Placebo BID	oral administration for 78 weeks
ELND005 250 mg BID	oral administration for 78 weeks
ELND005 1000 mg BID	oral administration for 78 weeks
ELND005 2000 mg BID	oral administration for 78 weeks
Total	Total of all reporting groups

Baseline Measures

	Placebo BID	ELND005 250 mg BID	ELND005 1000 mg BID	ELND005 2000 mg BID	Total
Overall Participants Analyzed [Units: Participants]	83	88	89	91	351

Age [Units: Years] Mean (Standard Deviation)	73.4 (7.83)	73.4 (7.26)	73.4 (7.56)	72.2 (8.20)	73.1 (7.7)

Gender [Units: Patients]
Female	47	51	48	51	197
Male	36	37	41	40	154

Region of Enrollment [Units: Patients]
United States	68	75	71	75	289
Canada	15	13	18	16	62

Outcome Measures

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1. Primary:

Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Full Analysis Set; FAS) [ Time Frame: Baseline and 78 weeks ]

Measure Type	Primary
Measure Title	Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Full Analysis Set; FAS)
Measure Description	The NTB assessment is comprised of 9 instruments that measure cognition and executive function. Three of these tests measure immediate memory, next three measure delayed memory, and remaining three assess executive function. The total score is a weighted mean of the nine tests, referred to as the Z-score. Typically, scores range from -3 and 3, with lower scores suggesting greater cognitive impairment.
Time Frame	Baseline and 78 weeks

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.
Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and completed the baseline visit and at least one post-baseline visit.

Reporting Groups

	Description
Placebo BID	oral administration for 78 weeks
ELND005 250 mg BID	oral administration for 78 weeks
ELND005 1000 mg BID	oral administration for 78 weeks
ELND005 2000 mg BID	oral administration for 78 weeks

Measured Values

	Placebo BID	ELND005 250 mg BID	ELND005 1000 mg BID	ELND005 2000 mg BID
Participants Analyzed [Units: Participants]	82	84	0	0
Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Full Analysis Set; FAS) [Units: Scores on a Scale] Mean (Standard Error)	-0.383 (0.075)	-0.350 (0.074)

Statistical Analysis 1 for Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Full Analysis Set; FAS)

Groups ^[1]	Placebo BID vs. ELND005 250 mg BID
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.71
Mean Difference (Final Values) ^[5]	0.03
95% Confidence Interval	-0.14 to 0.21
Standard Error of the mean	(0.09)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
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2. Primary:

Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Per Protocol Set; PPS) [ Time Frame: Baseline and 78 weeks ]

Measure Type	Primary
Measure Title	Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Per Protocol Set; PPS)
Measure Description	The NTB assessment is comprised of 9 instruments that measure cognition and executive function. Three of these tests measure immediate memory, next three measure delayed memory, and remaining three assess executive function. The total score is a weighted mean of the nine tests, referred to as the Z-score. Typically, scores range from -3 and 3, with lower scores suggesting greater cognitive impairment.
Time Frame	Baseline and 78 weeks

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.
Per Protocol Set (PPS): all randomized patients who received at least one dose of ELND005 250 mg or placebo, completed all scheduled visits up to Week 78, were at least 80% compliant with study drug, and met all inclusion/exclusion criteria.

Reporting Groups

	Description
Placebo BID	oral administration for 78 weeks
ELND005 250 mg BID	oral administration for 78 weeks
ELND005 1000 mg BID	oral administration for 78 weeks
ELND005 2000 mg BID	oral administration for 78 weeks

Measured Values

	Placebo BID	ELND005 250 mg BID	ELND005 1000 mg BID	ELND005 2000 mg BID
Participants Analyzed [Units: Participants]	47	49	0	0
Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Per Protocol Set; PPS) [Units: Scores on a Scale] Mean (Standard Error)	-0.369 (0.093)	-0.222 (0.095)

Statistical Analysis 1 for Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Per Protocol Set; PPS)

Groups ^[1]	Placebo BID vs. ELND005 250 mg BID
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.17
Mean Difference (Final Values) ^[5]	0.15
95% Confidence Interval	-0.06 to 0.36
Standard Error of the mean	(0.11)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

3. Primary:

Change From Baseline to Week 78 in Alzheimer‘s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) Score (Full Analysis Set; FAS) [ Time Frame: Baseline and 78 weeks ]

Measure Type	Primary
Measure Title	Change From Baseline to Week 78 in Alzheimer‘s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) Score (Full Analysis Set; FAS)
Measure Description	The ADCS-ADL is a 23-item scale that measures a subject's functional abilities as assessed by the subject's caregiver. This scale ranges from 0 to 78, with lower scores suggesting greater functional impairment.
Time Frame	Baseline and 78 weeks

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.
Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and completed the baseline visit and at least one post-baseline visit.

Reporting Groups

	Description
Placebo BID	oral administration for 78 weeks
ELND005 250 mg BID	oral administration for 78 weeks
ELND005 1000 mg BID	oral administration for 78 weeks
ELND005 2000 mg BID	oral administration for 78 weeks

Measured Values

	Placebo BID	ELND005 250 mg BID	ELND005 1000 mg BID	ELND005 2000 mg BID
Participants Analyzed [Units: Participants]	82	84	0	0
Change From Baseline to Week 78 in Alzheimer‘s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) Score (Full Analysis Set; FAS) [Units: Scores on a Scale] Mean (Standard Error)	-9.467 (1.641)	-10.861 (1.604)

Statistical Analysis 1 for Change From Baseline to Week 78 in Alzheimer‘s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) Score (Full Analysis Set; FAS)

Groups ^[1]	Placebo BID vs. ELND005 250 mg BID
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.49
Mean Difference (Final Values) ^[5]	-1.39
95% Confidence Interval	-5.41 to 2.62
Standard Error of the mean	(2.03)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

4. Primary:

Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Alzheimer‘s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) Score (Per Protocol Set; PPS) [ Time Frame: Baseline and 78 weeks ]

Measure Type	Primary
Measure Title	Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Alzheimer‘s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) Score (Per Protocol Set; PPS)
Measure Description	The ADCS-ADL is a 23-item scale that measures a subject's functional abilities as assessed by the subject's caregiver. This scale ranges from 0 to 78, with lower scores suggesting greater functional impairment.
Time Frame	Baseline and 78 weeks

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.
Per Protocol Set (PPS): all randomized patients who received at least one dose of ELND005 250 mg or placebo, completed all scheduled visits up to Week 78, were at least 80% compliant with study drug, and met all inclusion/exclusion criteria.

Reporting Groups

	Description
Placebo BID	oral administration for 78 weeks
ELND005 250 mg BID	oral administration for 78 weeks
ELND005 1000 mg BID	oral administration for 78 weeks
ELND005 2000 mg BID	oral administration for 78 weeks

Measured Values

	Placebo BID	ELND005 250 mg BID	ELND005 1000 mg BID	ELND005 2000 mg BID
Participants Analyzed [Units: Participants]	47	49	0	0
Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Alzheimer‘s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) Score (Per Protocol Set; PPS) [Units: Scores on a Scale] Mean (Standard Error)	-9.635 (1.779)	-8.987 (1.760)

Statistical Analysis 1 for Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Alzheimer‘s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) Score (Per Protocol Set; PPS)

Groups ^[1]	Placebo BID vs. ELND005 250 mg BID
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.77
Mean Difference (Final Values) ^[5]	0.65
95% Confidence Interval	-3.73 to 5.03
Standard Error of the mean	(2.20)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary:

Change in Alzheimer‘s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) Score From Baseline to Week 78 (Full Analysis Set; FAS) [ Time Frame: Baseline and 78 weeks ]

Measure Type	Secondary
Measure Title	Change in Alzheimer‘s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) Score From Baseline to Week 78 (Full Analysis Set; FAS)
Measure Description	The ADAS-Cog primarily measures cognitive ability. The version used in this study was comprised of 12 items with scores ranging from 0 to 75. Higher scores suggest greater cognitive impairment.
Time Frame	Baseline and 78 weeks

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.
Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and completed the baseline visit and at least one post-baseline visit.

Reporting Groups

	Description
Placebo BID	oral administration for 78 weeks
ELND005 250 mg BID	oral administration for 78 weeks
ELND005 1000 mg BID	oral administration for 78 weeks
ELND005 2000 mg BID	oral administration for 78 weeks

Measured Values

	Placebo BID	ELND005 250 mg BID	ELND005 1000 mg BID	ELND005 2000 mg BID
Participants Analyzed [Units: Participants]	82	84	0	0
Change in Alzheimer‘s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) Score From Baseline to Week 78 (Full Analysis Set; FAS) [Units: Scores on a Scale] Mean (Standard Error)	-8.239 (1.531)	-10.796 (1.540)

Statistical Analysis 1 for Change in Alzheimer‘s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) Score From Baseline to Week 78 (Full Analysis Set; FAS)

Groups ^[1]	Placebo BID vs. ELND005 250 mg BID
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.18
Mean Difference (Final Values) ^[5]	-2.56
95% Confidence Interval	-6.33 to 1.22
Standard Error of the mean	(1.90)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

6. Secondary:

Change in Clinical Dementia Rating – Sum of Boxes (CDR-SB) Score From Baseline to Week 78 (Full Analysis Set; FAS) [ Time Frame: Baseline and 78 weeks ]

Measure Type	Secondary
Measure Title	Change in Clinical Dementia Rating – Sum of Boxes (CDR-SB) Score From Baseline to Week 78 (Full Analysis Set; FAS)
Measure Description	The CDR-SB consists of 6 items; 3 measuring cognitive ability and 3 measuring functional ability. The score for each of the six items range from 0 to 3; hence the total score is between 0 and 18. Higher scores suggest greater cognitive impairment.
Time Frame	Baseline and 78 weeks

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.
Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and completed the baseline visit and at least one post-baseline visit.

Reporting Groups

	Description
Placebo BID	oral administration for 78 weeks
ELND005 250 mg BID	oral administration for 78 weeks
ELND005 1000 mg BID	oral administration for 78 weeks
ELND005 2000 mg BID	oral administration for 78 weeks

Measured Values

	Placebo BID	ELND005 250 mg BID	ELND005 1000 mg BID	ELND005 2000 mg BID
Participants Analyzed [Units: Participants]	82	84	0	0
Change in Clinical Dementia Rating – Sum of Boxes (CDR-SB) Score From Baseline to Week 78 (Full Analysis Set; FAS) [Units: Scores on a Scale] Mean (Standard Error)	-2.742 (0.363)	-2.452 (0.357)

Statistical Analysis 1 for Change in Clinical Dementia Rating – Sum of Boxes (CDR-SB) Score From Baseline to Week 78 (Full Analysis Set; FAS)

Groups ^[1]	Placebo BID vs. ELND005 250 mg BID
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.54
Mean Difference (Final Values) ^[5]	0.29
95% Confidence Interval	-0.63 to 1.21
Standard Error of the mean	(0.47)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

7. Secondary:

Change in Neuropsychiatric Inventory (NPI) Score From Baseline to Week 78 (Full Analysis Set; FAS) [ Time Frame: Baseline and 78 weeks ]

Measure Type	Secondary
Measure Title	Change in Neuropsychiatric Inventory (NPI) Score From Baseline to Week 78 (Full Analysis Set; FAS)
Measure Description	The NPI is used to obtain information on the presence of severity of neuropsychological symptoms, and was specifically designed for use in Alzheimer's disease subjects. The scale consists of 12 items with each item having outcomes from 0 to 12; hence the total score ranges from 0 to 144. Higher scores suggest greater psychiatric impairment.
Time Frame	Baseline and 78 weeks

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.
Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and completed the baseline visit and at least one post-baseline visit.

Reporting Groups

	Description
Placebo BID	oral administration for 78 weeks
ELND005 250 mg BID	oral administration for 78 weeks
ELND005 1000 mg BID	oral administration for 78 weeks
ELND005 2000 mg BID	oral administration for 78 weeks

Measured Values

	Placebo BID	ELND005 250 mg BID	ELND005 1000 mg BID	ELND005 2000 mg BID
Participants Analyzed [Units: Participants]	82	84	0	0
Change in Neuropsychiatric Inventory (NPI) Score From Baseline to Week 78 (Full Analysis Set; FAS) [Units: Scores on a Scale] Mean (Standard Error)	-6.132 (1.851)	-5.116 (1.814)

Statistical Analysis 1 for Change in Neuropsychiatric Inventory (NPI) Score From Baseline to Week 78 (Full Analysis Set; FAS)

Groups ^[1]	Placebo BID vs. ELND005 250 mg BID
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Mixed Models Analysis
P Value ^[4]	0.65
Mean Difference (Final Values) ^[5]	1.02
95% Confidence Interval	-3.43 to 5.46
Standard Error of the mean	(2.24)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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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
The two high dose groups of ELND005 were discontinued before study end, so the efficacy analysis was based only on placebo and ELND005 250 mg bid groups.

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: Investigator may publish after release of multi-center study publication, or 18 months after database lock of overall study. Sponsor has 60 days to review any proposed publication and request removal of Sponsor’s confidential information. Sponsor may request an additional 90 days if filing a patent.

Results Point of Contact:

Name/Title: Aleksandra pastrak, MD, PhD, Vice President, Clinical Development
Organization: Transition Therapeutics Ireland Limited
phone: +1 416 263 1227
e-mail: apastrak@transitiontherapeutics.com

Responsible Party:	Transition Therapeutics Ireland Limited
ClinicalTrials.gov Identifier:	NCT00568776 History of Changes
Other Study ID Numbers:	ELND005-AD201
Study First Received:	December 4, 2007
Results First Received:	September 27, 2011
Last Updated:	April 11, 2016

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