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Effect of LY450139 on the Long Term Progression of Alzheimer's Disease

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT00594568
First received: January 11, 2008
Last updated: March 13, 2015
Last verified: March 2015
Results First Received: November 6, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Alzheimer's Disease
Interventions: Drug: LY450139
Drug: Placebo

  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
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Placebo Participants received placebo orally once daily for the first 76 weeks. At the end of 76 weeks, placebo arm participants received LY450139 titrated up to 140 mg orally once daily until Week 88.
100 mg LY450139 Participants received 60 mg LY450139 orally once daily for 2 weeks, followed by 100 mg LY450139 orally once daily until Week 88.
140 mg LY450139 Participants received 60 mg LY450139 orally once daily for 2 weeks, followed by 100 mg LY450139 orally once daily for 2 weeks, then 140 mg LY450139 orally once daily until Week 88.

Participant Flow for 3 periods

Period 1:   Initial Treatment
    Placebo   100 mg LY450139   140 mg LY450139
STARTED   501   507   529 
Intent-to-treat (ITT)   501 [1]   506 [2]   527 [2] 
COMPLETED   189   153   121 
NOT COMPLETED   312   354   408 
Adverse Event                51                121                144 
Death                6                11                15 
Lost to Follow-up                4                1                4 
Physician Decision                3                2                4 
Protocol Violation                2                2                5 
Withdrawal by Subject                25                31                46 
Sponsor decision                193                142                147 
Caregiver decision                21                36                36 
Abnormal lab/electrocardiogram (ECG)                7                7                6 
Entry criteria exclusion                0                1                1 
[1] ITT population included all randomized participants (pts) who had at least 1 dose of study drug.
[2] ITT population included all randomized participants who had at least 1 dose of study drug.

Period 2:   Delayed Start
    Placebo   100 mg LY450139   140 mg LY450139
STARTED   189   153   121 
COMPLETED   91   76   55 
NOT COMPLETED   98   77   66 
Death                0                0                1 
Adverse Event                12                2                2 
Withdrawal by Subject                4                3                0 
Physician Decision                0                0                1 
Lost to Follow-up                0                0                1 
Caregiver Decision                5                6                2 
Sponsor Decision                77                66                59 

Period 3:   Safety Follow Up (SFU)-Optional
    Placebo   100 mg LY450139   140 mg LY450139
STARTED   290 [1]   223 [1]   214 [2] 
COMPLETED   229   168   172 
NOT COMPLETED   61   55   42 
Death                0                1                0 
Adverse Event                5                0                0 
Withdrawal by Subject                12                15                13 
Lost to Follow-up                2                1                2 
Caregiver Decision                17                16                9 
No safety visit or follow up                25                22                18 
[1] SFU was optional; pts entered from initial treatment and delayed start or did not enter SFU.
[2] SFU was optional, pts entered from initial treatment and delayed start or did not enter SFU.



  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 Participants received placebo orally once daily for the first 76 weeks. At the end of 76 weeks, placebo arm participants received LY450139 titrated up to 140 mg orally once daily until Week 88.
100 mg LY450139 Participants received 60 mg LY450139 orally once daily for 2 weeks, followed by 100 mg LY450139 orally once daily until Week 88.
140 mg LY450139 Participants received 60 mg LY450139 orally once daily for 2 weeks, followed by 100 mg LY450139 orally once daily for 2 weeks, then 140 mg LY450139 orally once daily until Week 88.
Total Total of all reporting groups

Baseline Measures
   Placebo   100 mg LY450139   140 mg LY450139   Total 
Overall Participants Analyzed 
[Units: Participants]
 501   506   527   1534 
Age 
[Units: Years]
Mean (Standard Deviation)
 73.9  (8.1)   73.6  (8.0)   73.9  (8.5)   73.8  (8.2) 
Gender 
[Units: Participants]
       
Female   278   279   263   820 
Male   223   227   264   714 
Race/Ethnicity, Customized 
[Units: Participants]
       
Caucasian   413   428   441   1282 
African   3   6   3   12 
Hispanic   33   22   24   79 
Native American   0   0   2   2 
East Asian   47   45   51   143 
West Asian   5   5   6   16 
Region of Enrollment 
[Units: Participants]
       
United States   192   194   199   585 
Finland   6   8   8   22 
Spain   24   24   25   73 
Chile   17   14   12   43 
Israel   22   21   21   64 
Italy   6   5   6   17 
United Kingdom   14   20   21   55 
India   10   9   11   30 
France   15   14   14   43 
Canada   20   21   18   59 
Argentina   24   23   26   73 
Poland   12   15   18   45 
Belgium   8   5   5   18 
Australia   20   25   24   69 
Denmark   5   5   4   14 
South Africa   26   28   30   84 
Germany   29   21   27   77 
Japan   41   37   43   121 
Sweden   10   17   15   42 
Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog11) Score [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 22.8  (9.1)   22.5  (8.9)   23.1  (8.8)   22.8  (8.9) 
[1] ADAS‑Cog11 consists of 11 items assessing areas of function most typically impaired in AD: orientation, verbal memory, language, and praxis. The scale ranges from 0 to 70, with higher scores indicating greater disease severity.
Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 60.5  (13.0)   62.3  (11.6)   60.5  (12.4)   61.1  (12.4) 
[1] The ADCS-ADL Inventory Score is a 23-item inventory developed as a Rater-administered questionnaire answered by the participant’s caregiver. It measures performance of basic and instrumental activities of daily living by participants. The total ADCS-ADL score ranges from 0 to 78, with lower scores indicating greater disease severity.


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 76 Weeks   [ Time Frame: Baseline (randomization), 76 weeks ]

2.  Primary:   Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 16 Weeks After Cessation of Study Drug   [ Time Frame: Baseline (randomization), 16 weeks following treatment cessation ]

3.  Primary:   Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score at 76 Weeks   [ Time Frame: Baseline (randomization), 76 weeks ]

4.  Primary:   Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score at 16 Weeks After Cessation of Study Drug   [ Time Frame: Baseline (randomization), 16 weeks following treatment cessation ]

5.  Secondary:   Percent Change From Baseline in Amyloid Beta (Aβ) 1-42 Plasma Concentration at 52 Weeks   [ Time Frame: Baseline (randomization), 52 weeks ]

6.  Secondary:   Change From Baseline in Positron Emission Tomography (PET) Using Fluorine-18 Fluorodeoxyglucose (18F-FDG) at 76 Weeks   [ Time Frame: Baseline (randomization), 76 weeks ]

7.  Secondary:   Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks   [ Time Frame: Baseline (randomization), up to 76 weeks ]

8.  Secondary:   Change From Baseline in Amyloid Imaging Positron Emission Tomography (AV-45 PET) up to 76 Weeks   [ Time Frame: Baseline (randomization), up to 76 weeks ]

9.  Secondary:   Change From Baseline in Tau Concentration in Spinal Fluid up to 76 Weeks   [ Time Frame: Baseline (randomization), up to 76 weeks ]

10.  Secondary:   LY450139 Population Pharmacokinetics: Clearance of LY450139   [ Time Frame: 6 weeks, 12 weeks, and 52 weeks ]

11.  Secondary:   LY450139 Population Pharmacokinetics: Volume of Distribution of LY450139   [ Time Frame: 6 weeks, 12 weeks, and 52 weeks ]

12.  Secondary:   Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score at 76 Weeks   [ Time Frame: Baseline (randomization), 76 weeks ]

13.  Secondary:   Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score at 76 Weeks   [ Time Frame: Baseline (randomization), 76 weeks ]

14.  Secondary:   Change From Baseline in Mini Mental State Examination (MMSE) Score at 76 Weeks   [ Time Frame: Baseline (randomization), 76 weeks ]

15.  Secondary:   Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score at 76 Weeks   [ Time Frame: Baseline (randomization), 76 weeks ]

16.  Secondary:   Change From Baseline in Neuropsychiatric Inventory (NPI) Score at 76 Weeks   [ Time Frame: Baseline (randomization), 76 weeks ]

17.  Secondary:   Change From Baseline in EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) Score at 76 Weeks   [ Time Frame: Baseline (randomization), 76 weeks ]

18.  Secondary:   Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Score (Number of Hospitalizations) up to 76 Weeks   [ Time Frame: Baseline (randomization), up to 76 weeks ]

19.  Secondary:   Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score at 16 Weeks After Cessation of Study Drug   [ Time Frame: Baseline (randomization), 16 weeks following treatment cessation ]

20.  Secondary:   Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score at 16 Weeks After Cessation of Study Drug   [ Time Frame: Baseline (randomization), 16 weeks following treatment cessation ]

21.  Secondary:   Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score at 4 Weeks After Cessation of Study Drug   [ Time Frame: Baseline (randomization), 4 weeks following treatment cessation ]

22.  Secondary:   Change From Baseline in Neuropsychiatric Inventory (NPI) Score at 4 Weeks After Cessation of Study Drug   [ Time Frame: Baseline (randomization), 4 weeks following treatment cessation ]

23.  Secondary:   Change From Baseline in Mini Mental State Examination (MMSE) Score at 4 Weeks After Cessation of Study Drug   [ Time Frame: Baseline (randomization), 4 weeks following treatment cessation ]

24.  Secondary:   Change From Baseline in EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) Score at 4 Weeks After Cessation of Study Drug   [ Time Frame: Baseline (randomization), 4 weeks following treatment cessation ]

25.  Secondary:   Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Score (Number of Hospitalizations) at 4 Weeks After Cessation of Study Drug   [ Time Frame: Baseline (randomization), 4 weeks following treatment cessation ]

26.  Secondary:   Change From Baseline in Amyloid Beta (Aβ) 1-42 Concentration in Spinal Fluid up to 76 Weeks   [ Time Frame: Baseline (randomization), up to 76 weeks ]

27.  Secondary:   Change From Baseline in Phosphorylated-Tau (P-Tau) Concentration in Spinal Fluid   [ Time Frame: Baseline (randomization), up to 76 weeks ]


  Serious Adverse Events


  Other Adverse Events


  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
Outcomes with 4-week after study drug cessation timeframe=All dosing stopped after protocol-specified interim review showed dose-dependent cognitive/functional worsening for LY450139 participants; followed for 32 weeks; not all assessments were made.


  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:
unchecked 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.
unchecked Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.


Results Point of Contact:  
Name/Title: Chief Medical Officer
Organization: Eli Lilly and Company
phone: 800-545-5979


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT00594568     History of Changes
Other Study ID Numbers: 7666
H6L-MC-LFAN ( Other Identifier: Eli Lilly and Company )
CTRI/2009/091/000090 ( Registry Identifier: India )
Study First Received: January 11, 2008
Results First Received: November 6, 2013
Last Updated: March 13, 2015
Health Authority: United States: Food and Drug Administration
Argentina: Ministry of Health
Australia: Department of Health and Ageing Therapeutic Goods Administration
Belgium: Federal Agency for Medicinal Products and Health Products
Canada: Health Canada
Chile: Ministry of Health
Denmark: Danish Medicines Agency
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Germany: Federal Office for Radiation Protection
India: Drugs Controller General of India
Israel: Ministry of Health
Italy: The Italian Medicines Agency
Japan: Ministry of Health, Labor and Welfare
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
South Africa: Department of Health
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Sweden: Medical Products Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency