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

Study Overview
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Brief Summary
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Alzheimer's disease (AD) is a fatal degenerative disease of the brain for which there is no cure. AD causes brain cells to die. AD is thought to be caused by an excess of beta-amyloid (β-amyloid), a sticky protein in the brain that forms amyloid plaques. At autopsy, AD patients are required to have these amyloid plaques in the brain in order to have a definitive diagnosis of AD. Inhibiting the enzyme gamma-secretase (γ-secretase) lowers the production of β-amyloid. Semagacestat (LY450139) is a functional γ-secretase inhibitor and was shown to lower β-amyloid in blood and spinal fluid in humans tested thus far and in blood, spinal fluid, and brain in animals tested thus far. This study used several different tests to measure the effect of semagacestat on both β-amyloid and amyloid plaques for some participants. The build-up of amyloid plaques was measured by a brain scan that takes a picture of amyloid plaques in the brain. Other tests measured the overall function of the brain and brain size in some participants. In this trial, participants who initially received placebo (inactive sugar pill) were, at a certain point in the study, switched over to active drug, semagacestat. In other words, all participants could eventually receive active drug. Participation could last approximately 2 years. Participants taking approved AD medications were permitted to participate in this study and continue taking these medications during the study. All participants who completed this study had the option to continue receiving semagacestat by participating in an open-label study. Preliminary results from this study (H6L-MC-LFAN [LFAN]) and another similar study (H6L-MC-LFBC [LFBC; NCT00762411]) showed semagacestat did not slow disease progression and was associated with worsening of clinical measures of cognition and the ability to perform activities of daily living. Study drug was stopped in all studies. Studies LFAN, LFBC, and open-label H6L-MC-LFBF (LFBF; NCT01035138) were amended to continue collecting safety data, including cognitive scores, for at least 7 months. The Clinical Trial Registry (CTR) will reflect results of analyses from the original LFAN protocol in addition to those from the amended LFAN protocol.

Official Title
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Effect of γ-Secretase Inhibition on the Progression of Alzheimer's Disease: LY450139 Versus Placebo

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: LY450139
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meets criteria for mild to moderate Alzheimer's disease (AD) with Mini-Mental State Examination (MMSE) score of 16-26 at Visit 1 Modified Hachinski Ischemia Scale score of less than or equal to 4 Geriatric Depression Scale score of less than or equal to 6 A magnetic resonance imaging (MRI) or computerized tomography (CT) scan in the last 2 years with no findings inconsistent with a diagnosis of AD If female, must be without menstruation for at least 12 consecutive months or have had both ovaries removed Exclusion Criteria: Is not capable of swallowing whole oral medication Has serious or unstable illnesses Does not have a reliable caregiver Chronic alcohol or drug abuse within the past 5 years Has ever had active vaccination for AD

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>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 milligrams (mg) orally once daily until Week 88. | Drug: Placebo<br>* Administered orally once daily<br>|
| Experimental: 100 mg LY450139<br>Participants received 60 mg LY450139 orally once daily for 2 weeks, followed by 100 mg LY450139 orally once daily until Week 88. | Drug: LY450139<br>* Administered orally once daily<br>* Other names: semagacestat;|
| Experimental: 140 mg LY450139<br>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. | Drug: LY450139<br>* Administered orally once daily<br>* Other names: semagacestat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 76 Weeks | ADAS-Cog11 was used as a primary efficacy measure. It consists of 11 items assessing areas of function most typically impaired in Alzheimer's disease (AD): orientation, verbal memory, language, and praxis. The scale ranges from 0 to 70, with higher scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. | Baseline (randomization), 76 weeks | 
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 16 Weeks After Cessation of Study Drug | ADAS-Cog11 consists of 11 items assessing areas of function most typically impaired in Alzheimer's disease (AD): orientation, verbal memory, language, and praxis. The scale ranges from 0 to 70, with higher scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. | Baseline (randomization), 16 weeks following treatment cessation | 
| Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score at 76 Weeks | ADCS-ADL 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 score ranges from 0 to 78, with lower scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. | Baseline (randomization), 76 weeks | 
| 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 | ADCS-ADL 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 score ranges from 0 to 78, with lower scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. | Baseline (randomization), 16 weeks following treatment cessation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Amyloid Beta (Aβ) 1-42 Plasma Concentration at 52 Weeks | Concentration of amino acid peptide, known as Aβ 1-42, in plasma. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. | Baseline (randomization), 52 weeks | 
| Change From Baseline in Positron Emission Tomography (PET) Using Fluorine-18 Fluorodeoxyglucose (18F-FDG) at 76 Weeks | Measurement of local cerebral glucose metabolism by PET using the radioactive tracer 18F-FDG. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the Pons. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. | Baseline (randomization), 76 weeks | 
| Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks | The vMRI assessment of left and right hippocampal volume is reported. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. | Baseline (randomization), up to 76 weeks | 
| Change From Baseline in Amyloid Imaging Positron Emission Tomography (AV-45 PET) up to 76 Weeks | A radioactive tracer for PET that is a ligand for amyloid called AV-45. This permits the visualization of amyloid in the brains of Alzheimer's participants. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the cerebellar gray matter. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. | Baseline (randomization), up to 76 weeks | 
| Change From Baseline in Tau Concentration in Spinal Fluid up to 76 Weeks | Concentration of total tau in spinal fluid. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. | Baseline (randomization), up to 76 weeks | 
| LY450139 Population Pharmacokinetics: Clearance of LY450139 | Model estimated apparent oral clearance. Clearance is defined as the volume of plasma that is completely cleared of drug (LY450139) per unit time. | 6 weeks, 12 weeks, and 52 weeks | 
| LY450139 Population Pharmacokinetics: Volume of Distribution of LY450139 | Model-estimated apparent volume of distribution. Volume of distribution is a measure of the extent to which the drug distributes in the body. | 6 weeks, 12 weeks, and 52 weeks | 
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score at 76 Weeks | ADAS-Cog12 is ADAS-Cog11 augmented with delayed free recall measure, resulting in a total score ranging from 0 to 80. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. | Baseline (randomization), 76 weeks | 
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score at 76 Weeks | ADAS-Cog14 is ADAS-Cog11 augmented with delayed free recall, digit cancellation, and maze completion measures. A score of 0 to 10 for delayed free recall and a conversion code of 0 to 5 for digit cancellation and maze completion provide total score ranges for this extended ADAS-Cog14 of 0 to 90. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, concomitant standard of care (SOC) medication. | Baseline (randomization), 76 weeks | 
| Change From Baseline in Mini Mental State Examination (MMSE) Score at 76 Weeks | MMSE is a brief screening instrument used to assess cognitive function (orientation, memory, attention, and ability to name objects, follow verbal and written commands, write a sentence, and copy figures) in elderly participants. The total score ranges from 0 to 30; Lower score indicates greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. | Baseline (randomization), 76 weeks | 
| Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score at 76 Weeks | CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. | Baseline (randomization), 76 weeks | 
| Change From Baseline in Neuropsychiatric Inventory (NPI) Score at 76 Weeks | NPI assesses psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with the participant's behavior. Total score ranges from 12 to 144; Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. | Baseline (randomization), 76 weeks | 
| 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 | EQ-5D (proxy version) measures mobility, self-care, usual activities, pain/discomfort, anxiety/depression; each has 3 severity levels (no, some, severe problems) coded to a 1-digit number (1-3). Digits are combined into 5-digit number describing health state. Numerals 1-3 are not added for total score. VAS assesses caregiver's impression of participant's overall health state; scores range from 0 to 100; Lower scores indicate greater disease severity. Least Squares (LS) Mean value controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. | Baseline (randomization), 76 weeks | 
| Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Score (Number of Hospitalizations) up to 76 Weeks | Assesses healthcare resource utilization (formal and informal care). Information gathered on both caregivers (caregiving time, work status) and participants (accommodation and healthcare resource utilization) was collected from baseline and follow-up interviews; Reported number of hospitalizations per participant up to 76 weeks. Least Squares (LS) Mean value was controlled for age and investigator. | Baseline (randomization), up to 76 weeks | 
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score at 16 Weeks After Cessation of Study Drug | ADAS-Cog12 is ADAS-Cog11 augmented with delayed free recall measure, resulting in a total score ranging from 0 to 80. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. | Baseline (randomization), 16 weeks following treatment cessation | 
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score at 16 Weeks After Cessation of Study Drug | ADAS-Cog14 is ADAS-Cog11 augmented with delayed free recall, digit cancellation, and maze completion measures. A score of 0 to 10 for delayed free recall and a conversion code of 0 to 5 for digit cancellation and maze completion provide total score ranges for this extended ADAS-Cog14 of 0 to 90. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, concomitant standard of care (SOC) medication. | Baseline (randomization), 16 weeks following treatment cessation | 
| Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score at 4 Weeks After Cessation of Study Drug | Semi-structured interview; Participant's cognitive status rated across 6 domains of functioning: memory, orientation, judgment/problem solving, community affairs, home/hobbies, personal care. Severity score assigned for each of 6 domains. Total score (SB) ranges: 0 to 18; Higher scores=greater disease severity. LS Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. LY450139 dosing stopped due to evidence of dose-dependent cognitive/functional worsening. Participants followed off-dose for 32 weeks, but CDR-SB not assessed. | Baseline (randomization), 4 weeks following treatment cessation | 
| Change From Baseline in Neuropsychiatric Inventory (NPI) Score at 4 Weeks After Cessation of Study Drug | NPI assesses psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with participant's behavior. Total score ranges from 12 to 144; Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. All LY450139 dosing stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but NPI was not assessed | Baseline (randomization), 4 weeks following treatment cessation | 
| Change From Baseline in Mini Mental State Examination (MMSE) Score at 4 Weeks After Cessation of Study Drug | MMSE is a brief screening instrument used to assess cognitive function (orientation, memory, attention, ability to name objects, follow verbal/written commands, write a sentence, copy figures) in elderly participants. Total score ranges from 0 to 30; Lower score indicates greater disease severity. LS Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. All LY450139 dosing was stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but MMSE was not assessed. | Baseline (randomization), 4 weeks following treatment cessation | 
| 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 | EQ-5D (proxy version) measures mobility, self-care, usual activities, pain/discomfort, anxiety/depression. 3 severity levels: no, some, severe problems. VAS assesses caregiver's impression of participant's health state; score ranges from 0 to 100; Lower score indicates greater disease severity. LS Mean value controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. All LY450139 dosing was stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but EQ-5D VAS was not assessed. | Baseline (randomization), 4 weeks following treatment cessation | 
| Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Score (Number of Hospitalizations) at 4 Weeks After Cessation of Study Drug | RUD-Lite assesses healthcare resource utilization (formal and informal care). Information gathered on both caregivers (care-giving time, work status) and participants (accommodation, healthcare resource utilization) is collected. Reported number of participant hospitalizations. Least Squares (LS) Mean value controlled for age and investigator. All LY450139 dosing was stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but RUD-Lite was not assessed. | Baseline (randomization), 4 weeks following treatment cessation | 
| Change From Baseline in Amyloid Beta (Aβ) 1-42 Concentration in Spinal Fluid up to 76 Weeks | Concentration of an amino peptide known as Aβ 1-42 in spinal fluid. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. | Baseline (randomization), up to 76 weeks | 
| Change From Baseline in Phosphorylated-Tau (P-Tau) Concentration in Spinal Fluid | Concentration of p-tau in spinal fluid. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. | Baseline (randomization), up to 76 weeks |