Progress of Mild Alzheimer's Disease in Participants on Solanezumab Versus Placebo

Study Overview
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Brief Summary
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To test the idea that solanezumab will slow the cognitive decline of Alzheimer's Disease (AD) as compared with placebo in participants with mild AD.

Official Title
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Effect of Passive Immunization on the Progression of Mild Alzheimer's Disease: Solanezumab (LY2062430) Versus Placebo

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Solanezumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meets National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria for probable AD Has a Modified Hachinski Ischemia Scale score of less than or equal to 4 Has a Mini-Mental State Examination (MMSE) score of 20 through 26 at Screening visit Has a Geriatric Depression Scale score of less than or equal to 6 (on the staff-administered short form) Has had a magnetic resonance imaging (MRI) or computerized tomography (CT) scan performed within the past 2 years that has confirmed no findings inconsistent with a diagnosis of AD Has a florbetapir positron emission tomography (PET) scan or cerebrospinal fluid (CSF) result consistent with the presence of amyloid pathology at screening Exclusion Criteria: Does not have a reliable caregiver who is in frequent contact with the participant (defined as at least 10 hours per week), will accompany the participant to the office and/or be available by telephone at designated times, and will monitor administration of prescribed medications Meets National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS/AIREN) criteria for vascular dementia Has current serious or unstable illnesses including cardiovascular, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic (other than AD), psychiatric, immunologic, or hematologic disease and other conditions that, in the investigator's opinion, could interfere with the analyses of safety and efficacy in this study; or has a life expectancy of <2 years Has had a history within the last 5 years of a serious infectious disease affecting the brain or head trauma resulting in protracted loss of consciousness Has a history within the last 5 years of a primary or recurrent malignant disease with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal prostate-specific antigen posttreatment Has a known history of human immunodeficiency virus (HIV), clinically significant multiple or severe drug allergies, or severe posttreatment hypersensitivity reactions Has received acetylcholinesterase inhibitor (AChEIs), memantine and/or other AD therapy for less than 4 months or has less than 2 months of stable therapy on these treatments Has received medications that affect the central nervous system (CNS), except treatments for AD, for less than 4 weeks Has a history of chronic alcohol or drug abuse/dependence within the past 5 years Has a Visit 1 MRI with results showing >4 Amyloid-related Imaging Abnormality (ARIA), -hemorrhage /hemosiderin deposition (ARIA-H) or presence of ARIA-E (edema/effusions)

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 90 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 |
| --- | --- |
| Experimental: Solanezumab<br>Solanezumab 400 milligrams (mg) every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who complete the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks. | Drug: Solanezumab<br>* Administered Intravenously (IV)<br>* Other names: A Beta Antibody;|
| Placebo Comparator: Placebo<br>Placebo every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who complete the full 80 weeks of treatment/assessment and decide to continue will switch to solanezumab 400 mg every 4 weeks for up to an additional 208 weeks. | Drug: Placebo<br>* Administered IV<br>|

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 14 Item Subscore (ADAS-Cog14) | The ADAS is a rater administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviors characteristic of persons with AD. The cognitive subscale of the ADAS that was used as the primary efficacy measure consists of 14 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation, and maze completion measures. The ADAS-Cog14 scale ranges from 0 to 90. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Alzheimer's Disease Cooperative Study- Instrumental Activities of Daily Living (ADCS-iADL) | The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures both basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive 11 Item Subscore (ADAS-Cog11) | The cognitive subscale of ADAS (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. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 
| Change From Baseline in Mini-Mental State Examination (MMSE) | 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, and 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, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 
| Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) | The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures both basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 
| Change From Baseline in Functional Activities Questionnaire (FAQ) | FAQ is a 10-item, caregiver-based questionnaire and was administered to the study partner who was asked to rate the participant's ability to perform a variety of activities ranging from financial management, shopping, playing games, food preparation, traveling, keeping appointments, keeping track of current events, and understanding media. FAQ total score was calculated by adding the scores from each of the 10 items. A negative change indicated an improvement from baseline. FAQ Total Score is the sum of 10 items, ranging from 0 (best possible outcome) to 100 (worst possible outcome). LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 
| Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) | 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. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 
| Change From Baseline in Neuropsychiatric Inventory (NPI) | 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. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 
| Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) | Assesses healthcare resource utilization (formal and informal care). Information gathered on both caregivers (care-giving time, work status) and participants (accommodation and healthcare resource utilization) was gathered from baseline and follow-up interviews. Reported number of hospitalizations per participant up to 76 weeks. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 
| Change From Baseline in Quality of Life in Alzheimer's Disease (QoL-AD) | Assesses QoL for AD: participant rates mood, relationships, memory, finances, physical condition, and overall QoL assessment. Each of 13 items, rated on a 4-point scale. Sum of items=total score (range: 13 to 52). Higher scores indicate greater QoL. Participant's primary caregiver asked to complete same measure. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 
| Change From Baseline in 5-Dimensional EuroQol Quality of Life Scale Proxy Version (EQ-5D Proxy) | EQ-5D (proxy version) measures mobility, self-care, usual activities, pain/discomfort, anxiety/depression. 3 severity levels: no, some, severe problems. Visual analog scale (VAS) assesses caregiver's impression of participant's health state; score ranges: 0 to 100 millimeter (mm). Lower scores=greater disease severity LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 
| Change From Baseline in Integrated Alzheimer's Disease Rating Scale (iADRS) | Integrated Alzheimer's Disease Rating Scale is used to assess that solanezumab slows down the cognitive and functional decline associated with AD compared with placebo. iADRS is a simple linear combination of ADAS-Cog 13 or 14 and the ADCS-iADL. The scale ranges from 0 to 146, where lower scores indicate worse performance. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 
| Percentage of Participants of Cognitive and Functional Responders | Assess the proportion of participants who reach certain levels of cognitive and functional decline. Decline in cognition was defined as worsening from baseline by at least 6 or 9 points on the ADAS Cog14. If there is a cognitive decline of a specified cut-off or more at any time then the participant is considered a nonresponder. Functional nonresponders are participants who have not had any of the following at any time point: Clinically evident decline in ability to perform one or more basic ADL present at baseline; A clinically evident decline in ability to perform 20% or more of the instrumental ADL present at baseline; An increase in global CDR score of 1 point or more compared with baseline. A decline from no impairment to mild impairment (bADL, iADL is not considered clinically significant, but other declines of 1 or more points and any participant discontinuation within the first 6 months will be considered a non-responder. | Baseline through Week 80 | 
| Change From Baseline in Plasma Amyloid-Beta (Aβ) Species | Concentration of amino acid peptide known as Aβ 1-42 in plasma. The change in plasma Aβ analytes after treatment were assessed separately for each plasma Aβ parameter. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 
| Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | The vMRI assessment of right and left hippocampal atrophy, is reported. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 | 
| Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of Solanezumab (LY2062430) | Area Under the Concentration versus Time Curve was evaluated for Solanezumab. | Visit 2 (Post-dose), Visit 5, 9, 15 (Pre-dose, Post-dose) and Visit 22 (Pre-dose): Pre-dose before the infusion, Post-dose 30 minutes End of Infusion | 
| Change From Baseline in Florbetapir Positron Emission Tomography (PET) Scan | Florbetapir PET imaging was used to confirm the presence of amyloid pathology consistent with AD. Change from baseline was done to test the hypothesis that amyloid burden was reduced in participants in the treatment group. The change from baseline to the postbaseline visit of the composite summary standard uptake value ratio of florbetapir F18 was calculated. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. The composite summary measure is an unweighted average of the 6 smaller regions (anterior cingulate, frontal medial orbital, parietal, posterior cingulate, precuneus, and temporal) normalized to whole cerebellum or subject-specific white matter. | Baseline, Week 80 | 
| Change From Baseline in Cerebrospinal Fluid (CSF) Aβ Levels | Concentration of CSF parameters includes amino acid peptide known as Aβ 1-42 and Aβ 1-42. Analyses of these CSF biomarkers was conducted in a subset of participants (as an addendum to the protocol). The dependent variable for each CSF parameter was its change from baseline to endpoint. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. | Baseline, Week 80 |