Continued Safety Monitoring of Solanezumab (LY2062430) in Alzheimer's Disease

Study Overview
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Brief Summary
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This study is an open-label extension study in Alzheimer's patients who have completed participation in either solanezumab Clinical Trial H8A-MC-LZAM (NCT00905372) or H8A-MC-LZAN (NCT00904683).

Official Title
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Continued Efficacy and Safety Monitoring of Solanezumab, an Anti-Amyloid β Antibody in Patients With Alzheimer's Disease

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 Alzheimer's Disease Has completed participation in solanezumab Study LZAM or Study LZAN through 80 weeks Must continue to have a reliable caregiver who is in frequent contact with the patient for the entire study Must have good vein access to administer infusions Agrees not to participate in studies of any other investigational compounds for the duration of their participation in Study LZAO Exclusion Criteria: Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label use of a drug or device (other than the study drug/device used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Meets LZAM or LZAN discontinuation criteria at the end of treatment in LZAM or LZAN study

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Solanezumab<br> | Drug: Solanezumab<br>* 400 mg of solanezumab administered once every 4 weeks by intravenous infusion (IV) for up to 8 years.<br>* Other names: LY2062430;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Participants were from feeder studies (LZAM or LZAN). Placebo administered intravenously every 4 weeks through Week 80.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the Number of Participants With One or More Drug-Related Adverse Events (AEs) or Any Serious AEs (SAEs) | The number of participants with 1 or more AEs assessed as related to the study drug and is summarized cumulatively. In addition, the number of participants with 1 or more serious AEs is summarized cumulatively. A serious AE is defined as an event that results in death, initial or prolonged hospitalization, is life-threatening, leads to persistent or significant disability/incapacity, is associated with congenital anomaly/birth defect, or is considered significant by the investigator for any other reason. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 104-week Endpoint in Alzheimer's Disease Assessment Scale - Cognitive 14-Item Scale (ADAS-Cog14) | 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 was determined by mixed model repeated measures (MMRM) methodology with baseline, pooled investigator, treatment, visit, feeder visit 1 Mini-Mental State Examination (MMSE) status (mild/moderate), concomitant acetylcholinesterase inhibitors (AChEI)/Memantine use at baseline (yes/no), baseline age and treatment*visit. | Baseline, Week 104 | 
| Change From Baseline to 104-week Endpoint in Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL) | 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. LS Mean was determined by MMRM methodology with baseline, pooled investigator, treatment, visit, feeder visit 1 MMSE status (mild/moderate), concomitant AChEI/Memantine use at baseline (yes/no), baseline age and treatment*visit. | Baseline, Week 104 | 
| Change From Baseline to 104-week Endpoint 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 was determined by MMRM methodology with baseline, pooled investigator, treatment, visit, feeder visit 1 MMSE status (mild/moderate), concomitant AChEI/Memantine use at baseline (yes/no), baseline age and treatment*visit. | Baseline, Week 104 | 
| Change From Baseline to 104-week Endpoint in Neuropsychiatric Inventory (NPI) | The NPI is a questionnaire administered to caregivers that quantifies behavioral changes in dementia. Each of the 12 behavioral domains the caregiver reports as present are scored for Frequency, scale: 1 (Occasionally) to 4 (Very Frequently), and Severity, scale: 1 (Mild) to 3 (Severe). If the domain is reported by the caregiver as 'Not Affected,' that domain is scored as 0. The individual domain scores are calculated by multiplying the frequency times the severity for each domain. NPI Total Score is calculated by adding the individual domain scores together for all 12 domains, with a scores range from 0 to 144. Lower scores indicated less severity and higher scores indicated a greater severity of neuropsychiatric disturbance. LS Mean was determined by MMRM methodology with baseline, pooled investigator, treatment, visit, concomitant AChEI/Memantine use at baseline (yes/no), baseline age and treatment*visit. | Baseline, Week 104 | 
| Change From Baseline to 104-week Endpoint in Resource Utilization in Dementia - Lite (RUD-Lite) Caregiver Hours | The RUD-Lite is a caregiver-completed assessment designed to assess the amount of formal and informal resources used by participants and the primary caregiver. It is completed by the caregiver and compiles data on the following resources: length of time the caregiver spends giving care, assisting participants with basic activities of daily living (BADL: eating dressing, grooming, bathing); assisting participants with instrumental activities of daily living (IADLs: shopping, cooking, housekeeping, laundry, transportation, taking medication, managing finances), and providing supervision. Scores range from 0 to 24 hours. Higher values indicate greater resource use. LS Mean was determined by MMRM methodology with baseline, pooled investigator, treatment, visit, concomitant AChEI/Memantine use at baseline (yes/no), baseline age and treatment*visit. | Baseline, Week 104 | 
| Change From Baseline to 104-week Endpoint in EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) | EQ-5D (proxy version) is a generic, multidimensional, health-related, quality-of-life instrument assessing caregiver's impression of participants overall health state. Profile allows caregivers to rate participant's health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood using a 3-level scale: 1 (no problem), 2 (some problems), and 3 (major problems). These attribute combinations are converted into a weighted Health-State Index Score according to the United States (US) population-based algorithm. EQ-5D US Population-Based Index Scores range from -0.11 to 1.0. A score of 1.0 indicated perfect health. The Overall Health State Index Score is caregiver-reported using a visual analogue scale marked 0 (worst imaginable health) to 100 (best imaginable health state). LS Mean was determined by MMRM methodology with baseline, pooled investigator, treatment, visit, concomitant AChEI/Memantine use at baseline (yes/no), baseline age and treatment*visit. | Baseline, Week 104 | 
| Change From Baseline to 104-week Endpoint in Quality of Life in Alzheimer's Disease (QoL-AD) | The QoL-AD (Caregiver Total Score) is a disease-specific measure of quality of life for an Alzheimer's Disease (AD) population administered to the participant's primary caregiver, who answers on behalf of the participant. The assessment consists of 13 items covering physical health, energy, mood, living situations, memory, family, marriage, friends, chores, fun, money, self and life as a whole. The assessment is scored on a 4-point Likert scale with scores ranging from 1 (poor) to 4 (excellent). QoL-AD Total Score is defined as the sum of the 13 items with a scores range from 13 to 52. Higher scores denote a better quality of life. LS Mean was determined by MMRM methodology with baseline, pooled investigator, treatment, visit, concomitant AChEI/Memantine use at baseline (yes/no), baseline age and treatment*visit. | Baseline, Week 104 | 
| Change From Baseline to 104-week Endpoint in Mini-Mental State Examination (MMSE) | The MMSE is an instrument used to assess a participant's cognitive function. The instrument is divided into 2 sections. The first section measures orientation, memory, and attention with scores ranging from 0 to 21 (lower scores indicate greater impairment). The second section tests the ability of the participant to name objects, follow verbal and written commands, write a sentence, and copy figures with scores ranging from 0 to 9 (lower scores indicate greater impairment). The range for MMSE Total Score is 0 to 30. Lower scores indicate more impairment. LS Mean was determined by MMRM methodology with baseline, pooled investigator, treatment, visit, concomitant AChEI/Memantine use at baseline (yes/no), baseline age and treatment*visit. | Baseline, Week 104 | 
| Change From Baseline to 52-week Endpoint in Plasma Amyloid Beta (Aβ) Levels | Concentration of the peptide Aβ 1-40 and Aβ 1-42 in plasma measured by immunoassay. The immunoassays for plasma Aβ 1-40 and Aβ 1-42 peptides were modified to render them tolerant to the presence of Solanezumab which would otherwise interfere with non-modified assays. LS Mean was determined by MMRM methodology with baseline, pooled investigator, treatment, visit, feeder visit 1 MMSE status (mild/moderate), concomitant AChEI/Memantine use at baseline (yes/no), baseline age and treatment*visit. | Baseline, Week 52 | 
| Change From Baseline to 104-week Endpoint in Volumetric Magnetic Resonance Imaging (vMRI) | The vMRI assessment of right and left hippocampal volume is reported. LS Mean was determined by MMRM methodology with baseline, pooled investigator, treatment, visit, feeder visit 1 MMSE status (mild/moderate), concomitant AChEI/Memantine use at baseline (yes/no), baseline age and treatment*visit. | Baseline, Week 104 | 
| Change From Baseline to 104-week Endpoint in Alzheimer's Disease Assessment Scale - Cognitive Subscore 11-Item Scale (ADAS-Cog11) | The cognitive subscale of the ADAS (ADAS Cog11) was used as a primary efficacy measure and consists of 11 items assessing areas of function most typically impaired in Alzheimer's disease: orientation, verbal memory, language, and praxis. The scale ranges from 0 to 70, with higher scores indicating greater disease severity. LS Mean was determined by MMRM methodology with baseline, pooled investigator, treatment, visit, feeder visit 1 MMSE status (mild/moderate), concomitant AChEI/Memantine use at baseline (yes/no), baseline age and treatment*visit. | Baseline, Week 104 | 
| Mean Change From Baseline to Endpoint in Amyloid Imaging Parameters in Subjects With Mild Alzheimer's Disease | Florbetapir PET imaging was used to test for change from baseline. The hypothesis that amyloid burden was reduced in participants between the treatment groups from the feeder studies was tested. The change from baseline to the postbaseline visit of the composite summary standard uptake value ratio of florbetapir F18 was calculated. 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 and to subject-specific white matter. | Baseline, Week 104 |