Alzheimer's Disease
Conditions
Brief summary
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.
Interventions
DRUGSolanezumab
Administered Intravenously (IV)
DRUGPlacebo
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to 90 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive 14 Item Subscore (ADAS-Cog14) | Baseline, Week 80 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive 11 Item Subscore (ADAS-Cog11) | Baseline, Week 80 | 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. |
| Change From Baseline in Mini-Mental State Examination (MMSE) | Baseline, Week 80 | 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. |
| Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) | Baseline, Week 80 | 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. |
| Change From Baseline in Functional Activities Questionnaire (FAQ) | Baseline, Week 80 | 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. |
| Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Baseline, Week 80 | 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. |
| Change From Baseline in Neuropsychiatric Inventory (NPI) | Baseline, Week 80 | 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. |
| Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) | Baseline, Week 80 | 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. |
| Change From Baseline in Quality of Life in Alzheimer's Disease (QoL-AD) | Baseline, Week 80 | 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. |
| Change From Baseline in Alzheimer's Disease Cooperative Study- Instrumental Activities of Daily Living (ADCS-iADL) | Baseline, Week 80 | 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. |
| Change From Baseline in Integrated Alzheimer's Disease Rating Scale (iADRS) | Baseline, Week 80 | 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. |
| Percentage of Participants of Cognitive and Functional Responders | Baseline through Week 80 | 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. |
| Change From Baseline in Plasma Amyloid-Beta (Aβ) Species | Baseline, Week 80 | 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. |
| Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Baseline, Week 80 | 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. |
| Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of Solanezumab (LY2062430) | 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 | Area Under the Concentration versus Time Curve was evaluated for Solanezumab. |
| Change From Baseline in Florbetapir Positron Emission Tomography (PET) Scan | Baseline, Week 80 | 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. |
| Change From Baseline in Cerebrospinal Fluid (CSF) Aβ Levels | Baseline, Week 80 | 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. |
| Change From Baseline in 5-Dimensional EuroQol Quality of Life Scale Proxy Version (EQ-5D Proxy) | Baseline, Week 80 | 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. |
Countries
Australia, Canada, France, Germany, Italy, Japan, Poland, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
Participants were excluded after study enrollment,if PET imaging or CSF results did not show evidence of brain amyloid pathology,a screening MRI with results \>4 ARIA-H(amyloid-related imaging abnormality-hemorrhage/hemosiderin deposition) or presence of ARIA-E(amyloid-related imaging abnormality-edema/effusions) and abnormal lab results were found.
Participants by arm
| Arm | Count |
|---|---|
| Solanezumab Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks. | 1,057 |
| Placebo 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.
Placebo: Administered IV | 1,072 |
| Total | 2,129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open Label Period | Adverse Event | 16 | 20 |
| Open Label Period | Death | 5 | 6 |
| Open Label Period | Lost to Follow-up | 1 | 1 |
| Open Label Period | Parent/Caregiver Decision | 33 | 34 |
| Open Label Period | Physician Decision | 4 | 4 |
| Open Label Period | Protocol Violation | 0 | 1 |
| Open Label Period | Sponsor Decision | 802 | 765 |
| Open Label Period | Withdrawal by Subject | 20 | 28 |
| Placebo Controlled Period | Adverse Event | 48 | 39 |
| Placebo Controlled Period | Caregiver Decision | 33 | 41 |
| Placebo Controlled Period | Death | 9 | 16 |
| Placebo Controlled Period | Entry Criteria Not Met | 5 | 9 |
| Placebo Controlled Period | Lost to Follow-up | 3 | 0 |
| Placebo Controlled Period | Physician Decision | 11 | 7 |
| Placebo Controlled Period | Protocol Violation | 1 | 7 |
| Placebo Controlled Period | Withdrawal by Subject | 33 | 45 |
Baseline characteristics
| Characteristic | Placebo | Total | Solanezumab |
|---|---|---|---|
| Age, Continuous | 73.26 years STANDARD_DEVIATION 7.966 | 72.98 years STANDARD_DEVIATION 7.894 | 72.69 years STANDARD_DEVIATION 7.814 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 49 Participants | 98 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 937 Participants | 1858 Participants | 921 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 71 Participants | 146 Participants | 75 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 33 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 894 Participants | 1772 Participants | 878 Participants |
| Region of Enrollment Australia | 36 Participants | 68 Participants | 32 Participants |
| Region of Enrollment Canada | 66 Participants | 127 Participants | 61 Participants |
| Region of Enrollment France | 86 Participants | 173 Participants | 87 Participants |
| Region of Enrollment Germany | 48 Participants | 96 Participants | 48 Participants |
| Region of Enrollment Italy | 52 Participants | 98 Participants | 46 Participants |
| Region of Enrollment Japan | 65 Participants | 132 Participants | 67 Participants |
| Region of Enrollment Poland | 50 Participants | 102 Participants | 52 Participants |
| Region of Enrollment Spain | 58 Participants | 114 Participants | 56 Participants |
| Region of Enrollment Sweden | 26 Participants | 52 Participants | 26 Participants |
| Region of Enrollment United Kingdom | 44 Participants | 89 Participants | 45 Participants |
| Region of Enrollment United States | 541 Participants | 1078 Participants | 537 Participants |
| Sex: Female, Male Female | 631 Participants | 1231 Participants | 600 Participants |
| Sex: Female, Male Male | 441 Participants | 898 Participants | 457 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 536 / 1,054 | 530 / 1,067 | 255 / 879 | 260 / 856 |
| serious Total, serious adverse events | 175 / 1,054 | 203 / 1,067 | 102 / 879 | 114 / 856 |
Outcome results
Primary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Solanezumab | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive 14 Item Subscore (ADAS-Cog14) | 6.65 Units on a scale | Standard Error 0.355 |
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive 14 Item Subscore (ADAS-Cog14) | 7.44 Units on a scale | Standard Error 0.356 |
p-value: 0.09595% CI: [-1.73, 0.14]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Solanezumab | Change From Baseline in 5-Dimensional EuroQol Quality of Life Scale Proxy Version (EQ-5D Proxy) | -1.10 mm | Standard Error 0.556 |
| Placebo | Change From Baseline in 5-Dimensional EuroQol Quality of Life Scale Proxy Version (EQ-5D Proxy) | -2.61 mm | Standard Error 0.562 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Solanezumab | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive 11 Item Subscore (ADAS-Cog11) | 5.22 Units on a scale | Standard Error 0.284 |
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive 11 Item Subscore (ADAS-Cog11) | 5.90 Units on a scale | Standard Error 0.285 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Solanezumab | Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) | -7.42 Units on a scale | Standard Error 0.386 |
| Placebo | Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) | -8.77 Units on a scale | Standard Error 0.387 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Solanezumab | Change From Baseline in Alzheimer's Disease Cooperative Study- Instrumental Activities of Daily Living (ADCS-iADL) | -6.17 Units on a scale | Standard Error 0.318 |
| Placebo | Change From Baseline in Alzheimer's Disease Cooperative Study- Instrumental Activities of Daily Living (ADCS-iADL) | -7.17 Units on a scale | Standard Error 0.32 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Solanezumab | Change From Baseline in Cerebrospinal Fluid (CSF) Aβ Levels | Free amyloid beta 1-42, CSF | -37.33 picogram/milliliter | Standard Error 7.507 |
| Solanezumab | Change From Baseline in Cerebrospinal Fluid (CSF) Aβ Levels | Modified amyloid beta 1-42, CSF | 315.69 picogram/milliliter | Standard Error 42.62 |
| Placebo | Change From Baseline in Cerebrospinal Fluid (CSF) Aβ Levels | Free amyloid beta 1-42, CSF | -9.27 picogram/milliliter | Standard Error 8.175 |
| Placebo | Change From Baseline in Cerebrospinal Fluid (CSF) Aβ Levels | Modified amyloid beta 1-42, CSF | -107.91 picogram/milliliter | Standard Error 42.907 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Solanezumab | Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) | 1.91 Units on a scale | Standard Deviation 2.442 |
| Placebo | Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) | 2.23 Units on a scale | Standard Deviation 2.692 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Solanezumab | Change From Baseline in Florbetapir Positron Emission Tomography (PET) Scan | Subject specific white matter corrected | 0.02 standard uptake value ratio | Standard Error 0.002 |
| Solanezumab | Change From Baseline in Florbetapir Positron Emission Tomography (PET) Scan | Mean whole cerebellum corrected | -0.01 standard uptake value ratio | Standard Error 0.005 |
| Placebo | Change From Baseline in Florbetapir Positron Emission Tomography (PET) Scan | Subject specific white matter corrected | 0.02 standard uptake value ratio | Standard Error 0.002 |
| Placebo | Change From Baseline in Florbetapir Positron Emission Tomography (PET) Scan | Mean whole cerebellum corrected | 0.00 standard uptake value ratio | Standard Error 0.005 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Solanezumab | Change From Baseline in Functional Activities Questionnaire (FAQ) | 5.17 Units on a scale | Standard Error 0.212 |
| Placebo | Change From Baseline in Functional Activities Questionnaire (FAQ) | 5.57 Units on a scale | Standard Error 0.213 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Solanezumab | Change From Baseline in Integrated Alzheimer's Disease Rating Scale (iADRS) | -12.92 units on a scale | Standard Error 0.533 |
| Placebo | Change From Baseline in Integrated Alzheimer's Disease Rating Scale (iADRS) | -14.59 units on a scale | Standard Error 0.537 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Solanezumab | Change From Baseline in Mini-Mental State Examination (MMSE) | -3.17 Units on a scale | Standard Error 0.154 |
| Placebo | Change From Baseline in Mini-Mental State Examination (MMSE) | -3.66 Units on a scale | Standard Error 0.156 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Solanezumab | Change From Baseline in Neuropsychiatric Inventory (NPI) | 2.26 Units on a scale | Standard Error 3.11 |
| Placebo | Change From Baseline in Neuropsychiatric Inventory (NPI) | 0.382 Units on a scale | Standard Error 0.387 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Solanezumab | Change From Baseline in Plasma Amyloid-Beta (Aβ) Species | Modified amyloid beta 1-40 | 172754.36 Picogram/milliliter | Standard Error 1613.534 |
| Solanezumab | Change From Baseline in Plasma Amyloid-Beta (Aβ) Species | Modified amyloid beta1-42 | 18485.26 Picogram/milliliter | Standard Error 104.913 |
| Placebo | Change From Baseline in Plasma Amyloid-Beta (Aβ) Species | Modified amyloid beta 1-40 | 262.98 Picogram/milliliter | Standard Error 1609.006 |
| Placebo | Change From Baseline in Plasma Amyloid-Beta (Aβ) Species | Modified amyloid beta1-42 | 15.75 Picogram/milliliter | Standard Error 105.237 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Solanezumab | Change From Baseline in Quality of Life in Alzheimer's Disease (QoL-AD) | -0.55 Units on a scale | Standard Error 0.158 |
| Placebo | Change From Baseline in Quality of Life in Alzheimer's Disease (QoL-AD) | -0.72 Units on a scale | Standard Error 0.161 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Solanezumab | Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) | Basic ADL | 0.34 Number of hospitalizations | Standard Error 0.058 |
| Solanezumab | Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) | Instrumental ADL | 0.55 Number of hospitalizations | Standard Error 0.099 |
| Solanezumab | Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) | Sum of Basic and Instrumental ADL | 0.91 Number of hospitalizations | Standard Error 0.132 |
| Solanezumab | Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) | Supervision | 0.72 Number of hospitalizations | Standard Error 0.125 |
| Placebo | Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) | Supervision | 0.88 Number of hospitalizations | Standard Error 0.127 |
| Placebo | Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) | Basic ADL | 0.35 Number of hospitalizations | Standard Error 0.058 |
| Placebo | Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) | Sum of Basic and Instrumental ADL | 0.86 Number of hospitalizations | Standard Error 0.134 |
| Placebo | Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) | Instrumental ADL | 0.50 Number of hospitalizations | Standard Error 0.1 |
Secondary
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.
Time frame: Baseline, Week 80
Population: All randomized participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Solanezumab | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Right entorhinal cortex atrophy | -77.3 Cubic millimeter (mm^3) | Standard Deviation 45.18 |
| Solanezumab | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Right hippocampal atrophy | -145.7 Cubic millimeter (mm^3) | Standard Deviation 75.42 |
| Solanezumab | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Left hippocampal atrophy | -142.3 Cubic millimeter (mm^3) | Standard Deviation 74.27 |
| Solanezumab | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Right hippocampal atrophy+Left hippocampal atrophy | -288.0 Cubic millimeter (mm^3) | Standard Deviation 135.19 |
| Solanezumab | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Left entorhinal cortex atrophy | -91.6 Cubic millimeter (mm^3) | Standard Deviation 47.6 |
| Solanezumab | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Right+Left entorhinal cortex atrophy | -169.0 Cubic millimeter (mm^3) | Standard Deviation 79.65 |
| Solanezumab | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Atrophy of whole brain volume | -22725.6 Cubic millimeter (mm^3) | Standard Deviation 11920.78 |
| Solanezumab | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Enlargement of Ventricular volume | 7055.4 Cubic millimeter (mm^3) | Standard Deviation 4580.36 |
| Placebo | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Enlargement of Ventricular volume | 7226.6 Cubic millimeter (mm^3) | Standard Deviation 4545.73 |
| Placebo | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Right entorhinal cortex atrophy | -80.8 Cubic millimeter (mm^3) | Standard Deviation 45.16 |
| Placebo | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Left entorhinal cortex atrophy | -95.2 Cubic millimeter (mm^3) | Standard Deviation 53.46 |
| Placebo | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Right hippocampal atrophy | -154.1 Cubic millimeter (mm^3) | Standard Deviation 81.06 |
| Placebo | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Atrophy of whole brain volume | -23500.5 Cubic millimeter (mm^3) | Standard Deviation 12000.09 |
| Placebo | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Left hippocampal atrophy | -146.3 Cubic millimeter (mm^3) | Standard Deviation 78.04 |
| Placebo | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Right+Left entorhinal cortex atrophy | -176.0 Cubic millimeter (mm^3) | Standard Deviation 86.11 |
| Placebo | Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Right hippocampal atrophy+Left hippocampal atrophy | -300.4 Cubic millimeter (mm^3) | Standard Deviation 138.52 |
Secondary
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.
Time frame: Baseline through Week 80
Population: All randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Solanezumab | Percentage of Participants of Cognitive and Functional Responders | Cognitive Responders: Cut-off 6 | 35.7 percentage of participants |
| Solanezumab | Percentage of Participants of Cognitive and Functional Responders | Cognitive Responders: Cut-off 9 | 55.2 percentage of participants |
| Solanezumab | Percentage of Participants of Cognitive and Functional Responders | Functional Responders | 38.0 percentage of participants |
| Placebo | Percentage of Participants of Cognitive and Functional Responders | Cognitive Responders: Cut-off 6 | 35.3 percentage of participants |
| Placebo | Percentage of Participants of Cognitive and Functional Responders | Cognitive Responders: Cut-off 9 | 52.3 percentage of participants |
| Placebo | Percentage of Participants of Cognitive and Functional Responders | Functional Responders | 36.8 percentage of participants |
Secondary
Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of Solanezumab (LY2062430)
Area Under the Concentration versus Time Curve was evaluated for Solanezumab.
Time frame: 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
Population: All randomized participants who received at least 1 dose of study medication (Solanezumab) with evaluable Solanezumab PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Solanezumab | Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of Solanezumab (LY2062430) | 43.2 milligram*hour per milliliter (mg*h/mL) | Geometric Coefficient of Variation 24.3 |