Alzheimer's Disease
Conditions
Keywords
anti-amyloid, monoclonal antibody
Brief summary
The main purpose of this study is to investigate the safety and efficacy of the study drug solanezumab in participants with prodromal Alzheimer's disease (AD).
Interventions
DRUGSolanezumab
Administered IV
DRUGPlacebo
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Has a diagnosis by the study investigator of a clinical syndrome of cognitive impairment consistent with prodromal AD per International Working Group (IWG) diagnostic criteria or mild cognitive impairment (MCI) due to AD per National Institute on Aging-Alzheimer's Association (NIA-AA) diagnostic criteria. * Scores 17-28 on Montreal Cognitive Assessment (MoCA) at screening. * Scores \<27 on free recall cutoff score from the Free and Cued Selective Reminding Test (FCSRT) (Picture version) at screening. * Scores ≤4 on Modified Hachinski Ischemia Scale (MHIS). * Scores \>0 on the Functional Activities Questionnaire (FAQ). * Has a florbetapir positron emission tomography (PET) scan or cerebrospinal fluid (CSF) result at screening consistent with the presence of amyloid pathology.
Exclusion criteria
* Has had MRI or computerized tomography (CT) of brain within previous 2 years showing pathology that would be inconsistent with a diagnosis of AD. * Has known allergy to humanized monoclonal antibodies. * Has an ongoing clinically significant laboratory abnormality, as determined by the investigator. * Has screening MRI with results showing \>4 amyloid related imaging abnormalities H (ARIA-H) micro-hemorrhages or presence of ARIA-E. * Has any contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or a cardiac pacemaker that is not compatible with MRI. * Has received treatment with a stable dose of an acetylcholinesterase (AChEI) inhibitor or memantine for less than 2 months before randomization. (If a participant has recently stopped AChEIs and/or memantine, he or she must have discontinued treatment at least 2 months before randomization.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Alzheimer´s Disease Assessment Scale- Cognitive Subscale (ADAS-Cog14) Score | Baseline, 24 Months | ADAS-Cog14 is ADAS-Cog11 augmented with 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline on the Mini Mental Status Examination (MMSE) | Baseline, 24 Months | 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. |
| Change From Baseline on the Montreal Cognitive Assessment (MoCA) | Baseline, 24 Months | The MoCA will be used as the global cognitive screening instrument. It will also be administered in the clinical trial at baseline and the final visits of each phase as a secondary outcome measure of global cognition. Scores on the MoCA range from 0-30 with 26-30 indicating normal global cognition. |
| Change From Baseline on the Functional Activities Questionnaire (FAQ) | Baseline, 24 Months | 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 Writing checks, Assembling tax records, shopping, playing games, food preparation, traveling, keeping appointments, Traveling out of neighborhood, keeping track of current events and understanding media. FAQ total score was calculated by adding the scores from each of the 10 items. Each activity is rated on a scale from 0 to 3 (Never did and would have difficulty now = 1; Never did \[the activity\] but could do now = 0; Normal = 0; Has difficulty but does by self = 1; Requires assistance = 2; Dependent = 3). The maximum FAQ total score is 30, with higher scores indicating greater impairment. |
| Change From Baseline on the Neuropsychiatric Inventory (NPI) | Baseline, 24 Months | The NPI is a tool for assessing psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with the participant's behavior. The score ranges from 12 to 144, with higher scores indicating greater disease severity. |
| Change From Baseline on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) | Baseline, 24 Months | 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. |
| Change From Baseline on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Baseline, 24 Months | RBANS is a brief neurocognitive battery with four alternate forms, measuring immediate and delayed memory, attention, language, and visuospatial/constructional skills. |
| Change From Baseline on the Free and Cued Selective Reminding Test (FCSRT) | Baseline, 24 Months | The FCSRT is a neuropsychological test of memory under conditions that control attention and cognitive processing in order to obtain an assessment of memory unconfounded by normal age-related changes in cognition. |
| Change From Baseline on Alzheimer´s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL) | Baseline, 24 Months | The ADCS-MCI-ADL is a functional evaluation scale for MCI patients, based on information provided by an informant that describes the performance of participants in several ADLs. Total score ranges from 0 to 69; lower score indicates greater disease severity. |
| Change From Baseline on the EuroQol 5-Dimensional Health-Related Quality of Life Scale (EQ-5D) | Baseline, 24 Months | 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. Visual analogue scale (VAS) assesses caregiver's impression of participant's overall health state; scores range: 0 to 100. Lower scores indicate greater disease severity. |
| Change From Baseline on the Quality of Life in Alzheimer's Disease Scale (QoL-AD) | Baseline, 24 Months | QoL for AD assess 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: 13-52). Higher scores=greater QoL. |
| Change From Baseline in Concentration of Plasma Amyloid-β Peptide (Aβ) and Plasma Solanezumab | Baseline, 24 Months | Concentration of amino acid peptide known as Aβ 1-42 in plasma. |
| Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) | Baseline, 24 Months | MRI will be used to assess the effect of treatment on rate of whole brain volume. |
| Change From Baseline in Florbetapir Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVr) | Baseline, 24 Months | Florbetapir F18 PET used to assess the treatment effect in brain amyloid plaque deposition from baseline through 18 months as measured by florbetapir F18 PET Standardized Uptake Uptake Value ratio. |
| Change From Baseline in Concentration of Cerebrospinal Fluid (CSF) Aβ and CSF Tau Proteins | Baseline, 24 Months | Changes in CSF parameters, including total and free Aβ1-40 and Aβ1-42 species and total tau and P-tau181 peptides, will be assessed. |
| Change From Baseline in Neocortical Tau Deposits Using 18F-AV-1451 PET | Baseline, 24 Months | Biomarker change will be analyzed to provide biomarker-based evidence that solanezumab affects the underlying disease pathology. |
| Change From Baseline on the Resource Utilization in Dementia-Lite (RUD-Lite) | Baseline, 24 Months | RUD-Lite assesses the healthcare resource utilization of participants and their caregivers to determine the level of formal and informal care attributable to Alzheimer's Disease (AD). Information on both caregivers (caregiving time, work status) and participants (accommodation and healthcare resource utilization) is collected from the baseline and follow-up interviews. |
Countries
Canada, Finland, France, Germany, Italy, Japan, Poland, Puerto Rico, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
Participants were randomized by site and by use of florbetapir positron emission tomography (PET) scanning or cerebrospinal fluid (CSF) for study eligibility.
Participants by arm
| Arm | Count |
|---|---|
| Solanezumab Solanezumab given IV once every 4 weeks for up to 2 years. | 13 |
| Placebo Placebo given IV once every 4 weeks for up to 2 years. | 13 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Terminated by sponsor | 12 | 13 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | Solanezumab |
|---|---|---|---|
| ADAS-Cog14 at Baseline | 25.92 units on a scale STANDARD_DEVIATION 6.37 | 27.77 units on a scale STANDARD_DEVIATION 3.63 | 24.08 units on a scale STANDARD_DEVIATION 8 |
| Age, Continuous | 74.54 years STANDARD_DEVIATION 5.49 | 75.62 years STANDARD_DEVIATION 4.93 | 73.46 years STANDARD_DEVIATION 6.01 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 13 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 12 Participants | 9 Participants |
| Region of Enrollment Canada | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Japan | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Poland | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment United States | 21 Participants | 11 Participants | 10 Participants |
| Sex: Female, Male Female | 10 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 16 Participants | 7 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 7 / 13 | 1 / 13 |
| serious Total, serious adverse events | 2 / 13 | 1 / 13 |
Outcome results
Primary
Change From Baseline in Alzheimer´s Disease Assessment Scale- Cognitive Subscale (ADAS-Cog14) Score
ADAS-Cog14 is ADAS-Cog11 augmented with 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.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline in Concentration of Cerebrospinal Fluid (CSF) Aβ and CSF Tau Proteins
Changes in CSF parameters, including total and free Aβ1-40 and Aβ1-42 species and total tau and P-tau181 peptides, will be assessed.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline in Concentration of Plasma Amyloid-β Peptide (Aβ) and Plasma Solanezumab
Concentration of amino acid peptide known as Aβ 1-42 in plasma.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline in Florbetapir Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVr)
Florbetapir F18 PET used to assess the treatment effect in brain amyloid plaque deposition from baseline through 18 months as measured by florbetapir F18 PET Standardized Uptake Uptake Value ratio.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline in Neocortical Tau Deposits Using 18F-AV-1451 PET
Biomarker change will be analyzed to provide biomarker-based evidence that solanezumab affects the underlying disease pathology.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI)
MRI will be used to assess the effect of treatment on rate of whole brain volume.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline on Alzheimer´s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL)
The ADCS-MCI-ADL is a functional evaluation scale for MCI patients, based on information provided by an informant that describes the performance of participants in several ADLs. Total score ranges from 0 to 69; lower score indicates greater disease severity.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline on the Clinical Dementia Rating Scale 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.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline on the EuroQol 5-Dimensional Health-Related Quality of Life Scale (EQ-5D)
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. Visual analogue scale (VAS) assesses caregiver's impression of participant's overall health state; scores range: 0 to 100. Lower scores indicate greater disease severity.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline on the Free and Cued Selective Reminding Test (FCSRT)
The FCSRT is a neuropsychological test of memory under conditions that control attention and cognitive processing in order to obtain an assessment of memory unconfounded by normal age-related changes in cognition.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline on the 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 Writing checks, Assembling tax records, shopping, playing games, food preparation, traveling, keeping appointments, Traveling out of neighborhood, keeping track of current events and understanding media. FAQ total score was calculated by adding the scores from each of the 10 items. Each activity is rated on a scale from 0 to 3 (Never did and would have difficulty now = 1; Never did \[the activity\] but could do now = 0; Normal = 0; Has difficulty but does by self = 1; Requires assistance = 2; Dependent = 3). The maximum FAQ total score is 30, with higher scores indicating greater impairment.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline on the Mini Mental Status 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.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline on the Montreal Cognitive Assessment (MoCA)
The MoCA will be used as the global cognitive screening instrument. It will also be administered in the clinical trial at baseline and the final visits of each phase as a secondary outcome measure of global cognition. Scores on the MoCA range from 0-30 with 26-30 indicating normal global cognition.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline on the Neuropsychiatric Inventory (NPI)
The NPI is a tool for assessing psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with the participant's behavior. The score ranges from 12 to 144, with higher scores indicating greater disease severity.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline on the Quality of Life in Alzheimer's Disease Scale (QoL-AD)
QoL for AD assess 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: 13-52). Higher scores=greater QoL.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
RBANS is a brief neurocognitive battery with four alternate forms, measuring immediate and delayed memory, attention, language, and visuospatial/constructional skills.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.
Secondary
Change From Baseline on the Resource Utilization in Dementia-Lite (RUD-Lite)
RUD-Lite assesses the healthcare resource utilization of participants and their caregivers to determine the level of formal and informal care attributable to Alzheimer's Disease (AD). Information on both caregivers (caregiving time, work status) and participants (accommodation and healthcare resource utilization) is collected from the baseline and follow-up interviews.
Time frame: Baseline, 24 Months
Population: Zero participants were analyzed as no data collected.