Alzheimer's Disease, Amnestic Mild Cognitive Impairment
Conditions
Keywords
Intranasal insulin, Alzheimer's disease, Amnestic mild cognitive impairment, Dementia, Brain diseases, Memory problems, Mental disorders, Cognitive disorders
Brief summary
An urgent need exists to find effective treatments for Alzheimer's disease (AD) that can arrest or reverse the disease at its earliest stages. The emotional and financial burden of AD to patients, family members, and society is enormous, and is predicted to grow exponentially as the median population age increases. Current FDA-approved therapies are modestly effective at best. This study will examine a novel therapeutic approach using intranasal insulin (INI) that has shown promise in short-term clinical trials. If successful, information gained from the study has the potential to move INI forward rapidly as a therapy for AD. The study will also provide evidence for the mechanisms through which INI may produce benefits by examining key cerebral spinal fluid (CSF) biomarkers and hippocampal/entorhinal atrophy. These results will have considerable clinical and scientific significance, and provide therapeutically-relevant knowledge about insulin's effects on AD pathophysiology. Growing evidence has shown that insulin carries out multiple functions in the brain, and that insulin dysregulation may contribute to AD pathogenesis. This study will examine the effects of intranasally-administered insulin on cognition, entorhinal cortex and hippocampal atrophy, and cerebrospinal fluid (CSF) biomarkers in amnestic mild cognitive impairment (aMCI) or mild AD. It is hypothesized that after 12 months of treatment with INI compared to placebo, subjects will improve performance on a global measure of cognition, on a memory composite and on daily function. In addition to the examination of CSF biomarkers and hippocampal and entorhinal atrophy, the study aims to examine whether baseline AD biomarker profile, gender, or Apolipoprotein epsilon 4 (APOE-ε4) allele carriage predict treatment response. In this study, 240 people with aMCI or AD will be given either INI or placebo for 12 months, following an open-label period of 6 months where all participants will be given active drug. The study uses insulin as a therapeutic agent and intranasal administration focusing on nose to brain transport as a mode of delivery.
Interventions
20 IU bid taken twice daily (approximately 30 minutes after breakfast and dinner) for a total of 40 IU daily, which will be administered intranasally. The device used to administer insulin releases a metered dose into a chamber covering the participant's nose. The insulin is then inhaled by breathing evenly over a specified period.
DRUGPlacebo
Placebo taken twice daily (approximately 30 minutes after breakfast and dinner), which will be administered intranasally. The device used to administer placebo releases a metered dose into a chamber covering the participant's nose. The placebo is then inhaled by breathing evenly over a specified period.
Sponsors
National Institute on Aging (NIA)
Alzheimer's Therapeutic Research Institute
Wake Forest University Health Sciences
University of Southern California
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 85 Years
Healthy volunteers
No
Inclusion criteria
* Fluent in English or Spanish * Diagnosis of aMCI by Petersen criteria or probable AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria * Mini Mental State Examination (MMSE) score at screening is greater than or equal to 20 * Clinical Dementia Rating is 0.5-1 at screening * Logical Memory is less than or equal to 8 for 16 or more years of education, less than or equal to 4 for 8-15 years of education, less than or equal to 2 for 0-7 years of education. Scores measured at screening on Delayed Paragraph Recall (Paragraph A only) from the Wechsler Memory Scale-Revised * Able to complete baseline assessments * Modified Hachinski score of less than or equal to 4 * A study partner able to accompany the participant to most visits and answer questions about the participant * The study partner must have direct contact with the participant more than 2 days per week (minimum of 10 hours per week) and provide supervision of drug administration as needed * Stable medical condition for 3 months prior to screening visit * Stable medications for 4 weeks prior to the screening and baseline visits * Stable use of permitted medications * At least six years of education or work history * Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be clinically insignificant by the investigator * Visual and auditory acuity adequate for neuropsychological testing
Exclusion criteria
* A diagnosis of dementia other than probable AD * Probable AD with Down syndrome * History of clinically significant stroke * Current evidence or history in past two years of epilepsy, focal brain lesion, head injury with loss of consciousness or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse * Sensory impairment that would preclude the participant from participating in or cooperating with the protocol * Diabetes (type 1 or type II) requiring pharmacologic treatment (including both insulin dependent and non-insulin dependent diabetes mellitus) * Current or past use of insulin or any other anti-diabetic medication * Evidence of any significant clinical disorder or laboratory finding that renders the participant unsuitable for receiving investigational drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, endocrine, metabolic, renal or other systemic disease or laboratory abnormality. * Active neoplastic disease, history of cancer five years prior to screening (history of skin melanoma or stable prostate cancer are not excluded) * History of seizure within the past five years * Pregnancy or possible pregnancy * Contraindications to Lumbar Puncture (LP) procedure: prior lumbosacral spine surgery, severe degenerative joint disease or deformity of the spine, platelets is less than 100,000 or history of bleeding disorder * Use of anticoagulants warfarin (Coumadin) and dabigatran (Pradaxa) due to LP requirement * Contraindications for MRI (claustrophobia, craniofacial metal implants of any kind, pacemakers) * Residence in a skilled nursing facility at screening * Use of an investigational agent within two months or screening visit * Regular use of narcotics, anticonvulsants, medications with significant anticholinergic activity, antiparkinsonian medications or any other exclusionary medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Global Measure of Cognition as Measured by the Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12) | 12 months (blinded phase) followed by 6 months (open label phase) | The ADAS-Cog is a psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. The ADAS-Cog12 version was used in this study which includes Delayed Word Recall - a measure of episodic memory. Scores from the original portion of the test range from 0 (best) to 70 (worse) and then number of items not recalled ranging from 0-10 is added for a maximum score of 80. A positive change indicates cognitive worsening. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Memory Composite as Measured by Story Recall (Immediate Paragraph Recall and Delayed Paragraph Recall) and Free and Cued Selective Reminding Test (FCSRT) | 12 months (blinded phase) followed by 6 months (open label phase) | Memory Composite is composed from Story Recall (both Immediate Paragraph Recall and Delayed Paragraph Recall) and the Free and Cued Selective Reminding Test (FCSRT). Each of the three component scores were normalized by subtracting the baseline sample mean, and dividing by the baseline sample standard deviation, to form three separately standardized z-scores with mean 0 and standard deviation 1. The three Z-scores were summed to form the memory composite. No other standardization was performed on the sum. If any of Immediate Paragraph Recall, Delayed Paragraph Recall and FCSRT is missing, the memory composite is missing. Higher scores indicate better performance. In this study the scores ranged from about -4.74 to 9.15 at baseline, and about -5.10 to 9.43 across all visits over 12 months. |
| Change in Daily Functioning as Measured by the ADCS-MCI Activities of Daily Living (ADCS-ADL-MCI) | 12 months (blinded phase) and 6 months (open label phase) | The Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale (ADCS-ADL) is an activities of daily living questionnaire aimed at detecting functional decline in people with Mild Cognitive Impairment (MCI). In a structured interview format, informants are queried as to whether participants attempted each item in the inventory during the prior 4 weeks and their level of performance. The questions focus predominantly on instrumental activities of daily living scales (e.g. shopping, preparing meals, using household appliances, keeping appointments, reading). The total score can range from 0-54. A higher score indicates greater functional ability. |
| Change in Cognitive Deficit as Measured by Clinical Dementia Rating - Sum of Boxes (CDR-SB) | 12 months (blinded phase) followed by 6 months (open label phase) | The Clinical Dementia Rating - Sum of Boxes (CDR-SB) is administered as a structured interview with the participant and study partner, where impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or box scores, are added together to give the CDR-Sum of Boxes which ranges from 0-18 with higher scores indicated more impairment. |
| Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI) | Screen and Month 12 | MRI will be used to assess the effect of treatment on rate of hippocampal and entorhinal atrophy, and conduct exploratory analyses of other brain regions. Volume change was normalized to the participant's own intracranial volume to account for each participant's brain size. |
| Change in CSF Biomarkers of AD | Baseline and Month 12 | Quantify Abeta and Tau biomarkers in CSF |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Insulin (Humulin® R U-100) 50% of participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily for a total of 40 IU daily for 12 months, followed by a 6-month open label period. | 121 |
| Placebo 50% of participants received placebo treatment twice daily for 12 months followed by a 6-month open label period where all participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily (total of 40 IU daily). | 119 |
| Total | 240 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Investigator Recommendation | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | LP uncessessful | 0 | 1 |
| Overall Study | Non-Compliance | 2 | 0 |
| Overall Study | Perceived Lack of Efficacy | 1 | 0 |
| Overall Study | Withdrawal by Study Partner | 3 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 7 |
Baseline characteristics
| Characteristic | Placebo | Insulin (Humulin® R U-100) | Total |
|---|---|---|---|
| Age, Continuous | 71.06 years STANDARD_DEVIATION 6.79 | 70.46 years STANDARD_DEVIATION 7.38 | 70.76 years STANDARD_DEVIATION 7.09 |
| Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12) | 24.73 units on a scale STANDARD_DEVIATION 7.56 | 25.91 units on a scale STANDARD_DEVIATION 8.28 | 25.33 units on a scale STANDARD_DEVIATION 7.94 |
| ApoE-e4 carrier status (Positive vs Negative) Negative | 42 Participants | 42 Participants | 84 Participants |
| ApoE-e4 carrier status (Positive vs Negative) Positive | 77 Participants | 79 Participants | 156 Participants |
| Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) | 3.35 units on a scale STANDARD_DEVIATION 1.51 | 3.59 units on a scale STANDARD_DEVIATION 1.51 | 3.47 units on a scale STANDARD_DEVIATION 1.51 |
| Education | 16.31 years STANDARD_DEVIATION 2.92 | 16.07 years STANDARD_DEVIATION 2.64 | 16.19 years STANDARD_DEVIATION 2.78 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 5 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 113 Participants | 116 Participants | 229 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Memory Composite (Story Recall and the Free and Cued Selective Reminding Test) | 0.25 units on a scale STANDARD_DEVIATION 2.59 | -0.16 units on a scale STANDARD_DEVIATION 2.47 | 0.04 units on a scale STANDARD_DEVIATION 2.53 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 3 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 108 Participants | 117 Participants | 225 Participants |
| Sex: Female, Male Female | 58 Participants | 59 Participants | 117 Participants |
| Sex: Female, Male Male | 61 Participants | 62 Participants | 123 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 121 | 0 / 119 |
| other Total, other adverse events | 98 / 121 | 91 / 119 |
| serious Total, serious adverse events | 18 / 121 | 10 / 119 |
Outcome results
Primary
Change in Global Measure of Cognition as Measured by the Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12)
The ADAS-Cog is a psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. The ADAS-Cog12 version was used in this study which includes Delayed Word Recall - a measure of episodic memory. Scores from the original portion of the test range from 0 (best) to 70 (worse) and then number of items not recalled ranging from 0-10 is added for a maximum score of 80. A positive change indicates cognitive worsening.
Time frame: 12 months (blinded phase) followed by 6 months (open label phase)
Population: Modified intent-To-Treat \[mITT\] population: All randomized participants in Impel Device with ADAS-Cog12 observed at baseline and at least one follow-up.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin (Humulin® R U-100) | Change in Global Measure of Cognition as Measured by the Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12) | Blinded Phase (M12 change from Baseline) | 3.893 Modeled change score on a scale | Standard Error 0.643 |
| Insulin (Humulin® R U-100) | Change in Global Measure of Cognition as Measured by the Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12) | Open Label Phase (M18 change from Baseline) | 7.091 Modeled change score on a scale | Standard Error 0.937 |
| Placebo | Change in Global Measure of Cognition as Measured by the Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12) | Blinded Phase (M12 change from Baseline) | 3.867 Modeled change score on a scale | Standard Error 0.65 |
| Placebo | Change in Global Measure of Cognition as Measured by the Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12) | Open Label Phase (M18 change from Baseline) | 6.164 Modeled change score on a scale | Standard Error 0.942 |
Secondary
Change in Cognitive Deficit as Measured by Clinical Dementia Rating - Sum of Boxes (CDR-SB)
The Clinical Dementia Rating - Sum of Boxes (CDR-SB) is administered as a structured interview with the participant and study partner, where impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or box scores, are added together to give the CDR-Sum of Boxes which ranges from 0-18 with higher scores indicated more impairment.
Time frame: 12 months (blinded phase) followed by 6 months (open label phase)
Population: Modified intent-To-Treat \[mITT\] population: All randomized participants in Impel Device with CDR-SB observed at screening and at least one follow-up.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin (Humulin® R U-100) | Change in Cognitive Deficit as Measured by Clinical Dementia Rating - Sum of Boxes (CDR-SB) | Blinded Phase (M12 change from Baseline) | 1.682 Modeled change in test score | Standard Error 0.195 |
| Insulin (Humulin® R U-100) | Change in Cognitive Deficit as Measured by Clinical Dementia Rating - Sum of Boxes (CDR-SB) | Open Label Phase (M18 change from Baseline) | 2.361 Modeled change in test score | Standard Error 0.247 |
| Placebo | Change in Cognitive Deficit as Measured by Clinical Dementia Rating - Sum of Boxes (CDR-SB) | Blinded Phase (M12 change from Baseline) | 1.402 Modeled change in test score | Standard Error 0.196 |
| Placebo | Change in Cognitive Deficit as Measured by Clinical Dementia Rating - Sum of Boxes (CDR-SB) | Open Label Phase (M18 change from Baseline) | 2.122 Modeled change in test score | Standard Error 0.249 |
Secondary
Change in CSF Biomarkers of AD
Quantify Abeta and Tau biomarkers in CSF
Time frame: Baseline and Month 12
Population: CSF collection was optional; only a subset of participants underwent the LP procedure
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin (Humulin® R U-100) | Change in CSF Biomarkers of AD | Total Tau | -4.717 pg/ml | Standard Deviation 263.81 |
| Insulin (Humulin® R U-100) | Change in CSF Biomarkers of AD | Abeta 42 | -15.552 pg/ml | Standard Deviation 61.884 |
| Insulin (Humulin® R U-100) | Change in CSF Biomarkers of AD | Abeta 40 | -264.851 pg/ml | Standard Deviation 1168.995 |
| Insulin (Humulin® R U-100) | Change in CSF Biomarkers of AD | p-Tau | -2.764 pg/ml | Standard Deviation 18.729 |
| Placebo | Change in CSF Biomarkers of AD | Abeta 40 | -127.539 pg/ml | Standard Deviation 1600.604 |
| Placebo | Change in CSF Biomarkers of AD | Total Tau | 1.937 pg/ml | Standard Deviation 291.16 |
| Placebo | Change in CSF Biomarkers of AD | p-Tau | -0.567 pg/ml | Standard Deviation 25.293 |
| Placebo | Change in CSF Biomarkers of AD | Abeta 42 | -4.456 pg/ml | Standard Deviation 82.156 |
Secondary
Change in Daily Functioning as Measured by the ADCS-MCI Activities of Daily Living (ADCS-ADL-MCI)
The Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale (ADCS-ADL) is an activities of daily living questionnaire aimed at detecting functional decline in people with Mild Cognitive Impairment (MCI). In a structured interview format, informants are queried as to whether participants attempted each item in the inventory during the prior 4 weeks and their level of performance. The questions focus predominantly on instrumental activities of daily living scales (e.g. shopping, preparing meals, using household appliances, keeping appointments, reading). The total score can range from 0-54. A higher score indicates greater functional ability.
Time frame: 12 months (blinded phase) and 6 months (open label phase)
Population: Modified intent-To-Treat \[mITT\] population: All randomized participants in Impel Device with ADCS-ADL-MCI observed at baseline and at least one follow-up.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin (Humulin® R U-100) | Change in Daily Functioning as Measured by the ADCS-MCI Activities of Daily Living (ADCS-ADL-MCI) | Blinded Phase (M12 change from Baseline) | -3.63 modeled change score on a scale | Standard Error 0.769 |
| Insulin (Humulin® R U-100) | Change in Daily Functioning as Measured by the ADCS-MCI Activities of Daily Living (ADCS-ADL-MCI) | Open Label Phase (M18 change from baseline) | -7.35 modeled change score on a scale | Standard Error 0.925 |
| Placebo | Change in Daily Functioning as Measured by the ADCS-MCI Activities of Daily Living (ADCS-ADL-MCI) | Blinded Phase (M12 change from Baseline) | -4.26 modeled change score on a scale | Standard Error 0.779 |
| Placebo | Change in Daily Functioning as Measured by the ADCS-MCI Activities of Daily Living (ADCS-ADL-MCI) | Open Label Phase (M18 change from baseline) | -6.56 modeled change score on a scale | Standard Error 0.934 |
Secondary
Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI)
MRI will be used to assess the effect of treatment on rate of hippocampal and entorhinal atrophy, and conduct exploratory analyses of other brain regions. Volume change was normalized to the participant's own intracranial volume to account for each participant's brain size.
Time frame: Screen and Month 12
Population: Intent-To-Treat \[ITT\] population: All randomized participants in Impel Device. Follow-up visits include month 12 and early termination 1 (et1) visits. Percent change data is available for 3 subjects with et1 visit and 187 subjects with month 12 as follow-up.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin (Humulin® R U-100) | Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI) | Normalized hippocampal volume change | -0.01 % change in volume | Standard Deviation 0.02 |
| Insulin (Humulin® R U-100) | Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI) | Normalized entorhinal volume change | -0.01 % change in volume | Standard Deviation 0.03 |
| Insulin (Humulin® R U-100) | Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI) | Normalized whole brain volume change | -1.35 % change in volume | Standard Deviation 1.09 |
| Placebo | Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI) | Normalized hippocampal volume change | -0.02 % change in volume | Standard Deviation 0.02 |
| Placebo | Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI) | Normalized entorhinal volume change | -0.01 % change in volume | Standard Deviation 0.03 |
| Placebo | Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI) | Normalized whole brain volume change | -1.41 % change in volume | Standard Deviation 1.18 |
Secondary
Change in Memory Composite as Measured by Story Recall (Immediate Paragraph Recall and Delayed Paragraph Recall) and Free and Cued Selective Reminding Test (FCSRT)
Memory Composite is composed from Story Recall (both Immediate Paragraph Recall and Delayed Paragraph Recall) and the Free and Cued Selective Reminding Test (FCSRT). Each of the three component scores were normalized by subtracting the baseline sample mean, and dividing by the baseline sample standard deviation, to form three separately standardized z-scores with mean 0 and standard deviation 1. The three Z-scores were summed to form the memory composite. No other standardization was performed on the sum. If any of Immediate Paragraph Recall, Delayed Paragraph Recall and FCSRT is missing, the memory composite is missing. Higher scores indicate better performance. In this study the scores ranged from about -4.74 to 9.15 at baseline, and about -5.10 to 9.43 across all visits over 12 months.
Time frame: 12 months (blinded phase) followed by 6 months (open label phase)
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin (Humulin® R U-100) | Change in Memory Composite as Measured by Story Recall (Immediate Paragraph Recall and Delayed Paragraph Recall) and Free and Cued Selective Reminding Test (FCSRT) | Open Label Phase (M18 change from Baseline) | -0.594 modeled change score on a scale | Standard Error 0.183 |
| Insulin (Humulin® R U-100) | Change in Memory Composite as Measured by Story Recall (Immediate Paragraph Recall and Delayed Paragraph Recall) and Free and Cued Selective Reminding Test (FCSRT) | Blinded Phase (M12 change from Baseline) | -0.496 modeled change score on a scale | Standard Error 0.163 |
| Placebo | Change in Memory Composite as Measured by Story Recall (Immediate Paragraph Recall and Delayed Paragraph Recall) and Free and Cued Selective Reminding Test (FCSRT) | Open Label Phase (M18 change from Baseline) | -0.802 modeled change score on a scale | Standard Error 0.184 |
| Placebo | Change in Memory Composite as Measured by Story Recall (Immediate Paragraph Recall and Delayed Paragraph Recall) and Free and Cued Selective Reminding Test (FCSRT) | Blinded Phase (M12 change from Baseline) | -0.433 modeled change score on a scale | Standard Error 0.162 |