Alzheimers Disease
Conditions
Keywords
Placebo controlled, APOE4 carriers, Homozygotes, Heterozygotes, Brain Amyloid, Aβ lowering, BACE-1 inhibitor, CNP520, elderly, preclinical Alzheimers disease, Alzheimers Disease, Prevention, Unimpaired cognition
Brief summary
The purpose of this study is to determine the effects of CNP520 on cognition, global clinical status, and underlying AD pathology, as well as the safety of CNP520, in people at risk for the onset of clinical symptoms of AD based on their age, APOE genotype and elevated amyloid.
Detailed description
This trial was a randomized, double-blind, placebo-controlled, parallel group, adaptive design with variable treatment duration planned in cognitively unimpaired participants aged 60 to 75 years, with at least one apolipoprotein E allele (APOE4), (homozygotes (HMs) or heterozygotes (HTs)) and, if HTs, with evidence of elevated brain amyloid. The participants were randomized to either CNP520 50 mg, CNP520 15 mg or placebo a 2:1:2 ratio and was stratified based on amyloid status. The planned treatment period of 5 to 8 years was not achieved due to early study termination.
Interventions
DRUGCNP520 15mg
15 mg capsule
DRUGCNP520 50mg
50 mg capsule
OTHERMatching placebo
Matching placebo for 15 and 50 mg capsules
Sponsors
Amgen
Banner Alzheimer's Institute
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* consent to receive disclosure of their risk estimates to develop clinical symptoms of AD based on their APOE genotype and, if Heterozygotes, evidence of elevated brain amyloid. * Male or female, age 60 to 75 years inclusive. Females must be considered post-menopausal and not of child bearing potential * Cognitively unimpaired as evaluated by memory tests performed at screening. * Participant's willingness to have a study partner. * Carrier of at least one APOE4 gene if Heterozygotes, elevated brain amyloid (as measured by CSF Abeta or amyloid PET imaging).
Exclusion criteria
* Any disability that could have prevented the participants from completing all study requirements. - * Current medical or neurological condition that could have impacted cognition or performance on cognitive assessments. * Advanced, severe progressive or unstable disease that could have interfered with the safety, tolerability and study assessments, or put the participant at special risk. * History of malignancy of any organ system, treated or untreated, within the past 60 months. * Indication for, or current treatment with ChEIs and/or another AD treatment (e.g. memantine). * Contraindication or intolerance to MRI. * Brain MRI results showing findings unrelated to AD that, in the opinion of the Investigator might be a leading cause to future cognitive decline, could have posed a risk to the participant, or could have prevented a satisfactory MRI assessment for safety monitoring. * Suicidal Ideation in the past six months, or Suicidal Behavior in the past two years. * A positive drug screen at Screening, if, in the Investigator's opinion, was is due to drug abuse. * Significantly abnormal laboratory results at Screening, not as a result of a temporary condition. * Current clinically significant ECG findings. * Clinically relevant depigmenting or hypopigmenting conditions (e.g. albinism, vitiligo) or active / history of chronic urticaria in the past year.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) | Baseline to last cognitive assessment performed (up to day 648) | Event was defined as the first confirmed diagnosis of MCI due to Alzheimer's disease (AD) or dementia due to AD (whichever occurred first) after adjudication by the progression adjudication committee (PAC) as triggered either by an investigator diagnosis or an increase in the Clinical Dementia Rating (CDR) global score. An event had to be confirmed by the PAC at two consecutive visits. In case no confirmed event was observed for a participant, the observation was censored, and the censoring date was defined as the last date where the diagnostic classification was assessed. The Study was terminated and only confirmed events collected up to the data cut-off point were counted. Due to the early termination of the study only a small number of events were observed and time-to-event could not be analyzed. Kaplan-Meyer (KM) estimates were provided to estimate probability that a subject would have an event prior to the specified visit. |
| Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score | Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) | APCC is a composite score derived from the specific scores from the Repeatable Battery for the Assessment of Neurological Status (RBANS), Mini-Mental State Examination (MMSE) and the Raven's Progressive Matrices. The APCC score is a weighted score with ranges from from 0 to 100 where higher scores correspond to better cognitive performance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Everyday Cognition Scale (ECog-Subject) Total Scores | Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) | Everyday Cognition Scale (ECog) measures cognitively-relevant everyday abilities comprised of 39 items covering 6 cognitively-relevant domains: Everyday Memory, Everyday Language, Everyday Visuospatial Abilities, Everyday Planning, Everyday Organization, and Everyday Divided Attention. The questionnaire is a self-reported measure completed by both participant and study partner (informant). The total score for the 39 items ranges from 39 to 195, with greater scores indicating worse daily function. |
| Change in the Everyday Cognition Scale (ECog-Informant) Total Scores | Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) | Everyday Cognition Scale (ECog) measures cognitively-relevant everyday abilities comprised of 39 items covering 6 cognitively-relevant domains: Everyday Memory, Everyday Language, Everyday Visuospatial Abilities, Everyday Planning, Everyday Organization, and Everyday Divided Attention. The questionnaire is a self-reported measure completed by both participant and study partner (informant). The total score for the 39 items ranges from 39 to 195, with greater scores indicating worse daily function. |
| Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | Baseline up to study termination approximately 617 days | Safety MRI included sequences necessary for ascertainment of possible ARIA-E (Amyloid Related Imaging Abnormality-Edema), ARIA-H (Amyloid Related Imaging Abnormality- Hemorrhage, including superficial siderosis and microhemorrhages), assessment of recent infarcts and white matter integrity examination (White matter disease worsening) and a general assessment of brain abnormalities. |
| Annualized Percent Change on Volume of Brain Regions | Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) | Annualized % change from baseline in volume of specific brain regions of interest (ROIs): whole brain (WB), hippocampus (Hip), and lateral ventricles (LV). Annualized percentage change was calculated as (percentage per participant / time interval (in days)) x 365.25. Time interval (in days) was derived as date of current MRI assessment on study drug - date of baseline MRI assessment + 1. |
| Change in CSF Levels of Amyloid Beta 40 (Aβ40) | Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) | Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 40 (Aβ40) |
| Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score | Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) | The CDR was obtained through semi-structured interviews of participants and informants, and cognitive functioning was rated on a 5-point scale of functioning in six domains: memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care. The CDR global score ranged from zero to three, while the CDR-SOB was the sum of the ratings from the six domains, ranging from 0 to 18 with a minimum increment of 0.5. Higher scores indicated greater disease severity |
| Change in Neurofibrillary Tangle Burden as Measured by Standardized Uptake Ratio (SUVR) of PET Scans With Tau Radiotracer (Where Available) | Baseline to Months 24 and 60 | To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers |
| Change in Amyloid Deposition as Measured by Standardized Uptake Ratio (SUVR) of Positron Emission Tomography (PET) Scan With Amyloid Radiotracer | Baseline to Months 24 and 60 | To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers |
| Change in CSF Levels of Total Tau and Phosphorylated Tau | Baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648) | Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): total tau protein and phosphorylated tau protein levels |
| Change in Serum Neurofilaments | Baseline to Week 26, baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648) | Alzheimer's Disease-related biomarkers analyzed in blood serum: light chain neurofilaments (NfL) |
| Number of Suicidal Ideation or Behavior Events | Baseline up to study termination approximately 617 days | Prospective suicidality assessment was performed with the use of Columbia-Suicide Severity Rating Scale (C-SSRS), a questionnaire using a detailed branched logic algorithm evaluating participant's suicidality ideation and behavior. Answer yes on item 4 or 5 of the Suicidal Ideation section or yes on any item of the Suicidal Behavior section was considered positive. |
| Change in CSF Levels of Amyloid Beta 42 (Aβ42) | Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) | Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 42 (Aβ42). |
| Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) | Repeatable Battery for the Assessment of Neurological Status (RBANS) is a clinical tool designed to detect and characterize the earliest neurocognitive changes associated with dementia. The RBANS generates age-adjusted index scores for five neurocognitive domains: Immediate Memory, Visuospatial/Constructional, Language, Attention and Delayed Memory, which are used to calculate a Total Scale Index score. Index scores and total score range from 40 to 160 and a higher score indicates better cognitive functioning. |
Countries
Argentina, Australia, Belgium, Canada, Chile, China, Finland, France, Germany, Iceland, Israel, Italy, Japan, Mexico, Netherlands, Portugal, Puerto Rico, Singapore, South Africa, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
8970 participants were screened
Participants by arm
| Arm | Count |
|---|---|
| CNP520 50 mg 50 mg capsule taken orally once daily | 455 |
| CNP520 15 mg 15 mg capsule taken orally once daily | 233 |
| Placebo Matching placebo to 15 and 50 mg CNP520 taken orally once daily | 456 |
| Total | 1,144 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 10 | 3 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 |
| Overall Study | Non-compliance with study treatment | 1 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 1 |
| Overall Study | Protocol deviation | 0 | 1 | 0 |
| Overall Study | Study terminated by Sponsor | 424 | 222 | 438 |
| Overall Study | Technical problems | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 18 | 7 | 13 |
Baseline characteristics
| Characteristic | CNP520 50 mg | CNP520 15 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Customized <=64 | 76 participants | 45 participants | 80 participants | 201 participants |
| Age, Customized 65-69 | 181 participants | 82 participants | 162 participants | 425 participants |
| Age, Customized >70 | 198 participants | 106 participants | 214 participants | 518 participants |
| Baseline cognitive scale assessment APCC score | 74.6 scores on a scale STANDARD_DEVIATION 6.68 | 75.8 scores on a scale STANDARD_DEVIATION 6.81 | 74.9 scores on a scale STANDARD_DEVIATION 7.16 | 75.0 scores on a scale STANDARD_DEVIATION 6.91 |
| Baseline cognitive scale assessment CDR-SOB | 0.19 scores on a scale STANDARD_DEVIATION 0.389 | 0.16 scores on a scale STANDARD_DEVIATION 0.358 | 0.14 scores on a scale STANDARD_DEVIATION 0.358 | 0.16 scores on a scale STANDARD_DEVIATION 0.371 |
| Baseline cognitive scale assessment RBANS Total | 100.5 scores on a scale STANDARD_DEVIATION 11.96 | 102.0 scores on a scale STANDARD_DEVIATION 12.09 | 100.7 scores on a scale STANDARD_DEVIATION 12.42 | 100.9 scores on a scale STANDARD_DEVIATION 12.18 |
| Race/Ethnicity, Customized Asian | 18 participants | 12 participants | 22 participants | 52 participants |
| Race/Ethnicity, Customized Black | 7 participants | 1 participants | 5 participants | 13 participants |
| Race/Ethnicity, Customized Caucasian | 416 participants | 213 participants | 422 participants | 1051 participants |
| Race/Ethnicity, Customized Native American | 3 participants | 2 participants | 1 participants | 6 participants |
| Race/Ethnicity, Customized Other | 4 participants | 2 participants | 0 participants | 6 participants |
| Race/Ethnicity, Customized Pacific Islander | 2 participants | 1 participants | 0 participants | 3 participants |
| Race/Ethnicity, Customized Unknown | 5 participants | 2 participants | 6 participants | 13 participants |
| Sex: Female, Male Female | 284 Participants | 148 Participants | 288 Participants | 720 Participants |
| Sex: Female, Male Male | 171 Participants | 85 Participants | 168 Participants | 424 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 455 | 0 / 233 | 0 / 456 |
| other Total, other adverse events | 137 / 455 | 62 / 233 | 89 / 456 |
| serious Total, serious adverse events | 15 / 455 | 9 / 233 | 15 / 456 |
Outcome results
Primary
Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score
APCC is a composite score derived from the specific scores from the Repeatable Battery for the Assessment of Neurological Status (RBANS), Mini-Mental State Examination (MMSE) and the Raven's Progressive Matrices. The APCC score is a weighted score with ranges from from 0 to 100 where higher scores correspond to better cognitive performance.
Time frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Population: Safety analysis set - only participants with a value at both Baseline and that visit are included. Last on-treatment is the last assessment before or at last day on study drug + 31 days. Last off-treatment is the last assessment after last day on study drug + 31 days.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNP520 50 mg | Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score | Last on-treatment n=269,144,275 | -2.2 Total scores | Standard Deviation 4.88 |
| CNP520 50 mg | Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score | Week 26 n=160,79,162 | -3.1 Total scores | Standard Deviation 5.2 |
| CNP520 50 mg | Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score | Last off-treatment n=255,124,260 | -0.8 Total scores | Standard Deviation 4.56 |
| CNP520 15 mg | Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score | Week 26 n=160,79,162 | -2.9 Total scores | Standard Deviation 5 |
| CNP520 15 mg | Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score | Last on-treatment n=269,144,275 | -0.8 Total scores | Standard Deviation 4.67 |
| CNP520 15 mg | Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score | Last off-treatment n=255,124,260 | -0.8 Total scores | Standard Deviation 4.38 |
| Placebo | Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score | Week 26 n=160,79,162 | -1.7 Total scores | Standard Deviation 4.44 |
| Placebo | Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score | Last off-treatment n=255,124,260 | -0.8 Total scores | Standard Deviation 4.64 |
| Placebo | Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score | Last on-treatment n=269,144,275 | -1.3 Total scores | Standard Deviation 5.21 |
Primary
Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD))
Event was defined as the first confirmed diagnosis of MCI due to Alzheimer's disease (AD) or dementia due to AD (whichever occurred first) after adjudication by the progression adjudication committee (PAC) as triggered either by an investigator diagnosis or an increase in the Clinical Dementia Rating (CDR) global score. An event had to be confirmed by the PAC at two consecutive visits. In case no confirmed event was observed for a participant, the observation was censored, and the censoring date was defined as the last date where the diagnostic classification was assessed. The Study was terminated and only confirmed events collected up to the data cut-off point were counted. Due to the early termination of the study only a small number of events were observed and time-to-event could not be analyzed. Kaplan-Meyer (KM) estimates were provided to estimate probability that a subject would have an event prior to the specified visit.
Time frame: Baseline to last cognitive assessment performed (up to day 648)
Population: Safety analysis set; n=number of participants at risk to experience an event at the time-point
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CNP520 50 mg | Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) | Week 52 n=52,24,57 | 0.97 probability of an event |
| CNP520 50 mg | Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) | Week 26 n=232,123,250 | 0.99 probability of an event |
| CNP520 50 mg | Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) | Week 78 n=6,2,2 | 0.97 probability of an event |
| CNP520 15 mg | Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) | Week 52 n=52,24,57 | 0.99 probability of an event |
| CNP520 15 mg | Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) | Week 26 n=232,123,250 | 1.00 probability of an event |
| CNP520 15 mg | Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) | Week 78 n=6,2,2 | 0.99 probability of an event |
| Placebo | Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) | Week 26 n=232,123,250 | 1.00 probability of an event |
| Placebo | Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) | Week 78 n=6,2,2 | 0.97 probability of an event |
| Placebo | Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) | Week 52 n=52,24,57 | 0.99 probability of an event |
Secondary
Annualized Percent Change on Volume of Brain Regions
Annualized % change from baseline in volume of specific brain regions of interest (ROIs): whole brain (WB), hippocampus (Hip), and lateral ventricles (LV). Annualized percentage change was calculated as (percentage per participant / time interval (in days)) x 365.25. Time interval (in days) was derived as date of current MRI assessment on study drug - date of baseline MRI assessment + 1.
Time frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Population: Safety analysis set - only participants with a value at both Baseline and that visit are included. Last on-treatment is the last assessment before or at last day on study drug + 31 days. Last off-treatment is the last assessment after last day on study drug + 31 days.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNP520 50 mg | Annualized Percent Change on Volume of Brain Regions | Hip Week 26 n=169,83,169 | -2.0993 Percentage of volume change | Standard Deviation 2.77159 |
| CNP520 50 mg | Annualized Percent Change on Volume of Brain Regions | WB Week 26 n=169,83,169 | -1.1016 Percentage of volume change | Standard Deviation 1.03196 |
| CNP520 50 mg | Annualized Percent Change on Volume of Brain Regions | LV Last on-treatment n=179,85,182 | 5.0974 Percentage of volume change | Standard Deviation 5.31542 |
| CNP520 50 mg | Annualized Percent Change on Volume of Brain Regions | WB Last off-treatment n=72,44,81 | -0.6984 Percentage of volume change | Standard Deviation 0.73644 |
| CNP520 50 mg | Annualized Percent Change on Volume of Brain Regions | LV Last off-treatment n=72,44,81 | 4.0014 Percentage of volume change | Standard Deviation 4.29087 |
| CNP520 50 mg | Annualized Percent Change on Volume of Brain Regions | Hip Last off-treatment n=72,44,81 | -1.3755 Percentage of volume change | Standard Deviation 1.90613 |
| CNP520 50 mg | Annualized Percent Change on Volume of Brain Regions | Hip Last on-treatment n=179,85,182 | -2.0052 Percentage of volume change | Standard Deviation 2.65898 |
| CNP520 50 mg | Annualized Percent Change on Volume of Brain Regions | WB Last on-treatment n=179,85,182 | -1.0427 Percentage of volume change | Standard Deviation 0.93751 |
| CNP520 50 mg | Annualized Percent Change on Volume of Brain Regions | LV Week 26 n=169,83,169 | 5.4388 Percentage of volume change | Standard Deviation 5.9187 |
| CNP520 15 mg | Annualized Percent Change on Volume of Brain Regions | Hip Week 26 n=169,83,169 | -1.9100 Percentage of volume change | Standard Deviation 2.31406 |
| CNP520 15 mg | Annualized Percent Change on Volume of Brain Regions | Hip Last on-treatment n=179,85,182 | -1.7909 Percentage of volume change | Standard Deviation 2.06883 |
| CNP520 15 mg | Annualized Percent Change on Volume of Brain Regions | Hip Last off-treatment n=72,44,81 | -1.2522 Percentage of volume change | Standard Deviation 2.23213 |
| CNP520 15 mg | Annualized Percent Change on Volume of Brain Regions | LV Week 26 n=169,83,169 | 5.3457 Percentage of volume change | Standard Deviation 4.67788 |
| CNP520 15 mg | Annualized Percent Change on Volume of Brain Regions | LV Last on-treatment n=179,85,182 | 5.0822 Percentage of volume change | Standard Deviation 3.88165 |
| CNP520 15 mg | Annualized Percent Change on Volume of Brain Regions | LV Last off-treatment n=72,44,81 | 3.9355 Percentage of volume change | Standard Deviation 5.17657 |
| CNP520 15 mg | Annualized Percent Change on Volume of Brain Regions | WB Week 26 n=169,83,169 | -0.9348 Percentage of volume change | Standard Deviation 0.85477 |
| CNP520 15 mg | Annualized Percent Change on Volume of Brain Regions | WB Last on-treatment n=179,85,182 | -0.9205 Percentage of volume change | Standard Deviation 0.75633 |
| CNP520 15 mg | Annualized Percent Change on Volume of Brain Regions | WB Last off-treatment n=72,44,81 | -0.9188 Percentage of volume change | Standard Deviation 0.94516 |
| Placebo | Annualized Percent Change on Volume of Brain Regions | Hip Week 26 n=169,83,169 | -1.2113 Percentage of volume change | Standard Deviation 2.71764 |
| Placebo | Annualized Percent Change on Volume of Brain Regions | WB Week 26 n=169,83,169 | -0.5552 Percentage of volume change | Standard Deviation 1.21385 |
| Placebo | Annualized Percent Change on Volume of Brain Regions | Hip Last off-treatment n=72,44,81 | -1.1929 Percentage of volume change | Standard Deviation 1.81333 |
| Placebo | Annualized Percent Change on Volume of Brain Regions | WB Last off-treatment n=72,44,81 | -0.5811 Percentage of volume change | Standard Deviation 0.75412 |
| Placebo | Annualized Percent Change on Volume of Brain Regions | WB Last on-treatment n=179,85,182 | -0.5378 Percentage of volume change | Standard Deviation 1.09542 |
| Placebo | Annualized Percent Change on Volume of Brain Regions | LV Last on-treatment n=179,85,182 | 3.4582 Percentage of volume change | Standard Deviation 4.35888 |
| Placebo | Annualized Percent Change on Volume of Brain Regions | Hip Last on-treatment n=179,85,182 | -1.1628 Percentage of volume change | Standard Deviation 2.56183 |
| Placebo | Annualized Percent Change on Volume of Brain Regions | LV Last off-treatment n=72,44,81 | 3.3851 Percentage of volume change | Standard Deviation 3.38576 |
| Placebo | Annualized Percent Change on Volume of Brain Regions | LV Week 26 n=169,83,169 | 3.5415 Percentage of volume change | Standard Deviation 4.75268 |
Secondary
Change in Amyloid Deposition as Measured by Standardized Uptake Ratio (SUVR) of Positron Emission Tomography (PET) Scan With Amyloid Radiotracer
To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers
Time frame: Baseline to Months 24 and 60
Population: No available data since no post-baseline (month 24 and 60) PET scan could be obtained due to the early termination of the trial.
Secondary
Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score
The CDR was obtained through semi-structured interviews of participants and informants, and cognitive functioning was rated on a 5-point scale of functioning in six domains: memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care. The CDR global score ranged from zero to three, while the CDR-SOB was the sum of the ratings from the six domains, ranging from 0 to 18 with a minimum increment of 0.5. Higher scores indicated greater disease severity
Time frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Population: Safety analysis set - only participants with a value at both Baseline and that visit are included. Last on-treatment is the last assessment before or at last day on study drug + 31 days. Last off-treatment is the last assessment after last day on study drug + 31 days.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNP520 50 mg | Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score | Last on-treatment n=265,144,267 | 0.15 Scores on a scale | Standard Deviation 0.557 |
| CNP520 50 mg | Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score | Week 26 n=160,78,160 | 0.17 Scores on a scale | Standard Deviation 0.606 |
| CNP520 50 mg | Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score | Last off-treatment n=254,117,256 | 0.09 Scores on a scale | Standard Deviation 0.525 |
| CNP520 15 mg | Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score | Last on-treatment n=265,144,267 | 0.08 Scores on a scale | Standard Deviation 0.449 |
| CNP520 15 mg | Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score | Week 26 n=160,78,160 | 0.20 Scores on a scale | Standard Deviation 0.451 |
| CNP520 15 mg | Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score | Last off-treatment n=254,117,256 | 0.07 Scores on a scale | Standard Deviation 0.401 |
| Placebo | Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score | Week 26 n=160,78,160 | 0.08 Scores on a scale | Standard Deviation 0.385 |
| Placebo | Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score | Last off-treatment n=254,117,256 | 0.10 Scores on a scale | Standard Deviation 0.565 |
| Placebo | Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score | Last on-treatment n=265,144,267 | 0.10 Scores on a scale | Standard Deviation 0.468 |
Secondary
Change in CSF Levels of Amyloid Beta 40 (Aβ40)
Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 40 (Aβ40)
Time frame: Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Population: Safety analysis set - only participants with a value at both Baseline and that visit are included. Last on-treatment is the last assessment before or at last day on study drug + 31 days. Last off-treatment is the last assessment after last day on study drug + 31 days.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNP520 50 mg | Change in CSF Levels of Amyloid Beta 40 (Aβ40) | AB40 Last on-treatment n=1,0,1 | -7.320 ng/mL | — |
| CNP520 50 mg | Change in CSF Levels of Amyloid Beta 40 (Aβ40) | AB40 Last off-treatment n=16,5,13 | -1.492 ng/mL | Standard Deviation 1.9263 |
| CNP520 15 mg | Change in CSF Levels of Amyloid Beta 40 (Aβ40) | AB40 Last off-treatment n=16,5,13 | 0.804 ng/mL | Standard Deviation 1.922 |
| Placebo | Change in CSF Levels of Amyloid Beta 40 (Aβ40) | AB40 Last on-treatment n=1,0,1 | -0.760 ng/mL | — |
| Placebo | Change in CSF Levels of Amyloid Beta 40 (Aβ40) | AB40 Last off-treatment n=16,5,13 | -1.172 ng/mL | Standard Deviation 1.7408 |
Secondary
Change in CSF Levels of Amyloid Beta 42 (Aβ42)
Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 42 (Aβ42).
Time frame: Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Population: Safety analysis set - only participants with a value at both Baseline and that visit are included. Last on-treatment is the last assessment before or at last day on study drug + 31 days. Last off-treatment is the last assessment after last day on study drug + 31 days.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNP520 50 mg | Change in CSF Levels of Amyloid Beta 42 (Aβ42) | AB42 Last on-treatment n=1,0,1 | -366.200 pg/mL | — |
| CNP520 50 mg | Change in CSF Levels of Amyloid Beta 42 (Aβ42) | AB42 Last off-treatment n=16,5,13 | 20.431 pg/mL | Standard Deviation 74.5595 |
| CNP520 15 mg | Change in CSF Levels of Amyloid Beta 42 (Aβ42) | AB42 Last off-treatment n=16,5,13 | -68.660 pg/mL | Standard Deviation 62.8505 |
| Placebo | Change in CSF Levels of Amyloid Beta 42 (Aβ42) | AB42 Last on-treatment n=1,0,1 | -61.300 pg/mL | — |
| Placebo | Change in CSF Levels of Amyloid Beta 42 (Aβ42) | AB42 Last off-treatment n=16,5,13 | 21.246 pg/mL | Standard Deviation 104.3395 |
Secondary
Change in CSF Levels of Total Tau and Phosphorylated Tau
Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): total tau protein and phosphorylated tau protein levels
Time frame: Baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648)
Population: Safety analysis set - only participants with a value at both Baseline and that visit are included. Last on-treatment is the last assessment before or at last day on study drug + 31 days. Last off-treatment is the last assessment after last day on study drug + 31 days.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNP520 50 mg | Change in CSF Levels of Total Tau and Phosphorylated Tau | Total tau - Last on-treatment n=1,0,1 | 40.000 pg/mL | — |
| CNP520 50 mg | Change in CSF Levels of Total Tau and Phosphorylated Tau | Total tau - Last off-treatment n=16,5,13 | -22.119 pg/mL | Standard Deviation 28.6218 |
| CNP520 50 mg | Change in CSF Levels of Total Tau and Phosphorylated Tau | Phosphorylated tau - Last on-treatment n=1,0,1 | -2.360 pg/mL | — |
| CNP520 50 mg | Change in CSF Levels of Total Tau and Phosphorylated Tau | Phosphorylated tau - Last off-treatment n=16,5,13 | -1.849 pg/mL | Standard Deviation 2.3397 |
| CNP520 15 mg | Change in CSF Levels of Total Tau and Phosphorylated Tau | Phosphorylated tau - Last off-treatment n=16,5,13 | -0.852 pg/mL | Standard Deviation 2.7005 |
| CNP520 15 mg | Change in CSF Levels of Total Tau and Phosphorylated Tau | Total tau - Last off-treatment n=16,5,13 | -3.320 pg/mL | Standard Deviation 21.1548 |
| Placebo | Change in CSF Levels of Total Tau and Phosphorylated Tau | Total tau - Last off-treatment n=16,5,13 | -3.238 pg/mL | Standard Deviation 23.4442 |
| Placebo | Change in CSF Levels of Total Tau and Phosphorylated Tau | Phosphorylated tau - Last on-treatment n=1,0,1 | -0.550 pg/mL | — |
| Placebo | Change in CSF Levels of Total Tau and Phosphorylated Tau | Total tau - Last on-treatment n=1,0,1 | -12.600 pg/mL | — |
| Placebo | Change in CSF Levels of Total Tau and Phosphorylated Tau | Phosphorylated tau - Last off-treatment n=16,5,13 | 0.065 pg/mL | Standard Deviation 1.3032 |
Secondary
Change in Neurofibrillary Tangle Burden as Measured by Standardized Uptake Ratio (SUVR) of PET Scans With Tau Radiotracer (Where Available)
To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers
Time frame: Baseline to Months 24 and 60
Population: No available data since no post-baseline (month 24 and 60) PET scan could be obtained due to the early termination of the trial.
Secondary
Change in Serum Neurofilaments
Alzheimer's Disease-related biomarkers analyzed in blood serum: light chain neurofilaments (NfL)
Time frame: Baseline to Week 26, baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648)
Population: Safety analysis set - only participants with a value at both Baseline and that visit are included. Last on-treatment is the last assessment before or at last day on study drug + 31 days. Last off-treatment is the last assessment after last day on study drug + 31 days.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNP520 50 mg | Change in Serum Neurofilaments | Last off-treatment n=5,2,1 | -2.764 pg/mL | Standard Deviation 3.0981 |
| CNP520 50 mg | Change in Serum Neurofilaments | Last on-treatment n=33,15,40 | 0.932 pg/mL | Standard Deviation 4.2494 |
| CNP520 50 mg | Change in Serum Neurofilaments | Week 26 n=33,17,38 | 0.622 pg/mL | Standard Deviation 4.5576 |
| CNP520 15 mg | Change in Serum Neurofilaments | Last on-treatment n=33,15,40 | 0.041 pg/mL | Standard Deviation 3.4144 |
| CNP520 15 mg | Change in Serum Neurofilaments | Week 26 n=33,17,38 | 0.901 pg/mL | Standard Deviation 4.6732 |
| CNP520 15 mg | Change in Serum Neurofilaments | Last off-treatment n=5,2,1 | 7.350 pg/mL | Standard Deviation 9.5884 |
| Placebo | Change in Serum Neurofilaments | Week 26 n=33,17,38 | -5.731 pg/mL | Standard Deviation 40.9042 |
| Placebo | Change in Serum Neurofilaments | Last off-treatment n=5,2,1 | 3.880 pg/mL | — |
| Placebo | Change in Serum Neurofilaments | Last on-treatment n=33,15,40 | -5.771 pg/mL | Standard Deviation 39.8254 |
Secondary
Change in the Everyday Cognition Scale (ECog-Informant) Total Scores
Everyday Cognition Scale (ECog) measures cognitively-relevant everyday abilities comprised of 39 items covering 6 cognitively-relevant domains: Everyday Memory, Everyday Language, Everyday Visuospatial Abilities, Everyday Planning, Everyday Organization, and Everyday Divided Attention. The questionnaire is a self-reported measure completed by both participant and study partner (informant). The total score for the 39 items ranges from 39 to 195, with greater scores indicating worse daily function.
Time frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Population: Safety analysis set - only participants with a value at both Baseline and that visit are included. Last on-treatment is the last assessment before or at last day on study drug + 31 days. Last off-treatment is the last assessment after last day on study drug + 31 days.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNP520 50 mg | Change in the Everyday Cognition Scale (ECog-Informant) Total Scores | Last on-treatment n=252,138,255 | 0.5 Total scores | Standard Deviation 7.58 |
| CNP520 50 mg | Change in the Everyday Cognition Scale (ECog-Informant) Total Scores | Week 26 n=153,76,153 | -0.3 Total scores | Standard Deviation 7.55 |
| CNP520 50 mg | Change in the Everyday Cognition Scale (ECog-Informant) Total Scores | Last off-treatment n=223,113,239 | 0.5 Total scores | Standard Deviation 6.97 |
| CNP520 15 mg | Change in the Everyday Cognition Scale (ECog-Informant) Total Scores | Last on-treatment n=252,138,255 | 0.7 Total scores | Standard Deviation 8.49 |
| CNP520 15 mg | Change in the Everyday Cognition Scale (ECog-Informant) Total Scores | Week 26 n=153,76,153 | 1.7 Total scores | Standard Deviation 7.77 |
| CNP520 15 mg | Change in the Everyday Cognition Scale (ECog-Informant) Total Scores | Last off-treatment n=223,113,239 | 0.0 Total scores | Standard Deviation 6.74 |
| Placebo | Change in the Everyday Cognition Scale (ECog-Informant) Total Scores | Week 26 n=153,76,153 | -1.2 Total scores | Standard Deviation 6.1 |
| Placebo | Change in the Everyday Cognition Scale (ECog-Informant) Total Scores | Last off-treatment n=223,113,239 | 1.2 Total scores | Standard Deviation 9.36 |
| Placebo | Change in the Everyday Cognition Scale (ECog-Informant) Total Scores | Last on-treatment n=252,138,255 | 0.2 Total scores | Standard Deviation 7 |
Secondary
Change in the Everyday Cognition Scale (ECog-Subject) Total Scores
Everyday Cognition Scale (ECog) measures cognitively-relevant everyday abilities comprised of 39 items covering 6 cognitively-relevant domains: Everyday Memory, Everyday Language, Everyday Visuospatial Abilities, Everyday Planning, Everyday Organization, and Everyday Divided Attention. The questionnaire is a self-reported measure completed by both participant and study partner (informant). The total score for the 39 items ranges from 39 to 195, with greater scores indicating worse daily function.
Time frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Population: Safety analysis set - only participants with a value at both Baseline and that visit are included. Last on-treatment is the last assessment before or at last day on study drug + 31 days. Last off-treatment is the last assessment after last day on study drug + 31 days.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNP520 50 mg | Change in the Everyday Cognition Scale (ECog-Subject) Total Scores | Last on-treatment n=266,143,268 | 1.6 Total scores | Standard Deviation 8.03 |
| CNP520 50 mg | Change in the Everyday Cognition Scale (ECog-Subject) Total Scores | Week 26 n=155,78,157 | 0.9 Total scores | Standard Deviation 7.9 |
| CNP520 50 mg | Change in the Everyday Cognition Scale (ECog-Subject) Total Scores | Last off-treatment n=249,122,255 | -0.1 Total scores | Standard Deviation 6.49 |
| CNP520 15 mg | Change in the Everyday Cognition Scale (ECog-Subject) Total Scores | Last on-treatment n=266,143,268 | 0.4 Total scores | Standard Deviation 5.62 |
| CNP520 15 mg | Change in the Everyday Cognition Scale (ECog-Subject) Total Scores | Week 26 n=155,78,157 | 0.2 Total scores | Standard Deviation 5.52 |
| CNP520 15 mg | Change in the Everyday Cognition Scale (ECog-Subject) Total Scores | Last off-treatment n=249,122,255 | 0.0 Total scores | Standard Deviation 7.02 |
| Placebo | Change in the Everyday Cognition Scale (ECog-Subject) Total Scores | Week 26 n=155,78,157 | 0.5 Total scores | Standard Deviation 6.76 |
| Placebo | Change in the Everyday Cognition Scale (ECog-Subject) Total Scores | Last off-treatment n=249,122,255 | 0.1 Total scores | Standard Deviation 7.47 |
| Placebo | Change in the Everyday Cognition Scale (ECog-Subject) Total Scores | Last on-treatment n=266,143,268 | 0.7 Total scores | Standard Deviation 8.25 |
Secondary
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
Repeatable Battery for the Assessment of Neurological Status (RBANS) is a clinical tool designed to detect and characterize the earliest neurocognitive changes associated with dementia. The RBANS generates age-adjusted index scores for five neurocognitive domains: Immediate Memory, Visuospatial/Constructional, Language, Attention and Delayed Memory, which are used to calculate a Total Scale Index score. Index scores and total score range from 40 to 160 and a higher score indicates better cognitive functioning.
Time frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Population: Safety analysis set - only participants with a value at both Baseline and that visit are included. Last on-treatment is the last assessment before or at last day on study drug + 31 days. Last off-treatment is the last assessment after last day on study drug + 31 days.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Immediate memory - Last on-treatment n=347,183,353 | -5.9 scores | Standard Deviation 13.01 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Total Last on-treatment n=356,183,353 | -3.4 scores | Standard Deviation 8.66 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Total Last off-treatment n=259,125,265 | -1.3 scores | Standard Deviation 8.12 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Immediate memory - Week 26 n=162,81,162 | -9.8 scores | Standard Deviation 11.85 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Total Week 26 n=162,81,162 | -5.8 scores | Standard Deviation 8.54 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Immediate memory - Last off-treatment n=259,125,266 | -3.1 scores | Standard Deviation 12.5 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Visuospatial Week 26 n=162,81,162 | -5.6 scores | Standard Deviation 15.11 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Visuospatial Last on-treatment n=347,183,353 | -3.7 scores | Standard Deviation 14.9 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Visuospatial Last off-treatment n=259,125,266 | -1.5 scores | Standard Deviation 14.87 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Language Week 26 n=162,81,162 | -0.8 scores | Standard Deviation 11.48 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Language Last on-treatment n=347,183,353 | -0.3 scores | Standard Deviation 11.95 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Language Last off-treatment n=259,125,265 | -1.0 scores | Standard Deviation 10.93 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Attention Week 26 n=162,81,162 | 0.1 scores | Standard Deviation 11.19 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Attention Last on-treatment n=347,183,353 | 0.0 scores | Standard Deviation 11.3 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Attention Last off-treatment n=259,125,265 | 1.6 scores | Standard Deviation 11.59 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Delayed memory - Week 26 n=162,81,162 | -5.5 scores | Standard Deviation 11.54 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Delayed memory - Last on-treatment n=346,183,353 | -3.0 scores | Standard Deviation 11.58 |
| CNP520 50 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Delayed memory - Last off-treatment n=259,125,265 | -1.0 scores | Standard Deviation 10.91 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Delayed memory - Last off-treatment n=259,125,265 | -2.5 scores | Standard Deviation 10.34 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Total Week 26 n=162,81,162 | -6.3 scores | Standard Deviation 8.58 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Language Week 26 n=162,81,162 | -1.8 scores | Standard Deviation 11.05 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Attention Week 26 n=162,81,162 | -0.1 scores | Standard Deviation 10.37 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Total Last on-treatment n=356,183,353 | -3.5 scores | Standard Deviation 8.87 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Attention Last off-treatment n=259,125,265 | 1.7 scores | Standard Deviation 10.65 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Delayed memory - Week 26 n=162,81,162 | -5.0 scores | Standard Deviation 11.68 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Total Last off-treatment n=259,125,265 | -2.4 scores | Standard Deviation 9.55 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Language Last on-treatment n=347,183,353 | -1.7 scores | Standard Deviation 11.69 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Delayed memory - Last on-treatment n=346,183,353 | -2.8 scores | Standard Deviation 10.56 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Immediate memory - Week 26 n=162,81,162 | -9.7 scores | Standard Deviation 12.1 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Visuospatial Last off-treatment n=259,125,266 | -0.7 scores | Standard Deviation 14.37 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Attention Last on-treatment n=347,183,353 | 0.0 scores | Standard Deviation 10.68 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Immediate memory - Last on-treatment n=347,183,353 | -4.0 scores | Standard Deviation 13.54 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Visuospatial Last on-treatment n=347,183,353 | -3.8 scores | Standard Deviation 15.14 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Language Last off-treatment n=259,125,265 | -2.0 scores | Standard Deviation 12.68 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Immediate memory - Last off-treatment n=259,125,266 | -4.8 scores | Standard Deviation 13.52 |
| CNP520 15 mg | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Visuospatial Week 26 n=162,81,162 | -5.4 scores | Standard Deviation 15.51 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Immediate memory - Last off-treatment n=259,125,266 | -3.0 scores | Standard Deviation 13 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Visuospatial Week 26 n=162,81,162 | -2.6 scores | Standard Deviation 15.26 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Visuospatial Last on-treatment n=347,183,353 | -1.2 scores | Standard Deviation 13.95 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Attention Last off-treatment n=259,125,265 | 1.1 scores | Standard Deviation 9.81 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Visuospatial Last off-treatment n=259,125,266 | -1.2 scores | Standard Deviation 14.56 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Delayed memory - Last off-treatment n=259,125,265 | -0.5 scores | Standard Deviation 10.57 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Language Week 26 n=162,81,162 | -3.1 scores | Standard Deviation 11.07 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Language Last on-treatment n=347,183,353 | -1.3 scores | Standard Deviation 12.58 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Delayed memory - Week 26 n=162,81,162 | -2.1 scores | Standard Deviation 11.69 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Language Last off-treatment n=259,125,265 | -3.4 scores | Standard Deviation 11.47 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Total Week 26 n=162,81,162 | -3.4 scores | Standard Deviation 8.35 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Total Last on-treatment n=356,183,353 | -0.5 scores | Standard Deviation 8.88 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Attention Week 26 n=162,81,162 | 0.1 scores | Standard Deviation 10.56 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Total Last off-treatment n=259,125,265 | -1.9 scores | Standard Deviation 8.56 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Immediate memory - Week 26 n=162,81,162 | -5.2 scores | Standard Deviation 11.26 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Immediate memory - Last on-treatment n=347,183,353 | -1.1 scores | Standard Deviation 13.04 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Attention Last on-treatment n=347,183,353 | 0.7 scores | Standard Deviation 10.99 |
| Placebo | Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Delayed memory - Last on-treatment n=346,183,353 | 0.8 scores | Standard Deviation 11.43 |
Secondary
Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities)
Safety MRI included sequences necessary for ascertainment of possible ARIA-E (Amyloid Related Imaging Abnormality-Edema), ARIA-H (Amyloid Related Imaging Abnormality- Hemorrhage, including superficial siderosis and microhemorrhages), assessment of recent infarcts and white matter integrity examination (White matter disease worsening) and a general assessment of brain abnormalities.
Time frame: Baseline up to study termination approximately 617 days
Population: Safety analysis set - only participants with a value at both Baseline and that visit are included. Last on-treatment is the last assessment before or at last day on study drug + 31 days. Last off-treatment is the last assessment after last day on study drug + 31 days.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CNP520 50 mg | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | Presence of ARIA-H | 0 Participants |
| CNP520 50 mg | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | Questionable presence of ARIA-E | 1 Participants |
| CNP520 50 mg | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | White matter disease worsening: 1-3 increase | 4 Participants |
| CNP520 50 mg | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | White matter disease worsening: 4- - >8 increase | 0 Participants |
| CNP520 50 mg | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | White matter disease worsening >8 | 0 Participants |
| CNP520 50 mg | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | Any other MRI abnormalities | 1 Participants |
| CNP520 15 mg | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | Any other MRI abnormalities | 0 Participants |
| CNP520 15 mg | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | Presence of ARIA-H | 0 Participants |
| CNP520 15 mg | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | White matter disease worsening: 4- - >8 increase | 0 Participants |
| CNP520 15 mg | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | White matter disease worsening >8 | 0 Participants |
| CNP520 15 mg | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | Questionable presence of ARIA-E | 0 Participants |
| CNP520 15 mg | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | White matter disease worsening: 1-3 increase | 2 Participants |
| Placebo | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | Questionable presence of ARIA-E | 2 Participants |
| Placebo | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | White matter disease worsening: 1-3 increase | 3 Participants |
| Placebo | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | Any other MRI abnormalities | 1 Participants |
| Placebo | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | White matter disease worsening: 4- - >8 increase | 0 Participants |
| Placebo | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | Presence of ARIA-H | 0 Participants |
| Placebo | Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) | White matter disease worsening >8 | 0 Participants |
Secondary
Number of Suicidal Ideation or Behavior Events
Prospective suicidality assessment was performed with the use of Columbia-Suicide Severity Rating Scale (C-SSRS), a questionnaire using a detailed branched logic algorithm evaluating participant's suicidality ideation and behavior. Answer yes on item 4 or 5 of the Suicidal Ideation section or yes on any item of the Suicidal Behavior section was considered positive.
Time frame: Baseline up to study termination approximately 617 days
Population: Safety analysis set which includes only participants with events
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CNP520 50 mg | Number of Suicidal Ideation or Behavior Events | Any suicidal ideation n=13,3,9 | 25 events |
| CNP520 50 mg | Number of Suicidal Ideation or Behavior Events | Any suicidal behavior n=1,0,1 | 1 events |
| CNP520 15 mg | Number of Suicidal Ideation or Behavior Events | Any suicidal ideation n=13,3,9 | 6 events |
| Placebo | Number of Suicidal Ideation or Behavior Events | Any suicidal ideation n=13,3,9 | 12 events |
| Placebo | Number of Suicidal Ideation or Behavior Events | Any suicidal behavior n=1,0,1 | 1 events |