A Study of CAD106 and CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease

Study Overview
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Brief Summary
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The purpose of this study was to test whether two investigational drugs called CAD106 and CNP520, administered separately, could slow down the onset and progression of clinical symptoms associated with Alzheimer's disease (AD) in participants at the risk to develop clinical symptoms based on their age and genotype.

Detailed Description
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The study (also known as the Generation Study 1, GS1) was conducted as part of the Alzheimer's Prevention Initiative (API) program. This trial was a randomized, double-blind, placebo-controlled, parallel group, adaptive design with variable treatment duration planned in cognitively unimpaired APOE4 homozygotes (HMs) aged 60 to 75 years. Participants were enrolled into Cohort I (CAD106) or Cohort II (CNP520). The planned treatment period of 5 to 8 years was not achieved due to early study termination. The study was terminated due to unexpected changes in cognitive function, brain volume loss, and body weight loss. Cohort II (CNP520) treatment was stopped and evaluated through an off-treatment follow-up period. After the decision to terminate Cohort II of the study (CNP520), treatment with CAD106 (Cohort I) was also terminated.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Two-cohort, Parallel Group Study to Evaluate the Efficacy of CAD106 and CNP520 in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease.

Conditions
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Alzheimers Disease

Intervention / Treatment
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* Biological: CAD106 Immunotherapy
* Other: Placebo to CAD106
* Drug: CNP520
* Other: Placebo to CNP520
* Other: Alum


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Consented to receive disclosure of their risk estimates to develop clinical symptoms of AD based on their APOE genotype. Male or female, age 60 to 75 years inclusive. Females were to be post-menopausal. Mini-Mental State Examination (MMSE) total score ≥ 24 and cognitively unimpaired as evaluated by memory tests Homozygous APOE4 genotype. Participant willing to have a study partner. Key Exclusion Criteria: Any disability that prevented the participant 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 may 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 60 months prior to screening. History of hypersensitivity to any of the investigational drugs or their excipients / adjuvant or to drugs of similar chemical classes. Indication or on current treatment with ChEIs and/or another AD treatment (e.g. memantine). Contraindication or intolerance to MRI or PET investigations (with fluorinated radio ligands). Brain MRI results showing findings unrelated to AD that, in the opinion of the Investigator could have been a leading cause to future cognitive decline, pose a risk to the participant, or prevent a satisfactory MRI assessment for safety monitoring. Suicidal Ideation in the past six months or Suicidal Behavior in the past two years, prior to screening. A positive drug screen at Screening, if, in the Investigator's opinion, this was due to drug abuse. Significantly abnormal laboratory results at Screening, or infection not as a result of a temporary condition. Current clinically significant ECG findings. For Cohort - I only: Participants with previous organ transplantation or stem cell transplantation, or indication for treatment with anti-coagulants. For Cohort - II only: Participants with depigmenting or hypopigmenting conditions (e.g. albinism vitiligo) or active / history of chronic urticarial in the past year.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort I (CAD106)<br>CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter | Biological: CAD106 Immunotherapy<br>* Participants will be given i.m. injections at Weeks 1, 7, 13 and quarterly i.m. injections (every 13 weeks) thereafter, until the last injection 3 month prior to completion of the Treatment Epoch.<br>Other: Alum<br>* Alum was mixed with reconstituted CAD106 as adjuvant therapy to maximize the effectiveness of CAD106<br>|
| Placebo Comparator: Cohort I (CAD106 Placebo)<br>Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter | Other: Placebo to CAD106<br>* Participants will be given i.m. injections at Weeks 1, 7, 13 and quarterly i.m. injections (every 13 weeks) thereafter, until the last injection 3 month prior to completion of the Treatment Epoch.<br>Other: Alum<br>* Alum was mixed with reconstituted CAD106 as adjuvant therapy to maximize the effectiveness of CAD106<br>|
| Experimental: Cohort II (CNP520)<br>CNP520 (50 mg) capsules taken orally once daily | Drug: CNP520<br>* CNP520 50 mg capsule p.o. for the duration of the Treatment Epoch.<br>|
| Placebo Comparator: Cohort II (CNP520 Placebo)<br>Matching Placebo to CNP520 capsules taken orally once daily | Other: Placebo to CNP520<br>* Placebo to CNP520 p.o. for the duration of the Treatment Epoch<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII | 
| 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. | CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment | 
| Change in the Total 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. | CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment | 
| Change in the 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. | CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment | 
| 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. | CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment | 
| 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. Cohort I=C I and Cohort II=C II. | CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment | 
| 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 since baseline) and a general assessment of brain abnormalities. Assessment of cerebral amyloid angiopathy (CAA) is included in the overall safety MRI findings results. | Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII | 
| 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. | CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment | 
| Change in Cerebrospinal Fluid (CSF) Levels of Amyloid Beta 40 (Aβ40) | Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 40 (Aβ40) | Baseline to last assessment | 
| Change in Cerebrospinal Fluid (CSF) Levels of Amyloid Beta 42 (Aβ42) | Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 42 (Aβ42) | Baseline to last assessment | 
| Change in Cerebrospinal Fluid (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 | Baseline to last assessment | 
| 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 tau pathology in the brain | Baseline to last assessment | 
| Cohort I : Annualized Change in Amyloid Deposition as Measured by Centiloids of Positron Emission Tomography (PET) Scan With Amyloid Radiotracer | To demonstrate the effects of CAD106 vs placebo on Alzheimer's Disease-related biomarkers | Baseline up to approximately Week 104 | 
| Change in Serum Neurofilaments | Alzheimer's Disease-related biomarkers analyzed in blood serum: light chain neurofilaments (NfL) | Baseline to Week 26 and week 52, CI baseline to last assessment. CII baseline to last on-treatment and to last off-treatment | 
| 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. | Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII | 
| Cohort I : Change in Cognition as Measured by APCC and CDR-SOB Scores and Antibody Response |  | Month 6 to Month 60 | 
| Cohort I: Peak Concentration (Cmax) of CAD106 Induced Abeta-specific Antibody Titers | Cmax is the maximum Titer Concentration of any post-baseline 'on treatment' visit. A visit is considered as 'on treatment' if visit date is within {last injection + 180 days}. - Geometric mean and CI's are back-transformed from the estimates for Log mean and CI's. | Week 9, 13, 15, 26 and quarterly thereafter (trough values) | 
| Cohort I: Area Under the Concentration Curve (AUC) of CAD106 Induced Abeta-specific Antibody Titers | AUC is calculated based on 'on treatment' visit only.(missing values for peak visits were linearly interpolated for calculation; missing values for trough visits were imputed by average of non-missing trough values.). | Week 9, 13, 15, 26 and quarterly thereafter (trough values) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BACE-1 inhibitor, Prevention, Unimpaired cognition, Randomization, Placebo controlled, Parallel-group, APOE4 Homozygotes, Preclinical Alzheimers Disease (AD), Aβ lowering, CNP520, CAD106, elderly, Brain Amyloid