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

Phase 2

Terminated

Conditions: Alzheimers Disease

Interventions: Biological: CAD106 Immunotherapy
Other: Placebo to CAD106
Drug: CNP520
Other: Placebo to CNP520
Other: Alum

Registration Number: NCT02565511

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 480

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort I (CAD106)	CAD106 Immunotherapy	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
Cohort I (CAD106)	Alum	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
Cohort I (CAD106 Placebo)	Placebo to CAD106	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
Cohort I (CAD106 Placebo)	Alum	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
Cohort II (CNP520)	CNP520	CNP520 (50 mg) capsules taken orally once daily
Cohort II (CNP520 Placebo)	Placebo to CNP520	Matching Placebo to CNP520 capsules taken orally once daily

Primary Outcome Measures

Name	Time	Method
Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD))	Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII	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	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	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 Outcome Measures

Name	Time	Method
Change in Cerebrospinal Fluid (CSF) Levels of Amyloid Beta 40 (Aβ40)	Baseline to last assessment	Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 40 (Aβ40)
Change in Cerebrospinal Fluid (CSF) Levels of Amyloid Beta 42 (Aβ42)	Baseline to last assessment	Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 42 (Aβ42)
Change in the Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).	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	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.
Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score	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	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 last assessment	To demonstrate the effects of CNP520 vs placebo on tau pathology in the brain
Cohort I : Annualized Change in Amyloid Deposition as Measured by Centiloids of Positron Emission Tomography (PET) Scan With Amyloid Radiotracer	Baseline up to approximately Week 104	To demonstrate the effects of CAD106 vs placebo on Alzheimer's Disease-related biomarkers
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	Week 9, 13, 15, 26 and quarterly thereafter (trough values)	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.
Change in the Total Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).	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	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.
Change in the Everyday Cognition Scale (ECog-Subject) Total Scores	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	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	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	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.
Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities)	Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII	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.
Annualized Percent Change on Volume of Brain Regions	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	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 Cerebrospinal Fluid (CSF) Levels of Total Tau and Phosphorylated Tau	Baseline to last assessment	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 and week 52, CI baseline to last assessment. CII baseline to last on-treatment and to last off-treatment	Alzheimer's Disease-related biomarkers analyzed in blood serum: light chain neurofilaments (NfL)
Number of Suicidal Ideation or Behavior Events	Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII	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.
Cohort I: Area Under the Concentration Curve (AUC) of CAD106 Induced Abeta-specific Antibody Titers	Week 9, 13, 15, 26 and quarterly thereafter (trough values)	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.).

Trial Locations

Locations (59): Banner Sun City Research Institute
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Sun City, Arizona, United States
California Neuroscience Research Medical Group, Inc.
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Sherman Oaks, California, United States
Advanced Clinical Research
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Meridian, Idaho, United States
JEM Research Institute
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Atlantis, Florida, United States
NYU Langone Medical Center
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New York, New York, United States
Novartis Investigative Site
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Manchester, United Kingdom
Banner Alzheimer's Institute
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Phoenix, Arizona, United States
ATP Clinical Research, Inc.
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Costa Mesa, California, United States
Great Lakes Clinical Trials
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Chicago, Illinois, United States
Irvine Center for Clinical Research
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Irvine, California, United States
New England Institute for Clinical Research
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Stamford, Connecticut, United States
Florida Atlantic University, Clinical Translational Research Unit
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Boca Raton, Florida, United States
Memory Health Center at Summit Research Network
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Portland, Oregon, United States
Brain Matters Research
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Delray Beach, Florida, United States
Triad Clinical Trials, LLC
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Greensboro, North Carolina, United States
University of Miami
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Miami, Florida, United States
NeuroStudies
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Decatur, Georgia, United States
Rush University Medical Center
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Chicago, Illinois, United States
IPS Research Company
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Oklahoma City, Oklahoma, United States
Cleveland Clinic Lou Ruvo Center for Brain Health
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Las Vegas, Nevada, United States
Kerwin Research Center & Memory Care
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Dallas, Texas, United States
Houston Methodist Hospital
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Houston, Texas, United States
University of Texas Health Science Center, Houston
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Houston, Texas, United States
The Medical College of WI
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Milwaukee, Wisconsin, United States
Toronto Memory Program
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Toronto, Ontario, Canada
The Centre for Memory and Aging
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Toronto, Ontario, Canada
University of Rochester Medical Center
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Rochester, New York, United States
University of Southern California Keck School of Medicine Alzheimer Disease Research Center
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Los Angeles, California, United States
Meridien Research
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Maitland, Florida, United States
Mount Sinai Medical Center - The Wien Center
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Miami Beach, Florida, United States
Progressive Medical Research
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Port Orange, Florida, United States
Indiana University
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Indianapolis, Indiana, United States
University of Kansas Alzheimer's Disease Center
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Fairway, Kansas, United States
The Nathan S. Kline Institute
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Orangeburg, New York, United States
Alzheimer's Memory Center
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Charlotte, North Carolina, United States
The Clinical Trial Center, LLC
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Jenkintown, Pennsylvania, United States
CNS Healthcare
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Memphis, Tennessee, United States
Clinical Trial Network
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Houston, Texas, United States
The Memory Clinic
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Bennington, Vermont, United States
Universal Research Group
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Tacoma, Washington, United States
Okanagan Clinical Trials
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Kelowna, British Columbia, Canada
Georgetown University
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Washington, District of Columbia, United States
Merritt Island Medical Research
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Merritt Island, Florida, United States
Medical Research & Health Education Foundation, Inc.
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Columbus, Georgia, United States
Memory Enhancement Center
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Eatontown, New Jersey, United States
The Memory Center of Northeastern New York
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Latham, New York, United States
University Hospitals Cleveland Medical Center / Case Western Reserve University
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Beachwood, Ohio, United States
Memory Disorders Program, Department of Neurological Sciences, University of Nebraska Medical Center
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Omaha, Nebraska, United States
Syrentis Clinical Research
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Santa Ana, California, United States
Sanders Brown Center on Aging, University of Kentucky
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Lexington, Kentucky, United States
Abington Neurological Associates
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Willow Grove, Pennsylvania, United States
Butler Hospital Memory and Aging Program
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Providence, Rhode Island, United States
Via Christi Research
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Wichita, Kansas, United States
Duke University Medical center
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Durham, North Carolina, United States
USF Health Byrd Alzheimer's Institute
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Tampa, Florida, United States
Senior Adults Specialty Research
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Austin, Texas, United States
Yale University Alzheimer's Disease Research Unit
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New Haven, Connecticut, United States
Compass Research
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Orlando, Florida, United States
Roper St. Francis - CBRI
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Charleston, South Carolina, United States