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

Alzheimers Disease Clinical Trial

— GS1  

Official title:

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.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02565511
• Other study ID #: CAPI015A2201J
• Secondary ID: 2015-002715-151U
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: November 30, 2015
• Est. completion date: April 30, 2020

Study information

• Verified date: July 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 480
• Est. completion date: April 30, 2020
• Est. primary completion date: April 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimers Disease

Intervention

Biological:
• CAD106 Immunotherapy
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.

Other:
• Placebo to CAD106
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.

Drug:
• CNP520
CNP520 50 mg capsule p.o. for the duration of the Treatment Epoch.

Other:
• Placebo to CNP520
Placebo to CNP520 p.o. for the duration of the Treatment Epoch
• Alum
Alum was mixed with reconstituted CAD106 as adjuvant therapy to maximize the effectiveness of CAD106

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Darlinghurst	New South Wales
Australia	Novartis Investigative Site	Heidelberg Heights	Victoria
Australia	Novartis Investigative Site	Nedlands	Western Australia
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Leuven
Canada	Novartis Investigative Site	Gatineau	Quebec
Canada	Novartis Investigative Site	Halifax	Nova Scotia
Canada	Okanagan Clinical Trials	Kelowna	British Columbia
Canada	Novartis Investigative Site	Kentville	Nova Scota
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Sherbrooke	Quebec
Canada	Novartis Investigative Site	Sherbrooke	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	The Centre for Memory and Aging	Toronto	Ontario
Canada	Toronto Memory Program	Toronto	Ontario
Finland	Novartis Investigative Site	Turku
Germany	Novartis Investigative Site	Bayreuth
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Boblingen
Germany	Novartis Investigative Site	Gottingen
Germany	Novartis Investigative Site	Halle
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Koeln
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Mannheim
Germany	Novartis Investigative Site	Münster
Germany	Novartis Investigative Site	Siegen
Germany	Novartis Investigative Site	Wenzenbach
Netherlands	Novartis Investigative Site	Amsterdam
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Donostia-San Sebastian
Spain	Novartis Investigative Site	Pozuelo de Alarcon	Madrid
Spain	Novartis Investigative Site	Terrassa	Barcelona
Switzerland	Novartis Investigative Site	Basel	CH
United Kingdom	Novartis Investigative Site	Avon
United Kingdom	Novartis Investigative Site	Birmingham
United Kingdom	Novartis Investigative Site	Dundee
United Kingdom	Novartis Investigative Site	Exeter	Devon
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	Guildford	Surrey
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Plymouth	Devon
United Kingdom	Novartis Investigative Site	Westbruy On Trym	Bristol
United States	Novartis Investigative Site	Atlanta	Georgia
United States	JEM Research Institute	Atlantis	Florida
United States	Senior Adults Specialty Research	Austin	Texas
United States	Novartis Investigative Site	Bangor	Maine
United States	Novartis Investigative Site	Basalt	Colorado
United States	University Hospitals Cleveland Medical Center / Case Western Reserve University	Beachwood	Ohio
United States	The Memory Clinic	Bennington	Vermont
United States	Florida Atlantic University, Clinical Translational Research Unit	Boca Raton	Florida
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Centerville	Ohio
United States	Roper St. Francis - CBRI	Charleston	South Carolina
United States	Alzheimer's Memory Center	Charlotte	North Carolina
United States	Great Lakes Clinical Trials	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Medical Research & Health Education Foundation, Inc.	Columbus	Georgia
United States	Novartis Investigative Site	Columbus	Ohio
United States	ATP Clinical Research, Inc.	Costa Mesa	California
United States	Kerwin Research Center & Memory Care	Dallas	Texas
United States	NeuroStudies	Decatur	Georgia
United States	Brain Matters Research	Delray Beach	Florida
United States	Duke University Medical center	Durham	North Carolina
United States	Memory Enhancement Center	Eatontown	New Jersey
United States	University of Kansas Alzheimer's Disease Center	Fairway	Kansas
United States	Triad Clinical Trials, LLC	Greensboro	North Carolina
United States	Clinical Trial Network	Houston	Texas
United States	Houston Methodist Hospital	Houston	Texas
United States	University of Texas Health Science Center, Houston	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	Irvine Center for Clinical Research	Irvine	California
United States	Novartis Investigative Site	Jacksonville	Florida
United States	The Clinical Trial Center, LLC	Jenkintown	Pennsylvania
United States	Novartis Investigative Site	Kalamazoo	Michigan
United States	Novartis Investigative Site	Knoxville	Tennessee
United States	Cleveland Clinic Lou Ruvo Center for Brain Health	Las Vegas	Nevada
United States	The Memory Center of Northeastern New York	Latham	New York
United States	Sanders Brown Center on Aging, University of Kentucky	Lexington	Kentucky
United States	University of Southern California Keck School of Medicine Alzheimer Disease Research Center	Los Angeles	California
United States	Meridien Research	Maitland	Florida
United States	CNS Healthcare	Memphis	Tennessee
United States	Advanced Clinical Research	Meridian	Idaho
United States	Merritt Island Medical Research	Merritt Island	Florida
United States	University of Miami	Miami	Florida
United States	Mount Sinai Medical Center - The Wien Center	Miami Beach	Florida
United States	The Medical College of WI	Milwaukee	Wisconsin
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Yale University Alzheimer's Disease Research Unit	New Haven	Connecticut
United States	NYU Langone Medical Center	New York	New York
United States	IPS Research Company	Oklahoma City	Oklahoma
United States	Novartis Investigative Site	Oklahoma City	Oklahoma
United States	Memory Disorders Program, Department of Neurological Sciences, University of Nebraska Medical Center	Omaha	Nebraska
United States	The Nathan S. Kline Institute	Orangeburg	New York
United States	Compass Research	Orlando	Florida
United States	Novartis Investigative Site	Orlando	Florida
United States	Novartis Investigative Site	Palo Alto	California
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Banner Alzheimer's Institute	Phoenix	Arizona
United States	Novartis Investigative Site	Phoenix	Arizona
United States	Progressive Medical Research	Port Orange	Florida
United States	Memory Health Center at Summit Research Network	Portland	Oregon
United States	Butler Hospital Memory and Aging Program	Providence	Rhode Island
United States	University of Rochester Medical Center	Rochester	New York
United States	Novartis Investigative Site	Saint Louis	Missouri
United States	Novartis Investigative Site	Saint Paul	Minnesota
United States	Novartis Investigative Site	San Diego	California
United States	Syrentis Clinical Research	Santa Ana	California
United States	Novartis Investigative Site	Scottsdale	Arizona
United States	Novartis Investigative Site	Sebastopol	California
United States	California Neuroscience Research Medical Group, Inc.	Sherman Oaks	California
United States	New England Institute for Clinical Research	Stamford	Connecticut
United States	Banner Sun City Research Institute	Sun City	Arizona
United States	Universal Research Group	Tacoma	Washington
United States	USF Health Byrd Alzheimer's Institute	Tampa	Florida
United States	Novartis Investigative Site	Temecula	California
United States	Georgetown University	Washington	District of Columbia
United States	Novartis Investigative Site	Washington	District of Columbia
United States	Via Christi Research	Wichita	Kansas
United States	Abington Neurological Associates	Willow Grove	Pennsylvania

Sponsors (4)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals	Amgen, Banner Alzheimer's Institute, National Institute on Aging (NIA)

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Finland,  Germany,  Netherlands,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII
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.	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	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
Secondary	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
Secondary	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
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.	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
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. 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
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 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
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.	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
Secondary	Change in Cerebrospinal Fluid (CSF) Levels of Amyloid Beta 40 (Aß40)	Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 40 (Aß40)	Baseline to last assessment
Secondary	Change in Cerebrospinal Fluid (CSF) Levels of Amyloid Beta 42 (Aß42)	Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 42 (Aß42)	Baseline to last assessment
Secondary	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
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 tau pathology in the brain	Baseline to last assessment
Secondary	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
Secondary	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
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.	Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII
Secondary	Cohort I : Change in Cognition as Measured by APCC and CDR-SOB Scores and Antibody Response		Month 6 to Month 60
Secondary	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)
Secondary	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)

External Links

•   Generation Program web site