Clinical trial NCT02565511: A Study of CAD106 and CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease
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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Alzheimers Disease
Keywords: Randomization
Placebo controlled
Parallel-group
APOE4 Homozygotes
Preclinical Alzheimers Disease (AD)
Aβ lowering
CNP520
CAD106
elderly
Brain Amyloid
BACE-1 inhibitor
Prevention
Unimpaired cognition
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: Banner Alzheimer's Institute
name: National Institute on Aging (NIA)
name: Amgen
First posted: 2015-10-01
Enrollment: 480
Sex: ALL
Minimum age (years): 60
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD))
timeFrame: Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII
measure: Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score
timeFrame: 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 outcomes:
measure: Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score
timeFrame: 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
measure: Change in the Total Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).
timeFrame: 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
measure: Change in the Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).
timeFrame: 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
measure: Change in the Everyday Cognition Scale (ECog-Subject) Total Scores
timeFrame: 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
measure: Change in the Everyday Cognition Scale (ECog-Informant) Total Scores
timeFrame: 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
measure: Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities)
timeFrame: Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII
measure: Annualized Percent Change on Volume of Brain Regions
timeFrame: 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
measure: Change in Cerebrospinal Fluid (CSF) Levels of Amyloid Beta 40 (Aβ40)
timeFrame: Baseline to last assessment
measure: Change in Cerebrospinal Fluid (CSF) Levels of Amyloid Beta 42 (Aβ42)
timeFrame: Baseline to last assessment
measure: Change in Cerebrospinal Fluid (CSF) Levels of Total Tau and Phosphorylated Tau
timeFrame: Baseline to last assessment
measure: Change in Neurofibrillary Tangle Burden as Measured by Standardized Uptake Ratio (SUVR) of PET Scans With Tau Radiotracer (Where Available)
timeFrame: Baseline to last assessment
measure: Cohort I : Annualized Change in Amyloid Deposition as Measured by Centiloids of Positron Emission Tomography (PET) Scan With Amyloid Radiotracer
timeFrame: Baseline up to approximately Week 104
measure: Change in Serum Neurofilaments
timeFrame: Baseline to Week 26 and week 52, CI baseline to last assessment. CII baseline to last on-treatment and to last off-treatment
measure: Number of Suicidal Ideation or Behavior Events
timeFrame: Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII
measure: Cohort I : Change in Cognition as Measured by APCC and CDR-SOB Scores and Antibody Response
timeFrame: Month 6 to Month 60
measure: Cohort I: Peak Concentration (Cmax) of CAD106 Induced Abeta-specific Antibody Titers
timeFrame: Week 9, 13, 15, 26 and quarterly thereafter (trough values)
measure: Cohort I: Area Under the Concentration Curve (AUC) of CAD106 Induced Abeta-specific Antibody Titers
timeFrame: Week 9, 13, 15, 26 and quarterly thereafter (trough values)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Banner Alzheimer's Institute
state: Arizona
city: Phoenix
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Scottsdale
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Sun City
country: United States
facility: Banner Sun City Research Institute
state: Arizona
city: Costa Mesa
country: United States
facility: ATP Clinical Research, Inc.
state: California
city: Irvine
country: United States
facility: Irvine Center for Clinical Research
state: California
city: Los Angeles
country: United States
facility: University of Southern California Keck School of Medicine Alzheimer Disease Research Center
state: California
city: Palo Alto
country: United States
facility: Novartis Investigative Site
state: California
city: San Diego
country: United States
facility: Novartis Investigative Site
state: California
city: Santa Ana
country: United States
facility: Syrentis Clinical Research
state: California
city: Sebastopol
country: United States
facility: Novartis Investigative Site
state: California
city: Sherman Oaks
country: United States
facility: California Neuroscience Research Medical Group, Inc.
state: California
city: Temecula
country: United States
facility: Novartis Investigative Site
state: California
city: Basalt
country: United States
facility: Novartis Investigative Site
state: Colorado
city: New Haven
country: United States
facility: Yale University Alzheimer's Disease Research Unit
state: Connecticut
city: Stamford
country: United States
facility: New England Institute for Clinical Research
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Washington
country: United States
facility: Novartis Investigative Site
state: District of Columbia
city: Atlantis
country: United States
facility: JEM Research Institute
state: Florida
city: Boca Raton
country: United States
facility: Florida Atlantic University, Clinical Translational Research Unit
state: Florida
city: Delray Beach
country: United States
facility: Brain Matters Research
state: Florida
city: Jacksonville
country: United States
facility: Novartis Investigative Site
state: Florida
city: Maitland
country: United States
facility: Meridien Research
state: Florida
city: Merritt Island
country: United States
facility: Merritt Island Medical Research
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center - The Wien Center
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Orlando
country: United States
facility: Novartis Investigative Site
state: Florida
city: Orlando
country: United States
facility: Compass Research
state: Florida
city: Port Orange
country: United States
facility: Progressive Medical Research
state: Florida
city: Tampa
country: United States
facility: USF Health Byrd Alzheimer's Institute
state: Florida
city: Atlanta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Columbus
country: United States
facility: Medical Research & Health Education Foundation, Inc.
state: Georgia
city: Decatur
country: United States
facility: NeuroStudies
state: Georgia
city: Meridian
country: United States
facility: Advanced Clinical Research
state: Idaho
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: Great Lakes Clinical Trials
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Fairway
country: United States
facility: University of Kansas Alzheimer's Disease Center
state: Kansas
city: Wichita
country: United States
facility: Via Christi Research
state: Kansas
city: Lexington
country: United States
facility: Sanders Brown Center on Aging, University of Kentucky
state: Kentucky
city: Bangor
country: United States
facility: Novartis Investigative Site
state: Maine
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Kalamazoo
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Saint Paul
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Saint Louis
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Omaha
country: United States
facility: Memory Disorders Program, Department of Neurological Sciences, University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: Cleveland Clinic Lou Ruvo Center for Brain Health
state: Nevada
city: Eatontown
country: United States
facility: Memory Enhancement Center
state: New Jersey
city: Latham
country: United States
facility: The Memory Center of Northeastern New York
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: Orangeburg
country: United States
facility: The Nathan S. Kline Institute
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Charlotte
country: United States
facility: Alzheimer's Memory Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical center
state: North Carolina
city: Greensboro
country: United States
facility: Triad Clinical Trials, LLC
state: North Carolina
city: Beachwood
country: United States
facility: University Hospitals Cleveland Medical Center / Case Western Reserve University
state: Ohio
city: Centerville
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Columbus
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Oklahoma City
country: United States
facility: IPS Research Company
state: Oklahoma
city: Oklahoma City
country: United States
facility: Novartis Investigative Site
state: Oklahoma
city: Portland
country: United States
facility: Memory Health Center at Summit Research Network
state: Oregon
city: Jenkintown
country: United States
facility: The Clinical Trial Center, LLC
state: Pennsylvania
city: Philadelphia
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Willow Grove
country: United States
facility: Abington Neurological Associates
state: Pennsylvania
city: Providence
country: United States
facility: Butler Hospital Memory and Aging Program
state: Rhode Island
city: Charleston
country: United States
facility: Roper St. Francis - CBRI
state: South Carolina
city: Knoxville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Memphis
country: United States
facility: CNS Healthcare
state: Tennessee
city: Nashville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Austin
country: United States
facility: Senior Adults Specialty Research
state: Texas
city: Dallas
country: United States
facility: Kerwin Research Center & Memory Care
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center, Houston
state: Texas
city: Houston
country: United States
facility: Clinical Trial Network
state: Texas
city: Bennington
country: United States
facility: The Memory Clinic
state: Vermont
city: Tacoma
country: United States
facility: Universal Research Group
state: Washington
city: Milwaukee
country: United States
facility: The Medical College of WI
state: Wisconsin
city: Darlinghurst
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Heidelberg Heights
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Nedlands
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Kelowna
country: Canada
facility: Okanagan Clinical Trials
state: British Columbia
city: Kentville
country: Canada
facility: Novartis Investigative Site
state: Nova Scota
city: Halifax
country: Canada
facility: Novartis Investigative Site
state: Nova Scotia
city: London
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Toronto Memory Program
state: Ontario
city: Toronto
country: Canada
facility: The Centre for Memory and Aging
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Gatineau
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Sherbrooke
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Sherbrooke
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Turku
country: Finland
facility: Novartis Investigative Site
city: Bayreuth
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Boblingen
country: Germany
facility: Novartis Investigative Site
city: Gottingen
country: Germany
facility: Novartis Investigative Site
city: Halle
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
city: Münster
country: Germany
facility: Novartis Investigative Site
city: Siegen
country: Germany
facility: Novartis Investigative Site
city: Wenzenbach
country: Germany
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Terrassa
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Pozuelo de Alarcon
country: Spain
facility: Novartis Investigative Site
state: Madrid
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Donostia-San Sebastian
country: Spain
facility: Novartis Investigative Site
city: Basel
country: Switzerland
facility: Novartis Investigative Site
state: CH
city: Westbruy On Trym
country: United Kingdom
facility: Novartis Investigative Site
state: Bristol
city: Exeter
country: United Kingdom
facility: Novartis Investigative Site
state: Devon
city: Plymouth
country: United Kingdom
facility: Novartis Investigative Site
state: Devon
city: Guildford
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Avon
country: United Kingdom
facility: Novartis Investigative Site
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: Dundee
country: United Kingdom
facility: Novartis Investigative Site
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: