A Study of CAD106 and CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (GS1)

• ClinicalTrials.gov Identifier: NCT02565511
• Recruitment Status: Terminated
• First Posted: October 1, 2015
• Results First Posted: July 8, 2021
• Last Update Posted: July 8, 2021
• Sponsor: Novartis Pharmaceuticals
• Collaborators: Banner Alzheimer's Institute; National Institute on Aging (NIA); Amgen
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: September 28, 2015
• First Posted Date: October 1, 2015
• Results First Submitted Date: April 29, 2021
• Results First Posted Date: July 8, 2021
• Last Update Posted Date: July 8, 2021
• Actual Study Start Date: November 30, 2015
• Actual Primary Completion Date: April 30, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 7, 2021)

• Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) [ Time Frame: 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 [ Time Frame: 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.

Original Primary Outcome Measures (submitted: September 29, 2015)

• Time to diagnosis of MCI or dementia due to Alzheimer's Disease [ Time Frame: Through study completion, an average of 5 years ]
  Time when diagnosis is confirmed by adjudication committee
• Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score [ Time Frame: Baseline to Month 60 ]
  Composite score derived from the specific tests from the Repeatable Battery for the Assessment of Neurological Status (RBANS), Mini-Mental State Examination (MMSE), Raven's Progressive Matrices

Current Secondary Outcome Measures (submitted: July 7, 2021)

• Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score [ Time Frame: 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 the Total Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). [ Time Frame: 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 Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). [ Time Frame: 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 the Everyday Cognition Scale (ECog-Subject) Total Scores [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 Amyloid Beta 40 (Aβ40) [ Time Frame: 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) [ Time Frame: Baseline to last assessment ]
  Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 42 (Aβ42)
• Change in Cerebrospinal Fluid (CSF) Levels of Total Tau and Phosphorylated Tau [ Time Frame: Baseline to last assessment ]
  Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): total tau protein and phosphorylated tau protein levels
• Change in Neurofibrillary Tangle Burden as Measured by Standardized Uptake Ratio (SUVR) of PET Scans With Tau Radiotracer (Where Available) [ Time Frame: 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 [ Time Frame: Baseline up to approximately Week 104 ]
  To demonstrate the effects of CAD106 vs placebo on Alzheimer's Disease-related biomarkers
• Change in Serum Neurofilaments [ Time Frame: 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 [ Time Frame: 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 : Change in Cognition as Measured by APCC and CDR-SOB Scores and Antibody Response [ Time Frame: Month 6 to Month 60 ]
• Cohort I: Peak Concentration (Cmax) of CAD106 Induced Abeta-specific Antibody Titers [ Time Frame: 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.
• Cohort I: Area Under the Concentration Curve (AUC) of CAD106 Induced Abeta-specific Antibody Titers [ Time Frame: 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.).

Original Secondary Outcome Measures (submitted: September 29, 2015)

• Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) score [ Time Frame: Baseline to Month 60 ]
  To assess the effects of CAD106 and CNP520, respectively, vs. placebo on global clinical status as measured by the change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) score.
• Number of participants with Adverse Events as a measure of Safety and Tolerability [ Time Frame: Through study completion, an average of 5 years ]
  To assess the safety and tolerability of CAD106 and CNP520, respectively, vs. placebo by measured adverse events (AEs), and changes in the brain MRI, laboratory tests, vital signs, electrocardioagram (ECG), and Columbia Suicide Severity Rating Scale (C-SSRS). Injection-related reactions will also be collected for participants from Cohort I.
• Change on the Total Scale score and individual neurocognitive domain index scores of the RBANS [ Time Frame: Baseline to Month 60 ]
  To assess the effects of CAD106 and CNP520, respectively, vs. placebo on cognition as measured by changes on the Total Scale score and individual neurocognitive domain index scores of the RBANS.
• Change in the Everyday Cognition scale (ECog) total scores [ Time Frame: Baseline to Month 60 ]
  To assess the effects of CAD106 and CNP520, respectively, vs. placebo on function as measured by the change on ECog total score reported by the participant and study partner.
• Change in Alzheimer's Disease related biomarkers [ Time Frame: Baseline to Months 24 and 60 ]
  To assess the effects of CAD106 and CNP520, respectively, vs. placebo on AD-related biomarkers (amyloid deposition and measures of neurodegeneration) as measured by changes on: amyloid tracer 18F-florbetapir and tau tracer 18F-AV-1451 obtained using brain positron emission tomography (PET) imaging, volumetric MRI measurements, and CSF Aβ, total tau and phosphorylated tau levels.
• Change in APCC Test Score [ Time Frame: Month 6 to Month 60 ]
  To assess the effects of antibody response to CAD106 vs. placebo on cognition as measured by changes on the APCC test score and CDR-SOB.
• Aβ-specific immune response [ Time Frame: Through study completion, an average of 5 years ]
  To describe Aβ-specific antibody titers as measured by peak concentration and area under the concentration curve (AUC) of antibody titers.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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.
• 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.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: 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
• Other: Alum
  Alum was mixed with reconstituted CAD106 as adjuvant therapy to maximize the effectiveness of CAD106

Study Arms

• Experimental: Cohort I (CAD106)
  CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
  Interventions:

  • Biological: CAD106 Immunotherapy
  • Other: Alum
• Placebo Comparator: Cohort I (CAD106 Placebo)
  Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
  Interventions:

  • Other: Placebo to CAD106
  • Other: Alum
• Experimental: Cohort II (CNP520)
  CNP520 (50 mg) capsules taken orally once daily
  Intervention: Drug: CNP520
• Placebo Comparator: Cohort II (CNP520 Placebo)
  Matching Placebo to CNP520 capsules taken orally once daily
  Intervention: Other: Placebo to CNP520

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: February 15, 2020): 480
• Original Estimated Enrollment (submitted: September 29, 2015): 1340
• Actual Study Completion Date: April 30, 2020
• Actual Primary Completion Date: April 30, 2020 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 60 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, Finland, Germany, Netherlands, Spain, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT02565511
• Other Study ID Numbers: CAPI015A2201J; 2015-002715-15 ( EudraCT Number ); 1UF1AG046150-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current

Collaborators

• Banner Alzheimer's Institute
• National Institute on Aging (NIA)
• Amgen

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: July 2021