A Study of CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (GS2)

• ClinicalTrials.gov Identifier: NCT03131453
• Recruitment Status: Terminated
• First Posted: April 27, 2017
• Results First Posted: August 5, 2021
• Last Update Posted: August 5, 2021
• Sponsor: Novartis Pharmaceuticals
• Collaborators: Amgen; Banner Alzheimer's Institute
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: April 5, 2017
• First Posted Date: April 27, 2017
• Results First Submitted Date: March 25, 2021
• Results First Posted Date: August 5, 2021
• Last Update Posted Date: August 5, 2021
• Actual Study Start Date: August 3, 2017
• Actual Primary Completion Date: March 26, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 18, 2021)

• Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) [ Time Frame: Baseline to last cognitive assessment performed (up to day 648) ]
  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: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) ]
  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: April 24, 2017)

• Time to event [ Time Frame: Through study completion, at least 5 years ]
  Event is defined as diagnosis of MCI due to AD or dementia due to AD, whichever occurs first during the course of the study, after confirmation by the 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: May 18, 2021)

• Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score [ Time Frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) ]
  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 and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [ Time Frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) ]
  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: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) ]
  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: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) ]
  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.
• Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) [ Time Frame: Baseline up to study termination approximately 617 days ]
  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) and a general assessment of brain abnormalities.
• Annualized Percent Change on Volume of Brain Regions [ Time Frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) ]
  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 CSF Levels of Amyloid Beta 40 (Aβ40) [ Time Frame: Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) ]
  Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 40 (Aβ40)
• Change in CSF Levels of Amyloid Beta 42 (Aβ42) [ Time Frame: Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648) ]
  Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 42 (Aβ42).
• Change in Neurofibrillary Tangle Burden as Measured by Standardized Uptake Ratio (SUVR) of PET Scans With Tau Radiotracer (Where Available) [ Time Frame: Baseline to Months 24 and 60 ]
  To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers
• Change in Amyloid Deposition as Measured by Standardized Uptake Ratio (SUVR) of Positron Emission Tomography (PET) Scan With Amyloid Radiotracer [ Time Frame: Baseline to Months 24 and 60 ]
  To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers
• Change in CSF Levels of Total Tau and Phosphorylated Tau [ Time Frame: Baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648) ]
  Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): total tau protein and phosphorylated tau protein levels
• Change in Serum Neurofilaments [ Time Frame: Baseline to Week 26, baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648) ]
  Alzheimer's Disease-related biomarkers analyzed in blood serum: light chain neurofilaments (NfL)
• Number of Suicidal Ideation or Behavior Events [ Time Frame: Baseline up to study termination approximately 617 days ]
  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.

Original Secondary Outcome Measures (submitted: April 24, 2017)

• Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) score [ Time Frame: Baseline to Month 60 ]
  To demonstrate the effects of CNP520, vs. placebo on global clinical status
• Change on the Total Scale score and individual neurocognitive domain index scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [ Time Frame: Baseline to Month 60 ]
  To demonstrate the effects of CNP520, vs. placebo on cognition
• Change in the Everyday Cognition scale (ECog) total scores [ Time Frame: Baseline to Month 60 ]
  To demonstrate the effects of CNP520, vs. placebo on function reported by the participant and study partner, respectively
• Change in cerebral amyloid angiopathy (CAA) [ Time Frame: Through study completion, at least 5 years ]
  To demonstrate the effects of CNP520 vs placebo on CAA, as measured by Magnetic Resonance Imaging (MRI)
• Change on volume of brain regions [ Time Frame: Baseline to Month 60 ]
  To demonstrate the effects of CNP520 vs placebo on brain atrophy, as measured by volumetric Magnetic Resonance Imaging (MRI)
• Change in amyloid deposition as measured by standardized uptake ratio (SUVR) of radiotracer positron emission tomography (PET) scan [ Time Frame: Baseline to Months 24 and 60 ]
  To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers
• Change in CSF levels of Aβ40, Aβ42 [ Time Frame: Baseline to Months 24 and 60 ]
  To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers
• Change in CSF levels of total tau and phosphorylated tau [ Time Frame: Baseline to Months 24 and 60 ]
  To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers
• Number of participants with adverse events as a measure of safety [ Time Frame: Through study completion, at least 5 years ]
  To demonstrate the safety and tolerability of CNP520 vs placebo

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

Descriptive Information

• Brief Title: A Study of 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, Parallel Group Study to Evaluate the Efficacy and Safety of CNP520 in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (AD).
• Brief Summary: The purpose of this study is to determine the effects of CNP520 on cognition, global clinical status, and underlying AD pathology, as well as the safety of CNP520, in people at risk for the onset of clinical symptoms of AD based on their age, APOE genotype and elevated amyloid.
• Detailed Description: This trial was a randomized, double-blind, placebo-controlled, parallel group, adaptive design with variable treatment duration planned in cognitively unimpaired participants aged 60 to 75 years, with at least one apolipoprotein E allele (APOE4), (homozygotes (HMs) or heterozygotes (HTs)) and, if HTs, with evidence of elevated brain amyloid. The participants were randomized to either CNP520 50 mg, CNP520 15 mg or placebo a 2:1:2 ratio and was stratified based on amyloid status. The planned treatment period of 5 to 8 years was not achieved due to early study termination.
• 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

• Drug: CNP520 50mg
  50 mg capsule
• Drug: CNP520 15mg
  15 mg capsule
• Other: Matching placebo
  Matching placebo for 15 and 50 mg capsules

Study Arms

• Experimental: CNP520 50 mg
  50 mg capsule taken orally once daily
  Intervention: Drug: CNP520 50mg
• Experimental: CNP520 15 mg
  15 mg capsule taken orally once daily
  Intervention: Drug: CNP520 15mg
• Placebo Comparator: Placebo
  Matching placebo to 15 and 50 mg CNP520 taken orally once daily
  Intervention: Other: Matching placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: July 22, 2020): 1145
• Original Estimated Enrollment (submitted: April 24, 2017): 2000
• Actual Study Completion Date: March 26, 2020
• Actual Primary Completion Date: March 26, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• consent to receive disclosure of their risk estimates to develop clinical symptoms of AD based on their APOE genotype and, if Heterozygotes, evidence of elevated brain amyloid.
• Male or female, age 60 to 75 years inclusive. Females must be considered post-menopausal and not of child bearing potential
• Cognitively unimpaired as evaluated by memory tests performed at screening.
• Participant's willingness to have a study partner.
• Carrier of at least one APOE4 gene if Heterozygotes, elevated brain amyloid (as measured by CSF Abeta or amyloid PET imaging).

Exclusion Criteria:

• Any disability that could have prevented the participants 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 could 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 the past 60 months.
• Indication for, or current treatment with ChEIs and/or another AD treatment (e.g. memantine).
• Contraindication or intolerance to MRI.
• Brain MRI results showing findings unrelated to AD that, in the opinion of the Investigator might be a leading cause to future cognitive decline, could have posed a risk to the participant, or could have prevented a satisfactory MRI assessment for safety monitoring.
• Suicidal Ideation in the past six months, or Suicidal Behavior in the past two years.
• A positive drug screen at Screening, if, in the Investigator's opinion, was is due to drug abuse.
• Significantly abnormal laboratory results at Screening, not as a result of a temporary condition.
• Current clinically significant ECG findings.
• Clinically relevant depigmenting or hypopigmenting conditions (e.g. albinism, vitiligo) or active / history of chronic urticaria in the past year.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 60 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Canada, Chile, China, Finland, France, Germany, Iceland, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Portugal, Puerto Rico, Singapore, South Africa, Spain, Switzerland, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03131453
• Other Study ID Numbers: CCNP520A2202J; 2016-002976-28 ( EudraCT Number )
• 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

• Amgen
• Banner Alzheimer's Institute

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: August 2021