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

Phase 3TerminatedNCT03131453

Novartis Pharmaceuticals1,145 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

1,145

Conditions

Alzheimers Disease

Interventions

CNP520 50mgDRUG

50 mg capsule

CNP520 15mgDRUG

15 mg capsule

Matching placeboOTHER

Matching placebo for 15 and 50 mg capsules

Eligibility

Sex: ALLMin age: 60 YearsMax age: 75 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Locations (194)

Outcomes

Primary Outcomes

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.

Time frame: Baseline to last cognitive assessment performed (up to day 648)

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.

Time frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Secondary Outcomes

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

Data from ClinicalTrials.gov

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Banner Alzheimer's Institute, 901 East Willetta Street

Phoenix, Arizona, United States

Banner Sun Health Research Institute, 10515 West Santa Fe Drive, Building B

Sun City, Arizona, United States

Novartis Investigative Site

Tucson, Arizona, United States

ATP Clinical Research Inc, 3151 Airway Avenue T 3

Costa Mesa, California, United States

Irvine Center for Clinical Res, 2515 McCabe Way

Irvine, California, United States

Torrance Clinical Research Institute, 25043 Narbonne Avenue

Lomita, California, United States

Novartis Investigative Site

Oxnard, California, United States

Novartis Investigative Site

Palo Alto, California, United States

Novartis Investigative Site

San Diego, California, United States

Syrentis Clinical Research, 1401 N Tustin Ave, Suite 130

Santa Ana, California, United States

...and 184 more locations

Time frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Change in the Total and 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.

Time frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

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.

Time frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

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)

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) and a general assessment of brain abnormalities.

Time frame: Baseline up to study termination approximately 617 days

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.

Time frame: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Change in CSF Levels of Amyloid Beta 40 (Aβ40)

Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 40 (Aβ40)

Time frame: Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Change in CSF Levels of Amyloid Beta 42 (Aβ42)

Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 42 (Aβ42).

Time frame: Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

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 Alzheimer's Disease-related biomarkers

Time frame: Baseline to Months 24 and 60

Change in Amyloid Deposition as Measured by Standardized Uptake Ratio (SUVR) of Positron Emission Tomography (PET) Scan With Amyloid Radiotracer

To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers

Time frame: Baseline to Months 24 and 60

Change in 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

Time frame: Baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648)

Change in Serum Neurofilaments

Alzheimer's Disease-related biomarkers analyzed in blood serum: light chain neurofilaments (NfL)

Time frame: Baseline to Week 26, baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648)

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.

Time frame: Baseline up to study termination approximately 617 days