Study of the Efficacy and Safety of Various Anti-inflammatory Agents in Participants With Mild Cognitive Impairment or Mild Alzheimer's Disease

Exploratory PLatform Trial on Anti-Inflammatory Agents in Alzheimer's Disease (EXPLAIN-AD): A Randomized, Placebo-controlled, Multicenter Platform Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of Various Anti-inflammatory Agents in Patients With Mild Cognitive Impairment Due to Alzheimer's Disease and Mild Alzheimer's Disease

The purpose of this platform study is to evaluate the effect of anti-inflammatory agents on cognition in early Alzheimer's disease. Additionally, the safety and tolerability of these anti-inflammatory agents and the effects on central and peripheral inflammation will be evaluated.

Study Overview

• Status: Active, not recruiting
• Conditions: Alzheimer Disease; Mild Cognitive Impairment
• Intervention / Treatment: Biological: Canakinumab; Other: Placebo

Detailed Description

This is a randomized, placebo-controlled, participant- and investigator-blinded study in participants with either mild cognitive impairment or mild Alzheimer's disease with evidence of peripheral inflammation. This study is using a platform design to be able to investigate different agents (therapies) in a perpetual manner. Each unique investigational agent will have a unique cohort of participants assigned. New cohorts of participants may be enrolled to investigate additional agents at unspecified timepoints throughout the study.

There are three periods in the study: screening period of 60 days that includes a baseline period of 7 days, a treatment period (20 weeks) and a follow-up period (28 days) and an additional follow-up visit for therapies with a longer washout.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2

Contacts and Locations

Study Locations

• Finland
  • Kuopio, Finland, 70210
    • Novartis Investigative Site
  • Turku, Finland, 20520
    • Novartis Investigative Site
• Iceland
  • Reykjavik, Iceland, 101
    • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, W1G 9JF
    • Novartis Investigative Site
  • Motherwell, United Kingdom, ML1 4UF
    • Novartis Investigative Site
  • Southampton, United Kingdom, SO30 3JB
    • Novartis Investigative Site
  • Devon
    • Plymouth, Devon, United Kingdom, PL6 8BT
      • Novartis Investigative Site
  • Surrey
    • Guildford, Surrey, United Kingdom, GU27YD
      • Novartis Investigative Site
• United States
  • Massachusetts
    • Charlestown, Massachusetts, United States, 02129
      • Novartis Investigative Site
  • New York
    • Stony Brook, New York, United States, 11794-8161
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female, age ≥ 45 years and ≤ 90 years at the time of signing the informed consent;
• Participant has a reliable study partner or caregiver can accompany the participant to all visits;
• A diagnosis of probable MCI due to AD or mild AD according to the National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria;
• Confirmed amyloid and tau positivity via CSF sampling performed at screening;
• Mini-Mental State Examination (MMSE) total score of 20 to 24 (inclusive) at screening; OR, MMSE total score of 25-30 (inclusive) plus a DSST score at least 0.5 standard deviation (SD) below normative data at screening.

Exclusion Criteria:

• Use of an investigational agent or an approved product with the intent to modulate inflammation or modulate the course of AD (e.g., Tau ASOs, gene therapy, amyloid or tau vaccine):

  • Previous use of small molecules is allowed if discontinued for at least five half-lives, or at least 30 days from when the expected pharmacodynamic effect has returned to baseline prior to screening, whichever is longer
  • Previous use of monoclonal or polyclonal antibodies or other biologics is allowed if discontinued for at least five half-lives prior to screening
• Current medical or neurological condition that might impact cognition or performance on cognitive assessments, e.g., MCI not due to AD, non-Alzheimer dementia, Huntington's disease, Parkinson's disease, stroke, schizophrenia, bipolar disorder, active major depression, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), active seizure disorder, or history of traumatic brain injury associated with loss of consciousness and ongoing residual transient or permanent neurological signs/symptoms including cognitive deficits, and/or associated with skull fracture;
• If a historical MRI or CT scan has been performed, signs of major cerebrovascular disease shown on such scans (i.e., presence of infarction in greater than 25% of white matter; more than one lacune within basal ganglia or more than 2 lacunes in white matter);
• Diagnosis of vascular dementia prior to screening (e.g.., modified Hachinski Ischaemic Scale score > 6 or those who meet the NINDS AIREN criteria for vascular dementia);

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Canakinumab; increasing doses of sub-cutaneous injections	Biological: Canakinumab; Biological sub-cutaneous injection; Other Names: ACZ885
Placebo Comparator: Placebo; Matching placebo sub-cutaneous injections	Other: Placebo; Matching placebo subcutaneous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in cognition as measured by the Neuropsychological Test Battery (NTB) total score	Neuropsychological Test Battery (NTB) is a composite of multiple globally-established neuropsychological tests that parovide a thorough assessment of the cognitive domains affect by early Alzheimer's Disease (AD), in particular, memory, executive function, attention and verbal fluency.	Baseline and at 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants who experience adverse events and serious adverse events	Clinically significant abnormalities of laboratory values, physical findings, electrocardiogram findings and other safety assessments will be recorded as adverse events if the findings meet the defined criteria for adverse events.	Baseline up to 30 days post last dose
Change from baseline in microglia activation as measured by Positron-Emission Tomography-Translocator Protein 18kDa - microglia activation	Positron-Emission Tomography-Translocator Protein 18kDa-microglia activation (PET TSPO) is considered a marker of central inflammation (a marker for activated microglia and astrocytes) and the signal strength has been shown to correlate with worsening clinical severity in participants with MCI or AD, measures of cognition and various clinical scores.	Baseline and at 12 weeks
Change from baseline in neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI) total score	Neuropsychiatric Inventory (NPI) total score is a globally recognized and the most frequently used assessment of neuropsychiatric symptoms in AD trials that covers twelve neuropsychiatric domains.	Baseline and at 24 weeks
Change from baseline in function (activities of daily living) as measured by the Everyday Cognition (eCog) total score	Everyday Cognition (eCog) scale measures cognitively-relevant everyday abilities and is comprised of 39 items covering six cognitively-relevant domains: Everyday Memory, Everyday Language, Everyday Visuospatial Abilities, Everyday Planning, Everyday Organization, and Everyday Divided Attention.	Baseline and at 24 weeks
Change from baseline in memory as measured by the total Neuropsychological Test Battery memory composite score and change from baseline in executive function as measured by the total Neuropsychological Test Battery executive function composite score	Total Neuropsychological Test Battery memory composite score is a "memory function" composite score and is obtained by averaging the following z-scores from the NTB: RAVLT immediate and delayed scores. The total Neuropsychological Test Battery executive function composite score is an "executive function" composite score that is obtained by averaging the following three z-scores from the NTB: Wechsler Memory Scale Digit Span, COWAT, and CFT.	Baseline and at 24 weeks
Change from baseline in pharmacokinetic concentrations and immunogenetic anti-agent antibody levels in serum and/or plasma and/or cerebrospinal fluid	Pharmacokinetic concentrations and Immunogenic anti-agent antibodies that are measured to assess how the study agent is transported around the body in the blood and CSF and if antibodies are produced by the body in response to the study agent.	Baseline through to 24 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2021
• Primary Completion (Estimated): March 13, 2024
• Study Completion (Estimated): March 13, 2024

Study Registration Dates

• First Submitted: March 10, 2021
• First Submitted That Met QC Criteria: March 10, 2021
• First Posted (Actual): March 12, 2021

Study Record Updates

• Last Update Posted (Actual): October 4, 2023
• Last Update Submitted That Met QC Criteria: October 2, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Inflammation; Adults; Mild Cognitive Impairment; Dementia; Alzheimer disease; Memory loss; Elderly adults; ADPT06
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Alzheimer Disease; Cognitive Dysfunction
• Other Study ID Numbers: CADPT06A12201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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 https://www.clinicalstudydatarequest.com/

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No