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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04795466

Collaborator

(none)

Enrollment

Locations

Arms

26.8

Anticipated Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Mild Cognitive Impairment Alzheimer Disease	Biological: Canakinumab Other: Placebo	Phase 2

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 5 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 Design

Study Type:

Interventional

Anticipated Enrollment :

90 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 28, 2021

Anticipated Primary Completion Date :

Jan 22, 2024

Anticipated Study Completion Date :

Jan 22, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Change from baseline in cognition as measured by the Neuropsychological Test Battery (NTB) total score [Baseline and at 24 weeks]
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.

Secondary Outcome Measures

Number of participants who experience adverse events and serious adverse events [Baseline up to 30 days post last dose]
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.
Change from baseline in microglia activation as measured by Positron-Emission Tomography-Translocator Protein 18kDa - microglia activation [Baseline and at 12 weeks]
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.
Change from baseline in neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI) total score [Baseline and at 24 weeks]
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.
Change from baseline in function (activities of daily living) as measured by the Everyday Cognition (eCog) total score [Baseline and at 24 weeks]
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.
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 [Baseline and at 24 weeks]
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.
Change from baseline in pharmacokinetic concentrations and immunogenetic anti-agent antibody levels in serum and/or plasma and/or cerebrospinal fluid [Baseline through to 24 weeks]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

45 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 30 (inclusive) and DSST score at least one standard deviation (SD) below normative data at point of screening.

Exclusion Criteria:

Use of other investigational agents prior to screening until: a) Small molecules: after five half-lives, or within 30 days until the expected pharmacodynamic effect has returned to baseline, whichever is longer; OR b) Biologicals: blood concentration has returned to baseline (or below serological responder threshold) for antibodies induced by active immunotherapy; or five half-lives for monoclonal antibodies or other biologicals;
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);
Previous exposure to amyloid vaccines or intravenous immunoglobulins meant to treat Alzheimer's disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Charlestown	Massachusetts	United States	02129
2	Novartis Investigative Site	Stony Brook	New York	United States	11794-8161
3	Novartis Investigative Site	Knoxville	Tennessee	United States	37920
4	Novartis Investigative Site	Fairfax	Virginia	United States	22031
5	Novartis Investigative Site	Turku		Finland	20520
6	Novartis Investigative Site	Reykjavik		Iceland	101
7	Novartis Investigative Site	Plymouth	Devon	United Kingdom	PL6 8BT
8	Novartis Investigative Site	Guildford	Surrey	United Kingdom	GU27YD
9	Novartis Investigative Site	London		United Kingdom	W1G 9JF
10	Novartis Investigative Site	Southampton		United Kingdom	SO30 3JB