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 was to evaluate the effect of anti-inflammatory agents on cognition in early Alzheimer's disease. Additionally, the safety and tolerability and their effects on central and peripheral inflammation were evaluated. Due to early termination only a single agent could be studied.

Study Overview

• Status: Terminated
• Conditions: Alzheimer Disease; Mild Cognitive Impairment
• Intervention / Treatment: Other: Placebo; Biological: Canakinumab

Detailed Description

This was 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 was originally planned as a platform study, designed to investigate different agents in a continuous manner. However, due to early termination of the study only one experimental arm was enrolled.

The study included a screening period (Day -60 to Day -8), followed by a baseline period of 7 days (Day -7 to Day -1), a treatment period of 20 weeks (Day 1 to Day 141), a study completion evaluation (EOC1) approximately 30 days after the last agent administration (Day 171) and a second end of cohort visit (EOC2) approximately 140 days after the last agent administration (Day 281).

• 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
      • Massachusetts General Hospital
  • New York
    • Stony Brook, New York, United States, 11794-8161
      • SUNY at Stony Brook

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;
• 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
Placebo Comparator: Placebo; Matching placebo sub-cutaneous injections	Other: Placebo; Matching placebo subcutaneous injection
Experimental: Canakinumab; Canakinumab 150 mg SC once every 4 weeks for the first 2 doses followed by 300 mg SC once every 4 weeks for the subsequent 4 doses.	Biological: Canakinumab; Biological subcutaneous injection; Other Names: ACZ885

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) Z-scores	NTB is a composite of multiple neuropsychological tests that provide a thorough assessment of the cognitive domains affected by early Alzheimer's Disease (AD), in particular, memory, executive function, attention and verbal fluency. 5 out of 9 NTB components were administered in the study, Rey Auditory Verbal Learning Test (RAVLT) immediate and delayed scores, Wechsler Memory Scale Digit Span, Controlled Word Association Test (COWAT) and Category Fluency Test (CFT). For each component a raw score was converted to z-score that indicates the number of standard deviations away from the mean. Total Z-score was derived by averaging all resulting z-scores. A change from baseline was calculated as post-baseline z-score minus pre-treatment z-score. A zero Z-score means no cognitive change, a negative value indicates decline, and a positive value means improvement.	Baseline and day 171

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Memory as Measured by the Total Composite NTB Memory Z-score	Total Neuropsychological Test Battery memory composite score is a "memory function" score composed of the NTB RAVLT immediate and delayed scores. For each component a raw score was converted to z-score that indicates the number of standard deviations away from the mean. Total Z-score was derived by averaging the two resulting z-scores. A change from baseline was calculated as post-baseline z-score minus pre-treatment z-score. A zero Z-score means no cognitive change, a negative value indicates decline, and a positive value means improvement.	Baseline and day 171
Change From Baseline in Executive Function as Measured by the Total Composite NTB Executive Function Z-score	The total Neuropsychological Test Battery executive function composite score is an "executive function" score composed of the NTB Wechsler Memory Scale Digit Span, COWAT, and CFT. For each component a raw score was converted to z-score that indicates the number of standard deviations away from the mean. Total Z-score was derived by averaging the two resulting z-scores. A change from baseline was calculated as post-baseline z-score minus pre-treatment z-score. A zero Z-score means no cognitive change, a negative value indicates decline, and a positive value means improvement.	Baseline and day 171
Change From Baseline in Digit Symbol Substitution Test (DSST) Score - CANTAB	The DSST is an attention-demanding component of the Wechsler Adult Intelligence Scale-IV. The DSST score is the number of digits coded correctly in a fixed amount of time. The DSST has a minimum of "0" correct responses and does not have a maximum; a higher number on the DSST represents better performance The test was administered using CANTAB web based testing	Baseline and day 171
Change From Baseline in Neuropsychiatric Symptoms as Measured by the Neuropsychiatric Inventory (NPI) Total Score	Neuropsychiatric Inventory (NPI) total score is globally recognized and the most frequently used assessment of neuropsychiatric symptoms in AD trials. NPI covers twelve neuropsychiatric domains. For each domain there are four scores, frequency (rated 1-4), severity (rated 1-3), domain total score (frequency x severity) and caregiver distress score (rated 0-5). The NPI total score was calculated by adding 12 domain total scores together, and ranges from 0 to 144, with higher values indicating greater severity.	Baseline and day 171
Change From Baseline in Neuropsychiatric Symptoms Associated Distress as Measured by the Neuropsychiatric Inventory Caregiver Distress (NPI-D) Score	Neuropsychiatric Inventory (NPI) total score is globally recognized and the most frequently used assessment of neuropsychiatric symptoms in AD trials. NPI covers twelve neuropsychiatric domains. For each domain there are four scores, frequency (rated 1-4), severity (rated 1-3), domain total score (frequency x severity) and caregiver distress score (rated 0-5). The caregiver distress score (NPI-D) was calculated by adding together the scores of the 12 individual NPI distress questions, and ranges from 0 to 60, with higher values indicating greater severity.	Baseline and day 171
Change From Baseline in Mean eNeuropsychiatric at Home Caregiver Assessment Score	Neuropsychiatric Inventory (NPI) total score is globally recognized and the most frequently used assessment of neuropsychiatric symptoms in AD trials. NPI covers twelve neuropsychiatric domains. For each domain there are four scores, frequency (rated 1-4), severity (rated 1-3), domain total score (frequency x severity) and caregiver distress score (rated 0-5). The eNeuropsychiatric at-home assessment was calculated the same way as the in-clinic NPI by adding the12 domain total scores together. The eNeuropsychiatric at-home assessments were completed more frequently than the single time-point in-clinic NPI assessment and the scores averaged. It ranges from 0 to 144, with higher values indicating greater severity.	Baseline, day 85
Change From Baseline in Everyday Cognition Scale (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. Each item is scored on a 4 point scale (1=better or no change compared to 10 years earlier, 2=questionable/occasionally worse, 3=consistently a little worse, 4=consistently much worse). An "I don't know" response is also included, in that case the item is not included in the calculation. The total ECog score is calculated as the sum of all 39 items, and ranges from 0 to 156. Lower total ECog scores indicate better performance.	Baseline and day 171
Change From Baseline in eCognitive Testing Scores - SWM Between Errors	Spatial Working Memory (SWM) is a test of the subject's ability to retain spatial information and to manipulate remembered items in working memory. A trial begins with several colored squares (boxes) being shown on the screen. The overall aim is that the subject should find a blue 'token' in each of the boxes and use them to fill up an empty column. The subject must touch each box in turn until one opens with a blue 'token' inside (a search). Returning to an empty box already sampled on this search is an error. SWM between errors is the number of times the subject incorrectly revisits a box in which a token has previously been found. It starts at 0 without a maximum limit with higher scores indicating a worse outcome.	Baseline, day 85
Change From Baseline in eCognitive Testing Scores - SWM Strategy	Spatial Working Memory (SWM) is a test of the subject's ability to retain spatial information and to manipulate remembered items in working memory. A trial begins with several colored squares (boxes) being shown on the screen. The overall aim is that the subject should find a blue 'token' in each of the boxes and use them to fill up an empty column. The subject must touch each box in turn until one opens with a blue 'token' inside (a search). Returning to an empty box already sampled on this search is an error. SWM Strategy is the number of times a subject begins a new search pattern from the same box they started with previously. If they always begin a search from the same starting point, we infer that the subject is employing a planned strategy for finding the tokens. SMW strategy ranges from 3 to 26, a low score indicates high strategy use, they always begin the search from the same box, and a high score indicates that they are beginning their searches from many different boxes.	Baseline, day 85
Change From Baseline in eCognitive Testing Scores - MTS Proportional Slowing 8-2 Patterns	Match to Sample Visual Search (MTS) assesses attention and visual searching, with a speed accuracy trade-off. The participant is shown a complex visual pattern in the middle of the screen. After a brief delay, a varying number of similar patterns are shown in a circle of boxes around the edge of the screen. Only one of these patterns matches the pattern in the center of the screen, and the participant must indicate which it is by selecting it. MTS proportional slowing 8-2 patterns is the difference in mean time between presentation of the response stimulus options and the subject selecting the correct box on their first attempt on the 8 pattern assessment trials compared to the 2 pattern assessment trials. It starts at 0 without a maximum limit, and with higher scores indicating a worse outcome.	Baseline, day 85
Change From Baseline in eCognitive Testing Scores - PAL First Attempt Memory Score	Pair associated learning (PAL): tests participants' visual memory/new learning using patterns randomly displayed in boxes on a screen. Participants are to touch the box where patterns first appeared. PAL first attempt memory score is the number of times a subject choses the correct box on their first attempt when recalling the pattern locations. Ranges from 0 to 20 with higher score indicates a better outcome.	Baseline, day 85
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. Relative % change from baseline in volume of distribution (Vt) of the radio tracer for TSPO after treatment. Since only one participant completed day 85 PET TSPO, no data is reported here in order to protect and maintain participant privacy/confidentiality.	Baseline and day 85
Serum Pharmacokinetic Concentrations of Canakinumab	Serum pharmacokinetic pre-dose concentrations of CanakinumabConcentrations below the LLOQ were reported as "zero".	Baseline, day29, day 57, day 85, day 141, day 171
Total Target (IL-1 Beta) Concentration in Serum and CSF	Serum and CSF samples were obtained and evaluated for total target concentrations (the sum of free and drug-bound target) as a pharmacodynamic (PD) marker for target engagement.	Baseline, day 29, day 57, day 85, day 141, day 171 for serum concentrations and Baseline and day 85 for CSF concentrations
Number of Participants With Anti-agent Antibodies in Serum	Number of participants with anti-agent antibodies in serum. Immunogenicity (IG) was assessed in serum of all participants treated with biotherapeutic drug.	Baseline, day 85, day 171
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 were recorded as adverse events if the findings meet the defined criteria for adverse events. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5. For CTCAE, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE	From first dose up to approximately 140 days post last dose (day 281)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2021
• Primary Completion (Actual): March 7, 2024
• Study Completion (Actual): March 7, 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 (Estimated): October 16, 2025
• Last Update Submitted That Met QC Criteria: October 8, 2025
• Last Verified: October 1, 2025

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: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Pathologic Processes; Neurobehavioral Manifestations; Neurocognitive Disorders; Cognition Disorders; Tauopathies; Neurodegenerative Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Cognitive Dysfunction; Alzheimer Disease; Inflammation; Dementia; Memory Disorders; canakinumab
• 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 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