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

Phase 2

Terminated

Conditions: Mild Cognitive Impairment
Alzheimer Disease

Interventions: Biological: Canakinumab
Other: Placebo

Registration Number: NCT04795466

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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.

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).

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 34

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Canakinumab	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.
Placebo	Placebo	Matching placebo sub-cutaneous injections

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Cognition as Measured by the Neuropsychological Test Battery (NTB) Z-scores	Baseline and day 171	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Memory as Measured by the Total Composite NTB Memory Z-score	Baseline and day 171	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.
Change From Baseline in Executive Function as Measured by the Total Composite NTB Executive Function Z-score	Baseline and day 171	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.
Change From Baseline in Digit Symbol Substitution Test (DSST) Score - CANTAB	Baseline and day 171	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
Change From Baseline in Neuropsychiatric Symptoms as Measured by the Neuropsychiatric Inventory (NPI) Total Score	Baseline and day 171	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.
Change From Baseline in Neuropsychiatric Symptoms Associated Distress as Measured by the Neuropsychiatric Inventory Caregiver Distress (NPI-D) Score	Baseline and day 171	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.
Change From Baseline in Mean eNeuropsychiatric at Home Caregiver Assessment Score	Baseline, day 85	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.
Change From Baseline in Everyday Cognition Scale (ECog) Total Score	Baseline and day 171	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.
Change From Baseline in eCognitive Testing Scores - SWM Between Errors	Baseline, day 85	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.
Change From Baseline in eCognitive Testing Scores - SWM Strategy	Baseline, day 85	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.
Change From Baseline in eCognitive Testing Scores - MTS Proportional Slowing 8-2 Patterns	Baseline, day 85	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.
Change From Baseline in eCognitive Testing Scores - PAL First Attempt Memory Score	Baseline, day 85	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.
Change From Baseline in Microglia Activation as Measured by Positron-Emission Tomography-Translocator Protein 18kDa - Microglia Activation	Baseline and day 85	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.
Serum Pharmacokinetic Concentrations of Canakinumab	Baseline, day29, day 57, day 85, day 141, day 171	Serum pharmacokinetic pre-dose concentrations of CanakinumabConcentrations below the LLOQ were reported as "zero".
Total Target (IL-1 Beta) Concentration in Serum and CSF	Baseline, day 29, day 57, day 85, day 141, day 171 for serum concentrations and Baseline and day 85 for CSF concentrations	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.
Number of Participants With Anti-agent Antibodies in Serum	Baseline, day 85, day 171	Number of participants with anti-agent antibodies in serum. Immunogenicity (IG) was assessed in serum of all participants treated with biotherapeutic drug.
Number of Participants Who Experience Adverse Events and Serious Adverse Events	From first dose up to approximately 140 days post last dose (day 281)	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

Trial Locations

Locations (3): Massachusetts General Hospital
🇺🇸
Charlestown, Massachusetts, United States
SUNY at Stony Brook
🇺🇸
Stony Brook, New York, United States
Novartis Investigative Site
🇬🇧
Southampton, United Kingdom