Alzheimer Disease, Mild Cognitive Impairment
Conditions
Keywords
Alzheimer disease, Mild Cognitive Impairment, Elderly adults, Adults, Memory loss, Dementia, Inflammation, ADPT06
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).
Interventions
BIOLOGICALCanakinumab
Biological subcutaneous injection
OTHERPlacebo
Matching placebo subcutaneous injection
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to 90 Years
Healthy volunteers
No
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);
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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 |
| 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. |
Countries
Finland, Iceland, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at 10 sites in 4 different countries
Pre-assignment details
There was a screening period (Day -60 to Day -8), followed by a baseline period of 7 days (Day -7 to Day -1), before first treatment.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 16 |
| Placebo Matching placebo subcutaneous injections | 18 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Canakinumab |
|---|---|---|---|
| Age, Continuous | 72.4 Years STANDARD_DEVIATION 6.71 | 71.8 Years STANDARD_DEVIATION 6.57 | 71 Years STANDARD_DEVIATION 6.53 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 34 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 34 Participants | 16 Participants |
| Sex: Female, Male Female | 8 Participants | 11 Participants | 3 Participants |
| Sex: Female, Male Male | 10 Participants | 23 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 18 | 0 / 34 |
| other Total, other adverse events | 13 / 16 | 16 / 18 | 29 / 34 |
| serious Total, serious adverse events | 2 / 16 | 1 / 18 | 3 / 34 |
Outcome results
Primary
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.
Time frame: Baseline and day 171
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change From Baseline in Cognition as Measured by the Neuropsychological Test Battery (NTB) Z-scores | 0.225 z-score | Standard Error 0.116 |
| Placebo | Change From Baseline in Cognition as Measured by the Neuropsychological Test Battery (NTB) Z-scores | 0.156 z-score | Standard Error 0.0905 |
Comparison: NTB Total z-score - day 171p-value: 0.638690% CI: [-0.178, 0.316]Mixed Models Analysis
Secondary
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
Time frame: Baseline and day 171
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change From Baseline in Digit Symbol Substitution Test (DSST) Score - CANTAB | 1.96 DSST score change from baseline | Standard Error 1.37 |
| Placebo | Change From Baseline in Digit Symbol Substitution Test (DSST) Score - CANTAB | 2.45 DSST score change from baseline | Standard Error 1.13 |
Comparison: DSST - day 171p-value: 0.78790% CI: [-3.56, 2.58]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, day 85
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change From Baseline in eCognitive Testing Scores - MTS Proportional Slowing 8-2 Patterns | 143.780 Change from baseline in milliseconds | Standard Deviation 2871.0641 |
| Placebo | Change From Baseline in eCognitive Testing Scores - MTS Proportional Slowing 8-2 Patterns | 77.573 Change from baseline in milliseconds | Standard Deviation 2824.3325 |
Secondary
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.
Time frame: Baseline, day 85
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change From Baseline in eCognitive Testing Scores - PAL First Attempt Memory Score | -0.17 PAL score change from baseline | Standard Deviation 2.716 |
| Placebo | Change From Baseline in eCognitive Testing Scores - PAL First Attempt Memory Score | 0.08 PAL score change from baseline | Standard Deviation 3.059 |
Secondary
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.
Time frame: Baseline, day 85
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change From Baseline in eCognitive Testing Scores - SWM Between Errors | -1.56 SWMBE score change from baseline | Standard Deviation 6.018 |
| Placebo | Change From Baseline in eCognitive Testing Scores - SWM Between Errors | -1.83 SWMBE score change from baseline | Standard Deviation 4.91 |
Secondary
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.
Time frame: Baseline, day 85
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change From Baseline in eCognitive Testing Scores - SWM Strategy | -0.28 scores on a scale | Standard Deviation 1.149 |
| Placebo | Change From Baseline in eCognitive Testing Scores - SWM Strategy | -0.92 scores on a scale | Standard Deviation 1.459 |
Secondary
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.
Time frame: Baseline and day 171
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change From Baseline in Everyday Cognition Scale (ECog) Total Score | 1.2 ECog total score change from Baseline | Standard Deviation 14.26 |
| Placebo | Change From Baseline in Everyday Cognition Scale (ECog) Total Score | 3.4 ECog total score change from Baseline | Standard Deviation 11.79 |
Secondary
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.
Time frame: Baseline and day 171
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change From Baseline in Executive Function as Measured by the Total Composite NTB Executive Function Z-score | 0.111 z-score change from baseline | Standard Error 0.1492 |
| Placebo | Change From Baseline in Executive Function as Measured by the Total Composite NTB Executive Function Z-score | -0.075 z-score change from baseline | Standard Error 0.1251 |
Comparison: Executive function- day 171p-value: 0.35190% CI: [-0.148, 0.52]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, day 85
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change From Baseline in Mean eNeuropsychiatric at Home Caregiver Assessment Score | 0.983 scores on a scale | Standard Deviation 3.7904 |
| Placebo | Change From Baseline in Mean eNeuropsychiatric at Home Caregiver Assessment Score | -1.094 scores on a scale | Standard Deviation 1.7083 |
Secondary
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.
Time frame: Baseline and day 171
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change From Baseline in Memory as Measured by the Total Composite NTB Memory Z-score | 0.461 z-score change from baseline | Standard Error 0.1382 |
| Placebo | Change From Baseline in Memory as Measured by the Total Composite NTB Memory Z-score | 0.463 z-score change from baseline | Standard Error 0.1062 |
Comparison: Memory function - day 171p-value: 0.991790% CI: [-0.3, 0.296]Mixed Models Analysis
Secondary
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.
Time frame: Baseline and day 85
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.~PET TSPO inferential analysis could only be performed if the number of participants with data allowed the analysis without compromising patient privacy/confidentiality.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Microglia Activation as Measured by Positron-Emission Tomography-Translocator Protein 18kDa - Microglia Activation | NA Percent change from baseline |
Secondary
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.
Time frame: Baseline and day 171
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change From Baseline in Neuropsychiatric Symptoms as Measured by the Neuropsychiatric Inventory (NPI) Total Score | -1.4 NPI total score change from Baseline | Standard Deviation 7.76 |
| Placebo | Change From Baseline in Neuropsychiatric Symptoms as Measured by the Neuropsychiatric Inventory (NPI) Total Score | 2.9 NPI total score change from Baseline | Standard Deviation 8.68 |
Secondary
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.
Time frame: Baseline and day 171
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change From Baseline in Neuropsychiatric Symptoms Associated Distress as Measured by the Neuropsychiatric Inventory Caregiver Distress (NPI-D) Score | -2.7 NPI-D score change from Baseline | Standard Deviation 7.7 |
| Placebo | Change From Baseline in Neuropsychiatric Symptoms Associated Distress as Measured by the Neuropsychiatric Inventory Caregiver Distress (NPI-D) Score | 1.2 NPI-D score change from Baseline | Standard Deviation 5.74 |
Secondary
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
Time frame: From first dose up to approximately 140 days post last dose (day 281)
Population: The safety analysis set included all participants who received any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Canakinumab | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with at least one AE | 14 Participants |
| Canakinumab | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with grade 1 AEs | 14 Participants |
| Canakinumab | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with grade 2 AEs | 6 Participants |
| Canakinumab | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with grade 3 AEs | 1 Participants |
| Canakinumab | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with study drug related AEs | 4 Participants |
| Canakinumab | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with serious AEs | 2 Participants |
| Canakinumab | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with AEs leading to treatment discontinuation | 3 Participants |
| Canakinumab | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with study drug related AEs leading to treatment discontinuation | 1 Participants |
| Placebo | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with study drug related AEs leading to treatment discontinuation | 0 Participants |
| Placebo | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with at least one AE | 16 Participants |
| Placebo | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with serious AEs | 1 Participants |
| Placebo | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with grade 1 AEs | 16 Participants |
| Placebo | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with grade 2 AEs | 6 Participants |
| Placebo | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with AEs leading to treatment discontinuation | 1 Participants |
| Placebo | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with grade 3 AEs | 0 Participants |
| Placebo | Number of Participants Who Experience Adverse Events and Serious Adverse Events | Participants with study drug related AEs | 5 Participants |
Secondary
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.
Time frame: Baseline, day 85, day 171
Population: Participants in the safety analysis (SA) set who received Canakinumab. The SA set included all participants who received any study drug.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Canakinumab | Number of Participants With Anti-agent Antibodies in Serum | Baseline | POSITIVE | 0 Participants |
| Canakinumab | Number of Participants With Anti-agent Antibodies in Serum | Baseline | NEGATIVE | 16 Participants |
| Canakinumab | Number of Participants With Anti-agent Antibodies in Serum | Day 85 | POSITIVE | 0 Participants |
| Canakinumab | Number of Participants With Anti-agent Antibodies in Serum | Day 85 | NEGATIVE | 12 Participants |
| Canakinumab | Number of Participants With Anti-agent Antibodies in Serum | Day 171 | POSITIVE | 0 Participants |
| Canakinumab | Number of Participants With Anti-agent Antibodies in Serum | Day 171 | NEGATIVE | 10 Participants |
Secondary
Serum Pharmacokinetic Concentrations of Canakinumab
Serum pharmacokinetic pre-dose concentrations of CanakinumabConcentrations below the LLOQ were reported as zero.
Time frame: Baseline, day29, day 57, day 85, day 141, day 171
Population: Participants in the pharmacokinetic (PK) analysis set who received Canakinumab. The PK analysis set included all participants with at least one available valid (i.e., not flagged for exclusion) PK concentration measurement, who received any study drug and with no protocol deviations that impact PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Canakinumab | Serum Pharmacokinetic Concentrations of Canakinumab | Baseline | 0.0 ng/mL | Standard Deviation 0 |
| Canakinumab | Serum Pharmacokinetic Concentrations of Canakinumab | Day 57 | 14230.8 ng/mL | Standard Deviation 4712.07 |
| Canakinumab | Serum Pharmacokinetic Concentrations of Canakinumab | Day 85 | 26575.0 ng/mL | Standard Deviation 10216.93 |
| Canakinumab | Serum Pharmacokinetic Concentrations of Canakinumab | Day 141 | 34000.0 ng/mL | Standard Deviation 11288.67 |
| Canakinumab | Serum Pharmacokinetic Concentrations of Canakinumab | Day 171 | 33170.0 ng/mL | Standard Deviation 6825.45 |
| Canakinumab | Serum Pharmacokinetic Concentrations of Canakinumab | Day 29 | 8921.3 ng/mL | Standard Deviation 2721.47 |
Secondary
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.
Time frame: Baseline, day 29, day 57, day 85, day 141, day 171 for serum concentrations and Baseline and day 85 for CSF concentrations
Population: Participants in the PD analysis set with an available value for the outcome measure. The PD (total target) analysis set for biotherapeutic agents included all participants with available (total target) PD data and no protocol deviations with relevant impact on (total target) PD data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Canakinumab | Total Target (IL-1 Beta) Concentration in Serum and CSF | Serum - Day 85 | 23.291 pg/mL | Standard Deviation 5.2984 |
| Canakinumab | Total Target (IL-1 Beta) Concentration in Serum and CSF | Serum - Baseline | 0.000 pg/mL | Standard Deviation 0 |
| Canakinumab | Total Target (IL-1 Beta) Concentration in Serum and CSF | Serum - Day 29 | 12.632 pg/mL | Standard Deviation 4.4949 |
| Canakinumab | Total Target (IL-1 Beta) Concentration in Serum and CSF | Serum - Day 57 | 20.818 pg/mL | Standard Deviation 10.2918 |
| Canakinumab | Total Target (IL-1 Beta) Concentration in Serum and CSF | Serum - Day 141 | 44.473 pg/mL | Standard Deviation 58.3963 |
| Canakinumab | Total Target (IL-1 Beta) Concentration in Serum and CSF | Serum - Day 171 | 28.460 pg/mL | Standard Deviation 18.4483 |
| Canakinumab | Total Target (IL-1 Beta) Concentration in Serum and CSF | CSF - Baseline | 0.000 pg/mL | Standard Deviation 0 |
| Canakinumab | Total Target (IL-1 Beta) Concentration in Serum and CSF | CSF - Day 85 | 0.000 pg/mL | Standard Deviation 0 |
| Placebo | Total Target (IL-1 Beta) Concentration in Serum and CSF | CSF - Day 85 | 0.023 pg/mL | Standard Deviation 0.0883 |
| Placebo | Total Target (IL-1 Beta) Concentration in Serum and CSF | Serum - Day 141 | 0.000 pg/mL | Standard Deviation 0 |
| Placebo | Total Target (IL-1 Beta) Concentration in Serum and CSF | Serum - Baseline | 0.000 pg/mL | Standard Deviation 0 |
| Placebo | Total Target (IL-1 Beta) Concentration in Serum and CSF | CSF - Baseline | 0.000 pg/mL | Standard Deviation 0 |
| Placebo | Total Target (IL-1 Beta) Concentration in Serum and CSF | Serum - Day 29 | 0.000 pg/mL | Standard Deviation 0 |
| Placebo | Total Target (IL-1 Beta) Concentration in Serum and CSF | Serum - Day 171 | 0.000 pg/mL | Standard Deviation 0 |
| Placebo | Total Target (IL-1 Beta) Concentration in Serum and CSF | Serum - Day 57 | 0.000 pg/mL | Standard Deviation 0 |
| Placebo | Total Target (IL-1 Beta) Concentration in Serum and CSF | Serum - Day 85 | 0.000 pg/mL | Standard Deviation 0 |