Trial Outcomes & Findings for Effect of CT1812 Treatment on Brain Synaptic Density (NCT NCT03493282)

Location Type: Medical Clinic

Each participant was screened between Day -60 and Day -1 prior to study drug administration. Participants could choose to participate in the optional double-blind extension treatment period of an additional 24 weeks (337 days +/-2).as well as a follow up visit at 2 weeks after the final treatment visit. In the study, 43 patients were enrolled. 23 participants were randomized, and 20 were screen failures.

Effect of CT1812 Treatment on Brain Synaptic Density

Number of subjects reported with AEs and the number of AEs reported following administration of the IP summarized by treatment and grouped according to system organ class and preferred term, using descriptive statistics. Summaries of AEs were also presented by severity and by relationship to investigational product. In these summaries, subjects were counted only once per MedDRA term, for the AE of highest severity or least favorable relationship. Summaries were also presented of SAEs and of AEs leading to study withdrawal.

The Distribution Volume Ratio (DVR) was used to determine the correlations with the cognitive and functional endpoints. For 11C UCB J, the imaging outcome measure was DVR as produced by the Simplified Reference Tissue Model (SRTM2) using dynamic scan data from 0 to 60 min and the whole cerebellum as a reference region. Change from baseline is calculated as the observed value minus the baseline value. A negative change from baseline indicates the progression of disease.

For 18F FDG, the primary imaging outcome measure was the SUVR from 60-90 min post injection using whole cerebellum as a reference region. For SUVR, a composite region was determined, including: prefrontal, lateral temporal, posterior cingulate/precuneus, anterior cingulate, lateral parietal, medial temporal, and lateral occipital regions. Change from baseline is calculated as the observed value minus the baseline value. A negative change from baseline indicates the progression of the disease.

A composite region of AD affected brain regions was determined, including prefrontal, lateral temporal, posterior cingulate/precuneus, anterior cingulate, lateral parietal, medial temporal, and lateral occipital regions. Baseline is defined as the last measurement taken before the first dose of study drug. Change from baseline is calculated as the observed value minus the baseline value. A negative change from baseline indicates the progression of disease.

For resting state functional MRI, the outcome was ICC. With this approach a map of the total connectivity of each voxel to all other voxels was computed. For ICC, a composite region of AD affected brain regions was determined, including prefrontal, lateral temporal, posterior cingulate/precuneus, anterior cingulate, lateral parietal, medial temporal, and lateral occipital regions. Change from baseline is calculated as the observed value minus the baseline value. A negative change from baseline indicates the progression of disease.

Change from baseline in CSF Aβ 40, CSF Aβ 42, CSF tau, CSF phospho-tau, CSF neurogranin (NRGN), CSF synaptotagmin, CSF(SNAP25), and CSF neurofilament light (NFL). Change from baseline is calculated as the observed value minus the baseline value.

The ADAS-Cog11 total score = the sum of all 11 individual items (word recall \[10\]; commands \[5\]; constructional praxis \[5\]; naming objects and fingers \[5\]; ideational praxis \[5\]; orientation \[8\]; word recognition \[12\]; remembering test instructions \[5\]; spoken language \[5\]; word finding \[5\]; and comprehension of spoken language \[5\]). The score range for ADAS-cog 11 is 0-70 where a higher score is worse performance. The ADAS-cog methodology is to sum scores for subscales. The results were calculated using the average change from baseline. Baseline is defined as the last measurement taken before the first dose of study drug is administered. Change is calculated as the observed value minus the baseline value. A negative change from baseline indicates improvement.

The ADAS-Cog13 total score includes all of the items in the ADAS-Cog11 and the delayed word recall and the number cancellation. For the ADAS-cog 13 the range is 0-85 (score range for Delayed Word Recall \[DWR\] score is 0-10 and for Number Cancellation \[NC\] is 0-5, thus the score is ADAS-cog 11\[0-70\] plus the scores for DWR and NC). A higher score indicates worse performance. The ADAS-cog methodology is to sum scores for subscales. The results were calculated using the average change from baseline. Baseline is defined as the last measurement taken before the first dose of study drug. Change is calculated as the observed value minus the baseline value. A negative change from baseline indicates improvement in cognitive function.

The ADAS-Cog14 total score includes all of the items in the ADAS-Cog13 \[0-85\] and the maze item which has a score range of 0-5. Thus, the total score for the ADAS-cog 14 is 0-90 where again a higher score is worst performance. The ADAS-cog methodology is to sum scores for subscales. The results were calculated using the average change from baseline. Baseline is defined as the last measurement taken before the first dose of study drug is administered. Change is calculated as the observed value minus the baseline value. A negative change from baseline indicates improvement in cognitive function.

The ADCS-ADL is a 23-item informant-administered assessment of functional impairment in terms of activities of daily living. Informants respond to 23 questions about the subject's involvement and level of performance across items representing daily living. The questions range from basic to instrumental activities of daily living. Each item is rated from the highest level of independent performance to complete loss. The total score range is from 0-78 with lower scores indicating greater functional impairment. A positive change from baseline indicates improvement in function. The results were calculated using the average change from baseline. Higher scores mean better outcome. Negative mean indicates worsening of function. Positive mean indicates improvement of function.

The MMSE assesses several aspects of memory and cognitive functioning including orientation, attention, concentration, comprehension, recall, and praxis. The total possible score is 30, with high scores indicating less impairment. Change from baseline is calculated as the observed value minus the baseline value. A positive change from baseline indicates improvement in cognition.

Scores were on a scale of 0 through 3, with 0=no dementia, 0.5=questionable dementia, 1=mild dementia, 2=moderate dementia, and 3=severe dementia. Cognitive and functional abilities that were assessed include Memory; Orientation; Judgment and Problem Solving; Community Affairs; Home and Hobbies; and Personal Care. Memory was considered as the primary driver for scoring and the other categories were secondary. The change from baseline in the CDR-SB total score was analyzed using the mixed model for repeated measures (MMRM). Change from baseline is calculated as the observed value minus the baseline value. Higher scores mean worsening of disease.

The scale consists of a format with which a clinician may address clinically relevant overall change, including 15 areas under the domains of cognition, behavior, and social and daily functioning. For ADCS-CGIC, the individual data listing presented the original score on the seven-point scale. In addition, the seven-point score was collapsed to 3 groups, combining scores 1-3 to "Improved", 4 to "No change", and 5-7 to "Worsening". Lower scores indicate improvement.

The Cognitive composite included: 1. 6 ADAS-Cog items: word recall, orientation, delayed word recall, word recognition, number cancellation, and maze 2. 4 Neuropsychological Test Battery (NTB) items: Trail Making Test (TMT) A, Trail Making Test (TMT) B, Category Fluency Test (CFT), Digit span. Each individual z-score was calculated by first computing the baseline mean and standard deviation at baseline for all subjects within each individual component. The z-scores were then derived for each subject and timepoint by subtracting the corresponding baseline mean from the observed value and then dividing by the standard deviation at baseline. The sign of the z-score for the following components was reversed when deriving the Composite scores: Word recall, Orientation, Delayed Word Recall, Word Recognition, Maze, TMT A, TMT B. Z-score = 0 represents the population at baseline Positive Z-score = indicates improvement Negative Z-score= indicates worsening

The memory composite includes 4 ADAS-COG (Alzheimer's Disease Assessment Scale - cognition subscale) items: word recall, orientation, delayed word recall, word recognition. The Memory composite score will be a composite z-score average similar to the Cognitive Composite score but will only be derived using the average of the ADAS-Cog Word Recall, Orientation, Delayed Word Recall, and Word Recognition items. If a subject is missing any of the four items at a timepoint, this composite score will not be derived. The score was calculated using z-scores of the items cited above where: Z-score = 0 represents the population at baseline. Positive Z-score = indicates improvement Negative Z-score= indicates worsening

The Attention composite score included: 1. 1 ADAS-COG (Alzheimer's Disease Assessment Scale -cognition subscale) item: Number Cancellation 2. 1 NTB item: Trail Making Test (TMT) A The Attention composite score will be a composite z-score average derived using the average of the Number Cancellation, Maze item from ADAS-Cog 14, and TMT A items. If a subject missed either of the three items at a timepoint, this composite score was derived. The score was calculated using z-scores of the items cited above where: Z-score = 0 represents the population at baseline. Positive Z-score = indicates improvement Negative Z-score= indicates worsening

The Executive composite included 1. 0 ADAS-COG (Alzheimer's Disease Assessment Scale - cognition subscale) items 2. 3 NTB (Neuropsychological Test Battery) items: CFT (Category Fluency Test), Digit Span, and Trail Making Test (TMT) B The Executive function composite score will be a composite z-score average derived using the average of the CFT Category Fluency Test), Digit Span, and TMT B items. If a subject is missing any of the three items at a timepoint, this composite score will not be derived. The score was calculated using z-scores of the items cited above where: Z-score = 0 represents the population at baseline. Positive Z-score = indicates improvement Negative Z-score= indicates worsening