Study of BHV-4157 in Alzheimer's Disease

The ADAS-Cog is a structured scale that evaluates memory (word recall, word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing a letter in an envelope) and constructional praxis (copying geometric designs). Ratings of spoken language, language comprehension, word finding difficulty, and ability to remember test instructions were also obtained. The test was scored in terms of errors on a scale ranging from 0 (best) to 70 (worse), with higher scores indicate poorer performance and greater impairment.

The CDR-sum of boxes is a validated composite rating of cognition and everyday functioning used in longitudinal AD research which incorporates both informant input and direct assessment of performance. It assesses through semi-structured interview 3 cognitive domains including memory, orientation, and judgement/problem solving and 3 everyday functional domains including community affairs, home and hobbies and personal care. The individual domain score ranging from 0 (none) to 3 (severe) but the scores in each of these were combined to obtain a composite score (sum of boxes) ranging from 0 (best) to 18 (worst), with higher scores indicate poorer performance and greater impairment. The individual domain scores are added to create a sum of the box scores.

Volumetric MRI allows the in vivo assessment of brain structure volume and provides a measure of atrophy rate. Results from MRI studies suggest that the patterns of atrophy in AD, which mirror the pathological progression of the disease, can reliably be detected and tracked across time. Hippocampal volume derived from MRI correlates with histological hippocampal volume and degree of neuronal loss and AD pathology, and entorhinal cortical thickness change appears to be an early and sensitive indicator of neurodegeneration associated with AD.

The ADCS-ADL inventory scale is validated questionnaire developed by the ADCS to assess instrumental and basic activities of daily living based on a 23-item structured interview of the AD study participant's partner. The scale ranging from 0 (none) to 78 (severe), with lower scores indicate greater impairment.

The NPI is a well-validated, reliable, multi-item instrument to assess psychopathology in AD dementia based on the results of an interview with the study partner. The NPI evaluates both the frequency and severity of 10 neuropsychiatric features, including delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability and lability, and aberrant motor behavior, as well as evaluates sleep and appetite/eating disorders. Frequency assessments range from 1 (occasionally, less than once per week) to 4 (very frequently, once or more per day or continuously). Severity assessments range from 1 (mild) to 3 (severe). The total score is the sum of all subscales ranging from 1 (mild) to 7 (severe), with higher scores indicate greater impairment.

The MMSE is a frequently used screening instrument for AD drug studies. It evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy 2 intersecting pentagons. The MMSE scale ranging from 0 (worse) to 30 (best), with a lower score indicate more cognitive impairment.

An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in participants or clinical investigation participants administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. A serious AE (SAE) is defined as any event that met any of the following criteria at any dose: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of a participant who received study drug; other important medical events that may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the other serious outcomes. An AE is considered "Related" for causality designations of possible, probable and definite.

Subgroup of participants MMSE Category = Mild. The MMSE scale ranging from 0 (worse) to 30 (best), with a lower score indicating more cognitive impairment. Mild are participants with a baseline MMSE score greater than or equal to 20.