A Study of JNJ-63733657 in Participants With Early Alzheimer's Disease

The ADAS-Cog was a rater administered instrument that was designed to assess the severity of dysfunction in cognition characteristic of persons with Alzheimer's Disease (AD). The ADAS-Cog13 item scale includes all items from the original ADAS-Cog11 (consisting of 11 tasks measuring the disturbances of memory, language, praxis, attention, and other cognitive abilities, often referred to as the core symptoms of AD) in addition of number cancellation task and a delayed free recall task, for a total of 85 points (0 to 85), with higher scores indicating worse cognitive performance.

The ADCS-ADL-MCI was a functional measure based on information provided by the study partner that describes the performance of participants in several activities of daily living. The ADCS-ADL-MCI scale consists of 17 instrumental items (example; shopping, preparing meals, using household appliances, etc) and 1 basic item (getting dressed). The ADCS-ADL-MCI scale version used in this study comprises 24 items of which 18 items are used for the standard analysis. The total score ranges from 0 to 53 with higher scores indicating less impairment. A positive change from baseline indicates healthy functioning while a negative change from baseline indicates a decline in independent functioning.

The RBANS was a battery developed for cognitive assessment, detection, and characterization of dementia. RBANS includes 12 subtests that are divided into 5 RBANS indices: Immediate memory (list learning and story memory), visuospatial/constructional (figure copy and line orientation), language (picture naming and semantic fluency), attention (digit span and coding) and delayed memory (list recall, list recognition, story recall, and figure recall). Index scores are expressed as an age-adjusted standard score with a normal mean of 100 and an standard deviation (SD) of 15. Sum of index scores was the sum of the 5 index scores, and the Sum of Index Scores was converted to an RBANS total scale index score via a mapping table. The RBANS total scale Index score was a norm-based t-score, based on a distribution with a mean of 100 and an SD of 15. Scores range from 40 to 160. Higher scores indicated better performance.

The RBANS was a battery developed for cognitive assessment, detection, and characterization of dementia. RBANS includes 12 subtests that are divided into 5 RBANS indices: Immediate memory (list learning and story memory), visuospatial/constructional (figure copy and line orientation), language (picture naming and semantic fluency), attention (digit span and coding) and delayed memory (list recall, list recognition, story recall, and figure recall). Index scores are expressed as an age-adjusted standard score with a normal mean of 100 and an standard deviation (SD) of 15. Sum of index scores was the sum of the 5 index scores, and the sum of index scores was converted to an RBANS total scale index score via a mapping table. The RBANS Total Scale Index Score was a norm-based t-score, based on a distribution with a mean of 100 and an SD of 15. Scores range from 40 to 160 each of the index scores. Higher scores indicated better performance.

The RBANS was a battery developed for cognitive assessment, detection, and characterization of dementia. RBANS includes 12 subtests that are divided into 5 RBANS indices: Immediate memory (list learning [0-40] and story memory [0-24]), visuospatial/constructional (figure copy [0-20] and line orientation [0-20]), language (picture naming [0-10] and semantic fluency [0-40]), attention (digit span [0-16] and coding [0-89]) and delayed memory (list recall [0-10], list recognition [0-20], story recall [0-12], and figure recall [0-20]). Index scores are expressed as an age-adjusted standard score with a normal mean of 100 and an SD of 15. Sum of index scores was the sum of the 5 index scores, and the Sum of Index Scores was converted to an RBANS total scale index score via a mapping table. Scores range from 40 to 160. Higher scores indicated better performance.

The CDR was a subjectively rated outcome measure that serves as a global clinical staging instrument. Six domains were assessed and then synthesized to assign a Global CDR score. It included 3 cognitive and 3 functional domains: 1) memory, 2) orientation, 3) judgment and problem solving, 4) involvement in community affairs, 5) home and hobbies, and 6) personal care based on the CDR interview. The CDR was scored 2 ways yielding a global CDR score (CDR-GS and CDR-SB). CDR was an ordinal parameter (scale 0 [least impairment] to 3 [severe impairment]). The CDR-SB was the sum of the 6 domains which ranged from 0 (least impairment) to 18 (severe impairment). Higher scores indicated worse disease state.

The NPI was a measure of psychobehavioral disturbances, assessing the frequency and severity of disturbances in 12 domains, based on a caregiver interview. For each domain, there was also an assessment of caregiver burden. Frequency for each domain was rated on a 4-point scale (from 1=rarely to 4=very often) and severity on a 3-point scale (from 1=mild to 3=severe), with the score for each domain being the product of the frequency and severity scores, such that each domain was scored from 1 to 12. The NPI total score was the sum of the 12 domain scores, ranged from 0 (best) to 144 (worst). Higher score indicated worst psychobehavior.

Percentage of participants with progression from CDR-GS 0 to 0.5 or higher, 0.5 to 1 or higher, and 1 to 2 or higher was reported. The CDR was a subjectively rated outcome measure that serves as a global clinical staging instrument. Six domains were assessed and then synthesized to assign a Global CDR score. It included 3 cognitive and 3 functional domains: (1) memory, (2) orientation, (3) judgment and problem solving, (4) involvement in community affairs, (5) home and hobbies, and (6) personal care based on the CDR interview. CDR was scored 2 ways yielding a global CDR score (CDR-GS and CDR-SB). CDR was an ordinal parameter (scale 0 [least impairment] to 3 [severe impairment]). The CDR-GS was derived based on an algorithm and was scored of 0 (normal), 0.5 (very mild dementia), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia). Score ranges from 0 to 3 and a high score on CDR-GS indicated a high disease severity.

Change from baseline in brain tau burden (tau naive composite Region of interest [ROI] standardized uptake value ratio [SUVR], cerebral cortex ROI SUVR, meta temporal ROI SUVR, spatial progression of tauopathy [SPOT] volume over cerebral cortex ROI) as measured by tau PET was reported. For tau naive ROI method, tau PET brain scans were assessed to measure change in SUVR over regions without evidence of tau burden at baseline (that is, within 1 standard deviation of a cognitively normal amyloid negative reference population). For SPOT method, tau PET brain scans were assessed to quantify extent of spread of tau by measuring difference in volume of elevated tau PET burden (defined as exceeding an SUVR threshold of 1.2) in cerebral cortex brain region at follow up versus that at baseline. Tau PET brain scans were assessed to measure spread of tau tangles using SUVR in cerebral cortex, meta temporal brain region, respectively.

Change from baseline in CSF concentration of total, free, and bound p27+tau fragments at Week 104 was reported.

CSF concentration of JNJ-63733657 was reported.

Serum concentration of JNJ-63733657 was reported.

Number of participants with treatment-emergent JNJ-63733657 ADA in serum was reported. Any ADAs occurring at or after the initial administration of study intervention through the day of last dose in the DB treatment period plus 90 days was considered to be treatment-emergent. Participants with treatment-emergent antibodies to JNJ-63733657 included participants with treatment-induced antibodies to JNJ-63733657 and treatment-boosted antibodies to JNJ- 63733657.

An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. Any AE occurring at or after the initial administration of study intervention through the day of last dose in the DB treatment period plus 90 days was considered to be treatment-emergent.

An AE is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. Serious adverse event (SAE) was any untoward medical occurrence that at any dose may result in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product. Any SAE occurring at or after the initial administration of study intervention through the day of last dose in the DB treatment period plus 90 days was considered to be treatment-emergent.

An AE is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. Treatment-emergent AESIs were collected in the eCRF and examined separately, grouped in the following categories including: hepatobiliary disorders/Liver enzyme abnormality, and Infusion-related reactions. Any AESI occurring at or after the initial administration of study intervention through the day of last dose in the DB treatment period plus 90 days was considered to be treatment-emergent.

Number of participants who discontinued the study treatment due to AE was reported.

Change from baseline in 12-lead ECG parameter (ECG mean heart rate supine) was reported.

Change from baseline in 12-lead ECG parameter (PR interval, QRS duration, QT interval, QTcB interval, QTcF interval, QTcL interval and RR interval) was reported.

Number of participants with treatment-emergent abnormalities in laboratory parameters (hematology, chemistry and urinalysis) were reported. Laboratory abnormalities meeting with lower limit of the normal range (LLN) and upper limit of the normal range (ULN) was reported. Any laboratory abnormalities occurring at or after the initial administration of study intervention through the day of last dose in the DB treatment period plus 90 days was considered to be treatment-emergent.

Number of participants with treatment-emergent abnormal findings in neurological examination (mental state, cranial nerves, motor ability: strength, tone, involuntary movements, coordination: finger-to-nose, gai, postural reflexes, sensation: proprioception, cold, light touch, deep tendon reflexes) was reported. Abnormalities in neurological examination was determined by the investigator. Any neurological abnormalities occurring at or after the initial administration of study intervention through the day of last dose in the DB treatment period plus 90 days was considered to be treatment-emergent.

Number of participants with treatment-emergent abnormal findings in physical examination (general appearance, skin, eye, ear, nose, throat, heart, head, neck, thyroid, chest, lung, abdomen, musculoskeletal, breast, neurological) was reported. Abnormal findings in physical examination was determined by the investigator. Any physical abnormalities occurring at or after the initial administration of study intervention through the day of last dose in the DB treatment period plus 90 days was considered to be treatment-emergent.

Number of participants with treatment-emergent potentially clinically significant vital signs including systolic blood pressure (standing and supine: less than (<) 90 millimeters of mercury (mmHg) and greater than (>) 180 mmHg), diastolic blood pressure (standing and supine: <50 mmHg and >105 mmHg), pulse (<45 bpm to >120 bpm), temperature (<35 degree Celsius and >38 degree Celsius) and weight (decrease of >=10% relative to baseline and increase of >=10% relative to baseline) were reported. Any clinically significant vital sign occurring at or after the initial administration of study intervention through the day of last dose in the DB treatment period plus 90 days was considered to be treatment-emergent.

Number of participants with brain MRI safety findings was reported. MRI safety-related observations from the central imaging vendor including vasogenic edema, cerebral macrohemorrhages, cerebral superficial siderosis and other findings was reported.

C-SSRS was a clinician-rated instrument that reports severity and frequency of suicide-related ideation and behaviors. Suicidal ideation was classified on a 5-item scale: 1 (wish to be dead), 2 (non-specific active suicidal thoughts), 3 (suicidal ideation without plan and intent), 4 (suicidal ideation intent to act without plan), and 5 (suicidal ideation with plan and intent). Suicidal behavior was classified on a 5-item scale: 6 (preparatory acts or behavior), 7 (aborted attempt), 8 (interrupted attempt), 9 (actual attempt [non-fatal]), and 10 (suicide). Total score from 10 categories was summarized into 3 categories: No suicidal ideation or behavior(0), suicidal ideation (1-5), suicidal behavior (6-10). Total score ranged from 0 to 10. Higher scores indicated more severe suicidal ideation and behavior.