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

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the effect of JNJ-63733657 versus placebo on clinical decline as measured by the Integrated Alzheimer's Disease Rating Scale (iADRS), a composite of cognition and function.

Detailed Description
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Alzheimer's disease (AD) is a fatal neurodegenerative disease that is manifested by progressive cognitive deficits including memory loss followed by loss of independent function as well as neuropsychiatric symptoms such as apathy, depression, anxiety, agitation and psychosis. JNJ-63733657 is a humanized monoclonal anti-tau antibody which binds to phosphorylated tau (P-tau). The study will evaluate whether JNJ-63733657 can slow clinical (cognitive and functional) decline in participants with Early AD with evidence of elevated brain tau (T+) and assess its safety and tolerability. The study consists of: screening period (13 weeks), double-blind treatment period (up to 232 weeks), and a follow-up period (13 weeks). Safety and tolerability assessments will include adverse events (AEs), vital signs, electrocardiogram (ECG), early discontinuations, physical and neurological examinations, safety laboratory evaluations, suicidality risks (Columbia Suicide Severity Rating Scale [CSSRS]) and brain MRI will be performed during the study. The maximum treatment duration is up to 232 weeks (4.5 years).

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Assess the Efficacy and Safety of JNJ-63733657, an Anti-tau Monoclonal Antibody, in Participants With Early Alzheimer's Disease

Conditions
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Alzheimer Disease, Cognitive Dysfunction, Dementia

Intervention / Treatment
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* Drug: JNJ-63733657
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Early Alzheimer's disease (AD): Gradual and progressive subjective decline in the participant's cognition over at least the past 6 months, as reported by the participant and informant (study partner) and Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 and memory box score greater than or equal to (>=) 0.5 at screening Participants must have positive tau PET results Able to read and write and with a minimum 5 years of formal education as reported by participant and study partner at screening Have a designated study partner who has adequate literacy to participate and be judged to have high likelihood of completing the study with the participant Male participants must agree not to donate sperm for the purpose of reproduction during the study and up to 16 weeks after receiving the last dose of study intervention Exclusion Criteria: Participants with CDR GS >=2 at predose baseline Clinical Dementia Rating (CDR) administration Participants who fulfill diagnostic criteria for Mild Cognitive Impairment (MCI) or dementia/mild or major neurocognitive disorder suspected to be due to any etiology other than AD (example, parkinson's disease, cerebrovascular disease, normal pressure hydrocephalus, head injury, drug or alcohol abuse/dependence, anoxic brain injury, (Et cetera[etc]) Geriatric Depression Scale (GDS) 30 score greater than (>) 12 Hachinski Ischemic Scale (HIS) >4 Has received medications that affect the central nervous system (CNS), except treatments for AD, for less than 2 months; that is, doses of chronic medications that effect the CNS should be stable for at least 2 months before the start of screening. If a participant has recently stopped a chronic medication that effects the CNS, he or she must have discontinued treatment at least 2 months before the start of screening. Chronic use of benzodiazepines is not permitted

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JNJ-63733657<br>Participants will receive single dose of JNJ-63733657 low dose or high dose administered by intravenous (IV) infusion every 4 weeks. | Drug: JNJ-63733657<br>* JNJ-63733657 low or high dose will be administered by IV infusion.<br>|
| Placebo Comparator: Placebo<br>Participants will receive single dose of matching placebo to JNJ-63733657 administered by IV infusion every 4 weeks. | Drug: Placebo<br>* Placebo matching to JNJ-63733657 will be administered by IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Integrated Alzheimer's Disease Rating Scale (iADRS) Total Score at Week 104 | The linear combination of the ADAS Cog13 and ADCS ADL MCI that serves as a composite of cognition and function (overall clinical status) of the participant and score range from 0 to 138 with lower scores indicating worse performance. The iADRS will be a combination of ADAS Cog13 (score 0 to 85, higher scores indicate worse cognitive performance) and ADCS-ADL MCI (yielding a score 0 to 53, lower scores indicate worse daily function). | Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Alzheimer's Disease Assessment Scale Cognitive subscale 13-item version (ADAS-Cog 13) Total Score at Week 104 | ADAS-Cog11 consists of 11 tasks measuring the disturbances of memory, language, praxis, attention, and other cognitive abilities. The modified ADAS-Cog 13 item scale includes all original ADAS-Cog items with the addition of a number cancellation task and a delayed free recall task, for a maximum total score of 85 points, with higher scores indicative of worse cognitive performance. Thus, a negative change from baseline represents improvement in cognition. Items are recorded on an electronic device which will provide the ADAS-Cog 13 total score. | Week 104 | 
| Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living for Mild Cognitive Impairment (ADCS-ADL MCI) Total Score at Week 104 | ADCS-ADL MCI is a functional measure based on information provided by the study partner (informant) that describes the performance of participants in several ADLs. It assesses 18 instrumental activities of daily living (higher level daily functions) and one basic daily function (dressing). Total score ranges from 0 to 53 with higher scores indicating less impairment. | Week 104 | 
| Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Index Score | The RBANS includes 12 subtests that are divided into 5 RBANS indices: 1-Immediate memory (List learning and story memory); 2-Visuospatial/constructional (figure copy and line orientation); 3-Language (picture naming and semantic fluency); 4-Attention (digit span and coding); 5-Delayed memory (list recall, list recognition, story memory, and figure recall) will be reported. Index scores are expressed as an age-adjusted standard score with a normal mean of 100 and an SD of 15. The sum of Index Scores is the sum of the 5 index scores, and the Sum of Index Scores is converted to an RBANS Total Scale Index Score via a mapping table. RBANS Total Scale Index Score is a norm-based t-score, based on a distribution with a mean of 100 and standard deviation (SD) of 15. Higher scores on each sub measure and index indicate better performance. | Baseline and up to 4.5 years (End of treatment) | 
| Change From Baseline in RBANS Indices | Change from baseline in RBANS indices will be assessed. The RBANS includes 12 subtests that are divided into 5 RBANS indices: 1-Immediate memory (List learning and story memory); 2-Visuospatial/constructional (figure copy and line orientation); 3-Language (picture naming and semantic fluency); 4-Attention (digit span and coding); 5-Delayed memory (list recall, list recognition, story memory, and figure recall) will be reported. | Baseline and up to 4.5 years (End of treatment) | 
| Change From Baseline in Clinical Dementia Rating- Sum of Boxes (CDR-SB) | CDR is a global clinical staging instrument that includes 3 cognitive and 3 functional ratings, including: memory, orientation, judgment and problem solving, involvement in community affairs, home and hobbies, and personal care based on the CDR interview. The CDR is scored 2 ways yielding a global CDR score (CDR GS, derived from an algorithm including categorical scoring of 0, 0.5, 1, 2, and 3), as well as CDR-Sum of Boxes (CDR-SB, the continuous sum of 6 domains, up to a total score of 18, with higher scores representing worse disease state). The Sum of boxes and global score is calculated from the overall CDR. | Baseline and up to 4.5 years (End of treatment) | 
| Change from Baseline in Neuropsychiatric Inventory (NPI) | The NPI is a measure of psychobehavioral disturbances, assessing the frequency and severity of disturbances in 12 domains. Frequency for each domain is 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 is scored from 1 to 12. The NPI total score is the sum of the 12 domain scores, ranging from 0 (best) to 144 (worst). | Baseline and up to 4.5 years (End of treatment) | 
| Percentage of Participants Progressing From Clinical Dementia Rating- Global Score (CDR-GS) 0 to 0.5 or Higher, 0.5 to 1 or Higher, 1 to 2 or Higher, from Baseline to Post-baseline | The CDR is a subjectively rated outcome measure that serves as a global clinical staging instrument that includes 3 cognitive and 3 functional ratings, including: 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 is scored 2 ways yielding a global CDR score (CDR GS, derived from an algorithm developed by the Knight Alzheimer Disease Research Center at Washington University School of Medicine in St. Louis, Missouri, US, and including categorical scoring of 0= cognitively unimpaired, 0.5= mild cognitive impairment, 1= mild dementia, 2= moderate dementia, and 3= severe dementia), as well as CDR-Sum of Boxes (CDR-SB, the continuous sum of 6 domains, up to a total score of 18, with higher scores representing worse disease state). | Baseline and up to 4.5 years (End of treatment) | 
| Change From Baseline in Brain tau Burden as Measured by tau PET | Change from baseline in brain tau burden, as measured by tau positron emission tomography (PET) will be assessed. | Baseline and up to 4.5 years (End of treatment) | 
| Change From Baseline in Cerebrospinal Fluid (CSF) concentrations of Total, Free, and Bound p217+tau Fragments | Change from baseline in CSF concentrations of total, free, and bound p217+tau (phosphorylated tau) fragments will be assessed. | Baseline and up to 4.5 years (End of treatment) | 
| CSF Concentrations of JNJ-63733657 | CSF concentrations of JNJ-63733657 will be assessed. | At Weeks 52, 104, 208 (End of Treatment) | 
| Serum Concentrations of JNJ-63733657 | Serum concentrations of JNJ-63733657 will be assessed. | At Weeks 4, 8, 12, 16, 20, 24, 36, 52, 76, 104, 128, 156, 180, 208, 232 (End of treatment) | 
| Anti-Drug Antibody to JNJ-63733657 | Anti-drug antibody to JNJ-63733657 will be assessed. | Up to 245 Weeks (90 days [+-7 days] after last dose of study intervention) | 
| Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability | An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to that medicinal product. | Up to 245 Weeks | 
| Number of Participants with Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability | An SAE is any untoward medical occurrence that at any dose results 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. | Up to 245 Weeks | 
| Number of Participants with Electrocardiogram (ECG) Abnormalities | Number of participants with ECG abnormalities will be reported. | Up to 245 Weeks | 
| Number of Participants with Clinical Laboratory Abnormalities | Number of participants with clinical laboratory (hematology, clinical chemistry, and urinalysis) abnormalities will be assessed. | Baseline and up to 245 Weeks | 
| Number of Participants with Physical and Neurological Examination Abnormalities | Number of participants with physical (body weight, height) and neurological (evaluation of mental status, cranial nerves, motor ability [including strength, tone, and involuntary movements], coordination [including finger-to-nose, gait, and postural reflexes], and sensation [including proprioception, cold, light touch, and deep tendon reflexes]) examination abnormalities will be reported. | Up to 245 Weeks | 
| Percentage of Participants with Vital Sign Abnormalities | Percentage of participants with vital sign abnormalities (temperature, pulse rate, systolic blood pressure [BP], diastolic BP) will be reported. | Up to 245 Weeks | 
| Changes From Baseline in Brain Magnetic Resonance Imaging (MRI) Safety Findings | Changes from baseline in brain MRI safety findings (brain tumors, aneurysm or atrioventricular malformations, territorial stroke (excluding smaller watershed strokes), recent hemorrhage (parenchymal or subdural), or obstructive hydrocephalus) will be assessed. | Baseline and Up to 4.5 years (End of treatment) | 
| Change From Baseline in Columbia Suicide Severity Rating Scale (C-SSRS) score | C-SSRS is semi structured clinician-administered questionnaire designed to solicit the occurrence, severity, and frequency of suicide-related ideation and behaviors . Total score ranges from 1 to 10, a score of 0 will be assigned (0=no event that can be assessed on the basis of C-SSRS). Higher scores indicate greater severity. The maximum score assigned for each participant will also be summarized into one of three broad categories: no suicidal ideation or behavior (0), suicidal ideation (1 to 5), suicidal behavior (6 to 10). | Baseline and Up to 245 Weeks |