A Study to Evaluate the Effects of JNJ-54861911 on Amyloid Beta Processing in Cerebrospinal Fluid and Plasma in Patients With Prodromal Alzheimer's Disease

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of JNJ-54861911 in patients with prodromal Alzheimer's disease (pAD).

Detailed Description
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This will be a multicenter, double-blind (neither investigator nor patient knows which treatment the patient receives), placebo-controlled (placebo is an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial), randomized (patients are assigned different treatments based on chance), multiple-dose, proof-of-mechanism (POM) study in pAD. Approximately 24 outpatients (n=8/treatment group) diagnosed with pAD, according to the inclusion and exclusion criteria, will participate in this 4-week treatment study. For all enrolled patients, this study will consist of an 8-week eligibility screening period, a 4-week double-blind treatment period, and a follow-up examination (7-14 days after the last dose). Patients will be assigned randomly to 1 of 3 treatment groups: placebo, JNJ-54861911 10 mg once daily, or JNJ-54861911 50 mg once daily. Safety assessments will be performed throughout the study. The maximal study duration for a patient will be 14 weeks.

Official Title
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A Double-blind, Placebo-Controlled, Randomized, 4-Week, Multiple-Dose, Proof-of-Mechanism Study in Subjects With Prodromal Alzheimer's Disease Investigating the Effects of JNJ-54861911 on Aβ Processing in CSF and Plasma

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: JNJ-54861911 10 mg
* Drug: JNJ-54861911 50 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have had sufficient education or work experience to exclude mental retardation Patients must have an abnormal cognitive performance consistent with mild cognitive impairment based on the computerized neuropsychological test battery (CANTAB Elect) that can effectively screen patients and identify cognitive deficits consistent with mild cognitive impairment Patients must have evidence of amyloid deposition by means of either 1) low cerebrospinal fluid amyloid beta 1-42 (CSF amyloid beta 1-42) levels and elevated CSF p-Tau and/or total tau levels at screening (cut off values for CSF amyloid beta 1-42 and CSF p-tau and/or total tau will be based on the values established by the Clinical Neurochemistry Lab, Sahlgrenska University Hospital, Mölndal, Sweden and specified in a separate lab manual) or 2) a positive 18F-flutematol amyloid positron emission tomography (PET) amyloid scan at screening (optional depending on the site's PET capability) or both Patients must have a body mass index (BMI=weight/height²) between 18 and 35 kg/m2, inclusive, at screening Women must be postmenopausal, permanently sterilized or otherwise be incapable of pregnancy Must adhere to required contraception during and for 3 months after study Patients must be otherwise healthy for their age group or medically stable with or without medication Patients must be able to be compliant with self-administration of medication Patients must be able to swallow drug as a whole Exclusion Criteria: Patient has evidence of brain disease, other than Alzheimer's Disease (AD), or any other abnormality (e.g. folic acid/Vitamin B12 deficiency) that could explain the cognitive deficit (including, but not limited to vascular encephalopathy or strokes, as imaged by cerebral MRI and Major Depression, as defined by DSM-IV criteria) Patient has been diagnosed with dementia due to AD, due to other diseases, or with AD and contribution of other disorders (mixed dementia) Patient has evidence of familial autosomal dominant AD Patient has a history of substance or alcohol abuse Relevant history of lower back pain or scoliosis and/or major (lumbar) back surgery Patient is allergic to local anesthetics and/or iodine or chlorhexidine Patient has taken aspirin (even low dose) within 5 days prior to lumbar puncture (screening or Day 1) Patient has taken Low Molecular Weight Heparin (LMWH) within 12 hours prior to lumbar puncture (screening or Day 1) Patient has taken any anticoagulant treatment (e.g. warfarin; besides LMWH described above) within 1 week prior to lumbar puncture (screening or Day 1)

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 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-54861911 10 mg<br>From Day 1 to Day 28 inclusive, patients will self-administer once daily study drug (JNJ-54861911 or placebo) with a glass of non-carbonated water (approximately 200 mL). | Drug: JNJ-54861911 10 mg<br>* JNJ-54861911 10 mg will be administered as two 5 mg oral tablets once daily.<br>|
| Experimental: JNJ-54861911 50 mg<br> | Drug: JNJ-54861911 50 mg<br>* JNJ-54861911 50 mg will be administered as two 25 mg oral tablets once daily.<br>|
| Placebo Comparator: Placebo<br>Patients will receive matching placebo. | Drug: Placebo<br>* Matching placebo will be administered as 2 oral tablets once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of amyloid beta 1-40 in cerebrospinal (CSF) after treatment at the intended target dose range |  | Up to 4 weeks | 
| Levels of amyloid beta 1-40 in plasma after treatment at the intended target dose range |  | Up to 4 weeks | 
| Maximum observed plasma concentration (Cmax) of JNJ-54861911 | Cmax is the observed maximum plasma concentration of study drug, taken directly from the plasma concentration-time profile | Up to 4 weeks | 
| Time to reach maximum observed plasma concentration of JNJ-54861911 | Time when Cmax is observed, taken directly from the plasma concentration-time profile | Up to 4 weeks | 
| Area under the plasma concentration time curve (AUC) from 0 to t hours of JNJ-54861911 | Area under the plasma concentration-time curve from 0 to t hours post dosing (time t is the dosing interval) | Up to 4 weeks | 
| Half-life of JNJ-54861911 | Elimination half-life associated with the terminal slope of the semi-logarithmic drug concentration-time curve, calculated as 0.693/terminal slope | Up to 4 weeks | 
| Cerebrospinal fluid exposure of JNJ-54861911 |  | Up to 4 weeks | 
| The number of volunteers who experience adverse events as a measure of safety and tolerability of JNJ-54861911 after multiple-dose administration in the anticipated target dose range |  | Up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of amyloid beta fragments (amyloid beta 1-37, 1-38, and 1-42) in cerebrospinal fluid after treatment at the intended target dose range |  | Up to 4 weeks | 
| Levels of amyloid beta fragments (amyloid beta 1-37, 1-38, and 1-42) in plasma after treatment at the intended target dose range |  | Up to 4 weeks | 
| Levels of amyloid precursor protein (APP) fragments (soluble amyloid precursor protein α [sAPPalpha], sAPPbeta, totalAPP) in CSF after treatment at the intended target dose range |  | Up to 4 weeks | 
| Compare the relationship of amyloid beta 1-40 levels in plasma and cerebrospinal fluid after treatment at the intended target dose range |  | Up to 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer Disease, Prodromal Alzheimer Disease, Safety, Tolerability, Pharmacokinetic, Proof of Mechanism, JNJ-54861911