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

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

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).

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.

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)