A Randomized, Two-Period, Double-Blind Placebo-Controlled and Open-Label, Multicenter Extension Study to Determine the Long-Term Safety and Tolerability of JNJ-54861911 in Subjects in the Early Alzheimer*s Disease Spectrum

JNJ-54861911 is a BACE inhibitor (BACEi) being developed by Janssen Research
and Development (JRD) for the treatment of early Alzheimer*s disease (AD) by
reducing production of amyloid-beta (A*) fragments.
This phase 2 study is an extension study for subjects in the early AD spectrum,
i.e., subjects described under the parent protocol as asymptomatic at risk for
Alzheimer*s dementia as well as subjects with prodromal Alzheimer*s disease
(pAD), who have completed a Phase 1b or Phase 2 clinical trial with
JNJ-54861911. This phase 2 extension study is performed to investigate
primarily the longer term safety and tolerability of JNJ-54861911, beyond
initial clinical trials, supporting longer term treatment with JNJ 54861911.
This extension study will continue to run until registration of JNJ-54861911 or
until emerging safety issues arise as defined by the Data Review Committee
(DRC) that would warrant termination of the study. Due to its potentially long
treatment duration in comparison to the parent protocols, subjects enrolled in
this extension study may be more likely to experience clinical benefit.

The primary objective of this study is to evaluate the long-term safety and
tolerability of JNJ-54861911 in subjects in the early AD spectrum that have
completed a Phase 1b or Phase 2 clinical trial with JNJ 54861911 (e.g., Study
54861911ALZ2002), who are willing to continue their assigned treatment.

The secondary objectives of this study in subjects in the early AD spectrum are:
* To assess the maintenance of JNJ 54861911 effects on markers of A* processing
(A*1-37, A*1-38, A*1-40, A*1-42) in cerebrospinal fluid (CSF) and plasma.
* To assess the relationship of changes in CSF and plasma A* species (A*1-37,
A*1-38, A*1-40, A*1-42) with safety.
* To assess changes in CSF p-tau, t-tau and/or additional alternate biomarkers
of neurodegeneration following long term treatment with JNJ-54861911.
* To assess the plasma and CSF pharmacokinetics of JNJ-54861911 in a patient
population using a population PK approach and explore its relationship with
efficacy and safety parameters.
* To provide ongoing access to JNJ-54861911.

The exploratory objectives are:
* To explore if JNJ 54861911 will slow the rate of cognitive decline, the
perceived cognitive function and performance of everyday activities.
* To assess the annual conversion rate of subjects treated with JNJ-54861911 to
the different stages/phases of the AD spectrum.
* To explore the potential relationship of markers of neurodegeneration
(volumetric magnetic resonance imaging [MRI], CSF t-tau or p-tau) with
cognitive decline and/or response to treatment with JNJ 54861911

This is a randomized, two-period, double-blind placebo controlled and
open-label, multi-center, parallel-group study assessing primarily the
long-term safety and tolerability of JNJ-54861911 in subjects in the early AD
spectrum that have completed a phase 1b or phase 2 clinical study with
JNJ-54861911.
This extension study will be an outpatient study. The Time and Events schedule
provides an overview on the visit frequency and assessments to be performed
each visit.
For subjects enrolled in this extension study, the study will consist of a
screening phase, 2 sequential treatment periods i.e., a 12-Month blinded
treatment phases (Treatment Period 1 [placebo-controlled]) and an open-label
treatment phase (Treatment Period 2 [active]), followed by an End-of-Treatment
visit. Treatment in Period 2 will continue until registration of JNJ-54861911;
unless safety issues emerge as determined by the DRC that would warrant
termination of the study.
Subjects in the early AD spectrum, enrolled in ongoing or future clinical
trials with JNJ-54861911 (Phase 1b or Phase 2 studies) will be provided the
opportunity to participate in this extension study upon completion of their
treatment period under the parent protocol. Subjects participating in this
extension study do not have to complete the End-of-Treatment visit (follow-up)
visit under the parent protocol.
Enrollment in the extension study should be completed (Day 1 Treatment Period
1) as soon as possible, but within 6 weeks, following completion of their
treatment period under the parent protocol of currently ongoing or any future
phase 1b or phase 2 studies with JNJ-54861911.
As a consequence no maximal number of subjects in the early AD spectrum to be
enrolled is currently defined.
Subjects will sign the informed consent and be screened for eligibility during
the Screening Phase. Eligibility in this study requires that subjects have
recently completed their treatment period as described under the parent
protocol in study 54861911ALZ2002 or any future phase 1b or phase 2
JNJ-54861911 clinical studies.
Eligible subjects enrolled in this extension study will receive either
JNJ-54861911 (10mg or 25 mg q.d.) or placebo (q.d.). Subjects will continue
with their current treatment regimen established in the parent JNJ-54861911
study (e.g. for 54861911ALZ2002 placebo or JNJ-54861911) for a period of 52
Weeks (12 Months)(Treatment Period 1; placebo-controlled). Subjects who have
received under the parent an active dose different from 10-mg or 25-mg
JNJ-54861911 will be receiving the closest dose available in Treatment Period 1
(10-mg or 25-mg JNJ-54861911; i.e. subjects receiving 50 mg in study
54861911ALZ2002 will be assigned to 25 mg JNJ-54861911).
Following the initial 52-Week (12-Month) treatment period (Treatment Period 1)
in the extension study, subjects receiving placebo in Treatment Period 1 will
be randomized with equal chance to one of two active JNJ-54861911 dose levels
(i.e., 5-mg q.d. JNJ-54861911 or 25-mg q.d. JNJ-54861911) for continuous
treatment in Treatment Period 2. As such during Treatment Period 2 all subjects
will receive active (JNJ-54861911) treatment (open-label).
In addition, subjects who were receiving 10 mg q.d. JNJ-54861911 will have
their dose reduced to 5 mg q.d. in order to harmonize the dosage with that of
the Phase 2b/3 program, while subjects who were receiving 25 mg q.d. will
continue to receive that dosage.

During the Treatment Phases (Treatment Period 1 and Treatment Period 2),
primarily safety and tolerability will be monitored at regular intervals (e.g.
MRI, physical and neurological examination, suicidality risk assessment, vital
signs, 12-lead electrocardiogram (ECG), safety labs, dermatologic and
ophthalmologic examinations, etc.). Pharmacokinetics (CSF and plasma), and
pharmacodynamics (PD) effects by means of biomarkers (fluid [CSF and plasma
samples] and imaging [volumetric MRI]) will be explored at the time points
listed in the Time and Events schedule. In addition, effects of JNJ-54861911 on
cognition (e.g., Repeatable Battery for the Assessment of Neuropsychological
Status (RBANS), Mini Mental State Examination (MMSE) and California Verbal
Learning Test * Second Edition [CVLT-II]) will be assessed at regular
intervals. The subject*s clinical status will be assessed during the study by
means of the Clinical Dementia Rating Scale (CDR). Investigators will monitor
and assess subjects for disease progression. Subjects in the early AD spectrum
who develop dementia due to AD during enrollment in this extension study will
be allowed to continue participation in the study, except if emerging data
would show continued treatment could potentially be harmful.
An End-of-Treatment visit (or phone call) for a safety assessment should take
place approximately 30 days after the last dose of study drug. The study is
considered completed with the last End-of-Treatment safety assessment for the
last subject participating in the study or upon a decision by the sponsor to
terminate the study.
The Time and Events schedule provides an overview on the visit frequency and
assessments to be performed for each treatment period.
Any serious adverse event (SAE) must be reported to the sponsor by study site
personnel within 24 hours of their knowledge of the event as outlined in the
protocol.
A DRC will be established to review the safety and tolerability data or any
other relevant data on an ongoing basis to ensure the continuing safety of the
subjects enrolled in this study.
In addition an interim review of blinded or unblinded data by an Interim
Analysis Committee may be performed at any time as described in Section 11.6,
Interim Analysis.

Study medication will be provided as JNJ-54861911 tablets, strengths 5-mg,
25-mg and matching placebo, blister packed. All tablets (JNJ-54861911/placebo)
are physically identical.
Eligible subjects enrolled in this extension study will participate in 2
sequential treatment phases/periods as described above, i.e.,
* Treatment Period 1: a 52-week (12 Months) placebo-controlled double-blind
treatment period. Eligible subjects enrolled in this extension study will
receive either JNJ-54861911 (10-mg or 25-mg q.d.) or placebo (q.d.). Subjects
will continue on their current treatment regimen assigned under the parent
protocol (placebo, 10-mg or 25-mg q.d. JNJ-54861911). Subjects who received an
active dose different from 10-mg or 25-mg JNJ-54861911 under the parent
protocol will be receiving the closest dose available in Treatment Period 1
(i.e. subjects receiving 50 mg in study 54861911ALZ2002 will be assigned to 25
mg JNJ-54861911).
* Treatment Period 2: an open label treatment period during which subjects who
received placebo in Period 1will be randomized with equal chance to one of two
JNJ-54861911 dose levels i.e. 5-mg q.d. JNJ-54861911; or 25-mg q.d.
JNJ-54861911. Subjects receiving JNJ-54861911 in Treatment Period 1 will
continue their treatment open-label in Treatment Period 2.
During the entire study (Treatment Period 1 and Treatment Period 2) subjects
will self-administer once daily (q.d.) study drug (JNJ-54861911/placebo) with a
glass of non-carbonated water, after completion of breakfast or a light snack,
during the morning hours, according to the instructions provided by the
investigator. During scheduled visits subjects will self-administer their study
medication on site as described above. On Day 1 study drug administration will
be administered following completion of all predose assessment and will not be
limited to morning hours.
If a subject realizes before 2:00 PM that he/she forgot to take their daily
dose, he/she will be instructed to take the daily dose even if late (before
2:00 PM).
If a subject realizes after 2:00 PM he/she forgot to take his/her daily dose,
he/she will be instructed not to take any dose during that day, but resume
dosing the following day.
Subjects who are no longer capable of ensuring treatment compliance in the
judgment of the investigator (e.g., due to progression to dementia) have to be
supported in study drug handling and administration (e.g., care giver or nurse
practitioner). In cases where support cannot be provided subjects should be
discontinued from treatment and withdrawn from the study.

In 12 previous clinical trials with JNJ-54861911 in humans, the dosing ranged
from a single dose to up to 1 month of daily dosing. In these studies no
specific risks were identified. Even the most common side effects were
infrequent, in the range of 2-4% (constipation, diarrhea, vomiting, fatigue,
nasopharyngitis, muscle stiffness, and sleepiness), and these were considered
as either not related or doubtfully related to JNJ-54861911. Headache was seen
in up to 20-30% of participants, but most likely related to CSF sampling
procedures, as a known side effect of this procedure. Overall, the conclusion
of these studies is that JNJ-54861911 was safe and well tolerated for the
treatment durations studied.

Based on animal studies in mice, rats, and dogs, additional possible side
effects of JNJ-54861911 in humans might include, but are not limited to:
* Epileptic seizure
* Lightening of hair and skin
The highest dose in this study will be 25 mg/day. Plasma drug concentrations in
human subjects dosed 25 mg/day were shown in a previous experiment to be
approximately 30 times lower than the concentration that caused convulsions in
the dog. The lightening of body hair has not been seen in all experiments and
as well only at very high doses. It has not been observed in earlier studies in
humans with JNJ-54861911. Detailed skin exams and a photo of your face,
including your hair are included in this study to understand if any
discoloration is seen related to JNJ-54861911.
There may be risks with the use of JNJ-54861911 that are not yet known.
Sometimes during a study the sponsor may learn new facts about the study drug.
It is possible that this information might make you change your mind about
being in the study. If new information is discovered, your study doctor will
tell you about it right away.

Side effects from tests:
* Blood draw: Taking blood may cause bruising at the place where the needle
goes into the skin. Fainting, and in rare cases infection, may occur.
* ECG: There is generally no risk with having an ECG. The sticky patches may
pull your skin or cause redness or itching.
* CSF Sampling: A very small needle used to draw the CSF is never in contact
with the spinal cord. Irritation of nerve roots may be caused upon insertion of
the needle. This may cause a sensation of tickling, tingling, burning,
pricking, or numbness to the skin area. Withdrawal of the needle results in
relaxation of the nerve root and end of the symptoms. There may be slight
discomfort or bruising of the skin where the needle was inserted, similar to
what may occur when one gives blood. In less than 10% of cases individuals
report a headache which usually responds to treatment with over-the-counter
pain relievers. In very rare instances, more severe headache may occur. All
precautions are taken to anticipate potential problems and minimize any risks.
* MRI Risk: There are no known risks or side effects with having an MRI. For
this study no use of contrast material is planned. Tell your study doctor if
you have a metal implants, including joint replacements or a pacemaker.
* OCT Risk: There are no known risks or side effects with having an OCT exam.
If dilating eye drops are used during the OCT testing, those can interfere with
your ability to drive or work for a few hours after the OCT procedure.
* Risk of Information on biomarker test: During the screening process biomarker
testing will be performed. The result may indicate a higher risk to develop
Alzheimer Disease. Only biomarker positive subjects will participate in the
study. Your physician can inform you on the implications and you can discuss if
you want to know this information or not. If you decide, that you don*t want to
know this information, you may reconsider your study participation.