Clinical trial NCT02406027
Conditions: Alzheimer Disease
Keywords: Alzheimer's Disease JNJ-54861911 Placebo
Sponsor: Janssen Research & Development, LLC
Start date: 2015-07-02; Completion date: 2018-06-28
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the long-term safety and tolerability of JNJ-54861911 in participants in the early Alzheimer's disease (AD \[progressive brain disease that slowly destroys memory and thinking skills, and eventually even the ability to carry out the simplest tasks\]) spectrum that have completed a Phase 1b or Phase 2 clinical trial with JNJ-54861911, who are willing to continue their assigned treatment.

Detailed description:
Participants in the early Alzheimer's Disease (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 study upon completion of their treatment period under the parent protocol. The study will consist of a Screening phase and 2 sequential treatment phases (a 12-month double-blind \[DB\] treatment phase \[placebo controlled\] and an open-label \[OL\] phase \[active\]) followed by an End-of-Treatment visit. Treatment in OL phase will continue until registration of JNJ-54861911; unless safety issues emerge as determined by the Data Review Committee (DRC) that would warrant termination of the study. Blood and cerebrospinal fluid (CSF) samples will be collected to evaluate the plasma and CSF pharmacokinetics of JNJ-54861911, as well as amyloid beta fragments. Participants' safety will be monitored throughout the study.

Arms: arm 1: Participants will continue with their current treatment regimen (10 milligram \[mg\] of JNJ-54861911) established in the parent study of JNJ-54861911. Participants will receive 10 milligram (mg) of JNJ-54861911 orally, once daily from Day 1 up Week 52 in the DB treatment phase. arm 2: Participants will continue with their current treatment regimen (25 mg of JNJ-54861911) established in the parent study of JNJ-54861911. Participants will receive 25 mg of JNJ-54861911 orally, once daily from Day 1 up Week 52 in the DB treatment phase. arm 3: Participants will continue with their current treatment regimen established in the parent study of JNJ-54861911. Participants will receive placebo matching to JNJ-54861911 orally, once daily from Day 1 up Week 52 in the DB treatment phase. arm 4: Participants who were receiving JNJ-54861911, 10 mg and placebo in the DB treatment phase, will receive the 5 mg JNJ-54861911 once daily up to end of treatment visit (until registration of JNJ-54861911 or any safety issue) in Open-label phase. arm 5: Participants who were receiving JNJ-54861911, 25 mg in the DB treatment phase, will continue to receive the same regimen in open-label treatment phase. Participants who were receiving placebo in the DB treatment phase will be randomly assigned to receive 25 mg of JNJ-54861911 once daily up to end of treatment visit (until registration of JNJ-54861911 or any safety issue) in the open-label treatment phase.
Interventions: intervention 1: JNJ-54861911, 10 mg intervention 2: JNJ-54861911, 25 mg intervention 3: Placebo intervention 4: JNJ-54861911, 5 mg
Intervention descriptions: intervention 1: Participants will self-administer JNJ-54861911 tablet, 10 mg (2\*5 mg), orally, once daily. intervention 2: Participants will self-administer 1 tablet of JNJ-54861911, containing 25 mg orally, once daily. intervention 3: Participants will self administer placebo matching to JNJ-54861911 orally once daily. intervention 4: Participants will self-administer JNJ-54861911 tablet, 5 mg, orally, once daily.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved,  Date: 6 September 2017
Janssen Research & Development*
Clinical Protocol
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
Protocol 54861911ALZ2004; Phase 2
Amendment 6
JNJ-54861911
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen R&D Ireland; or Janssen Research 
& Development, LLC. The term “sponsor” is used throughout the protocol to represent these various legal 
entities; the sponsor is identified on the Contact Information page that accompanies the protocol.  
EudraCT NUMBER:    2014-004274-41
Status:
Approved
Date:
6 September 2017
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica N.V.  
EDMS number:
EDMS-ERI-95824084, 7.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
2
Approved, Date: 6 September 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT FIGURES ........................................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 16
TIME AND EVENTS SCHEDULE .............................................................................................................. 22
TIME AND EVENTS SCHEDULE (OPEN-LABEL TREATMENT PHASE)............................................... 24
TIME AND EVENTS SCHEDULE (FOOTNOTES)..................................................................................... 25
ABBREVIATIONS ...................................................................................................................................... 27
1.
INTRODUCTION................................................................................................................................ 29
1.1.
Background .................................................................................................................................... 30
1.2.
Overall Rationale for the Study...................................................................................................... 38
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 40
2.1.
Objectives ...................................................................................................................................... 40
2.2.
Hypothesis ..................................................................................................................................... 41
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 41
3.1.
Overview of Study Design.............................................................................................................. 41
3.2.
Study Design Rationale.................................................................................................................. 43
3.3.
Interim Analysis of Data ................................................................................................................. 49
3.4.
Stopping Criteria ............................................................................................................................ 50
3.4.1.
Individual Criteria for Stopping Study Treatment........................................................................ 50
3.4.2.
Protocol Stopping Criteria........................................................................................................... 50
4.
SUBJECT POPULATION.................................................................................................................. 51
4.1.
Inclusion Criteria ............................................................................................................................ 51
4.2.
Exclusion Criteria ........................................................................................................................... 52
4.3.
Prohibitions and Restrictions ......................................................................................................... 52
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 53
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 55
7.
TREATMENT COMPLIANCE............................................................................................................ 56
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 57
9.
STUDY EVALUATIONS .................................................................................................................... 58
9.1.
Study Procedures........................................................................................................................... 58
9.1.1.
Overview..................................................................................................................................... 58
9.1.2.
Screening Phase ........................................................................................................................ 60
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 61
9.1.4.
Open-Label Treatment Phase .................................................................................................... 65
9.1.5.
End-of-Treatment Visit (Follow Up Visit) .................................................................................... 68
9.2.
Safety Evaluations ......................................................................................................................... 68
9.2.1.
Adverse Events........................................................................................................................... 69
9.2.2.
Colombia Suicide Severity Rating Scale (C-SSRS) ................................................................... 69
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
3
Approved, Date: 6 September 2017
9.2.3.
Vital Signs................................................................................................................................... 69
9.2.4.
Electrocardiogram....................................................................................................................... 69
9.2.5.
Physical and Neurological Examination ..................................................................................... 69
9.2.6.
Dermatologic Examination.......................................................................................................... 70
9.2.7.
Optical Coherence Tomography and Ophthalmologic Examination .......................................... 70
9.2.8.
Magnetic Resonance Imaging .................................................................................................... 71
9.2.9.
Clinical Laboratory Tests ............................................................................................................ 71
9.3.
Biomarkers ..................................................................................................................................... 73
9.3.1.
Fluid Biomarkers......................................................................................................................... 73
9.3.1.1.
CSF Biomarkers ...................................................................................................................... 73
9.3.1.2.
Plasma Biomarkers ................................................................................................................. 74
9.3.2.
Imaging Biomarkers.................................................................................................................... 74
9.3.2.1.
Magnetic Resonance Imaging................................................................................................. 74
9.4.
Cognition, Function and Clinical Status ......................................................................................... 74
9.4.1.
Cognitive Evaluations ................................................................................................................. 75
9.4.1.1.
Repeatable Battery for the Assessment of Neuropsychological Status.................................. 75
9.4.1.2.
Mini Mental State Examination................................................................................................ 75
9.4.1.3.
California Verbal Learning Test – Second Edition................................................................... 75
9.4.2.
Clinical Scales and Functional Measures................................................................................... 75
9.4.2.1.
Clinical Dementia Rating Scale – Sum of Boxes..................................................................... 75
9.4.2.2.
Cognitive Function Index (CFI)................................................................................................ 76
9.5.
Pharmacokinetics........................................................................................................................... 76
9.5.1.
Evaluations ................................................................................................................................. 76
9.5.2.
Analytical Procedures................................................................................................................. 77
9.5.3.
Pharmacokinetic Parameters ..................................................................................................... 77
9.6.
Sample Collection and Handling.................................................................................................... 78
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 78
10.1.
Completion ..................................................................................................................................... 78
10.2.
Discontinuation of Study Treatment............................................................................................... 79
10.3.
Withdrawal From the Study............................................................................................................ 79
11.
STATISTICAL METHODS................................................................................................................. 80
11.1.
Subject Information ........................................................................................................................ 80
11.2.
Sample Size Determination ........................................................................................................... 80
11.3.
Pharmacokinetic Analyses and Pharmacokinetic/Pharmacodynamic Analysis............................. 81
11.4.
Pharmacodynamic Analyses.......................................................................................................... 81
11.4.1.
Biomarker Analyses.................................................................................................................... 81
11.4.1.1.
Fluid Biomarkers...................................................................................................................... 81
11.4.1.2.
Imaging Biomarkers................................................................................................................. 81
11.4.2.
Cognition, Function and Clinical Status...................................................................................... 82
11.5.
Safety Analyses ............................................................................................................................. 82
11.6.
Interim Analysis.............................................................................................................................. 83
11.7.
Data Review Committee ................................................................................................................ 84
12.
ADVERSE EVENT REPORTING ...................................................................................................... 84
12.1.
Definitions ...................................................................................................................................... 85
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 85
12.1.2.
Attribution Definitions.................................................................................................................. 86
12.1.3.
Severity Criteria .......................................................................................................................... 86
12.2.
Special Reporting Situations.......................................................................................................... 87
12.3.
Procedures..................................................................................................................................... 87
12.3.1.
All Adverse Events...................................................................................................................... 87
12.3.2.
Serious Adverse Events ............................................................................................................. 88
12.3.3.
Pregnancy................................................................................................................................... 89
12.3.4.
Adverse Events of Special Interest............................................................................................. 89
12.3.5.
Adverse Drug Reactions............................................................................................................. 89
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 90
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
4
Approved, Date: 6 September 2017
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 90
13.1.
Procedures..................................................................................................................................... 90
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 90
14.
STUDY DRUG INFORMATION......................................................................................................... 90
14.1.
Physical Description of Study Drug(s) ........................................................................................... 90
14.2.
Packaging ...................................................................................................................................... 91
14.3.
Labeling.......................................................................................................................................... 91
14.4.
Preparation, Handling, and Storage............................................................................................... 91
14.5.
Drug Accountability ........................................................................................................................ 91
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 92
16.
ETHICAL ASPECTS ......................................................................................................................... 92
16.1.
Study-Specific Design Considerations........................................................................................... 92
16.2.
Regulatory Ethics Compliance....................................................................................................... 95
16.2.1.
Investigator Responsibilities ....................................................................................................... 95
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 95
16.2.3.
Informed Consent ....................................................................................................................... 96
16.2.4.
Privacy of Personal Data ............................................................................................................ 97
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 98
16.2.6.
Country Selection ....................................................................................................................... 98
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 98
17.1.
Protocol Amendments.................................................................................................................... 98
17.2.
Regulatory Documentation ............................................................................................................ 99
17.2.1.
Regulatory Approval/Notification ................................................................................................ 99
17.2.2.
Required Prestudy Documentation............................................................................................. 99
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 100
17.4.
Source Documentation................................................................................................................. 100
17.5.
Case Report Form Completion .................................................................................................... 101
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 101
17.7.
Record Retention ......................................................................................................................... 102
17.8.
Monitoring .................................................................................................................................... 102
17.9.
Study Completion/Termination..................................................................................................... 103
17.9.1.
Study Completion ..................................................................................................................... 103
17.9.2.
Study Termination..................................................................................................................... 103
17.10.
On-Site Audits .............................................................................................................................. 103
17.11.
Use of Information and Publication.............................................................................................. 104
REFERENCES.......................................................................................................................................... 106
INVESTIGATOR AGREEMENT ............................................................................................................... 114
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
5
Approved, Date: 6 September 2017
LIST OF ATTACHMENTS
Attachment 1:
Evaluation of Increased Liver Enzymes ................................................................... 110
Attachment 2: 
Adverse Events of Special Interest .......................................................................... 113
LIST OF IN-TEXT FIGURES
FIGURES
Figure 1:
Plasma Aβ1-40 Mean Percent Change From Baseline Following Single Dose 
Administration of JNJ-54861911............................................................................................... 35
Figure 2:
CSF Aβ1-40 Mean Percent Change From Baseline following Single Dose 
Administration of JNJ-54861911............................................................................................... 35
Figure 3:
Plasma Aβ1-40 Mean Percent Change on Day 14 in Relation to Baseline Day 1 
Following Multiple Dose Administration of JNJ-54861911. ...................................................... 36
Figure 4:
CSF Aβ1-40 Mean Percent Change on Day 14 in Relation to Baseline Day 1 Following 
Multiple Dose Administration of JNJ-54861911........................................................................ 36
Figure 5:
Modelling of CSF A1-40 Reduction in Subjects in the Early Alzheimer's Disease 
Spectrum................................................................................................................................... 45
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
6
Approved, Date: 6 September 2017
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
12 Feb 2015
Amendment 1
2 Oct 2015
Amendment 2
8 Apr 2016
Amendment 3
14 June 2016
Amendment 4
26 Oct 2016
Amendment 5
27 Mar 2017
Amendment 6
6 Sep 2017
Amendments below are listed beginning with the most recent amendment.
Amendment 6 (6 Sep 2017)
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment:
To provide information on how unblinding and analysis at the end of the double-blind treatment phase of the trial 
will be carried out; 
To indicated that a number of sites will be given the opportunity to use eMeds smart technologies to manage clinical 
trials supplies and drug compliance activities.
Applicable Section(s)
Description of Change(s)
Synopsis
Included text indicating that a number of sites will be given the opportunity to use 
the eMeds smart technologies to manage clinical trials supplies and drug compliance 
activities.
Section 1.1 Background
Updated the list of completed and ongoing studies to be aligned with the status as of 
the cutoff date of the present amendment (6 September 2017)
Section 3.1 Overview of 
Study Design
Included text indicating that a number of sites will be given the opportunity to use 
the eMeds smart technologies to manage clinical trials supplies and drug compliance 
activities.
Section 3.3 Interim Analysis 
of Data
Created a new section in the protocol to clarify under what circumstances the 
Sponsor may perform an unblinded review of safety and biomarker data prior to the 
last subject’s completion of the double-blind treatment phase. In addition it was 
clarified that when the parent study (eg, 54861911ALZ2002 [and potential future 
Phase 1b and Phase 2 studies]) is completed and its clinical database is closed, the 
randomization codes from the parent study will be released to the sponsor study 
team. The sponsor will be unblinded at that time, but the investigator and subjects 
will continue to be blinded to treatment during double-blind treatment phase, until 
the last subject has completed that phase, and the database from that phase has been 
reviewed, corrected as necessary, and locked. At that point, the sponsor will perform 
analyses of key safety, biomarker, and efficacy variables, as detailed in a 
prespecified statistical analysis plan.
Section 11.6 Interim 
Analysis
Applied editorial changes for clarity. Reiterated the newly-introduced text in Section 
3.3 Interim Analysis of Data, including the statement that following the sponsor’s 
review of additional analyses of key safety, biomarker, and efficacy variables, 
specific measures in place, including a locked database from the double-blind phase, 
will ensure that there will be no bias introduced by this measure
Section 16.2.3 Informed 
Consent
Included text to indicate that an appendix to the 54861911ALZ2004 Informed 
Consent Form will be used for subjects participating in eMeds
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
7
Approved, Date: 6 September 2017
Amendment 5 (27 Mar 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment:
To add new monitoring guidelines and stopping rules for liver enzymes during the first 3 months of treatment and to 
provide additional information on the management of elevated liver enzymes.
Applicable Section(s)
Description of Change(s)
Rationale: following a new safety report of drug-induced hepatotoxicity (based on biopsy results) in a subject in 
Study 54861911ALZ2003, whose treatment assignment was unblinded and the subject found to be on 25 mg 
JNJ-54861911, increased frequency of liver enzyme monitoring in the first 3 months of dosing has been introduced.
Guidelines for discontinuation of treatment due to abnormal liver enzymes and for the evaluation and management 
of such cases have been introduced
Synopsis - Time and Events 
Schedule and Section 1.2 
Overall rationale for the Study
Hematology and serum chemistry assessments to be performed every 2 weeks for 
12 weeks (from Week 52 to Week 64, inclusive)
Hematology and serum chemistry assessments to be performed every 4 weeks for 
12 weeks (from Week 64 to Week 76, inclusive)
Section 3.2 Study Design 
Rationale
Safety Evaluations
Specified that as a result of the newly identified case of drug-induced 
hepatotoxicity, if at any time during treatment a subject has an ALT or AST result 
that is ≥3× ULN, the test should be repeated within 24 - 72 hours and, if 
confirmed, the further evaluation and management procedures described in 
Attachment 1 should be followed
Section 3.3.1 Individual 
Criteria for Stopping Study 
Treatment
Updated the specific individual rules for stopping study treatment as a result of 
elevations of liver enzymes between Weeks 52 and 64, as well as after Week 64
Section 9.1.4 Open-Label 
Treatment Phase
Updated text to specify the frequency that subjects in the open-label phase of the 
study would have their safety laboratory tests monitored. The safety monitoring 
would take place every 2 weeks for the first 12 weeks, every 4 weeks for the next 
12 weeks, every 8 weeks for the next 24 weeks, and every 12 weeks thereafter. 
Section 10.2 Discontinuation 
of Study Treatment
Updated text to include liver enzyme elevation between Weeks 52 and 64:
clarified the different categories of ALT and AST elevations as well as total 
bilirubin and other symptoms. 
Updated text to also include liver enzyme elevations after Week 64: added the 
different categories of ALT and AST elevations as well as total bilirubin and other 
symptoms.
Section 12.3.5 Adverse Drug 
Reactions
Clarified that any SAE related to elevated liver enzymes should be reported as 
described in the study protocol. In addition, any cases of elevated liver enzymes 
that result in discontinuation of study treatment should be reported as an SAE, 
following the reporting requirements also described in the protocol
Attachment 1: Evaluation of 
Increased Liver Enzymes
Updated instructions were provided on the process to follow whenever per 
protocol assessments for a given subject indicated an elevation of ALT or AST
≥3×ULN
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
8
Approved, Date: 6 September 2017
Amendment 4 (26 Oct 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is to specify that hepatic enzyme 
elevations will be classified as “adverse drug reactions” (ADRs) and to clarify the reporting of those events that are 
considered serious. Additionally, the text is modified and updated related to dermatologic and ophthalmologic/OCT 
examinations. The text related to re-consenting subjects who have experienced cognitive decline is updated and 
clarified in sections regarding the informed consent process. An overall risk-benefit assessment is added in the 
protocol.
Applicable Section(s)
Description of Change(s)
Rationale: Cases of elevated liver enzymes are classified under “adverse drug reactions” with serious cases of liver 
enzymes elevation subject to expedited reporting per commitment to Health Authority. A new attachment is added 
to list the criteria for liver enzyme elevations and conditions of reporting the events related to these elevations.
12.3.2. Serious Adverse 
Events
Following statement was added:
Discontinuation of study treatment secondary to increased liver enzyme criteria 
(outlined in Section 10.2) will be reported as a serious adverse event.
12.3.5. Adverse Drug 
Reactions
New section added to clarify reporting events of drug-induced liver enzyme 
elevation.
Attachment 1
Addition of attachment “Liver Enzyme Elevation Reporting”
Rationale: Given that the events of lightening of hair, lightening of skin, or ophthalmologic abnormalities are 
possible safety signals for this compound, instructions on classification of these events and rules for reporting them 
are updated and clarified in all applicable sections of the protocol.
Synopsis, Overview of 
Study Design
Following text was added (in bold):
Any serious adverse event or adverse event of special interest (AESI) must be 
reported to the sponsor by study site personnel within 24 hours of their knowledge of 
the event as outlined in the protocol.
11.5. Safety Analyses
The following text was deleted and included under Section 12.3.4.
Lightening of hair, lightening of skin, and treatment-emergent ophthalmological AEs 
that indicate retinal pathology are AEs of special interest (AESI). Adverse events of 
special interest will require expedited reporting.
12 3.4. Adverse Events of 
Special Interest
A new section added to clearly list the 3 types of AESIs and the reporting of these 
AESIs, both to the Sponsor and to Health Authorities.
It was clarified that all ophthalmologic events and events of lightening of skin or 
lightening of the hair (serious and non-serious) are categorized as AESIs subject to 
expedited reporting.
Attachment 2
A new attachment added “Adverse Events of Special Interest”
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
9
Approved, Date: 6 September 2017
Applicable Section(s)
Description of Change(s)
Rationale: The section heading updated and text added for more clarity on criteria for discontinuation of study 
treatment
3.3.1. Individual Criteria for 
Stopping Study Treatment
Following text was added:
Events of elevated liver enzymes or increased QTc that require subjects to 
discontinue will be considered as serious and will be reported to Sponsor within 
24 hours of the knowledge of the event.
Re-initiation of study treatment after discontinuation should only be done after 
consultation with the sponsor’s medical monitor and in mutual agreement 
between the sponsor and the study center. For details, refer to Section 10.2, 
Discontinuation of Study Treatment.
Rationale: Exclusion criterion added to exclude patients with a history (within 1 year prior to enrollment) of 
clinically significant hepatic impairment or renal insufficiency. Subjects with ongoing clinically significant systemic 
diseases will also be excluded from the study.
4.2. Exclusion Criteria, 
Criterion #3
Following criterion was added:
Subject has a history of moderate or severe hepatic impairment or severe renal 
insufficiency unless completely resolved for more than a year. Subject has 
clinically significant ongoing hepatic, renal, cardiac, vascular, pulmonary, 
gastrointestinal, endocrine, hematologic, rheumatologic, psychiatric, or 
metabolic conditions (eg, requiring frequent monitoring or medication 
adjustments, or is otherwise unstable).
Rationale: The visit window for dermatological exam, MRI, and the OCT exam was extended to ±28 days, with a 
preference to have these procedures all performed before the scheduled visit date to allow the principal investigator 
to review at the same time he/she is seeing the subject
Time and Events Schedule, 
Footnote “w”
Footnote was updated to include an extended window period of ±28 days for 
dermatological exam, MRI, and OCT examinations.
Rationale: As other AEs are being assessed during the EOT visit, C-SSRS is included in the assessment.
Time and Events Schedule; 
9.1.5. End-of-Treatment 
(Follow Up Visit)
C-SSRS assessment added for EOT visit to check and monitor the suicidality events 
(if any)
Rationale: A risk-benefit evaluation of the study was added to inform the investigators about potential risks and 
benefits of JNJ-54861911.
1.2. Overall Rationale
Addition of risk-benefit evaluation subsection
Rationale: Language related to re-consenting subjects who have experienced cognitive decline to the point of 
clinical dementia during the study was modified and added. The subject will be allowed to remain in the study and 
assent or consent for continued participation (in accordance with the local law) provided that the investigator judges 
that the potential benefits of treatment outweigh the known and foreseeable risks.
Synopsis, Study Population; 
3.2. Study design Rationale
The following text (in bold) was added:
In case the subject progresses to a dementia state during the study, the subject may 
remain in the study, provided that the investigator judges that the potential benefits 
of treatment for this subject clearly outweigh the known and foreseeable risks and 
assent or consent (as applicable) for continued participation is obtained from a 
representative determined in accordance with the local law.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
10
Approved, Date: 6 September 2017
Applicable Section(s)
Description of Change(s)
4. Subject Population
In case the subject progresses to a dementia state during the study, the subject may 
remain in the study, provided that the investigator judges that the potential benefits 
of treatment for this subject clearly outweigh the known and foreseeable risks and 
assent or consent (as applicable) for continued participation is obtained from a 
representative determined in accordance with the local law
9.1.4. Open-label Treatment 
Phase
Text was modified as follows:
In case of progression to a dementia state (CDR ≥1) during the course of the study, 
the subject may go through the consenting process for which a legal representative 
may provide a renewed assent or consent, as applicable, in accordance with local 
regulations.
16.1. Study-Specific Design 
Considerations
Text was modified as follows:
In case the subject progresses to a dementia state during the study, the subject may 
remain in the study, provided that the investigator judges that the potential benefits 
of treatment for this subject clearly outweigh the known and foreseeable risks and 
assent or consent (as applicable) for continued participation is obtained from a 
representative determined in accordance with the local law.
16.2.3. Informed Consent
Following text was added:
A subject who has cognitive decline during the study to the point of clinical 
dementia may go through the consenting process to give renewed assent or consent 
(provided by a legally appointed representative), as applicable, in accordance with 
local law or guidance
Rationale: Text describing the need for a placebo-controlled observation period of 12 months (open-label phase) to 
monitor treatment-emergent ARIA-edema or effusion and ARIA-hemosiderin was considered redundant and hence 
deleted.
3.2. Study Design Rationale
The text was updated as follows:
In addition to the (safety) MRI assessments performed in ALZ2002 study (if 
applicable), safety MRIs will be collected in this study during both DB and OL 
treatment phases, as indicated in the Time and Events Schedule, to monitor any 
treatment-emergent abnormalities, including ARIA-edema or effusion (E) and 
ARIA-hemosiderin (H). As ARIA occurs in the absence of therapeutic interventions 
in some AD patients, an additional placebo controlled observation period of 12 
Months (Treatment Period 1) in the extension study is considered sufficient to 
monitor for treatment induced effects.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
11
Approved, Date: 6 September 2017
Applicable Section(s)
Description of Change(s)
Rationale: Text on dermatologic examination was updated to align it with other protocols for this compound and to 
improve clarity.
Time and Events Schedule, 
footnote “p”; 9.2.6. 
Dermatologic Examination
The updated text (bold) is as follows:
Subjects will undergo a comprehensive skin examination performed by a 
dermatologist at the time points listed in the Time and Events Schedule to exclude 
detect the presence of skin lesions or depigmentation. A digital photograph of the 
frontal scalp, open eyes, and eyebrows will be collected to document any findings to 
monitor for dermatological changes. This is an essential requirement of the 
safety monitoring in the trial.
Whenever a skin lesion not previously documented is reported by the study subject 
or the investigator, in addition to a dermatological exam by the dermatologist, if 
deemed medically/clinically relevant digital images of the lesion will be acquired at 
baseline at the time the lesion is discovered and at follow-up visits with a 
frequency which is deemed appropriate by the sponsor of the study. Duration of 
follow-up of newly documented skin lesions or depigmentation might extend beyond 
the treatment period, as judged adequate by the sponsor to ensure the safety of 
participants subjects in this study.
Rationale: The observations from studies support the safe coadministration of JNJ-54861911 together with BRCP 
substrates rosuvastatin and metformin without influencing the PK of either the BCRP substrates or JNJ-54861911.
Also updated text to reflect the fact that the clinical DDI study has been done and the data indicated no interaction
8. Prestudy and 
Concomitant Therapy
The following text was deleted:
As co-administration with JNJ-54861911 25 mg once daily may result in increase in 
drug concentrations of drugs that are substrates of BCRP, OCT-2, MATE1 or 
MATE2-K, clinical judgment should be used in the use of these substrates. A list of 
known substrates of BCRP, OCT-2, MATE1 or MATE2-K can be found in 
Attachment 1.
In vitro data indicate that JNJ-54861911 is an inhibitor of certain drug transporters 
(see Section 1.1, Background). A clinical DDI study is being planned to evaluate the 
clinical relevance of in vitro findings. Until the clinical DDI study results are 
available, concomitant use of procainamide, an OCT-2 substrate with a narrow 
therapeutic index is prohibited during the study.
Rationale: Text was updated to clarify that certain assessments will be performed prior to first dosing in this study 
only if these assessments were not adequately conducted in 54861911ALZ2002 study from which the subjects rolled 
over and continued in this study.
9.1.3. Double-blind 
Treatment Phase
The text (in bold) was updated as follows:
Following assessments will be performed prior to first dose in the current study 
at time points mentioned below only if no adequate assessments were conducted 
in ALZ2002 study (the assessments listed below 6 months and 9 months prior to 
dosing may also be performed during the screening period in case of any 
logistical issues).
9.2.7. Optical Coherence 
Tomography and 
Ophthalmologic 
Examination
The text was updated as follows:
A baseline (Day 1 [predose or earlier]) OCT and ophthalmologic examination will 
be conducted only if no adequate assessments were obtained in 54861911ALZ2002 
study within 9 months of first dosing in this study.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
12
Approved, Date: 6 September 2017
Applicable Section(s)
Description of Change(s)
Rationale: Text updated to align the information on changes in the ongoing and completed studies with the current 
version of the Investigator’s Brochure (IB)
1.1. Background
Section was updated with addition of description for 2 completed studies 
(54861911ALZ1008 and 54861911ALZ1011 studies) and 2 ongoing studies 
(54861911ALZ1012 and 54861911ALZ2003 studies). The QT findings for 
54861911ALZ1001 and 54861911ALZ1003 studies were deleted as they provide an 
additional rationale for the tQT study but are not definitive in themselves. The 
findings from the ongoing 54861911ALZ2002 study are also updated.
Rationale: The text was obsolete. Hence deleted from protocol.
Attachment 1
Deleted from text.
Rationale: To provide clarity to the text
Throughout the protocol 
(except Time and Events 
Schedule)
“Treatment Period 1” was replaced with “double-blind treatment phase” and 
“Treatment Period 2” was replaced with “open-label phase”
Throughout the protocol
The term “extension” from “extension study” was deleted; however it is retained in 
the protocol title.
Throughout the protocol
The term “liver function tests” replaced by “elevated liver enzymes”
Time and Events Schedule
The term “Treatment Period 1” was deleted from the heading.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 3 (14 June 2016)
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment:
The overall reason for the amendment is to add adverse events of special interest to Section 11.5 (Safety Analyses). 
Applicable Section(s)
Description of Change(s)
Rationale: Lightening of hair, lightening of skin, and treatment-emergent ophthalmological AEs that indicate retinal 
pathology will be recorded as AEs of special interest
11.5 Safety Analyses
Lightening of hair, lightening of skin and treatment-emergent ophthalmologic 
adverse events that indicate retinal pathology were added as adverse events of 
special interest. These events will now be recorded and have expedited reporting
Amendment 2 (8 April 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: To reduce the 10-mg treatment to 5-mg of JNJ-54861911 for Treatment 
Period 2, to increase the frequency of hematology and chemistry assessments in the study, and other required 
changes which were relevant to the study.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
13
Approved, Date: 6 September 2017
Applicable Section(s)
Description of Change(s)
Rationale: A new safety signal for potential liver injury has been identified and is under investigation. As the safety 
signal may be dose related, a strategic decision was made to decrease the low dose from 10 mg to 5 mg in order to 
increase the likelihood of having a dose that would ultimately not require monitoring of hepatic enzymes. The 5 mg 
dose still provides adequate target engagement -- modeled median Aβ1-40 decrease in CSF, based on 28 days 
treatment data, of 52% (95% CI: 27-72).
Synopsis;
3.1 Overview of Study 
Design;
3.2 Study Design Rationale;
5 Treatment Allocation and 
Blinding;
6 Dosage and 
Administration;
Throughout the protocol
References to the 10-mg dose were removed and replaced with the updated 5-mg 
dose for Treatment Period 2. 
Rationale: As a result of the identification of a new safety signal for potential liver injury, additional study visits 
were added to the study procedures for more frequent monitoring of liver function tests. Subjects entering 
Treatment Period 1 will already have had 6 months of monthly monitoring in the parent study; therefore, they will 
have monitoring every 8 weeks for the first 24 weeks of Treatment Period 1 and on 2 additional occasions for the 
remaining 28 weeks of Treatment Period 1 (i.e., Weeks 36 and 52). In Treatment Period 2, since subjects that had 
been receiving placebo will be for the first time exposed to JNJ-54861911, all subjects will be monitored monthly 
for 6 months, every 2 months for the next 6 months, and then every 3 months thereafter.
Time and Events Schedule
(Treatment Period 1); 
Time and Events Schedule 
(Treatment Period 2); 
9 Study Evaluations
For Treatment Period 1, added new study visits at Week 8 and Week 16 for 
additional monitoring of liver function tests. As such, liver function tests 
(hematology and chemistry assessments) will be performed at Weeks 8, 16, 24, 
36, and 52.
For Treatment Period 2, added an increase in the frequency of liver function tests 
(hematology and chemistry assessments) to be performed every 4 weeks for the 
first 24 weeks, 8 weeks for the next 24 weeks, and every 12 weeks thereafter.
Rationale: In the Introduction section, updated the safety and tolerability results for study 54861911ALZ2002 in 
order to include the new safety signal for potential liver injury.
1.1 Background
Updated the safety and tolerability results for study 54861911ALZ2002 in order 
to include the new safety signal for potential liver injury.
Rationale: Based on the dose reduction from 10 mg to 5 mg, Figure 5 was updated to highlight the 5 mg column, 
and the text was updated to match the figure.
3.2 Study Design Rationale
(Figure 5)
Adjustments were made to the text and to the figure on the expected reduction in 
CSF Aβ based on the dose reduction.
Rationale: Owing to the identification of a new safety signal for potential liver injury based on the results from 
study 54861911ALZ2002, the Individual Stopping Criteria section was updated to include elevation of liver 
enzymes.
3.3.1 Individual Stopping 
Criteria
Updated section to include individual stopping rules for subjects with 1 (or more) 
changes in liver function tests.
Rationale: Deleted an erroneous exclusion criterion.
4.2 Exclusion Criteria
Deleted exclusion criterion 2 regarding subjects having a reliable informant (relative, 
partner, or friend). This is an inclusion criterion that was erroneously added to the 
exclusion criteria section.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
14
Approved, Date: 6 September 2017
Applicable Section(s)
Description of Change(s)
Rationale: Updated language regarding treatment allocation and blinding for clarity.
5 Treatment Allocation and 
Blinding
Language pertaining to treatment allocation and blinding was updated in order to 
specify that an IWRS will be utilized to assign blinded study drug kits in this study 
(Treatment Period 1 and Treatment Period 2). In addition, both the investigator and 
subject will be blinded during Treatment Period 1 of the study.
Rationale: Because previous nonclinical in vitro data indicated that JNJ-54861911 might be an inhibitor of P-gp, a 
conservative approach was taken by not permitting digoxin or dabigatran etexilate use during the trial. New data 
shows there is no clinically relevant P-gp inhibition by JNJ-54861911.
8 Prestudy and Concomitant 
Therapy;
Attachment 1 Non-Restricted 
Substrates of BCRP, OCT-2, 
MATE1 or MATE2-K
P-gp was removed from the list of transporters.
Rationale: Added language in the Study Evaluations section to indicate that ophthalmologic examination and OCT 
will be carried out only in those subjects who had these in the parent protocol 54861911ALZ2002, for clarity.
9.1.3 Double-Blind 
Treatment Phase (Treatment 
Period 1); 
9.1.4 Open-Label Treatment 
Phase (Treatment Period 2); 
9.2.7 Optical Coherence 
Tomography and 
Ophthalmologic Examination
Added language to specify that ophthalmologic examination and OCT will be 
carried out only in those subjects who had these in the parent protocol 
54861911ALZ2002.
Rationale: Owing to the identification of a new safety signal for potential liver injury based on the results from 
study 54861911ALZ2002, the Discontinuation of Study Treatment section was updated to include elevation of liver 
enzymes.
10.2 Discontinuation of 
Study Treatment
Updated section to include that study treatment may be discontinued for subjects 
with 1 (or more) changes in liver function tests for clarity. Specified that liver 
function tests greater than 3x ULN should be repeated/confirmed within 48 to 72 
hours.
Rationale: Criteria pertaining to withdrawal from the study were updated for clarity.
10.3 Withdrawal From the 
Study
Updated for clarity.
Amendment 1 (2 October 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union 
The overall reason for the amendment: To clarify that subjects who have progressed to dementia (CDR≥1) in the 
parent protocol (54861911ALZ2002) will not be enrolled in Study 54861911ALZ2004, In addition, in the case 
where the subject progresses to a dementia state during the study, the subject may remain in the study, provided that 
the investigator judges that the potential benefits of treatment for this subject clearly outweigh the known and 
foreseeable risks and consent for continued participation is obtained from a representative determined in accordance 
with the local law.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
15
Approved, Date: 6 September 2017
Applicable Section(s)
Description of Change(s)
Rationale: To clarify that subjects who have progressed to dementia (CDR≥1) in the parent protocol 
(54861911ALZ2002) will not be enrolled in Study 54861911ALZ2004, and that a subject may remain in the study
if he or she progresses to a dementia state during Study 54861911ALZ2004
Synopsis Subject 
Population
Subjects who have progressed to dementia (CDR≥1) or who are incapable of providing 
informed consent will not be enrolled in the study. If a subject progresses to dementia 
during the study, the subject may remain in the study provided that the investigator judges 
that the potential benefits of treatment for the subject clearly outweigh the known and 
foreseeable risk, and consent for continued participation is obtained. Treatments indicated 
for this condition, such as memantine or cholinesterase inhibitors are permitted after the 
Sponsor has been notified
Section 3.2. Study 
Design Rationale
Idem as above
Section 4. Subject 
Population
Idem as above
Section 16.1. 
Study-Specific 
Design 
Considerations
Idem as above
Rationale: To remove reference to the caregiver co-signing the consent for subjects in a dementia state (CDR≥1) to 
enroll in the study
Section 9.1.2. 
Screening Phase
Deleted reference to the caregiver co-signing the consent for subjects in a dementia state 
(CDR≥1) to enroll in the study. Also deleted previous reference to a subject’s legal 
representative required to sign the informed consent depending on a subject’s disease state. 
Section 9.1.4. Open-
Label Treatment 
Phase (Treatment 
Period 2)
Deleted reference to the caregiver co-signing the consent for subjects in a dementia state 
(CDR≥1) to enroll in the study.
Section 16.2.3. 
Informed Consent
Clarified through a re-write, that “in the case of subjects that have become demented 
during the course of the study, a legally accepted representative, if applicable” must give 
written consent. Removed a previous reference to “care giver”. 
For grammatical clarity only, removed 2 additional references to this text
Rationale: To provide clarity to the text
Section 4.1. Inclusion 
Criteria
Inserted “of the parent protocol”
Section 8. Prestudy 
and Concomitant 
Therapy
Inserted “if clinically indicated, after notification of the Sponsor”
Section 16.1. Study-
Specific Design 
Considerations
Inserted “to become apparent”
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
16
Approved, Date: 6 September 2017
SYNOPSIS
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 (Aβ) 
fragments.
This Phase 2 study will include subjects in the early AD spectrum, i.e., subjects described under the 
parent protocol (Study 54861911ALZ2002) as asymptomatic at risk for Alzheimer’s dementia16,54,59 as 
well as subjects with prodromal Alzheimer’s disease (pAD)1,14,15,  who have completed a Phase 1b or 
Phase 2 clinical trial with JNJ-54861911. This Phase 2 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 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 with the parent 
protocols, subjects enrolled in this study may be more likely to experience clinical benefit.
OBJECTIVES AND HYPOTHESIS
Primary Objective
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 who 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.
Secondary Objectives
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 Aβ 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.
Exploratory Objectives
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.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
17
Approved, Date: 6 September 2017

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.
Hypothesis
This is a study to collect primarily long-term safety and tolerability data. There is no formal hypothesis 
testing planned for this long-term study which is an extension of 54861911ALZ2002 study.
OVERVIEW OF STUDY DESIGN
This is a randomized, two-period, double-blind (DB) placebo controlled and open-label (OL), 
multi-center, parallel-group study assessing primarily the long-term safety and tolerability of 
JNJ-54861911 in subjects in the early AD spectrum who have completed a Phase 1b or Phase 2 clinical 
study with JNJ-54861911. 
This 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 study, the study will consist of a screening phase, 2 sequential treatment 
periods i.e., a 12-Month DB treatment phase (placebo-controlled) and an open-label (OL) phase (active), 
followed by an End-of-Treatment visit. Treatment in OL phase 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 study upon completion 
of their treatment period under the parent protocol. Subjects participating in this study do not have to 
complete the End-of-Treatment visit (follow-up) visit under the parent protocol.
Enrollment in this study should be completed (Day 1 of DB treatment phase) as soon as possible, but 
within 6 weeks,
following completion of their treatment period under the parent protocol 
(54861911ALZ2002 study) 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 ongoing/future Phase 1b or Phase 2 
JNJ-54861911 clinical studies. 
Eligible subjects enrolled in this study will receive either JNJ-54861911 (10 mg or 25 mg once daily 
[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) (placebo-controlled DB treatment phase). 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 the DB treatment phase (10-mg or 25-mg JNJ-54861911; e.g. subjects receiving 50 mg in 
study 54861911ALZ2002 will be assigned to 25 mg JNJ-54861911). 
Following the initial 52-Week (12-Month) DB treatment phase in this study, subjects receiving placebo in 
the DB treatment phase 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 OL phase. 
As such all subjects will receive active (JNJ-54861911) OL treatment during the OL phase. In addition, 
subjects who were receiving 10 mg q.d. JNJ-54861911 will have their dose reduced to 5 mg q.d. in order 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
18
Approved, Date: 6 September 2017
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 (DB and OL treatment phases), primarily safety and tolerability will be 
monitored at regular intervals (e.g., magnetic resonance imaging [MRI], physical and neurological 
examination, suicidality risk assessment, vital signs, 12-lead electrocardiogram (ECG), safety labs, 
dermatologic and ophthalmologic examinations). 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 study will be allowed to continue participation in the study, except if 
emerging data would show continued treatment could potentially be harmful. 
A number of sites will be given the opportunity to use the eMeds smart technologies to manage clinical
trials supplies and drug compliance activities. This will be done following subject informed consent.
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 (DB and OL treatment phases).
Any serious adverse event or adverse event of special interest (AESI) 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.
SUBJECT POPULATION
Subjects in the early AD spectrum, i.e., subjects asymptomatic at risk for Alzheimer’s dementia and 
prodromal AD subjects at time of enrollment in 54861911ALZ2002 study, who have completed their 
treatment period as defined under the parent protocol in a Phase 1b or Phase 2 clinical study with 
JNJ-54861911 will be provided the opportunity to participate in this study. If not defined in 
54861911ALZ2002 study, completion of the treatment period is defined as having completed all study 
related procedures of the last visit of the treatment period under the in 54861911ALZ2002 study.
Subjects who have progressed to dementia in the in 54861911ALZ2002 study (CDR 1) or who are 
incapable of providing informed consent will not be enrolled. 
In case the subject progresses to a dementia state during the study, the subject may remain in the study, 
provided that the investigator judges that the potential benefits of treatment for this subject clearly 
outweigh the known and foreseeable risks and then the assent or consent (as applicable) for continued 
participation is obtained from a representative determined in accordance with the local law. In cases 
where a subject has progressed to dementia, treatments indicated for this condition (e.g., memantine or 
cholinesterase inhibitors) are permitted after notification of the sponsor.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
19
Approved, Date: 6 September 2017
Screening for eligible subjects should be performed as soon as possible, but within 6 weeks following 
completion of their treatment period in ALZ2002 study until administration of the study drug. A 
screening phase of up to 12 weeks may be allowed following written approval of the Sponsor.
The inclusion and exclusion criteria for enrolling subjects in this study are described in more detail in 
Section 4.
DOSAGE AND ADMINISTRATION
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 study will participate in 2 sequential treatment phases/periods as 
described above, i.e. 

Double-blind treatment phase: a 52-week (12 Months) placebo-controlled DB treatment phase.
Eligible subjects enrolled in this 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 in 
54861911ALZ2002 study (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 54861911ALZ2002 study will be 
receiving the closest dose available in DB treatment phase (e.g., subjects receiving 50 mg in study 
54861911ALZ2002 will be assigned to 25 mg JNJ-54861911).

Open-label phase: an open label treatment phase during which subjects who received placebo in DB 
treatment phase will 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 DB 
treatment phase will continue their treatment as open label in the OL phase.
During the entire study (DB and OL treatment phases) 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.
SAFETY EVALUATIONS
The primary objective of this study is to assess the long-term safety and tolerability of JNJ-54861911 in 
subjects in the early AD spectrum. As such, regular safety assessments will be performed as listed in the 
Time and Events Schedule. These safety assessments include but are not limited to: vital signs, ECG, 
physical and neurological examination, adverse events, safety labs, suicidality risks (Columbia Suicide 
Severity Rating Scale [C-SSRS]), dermatologic and ophthalmologic examinations and MRI. Protocol
amendment 5 was written to include more frequent monitoring of serum chemistry and hematology, 
guidelines for discontinuation of treatment due to abnormal liver enzymes and guidelines for evaluation 
and management of such cases. 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
20
Approved, Date: 6 September 2017
Specific dermatologic and ophthalmologic examinations have been implemented in this study as potential 
BACE1- or BACE2-linked toxicities (e.g. melanin deposition changes and retinal abnormalities) have 
been described in the literature (e.g., BACE1 or BACE2 knock-out mice). With the exception of fur 
discoloration resulting in progressive lightening of the fur from normal dark brown to paler cream or 
grey, which was seen in one species only (Tg mice in the 6 month carcinogenicity study), however, these 
toxicities have not been observed in nonclinical chronic studies with JNJ-54861911.
In addition to the (safety) MRI assessments performed in 54861911ALZ2002 (if applicable), safety MRIs 
will be collected in this study  during both DB and OL treatment phases, as indicated in the Time and 
Events Schedule, to monitor for amyloid related imaging abnormalities (ARIA)-edema or effusion (E) 
and ARIA-hemosiderin (H). In case of any safety related changes observed (e.g., ARIA-E or H), 
additional safety MRIs may be collected at a frequency as recommended by the DRC.
Any changes observed in any of the safety measures performed that are considered not clinically
significant or do not have a direct clinical symptomatology as assessed by the investigator, should be 
closely monitored, with a potential increased safety monitoring frequency as deemed appropriate by the 
investigator. In addition, these findings will be presented to the DRC, who will make recommendations 
regarding the safety and continuation of the study as per its charter.
PHARMACOKINETIC EVALUATIONS
Venous blood samples for analysis of JNJ-54861911 will be collected at the time points indicated in the 
Time and Events Schedule. 
CSF samples for analysis of JNJ-54861911 concentrations will be obtained at the time points indicated in 
the Time and Events Schedule.
COGNITION, FUNCTION AND CLINICAL STATUS
Cognitive evaluations (RBANS, MMSE and CVLT-II) and functional outcome measures (Cognitive 
Function Index [CFI]) will be applied in this study at different time points as indicated in the Time and 
Events Schedule to explore the subject’s cognitive performance/progression and function over time.
In addition during course of the study the subject’s clinical status will be assessed regularly by means of 
the Clinical Dementia Rating Scale as indicated in the Time and Events Schedule.
BIOMARKER EVALUATIONS
Fluid (CSF and plasma samples) biomarkers samples and imaging biomarker assessments (MRI) will be 
performed as listed in the Time and Events Schedule to assess the potential and continuous effects of 
JNJ-54861911 on the pathological and pathophysiological processes of AD. In addition, these biomarker 
assessments will be performed to assess if potential treatment effects of JNJ-54861911 are consistent with 
the putative effects of BACE inhibition.
During the course of the study the continuous effects of JNJ-54861911 on the pathophysiological 
processes of AD will be monitored by the DRC.
All subjects will undergo an MRI in this study at the time points indicated in the Time and Events 
Schedule for primarily safety reasons. However, potential treatment effects may be assessed with MRI as 
well.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
21
Approved, Date: 6 September 2017
STATISTICAL METHODS
Sample Size Determination
This study is not powered according to statistical calculations. The number of subjects enrolled will 
depend on the number of subjects from other JNJ-54861911 studies who are willing to enroll in this 
study.
Statistical Analysis
Descriptive statistical analyses will be performed for all subjects receiving at least one dose of study drug. 
Analyses may be prepared separately for DB and OL treatment phases, and may be performed separately 
for subgroups of subjects according to previous study participation as well as for the combined population 
of all subjects participating in this study, where appropriate. Summaries may also be presented by 
baseline CDR global score.
Data Review Committee (DRC)
A DRC will be established to review/monitor the study data on an ongoing basis to ensure the continuing 
safety of the subjects enrolled in this study. The committee will meet periodically to review interim study 
data including the biomarker data (fluid [CSF, plasma] and imaging [volumetric MRI]).  
After the review, the DRC will make recommendations regarding the safety and continuation of the study. 
The details will be provided in a separate DRC charter.
The DRC responsibilities, authorities, and procedures will be documented in its charter.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
22
Approved, Date: 6 September 2017
TIME AND EVENTS SCHEDULE
  Phase
Screening
Double-Blind Treatment Phase
Open-Label 
Treatment 
Phase
End-of-
Treatment 
Visit (or 
phone call) 
or Early 
Withdrawaln
Treatment Period
Period 1
Period 2
Time Period
Day 1 to Week 52
(Month 12)
>Week 52 
(>Month 12)
Study Visits: 
Day/Week/Month
0 to 6 
weeks
Day 1
Week 8
Week 12
Week 16
Week 24
Week 36
Week 52 
(Month 
12)n
30 days post 
last dose
Visit Window
0
+/- 12 days
+/- 12 days
+/- 12 days
+/- 12 days
+/- 12 days
+/- 12 days
+/- 12 days
+/- 12 days
Study Procedures
Screening/Administrative
See separate 
Time and 
Events 
Schedule 
Treatment 
Period 2
Informed consent
X
Inclusion/exclusion criteria
X
Medical History and 
Demographics
X
Prestudy therapy
X
Preplanned 
surgery/procedure(s)
X
Study Drug Administration
Randomization
Xo
Dispense study drug 
X
X
X
X
Xo
Self-Administer study druga
X------------------------------------------------------------------------------------------------------X
Drug accountability
X
X
X
X
X
Drug return
X
X
X
X
Safety Assessments
Physical and Neurological 
examination
Xb,c
X
Vital signs
Xb,c
X
X
Body Weight
Xb,c
X
12-lead ECGd
Xc,s
Xs
Xs
Temperature
Xb,c
X
X
Dermatologic Examinationp,x
Xc,e,f
X
X
Ophthalmologic Examination
Xc,e,f,
Xm
Xm
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
23
Approved, Date: 6 September 2017
  Phase
Screening
Double-Blind Treatment Phase
Open-Label 
Treatment 
Phase
End-of-
Treatment 
Visit (or 
phone call) 
or Early 
Withdrawaln
Treatment Period
Period 1
Period 2
Time Period
Day 1 to Week 52
(Month 12)
>Week 52 
(>Month 12)
Study Visits: 
Day/Week/Month
0 to 6 
weeks
Day 1
Week 8
Week 12
Week 16
Week 24
Week 36
Week 52 
(Month 
12)n
30 days post 
last dose
Visit Window
0
+/- 12 days
+/- 12 days
+/- 12 days
+/- 12 days
+/- 12 days
+/- 12 days
+/- 12 days
+/- 12 days
Study Procedures
OCTr,x
Xc,e,f,
X
X
C-SSRS (baseline)
Xc,g
C-SSRS (since last visit)
Xc,g
X
X
X
X
X
Cognitive & Functional 
Evaluationsh
See separate 
Time and 
Events 
Schedule 
Treatment 
Period 2
RBANS
Xb or i
X
X
MMSE
Xb or i
X
CVLT-II
X
CFI
Xb or i
X
X
Clinical Scalesh
CDR
Xb or i
X
Clinical Laboratory 
Assessments
Hematology, Chemistry
Xb,c
X
X
X
X
X
Urinalysis
Xb,c
X
X
Pharmacokinetics
Blood Sample collection
Xc,s
Xc,s
Xc,s
Fluid Biomarkers
Blood sample collection
Xc
Xc
Xc
CSF sample collectionj
Xc,k
Xj
Imaging
MRIq,x
Xc,f,i
X
X
Ongoing Subject Review
Concomitant therapy
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
24
Approved, Date: 6 September 2017
TIME AND EVENTS SCHEDULE (OPEN-LABEL TREATMENT PHASE)
Phase
Open-Label Treatment Phase
Treatment Period
Treatment Period 2
Time Period
>52 weeks
Study Visit
Every 2 
weeks
Every 4
weeks
Every 8
weeks
Every 12
weeks
Every 24 
weeks(*)
Every 48 
weeks(*)(#)
Every 96 
weeks(*)(#)(¥)
Visit Window
+/- 3 days
+/- 12 days
+/- 12 days
+/- 12 days
+/- 12 days
+/- 12 days
+/- 12 days
Study Procedures
Drug accountability/Treatment compliance
X
Drug return (previous visit)
X
Drug Dispensing
X
Self-Administer study druga
X-----------------------------------------------------------------------------------------------------------------X
Physical and Neurological examination
X
Body Weight
X
12 Lead ECG
Xl,s
Xs
Body Temperature
X
Supine and standing vital signs (systolic and diastolic 
blood pressure and pulse)
X
Clinical safety laboratory assessments – hematology, 
serum chemistry– under fasted conditions, when feasible
Xt
Xu
Xv
Xw
Clinical safety laboratory assessments – urinalysis–under 
fasted conditions, when feasible
X
Dermatological Examinationp,x
X
Ophthalmological Examinationm
X
OCTr,x
X
C-SSRS (since last visit)
X
RBANS
X
MMSE
X
CFI
X
CDR
X
Blood sample collection for plasma JNJ-54861911 
concentrations 
Xc,s
Blood sample collection for PD/biomarkers
Xc
CSF sample collection (~12 mL) by single lumbar 
puncture for PK/PD/biomarker assessment.j
Xj
MRIq,x
X
Adverse Event and Concomitant Medication 
X
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
25
Approved, Date: 6 September 2017
Abbreviations = CDR: Clinical Dementia Rating Scale; CFI: Cognitive Function Index; CSF: cerebrospinal fluid; C-SSRS: Columbia Suicide Severity Rating Scale;
CVLT-II: California Verbal Learning Test – Second Edition; DRC: Data Review Committee; ECG: electrocardiogram ; MRI: Magnetic Resonance Imaging; MMSE: 
Mini Mental State Examination; OCT: Optical Coherence Tomography; PK: pharmacokinetic(s); PD: pharmacodynamics; RBANS: Repeatable Battery for the 
Assessment of Neuropsychological Status.
TIME AND EVENTS SCHEDULE (FOOTNOTES)
Footnotes
a
Subjects will self-administer study drug (once daily) with a glass of water following breakfast or a light snack. Study drug administration will take place during 
the morning hours. During scheduled visits when ECG or blood samples for JNJ-54861911 concentrations in plasma are to be obtained subjects will self-
administer their study medication on site as described above. On Day 1 study drug administration will not be time limited.
b
Baseline (predose) only if no (adequate) assessment was obtained under the parent protocol at the last study visit of the treatment phase.
c
Must be performed predose.
d
At all time points, triplicate ECGs are required, i.e., 3 individual ECG tracings should be obtained as closely as possible in succession, but no more than 2 
minutes apart. The full set of triplicates should be completed in less than 4 minutes.
e
Only if no adequate assessment was obtained under the parent protocol within 9 months of first dosing in this study. 
f
May be performed during screening in case of logistical issues.
g
C-SSRS baseline: Only to be completed if no C-SSRS assessment was performed under the parent protocol; C-SSRS since last visit: to be completed if the 
C-SSRS assessment was performed under the parent protocol. 
h
The RBANS will be completed first followed by the CDR and MMSE if the raters for RBANS and CDR are independent. If the raters for RBANS and CDR 
are the same, the CDR will be performed first, followed by the RBANS and MMSE.
i
Only if no adequate assessment was obtained under the parent protocol 6 months prior to first dosing in this study.
j
CSF samples (12 mL/sample; baseline and on treatment samples) should be taken at approximately the same time of day (with an allowable window of 3 
hours), with the on treatment samples being collected postdose. In Treatment Period 2 (>52 weeks) it is intended to collect if possible on-treatment CSF 
samples every 96 weeks until study completion. Subjects may opt not to have these punctures being performed. CSF samples collected will be used for 
biomarker and PK analysis.
k
Only if no on-treatment CSF sample was collected under the parent protocol (54861911ALZ2002 study).
l
Only during the first 12 week visit of the open-label treatment phase.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
26
Approved, Date: 6 September 2017
m
Ophthalmologic examination will be performed only if: 1) if there was an abnormality present at the screening/baseline examination; 2) if the investigator 
detects new ophthalmological findings or visual symptoms; 3) if OCT reveals new findings. The ophthalmologic examination should be performed by the same 
ophthalmologist who completed the initial ophthalmologic examination at screening/baseline.
n
If a subject discontinues study treatment the subject will be asked to complete the Week 52 assessments, including CSF sampling, if not yet obtained earlier. In 
addition, and at a minimum the subject will be asked to complete the End-of-Treatment Visit (Follow-up visit) as per Time and Events Schedule.
o
At Week 52 subjects will be dosed according to treatment allocation assigned to in Treatment Period 1. Randomization to Treatment Period 2 and dispensation 
of study medication for Treatment Period 2 will only be performed following completion of all week 52 assessments.
p
Whenever a skin lesion not previously documented is reported by the study subject or the investigator, in addition to a dermatological exam by the 
dermatologist, digital images of the lesion will be acquired at the time the lesion is discovered and at follow-up visits with a frequency which is deemed 
appropriate by the sponsor of the study. Duration of follow-up of newly documented skin lesions or depigmentation might extend beyond the treatment period, 
as judged adequate by the sponsor to ensure the safety of subjects in this study.
q
Additional MRI scans may be collected based on emerging safety data with a frequency as recommended by the DRC. 
r
At sites where OCT is available.
s
2 to 4 hours postdose.
t
Hematology and serum chemistry assessments to be performed every 2 weeks for 12 weeks (from Week 52 to Week 64, inclusive).
u
Hematology and serum chemistry assessments to be performed every 4 weeks for 12 weeks (from Week 64 to Week 76, inclusive).
v
Hematology and serum chemistry assessments to be performed every 8 weeks for 24 weeks (> Week 76 and ≤Week 100).
w
Hematology and serum chemistry assessments to be performed every 12 weeks after Week 100.
x
Assessments can be done not only on the visit date but also within the visit window of +/- 28 days, with a preference to have these procedures performed prior 
to the scheduled visit.
* In addition to the assessments performed every 12 weeks. 
# In addition to the assessments performed every 24 weeks. 
¥ In addition to the assessments performed every 48 weeks.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
27
Approved, Date: 6 September 2017
ABBREVIATIONS
Aβ
amyloid β (beta)
AD
Alzheimer’s disease
ALT
alanine aminotransferase
APP
amyloid precursor protein
ARIA-E
Amyloid related imaging abnormality – edema
ARIA-H
Amyloid related imaging abnormality –hemosiderin
AST
aspartate aminotransferase
AUC
area under curve
BA
Bioavailability
BACE
-secretase
BACE1
-secretase 1 (also known as beta-site APP cleaving enzyme 1)
BACE2
-secretase 2 (also known as beta-site APP cleaving enzyme 2)
BACEi
BACE inhibitor
b.i.d.
Twice daily
BQL
below the limit of quantification
C-SSRS
Columbia Suicide Severity Rating Scale
CDR
Clinical Dementia Rating Scale
CDR-SB
Clinical Dementia Rating Scale – Sum of Boxes
CFI
Cognitive Function Index
CI
confidence interval
Cmax
maximum or “peak” concentration (Cmax) of a drug observed after its administration
CNS
central nervous system
CrCl
creatinine clearance rate
CRF
case report form (paper or electronic as appropriate for this study)
CSF
cerebrospinal fluid
CVLT-II
California Verbal Learning Test – Second Edition
CYP
cytochrome P450
DIAT
Diaminothiazine
DDI
drug-drug interaction
DRC
Data Review Committee
DTP
data transfer plan
ECG
Electrocardiogram
eDC
Electronic Data Capture
FLAIR
Fluid attenuated inversion recovery
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GSH
Glutathione
HDPE
high-density polyethylene
IC50
The concentration of a compound that is required for 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
International normalized ratio
IRB
Institutional Review Board
IWRS
Interactive Web Response System
JRD
Janssen Research and Development
LC-MS/MS
liquid chromatography/mass spectrometry/mass spectrometry
MAD
Multiple ascending dose
MCI
mild cognitive impairment
MedDRA
Medical Dictionary for Regulatory Activities
MMSE
Mini Mental State Examination
MRI
Magnetic resonance imaging
NFT
Neurofibrillary tangles
NOAEL
No observed adverse effect level
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
28
Approved, Date: 6 September 2017
pAD
Prodromal Alzheimer’s disease
OCT
Optical Coherence Tomography
PD
Pharmacodynamic(s)
PDPH
Post-dural puncture headache
PET
Positron emission tomography
PHFs
paired helical filaments
PK
Pharmacokinetic(s)
PQC
Product Quality Complaint
POM
Proof of mechanism
q.d.
once daily
RBANS
Repeatable Battery for the Assessment of Neuropsychological Status
RBC
Red blood cell
SAD
single ascending dose
sAPP
soluble amyloid precursor protein
SOP
Standard operating procedure
tmax
time to reach the maximum plasma/CSF concentration
WBC
white blood cells
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
29
Approved, Date: 6 September 2017
1.
INTRODUCTION
Alzheimer's disease (AD) is a neurodegenerative disease associated with aging. AD patients 
suffer from cognition deficits and memory loss as well as behavioral problems such as anxiety 
and agitation. With the increasing number of elderly in the population, AD is a growing medical 
concern. Currently available therapies for AD merely treat the symptoms of the disease and 
include acetylcholinesterase inhibitors to improve cognitive properties as well as anxiolytics and 
antipsychotics to control the behavioral problems frequently associated with AD.
The hallmark pathological features of AD patients are neurofibrillary tangles (NFT) which 
consist of hyperphosphorylated tau protein and amyloid plaques, whose main constituent is 
amyloid-beta (Aβ). Aβ1-42 peptide is over-represented in amyloid deposits. Aβ1-42 has a high 
tendency to aggregate, forming oligomers and fibrils, as well as amyloid in neuritic plaques. Aβ 
accumulation and amyloid deposition are believed to be early, key events in the pathogenesis of 
AD according to the amyloid cascade hypothesis.29,40 The oligomers and fibrils have been 
demonstrated to be neurotoxic.  
Agents that prevent the formation of Aβ overall or Aβ1-42 specific have been proposed to be 
disease-modifying agents for the treatment of AD. Aβ is generated from the amyloid precursor 
protein (APP). The N-terminus of Aβ is cleaved by β-secretase1 (BACE1), and then γ-secretase 
cleaves the C-terminal end. In this process, BACE1 cleavage is the first and rate limiting step. In 
addition to Aβ1-42, γ-secretase cleavage can result in other Aβ fragments (e.g., Aβ1-40, Aβ1-38, and 
Aβ1-37), from which Aβ1-40 is the predominant cleavage product. These Aβ forms can also 
aggregate to form oligomers and fibrils. Thus, inhibitors of BACE1 prevent the formation of 
Aβ1-42 as well as Aβ1-40, Aβ1-38, and Aβ1-37 and would be potential therapeutic agents in the 
treatment of AD. In support of this hypothesis is the observed correlation between the catalytic 
efficiency of BACE1 for its substrate APP and the occurrence of AD. The Swedish APP mutant 
(KM670/671NL), a more efficient substrate for BACE1 (10x), causes a rare familial form of AD 
that is inherited in the dominant Mendelian fashion. On the other end of the spectrum is an allelic 
variant of APP (A673T), a less efficient substrate for BACE1 (± 0.5x), which is protective 
against sporadic AD.38
JNJ-54861911 is a BACE inhibitor (BACEi) being developed by Janssen Research and 
Development (JRD) for the treatment of (early) AD by reducing production of Aβ fragments.
This Phase 2 study will include subjects in the early AD spectrum, i.e., subjects described as 
asymptomatic at risk for Alzheimer’s dementia16,54,59 as well as subjects with prodromal 
Alzheimer’s disease (pAD)1,14,15, who have completed a Phase 1b or Phase 2 clinical trial with 
JNJ-54861911. This Phase 2 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 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, subjects enrolled 
in this study may be more likely to experience clinical benefit.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
30
Approved, Date: 6 September 2017
For the most comprehensive nonclinical and clinical information regarding JNJ-54861911, refer 
to the latest version of the Investigator's Brochure and Addenda for JNJ-54861911.37
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
JNJ-54861911 is a BACE inhibitor being developed for the treatment of AD. JNJ-54861911 
reduces production of Aβ fragments by inhibiting BACE1 processing of APP, with the aim of 
reducing AP formation. JNJ-54861911 has been demonstrated to be potency potent reducer of 
Aβ, both in nonclinical models, as well as in initial clinical studies.37
Nonclinical Studies
Pharmacologic Profile
 
 
 
 
 
 
 
 
 
 
 
 
Safety Profile
 
 
 
 
 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
31
Approved, Date: 6 September 2017
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Clinical Studies
For the most comprehensive clinical information regarding JNJ-54861911, refer to the latest 
version of the Investigator's Brochure for JNJ-54861911.37
Study 54861911ALZ2004 will be an extension study for subjects in the early AD spectrum who
have completed a Phase 1b or Phase 2 clinical trial with JNJ-54861911. 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
32
Approved, Date: 6 September 2017
Study 54861911ALZ2004 is the third study in subjects in the early (predementia) AD spectrum 
following the proof of mechanism (POM) study (54861911ALZ1005) and the 6-month safety 
study (54861911ALZ2002). The POM study 54861911ALZ1005 is being performed to confirm 
a drug interaction with the intended enzyme (BACE) at the intended target location (brain) at the 
intended dose range (placebo q.d., 10 mg q.d. and 50 mg q.d. JNJ-54861911) following 1 month 
of treatment in subjects with early (predementia) AD, while the 6-month safety study 
(54861911ALZ2002) is being performed to provide safety information in preparation for the 
longer term treatment studies.
Twelve clinical studies have been completed; 9 of these studies were of short duration and in 
healthy subjects: Studies 54861911ALZ1001 and 54861911ALZ1002 evaluated the safety, 
tolerability, PK, and pharmacodynamics (PD) of single and multiple ascending oral doses of 
JNJ-54861911 in healthy subjects; Study 54861911ALZ1003 examined the relative 
bioavailability of a solid formulation of JNJ-54861911 in comparison with a suspension 
formulation and the effect of high fat/high calorie food on the PK of a 25 mg tablet formulation 
in healthy subjects; Study 54861911ALZ1006 evaluated the safety, tolerability, PK, and PD of 
single ascending doses in healthy Japanese male subjects; Study 54861911ALZ1007 was a 
thorough QT study to evaluate ECG intervals in healthy subjects; Study 54861911ALZ1009 
investigated the effects of strong CYP 3A4 and amide hydrolase inhibitor on the single-dose PK 
of JNJ-5481911 in healthy male subjects; Study 54861911ALZ1010 investigated effects of 
single and multiple daily doses of JNJ-54861911 once daily on the PK of midazolam, 
tolbutamide, and caffeine, (substrates of CYP3A4, CYP2C9, and CYP1A2, respectively) in 
healthy male subjects; Study 54861911ALZ1011 was a 3-period crossover study to evaluate the 
relative oral bioavailability and food effect of JNJ-54861911 tablet after single-dose 
administration in healthy elderly subjects; and Study 54861911ALZ1012 was an open-label, 
fixed-sequence, single-center, 2-panel study to investigate the PK interaction between 
JNJ-54861911 and transporter substrates rosuvastatin and metformin.
Three additional completed studies had treatment durations of 4 weeks and longer, as well as 
participants in the target population: Study 54861911ALZ1005 was a double-blind, 
placebo-controlled, randomized, 4-week, multiple-dose, proof-of-mechanism study in subjects 
with early Alzheimer’s disease investigating the effects of JNJ-54861911 on Aβ processing in 
CSF and plasma; Study 54861911ALZ1008 was a double-blind, placebo-controlled, randomized, 
4-week, multiple-dose, proof-of-mechanism study in Japanese subjects asymptomatic at risk for 
Alzheimer dementia (ARAD) investigating the effects of JNJ-54861911 on Aβ processing in 
cerebrospinal fluid (CSF) and plasma; Study 54861911ALZ2002 was a phase 2a randomized, 
double-blind, placebo-controlled, parallel-group, multi-center study investigating the safety and 
tolerability of JNJ-54861911 in subjects in the early (predementia) Alzheimer’s disease 
spectrum. 
As of 6 September 2017, there are 2 ongoing clinical studies: Study 54861911ALZ2003, a
phase 2b/3 randomized, double-blind, placebo-controlled, parallel group, multicenter study 
investigating the efficacy and safety of JNJ-54861911 in subjects who are asymptomatic at 
(risk for developing Alzheimer’s dementia, and Study 54861911ALZ2004, a randomized, 
2-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.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
33
Approved, Date: 6 September 2017
Pharmacokinetics
Final pharmacokinetic (PK) results from a SAD study are presented in this section. Preliminary 
PK results from multiple-ascending dose (MAD) and relative BA studies are also presented.
In the SAD study 54861911ALZ1001, 1-mg JNJ-54861911 was administered to healthy young 
subjects followed by single-dose administration of JNJ-54861911 in elderly subjects with doses 
ranging from 1 to 150 mg. The pharmacokinetics of JNJ-54861911 was characterized by rapid 
absorption and multiphasic decline in all treatment groups. Plasma JNJ-54861911 concentrations 
increased dose proportionally between 1 mg and 150 mg, reaching Cmax at approximately 0.75 to 
2.0 hours postdose. In elderly subjects, dose-normalized mean exposure results ranged from 4.93 
to 8.39 ng/mL for Cmax and 84.9 to 104 ng.h/mL for AUC∞across all doses. On average, mean 
half-life (t1/2) seemed to increase slightly from the 1- to 10-mg dose and seemed to be similar 
thereafter (range 9.0 to 16.1 hours). The 1-mg dose pharmacokinetics in young healthy subjects 
was comparable to that of the elderly subjects. JNJ-54861911 levels in CSF were assayed only in 
elderly subjects. All concentrations were below the limit of quantification (BQL) for the 2 lowest 
doses (1 and 3 mg), but increased dose-proportionally from 30 to 150 mg. Maximal mean 
concentrations were reached between 2.0 and 3.0 hours with levels ranging from 2.94 to 
22.7 ng/mL.
JNJ-54861911 in urine was analyzed only for the 2 highest doses (90 and 150 mg). The fraction 
excreted of unchanged JNJ-54861911 in urine as a percent of the dose was similar for both doses 
(0.315% and 0.381%, respectively) and represented renal clearance rates of 0.593 and 
0.780 mL/min for the 90- and 150-mg doses, respectively.
For assessable doses, JNJ-54861911 plasma exposure was similar between males and females 
with male:female ratios for Cmax of 0.987 and 0.820, and for AUClast of 0.814 and 0.667 for the 
30- and 150-mg dose groups, respectively.
In the MAD study 54861911ALZ1002, JNJ-54861911 steady-state plasma Cmax and AUCτ 
increased approximately dose-proportionally across the doses studied. Steady-state plasma levels 
were reached by Day 5. Median tmax was slightly delayed with multiple dosing compared to a 
single dose (multiple dose range: 2.00 to 4.00 hours; single dose range: 0.75 to 2.00 hours). The 
mean t1/2 on Day 14 ranged from 14.4 to 18.5 hours across all doses studied. Mean accumulation 
ratios across all doses for steady-state Cmax and AUCτ on Day 14 ranged from 1.27 to 1.73 and 
1.34 to 2.17, respectively. The mean renal clearance values between Day 1 and Day 14 were 
similar (0.111 vs 0.115 L/h).
Preliminary results from the ongoing 54861911ALZ1012 study showed the mean PK parameters 
of rosuvastatin and metformin were similar following single-dose administration with and 
without JNJ-548161911 25 mg at steady state. The 90% confidence interval (CI) of geometric 
mean ratios for Cmax and AUC were well within the 80% to 125% boundaries of no effect. 
Therefore, this study concluded no clinically significant drug-drug interaction between 
JNJ-548161911 and the substrates of transporters BCRP, MATE-1, MATE-2, and OCT-2.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
34
Approved, Date: 6 September 2017
In the relative BA/food-effect study 54861911ALZ1003 in older male subjects (aged 55 to 
75 years), comparable BA was observed between tablet and suspension formulations after 
administration of an oral dose of 25 mg. In this study, food had little effect on JNJ-54861911 
exposure across subjects after oral administration of tablet formulation in the presence of high 
fat/high calorie food. When Cmax and AUC∞in the fed state were compared to the fasted state 
(Frelfed/fasted) values of 96.1% and 114% were obtained for Cmax and AUC∞, respectively. Median 
tmax was delayed by 1.5 hours in the fed state (median tmax 3.00 hours [0.75 - 8.00]) in 
comparison with the fasted state (median tmax 1.50 hours [0.75 - 3.50]).
Only minor metabolites were observed in human plasma from Study 54861911ALZ1002, and 
none of them was human specific. In Studies 54861911ALZ1001 and 54861911ALZ1002, the 
AUC ratio of DIAT metabolite to parent compound was below 10% and the Cmax ratio of DIAT 
metabolite to parent compound ranged from 4% to 7%. Other metabolites identified in human 
plasma showed lower exposure.
The effect of once daily administration of 200 mg of itraconazole, a strong inhibitor of 
cytochrome P450 3A4 (CYP3A4) activity, on the pharmacokinetics of JNJ-54861911 was 
evaluated in a clinical DDI study (Study 54861911ALZ1009). Preliminary results indicate that in 
the presence of itraconazole 200 mg q.d., JNJ-54681911 Cmax and AUC∞increased by 13% and 
82% respectively. 
The clinical DDI study to evaluate the interaction potential of JNJ54861911 as perpetrator when 
co-administered with a drug cocktail of CYP3A4, CYP2C9, and CYP1A2 substrates (Study 
54861911ALZ1010) has recently been completed. Preliminary results of this trial do not show a 
clinically relevant effect of JNJ54861911 on the activity of CYP3A4, CYP1A2 or CYP2C9.
Pharmacodynamics
In Study 54861911ALZ1001, a dose-dependent decrease in plasma Aβ1-40 levels was observed 
(Figure 1). Onset of inhibition was fast, with strongest reduction of Aβ1-40 levels during the first 
4 hours postdose. At the 1 mg dose after 2.5 hours, 42% inhibition was achieved with no 
significant further Aβ1-40 reductions. At the 3 mg dose, 57% inhibition was achieved after 
4 hours; at higher doses (10, 30, 90, and 150 mg) 70% to 80% inhibition was achieved at 4 hours 
postdose. After 4 hours, the percent mean change from baseline values of Aβ1-40 levels remained 
relatively stable up to 36 hours postdose at higher doses, while lower doses (e.g., 1 mg) showed a 
trend towards normalization before that time point. No notable changes from baseline were 
observed in subjects receiving placebo. 
CSF was only collected in elderly subjects. CSF Aβ measurements showed an increase in CSF 
Aβ1-40 levels over baseline especially early. Over the first 6 hours, no apparent treatment effect 
was observed at any dose. At doses of 1 and 3 mg, no strong treatment effects were observed at 
any time during the observation period. At higher doses, after 6 hours a dose-dependent 
reduction of CSF Aβ1-40 levels was observed, which continued in the 150-mg group until the end 
of the observation period at 36 hours, while lower active doses trended towards normalization 
earlier (Figure 2).
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
35
Approved, Date: 6 September 2017
Figure 1:
Plasma Aβ1-40 Mean Percent Change From 
Baseline 
Following 
Single 
Dose 
Administration of JNJ-54861911
Figure 2:
CSF Aβ1-40 Mean Percent Change From 
Baseline 
following 
Single 
Dose 
Administration of JNJ-54861911
In Study 54861911ALZ1002, marked dose-dependent reductions in plasma Aβ1-40 levels were 
observed in subjects receiving a q.d. oral suspension of JNJ-54861911 at doses of 5, 30, 50, and 
90 mg, as well as 25-mg tablet (Figure 3). These reductions were relatively stable during the 
36-hour postdose observation period. In parallel, a dose-dependent decrease in the CSF Aβ1-40 
levels was observed compared with the Day 1 predose baseline (Figure 4). Similar to the 
observed Aβ1-40 reductions in plasma, all reductions were stable during the 36-hour postdose 
observational period. Towards the end of the observation period there was a trend towards 
normalization, which was more pronounced at the lowest dose of 5 mg. This trend was only seen 
24-hour postdose, at which time in a therapeutic situation the next dose would have been given. 
Aβ1-40 reductions were dose dependent: 50% at 5 mg/day, between 85% and 90% at 30 mg/day, 
around 90% at 50 mg/day, and between 90% and 95% at 90 mg/day. Reductions in subjects 
dosed with the 25-mg tablet were similar to the 30-mg oral suspension.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
36
Approved, Date: 6 September 2017
Figure 3:
Plasma Aβ1-40 Mean Percent Change on 
Day 14 in Relation to Baseline Day 1 
Following Multiple Dose Administration 
of JNJ-54861911.
Figure 4:
CSF Aβ1-40 Mean Percent Change on 
Day 14 in Relation to Baseline Day 1 
Following Multiple Dose Administration 
of JNJ-54861911
Pharmacokinetic/Pharmacodynamic Modeling
Single Dose Modeling: The main goal of this analysis was to develop a population 
PK/pharmacodynamic (PD) (PopPK/PD) model to characterize the kinetics of JNJ-54861911 in 
plasma and CSF, and to quantify the impact of JNJ-54861911 exposure on reduction of Aβ1-40 
levels in plasma and CSF following single doses. The CSF concentration of JNJ-54861911 that 
inhibits the CSF synthesis rate of Aβ1-40 by 50% was estimated as 0.77 ng/mL, which corresponds 
to a plasma concentration of approximately 24.44 ng/mL.
Multiple Dose Modeling: The main objective of this analysis was to develop an exploratory 
PopPK/PD model to describe the relationship between JNJ-54861911 PK and the PD effect on 
Aβ1-40, both in the CSF and in plasma, following multiple oral q.d. doses of JNJ-54861911. The 
PK and PD data included in this analysis were from Cohorts 1 to 4 of Study 54861911ALZ1002 
(dose levels of 30, 90, 5, and 50 mg q.d. of JNJ-54861911, oral suspension). The average plasma 
and CSF steady-state exposures as well as average CSF Aβ1-40 reductions following q.d. dosing of 
JNJ-54861911 were assessed. Results showed that the estimated daily dose providing 50% 
average CSF Aβ1-40 reduction at steady-state is approximately 6 mg, while a dose of 50 mg q.d.
achieves approximately 90% CSF Aβ1-40 reduction. For higher doses the dose-response curve 
levels off rapidly, and hence, the model-predicted response improves only marginally in the dose 
range of 50 to 150 mg.
QTcF Modeling: A model-based exploratory analysis of exposure and Fridericia-corrected QT 
(QTcF) data from Cohort 6 of Study 54861911ALZ1002 did not show a statistically significant 
relationship between JNJ-54861911 mean exposure and the associated mean QTcF change from 
Day 0 (i.e., a predose, full-baseline profile over 24 hours).
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
37
Approved, Date: 6 September 2017
Safety and Tolerability
In Study 54861911ALZ1001, 43 (76.8%) of 56 subjects experienced at least one adverse event 
(33 [78.6%] of 42 subjects who received a single oral dose of JNJ-54861911 and 10 [71.4%] of 
14 subjects who received placebo). In Study 54861911ALZ1002, 40 (76.9%) of 52 subjects who 
received JNJ-54861911 and 12 (66.7%) of 18 subjects who received placebo experienced at least 
one adverse event. In Study 54861911ALZ1003, no notable differences in the incidence of 
adverse events were observed specific to the type of formulation or dosing under fed or fasted 
conditions. 
The most common adverse events across these three clinical studies in subjects receiving 
JNJ-54861911 were headache and back pain. Both events are typically associated with the 
lumbar puncture procedure. In subjects receiving placebo (Studies 54861911ALZ1001 and 
54861911ALZ1002), the most common adverse events were headache, abdominal pain, and 
contact dermatitis. There were no severe or serious adverse events observed in subjects receiving 
JNJ-54861911 across the 3 studies, and no adverse events led to discontinuation of study drug. 
Most adverse events were considered by the investigator as not related or doubtfully related to 
the study drug. There were no clinically significant treatment- or dose-related effects observed in 
clinical laboratory evaluations, neurologic and physical examination, and or vital signs.
A 6-month Phase 2a safety study with JNJ-54861911 (54861911ALZ2002) in subjects who have
early AD (predementia) was initiated in December 2014, and this study was followed by the 
present study (54861911ALZ2004). Both studies provide information on the safety of 
JNJ-54861911 in the target population. In study 54861911ALZ2002 the blood values of hepatic 
enzymes in some patients were increased, indicating potential for liver injury. Importantly, there 
were no symptoms clearly related to these elevations, and upon discontinuation of the drug, the 
liver enzyme values have decreased toward normal, and there were no lasting effects. The further 
investigation of this signal is continuing; to date (17 March 2017), more than 200 subjects have 
received JNJ-54861911 or placebo in studies longer than 1 month of treatment. Eleven subjects 
(9 on active drug, 1 on placebo, 1 blinded) have experienced an elevation in liver enzymes 
>3×upper limit of normal (ULN) in these studies. None of these subjects had symptoms related 
to these elevations in liver enzymes. One of these subjects, participating in Study 
54861911ALZ2003 (a Phase 2b/3 study investigating the efficacy and safety of JNJ-54861911 in 
subjects who are asymptomatic at risk for developing Alzheimer’s dementia), was the subject of 
a new safety report of drug-induced hepatotoxicity (based on biopsy results). The treatment 
assignment was unblinded and the subject was found to be on 25 mg JNJ-54861911. As this 
subject’s increase in ALT and AST were observed in Month 1, increased frequency of 
monitoring in the first 3 months of dosing has been introduced.
Based upon this case, the protocol is being modified to include more frequent monitoring of 
serum chemistry and hematology (indicated in the Time and Events Schedule and Section 9.1.4), 
guidelines for discontinuation of treatment due to abnormal liver enzymes (Section 3.4.1 and 
Section 10.2), and guidelines for evaluation and management of such cases (Attachment 1).
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
38
Approved, Date: 6 September 2017
1.2.
Overall Rationale for the Study
This Phase 2 study in subjects in the early AD spectrum is performed to investigate primarily the 
long term safety and tolerability of JNJ-54861911, beyond initial clinical trials.  Subjects in the 
early AD spectrum who have completed a Phase 1b or Phase 2 clinical study with JNJ-54861911 
will be provided the opportunity to participate in this study. The study will provide safety and 
tolerability data supporting long term treatment with JNJ-54861911, which will be placebo-
controlled initially for the first 12 months, but will then continue with active dose arms only 
thereafter. This study will continue to run until registration of JNJ-54861911 or until emerging 
safety issues arise as defined by the DRC that would warrant termination of the study. Due to its 
potentially long treatment duration, subjects enrolled in this study may be more likely to 
experience clinical benefit.
Risk-Benefit Evaluation of Study 54861911ALZ2004
To date (29 July 2016), 9 clinical studies have been completed. Overall, JNJ-54861911 has been 
safe and well tolerated in the completed clinical studies at various dose ranges (1-10 mg, 25-50 
mg, and 90-150 mg) in healthy young male and healthy elderly male and female subjects and at 
dosages of 5 to 50 mg in subjects in the early AD spectrum.
Subjects in the early (predementia) AD spectrum, aged 50 to 85 years inclusive, who will receive 
no direct therapeutic benefits from study participation, will be enrolled in this study. This is an 
extension of the parent study, 54861911ALZ2002 which was the second study with 
JNJ-54861911 
in 
this 
population, 
following 
an 
earlier 
proof-of-mechanism 
study 
(54861911ALZ1005).
The early (predementia) AD spectrum defined in this study includes subjects who are 
asymptomatic but at risk for AD (aged 65 to 85 years inclusive) as well as subjects with pAD 
(aged 50 to 85 years inclusive). Subjects who are classified as asymptomatic at risk for AD are 
cognitively and functionally normal as defined by the Clinical Dementia Rating Scale (CDR; 
CDR of 0), but have a biomarker pattern consistent with AD. Subjects with pAD have some 
limited cognitive impairment (CDR = 0.5), are still functionally normal and have a biomarker 
pattern consistent with AD, but as yet are not demented (predementia stage).
Potential subjects have been fully informed of the risks and requirements of the study. Only 
subjects who are fully able to understand the risks, benefits, and potential adverse events of the 
study, and provide their consent voluntarily will be enrolled.
As a result of the newly identified case of drug-induced  hepatotoxicity, the protocol has been 
modified to include more frequent monitoring of serum chemistry and hematology (see Time and 
Events Schedule and Section 9.1.4), guidelines for discontinuation of treatment due to abnormal 
liver enzymes (Sections 3.4.1 and 10.2), and guidelines for evaluation and management of such 
cases (Attachment 1).
Based on the preclinical data, 3 potential risks of JNJ-54861911 in humans have been identified: 
QT interval prolongation, epileptic seizures, and hypopigmentation or discoloration of fur.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
39
Approved, Date: 6 September 2017
A thorough QT trial, has been performed in 64 healthy subjects using a 4-way, 7-day cross-over 
design evaluating a JNJ-54861911 dose of 50 mg/day as well as supratherapeutic dose of 
150 mg/day, and including moxifloxacin 400 mg to confirm assay sensitivity. The 150-mg dose 
showed a prolongation of QTc interval, i.e., the maximum mean difference and 90% confidence 
intervals (CI) between JNJ-54861911 150 mg and placebo was 15.5 msec (12.92, 18.06) at 
Day 7, 1 hour and 30 min. The 50-mg dose showed a maximum mean difference from placebo of 
6.6 msec (90% CI: 4.02, 9.12) at Day 7, 1 hour. In both groups the observed changes were 
pronounced 1-4 hours after dosing. Results of the PK/PD modelling data from the 
54861911ALZ1007 study showed that at a JNJ-54861911 once daily dose of 25 mg, the median 
changes in the QTcF, as well as the 90% population interval, are expected to be well below 
5 msec.
Preclinical data also suggest a potential risk of epileptic seizures, based on a 1-month dog 
toxicology study, in which short-lasting convulsions and tremors were reported within 2 hours 
after dosing 100mg/kg/day. The NOAEL in that study was 10mg/kg/day. The highest dose in this 
clinical 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 8 times lower than the concentration 
that cause no convulsions in the dog (e.g. 10 mg/kg/day). In the 9-month study dog no CNS 
effects up to the highest dose, i.e. 60 mg/kg/day were observed, with exposures of Cmax
3.55 g/mL (♂) and 5.35 g/mL (♀). Compared to the plasma drug concentrations expected in 
human subjects dosed 25 mg/day these are approximately 16.9 to 25.5 fold lower than the 
concentration in the 9-month study that did not cause any CNS side effects.
Fur discoloration (progressive lightening from normal dark brown to paler cream or grey) was 
observed from Day 85 onwards in animals dosed at 100 mg/kg/day or higher in a 6-month mouse 
carcinogenicity study that was conducted at doses ranging from 30 to 600 mg/kg/day. This 
discoloration appeared partly reversible after a 3-month recovery period. Histopathological 
examination did not reveal any changes in skin or pigmented parts of the eye, neither were 
ophthalmologic changes seen. This finding is in line with BACE2-linked toxicity (e.g. melanin 
deposition changes and retinal abnormalities), that have been described in the literature (e.g. 
BACE1- or BACE2 knock-out mice). In this study, cases of hypopigmentation or lightening of 
the hair should result in dermatological consultation with digital photography of the lesions; if 
these are deemed adverse events, they should be reported to the sponsor in an expedited manner.
Strong CYP3A4 inhibitors may have a modest effect on plasma concentrations of JNJ-54861911.
Based upon 2 studies (54861911ALZ1009 and 54861911ALZ1010), it is recommended that 
drugs that are moderate to strong inhibitors of CYP3A4 should be taken with care, under the 
assumption that a moderate increase of JNJ-54861911 could be seen. Additional to the potential 
compound-related risks, there are study procedure related risks. Most of these are standard 
clinical assessments with limited risk associated for the subject (e.g. blood draw, ECG, MRI and 
PET).
To reduce the maximum possible theoretical risks associated with lumbar punctures including 
cerebral herniation (due to pre-existing intracranial hypertension) and spinal epidural hematoma 
with compression of the cauda equina, additional eligibility criteria and other preventive action 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
40
Approved, Date: 6 September 2017
are put in place. Medical conditions contraindicating a lumbar puncture will be excluded. To 
reduce the risk of post-dural puncture headache (PDPH) caused by persistent CSF leakage, 
subjects are preferably placed on bed, rest in a supine position during sampling. To avoid the 
introduction of an infection into the CSF (which is a rare complication), lumbar puncture is 
performed under sterile conditions. Prior to the puncture, all subjects will be examined 
thoroughly for (possible) topical infections or local dermatological condition at the puncture site, 
of which their presence will lead to exclusion of the subject. All CSF collections will be 
performed under aseptic conditions. Irritation of nerve roots, possibly caused upon insertion of 
the needle is usually benign and self-limiting. The CSF puncture sites (L3-L4 or L4-L5) will 
prevent spinal cord trauma. Only experienced and qualified physicians are allowed to perform 
the applicable procedures. Coagulation tests at screening and an eye exam with fundoscopy are 
performed at screening to exclude intracranial hypertension.
The total blood volume to be collected will not exceed 450 mL annually, which is considered to 
be safe and acceptable in comparison to a Red Cross blood donation.
A placebo arm is necessary to allow for an accurate assessment of the safety and tolerability of 
the study drug; the use of placebo over the 6 month treatment period in the parent study, 
54861911ALZ2002, and in the first 12 months of this study, extends this assessment into the 
longer term. Since there is, at this moment, no treatment available for subjects at risk for AD or 
subjects in the earliest AD spectrum, the use of placebo is warranted. Throughout the course of 
the study, the Sponsor will have the option based on recommendations by the Data Review 
Committee, or based upon newly emerging safety, biomarker or efficacy data from ongoing or 
completed JNJ-54861911 studies, to revise the dose levels in this study.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
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.
Secondary Objectives
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 CSF and plasma.

To assess the relationship of changes in CSF and plasma Aβ 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.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
41
Approved, Date: 6 September 2017

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.
Exploratory Objectives
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.
2.2.
Hypothesis
This is a study to collect primarily long-term safety and tolerability data. There is no formal 
hypothesis testing planned for this long-term study which is an extension of 54861911ALZ2002 
study.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, two-period, double-blind (DB) placebo controlled and open-label (OL), 
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 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 study, the study will consist of a screening phase and 2 sequential
treatment phases, i.e., a 12-month double-blind (DB) treatment phase (placebo-controlled) and
an open-label (OL) phase (active), followed by an End-of-Treatment visit. Treatment in OL 
phase 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 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.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
42
Approved, Date: 6 September 2017
Subjects who provide consent to enroll in this protocol and who meet the inclusion criteria, may 
start at Day 1 of the DB treatment phase in lieu of the end of treatment visit in 
54861911ALZ2002 study. For subjects that have completed the end of treatment visit in the 
54861911ALZ2002 study enrollment in this study should be completed (Day 1 of DB treatment 
phase) as soon as possible, but within 6 weeks, following completion of their treatment period 
under the parent protocol (54861911ALZ202 study) of currently ongoing or any future Phase 1b 
or Phase 2 studies with JNJ-54861911. A screening phase of up to 12 weeks may be allowed 
following written approval of the Sponsor.
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 in study 54861911ALZ2002 or any future Phase 1b or Phase 2 JNJ-
54861911 clinical studies. 
Eligible subjects enrolled in this study will receive either JNJ-54861911 (10 mg 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) (placebo-controlled DB treatment phase). Subjects who have received 
an active dose different from 10-mg or 25-mg JNJ-54861911 in 54861911ALZ2002 study will 
be receiving the closest dose available in DB treatment phase (10-mg or 25-mg JNJ-54861911; 
e.g., subjects receiving 50 mg in study 54861911ALZ2002 will be assigned to 25 mg 
JNJ-54861911).
Following the initial 52-Week (12-Month) treatment phase (DB treatment phase) in this study, 
subjects receiving placebo in the DB treatment phase will be randomized with equal chance to 
one of 2 active JNJ-54861911 dose levels (i.e., 5-mg q.d JNJ-54861911 or 25-mg q.d. 
JNJ-54861911) for continuous treatment in OL phase. As such during OL phase, 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 (DB and OL treatment phases),  primarily safety and tolerability 
will be monitored at regular intervals (e.g., MRI, physical and neurological examination, 
suicidality risk assessment, vital signs, 12-lead ECG, safety labs, dermatologic and 
ophthalmologic examinations). Pharmacokinetics (CSF and plasma), and 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 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
43
Approved, Date: 6 September 2017
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.
A number of sites will be given the opportunity to use the eMeds smart technologies to manage 
clinical trials supplies and drug compliance activities. This will be done following subject 
informed consent.
The Time and Events Schedule provides an overview on the visit frequency and assessments to 
be performed for each treatment period (DB and OL treatment phases).
Any serious adverse event or adverse event of special interest (AESI) 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.
3.2.
Study Design Rationale
Blinding, Control, Study Phase/Periods, Treatment Groups and Treatment Duration
Subjects enrolled in this study will participate in 2 sequential treatment phases/periods:

DB treatment phase: a 52-Week (12-Month) placebo-controlled double-blind treatment 
phase. Eligible subjects enrolled 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
54861911ALZ2002 study (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 
in 
54861911ALZ2002 study will be receiving the closest dose available in the DB treatment 
phase (i.e. subjects receiving 50 mg in study 54861911ALZ2002 will be assigned to 25 mg 
JNJ-54861911).

OL treatment phase:  an open-label treatment phase during which subjects who received 
placebo in DB treatment phase will be randomized with equal chance to one of two 
JNJ-54861911 dose levels (5-mg q.d. or 25-mg q.d. JNJ-54861911). Subjects who were 
receiving 10 mg q.d. JNJ-54861911 will have their dose reduced to 5 mg q.d., while subjects 
who were receiving 25 mg q.d. will continue to receive that dosage.
A treatment duration of 52 weeks in the DB treatment phase combined with the duration of 
treatment under the parent protocols is deemed sufficient to assess any emergent safety aspects 
(treatment induced effects) of JNJ-54861911 in relation to placebo treatment as outlined below 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
44
Approved, Date: 6 September 2017
(‘Safety Evaluations’). A placebo control of 52 weeks in this study is considered to be acceptable 
as efficacy of JNJ-54861911 has not yet been demonstrated, no treatment is available yet and 
subjects can continue on normal standard care (symptomatic treatment) as outlined in Section 8. 
Prestudy and Concomitant Therapy. 
A placebo control will be used in the DB treatment phase (Day 1 to Week 52 [Month 12]; 
placebo-controlled) to explore the frequency and magnitude of changes in clinical endpoints that 
may occur in the absence of active treatment during the first year of treatment in this study. It is 
yet unclear in which time frame potential adverse event patterns may arise. It may be difficult to 
separate them from actual aging or AD-related patterns (e.g., cognitive decline, MRI 
microhemorrhages, amyloid related imaging abnormalities-edema or effusion [ARIA-E]). To 
control for these factors a placebo group is warranted over a limited time. 
Upon completion of the DB treatment phase, subjects receiving placebo will be randomized in to 
active treatment in the OL treatment phase. Randomization will be used to minimize bias in the 
assignment of previously treated placebo subjects to treatment groups and to increase the 
likelihood that known and unknown subject attributes (e.g., demographic and baseline 
characteristics) are evenly balanced across treatment groups. Blinded treatment in the DB 
treatment phase will be used to reduce potential bias during data collection and evaluation of 
clinical endpoints as well as adverse events.
For subjects enrolled in this study, each subject will continue study treatment (in the OL 
treatment phase):

until registration of JNJ-54861911

until emerging safety issues arise as determined by the DRC that would warrant termination 
of the study

until subject withdraws consent or other reasons for withdrawal as defined in Section 10.3.
Population
The population included in this study will be subjects in the early AD spectrum, enrolled in 
ongoing or future clinical trials with JNJ-54861911 (Phase 1b or Phase 2 studies) who completed 
their treatment period as defined under the parent protocol (54861911ALZ2002 study). If not 
defined in 54861911ALZ2002 study, completion of the treatment period is defined as having 
completed all study related procedures of the last visit of the treatment period in 
54861911ALZ2002 study. 
The early AD spectrum defined at time of enrollment in 54861911ALZ2002 study includes 
1) subjects who are classified as asymptomatic at risk for Alzheimer’s dementia who are 
cognitively and functionally normal (CDR = 0), but have a biomarker pattern consistent with 
early stage AD (preclinical stage); and 2) subjects with pAD who have some limited cognitive 
impairment (CDR = 0.5), are still functionally normal, and have a biomarker pattern consistent 
with early stage (predementia) AD, but have as yet no dementia (predementia stage). Subjects 
that have progressed to dementia in 54861911ALZ2002 study (CDR 1) or who are incapable of 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
45
Approved, Date: 6 September 2017
providing informed consent will not be enrolled. In case the subject progresses to a dementia 
state during the study, the subject may remain in the study, provided that the investigator judges 
that the potential benefits of treatment for this subject clearly outweigh the known and 
foreseeable risks and assent or consent (as applicable) for continued participation is obtained 
from a representative determined in accordance with the local law. In cases where a subject has 
progressed to dementia, treatments indicated for this condition (e.g., memantine or cholinesterase 
inhibitors) are permitted after notification of the sponsor.  
Rationale for Dose Selection
The optimal level of therapeutic Aβ reduction is not known and cannot be assumed from
preclinical models or early phase clinical studies, as the proposed effect on the disease pathology
is expected to require chronic treatment. Results from Phase 1 studies with JNJ-54861911 have
confirmed observations in transgenic animal models in showing that this compound results in
profound reductions in brain Aβ levels. As described in Section 1.1, data from completed SAD
and MAD studies in healthy older subjects and from the preliminary analyses of the proof of
mechanism study in a population with early AD spectrum showed dose-dependent reductions in
Aβ1-40 in plasma and CSF following oral JNJ-54861911 administration. As shown in Figure 5
below, preliminary data from the proof of mechanism study showed that the median reduction in
CSF Aβ1-40 with a 25 mg/day dose (84%) was only minimally increased (i.e., by ~ 6% to 91%) 
with a doubling of the dose to 50 mg/day. At a dose of 10 mg/day, the median reduction in CSF 
Aβ1-40 is about 67%, and at the lower dose of 5 mg/day, the median reduction is about 52%.
Figure 5:
Modelling of CSF A1-40 Reduction in Subjects in the Early Alzheimer's Disease Spectrum 
(preliminary data from study 54861911ALZ1005; Abbreviations CSF, cerebrospinal fluid)
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
46
Approved, Date: 6 September 2017
As noted in Section 1.1, PK/PD modeling based on a thorough QT trial, 54861911ALZ1007, 
showed that at a JNJ-54861911 dose of 25 mg q.d., the median changes in the QTcF, as well as 
the 90% population interval, are expected to be well below 5 msec.
During the course of the study, the Sponsor will, however, have the option based on 
recommendations by the DRC or based upon newly emerging safety, biomarker or efficacy data 
from ongoing or completed JNJ-54861911 studies, to revise the dose levels for OL treatment 
phase to:

Maintain the 2 selected active dose levels (equal randomization of the placebo treated 
subjects)

Adjust the dose level for one or both of the selected active doses

Drop one active dose level (subjects allocated in OL treatment phase to the dose level 
dropped will be reassigned in OL treatment phase to the remaining active dose level)

Assign all placebo subjects to a single active dose level
In the current study, subjects will be asked to take JNJ-54861911 with breakfast preferably or 
after a light snack, but no significant impact of food on drug exposure is expected. Considering 
that the target population in this study is an elderly age group, rationale to conduct this study 
under fed condition is mainly from the perspective of convenience to the study subjects.
Safety Evaluations
The primary objective of this study is to assess the long-term safety and tolerability of 
JNJ-54861911 in subjects in the Early AD spectrum. As such, regular safety assessments will be 
performed as listed in the Time and Events Schedule. These safety assessments include but are 
not limited to: vital signs, ECG, physical and neurological examination, adverse events, safety 
labs, suicidality risks (Columbia Suicide Severity Rating Scale [C-SSRS]), dermatologic and 
ophthalmologic examinations, and MRI. A more detailed description on the safety assessments 
applied is provided in Section 9.2, Safety Evaluations. The DRC may decide to reduce, drop or 
even increase frequency over time of specific safety assessments if (newly obtained) data 
collected in this study or from ongoing or future studies would support this decision.
Specific dermatologic and ophthalmologic examinations, as described in Section 9.2, Safety 
Evaluations have been implemented in this study as potential BACE1- or BACE2-linked 
toxicities (e.g. melanin deposition changes and retinal abnormalities) have been described in the 
literature (e.g. BACE1 or BACE2 knock-out mice). With the exception of fur discoloration
resulting in progressive lightening of the fur from normal dark brown to paler cream or grey, 
which was seen in one species only (Tg mice in the 6 month carcinogenicity study), however, 
these toxicities have not been observed in nonclinical chronic studies with JNJ-54861911. Note 
that cases of lightening of skin, lightening of hair or ophthalmological adverse events are 
considered adverse events of special interest (AESI) and are subject to reporting timelines as 
described in Section 12.3.4.  
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
47
Approved, Date: 6 September 2017
As a result of the newly identified case of drug-induced hepatotoxicity, if at any time during 
treatment a subject has an ALT or AST result that is ≥3× ULN, the test should be repeated within 
24 - 72 hours and, if confirmed, the further evaluation and management procedures described in 
Attachment 1 should be followed.
In addition to the (safety) MRI assessments performed under the 54861911ALZ2002 study
(if applicable), safety MRIs will be collected in this study during both DB and OL treatment 
periods, as indicated in the Time and Events Schedule, to monitor any treatment-emergent 
abnormalities including ARIA-edema or effusion (E) and ARIA-hemosiderin (H). Additional 
annual MRIs will be collected in OL period. If any safety related changes are observed 
(e.g. ARIA-E), additional safety MRIs may be collected at a frequency recommended by the 
DRC.
In case of any changes observed in any of the safety measures performed that are considered not 
clinically significant or do not have a direct clinical symptomatology as assessed by the 
investigator, they should be closely monitored, with a potential increased safety monitoring 
frequency as deemed appropriate by the investigator. In addition, these findings will be presented 
to the DRC, who will make recommendations regarding the safety and continuation of the study
as per its charter.
Biomarker Collection
Fluid (CSF and plasma) and imaging (MRI) biomarker assessments will be performed to assess 
the potential and continuous effects of JNJ-54861911 on the pathological and pathophysiological 
processes of AD. In addition, these biomarker assessments are performed to assess if potential 
treatment effects of JNJ-54861911 are consistent with the putative effects of BACE inhibition.
During the course of the study the continuous effects of JNJ-54861911 on the pathophysiological 
processes of AD will be monitored by the DRC. 
Reduction in CSF Aover time will confirm the continuous activity of JNJ-54861911 based on 
its mechanism of action. It will allow the confirmation that a continuous reduction in CSF Ais 
feasible over the entire treatment duration that may lead to a potential therapeutic effect. The 
primary CSF biomarker read out to confirm engagement of JNJ-54861911 at the intended target 
site is CSF Aβ1-40.
In addition to the hallmark pathological feature of brain amyloidosis, AD is also characterized by 
the downstream neuropathological feature of NFTs consisting mainly of hyperphosphorylated 
tau proteins, with properties that enable fibril formation. The work of Braak5 and others have 
shown the progressive increase of brain tau in disease using postmortem immunohistochemical 
methods. In addition, neurofibrillary (tau) tangles are linked to the duration and severity of AD.33
Tau PET imaging is an exploratory in vivo method to measure brain tau burden and can track 
accumulation. Early results with [18F]-T807 PET suggest that the signal intensity and spread is 
linked to the severity of the cognitive impairment9, which parallels earlier pathology based 
observations by Braak, Hyman and others. Further, as the neurons die, the tau fragments are 
released into the extracellular space and appear to be elevated in AD patient’s CSF.3,4 CSF t-tau
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
48
Approved, Date: 6 September 2017
and p-tau are suggested to reflect different aspects of brain damage; t-tau reflects acute/chronic 
neuronal damage, while p-tau reflects tau phosphorylation and tangle formation.30,49
Hyperphosphorylated epitopes of tau (high p-tau) in the CSF are rather specific to AD and, high 
p-tau is well correlated with high t-tau in subjects with AD.35 It can therefore be concluded that 
tau protein in CSF (t-tau and p-tau) is an indicator of neuronal degeneration, but an increase in p-
tau is more specific in AD and less prevalent in other neurodegenerative diseases.
Tau proteins are normally associated with tubulin polymers to stabilize the microtubule system 
essential for normal neuronal function.43 However, tau is abnormally phosphorylated in AD and 
is the main component in paired helical filaments (PHFs), which then associate laterally to form 
NFTs in the cytoplasm of many neurons.10,11,12,23,24 These tangles initially form intra-neuronally 
and as the neurons die, the tau tangles are released into the extracellular space and appear to be 
elevated in AD patient’s CSF.26 Together with low Aβ1-42, high p-tau in CSF can help 
differentiate between AD patients and healthy elderly and is the best predictive marker for 
progression of mild cognitive impairment (MCI) subjects into AD.4,6,18,19,20,27,28,44 The increase in 
hyperphosphorylated tau in CSF is relatively specific to AD and therefore separates AD from 
other neurodegenerative disorders.25  As change in CSF p-tau levels is a marker for 
neurodegeneration, they are believed to be predictive of changes in cognition over time.
Volumetric MRI has been used extensively to measure atrophy rates in treatment trials of AD as 
the relationship between atrophic changes and neuron loss is well established and correlates well 
with clinical measures.36,45,52,54,55,58,63,64,65
All subjects will receive MRIs at the time point 
indicated in the Time and Events 
Schedule to assess safety (monitor for ARIA-E and ARIA-
H).  The sequences included are described in a separate MRI imaging manual, but will also 
include a volumetric sequence besides the sequences for safety assessments. The global and 
regional brain volumes obtained from the volumetric MRI sequence will be reported.
Cognition and Functional Outcome Measures
Cognitive evaluations (RBANS, MMSE and CVLT-II) and functional outcome measures 
(Cognitive Function Index [CFI]) will be applied in this study at different time points as 
indicated in the Time and Events Schedule
to explore the subject’s cognitive 
performance/progression and function over time. A description of these tests is provided in 
Section 9.4, Cognition, Function and Clinical Status. The selected tests are included to test for 
signs of cognitive and functional decline. The cognitive measures used in this study are aligned 
to the measures applied in our Phase 1b (e.g., 54861911ALZ1005) and Phase 2 (e.g., 
54861911ALZ2002) studies.
The progression of cognitive deficits is the most prominent early marker of AD, but different 
cognitive domains have been demonstrated to progress at a different speed.57 The RBANS was 
selected as a cognitive measure to assess cognitive decline as it is a widely used measure to 
differentiate healthy normal subjects from those with early disease and AD patients, is predictive 
of functional status, correlates with the CDR31, biomarkers22,62 and cognition17 in this early 
population.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
49
Approved, Date: 6 September 2017
The MMSE is a brief, validated 30-point questionnaire that is widely used to screen for cognitive 
impairment.21 The lower the score the more pronounced the impairment. The MMSE will be 
used in this study to cross compare with other JNJ-54861911 trials.
The CVLT-II is a face-to-face comprehensive neuropsychological measure of verbal memory in 
individuals 16 to 89 years old, designed to quantify components of verbal learning, retention and 
retrieval.13 This test will be administered only to subjects who had completed it in the parent 
protocol.
The CFI is an instrument to track early changes in abilities to perform high-level activities of 
daily living and the subjects’ perception of their own ability to perform cognitively demanding 
functional tasks. 
The RBANS, MMSE, CVLT-II and CFI are described in more detail in Section 9.4.
Clinical Scales
The CDR is a global clinical scale with established diagnostic and severity-ranking utility widely 
used in clinical trials yielding global and Sum of Boxes (SB) scores. The CDR global score is 
used in AD trials as a global measure of disease progression. The CDR is well-established in 
MCI and AD studies.
The CDR is described in more detail in Section 9.4.2.
3.3.
Interim Analysis of Data
No prespecified interim analysis of unblinded data during the DB treatment phase is planned by 
the clinical team. However, depending on the recruitment, or in support of regulatory filings for 
upcoming studies, or for any other reason the Sponsor deems necessary, an unblinded review of 
safety and biomarker data prior to the last subject’s completion of the DB treatment phase might 
be conducted by an internal Interim Analysis Committee. If any such review is conducted it will 
be documented in an Interim Analysis Committee charter prior to the unblinding. The 
constitution of the Interim analysis committee will be documented in the Interim Analysis 
Committee charter and may include Sponsor study team members.
As noted in Section 5, when the parent study (eg, 54861911ALZ2002 and potential future 
Phase 1b and 2 studies) is completed and its clinical database is closed, the randomization codes 
from the parent study will be released to the sponsor study team. Thus, the sponsor will be 
unblinded at that time, but the investigator and subjects will continue to be blinded to treatment 
during the DB treatment phase, until the last subject has completed that phase, and the database 
from that phase has been reviewed, corrected as necessary, and locked. At that point, the sponsor 
will perform analyses of key safety, biomarker, and efficacy variables, as detailed in a 
prespecified statistical analysis plan.
Following the sponsor’s review of these analyses, information on an individual subject’s 
treatment allocation during the DB phase will be made available upon request by the 
investigator. As subjects that remain in the study will all be receiving open label JNJ-54861911 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
50
Approved, Date: 6 September 2017
at that time, and as no change or alteration of the locked database from the DB phase will be 
possible, there should be no bias introduced by this measure. 
3.4.
Stopping Criteria
3.4.1.
Individual Criteria for Stopping Study Treatment
In this Phase 2 study the following specific individual rules for stopping study treatment will 
apply (see Section 10.2 for details): 

A subject has a mean QTcF interval of >500 msec if confirmed upon repeat ECG, and/or 
mean QTcF increase versus baseline of >60 msec if confirmed upon repeat ECG, after 
consultation with the sponsor’s medical monitor (all based on triplicate recordings).

The investigator believes that for safety reasons (e.g., adverse event) it is in the best interest 
of the subject.

Between Weeks 52 and 64, treatment must be discontinued if any of the following occurs:

ALT or AST >5× ULN

ALT or AST >3× ULN and total bilirubin >2× ULN or international normalized ratio 
(INR) >1.5

ALT or AST >3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia >5%

After Week 64, treatment must be discontinued if any of the following occurs:

ALT or AST >8× ULN

ALT or AST >5× ULN for more than 2 weeks

ALT or AST >3× ULN and total bilirubin >2× ULN or INR >1.5

ALT or AST >3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia >5%

A subject who meets any of the withdrawal criteria described in Section 10.3.
Events of elevated liver enzymes or increased QTc that require subjects to discontinue will be 
considered as serious and will be reported to Sponsor within 24 hours of the knowledge of the 
event.
3.4.2.
Protocol Stopping Criteria
A DRC will be established to monitor data on an ongoing basis to ensure the continuing safety of 
the subjects enrolled in this study (see Section 11.7, Data Review Committee). The committee 
will meet periodically to review interim data. After the review, the DRC will make 
recommendations regarding the safety and continuation of the study. The details will be provided 
in a separate DRC charter.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
51
Approved, Date: 6 September 2017
4.
SUBJECT POPULATION
Subjects in the early AD spectrum, i.e., subjects asymptomatic at risk for Alzheimer’s dementia 
and prodromal AD subjects at time of enrollment under the parent protocol, who have completed 
a Phase 1b or Phase 2 clinical study with JNJ-54861911 will be provided the opportunity to 
participate in this study. Subjects that have progressed to dementia in the parent protocol 
(CDR 1) or who are incapable of providing informed consent will not be enrolled.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate sponsor representative before enrolling a subject 
in the study. In case the subject progresses to a dementia state during the study, the subject may 
remain in the study, provided that the investigator judges that the potential benefits of treatment 
for this subject clearly outweigh the known and foreseeable risks and assent or consent (as 
applicable) for continued participation is obtained from a representative determined in 
accordance with the local law. In cases where a subject has progressed to dementia, treatments 
indicated for this condition (e.g., memantine or cholinesterase inhibitors) are permitted after 
notification of the sponsor.
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
Criterion modified per amendment.
1.1
Subjects in the early AD spectrum at time of enrollment meeting all pertinent inclusion 
and exclusion criteria of the parent protocol, must have very recently completed their 
treatment
in a
Phase
1b or Phase
2 JNJ-54861911
clinical study (e.g.,
54861911ALZ2002) under the parent protocol. Enrollment in this study should be 
completed (Day 1 of DB treatment phase) as soon as possible, but within 6 weeks,
following completion of their treatment period under the parent protocol. If not defined 
under the parent protocol, completion of the treatment period is defined as having 
completed all study related procedures of the last visit of the treatment period under the 
parent protocol. A screening phase of up to 12 weeks may be allowed following written 
approval of the Sponsor.
2.
Subject must be willing and able to adhere to the prohibitions and restrictions specified 
in this protocol.
3.
Criterion modified per amendment.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
52
Approved, Date: 6 September 2017
3.1
Each subject must sign an informed consent form (ICF) indicating that he or she 
understands the purpose of and procedures required for the study and are willing to 
participate in the study.
4.
Subjects must have a reliable informant (relative, partner, or friend). The informant 
must be willing to participate as a source of information and has at least weekly contact 
with the subject (contact can be in-person, via telephone or other audio/visual
communication). The informant must have sufficient contact such that the investigator 
feels he/she can provide meaningful information about the subject’s daily function. If 
possible, an alternate informant meeting these criteria who can replace the primary 
informant should be identified prior to randomization.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1.
Any condition or situation which, in the opinion of the investigator, may put the subject 
at significant risk, may confound the study results, or may interfere significantly with 
subject’s participation in the study.
2.
The use of concomitant medications known to prolong the QT/QTc interval.
3.
Subject has a history of moderate or severe hepatic impairment or severe renal 
insufficiency unless completely resolved for more than a year. Subject has clinically 
significant ongoing hepatic, renal, cardiac, vascular, pulmonary, gastrointestinal, 
endocrine, hematologic, rheumatologic, psychiatric, or metabolic conditions (eg, 
requiring frequent monitoring or medication adjustments, or is otherwise unstable).
NOTE: Section 17.4, Source Documentation, describes the required documentation to support 
meeting the enrollment criteria.
4.3.
Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
Avoid donating blood for at least 90 days after completion (i.e., final dose 
administration) of the study.
2.
A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy is advised to use a barrier method of birth control e.g., either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
53
Approved, Date: 6 September 2017
3.
All men must also agree not to donate sperm during the study and for 3 months after 
receiving the last dose of study drug.
4.
For any prohibitions or restrictions related to concomitant medication see also Section 8. 
Prestudy and Concomitant Therapy.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Subjects enrolled in this study will participate in 2 sequential treatment periods i.e. 

DB treatment phase: a 52-Week (12-Month) placebo-controlled, double-blind, treatment 
period; and

OL treatment phase: a (partially) randomized open-label treatment period (until registration)
During the DB treatment phase, subjects will receive either JNJ-54861911 (10-mg or 25-mg q.d.) 
based on their current treatment/dosing regimen assigned under the parent protocol 
(54861911ALZ2002 or any future studies) as described in Section 6, Dosage and Administration. 
In the OL phase, subjects who received placebo in the DB treatment period will be automatically 
randomized to active treatment (JNJ-54861911 5-mg or 25-mg q.d.) as described in Section 6, 
Dosage and Administration. Subjects who were receiving 10 mg q.d. JNJ-54861911 in DB 
treatment phase will have their dose reduced to 5 mg q.d., while subjects who were receiving 25 
mg q.d. will continue to receive that dosage.
Procedures for Randomization
Subjects who received placebo during the DB treatment phase will be randomly assigned with 
equal chance to one of two treatment groups in the OL phase based on a computer-generated 
randomization schedule prepared before the study by or under the supervision of the sponsor.
The randomization will be balanced using permuted blocks across the 2 treatment groups.
For both DB and OL treatment phases, an interactive web response system (IWRS) will be 
utilized to assign the blinded study drug kits in this study. For DB treatment phase study drug 
kits will be assigned based on their treatment allocation in 54861911ALZ2002 study; for non-
placebo subjects in OL phase, subjects who were receiving 10 mg q.d. JNJ-54861911 in DB 
treatment phase will have their dose reduced to 5 mg q.d., while subjects who were receiving 
25 mg q.d. will continue to receive that dosage.
The blister packs and kit assignment will be managed by the IWRS for both the blinded and 
unblinded phase of the study.
Since the investigator will be blinded to treatment assignment in the DB treatment phase, the 
IWRS will automatically determine the appropriate medication kits to assign. Subjects who were 
receiving 10 mg q.d. JNJ-54861911 in the DB treatment phase will have their dose reduced to 
5 mg q.d. in the OL phase, while subjects who were receiving 25 mg q.d. will continue to receive 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
54
Approved, Date: 6 September 2017
that dosage. Subjects receiving placebo in the DB treatment phase will be randomized with equal 
chance to either 5 mg q.d or to 25 mg q.d. Neither the randomization number nor the fact that a 
subject was randomized for OL phase will be known to the investigator, thus allowing the blind 
to be maintained while DB treatment phase is still ongoing.  
The total number of subjects on placebo to be randomized to active treatment in this study will 
be determined by the number of subjects enrolling who previously were allocated to placebo in 
54861911ALZ2002 study.
Central randomization will be implemented in conducting OL phase of this study for subjects 
previously receiving placebo. Central randomization minimizes the imbalance in the distribution 
of the number of subjects across treatment. Based on the algorithm, the IWRS will assign a 
unique treatment code, which will dictate the treatment assignment and matching study drug kit 
for the subject.
Central randomization will be used to avoid bias in the assignment of subjects to treatment, to 
increase the likelihood that known and unknown subject attributes (e.g., demographics and 
baseline characteristics) are evenly balanced across treatment groups.
During the DB treatment phase (placebo-controlled), both the investigator and the subject will be 
blinded to reduce subjective influences on safety and tolerability data. 
Blinding
The investigator will not be provided with randomization codes for the parent protocol
(54861911ALZ2002 study) or the randomization numbers for this study until all subjects of the 
parent protocol have completed DB treatment phase and subsequent database lock or freeze has 
occurred. The codes will be maintained within the IWRS, which has the functionality to allow 
the investigator to break the blind for an individual subject.
Under normal circumstances, the blind should not be broken by the investigator until all subjects
from the 54861911ALZ2002 study enrolled in this study have completed DB treatment phase of 
the study and the DB treatment phase database for those subjects is finalized. 
Otherwise, the blind should be broken by the investigator only if specific emergency 
treatment/course of action would be dictated by knowing the treatment status of the subject. In 
such cases, the investigator may, in an emergency, determine the identity of the treatment by 
contacting the IWRS. It is recommended that the investigator contact the sponsor or its designee 
if possible to discuss the particular situation, before breaking the blind. Telephone contact with 
the sponsor or its designee will be available 24 hours per day, 7 days per week. In the event the 
blind is broken, the sponsor must be informed as soon as possible. The date, time, and reason for 
the unblinding must be documented by the IWRS, in the appropriate section of the case report 
form (CRF), and in the source document. The documentation received from the IWRS indicating 
the code break must be retained with the subject's source documents in a secure manner.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
55
Approved, Date: 6 September 2017
Subjects who have had their treatment assignment unblinded are not required to return for 
scheduled evaluations except for the End-of-Treatment visit (Follow-up visit).
When the parent study (e.g. 54861911ALZ2002 and potential future Phase 1b and 2 studies) is
completed and its clinical database is closed, the randomization codes from the parent study will 
be released to the sponsor study team. Thus the sponsor will be unblinded at that time, but the 
investigator and subjects will continue to be blinded to treatment during the DB treatment phase.  
6.
DOSAGE AND ADMINISTRATION
Study medication will be provided as JNJ-54861911 tablets, strengths 5-mg, 25-mg and 
matching placebo. Study medication will be blister packed. All tablets (JNJ-54861911/placebo) 
are physically identical. 
A study-site investigational product manual including instructions for dispensing, storage (on site 
and at home) and intake of the study medication will be supplied to the study-site. 
Study-site personnel will instruct subjects on how to store study drug for at-home use as 
indicated for this protocol.
Eligible subjects enrolled in this study will participate in 2 sequential treatment periods:

Double-blind treatment phase: a 52-week (12 Months) placebo-controlled, double-blind 
treatment phase. Eligible subjects enrolled 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 the DB treatment phase (i.e. subjects 
receiving 50 mg in study 54861911ALZ2002 will be assigned to 25 mg JNJ-54861911).

Open-label phase: an open-label treatment phase during which subjects who received 
placebo in the DB treatment phase will be randomized to one of two JNJ-54861911 dose 
levels:

5-mg q.d. JNJ-54861911; or

25-mg q.d. JNJ-54861911
Randomization (for placebo subjects) to OL phase and dispensing of study medication for OL 
phase will only be performed following completion of all Week 52 assessments. 
During the DB treatment phase, study drug kits will be assigned based on their treatment 
allocation under the parent protocol; for nonplacebo subjects in the OL phase, subjects who were 
receiving 10 mg q.d. JNJ-54861911 in the DB treatment phase will have their dose reduced to 5 
mg q.d., while subjects who were receiving 25 mg q.d. will continue to receive that dosage.
During the course of the study, the Sponsor will have the option based on recommendations by 
the DRC or based upon newly emerging safety, biomarker or efficacy data from ongoing or 
completed JNJ-54861911 studies, to revise the dose levels for OL phase to:
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
56
Approved, Date: 6 September 2017

Maintain the 2 selected active dose levels (equal randomization of the placebo treated 
subjects)

Adjust the dose level for one or both of the selected active doses

Drop one active dose level (subjects allocated in the OL phase to the dose level dropped will 
be reassigned in the OL phase to the remaining active dose level)

Assign all placebo subjects to a single active dose level
During the treatment phases of this study dispensing and redispensing of their study medication 
will take place at the visits indicated in the Time and Events Schedule. On Days of re-dispensing 
subjects will hand in their medication package dispensed previously and drug accountability will 
be performed.
Following last dosing, subjects will hand in their study medication received previously and final 
drug accountability will be performed.
During the study (DB and OL treatment phases) subjects will self-administer 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. 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.
7.
TREATMENT COMPLIANCE
The investigator or designated study-site personnel will maintain a log of all study drug 
dispensed and returned. Drug supplies for each subject will be inventoried and accounted for 
throughout the study. 
Study drug will be self-administered by subjects. As such the number of study drug dispensed 
will be recorded and compared with the number returned.
At study visits, study drug will be self-administered on site, which will be witnessed by 
designated study-site personnel at the study sites.
Subjects will receive instructions on compliance with study drug administration upon study 
medication (blisters) dispensed. During the course of the study, the investigator or designated 
study-site personnel will be responsible for providing additional instruction to re-educate any 
subject who is not compliant with taking the study drug.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
57
Approved, Date: 6 September 2017
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 case support cannot be provided
subjects should be discontinued from treatment and withdrawn from the study.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy therapies administered up to 30 days before screening must be recorded at screening. 
Concomitant therapies must be recorded throughout the study beginning with signing of the 
initial informed consent until the End-of-Treatment visit (Follow-up visit). Concomitant 
therapies should also be recorded beyond this time only in conjunction with new or worsening 
adverse events until resolution of the event. 
Progression of symptoms associated with AD should be recorded in the eCRF and any 
symptomatic treatment therefore will be documented until the End-of-Treatment visit (Follow up 
visit).
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; nonpharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study drug must be recorded in the CRF. 
Modification of an effective pre-existing therapy should not be made for the explicit purpose of 
entering a subject into the study.
Treatment with cognitive enhancers (e.g., cholinesterase inhibitors) or drugs intended for the 
treatment of cognitive deficits prior to enrollment in the extension study is allowed. 
New therapies or therapy adaptations that are expected to have an impact on cognitive 
performance (e.g., cholinesterase inhibitors or memantine), will be permitted if clinically 
indicated, after notification of the Sponsor. Before a subject starts, stops or changes a dose of a 
therapy expected to have an impact on cognition, the Sponsor’s medical monitor must be 
contacted in part to determine if specific clinical measures (e.g., cognitive measures) should be 
performed prior to the modification of concomitant medication regimen.  
Use of benzodiazepines for treatment on an as-needed basis for insomnia or daily dosing as 
anxiolytics is permitted.  If they are being given chronically, use of sedatives or hypnotics should 
be avoided for 24 hours before administration of cognitive tests.  If sedating medication is given 
for MRI at any visit or for any short-term use, then all cognitive assessments must be 
administered at least 4 half-lives hours after administration of the sedative.
Stable use of pain medications will be permitted.  Short-term use of narcotics is allowable if not 
administered within 4 half-lives hours prior to cognitive assessments.
Other concomitant medications that affect central nervous system (CNS) function may be given 
if efforts are made to keep the dose unchanged throughout the study. Doses of these compounds 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
58
Approved, Date: 6 September 2017
should remain constant from 6 weeks prior to first dosing (Day 1 of the DB treatment phase).  To 
avoid effects on cognitive measures, the following apply:

Subjects should not stop receiving any medications that affect CNS function during the 
study

Subjects should not add any medications that affect CNS function to the treatment regimen, 
unless medically necessary.

Subject should not change doses of medication that affect CNS function
In cases of unforeseen starting, stopping or changing of stable doses of a therapy that affect CNS 
function occurs during the study, the Sponsor’s medical monitor must be contacted to determine 
if the subject should continue in the study or not, and whether or not specific clinical measures 
(e.g., cognitive measures) should be performed.  
In relation to CSF sampling, unless otherwise specified in this section, local site instructions 
related to concomitant therapy will be followed.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the visits as well as the frequency and timing of 
assessments applicable to this study. A visit window of +/-12 calendar days will be allowed for 
all visits, unless otherwise indicated in the Time and Events Schedule. All visits are in principle 
single day visits however they may be performed over multiple days within the allowed visit 
window in cases of logistical issues or a subject’s preference.
All subjects within the early (predementia) AD spectrum enrolled in this study being subjects 
asymptomatic at risk for AD and subjects with pAD, will follow the same procedures as listed in 
this section unless otherwise specifically indicated.
Information regarding handling, shipment, and labeling of biological samples (including safety 
labs) will be provided in a separate lab manual.
For CSF sampling, local site standard operating procedures (SOPs) may be applied for 
performing the actual lumbar puncture (not the collection), provided they are at least as 
restrictive as the criteria defined in this protocol or lab manual.  
Separate imaging manuals and charters will be provided, describing the MRI imaging 
procedures, data acquisition and handling.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
59
Approved, Date: 6 September 2017
Any changes to the lab manual and imaging manuals/charters will not result in a protocol 
amendment.
In the event of abnormal safety findings during the conduct of the study, additional 
measurements may be made immediately and subsequently at a frequency considered 
appropriate by the attending physician.
The time points for individual measures may be changed (with or without affecting the overall 
frequency of these investigations) prior to and during the study based on newly obtained data 
(e.g., interim analysis, DRC) to allow for optimal fit to the actual safety or PK/PD profile of the 
study drug. This modification may result in a change in the overall frequency of the individual
measures (e.g., safety measures, blood and CSF samplings) provided the maximal total blood
and/or CSF volume collected per subject defined will not be exceeded. Such modifications, 
where performed only to allow optimal fit to the actual safety, PK/PD profile of the study drug, 
will not be considered to be an amendment to the protocol.
Cognitive testing should always be performed before medical procedures that could be stressful 
for the subjects (for example blood draws, CSF collection, etc.).  If sedating medication is given 
for MRI at any visit or for any short-term use then all cognitive assessments must be 
administered/completed either before or at least 4 half-lives after administration of the sedative. 
Additionally, all neuropsychological testing and CSF collections should be performed at 
approximately the same time on each day these are performed. All neuropsychological tests 
should be administered by the same rater to reduce potential variability. In between different 
cognitive tests, adequate breaks should be taken to ensure optimal performance. Details on the 
different cognitive tests and functional outcome measures, alternative versions and forms to be 
used, sequence of performance, rater training and staff qualification required, will be described 
in a separate manual. Any changes to this manual will not result in a protocol amendment.
Venous blood will be collected for all blood-based analysis. When assessments occur at the same 
time point, the blood samples for PK and Biomarker analysis must always be collected as close 
to the scheduled time as possible, followed by the CSF sample for PK and Biomarker analysis. 
Other measurements may be done earlier than specified time points if needed. Actual dates and 
times of assessments will be recorded in the source documentation and CRF or lab requisition 
form.
Blood may be drawn by using a cannula or by venipuncture.
The exact times for each blood draw or assessment will be recorded in the CRF or lab requisition 
form. The order of multiple assessments within one protocol time point should also be the same
throughout the study.
Vital signs will be recorded from the opposite arm from which the blood samples are being 
taken.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
60
Approved, Date: 6 September 2017
Blood pressures and ECGs should be recorded approximately 5 to 10 minutes before PK blood 
samples are taken.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
The volume of blood collected per subject will be detailed in a separate lab manual.
For each subject, the maximum amount of blood drawn from each subject in this study will not 
exceed 450 mL per calendar year. For CSF no more than 24 mL annually (2 CSF collections) 
will be collected.
9.1.2.
Screening Phase
Before any study specific procedures are conducted and following an explanation of the purpose 
and risks of the study, subjects will sign an informed consent form (ICF).
Subjects who provide consent to enroll in this protocol and who meet the inclusion criteria, may 
start at Day 1 of the DB treatment phase in lieu of the end of treatment visit in 
54861911ALZ2002 study. For subjects who have completed the end of treatment visit in the 
54861911ALZ2002 study, enrollment in this study should be completed (Day 1 of the DB 
treatment phase) 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. A screening phase of up to 12 weeks may be allowed following written 
approval of the Sponsor.
After giving initial written informed consent, subjects will be screened to assess their eligibility 
for the study according to the inclusion and exclusion criteria defined for this study.
Recording of adverse events/concomitant medication will start following consent and will 
continue until completion of the study.
During screening following assessments/procedures will be performed:

Review of inclusion and exclusion criteria

Complete/Review Medical History and Demographics

Complete/Review Prestudy Therapy

Review preplanned surgery/procedures

Record adverse events and concomitant medication
Eligible subjects will be provided the opportunity to participate in the DB treatment phase and 
OL phase of the study described further below.
Subjects participating in this study may progress to a dementia state (CDR 1) during course of 
the study. In such cases the informed consent may require a signature of the subject’s legal 
representative as per local regulations.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
61
Approved, Date: 6 September 2017
9.1.3.
Double-Blind Treatment Phase
Day 1
Subjects who successfully complete the screening examination will visit the clinical site on 
Day 1 of the DB treatment phase during the morning hours. 
Prior to dosing following (baseline) assessments will be performed:

C-SSRS (since last visit [or baseline if no C-SSRS was collected under the parent protocol])

Blood sample collection for plasma JNJ-54861911 concentrations 

Blood sample collection for pharmacodynamics/biomarkers

(Optional) CSF sample collection (~12 mL) by single lumbar puncture for PK/PD/biomarker 
assessment (baseline) after eligibility has been confirmed, provided no on-treatment sample 
was collected under the parent protocol

12-lead ECG recording

Adverse event and concomitant medication will be reviewed
Following assessments will be performed prior to first dose in the current study at time points 
mentioned below only if no adequate assessments were conducted in ALZ2002 study (the 
assessments listed below 6 months and 9 months prior to dosing may also be performed during 
the screening period in case of any logistical issues):
1. At the last study visit of the treatment period:
o
Physical examination
o
Neurological examination
o
Body weight
o
Body temperature
o
Supine and standing vital signs (systolic and diastolic blood pressure and pulse)
o
Clinical safety laboratory assessments under fasted conditions, when feasible 
(including hematology, serum chemistry, and urinalysis)
2. 6 months prior to first dosing in this study (the assessments listed below may also be 
performed during the screening period in case of any logistical issues):
o
MRI 
3. 9 months prior to first dosing in this study (the assessments listed below may also be 
performed during the screening period in case of any logistical issues).
o
Dermatological Examination
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
62
Approved, Date: 6 September 2017
o
Ophthalmological Examination (only in subjects completing the ALZ2002 parent 
study)
o
Optical Coherence Tomography (OCT; at sites where OCT is available, in 
subjects completing the 54861911ALZ2002 parent study)
Eligible subjects will be assigned on Day 1 predose to the same treatment regimen in this study 
as received under 54861911ALZ2002 study as described in Section 6, Dosage and 
Administration.
Study medication will be dispensed (incl. drug accountability) and administered as outlined in 
Section 6, Dosage and Administration. Subjects will self-administer their study medication q.d. 
as instructed.
On Day 1 dosing will not be time limited and will be performed following completion of the 
baseline (predose) assessments. 
Following dosing on Day 1 following assessments will be performed:

12-lead ECG recording at 2 to 4 hours postdose

Blood sample collection for plasma JNJ-54861911 concentrations at 2 to 4 hours postdose

MMSE*

CFI*

CDR*

RBANS*
* This assessment scheduled on Day 1 may be performed either predose or postdose provided 
they have not been collected under the parent protocol 1) at the last study visit of the treatment 
phase or 2) 6 months prior to first dosing in this extension study.
During DB treatment phase, following Day 1, subjects will return to the investigational site at 
regular time points as indicated in the Time and Events Schedule and further described below.   
Week 8
Subjects will visit the site at Week 8 during the morning hours. Study medication will be 
self-administered on site as outlined in Section 6, Dosage and Administration.
Clinical safety laboratory assessments (hematology and serum chemistry) will be performed
under fasted conditions, when feasible, as specified in the Time and Events Schedule. 
Assessments can be performed pre or post dose unless otherwise indicated.
Week 12
Subjects will visit the site at Week 12 during the morning hours. Study medication will be self-
administered on site as outlined in Section 6, Dosage and Administration.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
63
Approved, Date: 6 September 2017
The following assessments will be performed at Week 12 as specified in the Time and Events 
Schedule. Assessments can be performed pre or post dose unless otherwise indicated.

Drug accountability/Treatment compliance will be assessed. Study medication received on 
Day 1 will be handed in and new medication will be dispensed.

C-SSRS (since Day 1)

CVLT-II, in subjects who had this assessment in the parent study

Adverse events and concomitant medication will be reviewed
Week 16
Subjects will visit the site at Week 16 during the morning hours. Study medication will be self-
administered on site as outlined in Section 6, Dosage and Administration.
Clinical safety laboratory assessments (hematology and serum chemistry) will be performed 
under fasted conditions, when feasible, as specified in the Time and Events Schedule. 
Assessments can be performed pre or post dose unless otherwise indicated.
Week 24
Subjects will visit the site at Week 24 during the morning hours. Study medication will be self-
administered on site as outlined in Section 6, Dosage and Administration.
The following assessments will be performed at Week 24 as specified in the Time and Events 
Schedule. Assessments can be performed pre or postdose unless otherwise indicated.

Drug accountability/Treatment compliance will be assessed. Study medication received at 
Week 12 will be handed in and new medication will be dispensed.

12-lead ECG recording (2 to 4 hours postdose)

Body temperature

Supine and standing vital signs (systolic and diastolic blood pressure and pulse)

Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry and urinalysis)

Dermatological examination

Ophthalmological examination(*) (only in subjects completing the ALZ2002 parent study)

OCT (at sites where OCT is available, and only in subjects completing the ALZ2002 parent 
study)

C-SSRS (since last visit)

RBANS

CFI

Blood sample collection for plasma JNJ-54861911 concentrations (predose and 2 to 4 hours 
postdose) 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
64
Approved, Date: 6 September 2017

Blood sample collection for pharmacodynamics/biomarkers (predose) 

MRI

Adverse events and concomitant medication will be reviewed
(*) An ophthalmological examination will only be performed if: 1) if there was an abnormality 
present
at the screening/baseline
examination; 2) if the investigator detects new 
ophthalmological findings or visual symptoms; 3) if OCT reveals new findings. The 
ophthalmologic examination should be performed by the same ophthalmologist who completed 
the initial ophthalmologic examination at screening/baseline.
Week 36
Subjects will visit the site at Week 36 during the morning hours. Study medication will be self-
administered on site as outlined in Section 6, Dosage and Administration.
The following assessments will be performed at Week 36 as specified in the Time and Events 
Schedule. Assessments can be performed pre or post dose unless otherwise indicated.

Drug accountability/Treatment compliance will be assessed. Study medication received at 
Week 24 will be handed in and new medication will be dispensed.

C-SSRS (since last visit)

Clinical safety laboratory assessments under fasted conditions, when feasible (hematology 
and serum chemistry)

Adverse events and concomitant medication will be reviewed
Week 52 (last visit [DB treatment phase])
Subjects will visit the site at Week 52 during the morning hours. Study medication will be 
self-administered on site as outlined in Section 6, Dosage and Administration. At Week 52 
subjects will be dosed according to the treatment allocation assigned to in the DB treatment 
phase.
Randomization to OL treatment phase and dispensing of study medication for OL phase will 
only be performed following completion of all Week 52 assessments. 
The following assessments will be performed at Week 52 as specified in the Time and Events 
Schedule. Assessments can be performed pre or postdose unless otherwise indicated.

Physical and Neurological examination

Body Weight

12-lead ECG recording (2 to 4 hours postdose)

Body temperature

Supine and standing vital signs (systolic and diastolic blood pressure and pulse)
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
65
Approved, Date: 6 September 2017

Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry and urinalysis)

Dermatological examination

(For subjects who completed the parent study, ALZ2002) Ophthalmological examination(*)

(For subjects who completed the parent study, ALZ2002) OCT (at sites where OCT is 
available)

C-SSRS (since last visit)

RBANS

MMSE

CFI

CDR

Blood sample collection for plasma JNJ-54861911 concentrations (predose and 2 to 4 hours 
postdose) 

Blood sample collection for pharmacodynamics/biomarkers (predose) 

(Optional) CSF sample collection (~12 mL) by single lumbar puncture for PK/PD/biomarker
assessment. Baseline and Week 52 [Month 12] CSF samples should be taken at 
approximately the same time of day (with an allowable window of 3 hours), with the Week 
52 (Month 12) sample being collected postdose.

MRI

Adverse events and concomitant medication will be reviewed

Drug accountability/Treatment compliance will be assessed. Study medication received at 
Week 36 will be handed in and new medication (for OL phase) will be dispensed.

Randomization (OL phase): only following completion of all Week 52 assessments.
(*) An ophthalmological examination will only be performed if: 1) if there was an abnormality 
present
at the screening/baseline
examination; 2) if the investigator detects new 
ophthalmological findings or visual symptoms; 3) if OCT reveals new findings. The 
ophthalmologic examination should be performed by the same ophthalmologist who completed 
the initial ophthalmologic examination at screening/baseline.
Note: If a subject discontinues study treatment before completion of DB treatment phase or is 
withdrawn during DB treatment phase, he or she will be asked to complete the Month 12 (Week 
52 assessments).
9.1.4.
Open-Label Treatment Phase
Following completion of DB treatment phase (Week 52 assessments) subjects will continue in 
OL phase. In OL phase, subjects who received placebo in the DB treatment phase will be 
randomized to open-label active treatment (JNJ-54861911; Week 52 of DB treatment phase) as 
described above and in Section 6, Dosage and Administration. Subjects receiving JNJ-54861911 
in the DB treatment phase will continue their assigned treatment as open-label in OL phase. 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
66
Approved, Date: 6 September 2017
Study medication will be self-administered on site as outlined in Section 6, Dosage and 
Administration.
During OL treatment phase, the subjects will visit the investigational site at regular time points 
(morning hours) as indicated in the Time and Events Schedule.
In case of progression to a dementia state (CDR 1) during course of the study, the subject may 
go through the consenting process for which a legally appointed representative may provide a 
renewed assent or consent, as applicable, in accordance with local regulations.
Subjects entering the OL treatment phase will remain blinded with respect to prior treatment 
assignment (placebo vs active drug) in the 54861911ALZ2002 study and in the DB treatment 
phase of this study. During the OL treatment phase, all subjects will have monitoring of safety 
laboratory tests every 2 weeks for the first 12 weeks, every 4 weeks for the next 12 weeks, every 
8 weeks for the next 24 weeks, and every 12 weeks thereafter. The assessments to be performed
and the frequency of assessments during the OL treatment phase are described in the following 
Table.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
67
Approved, Date: 6 September 2017
Assessment/Frequency
Every 2 
weeks
Every 4
weeks
Every 8
weeks
Every 
12 
weeks
Every 
24 
weeks
(*)
Every 
48 
weeks
(*)(#)
Every 
96 
weeks 
(*)(#)(¥)
Drug accountability/Treatment 
compliance
X
Drug return (previous visit)
X
Drug Dispensing
X
Physical and Neurological 
examination
X
Body Weight
X
12 Lead ECG
X,£
X£
Body Temperature
X
Supine and standing vital signs 
(systolic and diastolic blood 
pressure and pulse)
X
Clinical safety laboratory 
assessments – hematology, serum 
chemistry – under fasted 
conditions, when feasible
Xβ
Xγ
Xδ
Xε
Clinical safety laboratory 
assessments – urinalysis – under 
fasted conditions, when feasible
X
Dermatological Examination
X
Ophthalmological Examination§
X
OCT (at sites where OCT is 
available)
X
C-SSRS (since last visit)
X
RBANS
X
MMSE
X
CFI
X
CDR
X
Blood sample collection for plasma 
JNJ-54861911 concentrations 
(predose)
X,£
Blood sample collection for 
PD/biomarkers (predose) 
X
CSF sample collection (~12 mL) 
by single lumbar puncture for 
PK/PD/biomarker assessment.
X
MRI 
X
Adverse Event and Concomitant 
Medication 
X
(*) In addition to the assessments performed every 12 weeks. (#) In addition to the assessments performed every 24 
weeks. (¥) In addition to the assessments performed every 48 weeks. (§) An ophthalmological examination will only 
be performed in subjects who had completed the parent study, ALZ2002, if: 1) if there was an abnormality present 
at the screening/baseline examination; 2) if the investigator detects new ophthalmological findings or visual 
symptoms; 3) if OCT reveals new findings. The ophthalmologic examination should be performed by the same 
ophthalmologist who completed the initial ophthalmologic examination at screening/baseline; () predose; (£) 2 to 
4 hours postdose; () only during the first 12 week visit of the OL treatment phase. (β) assessments performed every 
2 weeks for 12 weeks (> Week 52 and ≤Week 64). (γ) assessments performed every 4 weeks for 12 weeks (> Week 
64 and ≤ Week 76). (δ) assessments performed every 8 weeks for 24 weeks (> Week 76 and ≤ Week 100).
(ε) assessments performed every 12 weeks after Week 100.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
68
Approved, Date: 6 September 2017
In the OL treatment phase (>52 weeks) it is intended to collect if possible on-treatment CSF 
samples every 96 weeks until study completion. Subjects may opt not to have these punctures
being performed.
For subjects enrolled in this study, subjects will continue study treatment (in the OL phase):

until registration of JNJ-54861911

until emerging safety issues arise as determined by the DRC that would warrant termination 
of the study

until subject withdraws consent or other reasons for withdrawal as defined in Section 10.3.
Upon decision to stop study participation for any of the reasons described above subject will be 
asked to return to the investigational site to hand in their study medication. Drug accountability 
will be performed. No new medication will be dispensed.
In addition subjects will be asked to complete the End-Of-Treatment Visit as described in 
Section 9.1.5, End-of-Treatment Visit (Follow Up Visit).
9.1.5.
End-of-Treatment Visit (Follow Up Visit)
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. This will consist of at least a review of 
Adverse Events and concomitant medication and C-SSRS assessment (since the last visit). 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.
Investigators may recontact the subject to obtain long-term follow-up information to determine 
the subject's safety or survival status (refer to Section 16.2.3, Informed Consent).
9.2.
Safety Evaluations
During the treatment phases regular safety assessments will be performed as listed in the Time 
and Events Schedule. These safety assessments include but are not limited to: vital signs, ECG, 
physical and neurological examination, adverse events, safety labs, suicidality risks (C-SSRS), 
dermatologic and ophthalmologic examinations, and MRI. 
The DRC may decide to reduce, eliminate or even increase frequency over time of specific safety 
assessments in case (newly obtained) data collected in this extension study or from ongoing or 
future studies would support this decision.
Details regarding the DRC are provided in Section 11.7.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
69
Approved, Date: 6 September 2017
9.2.1.
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative) for the duration of the study. Adverse events 
will be followed by the investigator as specified in Section 12, Adverse Event Reporting.
9.2.2.
Colombia Suicide Severity Rating Scale (C-SSRS)
Consistent with regulatory guidance, any occurrence of suicide-related thoughts and behaviors 
will be assessed. An interview to assess the risk of suicidal ideation and behavior will be 
conducted at the time points listed in the Time and Events Schedule. 
The C-SSRS is a measure of the spectrum of suicidal ideation and behavior that was developed 
in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to 
assess severity and track suicidal events through any treatment48. The C-SSRS is a clinical 
interview providing a summary of both ideation and behavior that can be administered during 
any evaluation or risk assessment to identify the occurrence and intensity of suicidal thoughts 
and suicidal behaviors. It can also be used during treatment to monitor for clinical worsening. 
If a suicide-related thought or behavior is identified at any time during the study, a thorough 
evaluation will be performed by a study physician, and appropriate medical care will be 
provided.
9.2.3.
Vital Signs
Vital signs (body temperature, pulse/heart rate, blood pressure) will be collected at the time 
points indicated in the Time and Events Schedule.
9.2.4.
Electrocardiogram
Twelve-lead ECGs will be collected at the time points listed in the Time and Events Schedule.
At all-time points, triplicate ECGs are required, i.e., 3 individual ECG tracings should be 
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set of 
triplicates should be completed in less than 4 minutes.
During the study, the clinical investigator will review the ECG for immediate management and 
to mark abnormalities. A description of the overall assessment (i.e., normal or abnormal plus 
reason) will be made and a copy of the trace will be placed with the source data. 
All ECGs will additionally be transmitted to be read and interpreted by a central reader 
appointed by the sponsor.
9.2.5.
Physical and Neurological Examination 
The study investigator or other authorized and appropriately qualified designee will perform the 
physical and neurological examinations, including vibration sense (by use of a tuning fork).
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
70
Approved, Date: 6 September 2017
Newly presenting ophthalmological findings or visual symptoms will be assessed by the 
investigator, and if deemed medically relevant, the subject will be referred to the 
ophthalmologist for evaluation.
Body weight will be measured as per the Time and Events Schedule.
The neurological examination will assess at minimum cranial nerves, motor system, sensory 
function and coordination.
9.2.6.
Dermatologic Examination
Subjects will undergo a comprehensive skin examination performed by a dermatologist at the 
time points listed in the Time and Events Schedule to detect the presence of skin lesions or 
depigmentation. A digital photograph of the frontal scalp, open eyes, and eyebrows will be 
collected to monitor for dermatological changes. This is an essential requirement of the safety 
monitoring in the trial.
Whenever a skin lesion not previously documented is reported by the study subject or the 
investigator, in addition to a dermatological exam by the dermatologist, digital images of the 
lesion will be acquired at the time the lesion is discovered and at follow-up visits with a 
frequency which is deemed appropriate by the sponsor of the study. Duration of follow-up of 
newly documented skin lesions or depigmentation might extend beyond the treatment period, as 
judged adequate by the sponsor to ensure the safety of subjects in this study.
Comparison to the dermatological examinations performed in 54861911ALZ2002 study will be 
made if applicable.
9.2.7.
Optical Coherence Tomography and Ophthalmologic Examination
Both the ophthalmologic examination and OCT will be carried out only in those subjects who
had these in 54861911ALZ2002 study.
The ophthalmologic examination will include funduscopic and slit lamp examination, and testing 
of acuity and intraocular pressure, and will be performed at the time points listed in Time and 
Events Schedule. 
OCT will be performed in all subjects at sites where OCT is available at the time points indicated 
in the Time and Events Schedule. 
A baseline (Day 1 [predose or earlier]) OCT and ophthalmologic examination will be conducted 
only if no adequate assessments were obtained in 54861911ALZ2002 study within 9 months of 
first dosing in this study. Otherwise the assessment performed in 54861911ALZ2002 study will 
serve as baseline. Baseline assessments in this study may be performed during screening for 
logistical reasons. 
During the treatment phase, an ophthalmologic examination, as described above, will only be 
performed at the time points indicated in the Time and Events Schedule if: 1) if there was an 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
71
Approved, Date: 6 September 2017
abnormality present at the initial examination at screening/baseline; 2) if the investigator detects 
new ophthalmological findings or visual symptoms during a physical examination; 3) if OCT 
reveals new findings. 
At the times of follow-up general physical examinations indicated in the Time and Events 
Schedule, newly presenting ophthalmological findings or visual symptoms will be assessed by 
the same qualified person who completed the screening visit. If deemed medically relevant, the 
subject will be referred to the ophthalmologist for further evaluation.
The on-treatment ophthalmologic examinations
should be performed by the same 
ophthalmologist who completed the initial ophthalmologic examination at screening/baseline in 
the extension study or under the parent protocol.
9.2.8.
Magnetic Resonance Imaging 
All subjects will receive an MRI in this study at the time points indicated in the Time and Events 
scheduled for primarily safety reasons.  
An additional baseline MRI may be collected (during screening or Day 1) in case subjects are 
enrolled from future JNJ-54861911 studies who did not obtain an adequate MRI under the parent 
protocol 6 months prior to first dosing in this study. For subjects who participated in study 
54861911ALZ2002 no baseline MRI scan is to be collected as an MRI was collected at Month 6 
under the parent protocol.
Collection of MRI data is primarily for safety reasons. MRI scans will be collected during DB 
treatment phase (up to and including Week 52 [Month 12]) and OL treatment phase (annual). 
Additional MRI scans may be collected based on emerging safety data (e.g., ARIA-E or H) with 
a frequency as recommended by the DRC. 
Imaging sequences for all pre-specified protocol MRI studies will consist of an identical set of 
pulse sequences, including FLAIR and T2* sequences, as described in the MRI imaging manual.
Global and regional brain volumes and regional cortical thickness will be derived from the 
volumetric MRI sequence and will include both cross sectional absolute measurements and 
longitudinal volume change.  The regional volumes and regional cortical thicknesses that will be 
chosen for this study will include those anatomical areas that are most affected in AD.
All MRI data collected (screening and on treatment) will be sent to a core imaging lab for quality 
control purposes and for data management, image processing, data analysis, and archiving.
MRI image evaluation will be performed by a core imaging lab.
9.2.9.
Clinical Laboratory Tests 
Blood samples (under fasted conditions whenever feasible) for serum chemistry and hematology
and a random urine sample for urinalysis will be collected. The investigator must review the 
laboratory report, document this review, and record any clinically relevant changes occurring 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
72
Approved, Date: 6 September 2017
during the study in the adverse event section of the CRF. The laboratory reports must be filed 
with the source documents. The following tests will be performed at a central laboratory 
appointed by the Sponsor:

Hematology Panel 
-hemoglobin
-platelet count
-hematocrit
- red blood cell (RBC) count
- white blood cell (WBC) count with differential

Serum Chemistry Panel 

Urinalysis 
Dipstick
Flow Cytometry
-specific gravity
-RBC
-pH
-WBC
-glucose
-epithelial cells
-protein
-blood
-ketones
Sediment 
-bilirubin
-crystals
-urobilinogen
-casts
-nitrite
-bacteria
-leukocyte esterase
If there is discordance between the dipstick results and the flow cytometric results, the sediment 
will be examined microscopically.
-sodium
-alkaline phosphatase
-potassium
-creatine phosphokinase (CPK)
-chloride
-lactic acid dehydrogenase (LDH)
-bicarbonate
-uric acid
-blood urea nitrogen (BUN)
-calcium
-creatinine
- phosphate
-glucose
-albumin
-aspartate aminotransferase (AST)
-total protein
-alanine aminotransferase (ALT)
-cholesterol
-gamma-glutamyltransferase (GGT)
-triglycerides
-total and direct bilirubin
-high density lipid protein
-low density lipid protein
-magnesium
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
73
Approved, Date: 6 September 2017
The use of local laboratories is allowed in cases where initiation of treatment or safety follow-up 
is time-critical and the central laboratory results are not expected to be available before the need 
to begin dosing or if actions need to be taken for safety reasons.
9.3.
Biomarkers
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the 
end of the study, it becomes clear that the analysis described will not have sufficient scientific 
value for biomarker evaluation, or if there are not enough samples or responders to allow for 
adequate biomarker evaluation. In the event the study is terminated early, completion of 
biomarker assessments is based on justification and intended utility of the data
9.3.1.
Fluid Biomarkers
9.3.1.1.
CSF Biomarkers
During the DB treatment phase, all eligible subjects enrolled may have two optional CSF 
samples (12 mL per sample) collected by single lumbar punctures, one at baseline (only if no 
on-treatment CSF sample was collected under the parent protocol e.g., Month 6 CSF collection 
in study 54861911ALZ2002; otherwise the on-treatment CSF sample collected
in 
54861911ALZ2002 study may serve as baseline sample in this study) and one on-treatment 
(Week 52). 
In the OL treatment phase (>52 weeks) it is intended to collect if possible on-treatment CSF 
samples every 96 weeks until study completion. Subjects may opt not to have these punctures
being performed.
CSF samples should be taken at approximately the same time of day (with an allowable window 
of 3 hours), with the on-treatment samples being collected postdose. 
During the course of the study the continuous (therapeutic) effects of JNJ-54861911 on the 
pathophysiological processes of AD may be reviewed by the DRC (CSF Aand CSF tau 
peptides or an alternate biomarker of neurodegeneration). 
CSF p-tau (and possibly additional downstream markers of neurodegeneration) will be the 
primary CSF biomarker results used to assess and predict a potential therapeutic effect of 
JNJ-54861911.
CSF Aβ1-40, is the primary CSF biomarker result used to confirm target engagement by 
JNJ-54861911.  Aβ fragments of different length are produced by cleavage of the APP by BACE 
and the γ-secretase complex in the brain and excreted into CSF. While cleavage by BACE and 
γ-secretase leads to Aβ fragments, cleavage by α-secretase prevents Aβ fragment formation. 
BACE cleavage initiates the Aβ production at the N-terminal end of the Aβ fragment, which then 
is further processed at the C-terminal end by the γ-secretase complex. As Aβ turnover rates are 
rapid, inhibition of BACE results in a reduction of all Aβ fragments in CSF. 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
74
Approved, Date: 6 September 2017
In addition to CSF p-tau and CSF Aβ1-40, other amyloid, AD and compound-related biomarkers 
in CSF and plasma may be assessed such as, but not limited to, additional Aβ fragments (Aβ1-37, 
Aβ1-38, and Aβ1-42), soluble amyloid precursor proteins (sAPP), t-tau, and additional downstream 
biomarkers of neuroinflammation, neurodegeneration, and neuronal injury such as VILIP-1, 
YKL-40 and others. Where appropriate consent is obtained, samples will also be stored for future 
research after the clinical study is completed (where local regulations permit).
9.3.1.2.
Plasma Biomarkers
Aβ fragments can be measured in plasma, similar to in CSF, but are more difficult to measure 
due to interference with other plasma proteins. Current assays have not been validated to the 
same extent for plasma as for CSF.
Venous blood samples will be collected for the analysis of Aβ1-37,1-38,1-40,1-42  at the time points 
indicated in the Time and Events Schedule.
9.3.2.
Imaging Biomarkers
9.3.2.1.
Magnetic Resonance Imaging
All subjects will receive an MRI in the extension study at the time points indicated in the Time 
and Events Schedule for primarily safety reasons. However, potential treatment effects may be 
assessed with MRI as well. 
See Section 9.2.8, MRI for a description on the MRI assessment.
9.4.
Cognition, Function and Clinical Status
Cognitive evaluations (RBANS, MMSE, and CVLT-II) and functional measures (Cognitive 
Function Index [CFI]) will be applied in this study at different time points as indicated in the 
Time and Events Schedule to explore the subject’s cognitive performance/progression and 
function over time.
In addition during course of the study the subject’s clinical status will be assessed regularly by 
means of the CDR as indicated in the Time and Events Schedule.
During the course of the study on occasions when multiple cognitive assessments and clinical 
scares are to be performed the same visit day, the RBANS will be completed first followed by 
the CDR and MMSE if the raters for RBANS and CDR are independent. If the raters for RBANS 
and CDR are the same, the CDR will be performed first, followed by the RBANS and MMSE. 
For a given subject, the same sequence will be followed throughout the study.  
Details on the different cognitive tests, versions and forms to be used as well as their sequence of 
performance will be described in a separate manual.
The RBANS and CVLT-II must be conducted by an experienced, trained, and qualified 
neuropsychologist.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
75
Approved, Date: 6 September 2017
The CDR and MMSE may be conducted by a study physician, clinical psychologist, research 
assistant or clinical study nurse specialist who has been trained and qualified in the study 
processes.
9.4.1.
Cognitive Evaluations
9.4.1.1.
Repeatable Battery for the Assessment of Neuropsychological Status 
The RBANS is a 20 to 25 minute battery developed for cognitive assessment, detection, and 
characterization of dementia in the elderly as well as neuropsychological screening for younger 
patients50. The time to administer is dependent on disease severity, but shorter if the participant 
is more impaired.  The RBANS includes 12 subtests that measure the following 5 indices:(1)
Attention Index consists of Digit Span and Coding; (2) the Language Index consists of Picture 
Naming and Semantic Fluency subtests; (3) the Visuospatial/Construction Index is made up of
Figure Copy and Line Orientation subtests; (4) the Immediate Memory Index is comprised of 
List Learning and Story Memory subtests, and (5) the Delayed Memory Index consists of List 
Recall, List Recognition, Story Recall and Figure Recall subtests. Research has demonstrated 
that the RBANS is predictive of functional capacity (i.e., driving) in MCI patients2, correlated 
with the CDR in MCI and AD31 and AD biomarkers22,62 and cognition17.  The RBANS is 
administered face-to-face and available in over 30 languages and has been used in multinational 
clinical trials including AD trials.39,42,51
9.4.1.2.
Mini Mental State Examination
The MMSE is a brief, validated 30-point questionnaire that is used to screen for cognitive 
impairment.21 The MMSE rates subjects on orientation (total score, 10), registration (total score, 
3), attention, calculation (total score, 5), recall (total score, 3), and language (total score, 9). The 
maximum score is 30.  The lower the score the more pronounced the impairment.
9.4.1.3.
California Verbal Learning Test – Second Edition
The CVLT-II is a face-to-face comprehensive neuropsychological measure of verbal memory in 
individuals 16 to 89 years old. It is designed to quantify components of verbal learning, 
retention and retrieval.13 The CVLT-II differs from the original CVLT in that new word stimuli 
are used, new and larger normative database was collected, addition of a forced choice 
recognition procedure at the end, as well as computerized scoring. Sixteen (16) words are read 
out to the participants five times with the instruction to memorize as many words as possible 
each time. Each of the words belongs to one of four categories: thus, there are four fruits, four 
herbs and spices, etc. The participants are asked to recite the words they could recollect 
immediately following each presentation (immediate recall or IR) and after an interval of at least 
20 minutes (delayed recall or DR), which is then followed by a 32 item recognition subtest.
9.4.2.
Clinical Scales and Functional Measures
9.4.2.1.
Clinical Dementia Rating Scale – Sum of Boxes
The CDR is a global clinical scale with established diagnostic and severity-ranking utility widely 
used in clinical trials yielding global and Sum of Boxes (SB) scores (CDR-SB). The CDR global 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
76
Approved, Date: 6 September 2017
score is used in AD trials as a global measure of disease progression. The CDR is rated based on
subject and informant reports. It does not directly rely on psychometric tests thereby avoiding 
learning effects. The CDR has also been adapted for routine clinical use in tertiary clinics and 
chronic care facilities. The CDR assesses three domains of cognition (memory, orientation, 
judgment/problem solving) and three domains of function (community affairs, home/hobbies, 
personal care) using semi-structured interviews of both the study subject and a 
companion/informant carried out by a trained rater and scored using a standard methodology.
Each domain is rated on a 5-point scale of functioning as follows: (0) no impairment; (0.5)
questionable impairment; (1) mild impairment; (2) moderate impairment; and (3) severe 
impairment (personal care is scored on a 4-point scale without a 0.5 rating available). An 
algorithm is used for integrating the information obtained into an overall score, i.e., “CDR 
Global” score ranging from 0 to 3 with 0 having no dementia and 3 having severe dementia.
The scores for the six domains (ranging from 0 to 3) tested can be summed to obtain the CDR 
Sum of Boxes or CDR-SB score, with scores ranging from 0 to 18.
The CDR-SB scores can be used to stage patients.47
The CDR comprehensively assesses both cognitive and functional disability in AD patients and 
is expected to be particularly useful for studies in early stages of AD.7
During the study the CDR will be audiotaped (including informant information) and reviewed 
centrally. The subject’s and informant’s approval or disapproval for such recording will be 
documented in the source documents. 
9.4.2.2.
Cognitive Function Index (CFI)
The CFI is a modified version of the Mail-in Cognitive Function Screening Instrument60, a 
subject- and study partner-reported outcome measure developed by the Alzheimer’s Disease 
Cooperative Study (ADCS).  This assessment includes 15 questions that assess the subject’s 
perceived ability to perform high level functional tasks in daily-life and their sense of overall 
cognitive functional ability.  Study subjects and their study partners independently rate the 
subject’s abilities.
9.5.
Pharmacokinetics
9.5.1.
Evaluations 
Venous blood samples for analysis of JNJ-54861911 in plasma will be collected at the time-
points indicated in the Time and Events Schedule. 
Blood samples will be used to evaluate the plasma pharmacokinetics of JNJ-54861911. Samples 
collected for analyses of JNJ-54861911 plasma concentration may additionally be used to 
evaluate safety or efficacy aspects that address concerns arising during or after the study period 
or for the evaluation of relevant biomarkers.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
77
Approved, Date: 6 September 2017
The CSF samples (12 mL each) collected for biomarker research as outlined in Section 9.3.1.1
CSF Biomarkers, will be used, in addition to analysis of relevant biomarkers concentrations, for 
the analysis of JNJ-54861911 concentrations.
9.5.2.
Analytical Procedures
Pharmacokinetics
Plasma will be analyzed to determine concentrations of JNJ-54861911 using a validated, 
specific, and sensitive LC-MS/MS method by or under the supervision of the sponsor. 
JNJ-54861911 concentrations will be analyzed in CSF (only post-dose samples) with a qualified 
LC-MS/MS assay.
If required, some plasma and CSF samples may be analyzed to document the presence of 
circulating metabolites using a qualified research method.
9.5.3.
Pharmacokinetic Parameters
Population PK analysis of plasma and CSF concentration-time data of JNJ-54861911 will be 
performed using nonlinear mixed-effects modeling. Data may be combined with those of a 
selection of Phase 1 studies to support a relevant structural model. Based on the individual 
plasma and CSF concentration-time data, if sufficient data are available, the following PK 
parameters of JNJ-54861911 may be estimated at steady state in subjects receiving a dose of 
JNJ-54861911 using population PK modeling:
Cmax
maximum plasma/CSF concentration
AUC
area under the plasma/CSF concentration-time curve from 0 to hours post 
dosing (time is the dosing interval)
CSF-related parameters will only be estimated if allowed by the model, due to the limited 
number of samples collected for each subject. Additional analyses may be conducted according 
to a population PK analysis plan and results will be presented in a separate report.
The parameters of interest for the statistical analysis will be the log-transformed estimated dose 
normalized AUC and Cmax. All ratios will be calculated as differences of least square means of 
the appropriate model on the log-scale, and will be presented after back-transformation to the 
original sale with the corresponding 90% confidence intervals (CIs).
Based on the individual plasma concentration-time data, using the actual dose taken and the 
actual sampling times, PK parameters and exposure information of JNJ-54861911 will be 
derived using population PK modelling. Baseline covariates (e.g., body weight, age, sex, CrCL, 
race) may be included in the model, if relevant.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
78
Approved, Date: 6 September 2017
9.6.
Sample Collection and Handling
PK and PD (biomarker) sampling/assessment times and sampling volumes can be adapted 
without protocol amendment provided that the maximal volume collected per subject specified 
per protocol will not be exceeded.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
The exact dates and times of blood and CSF sampling must be recorded in the CRF or lab 
requisition form. 
Baseline and on-treatment CSF samples should be taken at approximately the same time of day 
(with an allowable window of 3 hours), with the on-treatment samples sample being collected 
postdose. 
For CSF sampling, local site SOPs may be applied for performing the actual lumbar puncture 
(not the collection), provided they are at least as restrictive as the criteria defined per protocol.
Instructions for the collection, handling, storage, and shipment of samples will be provided in a 
separate lab manual. Collection, handling, storage, and shipment of samples must be under the 
specified, and where applicable, controlled temperature conditions as indicated in the lab 
manual.
All the assays and instruments used in this study will be performed by trained operators at the 
Sponsor or designated laboratories in Europe or the US on coded samples. 
Venous blood samples and CSF samples may be stored and used for future analysis of 
JNJ-54861911 metabolites and exploratory proteomics and metabolomics or other markers 
related to AD or neuropsychiatric disorders.  Additionally markers of blood brain barrier 
integrity or subtle procedure related inflammatory changes may be examined.
Samples may be provided to external partners for exploratory (CSF) biomarker research related 
to AD upon completion of the study.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
Subjects are considered to have completed the study if they discontinued treatment with 
JNJ-54861911 (provided by the sponsor) for any reason (i.e., disease progression, unacceptable 
toxicity, sponsor terminates the study, or alternative access to JNJ-54861911 becomes available 
and feasible (i.e., commercial source of JNJ-54861911) and had a follow-up safety assessment 
approximately 30 days after the last dose of JNJ-54861911. Subjects who die while receiving 
treatment also are considered to have completed the study.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
79
Approved, Date: 6 September 2017
10.2.
Discontinuation of Study Treatment 
If a subject's study treatment must be discontinued before the end of the treatment regimen, this 
will not result in automatic withdrawal of the subject from the study. 
The following specific individual rules for stopping study treatment will apply:

Mean QTcF interval of > 500 msec if confirmed upon repeat ECG, and/or mean QTcF
increase versus baseline of > 60 msec if confirmed upon repeat ECG (all triplicate 
recordings).

The investigator believes that for safety reasons (e.g., adverse event) it is in the best interest 
of the subject.

Liver enzyme elevation between Weeks 52 and 64, including any of the following:

ALT or AST >5× ULN

ALT or AST >3× ULN and total bilirubin >2× ULN or INR >1.5

ALT or AST >3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia >5%

Liver enzyme elevation after Week 64, including any of the following:

ALT or AST >8× ULN

ALT or AST >5× ULN for more than 2 weeks

ALT or AST >3× ULN and total bilirubin >2× ULN or INR >1.5

ALT or AST >3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia >5%
Re-initiation of study treatment should only be done after consultation with the sponsor medical 
monitor and in mutual agreement between the sponsor and the study center. If a subject 
permanently discontinues study treatment before the end of the treatment phase, the subject will 
be asked to complete the Week 52 assessments, including CSF sampling, if not yet obtained
earlier. At a minimum, the subject will be asked to complete the End-of-Treatment Visit 
(Follow-up visit) as per the Time and Events Schedule.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent or assent

Death

Noncompliance
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow-up must be documented.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
80
Approved, Date: 6 September 2017
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. 
Subjects who are withdrawn will not be replaced.
Any subject who withdraws after receiving the study drug will be asked, if not yet obtained, to 
have the Week 52 assessment performed. At least the subjects should have a follow-up 
evaluation as described in Section 9.1.5
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the main ICF.
11.
STATISTICAL METHODS
Subjects enrolled in this study will be self-selected as they will be provided the option to 
participate in this study upon completion of treatment in a Phase 1b or Phase 2 study with 
JNJ-54861911. 
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Descriptive statistical analyses will be performed for all subjects receiving at least one 
dose of study drug in this study. Analyses may be performed separately for both DB and OL 
treatment phases. After all subjects have completed the DB treatment phase, a database lock for 
the DB treatment phase will take place upon which unblinded statistical analyses may be 
generated, and a study report for DB treatment phase may be prepared. Analyses may be 
performed separately for subgroups of subjects according to previous study participation as well 
as for the combined population of all subjects participating in this study, where appropriate.
Summaries may also be presented by baseline CDR global score.
11.1.
Subject Information
For all subjects who receive at least one dose of study drug descriptive statistics will be 
provided.
11.2.
Sample Size Determination
The study is not powered according to statistical calculations. The number of subjects enrolled 
will depend on the number of subjects from other JNJ-54861911 studies who are willing to 
enroll in this extension study.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
81
Approved, Date: 6 September 2017
11.3.
Pharmacokinetic Analyses and Pharmacokinetic/Pharmacodynamic 
Analysis
Population PK modeling of plasma and, if possible, CSF concentrations of JNJ-54861911 will be 
undertaken. In view of the sparse sampling foreseen for this study, data may be combined with a 
selection of Phase 1, Phase 1b, and Phase 2 data (e.g., from studies 54861911ALZ1001, 
54861911ALZ1002, 54861911ALZ1005, and/or 54861911ALZ2002) in order to support a 
relevant structural model.
PopPK/PD analysis of biomarkers and/or cognitive markers may also be performed, and a 
suitable dose- and/or exposure-response model may be developed. If necessary or relevant for 
the analysis, Phase 1 and Phase 2 data may be integrated to inform the model structure or key 
parameter values.
A snapshot date for PK samples to be analyzed may be defined, if required, and documented in a 
data transfer plan (DTP) according to the applicable standard operating procedures and work 
instructions. Samples collected before this date will be analyzed for JNJ-54861911 and included 
in the population PK analysis. Samples collected after the snapshot date will be analyzed at a 
later date, and may be included in a population PK re-analysis when they become available after 
database lock.
Details of the analyses will be described in a PopPK/PD analysis plan and results will be 
provided in a separate report.
11.4.
Pharmacodynamic Analyses 
11.4.1.
Biomarker Analyses 
11.4.1.1.
Fluid Biomarkers
Percent changes from baseline in CSF Aβ species (Aβ1-37, Aβ1-38, Aβ1-40, Aβ1-42) and sAPP total, 
as well as fragments (sAPPα, sAPPβ) will be summarized at each scheduled time point using 
descriptive statistics and presented graphically by treatment period and treatment group.
Similar analyses will be performed for plasma Aβ1-40 and sAPP total, as well as fragments 
(sAPPα, sAPPβ).
Exploratory analyses may be performed for CSF p-tau, t-tau and additional downstream 
biomarkers of neuroinflammation, neurodegeneration, and neuronal injury. Results of these 
analyses may be presented in a separate report.
11.4.1.2.
Imaging Biomarkers
Changes from baseline in brain volumes and cortical thickness (regional and global) as measured 
by volumetric MRI will be summarized using descriptive statistics. 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
82
Approved, Date: 6 September 2017
11.4.2.
Cognition, Function and Clinical Status
Cognitive evaluations (RBANS, MMSE, and CVLT-II) and functional measures (Cognitive 
Function Index [CFI]) will be applied in this study at different time points as indicated in the 
Time and Events Schedule to explore the subject’s cognitive performance/progression and 
function over time.
In addition during course of the study the subject’s clinical status will be assessed regularly by 
means of the Clinical Dementia Rating Scale as indicated in the Time and Events Schedule.
Measurements will be summarized at each scheduled time point using descriptive statistics.
11.5.
Safety Analyses
All subjects receiving at least one dose of study drug will be included in the safety analysis. 
Descriptive statistics will be computed. 
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events 
with onset during the treatment phase (i.e., treatment-emergent adverse events, and adverse 
events that have worsened since baseline) will be included in the analysis. For each adverse 
event, the percentage of subjects who experience at least one occurrence of the given event will 
be summarized by treatment group. Adverse events will also be tabulated by severity and by 
relationship to study drug and will be presented by treatment group. Serious adverse events will 
be summarized separately.
Summaries will be provided for all subjects receiving at least one dose of study drug in this 
study, and will include adverse events from this study as well as any preceding studies (e.g., 
study JNJ-54861911ALZ1005, JNJ-54861911ALZ2002 or any future Phase 1b or Phase 2 
JNJ-54861911 clinical studies) as applicable for subjects who previously participated in that 
study, where appropriate. 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who withdraw due to an adverse event, or who experience a severe or a serious 
adverse event. Subjects with AESIs may be counted or listed.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be 
calculated for each laboratory analyte at baseline and at each scheduled time point, and for 
changes from baseline.    
The number and percentage of subjects experiencing a laboratory result below or above normal
reference ranges will be provided for each laboratory analyte by treatment group. 
A listing of subjects with any laboratory result outside the reference ranges will be provided.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
83
Approved, Date: 6 September 2017
Electrocardiogram (ECG)
Heart rate and ECG intervals (RR, PR, QRS, and QT) as well as corrected QT intervals 
according to Bazett’s formula (QTcB) and Fridericia’s formula (QTcF) from the 12-lead ECG 
will be summarized at baseline and at each scheduled time point and for changes from baseline 
using descriptive statistics. 
The number and percentage of subjects with at least 1 occurrence of a treatment-emergent 
potentially clinically important QTc measurement (QTc value >450, >480, or >500 ms) or with a 
change from baseline in QTc >30 ms will be summarized by treatment group. 
Data listings of subjects with any potentially clinically important values (QTc value >450, >480, 
or >500 ms) or with a change from baseline in QTc >30 ms will be provided.
Vital Signs
Descriptive statistics of pulse, blood pressure (systolic and diastolic) (supine and standing), 
temperature and body weight values and changes from baseline will be summarized at each 
scheduled time point.
Physical and Neurological Examination
The number and percentage of subjects with a change from normal at baseline to abnormal at any 
postbaseline exam will be tabulated by treatment group. 
Subjects with abnormal findings will be presented in a data listing.
Dermatologic and Ophthalmologic Examination
Results of the dermatologic and ophthalmologic examinations (incl. OCT) will be presented by 
treatment group. Subjects with abnormal findings will be presented in a data listing.
Columbia Suicide Severity Rating Scale (C-SSRS)
Results from the C-SSRS will be tabulated by treatment group for all subjects receiving at least 
one dose of study drug in this study.
Safety MRI 
The number and percentages of subjects with presence of ARIA-E, ARIA-H, and other MRI 
abnormalities found in the safety MRI assessments will be tabulated by treatment group.
11.6.
Interim Analysis
No prespecified interim analysis of unblinded data during the DB treatment phase is planned by 
the clinical team. However, depending on the recruitment, or in support of regulatory filings for 
upcoming studies, or for any other reason the Sponsor deems necessary, an unblinded review of 
safety and biomarker data prior to the last subject’s completion of the DB treatment phase might 
be conducted by an internal Interim Analysis Committee. If any such review is conducted it will 
be documented in an Interim Analysis Committee charter prior to the unblinding. The 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
84
Approved, Date: 6 September 2017
constitution of the Interim analysis committee will be documented in the Interim Analysis 
Committee charter and may include Sponsor study team members.
As noted in Section 5, when the parent study (e.g. 54861911ALZ2002 and potential future 
Phase 1b and 2 studies) is completed and its clinical database is closed, the randomization codes 
from the parent study will be released to the sponsor study team. Thus, the sponsor will be 
unblinded at that time, but the investigator and subjects will continue to be blinded to treatment 
during the DB treatment phase, until the last subject has completed that phase, and the database 
from that phase has been reviewed, corrected as necessary, and locked. At that point, the sponsor 
will perform analyses of key safety, biomarker, and efficacy variables, as detailed in a 
prespecified statistical analysis plan.
Following the sponsor’s review of these analyses, information on an individual subject’s 
treatment allocation during the DB phase will be made available upon request by the 
investigator. As subjects that remain in the study will all be receiving open label JNJ-54861911 
at that time, and as no change or alteration of the locked database from the DB phase will be 
possible, there will be no bias introduced by this measure. 
11.7.
Data Review Committee
A DRC will be established to monitor the study data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled in this study. The committee will meet periodically to 
review interim study data including the safety data as well as biomarker data (fluid [CSF, 
plasma] and imaging [vMRI]).  
The CSF and Imaging biomarker data (e.g., CSF Aand CSF tau peptides or another marker of 
neurodegeneration; vMRI) will be reviewed periodically by the DRC to assess the continuous 
potential therapeutic effect of JNJ-54861911 over time on the pathophysiologic processes 
underlying AD in subjects asymptomatic at risk for developing Alzheimer’s dementia.  
After the review, the DRC will make recommendations regarding the safety and continuation of 
the study. The details will be provided in a separate DRC charter.
The DRC will consist of at least one medical expert in AD and at least one statistician. The DRC
statistician will not be part of the Sponsor study team and as such will not otherwise be involved 
in the study conduct or the final statistical analysis of this study. The DRC responsibilities, 
authorities, and procedures will be documented in its charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established SOPs (SOPs) in conformity with 
regulatory requirements worldwide to ensure appropriate reporting of safety information; all 
clinical studies conducted by the sponsor or its affiliates will be conducted in accordance with 
those procedures.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
85
Approved, Date: 6 September 2017
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH])34
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

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

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (e.g., death from anaphylaxis), the event must 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
86
Approved, Date: 6 September 2017
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (e.g., all-cause mortality). 
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For JNJ-54861911, the expectedness of an 
adverse event will be determined by whether or not it is listed in the Investigator's Brochure
(Reference Safety Information included the IB).37
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, e.g., concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
e.g., concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(e.g., confirmed by dechallenge). An alternative explanation is less likely, e.g., concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, e.g., concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (e.g., it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
87
Approved, Date: 6 September 2017
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (e.g., laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, e.g., name confusion)

A subject experiences elevations in liver enzymes as specified in Attachment 1.
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure (which may include contact for follow-up of safety). Serious adverse 
events, including those spontaneously reported to the investigator within 30 days after the last 
dose of study drug, must be reported using the Serious Adverse Event Form. The sponsor will 
evaluate any safety information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol.
All other events that meet the definition of a serious adverse event will be reported as serious 
adverse events, regardless of whether they are protocol-specific assessments.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
88
Approved, Date: 6 September 2017
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all serious adverse events that are unlisted (unexpected) and associated 
with the use of the study drug. The investigator (or sponsor where required) must report these 
events to the appropriate Independent Ethics Committee (IEC) that approved the protocol unless 
otherwise required and documented by the IEC. 
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following: 

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding all serious adverse events will be transmitted to the sponsor using the 
Serious Adverse Event Form, which must be completed and signed by a physician from the study 
site, and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
89
Approved, Date: 6 September 2017

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Discontinuation of study treatment secondary to increased liver enzyme criteria (outlined in 
Section 10.2) will be reported as a serious adverse event.
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (e.g., social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.

For convenience the investigator may choose to hospitalize the subject for (part of) the 
duration of the treatment period. 
The cause of death of a subject in a study, whether or not the event is expected or associated with 
the study drug, is considered a serious adverse event.
12.3.3.
Pregnancy
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported by the study-site personnel within 24 hours of their 
knowledge of the event using the appropriate pregnancy notification form.
12.3.4.
Adverse Events of Special Interest
All initial reports of lightening of skin or hair, or treatment-emergent ophthalmologic AEs must 
be reported to the Sponsor by the investigational staff within 24 hours of their knowledge of the 
event even if these events do not meet the definition of an SAE. Additional information on the 
reporting of AESIs is found in Attachment 2.
12.3.5.
Adverse Drug Reactions 
Elevated liver enzymes have been identified as an ADR. Any SAE related to elevated liver 
enzymes should be reported as described in Section 12.3.2. In addition, any cases of elevated 
liver enzymes that result in discontinuation of study treatment should be reported as an SAE, 
following reporting requirements outlined in Section 12.3.2.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
90
Approved, Date: 6 September 2017
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, i.e., any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established 
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting 
of PQC information; all studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel as soon as possible 
after being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be maintained 
for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
The JNJ-54861911 solid dosage formulation will be supplied as 5- and 25-mg film-coated 
tablets. These are round, white to off-white tablets, containing 5- or 25-mg of JNJ-54861911, 
compendial-grade of D-mannitol, low-substituted hydroxypropyl cellulose, triethyl citrate, 
hydroxypropyl cellulose, magnesium stearate, and Opadry 03A48081.
The JNJ-54861911 placebo tablets will be supplied as film-coated tablets, matching visually to 
the active tablets. These are round, white to off-white tablets, containing compendia grade of 
D-mannitol, microcrystalline cellulose, magnesium stearate triethyl citrate, and Opadry 
03A48081. JNJ-54861911/placebo will be manufactured and provided under the responsibility of 
the sponsor. 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
91
Approved, Date: 6 September 2017
14.2.
Packaging
The study drug will be blister packed. For both DB and OL treatment phases, blinded study drug 
kits will be assigned based on their treatment allocation under the parent protocol. However for 
OL treatment phase investigator and subject can be unblinded to treatment despite the use of 
blinded treatment kits (for logistical reasons). All JNJ-54861911/placebo solid formulation study 
drug will be dispensed in child-resistant packaging.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
All study medication will be stored in a secure area with restricted access.
The JNJ-54861911 and placebo solid dosage formulation must be stored at controlled room 
temperatures ranging from 15°C to 30°C, as indicated on the product specific labeling.
Additional guidance and detailed instructions for the clinical site dosing procedures and storage 
conditions are described in the Dose Preparation Instructions/ Pharmacy manual or equivalent 
document.
Refer to the Dose Preparation Instructions/Pharmacy Manual for additional guidance on study 
drug dispensing, dosing process, and handling.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects must be instructed to return all original containers, whether empty 
or containing study drug. 
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the drug return form. When the study site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes, and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
92
Approved, Date: 6 September 2017
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with, but not limited to, the following supplies:

Investigator Brochure for JNJ-54861911

Pharmacy manual/study site investigational product manual

Laboratory manual

Imaging Manual

Cognition Manual

IWRS Manual

eDC Manual

Sample ICF

Subject diaries
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Subjects in the early AD spectrum who have completed a Phase 1b or Phase 2 clinical study with 
JNJ-54861911 will be provided the opportunity to participate in this study, focused on providing
primarily safety and tolerability data supporting long-term treatment with JNJ-54861911 in 
subsequent studies (Phase 3) as well as ongoing access to JNJ-54861911. The study treatment 
duration in this study of subjects in the early (predementia) AD spectrum is supported by the 
available toxicology and clinical data (see Investigator’s Brochure).37
The early (predementia) AD spectrum defined in this study includes subjects who are 
asymptomatic but at risk for Alzheimer’s dementia as well as subjects with pAD who recently 
completed a Phase 1b or Phase 2 JNJ-54861911 study.
Examples of JNJ-54861911 studies in the same target population are an earlier POM study 
(54861911ALZ1005) and a 6-month safety study (54861911ALZ2002).
Potential subjects will be fully informed of the risks and requirements of the study and, during 
the study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may 
be withdrawn at any time with no reason given and without penalty or loss of benefits to which 
they would otherwise be entitled. Only subjects who are fully able to understand the risks, 
benefits, and potential adverse events of the study, and provide their consent voluntarily will be 
enrolled. 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
93
Approved, Date: 6 September 2017
Subjects that have progressed to dementia (CDR 1) in the parent study 54861911ALZ2002, or 
who are incapable of providing informed consent will not be enrolled. In case the subject 
progresses to a dementia state during the study, the subject may remain in the study, provided 
that the investigator judges that the potential benefits of treatment for this subject clearly 
outweigh the known and foreseeable risks and assent or consent (as applicable) for continued 
participation is obtained from a representative determined in accordance with the local law. In 
cases where a subject has progressed to dementia, treatments indicated for this condition (e.g., 
memantine or cholinesterase inhibitors) are permitted after notification of the sponsor. 
A DRC has been established to monitor the study data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled in this study. 
Specific dermatologic and ophthalmologic examinations, as described in Section 9.2, Safety 
Evaluations, have been implemented in this study as potential BACE1- or BACE2-linked 
toxicities (e.g. melanin deposition changes and retinal abnormalities) have been described in the 
literature (e.g. BACE1 or BACE2 knock-out mice). With the exception of fur discoloration
resulting in progressive lightening of the fur from normal dark brown to paler cream or grey, 
which was seen in one species only (Tg mice in the 6 month carcinogenicity study), these 
toxicities have not been observed in preclinical studies with JNJ-54861911.
Subjects participating in this study may have direct benefit as a consequence of the longer
treatment duration, however to date efficacy of this compound has not been proven. Effects on 
slowing down the rate of cognitive decline are only expected to become apparent after a 
treatment duration of approximately 3 years based on evidence from previous longitudinal 
studies in this field (Alzheimer’s Disease Neuroimaging Initiative [ADNI] and the Australian 
Imaging, Biomarkers and Lifestyle Flagship Study of Ageing [AIBL]). 
A placebo arm is warranted and necessary to allow for an accurate assessment of the safety and 
tolerability of the study drug. The placebo arm will be limited in time to the first 12 months of 
this study. Combined with the duration of treatment under the parent protocols (e.g., 6 months) 
an additional 12-month placebo-controlled period in this study is deemed sufficient to assess any 
emergent safety aspects (treatment induced effects) of JNJ-54861911 in relation to placebo 
treatment. In addition at this moment there is no treatment available for subjects at risk for 
Alzheimer’s dementia or subjects in the earliest AD spectrum so the use of placebo in an 
individual subject is not harmful, nor does it prevent them from the use of an indicated active 
treatment. Treatment with placebo dosing is not equivalent to non-treatment. All medication 
treatment will occur within the context of carefully supervised and supportive care.
The optimal level of therapeutic Aβ reduction is not known and cannot be assumed from
preclinical models or early phase clinical studies, as the proposed effect on the disease pathology
is expected to require chronic treatment. Results from Phase 1 studies with JNJ-54861911 have
confirmed observations in transgenic animal models in showing that this compound results in
profound reductions in brain Aβ levels. As described in Section 1.1, data from completed SAD
and MAD studies in healthy older subjects and from the preliminary analyses of the proof of
mechanism study in a population with early AD spectrum showed dose-dependent reductions in
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
94
Approved, Date: 6 September 2017
Aβ1-40 in plasma and CSF following oral JNJ-54861911 administration. As shown in Figure 5
below, preliminary data from the proof of mechanism study showed that the median reduction in
CSF Aβ1-40 with a 25 mg/day dose (84%) was only minimally increased by ~ 7% (i.e., to 91%)
with a doubling of the dose to 50 mg/day. At a lower dose of 10 mg/day, the majority of subjects 
in this study showed more than a 50% reduction in CSF Aβ1-40. However, during the course of 
the study as indicated in Section 3.2. Study Design Rationale, the Sponsor will have the option 
based on recommendations by the DRC or based upon newly emerging safety, biomarker or 
efficacy data from ongoing or completed JNJ-54861911 studies, to revise the dose levels for the 
OL treatment phase.
A thorough QT trial, 54861911ALZ1007, has been performed in 64 healthy subjects (final report 
not yet available) using a 4-way, 7-day cross-over design evaluating a JNJ-54861911 dose of 
50 mg/day as well as supratherapeutic dose of 150 mg/day, and including moxifloxacin 400 mg 
to confirm assay sensitivity as described in Section 1.1, Background. PK/PD modeling was 
performed to assess the relationship between JNJ-54861911 plasma concentrations and effect on 
QTcF prolongation, using data from the 54861911ALZ1007 study. Results of this modeling 
activity showed that at a JNJ-54861911 once daily (q.d.) dose of 25 mg, the median changes in 
the QTcF, as well as the 90% population interval, are expected to be well below 5 msec.
The normal choroid plexus produces CSF at a continuous rate of 20 mL/hour resulting in a daily 
CSF production of 500 mL on average. The total CSF volume at any given time is about 150 mL, 
so in normal conditions there is a complete wash-out of the CSF volume approximately 4 times 
per day.45 At each CSF sampling point a sample of 12 mL will be collected, which is considered 
to be acceptable, in reference to the daily CSF production rate. Equal and even higher volumes of 
CSF up to 108 mL (over 36 hours) have been collected in previous studies (54861911ALZ1001 
and 54861911ALZ1002) and were well tolerated by subjects in the same age range as that of 
subjects who will be included in the current study. 
Possible theoretical risks associated with lumbar punctures include: procedural pain during 
insertion of needle, spinal headache (also called post-dural puncture headache [PDPH]), epidural 
infection, spinal cord trauma / nerve root trauma, spinal / epidural hematoma and cerebral 
herniation. To reduce these possible risks maximally, additional eligibility criteria and other 
preventive action were put in place under the parent protocols.
PDPH is the most common and most important complication inherent to the dural puncture. 
PDPH is caused by persistent CSF leakage. To reduce the risk of CSF leakage subjects are 
preferably placed on bed, rest in a supine position during sampling.
The possible introduction of an infection into the CSF (e.g. resulting in meningitis) is a rare 
complication. To avoid this, the lumbar puncture is performed under strict sterile conditions. 
Local SOPs will be followed for the performance of the lumbar puncture. All CSF collections 
will be performed under aseptic conditions.
The normal puncture sites will be respected in this study (L3-L4 or L4-L5).
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
95
Approved, Date: 6 September 2017
Only experienced and qualified physicians are allowed to perform the applicable procedures.
The total blood volume to be collected will not exceed 450 mL annually, which is considered to 
be acceptable in comparison to a Red Cross blood donation.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/institutional review board (IRB) with current and complete copies of the following 
documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
96
Approved, Date: 6 September 2017
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB
about the study completion [(if applicable, the notification will be submitted through the head of 
investigational institution)].
16.2.3.
Informed Consent
Each subject (or, in the case of subjects that have become demented during the course of the 
study, a legally acceptable representative, if applicable) must give written consent according to 
local requirements after the nature of the study has been fully explained. The ICF(s) must be 
signed before performance of any study-related activity. The ICF(s) that is/are used must be 
approved by both the sponsor and by the reviewing IEC/IRB and be in a language that the 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
97
Approved, Date: 6 September 2017
subject can read and understand. The informed consent should be in accordance with principles 
that originated in the Declaration of Helsinki, current ICH and GCP guidelines, applicable 
regulatory requirements, and sponsor policy. An appendix to the 54861911ALZ2004 ICF will be 
used for subjects participating in eMeds. 
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate, will not 
affect the care the subject will receive for the treatment of his or her disease. Finally, they will be 
told that the investigator will maintain a subject identification register for the purposes of long-
term follow up if needed and that their records may be accessed by health authorities and 
authorized sponsor personnel without violating the confidentiality of the subject, to the extent 
permitted by the applicable law(s) or regulations. By signing the ICF the subject, is authorizing 
such access, including permission to obtain information about his or her survival status, and 
agrees to allow his or her study physician to recontact the subject for the purpose of obtaining 
consent for additional safety evaluations, if needed, and subsequent disease-related treatments, or 
to obtain information about his or her survival status.
The subject (or legally acceptable representative if applicable), will be given sufficient time to 
read the ICF and the opportunity to ask questions. After this explanation and before entry into the 
study, consent should be appropriately recorded by means of either the subject's (or his or her 
legally acceptable representative's) personally dated signature. After having obtained the consent, 
a copy of the ICF must be given to the subject.
If the subject (or legally acceptable representative if applicable) is unable to read or write, an 
impartial witness should be present for the entire informed consent process (which includes 
reading and explaining all written information) and should personally date and sign the ICF after 
the oral consent of the subject (or legally acceptable representative, if applicable) is obtained.
A subject who has cognitive decline during the study to the point of clinical dementia may go 
through the consenting process to give renewed assent or consent (provided by a legally 
appointed representative), as applicable, in accordance with local law or guidance.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
98
Approved, Date: 6 September 2017
The informed consent obtained from the subject (or his or her legally acceptable representative, 
if applicable) includes explicit consent for the processing of personal data and for the 
investigator/institution to allow direct access to his or her original medical records (source 
data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory inspection. 
This consent also addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory biomarker and PK research is not conducted under standards appropriate for the 
return of data to subjects. In addition, the sponsor cannot make decisions as to the significance of 
any findings resulting from exploratory research. Therefore, exploratory research data will not be 
returned to subjects or investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand JNJ-54861911, to 
understand AD, to understand differential drug responders, and to develop tests/assays related to 
JNJ-54861911 and AD.  The research may begin at any time during the study or the post-study 
storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal From the Study (Withdrawal From the Use 
of Samples in Future Research).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance,
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
99
Approved, Date: 6 September 2017
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (e.g., Form FDA 1572), if applicable

Documentation of investigator qualifications (e.g., curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
100
Approved, Date: 6 September 2017

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (e.g., curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(e.g., accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; study discussion 
and date of signed informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol; record of all adverse events and follow-up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; study drug administration 
information; and date of study completion and reason for early discontinuation of study drug or 
withdrawal from the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
Subject- and investigator-completed scales and assessments designated by the sponsor (such as 
but not limited to RBANS and CDR) may be recorded directly into an electronic device and in 
such instances will be considered source data.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
101
Approved, Date: 6 September 2017
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (e.g., physical examination, 
laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
CRFs are provided for each subject in electronic format. 
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an electronic CRF, and transmitted in a 
secure manner to the sponsor within the timeframe agreed upon between the sponsor and the 
study site. The electronic file will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
English. Study site personnel must complete the CRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (e.g., pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible. The investigator must verify that all data entries in the CRFs are accurate and correct.
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or 
study-site personnel must adjust the CRF (if applicable) and complete the query. 
If corrections to a CRF are needed after the initial entry into the CRF, this can be done in 
3 different ways:

Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).

Study site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, direct 
transmission of clinical laboratory and ECG data from a central laboratory into the sponsor's data 
base. Written instructions will be provided for collection, handling, storage, and shipment of 
samples. 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
102
Approved, Date: 6 September 2017
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review CRFs for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the CRFs with the hospital or clinic records (source 
documents). The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the CRF are known to the sponsor and study-site 
personnel and are accessible for verification by the sponsor study-site contact. If electronic 
records are maintained at the study site, the method of verification must be discussed with the 
study-site personnel. 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
103
Approved, Date: 6 September 2017
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. Findings 
from this review of CRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last study assessment for the last subject 
participating in the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject assessment at that study site, in the time frame 
specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the CRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
104
Approved, Date: 6 September 2017
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding JNJ-54861911 or the 
sponsor's operations (e.g., patent application, formulas, manufacturing processes, basic scientific 
data, prior clinical data, formulation information) supplied by the sponsor to the investigator and 
not previously published, and any data, including exploratory biomarker research data, generated 
as a result of this study, are considered confidential and remain the sole property of the sponsor. 
The investigator agrees to maintain this information in confidence and use this information only 
to accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of JNJ-54861911, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain CRF data from all study sites that participated in the study, and direct transmission 
of clinical laboratory data from a central laboratory into the sponsor's database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomic or
exploratory biomarker analyses performed after the Clinical Study Report has been issued will 
be reported in a separate report and will not require a revision of the Clinical Study Report. 
Study subject identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
105
Approved, Date: 6 September 2017
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study 
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as
required by law.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
106
Approved, Date: 6 September 2017
REFERENCES
1.
Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer's 
disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on 
diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 ;7(3):270-279.
2.
Badenes Guia, D., Casas Hernanz, L., Cejudo Bolivar, J. C., & Aguilar Barbera, M. (2008). [Evaluation of the 
capacity to drive in patients diagnosed of mild cognitive impairment and dementia]. Neurologia, 23(9), 575-
582. 
3.
Blennow K, Hampel H. CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2003; 2(10): 605-613.
4.
Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer 
disease. Nat Rev Neurol 2010; 6(3): 131-144.
5.
Braak H, Rüb U, Schultz C, et al. Vulnerability of cortical neurons to Alzheimer’s and Parkinson’s diseases. 
In: Perry G, editor. Alzheimer’s disease: a century of scientific and clinical research. IOS Press; 2006. p. 35–44
6.
Buerger K, Ewers M, Andreasen N, et al.. Phosphorylated tau predicts rate of cognitive decline in MCI 
subjects: a comparative CSF study. Neurology. 2005 ;65(9):1502-1503.
7.
Cedarbaum JM, Jaros M, Hernandez C, et al. Alzheimer's Disease Neuroimaging Initiative. Rationale for use 
of the Clinical Dementia Rating Sum of Boxes as a primary outcome measure for Alzheimer's disease clinical 
trials. Alzheimers Dement. 2013;9(1 Suppl):S45-55.
8.
Cheret C, Willem M, Fricker FR et al. Bace1 and neuregulin-1 cooperate to control formation and maintenance
of muscle spindles. EMBO J. 2013; 32(14): 2015-2028.
9.
Chien DT, Bahri S, Szardenings AK, et al. Early clinical PET imaging results with the novel PHF-tau 
radioligand [F-18]-T807. J Alzheimers Dis. 2013;34(2):457-468.
10.
Crowther T, Goedert M, Wischik CM. The repeat region of microtubule-associated protein tau forms part of 
the core of the paired helical filament of Alzheimer's disease. Ann Med. 1989;21(2):127-132. Review.
11.
Crowther RA, Olesen OF, Jakes R, Goedert M. The microtubule binding repeats of tau protein assemble into 
filaments like those found in Alzheimer's disease. FEBS Lett. 1992;309(2):199-202.
12.
Crowther RA, Olesen OF, Smith MJ, Jakes R, Goedert M. Assembly of Alzheimer-like filaments from full-
length tau protein. FEBS Lett. 1994; 337(2):135-138.
13.
Delis D, Kaplan E, Kramer J, Ober B. The California Verbal Learning Test – II, San Antonio, TX. The 
Psychological Corporation, 2000.
14.
Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer's disease: revising the 
NINCDS-ADRDA criteria. Lancet Neurol. 2007;6(8):734-746.
15.
Dubois, B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer's disease: a new lexicon. Lancet 
Neurol. 2010;9(11):1118-1127.
16.
Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer's disease: the 
IWG-2 criteria. Lancet Neurol 2014;13(6): 614—629
17.
Duff K, Foster NL, Dennett K, et al. Amyloid deposition and cognition in older adults: The effects of 
premorbid intellect. Arch Clin Neuropsychol. 2013;28(7):665-671.
18.
EMA/CHMP/SAWP/102001/2011. Qualification Opinion of Alzheimer’s Disease Novel 
Methodologies/biomarkers for BMS-708163.
19.
Fagan AM, Mintun MA, Shah AR, et al. Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid
deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease. 
EMBO Mol Med. 2009;1(8-9):371-380.
20.
Fagan AM, Shaw LM, Xiong C, et al. Comparison of analytical platforms for cerebrospinal fluid measures of 
β-amyloid 1-42, total tau, and p-tau181 for identifying Alzheimer disease amyloid plaque pathology. Arch 
Neurol. 2011;68(9):1137-1144.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
107
Approved, Date: 6 September 2017
21.
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state 
of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198.
22.
Forster, S., Teipel, S., Zach, C., Rominger, A., et al. FDG-PET mapping the brain substrates of visuo-
constructive processing in Alzheimer's disease. J Psychiatr Res. 2010;44(7), 462-469.
23.
Goedert M, Crowther RA. Amyloid plaques, neurofibrillary tangles and their relevance for the study of 
Alzheimer's disease. Neurobiol Aging 1989; 10(5): 405-406.
24.
Goedert M. Tau protein and the neurofibrillary pathology of Alzheimer's disease. Trends  Neurosci 1993; 
16(11):460-465.
25.
Hampel H, Blennow K. CSF tau and β-amyloid as biomarkers for mild cognitive impairment. Dialogues Clin 
Neurosci. 2004;6(4):379-390.
26.
Hampel H, Blennow K, Shaw LM, Hoessler YC, Zetterberg H, Trojanowski JQ. Total and phosphorylated tau 
protein as biological markers of Alzheimer's disease. Exp Gerontol. 2010;45(1):30-40.
27.
Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF 
biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. 
Lancet Neurol. 2006;5(3):228-234. Erratum in: Lancet Neurol. 2006;5(4):293.
28.
Hansson O, Buchhave P, Zetterberg H, Blennow K, Minthon L, Warkentin S. Combined rCBF and CSF 
biomarkers predict progression from mild cognitive impairment to Alzheimer's disease. Neurobiol Aging. 2009 
Feb;30(2):165-173. Epub 2007 Jul 23. 
29.
Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science 1992; 256 (5054): 
184-185.
30.
Hesse, C. Rosengren L, Andreasen N, et al. Transient increase in total tau but not phospho tau in human 
cerebrospinal fluid after acute stroke. Neurosci. Lett. 2001;297(3):187–190.
31.
Hobson VL, Hall JR, Humphreys-Clark JD, Schrimsher GW, & O'Bryant SE. Identifying functional 
impairment with scores from the repeatable battery for the assessment of neuropsychological status (RBANS). 
Int J Geriatr Psychiatry. 2010;25(5):525-530.
32.
Hu X, Zhou X, He W et al. BACE1 deficiency causes altered neuronal activity and neurodegeneration. J 
Neurosci. 2010; 30(26):8819-8829.
33.
Hyman BT, Tanzi RE. Amyloid, dementia and Alzheimer's disease. Curr Opin Neurol Neurosurg. 
1992;5(1):88-93. Review. 
34.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use. ICH Harmonized Tripartite Guideline E14: Clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs. ICH 12 May 2005.
35.
Itoh N, Arai H, Urakami K, et al. Large-scale, multicenter study of cerebrospinal fluid tau protein 
phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer’s disease. Ann Neurol 
2001;50(2):150-156.
36.
Jagust WJ, Zheng L, Harvey DJ, Mack WJ, Vinters HV, Weiner MW, et al. Neuropathological basis of 
magnetic resonance images in aging and dementia. Ann Neurol 2008;63(1):72-80.
37.
JNJ-54861911 Investigator's Brochure Edition 7, 24 August 2017. Document. ID No. EDMS- ERI-
56624413:10.0.
38.
Jonsson T, Atwal J, Steinberg S, et al.  A mutation in APP protects against Alzheimer’s disease and age-related 
cognitive decline. Nature 2012;488(7409): 96–99. 
39.
Karantzoulis S, Novitski J, Gold M, Randolph C. The Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS): Utility in Detection and Characterization of Mild Cognitive Impairment 
due to Alzheimer's Disease. Arch Clin Neuropsychol. 2013;28(8):837-844.
40.
Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal 
for the development of therapeutics. Nat Rev Drug Discov 2011;10(9):698-712.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
108
Approved, Date: 6 September 2017
41.
Kobayashi D, Zeller M, Cole T et al. BACE1 gene deletion: impact on behavioral function in a model of 
Alzheimer's disease. Neurobiol Aging. 2008; 29(6):861-873.
42.
Kotani S, Sakaguchi E, Warashina S, et al. Dietary supplementation of arachidonic and docosahexaenoic acids 
improves cognitive dysfunction. Neurosci Res. 2006;56(2), 159-164.
43.
Lee VM, Trojanowski JQ. Progress from Alzheimer's tangles to pathological tau points towards more effective 
therapies now. J Alzheimers Dis. 2006;9(3 suppl):257-262. Review.
44.
Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with 
mild cognitive impairment. JAMA. 2009; 302(4):385-393. 
45.
McDonald CR, McEvoy LK, Gharapetian L, Fennema-Notestine C, Hagler DJ, Holland D. Regional rates of
neocortical atrophy from normal aging to early Alzheimer disease. Neurology 2009;73(6):457-465.
46.
Milhorat TH and Hammock MK, Cerebrospinal fluid as reflection of internal milieu of brain In: J.H. Wood, 
Editors, Neurobiology of Cerebrospinal Fluid vol. 2, Plenum, New York (1983), pp. 1–23.
47.
O'Bryant SE, Waring SC, Cullum CM, et al. Texas Alzheimer's Research Consortium. Staging dementia using 
Clinical Dementia Rating Scale Sum of Boxes scores: a Texas Alzheimer's research consortium study. Arch 
Neurol. 2008;65(8):1091-1095.
48.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide 
Assessment (C-CASA): Classification of suicidal events in the FDA’s pediatric suicidal risk analysis of 
antidepressants. Am J Psychiatry. 2007;164(7):1035–1043.
49.
Riemenschneider, M, Wagenpfeil S, Vanderstichele H, et al. Phospho‑Tau/total Tau ratio in cerebrospinal 
fluid discriminates Creutzfeldt–Jakob disease from other dementias. Mol Psychiatr. 2003;8(3):343–347.
50.
Randolph, C. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). San Antonio: 
Harcourt, TX: The Psychological Corporation. 1998a.
51.
Randolph C, Tierney MC, Mohr E, & Chase T N. The Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS): Preliminary Clinical Validity. Journal of Clinical and Experimental 
Neuropsychology, 1998b;20(3):310-319. 
52.
Risacher SL, Shen L, West JD, Kim S, McDonald BC, Beckett LA, et al. the Alzheimer’s Disease 
Neuroimaging Initiative (ADNI). Longitudinal MRI atrophy biomarkers: relationship to conversion in the 
ADNI cohort. Neurobiol Aging 2010;31(8):1401-1418.
53.
Rochin L, Hurbain I, Serneels L et al. BACE2 processes PMEL to form the melanosome amloid matrix in 
pigment cells. Proc Natl Acal Sci USA. 2013; 110(26): 10658-10663.
54.
Salloway S1, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, 
Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu 
E, Grundman M, Yuen E, Black R, Brashear HR (2014). Two phase 3 trials of bapineuzumab in mild-to-
moderate Alzheimer's disease. N Eng J Med 370, 322-333.
55.
Silbert LC, Quinn JF, Moore MM, Corbridge E, Ball MJ, Murdoch G, et al. Changes in premorbid brain 
volume predict Alzheimer’s disease pathology. Neurology 2003;61(4):487-492.
56.
Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer's disease: 
Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic 
guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):280-292.
57.
Storandt M, Mintun MA, Head D, Morris JC. Cognitive decline and brain volume loss as signatures of cerebral 
amyloid-beta peptide deposition identified with Pittsburgh compound B: cognitive decline associated with 
Abeta deposition. Arch Neurol. 2009;66(12):1476-1481.
58.
Vemuri P, Simon G, Kantarci K, Whitwell JL, Senjem ML, Przybelski SA, et al. Antemortem differential
diagnosis of dementia pathology using structural MRI: Differential-STAND. Neuroimage 2011;55(2): 522-
531.
59.
Vos SJ, Xiong C, Visser PJ, et al. Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. 
Lancet Neurol. 2013;12(10): 957-965.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
109
Approved, Date: 6 September 2017
60.
Walsh SP, Raman R, Jones KB, Aisen PS; Alzheimer’s Disease Cooperative Study Group. ADCS Prevention 
Instrument Project: the Mail-In Cognitive Function Screening Instrument (MCFSI). Alzheimer Dis Assoc 
Disord. 2006;20(4 Suppl 3):S170-S178.
61.
Willem M, Garratt AN, Novak B et al. Control of peripheral nerve myelination by the ß-secretase BACE1. 
Science. 2006; 314 (5799):664-666.
62.
Wilson JS, Mruthinti S, Buccafusco JJ, et al. S. Anti-RAGE and Abeta immunoglobulin levels are related to 
dementia level and cognitive performance. J Gerontol A Biol Sci Med Sci. 2009;64(2): 264-271.
63.
Whitwell JL, Jack Jr CR, Pankratz VS, Knopman DS, Boeve BF, Petersen RC, et al. Rates of brain atrophy 
over time in autopsy-proven frontotemporal dementia and Alzheimer disease. Neuroimage 2008;39(3): 1034-
1040.
64.
Whitwell JL, Jack Jr CR, Przybelski SA, Parisi JE, Senjem ML, Boeve BF, et al. Temporoparietal atrophy: a 
marker of AD pathology independent of clinical diagnosis. Neurobiol Aging 2011;32(9):1531-41.
65.
Zarow C, Vinters HV, Ellis WG, Weiner MW, Mungas D, White L, et al. Correlates of hippocampal neuron 
number in Alzheimer’s disease and ischemic vascular dementia. Ann Neurol 2005;57(6):896-903.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
110
Approved, Date: 6 September 2017
Attachment 1: Evaluation of Increased Liver Enzymes
The following process should be followed whenever per protocol assessments for a given subject 
indicate an elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
≥3× upper limit of normal (ULN):
1.
Initial Investigation
Within 24 to 72 hours of receipt of abnormal laboratory results, the investigator and study site 
are to perform the following: 
a.
Repeat blood sampling: 
o
Chemistry (include amylase if subject has abdominal pain or vomiting)
o
Complete hematology with eosinophil count
o
International normalized ratio (INR)
o
Hepatitis serology: 
o
Hepatitis A: anti HAV IgG, anti HAV IgM 
o
Hepatitis B : HBsAg, anti-HBc, anti-HBs
o
Hepatitis C: anti-HCV
o
Hepatitis E: anti-HEV IgG and IgM
o
Epstein Barr virus (EBV): anti-VCA IgG and IgM, anti-EBNA IgG
o
CMV: anti-CMV IgG and IgM.)
o
Anti-nuclear antibody (ANA)
o
One 5 mL sample of plasma for exploratory studies to evaluate the potential cause 
or risk factors for drug-related liver injury.
b. Collect detailed history of present illness and additional medical history, to include:
o
Recent abdominal pain, pruritis, rash
o
Prior abnormal liver tests, liver disease, exposure to hepatotoxins, diabetes, obesity, 
marked hypertriglyceridemia, gallstone disease or family history of gallstone or 
liver disease  
o
Record alcohol use, other medications including acetaminophen, nonsteroidal 
anti-inflammatory drugs and over-the-counter herbal, vitamin, special diets, or 
nutritional supplements; any recent change in prescription drugs with start and stop 
dates; exposure to environmental chemical agents, or recreational drug use.
c.
Perform a full physical exam, with specific comments on:
o
Palpable liver, size, tenderness
o
Palpable spleen, size, tenderness
o
Jaundice
o
Stigmata of chronic liver disease: spider angiomata, gynecomastia, palmar 
erythema, testicular atrophy
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
111
Approved, Date: 6 September 2017
d. Schedule  mandatory hepatic/pancreatic ultrasound 
2.
Follow-up Blood Sampling and Ongoing Contact with Medical Monitor 
After the initial investigation, regardless of results, serum chemistry is to be performed (using the 
central lab retest kit) per the schedule below (Table 1) and close contact with the medical 
monitor with a minimal contact frequency (as outlined in the table) is also expected.
Table 1:
Minimum Schedule for Follow-Up Blood Sampling and Contact with Medical Monitor 
AST or ALT Levels From Most Recent Laboratory Values
>5×ULN
>3, <5×ULN
>1, <3×ULN
WNL
Blood sampling 
frequency
2× per week
1× per week
Once every 2 
weeks until 
sponsor 
approves 
reduction to 1× 
per month
1× per month until 3 consecutive 
months within normal limits, then 
Resume the standard, per protocol 
schedule
Frequency of 
site contact with 
medical monitor
1× per week
1 x per week
1× per month
Once, just prior to resumption of the 
standard, per protocol schedule
Abbreviations: ALT=alanine aminotransferase, AST=aspartate aminotransferase; ULN=upper limit of normal; WNL=within 
normal limits
3.
Hepatology/Gastroenterology Consult
Mandatory, urgent hepatology/gastroenterology consult must be conducted if any of the 
following occurs: 

AST or ALT ≥8× ULN

AST or ALT ≥3× ULN with symptoms

AST or ALT ≥3× ULN and total bilirubin ≥2 mg/dL

AST or ALT ≥5× ULN persists for >1 week

AST or ALT ≥3× ULN persists for >2 weeks
4.
Discontinuation of Study Treatment:
Between Weeks 52 and 64, treatment must be discontinued if any of the following occurs:

ALT or AST >5× ULN

ALT or AST >3× ULN and total bilirubin >2× ULN or INR >1.5

ALT or AST >3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia >5%
After Week 64, treatment must be discontinued if any of the following occurs:

ALT or AST >8× ULN
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
112
Approved, Date: 6 September 2017

ALT or AST > 5× ULN for more than 2 weeks

ALT or AST >3× ULN and total bilirubin >2× ULN or INR >1.5

ALT or AST >3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia >5%
5.
SAE Reporting
Subjects who meet the criteria for discontinuation of study treatment should have the event 
reported as an SAE and should follow the SAE reporting process as outlined in Section 12.3.2 of 
the protocol. 
6.
Continuation or Resumption of Study Treatment: 
Study treatment may continue in asymptomatic subjects who do not meet the discontinuation 
rules, however, the investigator/site must adhere to the blood sampling and contact with Medical 
Monitor schedule in Table 1. 
For subjects resuming treatment after an interruption of less than 7 days, the blood sampling 
schedule in Table 1 should be followed. In case treatment is resumed after interruption of more
than 7 days, resumption of treatment must be discussed with and approved by the sponsor 
medical monitor. In these cases, follow-up blood sampling should occur weekly for the first 
month and thereafter Table 1 should be followed.  Dosages should be at the same level as before 
the interruption. 
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
113
Approved, Date: 6 September 2017
Attachment 2: Adverse Events of Special Interest
The following events are considered to be events of special interest:

Lightening of skin

Lightening of hair

Ophthalmologic adverse events 
Cases of lightening of skin or lightening of hair should result in dermatological consultation with 
digital photography of the lesions; if these are deemed adverse events, they are to be categorized 
as AESIs, and should be reported to the sponsor within 24 hours of the knowledge of the event. 
Site to record these events on the adverse events eCRF page checked as AESI, with expedited 
reporting.
Treatment-emergent ophthalmological adverse events should be categorized as AESIs. Site to 
record this adverse event on the adverse event eCRF page checked as “AESI”, with expedited 
reporting. An examination by the ophthalmologist who performed the initial examination at 
screening should be requested when new ophthalmological findings or visual symptoms emerge, 
or if OCT reveals new findings.
NCT02406027


JNJ-54861911
Clinical Protocol 54861911ALZ2004 Amendment 6
114
Approved, Date: 6 September 2017
INVESTIGATOR AGREEMENT
NCT02406027

SAP_001.pdf: 
1
Approved, Date: 24 September 2018
Janssen Research & Development *
Statistical Analysis Plan
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
Protocol 54861911ALZ2004; Phase 2
JNJ-54861911 (atabecestat)
Status:
Approved  
Date:
24 September 2018
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-118270350
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
2
Approved, Date: 24 September 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 3
ABBREVIATIONS ........................................................................................................................................ 3
1.
INTRODUCTION ................................................................................................................................ 4
1.1.
Trial Objectives.................................................................................................................................. 4
1.2.
Trial Design ....................................................................................................................................... 4
1.3.
Statistical Hypotheses for Trial Objectives............................................................................................ 5
1.4.
Sample Size Justification..................................................................................................................... 5
1.5.
Randomization and Blinding................................................................................................................ 5
2.
GENERAL ANALYSIS DEFINITIONS ............................................................................................... 6
2.1.
Analysis Phase ................................................................................................................................... 6
2.2.
Treatment Groups............................................................................................................................... 6
2.3.
Analysis Sets...................................................................................................................................... 6
2.4.
Study Days......................................................................................................................................... 6
2.5.
Visit Windows.................................................................................................................................... 7
2.6.
Pooling Algorithm for Analysis Centers ............................................................................................... 7
3.
SUBJECT INFORMATION ................................................................................................................. 7
3.1.
Demographics and Baseline Characteristics .......................................................................................... 7
3.2.
Disposition Information ...................................................................................................................... 7
3.3.
Prior and Concomitant Medications...................................................................................................... 7
3.4.
Extent of Exposure ............................................................................................................................. 8
3.5.
Protocol Deviations............................................................................................................................. 8
4.
SAFETY............................................................................................................................................... 8
4.1.
Adverse Events................................................................................................................................... 8
4.2.
Clinical Laboratory Tests .................................................................................................................... 9
4.3.
Electrocardiogram (ECG).................................................................................................................. 11
4.4.
Vital Signs ....................................................................................................................................... 12
5.
PHARMACOKINETIC AND PK/PHARMACODYNAMIC RELATIONSHIP ANALYSES.............. 12
6.
PHARMACODYNAMIC/BIOMARKER ANALYSES ....................................................................... 12
6.1.
CSF................................................................................................................................................. 13
7.
CLINICAL SCALES AND FUNCTIONAL ASSESSMENT ANALYSES ........................................... 13
7.1.
Clinical Dementia Rating Scale (CDR)............................................................................................... 13
7.2.
Cognitive Function Index (CFI) ......................................................................................................... 14
8.
COGNITIVE ASSESSMENT ANALYSES ......................................................................................... 15
8.1.
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) .................................... 15
8.2.
Mini Mental State Examination (MMSE)............................................................................................ 16
8.3.
California Verbal Learning Test – Second Edition (CVLT-II)............................................................... 17
9.
REFERENCES................................................................................................................................... 18
ATTACHMENTS ........................................................................................................................................ 18
1.
PCI CRITERIA FOR CLINICAL LABORATORY RESULTS AND VITAL SIGNS ......................... 18
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
3
Approved, Date: 24 September 2018
AMENDMENT HISTORY
ABBREVIATIONS
Aβ
amyloid β (beta)
AD
Alzheimer’s disease
AE
adverse event
APP
amyloid precursor protein
BACE
-secretase
BMI
body mass index
CDR
Clinical Dementia Rating Scale
CDR-SB
Clinical Dementia Rating Scale – Sum of Boxes
CFI
Cognitive Function Index
CI
confidence interval
CRF
case report form
CSF
cerebrospinal fluid
CSR
Clinical Study Report
CVLT-II
California Verbal Learning Test – Second Edition
ECG
Electrocardiogram
eCRF
electronic case report form
ICF
informed consent form
MedDRA
Medical Dictionary for Regulatory Activities
MMSE
Mini Mental State Examination
PCI
potentially clinically important
PD
Pharmacodynamic
PK
pharmacokinetic(s)
RBANS
Repeatable Battery for the Assessment of Neuropsychological Status
SAE
serious adverse event
sAPP
soluble amyloid precursor protein
SAP
Statistical Analysis Plan
SD
standard deviation
TE
treatment-emergent
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
4
Approved, Date: 24 September 2018
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for the safety, pharmacodynamic (PD)/biomarker, clinical and cognitive 
evaluation analyses for Periods 1 and 2.
1.1.
Trial Objectives
Primary Objective
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. 
Secondary Objectives
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 CSF and plasma.

To assess the relationship of changes in CSF and plasma Aβ 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
Exploratory Objectives

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.
1.2.
Trial Design
This is a randomized, two-period, double-blind (DB) placebo controlled and open-label (OL), 
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. 
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
5
Approved, Date: 24 September 2018
Subjects who provide consent to enroll in this study and who meet the inclusion criteria, may 
start at Day 1 of the DB treatment phase in lieu of the end of treatment visit in 
54861911ALZ2002 study. For subjects that have completed the end of treatment visit in the 
54861911ALZ2002 study enrollment in this study should be completed (Day 1 of DB treatment 
phase) as soon as possible, but within 6 weeks, following completion of their treatment period 
under the parent protocol (54861911ALZ2002 study) of currently ongoing or any future Phase 
1b or Phase 2 studies with JNJ-54861911.
Eligible subjects enrolled in this study will receive either JNJ-54861911 (10 mg 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) (placebo-controlled DB treatment phase).
Following the initial 52-Week (12-Month) treatment phase (DB treatment phase) in this study, 
subjects receiving placebo in the DB treatment phase will be randomized with equal chance to 
one of 2 active JNJ-54861911 dose levels (i.e., 5-mg q.d JNJ-54861911 or 25-mg q.d. JNJ-
54861911) for continuous treatment in OL phase. As such during OL phase, 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.
1.3.
Statistical Hypotheses for Trial Objectives
This is a study to collect primarily long-term safety and tolerability data. There is no formal 
hypothesis testing planned for this long-term study which is an extension of 54861911ALZ2002 
study.
1.4.
Sample Size Justification
The study is not powered according to statistical calculations. The number of subjects enrolled 
will depend on the number of subjects from other JNJ-54861911 studies who are willing to 
enroll in this extension study.
1.5.
Randomization and Blinding
During the DB treatment phase, subjects will receive either JNJ-54861911 (10-mg or 25-mg q.d.) 
based on their current treatment/dosing regimen assigned under the parent protocol 
(54861911ALZ2002).
Both the investigator and subject will be blinded during Treatment Period 1 of the study.
Regarding the sponsor, when the parent study (54861911ALZ2002) is completed and its clinical 
database is closed, the randomization codes from the parent study will be released to the sponsor 
study team. Thus, the sponsor will be unblinded at that time, but the investigator and subjects 
will continue to be blinded to treatment during DB treatment phase. (cf. Protocol Amendment 2)
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
6
Approved, Date: 24 September 2018
2.
GENERAL ANALYSIS DEFINITIONS
Statistical analyses will be performed for all subjects receiving at least one dose of study drug in 
this study Period 1. This analysis summarizes double-blind treatment Period 1 and open-label 
Period 2. All analyses will be performed using SAS Version 9.41 or higher.
2.1.
Analysis Phase
Period 1 start date will be the date and time of first administration of double-blind study 
medication. Period 1 end date will be equal to the date of the last Period 1 visit or the date of 
discontinuation if the subject discontinues during Period 1. 
Period 2 start date will be the date/time of first administration of open-label study medication. 
Period 2 end date will be equal to the date of the last Period 2 visit or the date of discontinuation 
if the subject discontinues during Period 2.
2.2.
Treatment Groups
Tables for double-blind Period 1 summarizing data by the treatment group will have columns for 
‘Placebo’, ‘Ata 10mg’ and ‘Ata 25mg’ and a ‘Total’ column. The Total includes all 3 groups. 
Summaries will be by planned treatment. For tables summarizing data by treatment group and 
baseline CDR status (‘Prodromal’ or ‘Asymptomatic at Risk’) within treatment group, the 
baseline CDR status is the pre-dose baseline from the parent study (ALZ2002).
Tables for open-label Period 2 will have columns indicating the double-blind to open-label 
treatment sequence as follows: ‘Placebo / Ata 5mg’, ‘Placebo / Ata25 mg’, ‘Ata 10mg / Ata 
5mg’, ‘Ata 25mg/ Ata 25mg’, and ‘Total’, where Total includes all 4 groups. The double-blind 
part of the treatment sequence is the planned treatment from double-blind Period 1. For subjects 
who were on placebo in Period 1, the open-label treatment is determined from ZR.ZRORRES 
where ZRTESTCD= “TXP”. For subjects in Ata 10mg in Period 1, the open-label treatment is 
‘Ata 5mg’, and for subjects in Ata 25mg in Period 1, the open-label is Ata 25mg.
2.3.
Analysis Sets
The DB Safety Analysis Set is defined as all subjects who receive study treatment during Period 
1. 
The OL Safety Analysis Set is defined as all subjects who received study treatment during Period 
2.
2.4.
Study Days
Study day will be calculated relative to each subject’s first dose in Period 1 in this study. 
If the measurement date is on or later than the first dose date then:
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
7
Approved, Date: 24 September 2018
study day = measurement date – first dose date + 1
If the measurement date is earlier than the first dose date:
study day = measurement date – first dose date.
Where applicable, study day will also be calculated relative to the first dose in the parent study 
ALZ2002.
For subjects in the OL Safety Analysis Set, an OL study day will be calculated relative to the 
first dose in Period 2.
2.5.
Visit Windows
All “by-visit” analyses will be presented by scheduled study visit as recorded on the eCRF; no 
visit windows will be used. Unscheduled assessments will be presented in by-subject data 
listings. All visit names will include identifiers for the study (e.g. Day 1 ALZ2002, Week 52 
ALZ2004). 
2.6.
Pooling Algorithm for Analysis Centers
Data from all investigative sites (centers) will be combined for analysis irrespective of the site in 
which the subject undergoes evaluations.
3.
SUBJECT INFORMATION
3.1.
Demographics and Baseline Characteristics
The following demographics and baseline characteristics will be summarized using descriptive 
statistics by treatment group: age (continuous as well as by age group [<65, 65-75, >75 years]), 
sex, race, ethnicity, early AD spectrum status (asymptomatic at risk or prodromal) based on CDR 
at baseline in ALZ2002, baseline height (HT, cm), baseline weight (WT, kg); baseline BMI 
calculated as WT / (HT/100)2. 
The number of subjects enrolled will be tabulated by country and site for the DB Safety analysis 
set and for the OL Safety analysis set, separately.
3.2.
Disposition Information
Completion on the eCRF is not documented separately for Periods 1 and 2.  The disposition for 
subjects in the DB Safety analysis set will be summarized for Period 1 according to the Period 1 
analysis start/end dates. Subjects who did not discontinue during Period 1 and are part of the OL 
Safety analysis set will be considered to have completed the Period 1. Disposition for subjects in 
the OL Safety analysis set will be summarized separately.
3.3.
Prior and Concomitant Medications
Medications received from the signing of the ICF prior to this study start and concomitantly 
during this study Period 1 will be tabulated for the DB Safety Analysis Set. The number and 
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
8
Approved, Date: 24 September 2018
percentage of subjects receiving each concomitant medication will be tabulated by ATC class
and generic term and treatment group, where concomitant for Period 1 is defined as medications 
taken during Period 1 this study (excludes medications that were stopped prior to first dose of 
study drug in ALZ2004 or those which were started on or after the first dose of Period 2). 
Similar tabulations will be prepared for subjects in the OL Safety Analysis Set, where 
concomitant for Period 2 is defined as medications taken during Period 2 of the study (excludes 
medications that were stopped prior to the first dose of study drug in Period 2). Study days of the 
start of the concomitant medication relative to the first dose of study drug in Period 1 (for all 
subjects) and relative to the first dose in Period 2 (for subjects in the OL Safety analysis set) will 
be included in the listings.
3.4.
Extent of Exposure
The total number of subjects who received study drug in Period 1 in this study will be presented 
by treatment group. Duration of exposure to study drug in Period 1 of this study will be 
summarized by treatment group.  Duration of exposure will be defined as the study day (relative 
to start of ALZ2004) of the last Period 1 record in the exposure dataset.  Tables for Period 1 
exposure will be summarized by treatment group for the DB Safety Analysis Set. Similar tables 
will be summarized for Period 2 for the OL Safety analysis set, where duration of exposure will 
be defined as the date of last dose in OL Period 2 – date of first dose in OL Period 2 + 1.
3.5.
Protocol Deviations
Major protocol deviations during the screening and blinded treatment periods of the study will be 
tabulated for the DB Safety analysis set. Major protocol deviations for the open-label period will 
be tabulated for the OL Safety analysis set.
4.
SAFETY
The safety data will be summarized using descriptive statistics unless otherwise specified.
4.1.
Adverse Events
The verbatim terms used in the CRFs by investigators to identify adverse events will be coded 
using the current Medical Dictionary for Regulatory Activities (MedDRA Version 19.1 or later 
version) maintained by the sponsor. All reported adverse events with onset on or after the start of 
study treatment in Period 1 and before the start of Period 2 will be will be included in the 
summary tables for DB Period 1 for the DB Safety analysis set (this will also include adverse 
events that have worsened since baseline). For a subject who withdrew before completion of 
treatment Period 1, adverse events through the day of last dose of study drug plus 7 days are 
included as treatment-emergent for Period 1. All reported adverse events with onset on or after 
the start of study treatment in Period 2 through the day of last dose in Period 2 plus 7 days will 
be will be included as treatment-emergent in the summary tables for OL Period 2 for the OL 
Safety analysis set.
The number and percentage of subjects who have experienced at least 1 occurrence of the given 
adverse event will be summarized by system organ class, preferred term and treatment group. In 
addition, serious adverse events (SAEs), AEs that result in death, and AEs that lead to study 
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
9
Approved, Date: 24 September 2018
discontinuation will be summarized by system organ class, preferred term and treatment group. 
The summaries will be presented for the DB Safety analysis set and separately for the OL Safety 
analysis set.
Incidence of other treatment-emergent adverse events of special interest defined below will be 
summarized for the DB Safety analysis set and separately for the OL Safety analysis set.
Treatment-emergent adverse events related to abnormal liver function tests (LFTs) will be 
summarized. Adverse events related to abnormal LFTs are defined as follows:

Events belonging to the MedDRA Sub_SMQ1= “Drug related hepatic disorders -
comprehensive search (SMQ)”.
Dermatological and ophthalmological events are identified by the investigator on the AE eCRF 
page and include:

Dermatological Events
o
Lightening of hair
o
Skin coloration (hypopigmentation)

Ophthalmological Events
o
Iris coloration (hypopigmentation)
o
Retinal changes
o
Other
The following subject data listings will be prepared. All AEs during this study, before first dose, 
during Period 1, during Period 2, or after last dose, (regardless of whether considered treatment-
emergent), will be included in the listings. Study days relative to the first dose in Period 1 (for all 
subjects) and study days relative to the first dose in Period 2 (for subjects in the OL Safety 
analysis set) will be included in the listings.

subjects with any AEs

subjects with serious adverse events (SAEs) 

subjects who die

subjects with AEs resulting in study discontinuation

subjects with hepatic AEs

subjects with dermatological or ophthalmological AEs. 
4.2.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test by treatment group for the DB 
Safety Analysis Set and the OL Safety analysis set.
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
10
Approved, Date: 24 September 2018
Baseline for the DB Safety analysis set will be defined as the most recent (last) value taken on or 
prior to the day of first dose of study drug in parent study ALZ2002.  Baseline for the OL Safety 
analysis set will be defined as the most recent (last) value taken on or before the day of first dose 
of study drug in OL Period 2.
Descriptive statistics will be summarized for each laboratory test at baseline and at each Period 1 
post-baseline scheduled time point, and for the change from baseline, by treatment group, for the 
DB Safety Analysis Set. A similar summary will be presented for baseline and each Period 2 
scheduled time point for the OL Safety Analysis Set.
Shifts in laboratory test values from baseline to each post-baseline scheduled time point in Period 
1 will be cross-tabulated using the laboratory normal range categories (L, N, H; for below, 
within, and above normal ranges, respectively) for each treatment group for the DB Safety 
analysis set.  Similar tabulations will be presented for Period 2 for the OL Safety analysis set.  A 
listing of subjects with any laboratory results outside the normal ranges will be provided.
Potentially clinically important (PCI) hematology, chemistry, and urinalysis laboratory values 
will be flagged using the criteria in Attachment 1 below. A treatment-emergent (TE) PCI value 
for Period 1 or Period 2 is defined as a post-baseline value during Period 1 or Period 2, 
respectively, that meets the criteria, but the baseline value did not meet the criteria. The number 
and percentage of subjects with TE PCI values will be summarized separately for Period 1 and 
Period 2 by treatment group. A listing of subjects with any TE PCI values will be provided.
The number of subjects with at least 1 abnormal (>1xULN) postbaseline ALT or AST value in 
Period 1 will be summarized by treatment group for the DB Safety analysis set. The categories 
are shown below. A similar summary for Period 2 will be presented for the OL Safety analysis 
set.
AST or ALT
<=ULN
>ULN-<=2*ULN
>2*ULN-<=3*ULN
>3*ULN
Kaplan-Meier estimates of time to first occurrence of ALT elevation (>1xULN and >3xULN) in 
Period 1 will be presented graphically by treatment group for the DB Safety analysis set. 
Subjects who have an ALT elevation will be considered an “event” and the time will be the study 
day of the first ALT elevation in Period 1. Subjects who do not have an ALT elevation in Period 
1 will be censored at the day of the last ALT measurement in Period 1. 95% confidence intervals 
for the quartiles of the time to event will be estimated for each treatment group using the Kaplan-
Meier method. Similar analyses will be presented for Period 2 only for the “Placebo / Ata 5mg” 
and “Placebo / Ata 25mg” groups of the OL Safety analysis set.
The peak Period 1 TB (total bilirubin) times the upper limit of the reference range (ULRR) will 
be plotted against the peak Period 1 ALT times the ULRR, on a log10 scale (eDISH plot). A 
similar plot will be presented for Period 2.
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
11
Approved, Date: 24 September 2018
4.3.
Electrocardiogram (ECG)
The ECG parameters that will be analyzed are RR interval, PR interval, QRS interval, QT 
interval and corrected QT (QTc). If there is more than one value at the same time point on the 
same visit day for a subject, the average of these will be used for the analysis value. ECG 
parameters will be summarized by treatment group for the DB Safety Analysis Set and the OL 
Safety analysis set.
If not provided in SDTM data, QTcB and QTcF will be calculated using QT and RR interval 
from each time point as below, where the QT interval is measured in msec and the RR interval is 
measured in seconds.  QTcF is the primary correction of QT interval for the heart rate. 
Bazett’s correction (QTcB) = QT/RR1/2 (FDA Guidance E14 2005)
Fridericia’s correction (QTcF) = QT/RR1/3 (FDA Guidance E14 2005)
Baseline for the DB Safety analysis set will be defined as the most recent (last) measurement on 
or prior to the day of first dose of study drug in the parent study ALZ2002.  Baseline for the OL 
Safety analysis set will be defined as the most recent (last) measurement on or before the day of 
first dose of study drug in OL Period 2.
Descriptive statistics will be summarized for each ECG parameter at baseline and at each Period 
1 post-baseline scheduled time point, and for the change from baseline, by treatment group, for 
the DB Safety Analysis Set. A similar summary will be presented for baseline and each Period 2 
scheduled time point for the OL Safety Analysis Set.
The number and percentage of subjects who are flagged with abnormal values in Period 1 will be 
summarized by treatment group for the DB Safety analysis set. A similar summary for Period 2 
will be presented for the OL Safety analysis set. Subjects with abnormal ECG values will be 
presented in a data listing.  The following abnormality limits will be used for observed ECG 
parameters.

Heart rate: L < 50 bpm; H > 100 bpm 

PR interval: L < 120 msec; H > 200 msec 

QRS interval: L < 70 msec; H > 120 msec 

QT interval: H > 500 msec 

QTc interval: H > 450 msec 

QTc interval: L <330 msec 
In addition, potentially clinically important (PCI) QTc values and changes from baseline during 
Period 1 for the DB Safety Analysis Set will be flagged using the criteria below. The number and 
percentage of subjects with PCI QTc values and changes from baseline will be summarized by 
treatment group. A similar summary for Period 2 will be presented for the OL Safety analysis 
set. A listing of subjects with any PCI QTc values and changes from baseline will be provided.
Criteria for Potentially Clinically Important QTc Values and Changes From Baseline
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
12
Approved, Date: 24 September 2018
Classification
QTc change from baseline
No concern
30
Concern
>30 – 60
Clear concern
> 60
QTc value (Males)
Normal
450
>450-480
>450 – 480
>480-500
>480 – 500
>500
>500
QTc value (Females)
Normal
470
>470-500
>470 – 500
>500
>500
These criteria are based on the ICH E14 Guideline
4.4.
Vital Signs
Supine and standing vital signs (systolic and diastolic blood pressure and pulse), body 
temperature and body weight will be summarized at each scheduled time point.
Baseline for the DB Safety analysis set will be defined as the most recent (last) measurement on 
or prior to the day of first dose of study drug in the parent study ALZ2002.  Baseline for the OL 
Safety analysis set will be defined as the most recent (last) measurement on or before the day of 
first dose of study drug in OL Period 2.
Descriptive statistics will be summarized for each vital sign measurement at baseline and at each 
Period 1 post-baseline scheduled time point, and for the change from baseline, by treatment 
group, for the DB Safety Analysis Set. A similar summary will be presented for baseline and 
each Period 2 scheduled time point for the OL Safety Analysis Set.
Potentially clinically important (PCI) values and changes from baseline and incidence of 
orthostatic hypotension during Period 1 for the DB Safety Analysis Set will be flagged using the 
criteria in Attachment 1 below. The number and percentage of subjects with PCI values and 
changes from baseline will be summarized by treatment group. A similar summary for Period 2 
will be presented for the OL Safety analysis set. A listing of subjects with any PCI values and 
changes from baseline will be provided.
5.
PHARMACOKINETIC AND PK/PHARMACODYNAMIC RELATIONSHIP 
ANALYSES
None planned.
6.
PHARMACODYNAMIC/BIOMARKER ANALYSES
All summaries of biomarker data will include subjects in the DB Safety Analysis Set, by 
treatment group and baseline CDR status.  The biomarker data will be summarized using 
descriptive statistics unless otherwise specified. If any biomarker values are reported as being 
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
13
Approved, Date: 24 September 2018
below the LLoQ then the respective LLoQ value will be used to calculate percent baseline 
reduction in order to be conservative. No biomarker summaries are planned for Period 2 for the 
OL Safety Analysis set.
6.1.
CSF
CSF samples will be obtained for measuring Aβ fragments, as well as exploratory markers, such 
as but not limited to BACE, sAPP fragments, t-tau/p-tau, and other biomarkers that may be down 
stream of amyloid.  While different Aβ fragments (Aβ1-37, Aβ1-38, Aβ1-40 and Aβ1-42) will be 
measured, Aβ1-40 is the most prevalent and will be the primary measure for determining the 
activity of JNJ-54861911.
CSF samples will be collected in ALZ2004 Period 1 at the following time points: Day 1 Predose 
(only if no on-treatment CSF sample was collected under the parent protocol) and Week 52.
Re-assay samples of studies ALZ1005 and ALZ2002 will be available at the following time 
points: ALZ1005 Baseline, ALZ1005 Day 28, ALZ2002 Baseline and ALZ2002 Day 168. 
Re-assay baseline samples of ALZ1005 or ALZ2002 will be used when assessing changes from 
baseline. For subjects who previously participated in the ALZ1005 study, the ALZ1005 baseline 
will be used. For subjects who did not participate in ALZ1005, ALZ2002 baseline will be used
Descriptive statistics will be summarized for each test at Baseline, at ALZ1005 Day 28, at 
ALZ2002 Day 168 and at ALZ2004 Week 52, and for the percent change from baseline, by 
treatment group. Corresponding time profile plots (mean and individual) for the percent change 
from baseline will be provided. 
In addition, box-whisker plots for the mean percentage change from baseline to ALZ2004 Week 
52 for each CSF biomarker will be provided by treatment group and baseline CDR status. 
7.
CLINICAL SCALES AND FUNCTIONAL ASSESSMENT ANALYSES
7.1.
Clinical Dementia Rating Scale (CDR)
The CDR assesses three domains of cognition

Memory, 

Orientation, 

Judgment/problem solving.
and three Domains of Function: 

Community affairs, 

Home/hobbies, 
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
14
Approved, Date: 24 September 2018

Personal care.
using structured interviews of both the study subject and a companion/informant.  It is carried 
out by a trained rater and scored using a standard methodology. Each domain is rated on a 5-
point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild 
impairment; 2, moderate impairment; and 3, severe impairment (Personal care is scored on a 4-
point scale without a 0.5 rating available). 
The CDR Sum of Boxes (CDR-SB) total score is calculated at the site as the sum of the ratings 
from the 6 domains.  A global CDR is also calculated from the ratings of the 6 domains. The 
CDR global score is derived from the CDR domain ratings at the site using scoring rules per 
Morris, J.C. (1993)2.
For all CDR domain ratings, CDR-SB total score and CDR global score, a higher score indicates 
greater impairment. 
The primary outcome of interest is the CDR-SB total score.  Other outcomes of interest are the 
CDR domain ratings and CDR global score. These scores during Period 1 will be summarized 
using descriptive statistics for the DB Safety analysis set, and scores during Period 2 will be 
summarized for the OL Safety analysis set. Baseline for both Period 1 and Period 2 here is 
defined as the most recent (last) measurement on or prior to the day of first dose of study drug in 
the parent study ALZ2002.
In addition, progression of CDR global score after dosing in Period 1 of ALZ2004 will be 
summarized using descriptive statistics for the DB Safety analysis set. A similar summary for 
Period 2 will be presented for the OL Safety analysis set, using the original CDR baseline from 
the parent study ALZ2002 for baseline.
7.2.
Cognitive Function Index (CFI)
The CFI is a modified version of the Mail-in Cognitive Function Screening Instrument4, a 
subject- and study partner-reported outcome measure developed by the Alzheimer’s Disease 
Cooperative Study (ADCS). Study subjects and their study partners independently rate the 
subject’s abilities in this study before dosing on Day 1, at Weeks 24 and 52 of Period 1, and 
every 24 weeks in Period 2. CFI was not assessed in the parent study. 
The questionnaire consists of 15 items, the first 14 of which assess the subject’s perceived ability 
to perform high-level functional tasks in daily life and sense of overall cognitive functional 
ability and are scored as “yes,” “maybe,” and “no”, and 1 additional question about whether the 
subject has seen a doctor in the last year about memory concerns. The first 14 item responses for 
the participant version are found in the QS dataset as QSCAT = “ADLS CFI PARTICIPANT” 
and QSTESTCD in (CFI0101, CFI0102, …, CFI0114), and for the study partner version as 
QSCAT = “ADLS CFI STUDY PARTNER” and QSTESTCD in (CFI0201, CFI0202, …, 
CFI0214). These 14 responses will be converted to corresponding numeric scores as follows: 
yes=1, maybe=0.5, and no/does not apply=0. The ADCS-CFI Total score is calculated as the 
sum of the 14 items, ranging from 0 to 14. Higher scores indicate greater impairment.
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
15
Approved, Date: 24 September 2018
In the case of missing items, if there are < 5 (<30%) missing items, an imputed total score will be 
calculated as a prorated total based on the observed items: 
14 ∗ Total score of nonmissing items
Total number of nonmissing items
Imputed total scores will be rounded to 1 decimal place. If there are 5 or more missing items, the 
ADCS-CFI Total score will be missing.
Baseline for the DB Safety analysis set will be defined as the most recent (last) assessment on or 
prior to the day of first dose of study drug in Period 1 of this study (Day 1). Baseline for the OL 
Safety analysis set will be defined as the most recent (last) assessment on or before the day of 
first dose of study drug in OL Period 2 (expected to be the Week 52 value from Period 1). 
Descriptive statistics for the ADCS-CFI Total scores (both the participant version and the study 
partner version) will be summarized at baseline and each scheduled visit in Period 1, and for the 
change from baseline, by treatment group and baseline CDR status for the DB Safety analysis 
set. A similar summary will be presented at baseline and each scheduled visit in Period 2 and for 
the change from baseline, by treatment group for the OL Safety analysis set.
8.
COGNITIVE ASSESSMENT ANALYSES
8.1.
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
The RBANS was selected because it is a widely used measure to differentiate healthy normal 
subjects from those with early disease and AD patients, is predictive of functional status, 
correlates with the CDR, biomarker and cognition in this early population. 
The RBANS is a battery of tests developed for cognitive assessment, detection, and 
characterization of dementia. The RBANS includes 12 subtests that measure 5 indices; 

Attention:  Digit Span and Coding 

Delayed Memory: List Recall, List Recognition, Story Recall and Figure Recall  

Immediate Memory: List Learning and Story Memory 

Language: Picture Naming and Semantic Fluency 

Visuospatial/Construction: Figure Copy and Line Orientation  
The raw scores from the subtests are scaled together using an RBANS conversion table to create 
index scores.  Index scores are summed to form the Sum of Index scores. The Sum of Index 
Scores is converted to the Total Scale using the RBANS Conversion Table3. 
All RBANS outcome measurements are calculated at the site.
Baseline for the DB Safety analysis set will be defined as the most recent (last) assessment on or 
prior to the day of first dose of study drug in the parent study ALZ2002. Baseline for the OL 
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
16
Approved, Date: 24 September 2018
Safety analysis set will be defined as the most recent (last) assessment on or before the day of 
first dose of study drug in OL Period 2. 
Descriptive statistics will be summarized for each score (Total Scale, Attention Index, Delayed 
Memory Index, Immediate Memory Index, Language Index, and Visuospatial/Constructional 
Index) at baseline (from ALZ2002) and at Weeks 24 and 52 in Period 1, and for the change from 
baseline, by treatment group and baseline CDR status for the DB Safety analysis set. A similar 
summary will be presented for Period 2 by treatment group for the OL Safety analysis set.
The change from baseline to Period 1 Week 52 for the RBANS Total Scale score will be 
analyzed with an ANCOVA model that includes treatment group, actual baseline CDR status and 
baseline score as a covariate for the DB Safety analysis set. The Least Squares (LS) means and 
treatment differences relative to placebo with the corresponding 95% confidence intervals will be 
provided.
The change from baseline at Period 1 Weeks 24 and 52 for the Total Scale score will be plotted 
across treatment groups by baseline CDR status to visually evaluate the dose response trend.  A 
mean plot of the observations will be plotted at each dose level by Baseline CDR Status for the 
DB Safety analysis set. 
The change from baseline at Period 1 Week 52 in the Total Scale score will be plotted against the 
change from baseline at Period 1 Week 52 in CSF Aβ1-40 for the DB Safety analysis set. Scatter 
plots of individual paired data will be produced. The points will be identified visually for each 
dose group by different colors. 
8.2.
Mini Mental State Examination (MMSE)
The Mini-Mental State Examination (MMSE) is a brief, validated 30-point questionnaire that is 
widely used to screen for cognitive impairment. The MMSE rates subjects on the following 
components: 

Orientation (to place and to time, 10 total), 

Registration (3 total),

Attention and calculation (5 total), 

Recall (3 total), and 

Language (comprehension, drawing, naming, reading, repetition, writing, 9 total). 
Each question is rated as 1 for a correct answer or 0 otherwise. The item scores in each 
component are summed to get the component score. If an item score is missing in a component, 
then that component score will be missing. An overall total score is obtained by summing all the 
item scores.  The maximum total score is 30.  The lower the score the more pronounced the 
impairment. 
The primary MMSE Outcome of interest is Total Score. 
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
17
Approved, Date: 24 September 2018
In the case of missing item scores, if there are <10 (<30%) missing items, an imputed total score 
will be calculated as a prorated total based on the observed items: 
30 ∗ Total number of correct answers
Total number of nonmissing items
Imputed total scores will be rounded to 1 decimal place. If there are 10 or more missing items, 
the total score will be missing.
Baseline for the DB Safety analysis set is defined as the baseline in parent study ALZ2002.  
Baseline for the OL Safety analysis set will be defined as the most recent (last) assessment on or 
before the day of first dose of study drug in OL Period 2. The MMSE Total Score will be 
summarized at baseline and Period 1 Week 52, and for the change from baseline, by treatment 
group and baseline CDR status for the DB Safety analysis set using descriptive statistics. A 
similar summary will be presented for Period 2 by treatment group for the OL Safety analysis 
set.
The change from baseline to Period 1 Week 52 for the MMSE Total Score will be analyzed with 
an ANCOVA model that includes treatment group, actual baseline CDR status and baseline score 
as a covariate for the DB Safety analysis set. The Least Squares (LS) means and treatment 
differences relative to placebo with the corresponding 95% confidence intervals will be 
provided.
The change from baseline at Period 1 Week 52 for the MMSE Total Score will be plotted across 
treatment groups and baseline CDR status to visually evaluate the dose response trend.  A mean 
plot of the observations will be plotted for each dose level by Baseline CDR Status for the DB 
Safety analysis set. 
The change from baseline at Period 1 Week 52 in the MMSE Total Score will be plotted against 
the change from baseline at Period 1 Week 52 in CSF Aβ1-40 for the DB Safety analysis set. 
Scatter plots of individual paired data will be produced. The points will be identified visually for 
each dose group by different colors. 
8.3.
California Verbal Learning Test – Second Edition (CVLT-II)
The CVLT-II is a face-to-face comprehensive neuropsychological measure of verbal memory in 
individuals 16 to 89 years old, designed to quantify components of verbal learning, retention and 
retrieval. This test will be administered only to subjects who had completed it in the parent 
protocol ALZ2002. This test was performed on Day 1, prior to dosing in ALZ2002, and at Week 
12 in Period 1 of this study ALZ2004 (baseline).
The following scores will be derived: Immediate recall, Short-delay recall, Long-delay recall, All 
recall types, and Long-delay recognition. These scores were already derived at baseline in 
ALZ2002 by summing the scores from the ALZ2002 tests listed in the table below. The scores 
for Period 1 Week 12 in ALZ2004 will be derived by summing the scores of the corresponding 
ALZ2004 tests listed below. 
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
18
Approved, Date: 24 September 2018
Derived Test Name
Test Name (FTTEST) in ALZ2002
Test Name (FTTEST) in ALZ2004
1. Immediate recall 
CVLT01-List B Free Recall Immediate
List B Free Recall
1. Immediate recall 
CVLT01-List A Free Recall Immed Total
Trial 1-5
2. Short-delay recall 
CVLT01-List A Cued Recall Short Delay
Short-Delay Cued Recall
2. Short-delay recall 
CVLT01-List A Free Recall Short Delay
Short-Delay Free Recall
3. Long-delay recall 
CVLT01-List A Cued Recall Long Delay
Long-Delay Cued Recall
3. Long-delay recall 
CVLT01-List A Free Recall Long Delay
Long-Delay Free Recall
4. All recall types
CVLT01-Cued Recall Intrusions
Cued-Recall Intrusions
4. All recall types
CVLT01-Free Recall Intrusions
Free-Recall Intrusions
4. All recall types
CVLT01-Total Intrusions
Total Intrusions
4. All recall types
CVLT01-Total Repetitions
Total Repetitions
5. Long-delay recognition
CVLT01-List A Yes/No False-Positives
Long-Delay Recognition False-Positives
5. Long-delay recognition
CVLT01-List A Yes/No Hits
Long-Delay Recognition Hits
Descriptive statistics will be summarized for each derived score at baseline and at Period 1 Week 
12, and for the change from baseline, by treatment group and baseline CDR status, for the DB 
Safety analysis set.
9.
REFERENCES
1.
SAS Institute, Inc., Version 9.4, Cary, NC.
2.
Morris, J.C. (1993). The clinical dementia rating (CDR): Current version and scoring rules. Neurology, 43(11), 
2412-2414.
3.
Randolph, Christopher. RBANS Repeatable Battery for assessment of Neuropsychological status.
4.
Walsh SP, Raman R, Jones KB, Aisen PS; Alzheimer’s Disease Cooperative Study Group. ADCS Prevention 
Instrument Project: the Mail-In Cognitive Function Screening Instrument (MCFSI). Alzheimer Dis Assoc 
Disord. 2006; 20(4 Suppl 3):S170-S178.
ATTACHMENTS
1.
PCI CRITERIA FOR CLINICAL LABORATORY RESULTS AND VITAL 
SIGNS
Test
Criteria for Low PCI 
Values
Criteria for High PCI 
Values
Hematology
WBC Leukocytes (x10E9/L)
<3
>16
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
19
Approved, Date: 24 September 2018
Eosinophils (x10E9/L)
NA
> 0.6
Lymphocytes (x10E9/L)
<0.8
NA
Monocytes (x10E9/L)
NA
> 1.0
Neutrophils, Segmented 
(x10E9/L)
<1.5
> 8.0
Platelets (x10E9/L)
< 75
> 700
Hematocrit (fraction)
<0.3
> 0.5 females, 
> 0.55 males
Hemoglobin (g/L)
value <100 or 
change from baseline <= 
- 20
>165 females,
>185 males
MCV (fL)
< 75
>105 
Chemistry
Serum Albumin (g/L)
< 30
NA
Alkaline Phosphatase  (U/L)
NA
> 2.5 ULN
ALT (U/L)
NA
> 3 ULN
AST (U/L)
NA
> 3 ULN
Bicarbonate (mmol/L)
< 17 
> 32 
Direct Bilirubin (umol/L)
NA
> 1.5 ULN
Total Bilirubin (umol/L)
NA
> 1.5 ULN
BUN (mmol/L)
NA
> 1.5 ULN
Calcium (mmol/L)
< 2.0
> 2.7
Chloride (mmol/L)
< 94 
> 112 
Cholesterol (mmol/L)
Creatine Kinase (U/L)
NA
> 1.5 ULN
Creatinine (umol/L)
NA
> 1.5 ULN 
GGT (U/L)
NA
> 75 
Glucose (mmol/L)
< 3.9
> 5.6
HDL Cholesterol (mmol/L)
LDH (U/L)
Phosphate (mmol/L)
< 0.7
> 1.7
Potassium (mmol/L)
< 3
> 5.5
Protein (g/L)
< 60
> 80
Sodium (mmol/L)
< 135
> 145
Triglycerides (mmol/L)
Urate (umol/L)
< 150
> 500
Urinalysis
pH
< 4
> 8
Specific Gravity
NA
> 1.035
Vital Signs
Systolic BP (mmHg)
< 90
>180
Diastolic BP (mmHg)
<50
>105
Pulse (beats/min)
<50
>120
Temperature (C)
<36
>38
NCT02406027


JNJ-54861911 (atabecestat)
Statistical Analysis Plan 54861911ALZ2004
20
Approved, Date: 24 September 2018
Weight (kg)
Decrease of 10% relative 
to baseline
Increase of 10% relative 
to baseline
Orthostatic Hypotension
Decrease in systolic 
(>20 mm Hg) or diastolic 
(>10 mm Hg) blood 
pressure after standing 
for at least 2 minutes 
relative to supine 
position with an increase 
in pulse rate of >15 beats 
per minute.
NCT02406027