Clinical trial NCT02080364
Conditions: Alzheimer's Disease
Keywords: Alzheimer's disease RAGE ADAS-cog CDR-sb
Sponsor: vTv Therapeutics
Start date: 2015-04-01; Completion date: 2018-06-01
Enrollment: 880 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study to evaluate the efficacy and safety of azeliragon in patients with mild Alzheimer's disease. Patients will receive either azeliragon or placebo with a patient's participation lasting approximately 18 months.

Detailed description:

Arms: arm 1: Azeliragon (TTP488) 5mg orally once daily for 18 months arm 2: Placebo orally once daily for 18 months
Interventions: intervention 1: Azeliragon intervention 2: Placebo
Intervention descriptions: intervention 1: Azeliragon 5mg administered orally, once daily for 18 months intervention 2: Placebo administered orally, once daily for 18 months

Protocol documents:
Prot_000.pdf: 
 
 
 
 
vTv THERAPEUTICS LLC 
 4170 MENDENHALL OAKS PKWY 
 HIGH POINT, NC 27265 
 
 
TITLE PAGE 
 
CLINICAL TRIAL PROTOCOL
 
 
RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, MULTI-CENTER 
REGISTRATION TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF TTP488 
IN PATIENTS WITH MILD ALZHEIMER'S DISEASE RECEIVING 
ACETYLCHOLINESTERASE INHIBITORS AND/OR MEMANTINE 
 
 
Investigational Product:     
TTP488 
Investigational Product Name:    
Azeliragon 
US IND Number:     
 
68,445 
Health Canada File Number: 
9427-T1538-21C 
EudraCT Number:  
 
2016-002005-19 
Protocol and Study Number:    
TTP488-301 
Clinical Phase: 
 
 
Phase 3 
Version and Date: 
 
 
AMENDMENT 7 
  
 
 
 
 
28 NOVEMBER 2017 
 
 
CONFIDENTIAL 
 
This protocol is the property of vTv Therapeutics LLC  
and may not – in full or in part – be passed on, reproduced, published,  
or otherwise used without the express permission of  
vTv Therapeutics LLC


SIGNATURE CONFIRMATION PAGE 
Investigational Product: 
Azeliragon (TTP488) 
Study Number: 
TIP488-301 
Protocol Title: 
RANDOMIZED, DOUBLE-BLIND, PLACEBO 
CONTROLLED, MULTI-CENTER REGISTRATION TRIAL 
TO EVALUATE THE EFFICACY AND SAFETY OF TTP488 
IN PATIENTS WITH MILD ALZHEIMER'S DISEASE 
RECEIVING ACETYLCHOLINESTERASE INHIBITORS 
AND/OR MEMANTINE 
Protocol Dated: 
Amendment 7 dated 28 NOVEMBER 2017 
I have reviewed and approved of the protocol listed above. 
Dr. Larry Altstiel, M.D., Ph.D. 
Executive Vice President, Chief Medical Officer 
vTv Therapeutics LLC 
Imogene Dunn, Ph.D. 
Senior Vice President, Biometrics and Regulatory Affairs 
vTv Therapeutics LLC 
Aaron Burstein, Pharm.D. 
Senior Vice President, Clinical Development 
vTv Therapeutics LLC 
Signature 
Signature 
Signature 
Date 
Date 
Date 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 3 
Document Revision History 
Document 
Version Date 
Summary of Changes 
Amendment 7 
28 NOV 2017 
• 
Table 1  Removed dosing from the list of study 
procedures to be completed at the Month 18 visit.  
Added Early Termination PET to be consistent with 
Section 6.2.11. 
• 
Section 4.2 Exclusion Criteria 
o 19.  Removed exclusion for participants who 
are taking or are expected to use drugs 
known to be strong CYP3A4 inhibitors. 
• 
Section 4.3.  Added male contraceptive advice for 
fertile sexually active males to align with UK and 
IRL protocols. 
• 
Section 5.5.  Removed CYP3A4 inhibitors from list 
of prohibited conmeds. 
• 
Section 6.2.9.  Removed dosing from the list of study 
procedures to be completed at the Month 18 visit.   
• 
Section 6.2.10.  Added description of when a Follow-
up Visit should be performed (i.e., 3 months after 
Month 18 or 3 months after last dose when a subject 
discontinues early). 
• 
Section 6.3.  Modified Early Termination Visit 
procedures to perform neuropsychological 
assessments only if the visit is within 30 days of the 
last dose of study drug.  Added reference to follow-
up visit performed 3-months after the last dose when 
a subject discontinues early. 
• 
Section 6.4.  Added reference to follow-up visit for 
subjects who withdraw early. 
• 
Section 7.6.  Modified MRI analyses to be unblinded 
to time sequence. 
• 
Section 7.8.  Modified PET analyses to be unblinded 
to time sequence. 
• 
Section 8.4.  Clarified that adverse event assessment 
of relationship to study drug falls into one of two 
categories:  related / not related. 
• 
Section 11.1.  Added cross reference to eCRF 
Completion Guidelines. 
• 
Appendix 2.  Modified Prohibited Medication List to 
remove CYP3A4 inhibitors, and update list of strong 
CYP2C8 inhibitors based on updated references. 
Amendment 6-UK 
(United Kingdom) 
28 Sep 2016 
 
• 
Title Page.  Addition of Health Canada file number 
and EudraCT number. 
• 
Section 1.1.3.  Presentation of TTP488-203 data 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 4 
Document 
Version Date 
Summary of Changes 
 
Amendment 6 
 
 
15 Jun 2016 
 
revised to include mild subgroup (MMSE21-26) 
analysis. 
• 
Section 4.2.  Exclusion criterion 20 removed based 
on the completed concentration-QTc analysis 
showing no deleterious effect of azeliragon on QT at 
therapeutic and supratherapeutic doses.   
• 
Section 5.3.2.  Dosage instructions added for clarity. 
• 
Section 5.5.  Removed restriction for drugs known to 
significantly increase QTc based on completed 
concentration-QTc analysis showing no deleterious 
effect of azeliragon on QT at therapeutic and 
supratherapeutic doses.   
• 
Section 9.12.  Removed restrictions of materials to be 
provided to the IDMC, thereby giving liberty to the 
IDMC to request any material needed to review 
accruing data for safety evaluation. 
• 
Appendix 2.  Revised to remove list of prohibited 
drugs known to significantly increase QTc. 
Amendment 5-UK 
(United Kingdom) 
08 July 2016 
• 
Section 4.3.  Inclusion of contraception advice for 
fertile sexually active males for submission to 
MHRA.   
Amendment 5 
23 Mar 2016 
• 
Sections 4.1, 6.1, and 12.3.  Clarified that the 
assent process is only applicable where it is in 
accordance with local laws, regulations and ethics 
committee policy. 
• 
Section 4.1.  Modified inclusion criterion 11 to allow 
acetylcholinesterase inhibitors and memantine 
approved by any regulatory authority. 
• 
Section 4.2.  Clarified application of exclusion 
criterion 25 regarding QTc values at screening and 
baseline visits. 
• 
Sections 5.5, 6.0, 6.2.1, 6.2.7, 6.2.9, 6.3, 7.8, and 9.1.  
Clarified that the FDG-PET substudy is being 
performed only at select sites in the United States 
and Canada. 
• 
Section 7.1.5.2.  Clarified the abnormal laboratory 
values that elicit further evaluation as potential cases 
of drug-induced liver injury.  Specifically, for sub-
item “b” inclusion of text defining the bilirubin value 
to provide consistency with the definition provided in 
sub-item “a”. 
• 
Sections 9.12 and 9.13.  In compliance with requests 
from the IDMC, vTv will provide safety tables only 
(no efficacy) for the IDMC to review for which the 
data tables represent subjects split into treatment 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 5 
Document 
Version Date 
Summary of Changes 
groups labeled “X” and “Y”. 
Amendment 4 
30 Sep 2015 
• 
Replacement of TransTech Pharma with vTv 
Therapeutics LLC 
• 
Revision of plan for assignment of sites to Study A 
and Study B. 
• 
Table 1, Section 6.1.  Revised Screening 
Confirmation Form to Eligibility Assessment Form 
to reflect actual name of form in use. 
• 
Table 1.  Clarification of allowable window for 
completion of baseline procedures and timing of 
baseline procedures relative to randomization and 
dosing.  Added footnote “e” to clarify intention for 
first dose (Month 0) to be administered in the clinic 
following the completion of Baseline procedures. 
• 
Exclusion criteria 
o Clarification of Exclusion Criterion 2 
allowing individuals from families with any 
number of late onset AD affected family 
members to participate in the study. 
o Clarification of Exclusion Criterion 5 to 
include ≥10 microhemmorrhages and grade 3 
white matter changes as exclusionary. 
o Clarification of Exclusion Criterion 14 to 
reflect screening test is for drugs of abuse 
and does not include alcohol. 
o Revision of Exclusion Criterion 18 (and 
Section 5.5) to differentiate between prior 
investigational disease modifying, non-
disease modifying, and active 
immunotherapy exposures.  
o Revision of Exclusion Criterion 20 to 
remove “with limited use” allowances for 
some prohibited concomitant medications. 
o Clarification of application of Exclusion 
Criterion 25.  Also added allowances for 
participants with bundle branch block or 
functioning pacemaker. 
o Clarification of Exclusion Criterion 26 with 
regard to subjects with atrial fibrillation on 
anticoagulant therapy. 
• 
Section 5.1.  Revision of randomization scheme to 
reflect that it will be blocked by substudy and 
investigative site. 
• 
Section 5.1.  Clarification that stratification will be 
based on ADAS-cog assessed at the Screening visit. 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 6 
Document 
Version Date 
Summary of Changes 
• 
Sections 5.3.2, 6.2.2.  Clarification that the first dose 
of study medication will be administered in the clinic 
at the conclusion of the Baseline visit. 
• 
Section 5.5.  Revised instructions related to Pre-
medication for PET assessment to be consistent with 
the PET Manual.  Removed allowances for limited 
use of some prohibited concomitant medications.  
Clarified transient use of medications that may affect 
the CNS or cognition as no more than 4 weeks in 
duration. 
• 
Section 6.0, 6.1.  Clarification of the order of 
cognitive / functional assessments at the Screening 
Visit to be consistent throughout protocol.  Clarified 
dosing should occur in the clinic on study visit days. 
• 
Section 6.1.  Added circumstances where re-
screening is permitted. 
• 
Section 6.2.1.  Clarification of allowable window for 
completion of baseline procedures and timing of 
baseline procedures relative to randomization and 
dosing 
• 
Section 6.3.  Added FDG-PET assessment at Early 
Termination for those subjects participating in the 
PET sub-study who were on study for ≥ 3 months. 
• 
Section 7.1.2.  Clarification of the application of 
Criterion 25 for participants with bundle branch 
block or functioning pacemaker. 
• 
Section 7.1.5.1.  Clarified that serum FSH will be 
measured for all female subjects at Screening. 
• 
Section 7.2.  Clarification of the order of cognitive / 
functional assessments at the Screening Visit to be 
consistent throughout protocol. 
• 
Section 7.7.  Added reference to MRI procedures 
manual for instructions on submission of head CT 
scan. 
• 
Section 7.8.  Revision to reflect that Baseline FDG-
PET must be performed within the 7 days prior to the 
baseline visit. 
• 
Section 8.7.1.  Revision to add Safety Monitor as the 
recipient of SAE reports and removed text regarding 
the separation of SAE report and AE CRF due to the 
use of a combined solution. 
• 
Section 9.0.  Revision of the description of A-study 
and B-study to reflect assignment of the first 
approximately 400 patients to the A-study and the 
remaining approximately 400 patients to the B-study. 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 7 
Document 
Version Date 
Summary of Changes 
• 
Section 9.2.  Addition of text to state specific 
statistical methodology for the MRI measures will be 
included in the SAP. 
• 
Section 9.5.  Revision of the description of A-study 
and B-study to reflect assignment of the first 
approximately 400 patients to the A-study and the 
remaining approximately 400 patients to the B-study. 
• 
Section 9.14 and 11.1.  Addition of description to 
clarify that the databases for each substudy (A-study 
and B-study) will be locked, unblinded, analyzed, 
and reported separately. 
• 
Appendix 2.  Updated list of prohibited concomitant 
medications due to a known risk of Torsades de 
Pointe.   
Amendment 3 
31 Mar 2015 
• 
Replacement of TTP488 with the INN name 
azeliragon  
• 
Change laboratory sample collections from fasting to 
non-fasted.   
• 
Addition of concomitant medication exclusion of 
prescription medical food (i.e. Axona) intended for 
the dietary management of the metabolic processes 
associated with Alzheimer’s disease. 
• 
Clarify order of procedures (Section 6.0) with regard 
to timing of conduct of cognitive/functional/ 
behavioral assessments relative to other procedures 
• 
Clarification of the application of consistent 
exclusion criteria across the screening and baseline 
visit for QTc values.    
• 
Clarification that ECG performed in triplicate only at 
baseline visit and as single measures at all other time 
points. 
• 
Addition of the following text to Exclusion Criteria 
18.  Previous exposure to any other investigational 
drug as part of a clinical trial, including 
investigational therapies for Alzheimer’s disease that 
are being investigated for non-disease modifying 
purposes, within 6 months prior to screening.  
• 
Clarification of exclusion criteria that unstable 
diabetes or requirement for insulin is exclusionary. 
• 
Clarification that a response of “yes” to items 4 and 5 
on the C-SSRS at screening and baseline will result 
in subjects not being included in the study. 
• 
Elimination of the requirement of a healthy volunteer 
test scan for MRI QA/QC and a patient volunteers 
test scan for PET QA/QC.   Scan of ACR and 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 8 
Document 
Version Date 
Summary of Changes 
Hoffman phantoms is required for monitoring of 
optimal scan parameters. 
• 
Allowance of computed tomography as an alternate 
imaging modality at screening for subjects with 
contraindications to MRI.  Results of CT will be used 
to determine eligibility in trial.  For those subjects 
using CT based qualification for study no Month 18 
or Early Term MRI will be required. 
 
 
Amendment 2 
10 Feb 2015 
• 
Addition of Trail Making Test (Versions A and B to 
the secondary endpoints and objectives) as a measure 
of executive function potentially sensitive to change 
in a patient with mild AD.  Test to be performed at 
Baseline and Months 3, 6, 12, 18, Follow-up, and 
Early Termination (if applicable) Visits. 
• 
Clarification that RUD referred to the RUD Lite.  
Addition of “Lite” after each instance of word RUD 
• 
Elimination of Month 1 and Month 2 visits to clinic 
and replacing with Telephone Calls for assessment of 
Adverse Events and/or concomitant medication 
changes.  Subjects may be brought into clinic for 
unplanned study visit based on information obtained 
from telephone calls.  Change results in 9 outpatient 
visits including Screening and Follow-up. 
• 
Addition of ADAS-cog and CDR to screening visit.   
The ADAS-cog at screening will be used as a 
stratification variable in the randomization scheme.    
• 
Brain MRI eliminated at Months 6 and 12 in 
response to letter from FDA eliminating the need for 
MRIs for evaluation of ARIA with small molecules 
• 
Update of Abbreviations to include C-SSRS, MMA, 
and NASH 
• 
Description of staff members (PI, Coordinator, Rater, 
CDR Rater) and clarification of the instruments 
he/she may be permitted to administer.  
• 
Inclusion  Criteria 
 
Modification of language to describe legally 
authorized representative, caregiver/informant 
instead of caregiver 
 
Modification of MMSE criteria to specify needs 
to be within 21-26 at Screening.  Elimination of 
requirement for value to be within range at 
baseline visit 
 
Addition of CDR global score of 0.5 or 1 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 9 
Document 
Version Date 
Summary of Changes 
 
Item 12.  Addition of text “If the results of 
clinical laboratory testing are outside normal 
reference ranges, the subject may be enrolled 
but only if these findings are determined to be 
not clinically significant by the investigator.  
This determination must be recorded in the 
subject’s source documents. 
• Exclusion Criteria 
 
Item 1.  Addition of text “proximate to the onset 
of dementia, participation in contact sports 
characterized by repeated head injuries” and 
“current major depression, bipolar disorder, 
alcohol or substance abuse or dependence, 
neurosyphilis, vitamin B12 deficiency (see 
Exclusion 3, below), thyroid disease (unless 
adequately treated for at least 3 months with 
normalization of laboratory values) or any form 
of dementia other than AD.”. 
 
Item 5.  Elimination of text describing specific 
findings on MRI that would result in exclusion 
from trial because  the MRI requirements for 
inclusion in the trial are adequately addressed in 
Inclusion Criteria 7. 
 
Elimination of Item 8. Clinically significant 
depression as determined by scores on the NPI 
depression domain.  Original intent was that this 
itself does not warrant exclusion but rather is 
used in evaluation of suicidality risk and as 
trigger for risk assessment by qualified health 
care professional.  Amendment now bases 
evaluation of suicidality risk solely on C-SSRS. 
 
Item 8.  Addition of “or cervical carcinoma in-
situ” 
 
Item 9.  Increase BMI cutoff to 35 kg/m2 
 
Item 11. Modified to clarify criteria “Patients 
with unstable, uncontrolled diabetes and those 
with insulin dependent diabetes mellitus” 
 
Item 15.  Modified to clarify criteria.  Intent was 
not to exclude “Participants with mild chronic 
pulmonary disease which has been stable on 
treatment without hospitalization or emergency 
room treatment for 2 years.” 
 
Item 18.  Modified to clarify intent to be 
“Previous exposure to investigational therapies 
for Alzheimer’s disease that are being 
investigated for possible disease modification 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 10 
Document 
Version Date 
Summary of Changes 
activity (e.g., TTP488, immunotherapies and 
secretase inhibitors) within 6 months of screening 
for the current protocol.” 
 
Elimination of former Item 24 “participants 
cannot participate in other clinical drug trials or 
other nondrug methodology trials for the duration 
of the study.”  Other drug trials covered under 
Item 18.  Non-drug trials permitted. 
 
Item 24.  QTc criteria updated to exclude 
QTcF>470 msec for females and >450 msec for 
males. 
• 
Section 5.2  Addition of text “The sponsor or 
representative should be consulted prior to breaking 
the blind except in emergent circumstances.” 
• 
Section 5.3.3 Addition of text 
“Caregivers/Informants will be instructed to assist 
with monitoring dosing compliance.” 
• 
Section 5.5 Concomitant Medications:   Section 
added to clarify that “Considerations for use of 
medications that may affect the CNS or cognition. 
Generally, medications that affect cognition are not 
allowed. In such case that there is an acute need for 
use of a medication that may negatively affect 
cognition or the CNS in general (e.g., 
sedatives/anxiolytics, antipsychotics, opiates), their 
use should be transient, must be stable for at least 
one week prior to any cognitive assessments, and 
discussed with the sponsor’s medical monitor prior 
to use (or as soon as possible following discovery of 
their use). Chronic use of these medications is not 
permitted. Should their use be deemed to be chronic 
(spanning months), discussion with the Sponsor’s 
medical monitor is required with a view to 
discontinuing the subject from participation.”  
Elimination of text “Participants may receive 
medication that may negatively affect cognitive 
function (e.g., sedatives/anxiolytics, antipsychotics) 
only if used to manage transient fluctuation in 
mental status (e.g., confusion due to UTI or transient 
insomnia).  All such cases need to be discussed and 
approved by the Sponsor’s medical monitor and 
documented in source documentation.  Such 
medications may not be introduced for chronic 
usage to manage chronic deterioration of the 
subject’s mental status due to disease progression.  
Participants who need to start a behavioral 
medication or need to change the dose of a 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 11 
Document 
Version Date 
Summary of Changes 
behavioral medication during the study should be on 
a stable dose for at least one week prior to any 
clinical assessments.” 
Exclusion of grapefruit and grapefruit juice 
 
 
• 
Section 6.0 Study Procedures:   
 
Updating to reflect changes previously described 
above 
 
Addition of text “Note, the initial rating scales 
should be the ADAS-cog to minimize subject 
fatigue, followed by the MMSE. Additionally, to 
avoid subject fatigue, it is recommended that the 
CDR is performed on a separate visit day than 
the other cognitive tests. If it is to be done the 
same day, then the CDR should follow the 
MMSE as above.   The exception to this is the 
Screening visit during which the MMSE will be 
performed first, followed by the ADAS-cog and 
CDR if the subject is eligible based on their 
MMSE score.” 
 
Elimination of allowance of up to 90 days from 
MRI to dosing.  Only time this will be permitted 
is in the event of rescreening a subject 
 
Rescreening a subject will be permitted for 
“Hypertension discovered at screening that is 
subsequently actively managed and the blood 
pressure values are within acceptable limits” 
 
Addition of a review of drug accountability at 
each visit to study site. 
 
Vitamin B12 level revised to 211 to reflect 
LabCorp reference value. 
• 
Section 7.1.2 Addition of text “At any time during 
the study, a subject with any of the above ECG 
values should prompt a call to the Sponsor for 
guidance on how to proceed.” 
• 
Section 7.1.5.2  Addition of text requiring Medical 
Monitor be contacted to discuss patient condition 
• 
Section 7.2.1  Addition of text to describe the Trail 
Making Tests 
• 
Section 7.3   Elimination of the NPI depression 
domain as part of the evaluation of potential 
suicidality risk.   Risk evaluation will be based on 
the C-SSRS 
• 
Section 7.4.  Update title of section to reflect that 
plasma will be collected for analysis of TTP488 and 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 12 
Document 
Version Date 
Summary of Changes 
metabolites. Correction of inconsistency in sample 
collection times.  Reduction of sample volume from 
5 mL to 4 mL.  Text includes statement “For 
TTP488 metabolites, samples may be analyzed at 
the Sponsor’s discretion.” 
 
• 
Section 7.6  Intent is that MRI will be centrally read 
with results of central reader being definitive result.  
Section of text describing baseline scans being read 
by neuroradiologist at site within 48 hours removed. 
• 
Section 7.9  Section updated to correct inconsistency 
of sampling times across protocol.  Sample storage 
conditions updated to -70oC. 
• 
Section 7.10 Blood volume:  updated to eliminate 
redundant sampling for exploratory biomarkers and 
removal of Month 1 labs.   
• 
Section 8.6:  redundant text regarding follow-up for 
ongoing adverse events deleted   
• 
Section 9.12 updated to reflect intent to have at least 
3 members on IDMC 
• 
Section 12.3 updated to include text “(or assent in 
the case of participants who are deemed to be unable 
to have the cognitive ability to provide consent).” 
Amendment 1 
(Canada) 
16 Dec 2014 
Addition of country-specific language and references for 
submission to Health Canada. 
Original Protocol 
21 Jan 2014 
N/A 
 
 
 
 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 13 
PROTOCOL SUMMARY 
Background and Rationale: 
Azeliragon (TTP488) is an orally bioavailable antagonist of Receptor for Advanced Glycation 
Endproducts (RAGE) that is being developed as a potential treatment for AD. 
Substantial data suggest that RAGE is involved in the pathogenesis of AD, and that sustained Aβ 
interaction with RAGE on blood brain barrier (BBB) and/or neuronal cells and/or microglial cells 
is an important element of amyloid plaque formation and chronic neuronal dysfunction.  The non-
clinical and clinical data obtained to date indicate that azeliragon plus standard of care (SoC), at 5 
mg/day, is well tolerated in humans and results in statistically significant differences (=3.1, 
p<0.008) from placebo plus SoC in change in ADAS-cog after 18 months of treatment.  Thus, 
azeliragon has the potential to provide effective treatment of AD. 
Objectives: 
The primary objective of this study is: 
• To evaluate the efficacy of azeliragon on cognitive [Alzheimer's Disease Assessment 
Scale-cognitive subscale (ADAS-cog)] and global function [Clinical Dementia Rating 
Scale Sum of Boxes (CDR-sb)] measures in patients with mild AD. 
The secondary objectives of this study are: 
Key Secondary 
• To examine the effect of azeliragon on MRI volumetrics (e.g., whole brain volume, 
ventricular volume, hippocampal volume). 
* note: the decision as to the specific key secondary to support disease modification 
claim will be made prior to database lock. 
Secondary: 
• To evaluate the safety and tolerability of 18 months treatment with azeliragon plus standard 
of care relative to placebo plus standard of care. 
• To evaluate the time course of the effect of azeliragon on the cognitive (ADAS-cog) and 
global functional outcome (CDR-sb) measures. 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 14 
• To evaluate the efficacy of azeliragon on behavioral symptoms as assessed by the 
Neuropsychiatric Inventory (NPI). 
• To evaluate the efficacy of azeliragon on cognition as assessed by the Mini-Mental State 
Examination (MMSE). 
• To evaluate the efficacy of azeliragon on the Alzheimer’s Disease Cooperative Study - 
Activities of Daily Living Scale (ADCS-ADL). 
• To evaluate the efficacy of azeliragon on cognition as assessed by the Continuous Oral 
Word Association Task (COWAT), Category Fluency Test (CFT) and Trail Making Test 
(Versions A and B). 
• To evaluate the effect of azeliragon on health status, health care resource utilization, and 
health-related quality of life as assessed by Resource Utilization in Dementia (RUD Lite), 
and Dementia Quality of Life (DEMQOL-proxy) 
• To evaluate the effect of azeliragon on regional and global brain glucose metabolism using 
FDG-PET. 
• To evaluate the effect of azeliragon on plasma Aβ biomarkers. 
• To evaluate azeliragon exposure-response relationships for selected efficacy, safety and 
biomarker endpoints (e.g., ADAS-cog, ADCS-ADL, adverse events, vital signs, plasma 
concentrations of Aβ). 
Endpoints: 
Primary Endpoints: 
Co-primary Endpoints: 
• Change from Baseline in the ADAS-cog at Month 18. 
• Change from Baseline in the CDR-sb at Month 18.  
 
 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 15 
Secondary Endpoints: 
Key Secondary Endpoints: 
• Change from Baseline in brain volumetrics (e.g., whole brain volume, ventricular volume, 
hippocampal volume) at Month 18. 
Other Secondary Endpoints: 
• Adverse events, clinical safety laboratory tests, MRI, ECG, vital signs. 
• Responder analysis at Months 6, 12 and 18 based on the ADAS-cog. 
• Responder analysis at Months 6, 12 and 18 based on the CDR-sb. 
• The slope of change over time in ADAS-cog, MMSE and CDR-sb scales through 
Month 18. 
• Time to loss of one global stage on the CDR score through Month 18. 
• Proportion of participants experiencing a loss of one global stage on the CDR global score 
at Months 6, 12, and 18. 
• Change from Baseline on the ADAS-cog and CDR-sb total scores at Months 6 and 12. 
• Change from Baseline in the ADCS-ADL total score at Months 6, 12 and 18. 
• Change from Baseline in the NPI total score at Months 3, 6, 12 and 18. 
• Change from Baseline in the MMSE total score at Months 3, 6, 12 and 18. 
• Change from Baseline in the COWAT and CFT score at Months 3, 6, 12 and 18. 
• Change from Baseline in Trail making Test (versions A and B) time at Months 3, 6, 12 and 
18. 
• Individual item responses on the RUD Lite questionnaire and the total caregiver/informant 
time spent assisting the patients based on the RUD Lite questionnaire at Months 6, 12 and 
18. 
• Proportion of participants who enter intermediate or long-term residential care (RUD Lite). 
• Change from Baseline in the DEMQOL-proxy total score at Month 18. 
• Change from Baseline in regional and global brain glucose metabolism using FDG- PET 
at Month 18 
• Change from Baseline in plasma concentrations of Aβ species at Month 18. 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 16 
• Exposure response relationships based on selected efficacy, safety, and biomarker 
outcomes. 
 
Study Design: 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel-group study 
evaluating the efficacy and safety of 18 months of treatment with azeliragon relative to placebo 
conducted in approximately 800 mild AD patients who are on background SoC.  Patients will be 
randomly assigned to 1 dose level (5 mg/day) or placebo in a 1:1 randomization (approximately 
n=400/group). 
Statistics: 
This protocol describes two studies with a common infrastructure. Statistical analysis for clinical 
efficacy will be analyzed as 2 separate studies. Analysis for safety and for imaging data will be 
analyzed as one study as a whole. 
Sample Size and Randomization 
A total of approximately 800 patients will be randomized into this study. Subjects will be enrolled 
and randomized according to a fixed randomization scheme blocked by study investigative site. 
Severity of AD will be determined by MMSE (21-26) at screening.  ADAS-cog at Screening will 
be used as a stratification variable in the randomization scheme: 
• ADAS-cog 19 or less 
• ADAS-cog more than 19. 
Randomization will have balanced allocation (1:1) between active plus SoC and placebo plus SoC.  
Dropouts will not be replaced. 
This study comprises two studies in one main study for purposes of independent replication for the 
co-primary variables: A-study is composed of the first approximately 400 patients randomized; 
B-study is composed of the remaining approximately 400 patients.  Each A-study and B-study is 
powered independently and is expected to randomize approximately N=400 patients (each). 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 17 
Sample size calculations are done to power each study (A-study and B-study) separately. It is 
anticipated that each A-study and B-study will randomize approximately N=400 each. 
Assuming a standard deviation of the change from Baseline to Month 18 in ADAS-cog of 9 (based 
on Study TTP488-203), using alpha = 0.05, a total sample size of 282 patients in balanced 
allocation (141 patients per group) provides at least 90% power to detect a difference between 
treatment groups of 3.5 (based on data from mild AD patients in Study TTP488-203) using a 
2-sided, 2-sample t-test.  Assuming a dropout rate of 20% or less, randomization of 354 patients 
provides adequate statistical power for this study to demonstrate superiority of azeliragon plus SoC 
over placebo plus SoC based on the ADAS-cog. 
Assuming a standard deviation of the change from Baseline to Month 18 in CDR-sb of 2.4, using 
alpha = 0.05, a total sample size of 304 patients in balanced allocation (152 patients per group) 
provides at least 90% power to detect a difference between treatment groups of 0.9 (based on data 
from mild AD patients in Study TTP488-203) using a 2-sided, 2-sample t-test. Assuming a dropout 
rate of 20% or less, randomization of 380 patients provides adequate statistical power for this study 
to demonstrate superiority of azeliragon plus SoC over placebo plus SoC based on CDR-sb. 
For purposes of increased exposure in the study, a total of 800 AD patients are planned for this 
study. 
Populations of Analysis 
The following population of analysis will be used for all statistical analysis: 
• The full analysis set (FAS) includes all randomized subjects who receive any study 
medication and have at least one post-baseline assessment. 
• The per-protocol set (PPS) includes all subjects in the FAS excluding subjects who have 
major protocol violations. 
• The safety set (SAF) includes all subjects who receive any study medication. 
The FAS will be used for all hypothesis tests of efficacy. The PPS is used for supportive efficacy 
analysis. The SAF will be used for safety analyses. 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 18 
Efficacy Analysis 
For inferential purposes, each (independent) study A-study and B-study) will be analyzed 
separately for the co-primary variables. The study as a whole will be analyzed for specified 
inferential purposes. 
A 2-stage conditional sequence of statistical hypothesis tests, will be used. The testing sequence 
will be as follows: 
• Stage 1:  4 concurrent analyses will be done: 
 A-study analysis of co-primary variables: 
▪ 
ADAS-cog is analyzed in A-Study. 
▪ 
CDR-sb is analyzed in A-Study 
 B-study analysis of co-primary variables: 
▪ 
ADAS-cog is analyzed in B-study. 
▪ 
CDR-sb is analyzed in B-study 
• Stage 2:  Conditional on statistical significance of both A-study and B-study in both 
co-primary variables, testing will continue: 
 MRI assessment is analyzed in the study (as a whole). 
The primary analysis will use the intent-to-treat (ITT) methodology and a main-effects model for 
mixed-models repeated measures (MMRM) analysis with adjustment for baseline ADAS-cog 
(CDR-sb) measures.  The primary analysis will be supported by multiple-imputation methods, also 
with last-observation-carried-forward (LOCF) methods, and also an observed cases analysis (no 
imputation, no deletion). The primary MMRM analysis will include treatment, time and treatment-
by-time interaction as fixed effects, baseline as covariate, baseline stratum as a covariate, and 
subject as a random effect.  Supportive modeling will also include MMRM main-effects model 
with treatment, time, and subject. 
Descriptive summaries will be produced of the observed values and change from baseline in 
co-primary variables by treatment group at each individual time point and at endpoint (final 
on-treatment assessment for each subject).  For statistical analyses, 95% confidence intervals will 
be produced for the least-squares means (LSM) in each treatment group, as well as the LSM 
differences as compared to placebo plus SoC. 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 19 
SCHEDULE OF ACTIVITIES  
Table 1. 
Schedule of Activities 
Protocol Activity 
Screening Baseline 
Treatment 
Early 
Term 
Follow-upa 
Day -60 to 
Day -1 
Day -7 to 
Day 1 
Month 
0 
Month 
1 
Month 
2 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Month 
15 
Month 
18 
 
Month 21 
Study Days 
 
 
1 
30 
60 
90 
180 
270 
360 
450 
540 
 
630 
Window 
 
 
±4d 
±4d 
±4d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
 
± 7d 
Sign informed consent / provide 
assentf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment  Form (EAF)b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Registration/Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Drug, Alcohol, Tobacco Use History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Neuro Exam & Physical 
Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Rosen-Modified Hachinski Ischemic 
Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ApoE genotyping 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Telephone contact 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Brief Neuro & Physical Exams 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Review Concomitant Medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Pressure and Pulse Rate 
(supine) 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECGd 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Assessment 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study Drug 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
Table 1. 
Schedule of Activities (continued) 
 
 
Page 20 
Protocol Activity 
Screening Baseline 
Treatment 
Early 
Term 
Follow-upa 
Day -60 to 
Day -1 
Day -7 to 
Day 1 
Month 
0 
Month 
1 
Month 
2 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Month 
15 
Month 
18 
 
Month 21 
Study Days 
 
 
1 
30
60
90
180
270
360
450
540 
 
630 
Window 
 
 
±4d 
±4d
±4d
±7d
±7d
±7d
±7d
±7d
±7d 
 
± 7d 
Study Drug Dosinge 
 
 
X 
 
 
 
 
 
 
 
 
 
 
MMSE 
X 
X 
 
 
 
X 
X 
 
X 
 
X 
Xh 
X 
ADAS-cog 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Xh 
X 
CDR 
X 
X 
 
 
 
X 
X 
 
X 
 
X 
Xh 
X 
NPI 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Xh 
X 
ADCS-ADL 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Xh 
X 
COWAT 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Xh 
X 
CFT 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Xh 
X 
Trail Making Test (Versions A and B) 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Xh 
X 
Columbia Suicide Severity Scale 
(C-SSRS)c 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
RUD Lite 
 
X 
 
 
 
 
X 
 
X 
 
X 
Xh 
 
DEMQOL-proxy 
 
X 
 
 
 
 
X 
 
X 
 
X 
Xh 
 
FSH (females only), hepatitis, VDRL, 
Thyroid function tests, Vitamin B12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Chemistry (incl HbA1c) 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Brain MRI 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Brain CT (for subjects with 
contraindications to MRI) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Brain FDG-PETg 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
Table 1. 
Schedule of Activities (continued) 
 
 
Page 21 
Protocol Activity 
Screening Baseline 
Treatment 
Early 
Term 
Follow-upa 
Day -60 to 
Day -1 
Day -7 to 
Day 1 
Month 
0 
Month 
1 
Month 
2 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Month 
15 
Month 
18 
 
Month 21 
Blood Sample for Plasma Retention 
and Storage 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
Pharmacokinetic Blood Sampling 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
Pharmacodynamic blood sampling 
(Aβ) 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
a 
Follow-up visit required for those participants completing the study but choosing to not participate in an open label extension stud y. 
b 
Following completion of Screening visit assessments but prior to scheduling baseline visit, obtain approval from the sponsor for the patient to participate in the study. 
c 
C-SSRS is administered to subject jointly with care-giver. 
d 
ECGs at Baseline visit performed in triplicate 
e 
First dose (Month 0) in the clinic following baseline visit procedures. 
f 
Where assent is in accordance with local laws, regulations and ethics committee policy 
g 
Only applicable at select sites in the United States and Canada. 
h     Neuropsychological assessments are performed at the Early Termination Visit only when the visit is within 30 days of the last dose of study drug. 
 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 22 
TABLE OF CONTENTS 
 
Page 
TITLE PAGE ...................................................................................................................................................1 
SIGNATURE CONFIRMATION PAGE ......................................................................................................2 
PROTOCOL SUMMARY ............................................................................................................................ 13 
TABLE OF CONTENTS .............................................................................................................................. 22 
LIST OF TABLES ......................................................................................................................................... 25 
LIST OF ABBREVIATIONS ....................................................................................................................... 26 
1.0 
INTRODUCTION ........................................................................................................................... 28 
1.1 
BACKGROUND AND RATIONALE ............................................................................................. 28 
1.1.1 
Alzheimer’s Disease ......................................................................................................... 28 
1.1.2 
Mechanism of Action ....................................................................................................... 28 
1.1.3 
Clinical Studies ................................................................................................................. 29 
1.1.4 
Dose Selection Rationale .................................................................................................. 32 
1.1.5 
Single Reference Safety Document................................................................................... 34 
2.0 
STUDY OBJECTIVES AND ENDPOINTS.................................................................................. 35 
2.1 
OBJECTIVES ................................................................................................................................... 35 
2.2 
ENDPOINTS ..................................................................................................................................... 36 
3.0 
STUDY DESIGN ............................................................................................................................. 38 
4.0 
SUBJECT SELECTION ................................................................................................................. 40 
4.1 
INCLUSION CRITERIA .................................................................................................................. 40 
4.2 
EXCLUSION CRITERIA ................................................................................................................. 42 
4.3 
CONTRACEPTION REQUIREMENTS AND STUDY PARTICIPANT INSTRUCTION ............ 46 
4.3.1 
Males ................................................................................................................................ 46 
5.0 
STUDY TREATMENTS................................................................................................................. 48 
5.1 
RANDOMIZATION TO STUDY TREATMENT ............................................................................ 48 
5.2 
BREAKING THE BLIND ................................................................................................................ 48 
5.3 
DRUG SUPPLIES ............................................................................................................................. 49 
5.3.1 
Formulation and Packaging .............................................................................................. 49 
5.3.2 
Administration ................................................................................................................... 49 
5.3.3 
Compliance........................................................................................................................ 49 
5.4 
DRUG STORAGE AND DRUG ACCOUNTABILITY .................................................................. 50 
5.5 
CONCOMITANT MEDICATION(S) .............................................................................................. 50 
6.0 
STUDY PROCEDURES ................................................................................................................. 53 
6.1 
SCREENING .................................................................................................................................... 54 
6.2 
STUDY PERIOD .............................................................................................................................. 57 
6.2.1 
Baseline (approximately Day -7-Day 1) ........................................................................... 57 
6.2.2 
Month 1 (± 4 days) ........................................................................................................... 58 
6.2.3 
Month 2 (± 4 days) ........................................................................................................... 58 
6.2.4 
Month 3 (± 7 days) ........................................................................................................... 58 
6.2.5 
Month 6 (± 7 days) ........................................................................................................... 59 
6.2.6 
Month 9 (± 7 days) ........................................................................................................... 60 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
TABLE OF CONTENTS (continued) 
 
     Page 
 
 
 
Page 23 
6.2.7 
Month 12 (± 7 days) ......................................................................................................... 60 
6.2.8 
Month 15 (± 7 days) ......................................................................................................... 61 
6.2.9 
Month 18 (± 7 days) ......................................................................................................... 62 
6.2.10 
Follow-Up ......................................................................................................................... 63 
6.3 
EARLY TERMINATION ................................................................................................................. 63 
6.4 
SUBJECT WITHDRAWAL ............................................................................................................. 65 
7.0 
ASSESSMENTS .............................................................................................................................. 66 
7.1 
SAFETY AND TOLERABILITY .................................................................................................... 66 
7.1.1 
Vital Signs ........................................................................................................................ 66 
7.1.2 
Electrocardiogram ............................................................................................................. 66 
7.1.3 
Physical Examination ....................................................................................................... 67 
7.1.4 
Neurological Examination ................................................................................................ 67 
7.1.5 
Laboratory ........................................................................................................................ 67 
7.2 
NEUROPSYCHOLOGICAL ASSESSMENTS ................................................................................ 70 
7.2.1 
Cognitive Assessments ..................................................................................................... 70 
7.2.2 
Functional/Global Assessments ........................................................................................ 72 
7.2.3 
Other Assessments ............................................................................................................ 73 
7.3 
SUICIDALITY ASSESSMENTS ..................................................................................................... 74 
7.4 
PLASMA FOR ANALYSIS OF AZELIRAGON AND METABOLITE CONCENTRATIONS ...... 75 
7.5 
PLASMA FOR ANALYSIS OF TOTAL A, A (1-40), A(1-42)................................................. 76 
7.6 
MRI ................................................................................................................................................... 76 
7.7 
CT SCANS ........................................................................................................................................ 77 
7.8 
FDG-PET .......................................................................................................................................... 78 
7.9 
APOE GENOTYPING ...................................................................................................................... 78 
7.10 
BLOOD SAMPLING FOR PLASMA STORAGE AND RETENTION .......................................... 79 
7.11 
BLOOD VOLUME ........................................................................................................................... 79 
8.0 
ADVERSE EVENT REPORTING ................................................................................................ 80 
8.1 
ADVERSE EVENTS ........................................................................................................................ 80 
8.2 
REPORTING PERIOD ..................................................................................................................... 80 
8.3 
ASSESSMENT OF SEVERITY ....................................................................................................... 81 
8.4 
ASSESSMENT OF RELATIONSHIP TO STUDY DRUG ............................................................. 81 
8.5 
SERIOUS ADVERSE EVENTS ....................................................................................................... 82 
8.5.1 
Life Threatening Adverse Event ....................................................................................... 82 
8.5.2 
Disability .......................................................................................................................... 83 
8.5.3 
Unexpected Adverse Event ............................................................................................... 83 
8.6 
DOCUMENTATION OF ADVERSE EVENTS .............................................................................. 83 
8.7 
REPORTING REQUIREMENTS ..................................................................................................... 83 
8.7.1 
Serious Adverse Events Reporting Requirements ............................................................. 84 
9.0 
DATA ANALYSIS/STATISTICAL METHODS .......................................................................... 86 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
TABLE OF CONTENTS (continued) 
 
     Page 
 
 
 
Page 24 
9.1 
SAMPLE SIZE DETERMINATION ................................................................................................ 87 
9.2 
STATISTICAL HYPOTHESES ....................................................................................................... 88 
9.3 
POPULATIONS OF ANALYSIS ..................................................................................................... 91 
9.4 
DISPOSITION, DEMOGRAPHIC, AND BASELINE DATA ......................................................... 92 
9.5 
EFFICACY ANALYSIS ................................................................................................................... 93 
9.5.1 
Efficacy Variables of Analysis ......................................................................................... 93 
9.5.2 
Statistical Methodology for Primary Analysis .................................................................. 95 
9.5.3 
Statistical Methodology for Secondary and Other Efficacy Analysis ............................... 98 
9.5.4 
Subgroup Analyses ........................................................................................................... 99 
9.5.5 
Adjustment for Multiple Comparisons ............................................................................. 99 
9.6 
SAFETY ANALYSIS ..................................................................................................................... 100 
9.6.1 
Safety Variables of Analysis ........................................................................................... 100 
9.6.2 
Statistical Methodology for Safety Analysis ................................................................... 101 
9.7 
BRAIN MRI .................................................................................................................................... 102 
9.8 
PHARMACODYNAMIC DATA ................................................................................................... 102 
9.9 
PHARMACOKINETIC DATA ....................................................................................................... 103 
9.10 
DEMQOL AND OTHER QUESTIONNAIRES ............................................................................. 103 
9.11 
HANDLING MISSING DATA....................................................................................................... 104 
9.12 
DATA MONITORING COMMITTEE........................................................................................... 105 
9.13 
INTERIM ANALYSIS.................................................................................................................... 105 
9.14 
DATA MANAGEMENT CONSIDERATIONS ............................................................................. 105 
10.0 
QUALITY CONTROL / MONITORING OF THE STUDY ..................................................... 106 
11.0 
DATA HANDLING AND RECORD KEEPING........................................................................ 107 
11.1 
CASE REPORT FORMS/ELECTRONIC DATA RECORD ......................................................... 107 
11.2 
RECORD RETENTION ................................................................................................................. 107 
12.0 
ETHICS .......................................................................................................................................... 109 
12.1 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD (REB) .................. 109 
12.2 
ETHICAL CONDUCT OF THE STUDY....................................................................................... 109 
12.3 
SUBJECT INFORMATION AND CONSENT .............................................................................. 109 
13.0 
STUDY TERMINATION CRITERIA ........................................................................................ 111 
14.0 
CONFIDENTIALITY AND PUBLICATION OF STUDY RESULTS .................................... 112 
15.0 
REFERENCES .............................................................................................................................. 113 
APPENDICES .............................................................................................................................................. 117 
APPENDIX 1 ................................................................................................................................................ 118 
APPENDIX 2 ................................................................................................................................................ 120 
 
 
 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 25 
LIST OF TABLES 
 
Page 
 
Table 1. 
Schedule of Activities ................................................................................................................ 19 
Table 2. 
Descriptive Statistics on Trough Concentrations ....................................................................... 33 
 
 
 
 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
 
 
Page 26 
LIST OF ABBREVIATIONS 
 
 
Aβ 
Aβ peptide fragment of the amyloid precursor protein 
Aβ (1–40) 
1–40 amino acids of Aβ 
Aβ (1–42) 
1–42 amino acids of Aβ 
AD 
Alzheimer’s Disease 
ADAS-cog 
Alzheimer’s Disease Assessment Scale - cognitive measure 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale 
ADL 
Activities of Daily Living 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
ADRDA 
Alzheimer’s Disease and Related Disorders Association 
AE 
Adverse Event 
AGE 
Advanced Glycation Endproduct 
ALT 
Alanine Aminotransferase 
APP 
Amyloid Precursor Protein 
AST 
Aspartate Aminotransferase 
BBB 
Blood Brain Barrier 
β-hCG 
β-Human Chorionic Gonadotropin 
BUN 
Blood Urea Nitrogen 
CDR 
Clinical Dementia Rating Scale 
CDR-SB 
Clinical Dementia Rating Scale-Sum of Boxes 
CFT 
Category Fluency Test 
COWAT 
Continuous Oral Word Association Task 
CPK 
Creatine Phosphokinase 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CT 
Computed Tomography 
DEMQOL 
Health-Related Quality of Life for People with Dementia 
IDMC 
Independent Data Monitoring Committee 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders, 4th ed Text Revision 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
FDG 
Fluorodeoxyglucose 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyltransferase 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMA 
Methylmalonic Acid 
MMSE 
Mini-Mental State Exam 
MRI 
Magnetic Resonance Imaging 
NASH 
Nonalcoholic Steatohepatitis 
NIA 
National Institute on Aging 
NINCDS 
National Institute of Neurological Communicative Disorders and Stroke 
NPI 
Neuropsychiatric Inventory Questionnaire 
PD 
Pharmacodynamic 
PET 
Positron Emission Tomography 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
 
LIST OF ABBREVIATIONS (continued) 
 
 
Page 27 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PPS 
Per-protocol set 
RAGE 
Receptor for Advanced Glycation Endproducts 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SAF 
Safety set 
SAP 
Statistical Analysis Plan 
sRAGE 
Soluble Form of Receptor for Advanced Glycation Endproducts 
TEAE 
Treatment-Emergent Adverse Event 
TEAV 
Treatment-Emergent Abnormal Value 
TSH 
Thyroid Stimulating Hormone 
TTP488 
Azeliragon 
ULN 
Upper Limit of Normal 
QD 
Taken Once Daily 
QoL 
Quality of Life 
QTcＢ 
QT interval calculated using Bazett’s correction factor 
QTcF 
QT interval calculated using Fridericia’s correction factor 
WHO 
World Health Organization 
WHODD 
WHO Drug Dictionary 
 
 
 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-301 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 7, 28 Nov 2017 
High Point, NC 27265 
Page 28 
1.0 
1.1 
1.1.1 
1.1.2 
INTRODUCTION 
This Phase 3 study is designed to evaluate the efficacy and safety of azeliragon 
(TTP488) in participants with mild Alzheimer’s disease (AD). 
BACKGROUND AND RATIONALE 
Alzheimer’s Disease 
Alzheimer disease (AD) is a neurodegenerative disorder characterized by 
progressive loss of memory and cognitive function.  AD is the most common form 
of dementia, is currently estimated to afflict approximately 5.4 million people in the 
United States and represents the 6th leading cause of death.  Worldwide there are 
currently 35.6 million people with dementia, and the number is expected to double 
by the year 2050. (Alzheimer’s Association 2012) 
Mechanism of Action 
Azeliragon is an orally bioavailable antagonist of the Receptor for Advanced 
Glycation Endproducts (RAGE) that is being developed as a potential treatment for 
AD. 
An overproduction of amyloid beta (Aβ) has been implicated as the leading 
mechanistic factor in AD pathology.  Aβ is known to bind to RAGE, an 
immunoglobulin supergene family member expressed on multiple cell types in the 
brain and the periphery (Yan et al., 1996; Schmidt et al., 2009).  RAGE is found on 
the cells of the neurovascular compartment: endothelial cells and microglia 
prominently express RAGE whose expression is upregulated in AD (Yan et al., 
2007; Yan et al, 2009).  RAGE ligands include Aβ, S100b, HMGB1, and Advanced 
Glycation Endproducts.  RAGE-ligand interactions lead to sustained inflammatory 
states that play a role in chronic diseases such as diabetes, inflammation, and AD 
(Stern et al., 2002; Bierhaus et al., 2005).  RAGE has been proposed to contribute to 
AD pathology by: promoting vascular leakage, promoting influx of peripheral Aβ 
into brain; mediating Aβ-induced oxidative stress and Aβ-mediated neuronal death 
(Deane et al., 2003; Carrano et al., 2011; Hartz et al., 2012; Kook et al., 2012). 


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The pleiotropic role of RAGE in AD pathology has been described using rodent 
models. Mice expressing the human amyloid precursor protein (APP) transgene in 
neurons develop significant biochemical and behavioral changes reminiscent of 
human AD.  Double transgenic mouse overexpressing wild type RAGE in the APP 
transgene background exhibit accelerated behavioral changes, whereas double 
transgenic animals expressing a dominant negative mutant of RAGE are protected 
(Arancio et al., 2004).  This data suggests that RAGE plays a role in augmenting the 
chronic inflammatory state caused by overproduction of Aβ. 
RAGE is thought to be involved in the transport of Aβ from peripheral to central 
nervous system compartments (Tanzi et al., 2004).  In vivo, Aβ uptake into brain is 
dependent on RAGE as shown in RAGE null mice (Deane et al., 2003).  Similarly, 
Aβ uptake in brain can be inhibited using either the secreted, soluble form of RAGE 
(called sRAGE) or an anti- RAGE antibody (Deane et al., 2003).  In addition, plaque 
formation in a mouse model of cerebral amyloidosis was inhibited using sRAGE 
(Yan et al., 2000; Rocken et al., 2003). These data suggest that RAGE is intimately 
involved in the pathogenesis of AD, and that sustained Aβ interaction with RAGE 
on blood-brain barrier and/or neuronal cells is an important element of amyloid 
plaque formation and chronic neuronal dysfunction. 
1.1.3 
Clinical Studies 
A summary of the Phase 1 program and the 10-week Phase 2 safety study in patients 
with mild-to-moderate AD is provided in the Investigator’s Brochure.  In addition a 
6 months study of azeliragon in 110 patients with Type 2 diabetes and persistent 
albuminuria and an 18 month study of azeliragon in 399 patients with mild to 
moderate Alzheimer’s disease have been completed. 
The first study of chronic administration of azeliragon as a treatment for AD was 
TTP488-203, a Phase 2, double-blind, placebo-controlled, randomized, multicenter 
study evaluating the efficacy and safety of 18 months of treatment with azeliragon.  
The study was conducted in 399 participants diagnosed with mild to moderate AD 
with a Mini-Mental State Exam (MMSE; score between 14-26). Participants were 
randomized 1:1:1 to one of 2 dose regimens of azeliragon or placebo and dosed with 
investigational drug every morning for 18 months.  Treatment began on the baseline 


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visit with 60 mg/day for 6 days and 20 mg/day thereafter, 15 mg/day for 6 days and 
5 mg/day thereafter, or placebo once daily in the morning with food for 18 months. 
Study visits occurred at screening, baseline, then at 4 weeks, 3, 6, 9, 12, 15, and 
18 months, with a safety follow-up visit at 21 months.  Visits included clinical and 
safety evaluations, blood draw for plasma biomarker and PK analysis, and pill counts 
to assess compliance. Brain MRIs (using standard Alzheimer’s Disease 
Neuroimaging Initiative [ADNI] acquisition parameters) were obtained at baseline, 
12 and 18 months. 
The primary efficacy measure was the Alzheimer’s Disease Assessment Scale-
Cognitive (ADAS-cog).  The ADAS-cog/12-item scale (Scored 0-80) was 
administered before the first dose, and at 3, 6, 9, 12, 15, and 18 months with the 
prespecified analyses being on the ADAS-cog/11-item scale (Scored 0-70).  Primary 
safety measures included reports of AEs, blood and urine tests, and ECG measures. 
Secondary clinical measures included the Clinical Dementia Rating - Sum of Boxes 
(CDR- sb) (key secondary); Alzheimer’s Disease Cooperative Study - Activities of 
Daily Living Scale (ADCS-ADL), Neuropsychiatric Inventory (NPI) and MMSE.  
These were administered prior to dosing and at Months 6, 12, and 18. 
Blood samples for azeliragon PK analysis were collected prior to dosing at Week 1, 
at Months 1, 3, 6, 9, 12, 15, 18, and 21, and at Early Termination. 
Three interim analyses were planned during the study.  The first interim analysis was 
conducted 6 months after approximately 50% of participants had been randomized.  
This analysis was conducted for the purposes of safety and for informing internal 
development decisions.  The second interim analysis was conducted 12 months after 
all participants were randomized to assess futility, as well as for safety and to inform 
internal development decisions.  A third interim analysis to inform internal 
development decisions was to be conducted when all continuing participants 
completed the Month 18 visit. 
The first pre-specified interim safety analysis revealed an increased frequency of 
AEs (concentration related and reversible upon discontinuation of treatment), in 
particular falls and confusion, in the 20 mg/day group relative to the 5 mg/day and 


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placebo groups.  This was associated with a higher percentage of participants in the 
20 mg/day group declining by ≥10 points on the ADAS-cog (relative to Baseline 
scores) at Months 3 and 6 (concentration related and stabilized/reversible upon 
discontinuation of treatment).  These findings were not noted for the 5 mg/day group 
or the placebo group.  On the recommendation of the Data and Safety Monitoring 
Board (IDMC), participants randomized to the 20-mg/day dose discontinued study 
drug, received a safety evaluation, and were asked to consent to continue to be 
followed for safety clinical and laboratory assessments. 
Approximately 12 months after all participants were randomized, the second 
pre-specified interim analysis compared 5 mg/day and placebo for futility based on 
results of the completer population (i.e. those with available 18-month ADAS-cog 
data) Conditional power was computed based on assumed continuation of the 
observed trend. 
While safety data raised no concerns, criterion for futility (<10% conditional power 
to observe a significant difference between 5 mg/day and placebo at 18 months) was 
met and treatment was discontinued.  The third interim analysis was not performed 
as the study was terminated due to futility.  Attempts to replicate the futility analysis, 
using a data set representative of that which would have been used for the futility 
analysis (constructed from the final data set) have been unsuccessful with 
conditional probabilities consistently computed as  >20%. 
Upon completion of the study and locking the database, protocol-planned analysis 
of ADAS-cog data from 100% of subjects who were ongoing or who had completed 
18 months at the time of study termination were performed.  Analysis showed a 
beneficial effect of less cognitive decline in the 5 mg/day group compared to placebo 
at Month 18 (delta = 3.1, p = 0.008, analysis of covariance [ANCOVA] with 
multiple imputation).  To confirm robustness of effect to statistical analysis 
procedures, this difference was found to be significant using other statistical models 
(ANCOVA with last observation carried forward [LOCF; p = 0.03] and generalized 
estimating equations [GEE; p = 0.03]). 
Analysis was done to examine the impact of off-treatment data on analysis 
conclusions. Statistical analysis on ADAS-cog was performed using all available on-
treatment data (“on treatment” defined as data collected within 45 days of the last 


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dose of study medication). Forty-five days was selected based on the long half-life 
of azeliragon (mean = 18 days in elderly participants) and the demonstration of 
measureable, appreciable concentrations during that time frame following the last 
dose.  Mean changes in ADAS-cog show numerical active-placebo differences 
favoring the 5 mg/day dose group over time at all time points, with nominal 
significance at Month 18 (delta=2.7, p = 0.03). 
The key secondary measure of CDR-sb at 18 months showed a numerical difference 
favoring 5 mg azeliragon over placebo CDR-sb (LOCF, delta = 0.73, p = 0.1) 
The current study will enroll patients with mild Alzheimer’s disease.   Subgroup 
analyses of data in Study TTP488-203 based on baseline severity of AD (mild or 
moderate), planned in the protocol and SAP, showed a more pronounced benefit of 
treatment with azeliragon among subjects with mild disease (MMSE 21 or more).  
In patients with mild AD, the difference in ADAS-cog mean change from baseline 
at 18 months was 4.0 (p = 0.018).  In addition, a nominally statistically significant 
difference in CDR-sb mean change from baseline was demonstrated (delta = 1, 
p = 0.02) when comparing azeliragon 5 mg + SoC with placebo + SoC at Month 18.  
Thus, in the Phase 2 trial statistically significant differences between azeliragon 5 
mg/day and placebo on cognition and global performance (using USA FDA agreed 
upon Phase 3 registration measures of ADAS-cog and CDR-sb) have been 
demonstrated.    
1.1.4 
Dose Selection Rationale 
The azeliragon dose (5 mg daily) for the registration studies was selected following 
review of single- and multiple-dose PK, pharmacodynamics (PD), and safety data, 
and the clinical efficacy data from the Phase 2 study (TTP488-203). 
Exploratory analyses relating azeliragon trough concentrations to ADAS-cog values 
and changes in ADAS-cog utilized a subject-level concentration value derived by 
2 methods: (1) the maximum of the trough concentration values for that subject over 
the 18-month period, and (2) the median concentration value for that individual.  
Analyses were done at the subject level.  Each subject’s value was analyzed using 
descriptive statistics.  A summary of the results is found in Table 2. 
 


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Table 2. 
Descriptive Statistics on Trough Concentrations 
Concentration 
Value for Each 
Subject 
Azeliragon 
Dose 
Group 
Mean Concentration 
for Dose Group (each 
subject contributes a 
single value) 
Median 
Concentration for  
Dose Group  
(each subject 
contributes a single 
value) 
95% Confidence 
Interval of the Mean 
Median of trough 
values 
15/5 mg 
(n = 131) 
13.02 
12.25 
[11.74, 14.31] 
60/20 mg 
(n = 134) 
68.57 
64.58 
[63.46, 73.69] 
Maximum of trough 
values 
15/5 mg 
(n = 131) 
16.22 
14.90 
[14.59, 17.85] 
60/20 mg 
(n = 134) 
83.75 
75.05 
[77.40, 90.10] 
 
 
Participants were subsequently classified into concentration groups according to cut-
points in the distribution of trough concentration values ignoring administered dose.  
To assess the sensitivity of analysis results to choice of cut-points, analysis included 
the following cuts: 
• Tertile 
• Quartile 
• Quintile 
• Decile 
Results of analyses of the 4 classification schemes were consistent.  Results 
indicated that within certain trough concentration ranges, delineation from placebo 
in changes in ADAS- cog at 18 months for azeliragon was more pronounced than in 
other ranges.  As expected, higher trough concentrations tended to be observed for 
participants in the 20 mg dose group, and lower trough concentrations tended to be 
observed for participants in the 5 mg dose group. 
Exploratory analysis of concentration-driven assessment of PK/PD effects included 
the quantile cuts described above and also iterative analysis focused on identification 
of a concentration range that was associated with optimal effectiveness for efficacy 
measures (primary and secondary measures). The iterative analysis included 
construction of groups with minimum trough concentrations ranging from 1 to 20 
ng/ml. Within these groups, ranges were derived using optimization techniques to 
identify concentration groups that maximized efficacy. The results of the exploratory 


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PK/PD analysis concluded that the optimal trough concentration range was 8-15 
ng/ml over the 18-month period. 
Based on the considerations outlined above, a 5 mg/day dose was selected.  Doses 
below 5 mg/day and between 5 mg/day and 20 mg/day were considered.  Doses 
below 5 mg/day are expected to provide non-efficacious concentrations.  Doses 
above 5 mg/day (ex: 10 mg/day) are not expected to provide significantly improved 
efficacy relative to the potential for achieving concentrations associated with acute, 
reversible cognitive worsening. 
Preliminary evaluation of the effect of food on the pharmacokinetics of azeliragon 
has been performed from data collected in the TTP488-101 and TTP488-102 studies.  
Comparison of dose normalized pharmacokinetics for data obtained from Study 
TTP488-101 (single, ascending doses administered under fasting conditions; 5, 10, 
20, 35, 50, and 65 mg) and the first administered dose, under fed conditions, from 
Study TTP488-102 (multiple dose administration; 15, 30, 60, and 30 mg in elderly 
subjects) demonstrate up to an approximate 
30% decrease in Cmax and AUC0-24 when administered in the fed state. This 
magnitude of difference in PK between fed and fasted state is not anticipated to be 
clinically meaningful for subjects dosed with 5 mg/d (anticipated concentration 8 to 
15 ng/mL fasted; 10 to 20 ng/mL fed) as concentrations will be within the range 
associated with efficacy in TTP488-203 and well below those associated with the 
acute, reversible cognitive worsening in the 20 mg/d group (>47 ng/mL). 
1.1.5 
Single Reference Safety Document 
The single reference safety document for this protocol is the Investigators Brochure. 
 
 


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2.0 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
OBJECTIVES 
Primary objective: 
• To evaluate the efficacy of azeliragon on cognitive [Alzheimer's Disease 
Assessment Scale-cognitive subscale (ADAS-cog)] and global function 
[Clinical Dementia Rating Scale Sum of Boxes (CDR-sb)] measures in patients 
with mild AD. 
Key secondary objective: 
• To examine the effect of azeliragon on MRI volumetrics (e.g., whole brain 
volume, ventricular volume, hippocampal volume). 
* note: the decision as to the specific key secondary to support disease 
modification claim will be made prior to database lock. 
Secondary objectives: 
• To evaluate the safety and tolerability of 18 months treatment with azeliragon 
plus standard of care relative to placebo plus standard of care. 
• To evaluate the time course of the effect of azeliragon on the cognitive 
(ADAS-cog) and global functional outcome (CDR-sb) measures. 
• To evaluate the efficacy of azeliragon on behavioral symptoms as assessed by 
the Neuropsychiatric Inventory (NPI). 
• To evaluate the efficacy of azeliragon on cognitive symptoms as assessed by the 
Mini-Mental State Examination (MMSE). 
• To evaluate the efficacy of azeliragon on the Alzheimer’s Disease Cooperative 
Study - Activities of Daily Living Scale (ADCS-ADL). 
• To evaluate the efficacy of azeliragon on cognition as assessed by the 
Continuous Oral Word Association Task (COWAT), Category Fluency Test 
(CFT) and Trail Making Test  (Versions A and B). 


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• To evaluate the effect of azeliragon on health status, health care resource 
utilization, and health-related quality of life as assessed by Resource Utilization 
in Dementia (RUD Lite), and Dementia Quality of Life (DEMQOL-proxy). 
• To evaluate the effect of azeliragon on regional and global brain glucose 
metabolism using FDG-PET. 
• To evaluate the effect of azeliragon on plasma Aβ biomarkers. 
• To evaluate exposure-response relationships for selected efficacy and biomarker 
endpoints (e.g., ADAS-cog, ADCS-ADL, adverse events, vital signs). 
2.2 
ENDPOINTS 
Primary Endpoint (Co-primary endpoints): 
• Change from Baseline in the ADAS-cog at Month 18. 
• Change from Baseline in the CDR-sb at Month 18. 
Key Secondary Endpoints: 
• Change from Baseline in brain volumetrics (e.g., whole brain volume, 
ventricular volume, hippocampal volume) at Month 18 
Other Secondary Endpoints: 
• Adverse events, clinical safety laboratory tests, MRI, ECG, vital signs. 
• Responder analysis at Months 6, 12 and 18 based on the ADAS-cog. 
• Responder analysis at Months 6, 12 and 18 based on the CDR-sb. 
• The slope of change over time in ADAS-cog, MMSE and CDR-sb scales through 
Month 18. 
• Time to loss of one global stage on the CDR score through Month 18. 
• Proportion of participants experiencing a loss of one global stage on the CDR 
global score at Months 6, 12, and 18. 


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• Change from Baseline on the ADAS-cog and CDR-sb total scores at Months 6 
and 12. 
• Change from Baseline in the ADCS-ADL total score at Months 6, 12 and 18. 
• Change from Baseline in the NPI total score at Months 3, 6, 12 and 18. 
• Change from Baseline in the MMSE total score at Months 3, 6, 12 and 18. 
• Change from Baseline in the COWAT and CFT score at Months 3, 6, 12 and 18. 
• Change from Baseline in Trail Making Test (versions A and B) time at Months 
3, 6, 12 and 18. 
• Individual item responses on the RUD Lite questionnaire and the total 
caregiver/informant time spent assisting the patients based on the RUD Lite 
questionnaire at Months 6, 12 and 18. 
• Proportion of participants who enter intermediate or long-term residential care 
(RUD Lite). 
• Change from Baseline in the DEMQOL-proxy total score at Month 18. 
• Change from Baseline in regional and global brain glucose metabolism using 
FDG- PET at Month 18 
• Change from Baseline in plasma concentrations of Aβ species at Month 18. 
• Exposure response relationships based on selected efficacy, safety, and 
biomarker outcomes. 
 
 


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3.0 
STUDY DESIGN 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel-group 
study evaluating the efficacy and safety of 18 months of treatment with azeliragon 
relative to placebo.  The study will be conducted in approximately 800 patients 
diagnosed with mild AD (MMSE 21-26) who are on background SoC.  Participants 
will be randomly assigned one dose of azeliragon (5 mg/day plus SoC) or placebo 
plus SoC in a 1:1 randomization (approximately n=400/group).  Randomization will 
be stratified based on severity of disease and will be blocked by substudy (A-Study 
and B-Study), and randomization will be blocked by investigative site. Approximately 
160 of these subjects will be targeted for participation in FDG-PET. 
Participants are required to be on SoC of a stable background (defined as at least 
3 months on a consistent dose prior to randomization) acetylcholinesterase inhibitor 
therapy and continue the therapy for the duration of the trial, unless the investigator 
judges that the dose needs to be reduced or stopped due to a safety and/or tolerability 
reason.  Participants on memantine similarly must be on a stable dose for at least 3 
months prior to randomization and continue therapy for the duration of the trial unless 
the investigator judges that the dose needs to be reduced or stopped due to a safety 
and/or tolerability reason. 
Behavioral medications (including antidepressants, antipsychotics and anxiolytics) 
must be on stable doses for at least 4 weeks prior to randomization.  In the case 
where a behavioral medication is initiated during the trial, at least one week period 
at a stable dose must elapse before clinical assessments are obtained. 
Subject will participate in approximately 9 outpatient visits including screening and 
follow up visit. 
A minimum of three staff members will be required to conduct the protocol at each 
site.  Details will be provided in the procedures manual. 
• 
Principal Investigator (PI) – This person is responsible for the clinical 
evaluation of all participants, ensuring enrollment and protocol adherence, 
endpoint determinations, and decisions regarding breaking the blind.  The PI 


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will supervise project personnel and ensure that raters maintain a high level of 
skill and accuracy in conducting assessments.   
• 
Study Coordinator  – This person will be responsible for managing day-to-day 
conduct of the trial, track recruitment, and ensure accurate administration of all 
instruments at the site, supervise data collection, processing of laboratory 
samples, and maintain a log of treatment adherence.  The study coordinator may 
serve as a rater, but may not perform the CDR-SB if s/he is responsible for study 
oversight. 
• 
Rater – This person will have at least a bachelor’s degree in health care 
psychology, social work or a related field, or be an RN and meet the clinical 
and scale experience requirements set by TTP.  This person can conduct all 
ratings and assessments.   
• 
CDR Rater – This person will render the CDR-SB rating based on clinical 
assessment of participant and study partner, using worksheets provided by the 
Sponsor, but without access to the ADAS-cog.  Since the CDR-SB is a co- 
primary endpoint with the ADAS-cog, it is important for the CDR rater to 
remain blinded to ADAS-cog data and all other scales for that subject.   
 
 


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4.0 
SUBJECT SELECTION 
4.1 
INCLUSION CRITERIA 
Subject eligibility should be reviewed and documented by an appropriately qualified 
member of the Principal Investigator’s (PI's) study team before participants are 
included in the study. 
1. Evidence of a personally signed and dated informed consent document 
indicating that the subject (or a legally authorized representative) and 
caregiver/informant has been informed of all pertinent aspects of the study.  
Participants must be able to provide assent (where this is in accordance with local 
laws, regulations and ethics committee policy) and assent may be re-evaluated 
during the study at regular intervals. 
2. Participants and caregiver/informants who are willing and able to comply with 
scheduled visits, treatment plan, laboratory tests, and other study procedures. 
3. The subject must have a reliable caregiver/informant with regular contact (i.e., 
10 hours a week as combination of face-to-face visits and telephone contact 
acceptable) who will facilitate the subject’s full participation in the study.  
Caregivers/informant must have sufficient subject interaction to be able to 
provide meaningful input into the rating scales administered in this study where 
caregiver/informant input is required, in particular the CDR and evidence of this 
should be documented in source documentation.  Participants who reside in 
assisted 
living 
facilities 
are 
permitted 
provided 
that 
they 
meet 
caregiver/informant criteria. 
4. Participants and caregiver/informants must be able to read, write, and speak the 
language in which psychometric tests are provided with visual and auditory 
acuity (corrected) sufficient to allow for accurate psychometric testing. 
5. Males and females (of non-childbearing potential) ages ≥50 years of age at 
screening. 


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6. Diagnosis of probable AD, consistent with the criteria from the 2011 National 
Institute on Aging and the Alzheimer’s Association workgroup (McKhann et al., 
2011). 
Evidence of progression needs to be documented in source 
documentation at the time of screening based on review of prior medical records 
and/or information gathered from the subject or caregiver/informant(s).  
Biomarker evidence of the pathophysiological process or neuronal injury 
associated with AD should be documented if data is available in participant’s 
medical records (not specifically measured for inclusion in this study).   
7. MRI consistent with a diagnosis of probable Alzheimer’s disease.  A head CT 
scan may be used for evaluation if there is a documented contraindication to an 
MRI (e.g. pacemaker).   
8. Mini-Mental State Exam (MMSE) score of 21-26 inclusive at screening. 
9. CDR global score of 0.5 or 1 at screening. 
10. Rosen-Modified Hachinski Ischemia Score ≤4 at screening. 
11. Participants must be on a stable dose of a background cholinesterase inhibitor 
and/or memantine (approved by the relevant health authority where the trial is 
being conducted) at least 3 months prior to randomization and must agree not to 
change the dose during the study period unless the investigator judges that the 
dose needs to be reduced or stopped due to a safety and/or tolerability reason. 
12. No clinically significant, (in the opinion of the investigator) laboratory 
abnormalities at screening.  If the results of clinical laboratory testing are 
outside normal reference ranges, the subject may be enrolled but only if these 
findings are determined to be not clinically significant by the investigator.  This 
determination must be recorded in the subject’s source documents.  A summary 
of values of potential clinical concern is provided in APPENDIX 1. 
13. Subject must be able to ingest oral medications. 
 


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4.2 
EXCLUSION CRITERIA 
Participants presenting with any of the following will be excluded from participation 
in the study. 
1. Current evidence or history of neurological, psychiatric, and any other illness 
that could contribute to dementia including, but not limited to other 
neurodegenerative disorders (e.g., Lewy body disease, fronto-temporal 
dementia, vascular dementia), head injury with loss of consciousness proximate 
to the onset of dementia, participation in contact sports characterized by repeated 
head injuries, DSM-IV-TR criteria for any major psychiatric disorder including 
psychosis, current major depression, bipolar disorder, alcohol or substance abuse 
or dependence, neurosyphilis, vitamin B12 deficiency (see Exclusion 3, below), 
thyroid disease (unless adequately treated for at least 3 months with 
normalization of laboratory values) or any form of dementia other than AD. 
2. Participants from a family with known autosomal dominant AD associated with 
mutations in APP, PS1 or PS2 genes or strongly suspected, but not yet identified 
mutations in APP, PS1 or PS2 genes, or Down’s syndrome.  Individuals from 
families with any number of late onset AD affected family members may 
participate in this study. 
3. Vitamin B12 levels lower than laboratory reported normal limits (and remains 
below on repeat testing).  Participants may be enrolled following the initiation 
of B12 therapy for 4 weeks prior to dosing and confirmed within normal limits 
upon repeat. 
4. Diagnosis or history of cerebrovascular stroke, severe carotid stenosis, cerebral 
hemorrhage, intracranial tumor, subarachnoid hemorrhage that, as determined 
by the investigator, could either contribute to the patient’s current cognitive or 
functional status, impair his/her ability to fully participate in the trial or that may 
impact his/her status during an 18-month trial. 


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5. Specific exclusionary brain MRI findings (as identified on the central MRI read) 
as determined by the investigator that could either significantly contribute to the 
patient’s current cognitive or functional decline, impair his/her ability to fully 
participate in the trial or that may impact his/her status during 18-month course 
of the trial. In any case, 10 or more microhemorrhages as identified by the central 
reading, is exclusionary. Grade three deep white matter changes (diffuse 
involvement of entire region) on the central reading report is exclusionary. If a 
head CT is used for assessment of eligibility, structural abnormalities as 
determined by the investigator that could either significantly contribute to the 
patient’s current cognitive or functional decline, impair his/her ability to fully 
participate in the trial or that may impact his/her status during 18-month course 
of the trial would be exclusionary.   
6. A current primary diagnosis of major psychiatric disorder, e.g., schizophrenia, 
bipolar disorder, major depressive disorder, or other severe psychiatric illness 
per the DSM-IV-TR criteria per the investigator’s judgment. 
7. Serious suicide risk per the following criteria: 
• Suicidal ideation associated with intent and/or plan within the previous year 
as indicated by a “yes” answer on Items 4 or 5 of the C-SSRS or, 
• History of suicidal behavior within the previous 10 years as indicated by a 
“yes” answer to any of the suicidal behavior items of the C-SSRS with a 
behavior occurring within the previous 10 years or, 
• Lifetime history of serious or recurrent suicidal behavior. 
8. History of cancer within the last 5 years except adequately treated cervical 
carcinoma in-situ, cutaneous basal cell or squamous cell cancer, or 
non-progressive prostate cancer not requiring treatment. 
9. Current (e.g., within the last 3 months) body mass index (BMI) of greater than 
or equal to 35 kg/m2 or a current (e.g., within the last 3 months) weight less 
than 45 kg. 
10. Any clinically significant hepatic or renal disease, elevated transaminase levels 
of greater than 1.5 times the upper limit of normal (ULN), creatinine greater 
than 1.5 x ULN. 


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11. Patients with unstable, uncontrolled diabetes (HbA1c > 7.7%) and those 
requiring insulin. 
12. Participants with poorly controlled hypertension with or without existing 
therapy (systolic≥160 or diastolic≥100). Subjects will be allowed to participate 
with management of blood pressure below the exclusionary levels with 
introduction of an allowable medication and the subject has been on the drug 
for 4 weeks prior to baseline.  
13. Participants with evidence or history of severe drug allergies (such as resulting 
in dyspnea or severe rash) or allergy to any constituents of the study drug as 
formulated. 
14. Known history of alcohol or drug abuse or dependence (as defined by the DSM-
IV-TR) within 5 years prior to dosing or a positive result on the drug screening 
test (unless due to a permitted concomitant medication (i.e., a benzodiazepine 
as a sleep aid). 
15. Patients with pulmonary hypertension are excluded. 
16. Any contraindications to the MRI procedure based on local operating 
procedures and instructions (e.g., clinically significant claustrophobia, non-
removable ferromagnetic implants).  It is acceptable to premedicate patients per 
usual local practice provided this medication is not administered within 5 
half-lives preceding any efficacy assessments.  Patients with contraindications 
to MRI (ex: pacemakers) may undergo computed tomography (CT) on approval 
by Sponsor.   
17. Any contraindications to the FDG-PET study (e.g. allergy to any component of 
the FDG dose) in the mild AD dementia subject cohort undergoing a PET scan. 
18. Previous exposure to investigational therapies for Alzheimer’s disease that are 
being investigated for possible disease modification activity (e.g., azeliragon, 
passive immunotherapies and secretase inhibitors) within 4  months of 
screening for the current protocol. Subjects who were exposed to vaccine 
therapy or other active immunization (if they were randomized to active 
treatment) will not be allowed in the trial. Previous exposure to any other 
investigational drug as part of a clinical trial, including investigational therapies 


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for Alzheimer’s disease that are being investigated for non-disease modifying 
purposes, within 60 days   or 5 half-lives whichever is longer, prior to screening.  
19. Participants who are taking or are expected to use drugs known to be strong 
CYP2C8 inhibitors or (See APPENDIX 2 for a list of such medications). 
20. Participants receiving systemic steroids.  Topical corticosteroid application to 
the skin is allowed, as are localized corticosteroid injections if administered no 
more than once every 6 months during the last year and are expected to be 
administered no more frequently during the study.  Use of inhaled, intranasal or 
otic steroids are not excluded.  
21. Participants receiving medications that may negatively affect cognitive function 
(e.g., antidepressants, sedatives/anxiolytics) unless such medications have been 
taken at a stable dose for at least 4 weeks prior to randomization (i.e., in the 
investigators judgment, efficacy and tolerability have been optimized) and are 
expected to continue on a stable dose for the duration of the trial. 
22. Prescription medical food (i.e. Axona) intended for the dietary management of 
the metabolic processes associated with Alzheimer’s disease. 
23. Participants may not donate blood within 8 weeks prior to the first dose of study 
drug and for 6 months after the last administration of study drug. 
24. Subjects demonstrating a QTcF > 470 msec for females or > 450 msec for males 
on the screening ECG, as confirmed by the central reading.  If the average of 
three locally read ECGs performed at baseline exceeds these values, then a 
determination of the subject’s eligibility will be delayed until the baseline QTcF 
result is obtained from the central reading.  If the average of the three centrally 
read values exceeds 470 msec for females or 450 msec for males, the subject will 
not be randomized.  Subjects with an average of three locally read ECGs 
performed at baseline ≤470 msec for females or ≤450 msec for males will be 
randomized.  For these randomized subjects, if the baseline average QTcF on the 
central reading of the ECG subsequently is > 470 msec for females or 
> 450 msec for males, the sponsor’s medical monitor will be consulted for a 
determination regarding the acceptability of continued dosing with study 
medication.  Participants with known history of bundle branch block (either 
right or left) are allowed if absolute QTcF value does not exceed 500 ms.  


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Participants with a functioning pacemaker, indicated by an ECG displaying 
paced rhythm, are allowed with no QTc upper limit. 
25. History of clinically significant cardiac disease as determined by the PI and in 
consultation with the Sponsor.  Examples of cardiac disease that would be 
unlikely to allow study enrollment include 2nd degree or greater heart block 
without a pacemaker, sick sinus syndrome, ventricular tachycardia or 
fibrillation, sustained supraventricular tachycardia, symptomatic bradycardia, 
congenital long QT interval syndrome, atrial fibrillation, clinically significant 
angina/coronary artery disease, myocardial infarction in the past year, 
congestive heart failure, cardiomyopathy, myocarditis, left ventricular 
hypertrophy, valvular heart disease requiring treatment or life style 
modification. Subjects with atrial fibrillation on anticoagulant therapy and who 
have had no thromboembolic events or other referable cardiac events in the 
preceding 1 year are considered stable and may be screened.  
26. Other acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may prevent the subject from 
completing the 18-month study or may interfere with the interpretation of study 
results and, in the judgment of the investigator, would make the subject 
inappropriate for entry into this trial. 
4.3 
CONTRACEPTION REQUIREMENTS AND STUDY PARTICIPANT 
INSTRUCTION 
4.3.1 
Males 
A fertile male study participant, whose sexual partner is female and of childbearing 
potential, must agree to use one of the following methods of contraception for the 
duration of the study (from the first dose until 90 days after the final dose of the 
study medication):  abstinence, use of condom plus their female partners must use 
another form of contraception including implants, injectables, combined oral 
contraceptives, barrier contraception methods, spermicides, intrauterine devices 
(IUDs), transdermal contraceptives, and intravaginal contraception rings. The male 
study participant should also agree to no sperm donation for 90 days after the final 
dose of study medication. 


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At appropriate study visits, all study participants are reminded of contraception 
requirements as described above.  Upon discharge from the study, subjects will be 
instructed to notify the Study Site if a female study participant or female partner of 
a male study participant becomes pregnant within 90 days of last dose of study 
medication. 
 
 


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5.0 
STUDY TREATMENTS 
5.1 
RANDOMIZATION TO STUDY TREATMENT 
Subjects will be screened by Investigators or qualified designees to assess eligibility 
for randomization into the study.  An interactive voice response system (IVRS)/ 
interactive web response system (IWRS) will be used for assignment of treatment. 
Subjects will be enrolled and randomized according to a fixed randomization scheme 
blocked by substudy (A-Study and B-Study will be randomized separately) and study 
investigative site. Severity of AD will be determined by MMSE at screening.  
ADAS-cog at Screening will be used as a stratification variable in the randomization 
scheme: 
• ADAS-cog 19 or less. 
• ADAS-cog more than 19. 
Randomization will have balanced allocation (1:1) between azeliragon plus SoC and 
placebo plus SoC.  Dropouts will not be replaced. 
A randomization plan will be developed to guide the programming and security of 
the randomization scheme for this study. 
5.2 
BREAKING THE BLIND 
The study will be double-blind.  At the initiation of the study, the study site will be 
instructed on the electronic process for breaking the blind.  Blinding should only be 
broken in emergency situations when knowledge of the treatment assignments is 
necessary for subject safety.  Upon breaking the blind, the reason must be 
documented in the electronic data capture system. The sponsor or representative 
should be consulted prior to breaking the blind except in emergent circumstances.  


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5.3 
DRUG SUPPLIES 
Drug supplies will consist of a 5 mg and matching placebo formulation supplied as 
a Size 2 hard gelatin capsule in a double-blind fashion.  The recommended storage 
condition for the product is room temperature at 15oC to 30oC (59oF to 86oF). 
5.3.1 
Formulation and Packaging 
Azeliragon and matching placebo capsules will be packaged into child-resistant, 
high density polyethylene (HDPE) bottles with heat induction seal (HIS) closures.  
Supplies will be packaged in a blinded fashion.  All formulations are identical in 
appearance and packaging. 
Storage conditions and participant dosing instructions will be listed on the 
packaging. 
5.3.2 
Administration 
Treatment will begin in the clinic at the baseline visit immediately following 
randomization, as long as all study procedures have been completed and the subject 
is deemed qualified to randomize and has been randomized and assigned drug. One 
capsule will be administered with a glass of water.  Participants will be instructed to 
take one capsule per day by mouth for the duration of the 18-month treatment period.  
The day’s dose of study medication will be administered in the clinic at each 
subsequent study visit.  Study medication may be administered without regard to 
meals. 
5.3.3 
Compliance 
Participants will bring all unused azeliragon/placebo capsules to each study visit.  
The number of capsules will be counted and documented.  If more than expected are 
returned, participants will be asked to account for missed doses.  If the number of 
capsules is less than expected, participants will be asked to account for the missing 
capsules (e.g., capsules that are lost vs. excessive dosing of study medication). 
Caregivers/Informants will be instructed to assist with monitoring dosing 
compliance.  


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5.4 
DRUG STORAGE AND DRUG ACCOUNTABILITY 
Study drug supplies must be stored at room temperature (15C –30C [59F-86F]) 
in a secure and locked area.  The pharmacist or designee at the study site will manage 
and store the study drug. 
Study drugs will be accounted for in the case report form and drug accountability 
inventory forms as instructed by the Sponsor.  At the end of the study, all drug 
supplies not dispensed or unused by the participants must be returned to the location 
designated by the Sponsor. 
5.5 
CONCOMITANT MEDICATION(S) 
Concomitant medications and over the counter medications and supplements taken 
during the study must be recorded with indication, daily dose, and start and stop 
dates of administration.  All participants will be questioned about concomitant 
medication and supplements at each clinic visit. 
Participants must be on a stable dose of background cholinesterase inhibitor and/or 
memantine at least 3 months prior to dosing.  Dose reductions of background 
cholinesterase inhibitor and/or memantine are permitted during the course of the trial 
(e.g., due to safety/tolerability or to conform with local standard of care).  Dose 
increases of background cholinesterase inhibitor and/or memantine are not permitted 
during the course of the trial. 
Medications taken within 60 days prior to screening must be documented as a prior 
medication.  All past medications/therapies for Alzheimer’s disease must be 
recorded.  Medications taken after the first dose of study medication must be 
documented as concomitant medications. 
Medications that may negatively affect cognitive function (e.g., antidepressants, 
sedatives/anxiolytics) must be at a stable dose (i.e., in the investigators judgment, 
efficacy and tolerability have been optimized) for at least 4 weeks prior to 
randomization and are expected to continue on a stable dose for the duration of the 
trial. (Dose adjustments are permitted however participants should be on a stable 
dose at least one week prior to any protocol-specified clinical assessments). 


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Exceptions to medications that may negatively affect cognitive function are as 
follows: 
• Participants may receive pre-medication (e.g., sedative or anxiolytic) for the 
MRI or CT scan assessment.  This medication should not be administered within 
5 half-lives preceding any efficacy assessments. 
• Participants should not receive pre-medication (e.g. sedative for anxiolytic) for 
the PET assessment (PET substudy applies only for select sites in the US and 
Canada). 
•  Considerations for use of medications that may affect the CNS or cognition 
following randomization. Generally, medications that affect cognition are not 
allowed. In such case that there is an acute need for use of a medication that may 
negatively affect cognition or the CNS in general (e.g., sedatives/anxiolytics, 
antipsychotics, opiates), their use should be transient (no more than 4 weeks), 
must be stable for at least one week prior to any cognitive assessments, and 
discussed with the sponsor’s medical monitor prior to use (or as soon as possible 
following discovery of their use). Chronic use of these medications is not 
permitted. Should their use be deemed to be chronic (spanning months), 
discussion with the Sponsor’s medical monitor is required with a view to 
discontinuing the subject from participation.  
The use of following concomitant medications is not allowed: 
• Drugs known to be potent CYP2C8 inhibitors (See APPENDIX 2 for a list). 
• Any use of steroid treatment. Allowable exceptions: a) topical, otic, nasal or 
inhaled corticosteroid applications to the skin, and b) localized corticosteroid 
injections, no more than once every 6 months. 
• Prescription medical food (i.e. Axona) intended for the dietary management of 
the metabolic processes associated with Alzheimer’s disease. 
No investigational therapies for Alzheimer’s disease that are being investigated for 
possible disease modification activity (e.g., azeliragon, passive immunotherapies 
and secretase inhibitors) within 4 months of screening for the current protocol.  


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No investigational therapies that are being investigated for non-disease modifying 
purposes, within 60 days or 5 half-lives whichever is longer, prior to screening. 
Subjects who were exposed to vaccine therapy or other active immunization (if they 
were randomized to active treatment) will not be allowed in the trial.   
During the study, participants should be instructed to review new prescriptions and 
over-the-counter preparations with the investigator prior to taking any medications. 
All medications should be approved by the investigator prior to use and recorded on 
the Case Report Form (CRF).  If the medication is started because of an adverse 
event (AE), this event should be reported on the appropriate CRF. 
Any additional questions regarding medications should be addressed to the 
Sponsor’s medical monitor. 
 
 


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6.0 
STUDY PROCEDURES 
• Study participants should consume a meal or snack prior to their clinic visit.  
Upon arrival, the Site staff will confirm the subject has consumed a meal or 
snack prior to beginning study procedures.  The time of the finishing the 
meal/snack will be documented in the source documents.  Thus clinical 
laboratories will be obtained under non-fasting conditions at all visits.   
• Cognitive/functional assessments (in particular the ADAS-cog, MMSE and 
CDR-sb) should be performed as first procedures during a study visit. 
• It is recommended that cognitive/functional assessments should be performed in 
the following order:  ADAS-cog, MMSE, CDR when administered on the same 
day.  The same rater should follow a particular subject for any given assessment 
for the duration of the study whenever possible.  Note, the initial rating scales 
should be the ADAS-cog to minimize subject fatigue, followed by the MMSE. 
Additionally, to avoid subject fatigue, the CDR may be performed on a separate 
visit day than the other cognitive tests. If it is to be done the same day, then 
the CDR should follow the MMSE as above.  The exception to this is the 
Screening visit during which the MMSE will be performed first.  If the subject 
is eligible based on their MMSE score, proceed with the remaining screening 
assessments. 
• Following completion of the cognitive/functional assessments the remainder of 
study visit procedures will be completed.  
• ECGs: obtain prior to blood sampling. Obtain in triplicate at baseline visit and 
as single tracings at all other study days.  
• Vital signs: obtain prior to blood sampling.  
• Blood sampling should be the last procedure performed prior to dosing during a 
study visit. 
• Dosing should occur in the clinic on study visit days. 
• Patient blood glucose level should be assessed immediately prior to 
administration of the FDG-PET dose (for those subjects participating in the PET 
substudy). This blood sample may be fasting or non-fasting.  


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6.1 
SCREENING 
For logistical purposes, up to 60 days will be allowed for screening to confirm that 
participants meet all selection criteria for the study.  It is strongly encouraged that 
the screening period is minimized to the shortest possible duration whenever 
possible.  The investigator (or an appropriate delegate at the investigator site) will 
obtain informed consent from each subject, caregiver/informant, and where 
appropriate, legally authorized representative in accordance with Subject 
Information and Informed Consent/Assent (where this is in accordance with local 
laws, regulations and ethics committee policy).  The screening assessments may be 
separated out into more than one visit if required.  Refer to the Schedule of Events 
for a tabular presentation for screening activities. 
The following activities will be completed: 
• Complete informed consent/assent process (where this is in accordance with 
local laws, regulations and ethics committee policy) resulting in a signed ICF(s) 
by the appropriate parties. 
• Assign screening identification number. 
• Complete MMSE to determine subject eligibility.  If subject is eligible based on 
the MMSE, proceed with the remainder of screening visit in any order.  
• ADAS-Cog 
• The Columbia Suicide Severity Scale (C-SSRS) 
• CDR (calculation of both global score and sum of boxes score global) 
• Demographic information (i.e., sex, date of birth, race/ethnicity). 
• Complete medical and surgical history, including family medical history of 
dementia. 
• Record and review concomitant medications and any discontinued medication 
in the 60 days prior to the Screening visit. 
• History of drug, alcohol and tobacco use. 


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• Complete physical and neurological exams. 
• Rosen-Modified Hachinski Ischemia Scale 
• Height and body weight. 
• Vital signs: blood pressure (supine), pulse rate. 
• Single 12-lead electrocardiogram (ECG). 
• Review of inclusion and exclusion criteria. 
• Blood and urine specimens for safety laboratory tests (serum chemistry, 
hematology, UA) will be collected, in addition to the following: 
 Serum glucose and HbA1c; 
 Hepatitis screens (including hepatitis B surface antigen, hepatitis B core 
antibody, hepatitis B surface antibody, and hepatitis C antibody); 
 Syphilis test. If positive, a standard confirmation test will be obtained; 
 Thyroid function (T3, T4, and TSH); 
 Vitamin B12 (and MMA if indicated, e.g., if serum B12 level <211 pg/mL); 
 Serum FSH concentrations in all female participants to confirm post- 
menopausal status and  eligibility regarding non-child bearing potential; 
 Urine drug screen. 
• Brain MRI performed at least 14 days prior to Month 0/Day 1 dosing; The MRI 
may also include gadolinium contrast if determined to be appropriate by the 
investigator. For subjects with a contraindication to MRI scanning (e.g. 
pacemaker), a CT scan will fulfill the requirements for assessing subject 
eligibility.  Use of contrast is allowed upon investigator discretion. 
• Upon completion of screening procedures, and prior to the Baseline visit, 
approval from the Sponsor on the Eligibility Assessment  Form (EAF) must be 
obtained before proceeding to the Baseline visit. 
 
 


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Re-screening of a Participant 
Participants previously screened but not dosed in another AD study, including a 
azeliragon study may participate in this study provided they meet the subject 
selection criteria.  All screening data must be obtained within 60 days prior to the 
first dose of study medication.  
Participants who had been screened and failed to join the study based on the 
following reasons are allowed to re-screen if the subject is beyond the original 
60 day screening window.  Participants do not have to repeat the MRI if dosing 
occurs within 90 days from the initial screening visit. 
• Participants with Vitamin B12 below the normal limits at initial screening. 
Participants must subsequently have been taking Vitamin B12 for at least 4 
weeks after initial screen failure and have repeat B12 level within the normal 
range.   
• Participants who are not on a stable dose of acetylcholinesterase inhibitors or/and 
memantine for at least 3 months prior to planned dosing may rescreen once they 
have reached 3 months of stable dosing of acetylcholinesterase inhibitors or/and 
memantine. 
• Participants excluded because of potentially undiagnosed type 2 diabetes, 
provided that their disease and serum glucose values are now controlled and 
being actively managed, per the investigator's judgment. 
• Hypertension discovered at screening that is subsequently actively managed and 
the blood pressure values are within acceptable limits. 
• Subjects who have a CDR of 0 or an MMSE score >26 may rescreen upon 
approval of the sponsor’s medical monitor. CDR scores greater than 1 or MMSE 
scores less than 21 may not rescreen. The time to rescreen a subject is up to the 
investigator but in any case may not be within 3 months with no upper time limit. 
They may rescreen only once. Subjects who score out of range are considered a 
screen fail, even if they are planning to rescreen.    


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6.2 
STUDY PERIOD 
6.2.1 
Baseline (approximately Day -7-Day 1) 
• ADAS-cog, MMSE, CDR-sb, ADCS-ADL, COWAT, CFT, Trail Making Test 
(Versions A and B), NPI, RUD Lite, DEMQOL-proxy  
• C-SSRS. 
• Review of inclusion and exclusion criteria including the results of the MRI scan. 
• Brief physical and neurologic examination. 
• Update concomitant medications. 
• Weight. 
• Assess baseline symptoms/adverse events. 
• 12-lead electrocardiogram (ECG) (performed in triplicate). 
• Vital signs: blood pressure (supine), pulse rate. 
• Baseline FDG-PET (if applicable). 
• Collect blood sample for plasma retention and storage. 
• Blood sample for ApoE genotyping. 
• Blood and urine sampling for safety labs including HbA1c. 
• Collect blood samples for PK and PD. 
• Randomize subject if eligible. 
• Dispense study drug if eligible. 
• Subject begins taking study medication in the clinic as soon as baseline 
procedures are completed (noted as Month 0 [Day 1] on Table 1. Schedule of 
Activities). 
If the baseline assessments are performed on more than one day, up to 7 days are 
allowed for completion of baseline procedures prior to subject randomization and 
dosing.  The 7 day window will begin on the day that the first baseline assessment 
is performed and ends on the day when the subject is randomized and study drug is 
administered. 


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If it is necessary to extend the 7 day period for any other reason (e.g., schedule 
conflicts, patient/caregiver/informant illness, inclement weather) the Sponsor should 
be contacted for approval and the visit window may be extended up to 7 days.  In 
this case, re-review of the inclusion/exclusion criteria and concomitant medications 
should occur within 7 days prior to the first dose to ensure that the patient continues 
to be appropriate for the study.  Other baseline procedures may be repeated at the 
discretion of the Investigator, but are not required.  The 60 day period from screening 
to first dose will remain in effect.  Should the overall screening time exceed 60 days, 
re-screening will be required. 
6.2.2 
Month 1 (± 4 days) 
• Telephone contact. 
• Review and record new concomitant medications. 
• Assess symptoms/adverse events by asking the participants to respond to a non- 
leading question such as “How have you been feeling?” 
• Assess drug compliance with the question “Have you been taking your 
medication every day as instructed?” 
6.2.3 
Month 2 (± 4 days) 
• Telephone contact. 
• Review and record new concomitant medications. 
• Assess symptoms/adverse events and by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
• Assess drug compliance with the question “Have you been taking your 
medication every day as instructed?” 
6.2.4 
 Month 3 (± 7 days) 
• ADAS-cog, MMSE, CDR, ADCS-ADL, COWAT, CFT and Trail making test 
(Versions A and B), and NPI. 
• C-SSRS.  


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• Review and record new concomitant medications. 
• Assess symptoms/adverse events by asking the participants to respond to a non-
leading question such as “How have you been feeling?” 
• Brief physical and neurologic examination. 
• Body weight. 
• ECG. 
• Vital signs: blood pressure (supine) and pulse rate. 
• Collect blood sample for plasma retention and storage. 
• Blood and urine sampling for safety laboratory testing including HbA1c. 
• Collect blood samples for PK and PD.  
• Drug accountability. Any discrepancies are recorded in the source and the 
subject and caregiver/informant are counseled regarding proper dosing 
compliance. 
• Dispense study drug.  Subjects take their dose of study medication in the clinic. 
6.2.5 
Month 6 (± 7 days) 
• ADAS-cog, MMSE, CDR, ADCS-ADL, COWAT, CFT, Trail making test 
(Versions A and B), NPI, RUD Lite and DEMQOL- proxy. 
• C-SSRS. 
• Review and record new concomitant medications. 
• Assess symptoms/adverse events and by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
• Brief physical and neurologic examination. 
• Body weight. 
• ECG. 
• Vital signs: blood pressure (supine) and pulse rate.  
• Collect blood sample for plasma retention and storage. 
• Blood and urine sampling for safety laboratory testing including HbA1c. 


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• Collect blood samples for PK and PD  
• Drug accountability. Any discrepancies are recorded in the source and the 
subject and caregiver/informant are counseled regarding proper dosing 
compliance. 
• Dispense study drug.  Subjects take their dose of study medication in the clinic. 
6.2.6 
Month 9 (± 7 days) 
• ADAS-cog. 
• C-SSRS. 
• Review and record new concomitant medications. 
• Assess symptoms/adverse events and by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
• Brief physical and neurologic examination. 
• Body weight. 
• ECG. 
• Vital signs: blood pressure (supine) and pulse rate. 
• Blood and urine sampling for safety laboratory testing including HbA1c. 
• Drug accountability. Any discrepancies are recorded in the source and the 
subject and caregiver/informant are counseled regarding proper dosing 
compliance  
• Dispense study drug.  Subjects take their dose of study medication in the clinic. 
6.2.7 
Month 12 (± 7 days) 
• ADAS-cog, MMSE, CDR, ADCS-ADL, COWAT, CFT, Trail making test 
(Versions A and B), NPI, RUD Lite and DEMQOL- proxy. 
• C-SSRS. 
• Review and record new concomitant medications. 


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• Assess symptoms/adverse events and by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
• Brief physical and neurologic examination. 
• Body weight. 
• ECG. 
• Vital signs: blood pressure (supine) and pulse rate. 
• FDG-PET (if applicable) 
• Collect blood sample for plasma retention and storage. 
• Blood and urine sampling for safety laboratory testing including HbA1c. 
• Collect blood samples for PK and PD. 
• Drug accountability. Any discrepancies are recorded in the source and the 
subject and caregiver/informant are counseled regarding proper dosing 
compliance. 
• Dispense study drug.  Subjects take their dose of study medication in the clinic. 
6.2.8 
Month 15 (± 7 days) 
• ADAS-cog. 
• C-SSRS. 
• Review and record new concomitant medications. 
• Assess symptoms/adverse events and by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
• Brief physical and neurologic examination. 
• Body weight. 
• ECG. 
• Vital signs: blood pressure (supine) and pulse rate. 
• Blood and urine sampling for safety laboratory testing including HbA1c. 


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• Drug accountability. Any discrepancies are recorded in the source and the 
subject and caregiver/informant are counseled regarding proper dosing 
compliance. 
• Dispense study drug.  Subjects take their dose of study medication in the clinic. 
6.2.9 
Month 18 (± 7 days) 
• ADAS-cog, MMSE, CDR, ADCS-ADL, COWAT, CFT, Trail making test 
(Versions A and B), NPI, RUD Lite and DEMQOL- proxy. 
• C-SSRS. 
• Review and record new concomitant medications. 
• Assess symptoms/adverse events and by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
• Brief physical and neurologic examination. 
• Body weight. 
• ECG. 
• Vital signs: blood pressure (supine) and pulse rate. 
• MRI if one was obtained during the screening period.  If a CT scan was used for 
assessing eligibility, then the 18 month MRI scan will not be performed, and the 
CT scan will not be repeated.  
• FDG-PET (if applicable). 
• Collect blood sample for plasma retention and storage. 
• Blood and urine sampling for safety laboratory testing including HbA1c. 
• Collect blood samples for PK and PD. 
• Drug accountability. Any discrepancies are recorded in the source and the 
subject and caregiver/informant are counseled regarding proper dosing 
compliance. 


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6.2.10 
Follow-Up  
A Follow-up Visit should be completed 3 months [±7 days] after a subject completes 
Month 18 for those participants who choose not to participate in the open label 
extension.   
A follow-up Visit should be completed 3 months [±7 days] after the last dose of 
study drug if the subjects discontinues the study prior to Month 18.   
If a subject does not complete a follow up visit, the reason should be documented in 
the source and EDC.  
At any point, if a participant withdraws consent, no further evaluations should be 
performed, and no additional data should be collected.   
• ADAS-cog, MMSE, CDR, ADCS-ADL COWAT, CFT, Trail making test 
(Versions A and B), and NPI. 
• C-SSRS. 
• Review and record new concomitant medications. 
• Assess symptoms/adverse events and by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
• Brief physical and neurologic examination. 
• ECG. 
• Vital signs: blood pressure (supine) and pulse rate. 
• Collect blood sample for plasma retention and storage. 
• Blood and urine sampling for safety laboratory testing including HbA1c. 
• Collect blood samples for PK and PD. 
6.3 
EARLY TERMINATION 
In the event a subject discontinues participation prior to completion of the Month 18 
Visit, the Early Termination Visit should be completed performing the study 
procedures as follows.  A  Follow-up Visit should be performed 3 months after the 


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last dose of study drug.  However, if a participant withdraws consent prior to early 
termination, no further evaluations should be performed, and no additional data 
should be collected.   
• ADAS-cog, MMSE, CDR, ADCS-ADL, COWAT, CFT, Trail Making Tests 
(Versions A and B), NPI, RUD Lite and DEMQOL- proxy. (These 
neuropsychological assessments are only performed at the Early Termination 
visit if within 30 days of the last dose of study drug) 
• C-SSRS. 
• Review and record new concomitant medications. 
• Assess symptoms/adverse events and by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
• Brief physical and neurologic examination. 
• Body weight. 
• ECG. 
• Vital signs: blood pressure (supine) and pulse rate. 
• MRI if one was obtained during the screening period.  If a CT scan was used for 
assessing eligibility, then this MRI scan will not be performed and a CT scan 
will not be performed at this visit.   
• FDG-PET if participant was on study for ≥ 3 months (if applicable) and if an 
MRI scan has been performed and passed the central reader’s quality control 
review. In all cases, it should only be performed if the subject was taking study 
drug at the time of the PET scan. 
• Collect blood sample for plasma retention and storage. 
• Blood and urine sampling for safety laboratory testing including HbA1c. 
• Collect blood samples for PK and PD.  
• Drug accountability. Any discrepancies are recorded in the source.  


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6.4 
SUBJECT WITHDRAWAL 
Participants may withdraw from the study at any time at their own request or the 
request of their study partner, caregiver/informant/guardian, or they may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety, 
behavioral, compliance, or administrative reasons.  If a participant does not return 
for a scheduled visit, every effort should be made to contact the participant including 
certified letter, return receipt requested.  The investigator should inquire about the 
reason for withdrawal, request that the participant return all unused investigational 
product(s), request that the participant return for an Early Termination and Follow-
up Visit and follow-up with the participant regarding any unresolved adverse events. 
If the participant withdraws from the study, and also withdraws consent for 
disclosure of future information, no further evaluations should be performed, and no 
additional data should be collected.  The Sponsor may retain and continue to use any 
data collected before such withdrawal of consent.  An individual patient enrolled in 
the trial may be discontinued from dosing (and continue into the follow-up period) 
based on a specific adverse event profile as recommended by either the IDMC and/or 
the Sponsor in discussions with the PI.  The IDMC or the Sponsor may temporarily 
stop dosing of enrolled subjects and/or additional enrollment of new patients at any 
time, and may permanently terminate the study at any time. 
Any emergent medical condition or safety finding that, in the opinion of the 
Investigator, may jeopardize the participant’s safety if he/she continues in the study 
will be sufficient reason for participant discontinuation from the study. The 
participant should be followed as indicated for the AE until resolved, declared stable 
or the participant is lost to follow up.  Safety data will be obtained from the physical 
and neurological examination, vital signs, routine laboratory tests, ECG, brain MRI 
and neuropsychological testing batteries. 
 


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7.0 
ASSESSMENTS 
7.1 
SAFETY AND TOLERABILITY 
7.1.1 
Vital Signs 
Vital signs measurements will consist of blood pressure and pulse rate while the 
participant is supine.  Vital signs will be conducted at all the study visits.  Participant 
should have been supine at least 5 minutes prior to vital signs determination. 
7.1.2 
Electrocardiogram 
12–lead ECG should be recorded after participants have been resting at least 
5 minutes in the supine position.  Digital ECG tracings will be performed using 
equipment from and analyzed by a central ECG laboratory.  The cardiologist reading 
the ECGs will be blinded regarding study drug assignment.  All standard intervals 
will be measured. 
When assessing eligibility at the Screening visit, the presence of BBB (either left or 
right) is allowable as long as the absolute QTcF value does not exceed 500 ms and 
the subject does not have any other cardiac exclusions as described in exclusion 
criterion 26.  When an ECG displays a paced rhythm indicating a functioning 
pacemaker is present, there is no upper limit as long as there are no related cardiac 
exclusions (reference exclusion criterion 26).  Note. If there is no known history of 
BBB (either right or left), the discovery of such should prompt further investigation 
prior to proceeding with screening.  
At the Baseline visit, the participant will have an ECG obtained (in triplicate) in 
order to verify continued eligibility for the study.  If the QTcF is >450 msec for 
males or >470 msec for females is determined based on the average of the 3 QTcFs 
obtained from the local reading, a subject should not be dosed, pending central 
reading of the ECG.   
When the site receives the Baseline Visit Central ECG Laboratory reading(s), if 
QTcF is confirmed as exclusionary (using the criteria immediately above), the 
subject should be excluded. If the central reading does not confirm the exclusion, 


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the patient may be dosed as soon as convenient/possible.  If a patient was dosed 
based on local reading that determined to be acceptable (using the criteria above) 
and the central reading is nevertheless determined to be exclusionary, the site should 
contact the Sponsor for guidance on how to proceed. 
At any time during the study, a subject with any of the above ECG values should 
prompt a call to the Sponsor for guidance on how to proceed.  
7.1.3 
Physical Examination 
Complete physical examination will include skin, eyes, ears, nose and throat, 
cardiac, respiratory, abdomen, and extremities.  Complete physical examination will 
be conducted at the Screening visit.  Brief physical examination will include skin, 
eyes, oral mucosa, cardiac, and respiratory. A brief physical examination will be 
conducted at all the study visits.  Body weight will be also examined at all study 
visits. 
7.1.4 
Neurological Examination 
Complete neurological examination will include cortical function, meningeal 
irritation assessment, cranial nerves, motor and sensory function, coordination, deep 
tendon reflexes, stance and gait.  Complete neurological examination will be 
conducted at Screening. 
Brief neurological examination will include meningeal irritation assessment, cranial 
nerves, motor and sensory function, coordination, deep tendon reflexes, stance and 
gait.  Brief neurological examination will be conducted at all the study visits. 
7.1.5 
Laboratory 
7.1.5.1 
Standard Safety Laboratory Tests 
Unless noted otherwise, the following safety laboratory tests will be performed at 
Screening, Baseline, Month 3, 6, 9, 12, 15, 18, 21 and at time of premature 
discontinuation.  All routine laboratory tests will be analyzed by a central laboratory 
which will provide instructions and supplies. 


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Hematology 
Chemistry 
Urinalysis 
Otherc 
Hemoglobin 
Hematocrit RBC count 
Platelet count WBC count 
MCV 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
BUN and Creatinine 
Glucose 
Calcium 
Sodium  
Potassium  
Chloride 
Total CO2 (Bicarbonate) 
AST 
ALT 
GGT  
LDH 
Total Bilirubin  
Alkaline phosphatase  
Uric acid 
Albumin 
Total protein 
HbA1c 
pH 
Glucose (qual) Protein 
(qual) Blood (qual) 
Ketones Nitrites 
Leukocyte esterase 
Microscopya 
FSHb 
Urine drug screen  
T3, T4, TSH  
Vitamin B12 
Syphilis 
Hepatitis B, C 
a 
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.  
b 
Females. 
c 
At screening. 
 
 
• Hepatitis screens include hepatitis B surface antigen, hepatitis B core antibody, 
hepatitis B surface antibody, and hepatitis C antibody.  
• Minimum requirement for urine drug testing includes: cocaine, THC, opiates, 
benzodiazepines and amphetamines. 
7.1.5.2 
Assessment of Potential Cases of Drug Induced Liver Injury 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase 
(ALT) concurrent with abnormal elevations in total bilirubin that meet the criteria 
outlined below, in the absence of other causes of liver injury, are considered 
potential cases of drug-induced liver injury.  These events should be considered 
important medical events, and reported as serious adverse events. 
Participants who present with the following laboratory abnormalities should be 
evaluated further to definitively determine the etiology of the abnormal laboratory 
values: 


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a. Participants with AST or ALT baseline values within the normal range who 
subsequently present with AST or ALT ≥3 times the upper limit of normal 
concurrent with a total bilirubin ≥2 times the upper limit of normal with no 
evidence of 1) hemolysis,  2) cholestasis (elevated  alkaline phosphatase 
≥2 times the upper limit of normal or not available) or 3) Gilbert’s Syndrome 
(common benign condition associated with intermittent elevations of primarily 
indirect, unconjugated, bilirubin to about 2 X upper limit of normal.) 
b. Participants with pre-existing AST or ALT baseline values above the normal 
range who subsequently present with AST or ALT ≥2 times the baseline values 
and ≥3 times the upper limit of normal concurrent with a total bilirubin ≥2 times 
the upper limit of normal with no evidence of 1) hemolysis,  2) cholestasis 
(elevated  alkaline phosphatase ≥2 times the upper limit of normal or not 
available) or 3) Gilbert’s Syndrome (common benign condition associated with 
intermittent elevations of primarily indirect, unconjugated, bilirubin to about 2 
X upper limit of normal.) 
Increases defined above should be confirmed with repeat testing within 48 to 
72 hours.   In addition to repeating AST and ALT, laboratory tests should include 
albumin, amylase, creatine kinase, total bilirubin, direct and indirect bilirubin, 
gamma-glutamyl transferase (GGT), international normalized ratio (INR) and 
alkaline phosphatase.  Symptoms should be assessed.  The medical monitor should 
be contacted to discuss the patient’s condition. 
Close observation should be immediately initiated if symptoms persist and/or repeat 
testing confirm the abnormalities described above.  Evaluation should include 
repeating laboratory tests (two or three time weekly; frequency may decrease to once 
a week or less if abnormalities stabilize or trial drug is discontinued and the subject 
is asymptomatic), and a detailed medical history and physical assessment.  A 
detailed history, including relevant information, such as history of symptoms or 
concurrent illnesses, concomitant medication use (including review of 
acetaminophen use and herbal/dietary supplements), alcohol consumption, 
recreational drug use and special diets.   Additionally family history, sexual history, 
travel history, history of contact with a jaundiced subject, surgery, blood transfusion, 
history of liver or allergic disease, and work exposure, should be collected.  Ruling 
out acute hepatitis A, B, C, D, and E infection, autoimmune or alcoholic hepatitis, 


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NASH, hypoxic/ischemic hepatopathy, Epstein-Barr virus, cytomegalovirus, herpes 
simplex virus, toxoplasmosis, varicella, parvovirus and biliary tract disease (gall 
bladder/ductal  imaging may be warranted). 
All cases confirmed on repeat testing, with no other cause for LFT abnormalities 
identified at the time should be considered potential drug induced liver injury 
irrespective of availability of all the results of the investigations performed to 
determine etiology of the abnormal LFTs. 
7.2 
NEUROPSYCHOLOGICAL ASSESSMENTS 
The following cognitive/functional/global test batteries will be conducted at selected 
time points as described below and in the Schedule of Activities.  Participants should 
not have initiated treatment with a behavioral medication within 1 week of next 
clinical assessment.  If there is any condition that, in the opinion of the investigator, 
may jeopardize the accurate evaluation of participant’s function, participants should 
not receive neuropsychological tests, and reserve an additional visit to evaluate 
function within the allowance of the visit window. Neuropsychological assessments 
should not be performed if the patient is fasting.  The same rater should follow a 
particular participant for any given assessment for the duration of the study 
whenever possible.  It is recommended that the scales be administered in the 
following order if they are specified to occur at the same visit:  ADAS-cog, MMSE, 
CDR, ADCS-ADL, COWAT, CFT, Trail Making Test (Versions A and B), NPI, 
RUD Lite, and DEMQOL.  The exception to this is the Screening visit during which 
the MMSE will be performed first.  If the subject is eligible proceed with the 
remainder of screening visit in any order.  
The CDR may be performed at a separate visit.  For the Baseline and Month 18 
visits, the CDR may be done on a separate proximal visit day to avoid patient fatigue 
if feasible.  It is acceptable for the CDR, ADCS-ADL, and the NPI to be performed 
together on a separate visit day from the other cognitive assessments.  All cognitive 
assessments must be performed by a trained rater.   
7.2.1 
Cognitive Assessments 
Alzheimer's Disease Assessment Scale - Cognitive Subscale 70 point (ADAS-cog): 


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The ADAS-cog is a structured scale (approximately 40 minutes to complete) that 
evaluates memory, orientation, attention, reasoning, language and constructional 
praxis (Rosen, 1984). The ADAS-cog scoring range for the version used in this study 
is from 0 to 70, with higher scores indicating greater cognitive impairment.  The 
ADAS-cog will be conducted at Screening, Baseline and at Months 3, 6, 9, 12, 15, 
18, and 21 or in the event of early termination.  The ADAS-cog should always be 
administered prior to other cognitive measures. 
Mini Mental State Examination (MMSE): The MMSE is a brief 30-point test that is 
used to assess cognition (Folstein, 1975).  It is commonly used to screen for 
dementia. In the time span of about 10 minutes, it samples various functions, 
including arithmetic, memory and orientation.  The MMSE will be administered at 
Screening, Baseline, and at Months 3, 6, 12, 18, and 21 or in the event of early 
termination.  Scores range from 0-30 with lower scores indicating greater cognitive 
impairment.  Participants with scores of 21-26 will be eligible for participation in 
the study. 
Controlled Oral Word Association Test (COWAT):   The COWAT is a measure of 
verbal fluency in which the participant is asked to generate orally as many words as 
possible that begin with the letters “F”, “A”, and “S”, excluding proper names and 
different forms of the same word. (Borkowski, 1967, Loonstra 2001)  For each letter, 
the participant is allowed one minute to generate the words.   Performance is 
measured by the total number of correct words produced summed across the three 
letters.  Perseverations (i.e., repetitions of a correct word) and intrusions (i.e., words 
not beginning with the designated letter) are noted. 
Although fluency tests are sensitive to language dysfunction and deterioration of 
semantic knowledge, they can also reflect an inability to initiate systematic retrieval 
of information in semantic storage.  The COWAT will be administered at Baseline, 
and at Months 3, 6, 12, 18, and 21 or in the event of early termination. 
Category fluency test (CFT): Study participants are given one minute to provide 
exemplars of the category ‘animals’.  The CFT will be administered at Baseline, and 
at Months 3, 6, 12, 18, and 21 or in the event of early termination. 


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Trail Making Test, Parts A and B: (from the Halstead Reitan Neuropsychological 
Test Battery; Reitan, 1958).  Part A consists of 25 circles numbered 1 through 
25 semi-randomly distributed over a white sheet of 8 1/2" X 11" paper.  The 
participant is instructed to connect the circles with a pencil line as quickly as possible 
in ascending numerical order.  Part B also consists of 25 circles, but these circles are 
either numbered (1 through 13) or contain letters (A through L).  Now the participant 
must connect the circles while alternating between numbers and letters in an 
ascending order (eg, A to 1; 1 to B; B to 2; 2 to C).  Trails A and B are available in 
multiple forms of equal difficulty for purposes of repeated evaluations.  The 
participant's performance can be judged in terms of the time (in seconds) required to 
complete each trail and by the number of errors of commission and omission.  The 
time to complete Trails A (150 second maximum) and B (300 second maximum) 
will be the measures of interest.  Whereas both Trails A and B depend on attention, 
visuomotor, and perceptual scanning skills, Trails B also requires considerable 
flexibility in shifting from number to letter sets under time pressure.  Thus, 
participants who perseverate their current response set will encounter special 
difficulty with Trails B.  The Trail Making Test (Parts A and B) will be administered 
at Baseline, and at Months 3, 6, 12, 18, and 21 or in the event of early termination. 
7.2.2 
Functional/Global Assessments 
Alzheimer’s  Disease  Cooperative  Study  Activities  of   Daily  Living  Scale (ADCS-
ADL):  The ADCS-ADL is an activity of daily living inventory developed by the 
ADCS to assess functional performance in participants with AD (Galasko et al., 
1997).  Informants are queried via a structured interview format as to whether 
participants attempted each item in the inventory during the preceding 4 weeks, as 
well as their level of performance. The ADCS-ADL will be administered at Baseline, 
and at Months 3, 6, 12, 18, and 21 or in the event of early termination.  Scores range 
from 0-78 with lower scores indicating greater functional impairment. 
Clinical Dementia Rating Scale (CDR): The CDR scale is used as a global measure 
of dementia and is completed by a clinician in the setting of detailed knowledge of 
the individual patient collected from interviews with the patient and caregiver (Berg, 
1988).  The CDR describes 5 degrees of impairment in performance on each of 6 
categories including memory, orientation, judgment and problem solving, 
community affairs, home and hobbies, and personal care.  Much of the information 


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will therefore already have been gathered, either as part of normal clinical practice 
or as part of a research study.  The interview takes approximately 40 minutes to 
administer. 
CDR ratings are 0 for healthy individuals, 0.5 for questionable dementia and 1, 2 
and 3 for mild, moderate and severe dementia as defined in the CDR scale.  The 
scores for each category can also be summed and this is known as the sum of box 
score (CSR-SB).  Sum of box scores range from 0 to 18 with higher scores indicating 
greater cognitive impairment. 
The CDR will be conducted at Screening, Baseline and at Months 3, 6, 12, 18, and 
21 or in the event of early termination. CDR should be done on a separate proximal 
visit day to avoid patient fatigue if feasible, particularly at baseline and Month 18.  
7.2.3 
Other Assessments 
Neuropsychiatric Inventory (NPI): The NPI is a well-validated, reliable, multi-item 
instrument to assess psychopathology in AD based on an interview with the 
caregiver (Cummings et al, 1994).  The interview is also relatively brief 
(15 minutes).  It evaluates both the frequency and severity of 12 behavioral areas 
including 
delusions, 
hallucinations, 
dysphoria 
(depression) 
anxiety, 
agitation/aggression, euphoria, disinhibition, irritability, lability, apathy, aberrant 
motor behavior, appetite and eating changes and night-time behaviors. 
Frequency assessments range from 1 (occasionally, less than once per week) to 4 
(very frequently, once or more per day or continuously) as well as severity (1= mild, 
2 = moderate, 3 = severe).  Distress is rated by the study partner or caregiver and 
ranges from 0 (no distress) to 5 (very severe or extreme).  The overall score and the 
score for each subscale are the product of severity and frequency.  Scores range from 
0-144 with higher scores indicating a greater presence of neuropsychiatric 
symptoms.  The NPI will be administered at Screening, Baseline, and at Months 3, 
6, 12, 18, and 21 or in the event of early termination. 
Resource Utilization in Dementia (RUD Lite): The RUD Lite is a validated and 
reliable questionnaire which assesses the health care resource utilization (HCRU) of 
the patient and caregiver and measures the level of formal and informal care 


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(Wimo et al, 2012).  The RUD Lite consists of items about caregiver time, caregiver 
work status, caregiver HCRU (e.g., hospitalization, ER visits, health care 
professional visits and medication), patient living accommodation, and patient 
HCRU.  It takes approximately 15-20 minutes to complete and is usually interview 
administered by any health care professional.  This scale will be administered at 
Baseline and at Months 6, 12 and 18 or in the event of early termination. 
Dementia Quality of Life (DEMQOL) – Proxy: The DEMQOL-Proxy questionnaire 
is a validated and reliable questionnaire that is interview administered and completed 
by the caregiver about the patient’s health related quality of life (Smith et al, 2005).  
It consists of 31 items representing 5 domains (daily activities and looking after 
yourself, health and well-being, cognitive functioning, social relationships, and self-
concept) and takes approximately 20 minutes to complete.  Higher scores indicate 
better health related quality of life.  This scale will be administered at Baseline and 
at Months 6, 12 and 18 or in the event of early termination. 
Rosen-Modified Hachinski Ischemia Score: this brief rating scale is used to assess 
if dementia could be attributed to vascular causes (Rosen et al., 1984).  The scale 
ranges from 0-18 with higher scores indicating a greater presence of vascular risk 
factors.  Dementia is not likely to be due to vascular causes if the score is 4 or less.  
This scale is only performed at Screening Visit to rule out vascular dementia. 
7.3 
SUICIDALITY ASSESSMENTS 
The Columbia Suicide Severity rating Scale (C-SSRS) is a joint interview with the 
caregiver and patient that systemically assesses suicidal ideation and suicidal 
behavior (Posner et al, 2011).  This scale will be administered at Screening Visit to 
evaluate life time suicide attempt, suicide behaviors, and other non-suicidal 
self-injuries.  Positive responses on the C-SSRS will be mapped to the Columbia 
Classification Algorithm of Suicide Assessment (C-CASA) for classification and 
reporting using a standard algorithm. 
At the Screening and Baseline Visit, the C-SSRS will be used to detect possible 
suicidality prior to dosing.  If the patient’s responses indicate: (1) the subject may 
have had suicide ideation associated with actual intent and/or plan in the past year, 
(2) any history of suicidal behavior in the past 10 years, (3) any lifetime history of 


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recurrent suicidal behavior the subject should be excluded.  In the event that the 
subject answers “Yes” to the suicidal ideation items 4 or 5 of the C-SSRS or a history 
of suicidal behavior within the previous 10 years as indicated by a “yes” answer to 
any of the suicidal behavior items of the C-SSRS at the screening or baseline visit, 
that subject will not be eligible for inclusion in the study.  
The C-SSRS will be used to assess suicide ideation or behavior at each study visit.  
Following dosing (after the Baseline / randomization visit, if there are “yes” answers 
on items 4, 5 or on any behavioral question of the C-SSRS, a professional suicide 
risk assessment should be done as soon as possible to determine whether it is safe 
for the subject to continue participation in the trial.  A risk assessment will be done 
by a qualified mental health professional with expertise in the evaluation of 
suicidality in the elderly (e.g., psychiatrist, geriatrician or neurologist specializing in 
treatment of patients with AD) to determine whether it is safe for the subject to 
participate in the study. A change from baseline to a yes on any of these items will 
also constitute an AE and will be documented as such.  
7.4 
PLASMA FOR ANALYSIS OF AZELIRAGON AND METABOLITE 
CONCENTRATIONS 
Blood samples for pharmacokinetic analysis will be collected prior to dosing at 
Baseline, Months 3, 6, 12, 18 and 21 or at Early Termination. 
Blood samples (4 mL) to provide plasma for pharmacokinetic analysis will be 
collected into appropriately labeled tubes containing dipotassium (K2) EDTA at 
times specified above. 
Samples will be centrifuged at approximately 1700 g for about 10 minutes at 4°C.  
The plasma will be stored in appropriately labeled screw-capped polypropylene 
tubes at approximately -20°C within 1 hour of collection. 
For azeliragon metabolites, samples may be analyzed at the Sponsor’s discretion. 
Samples will be analyzed using a validated analytical method. 


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The shipment address and assay lab’s contact information will be provided to the 
investigator site prior to initiation of the trial. 
7.5 
PLASMA FOR ANALYSIS OF TOTAL A, A (1-40), A(1-42) 
Blood samples for plasma biomarkers analysis will be collected prior to dosing on 
Baseline, Months 3, 6, 12, 18, 21 or at Early Termination. 
Blood samples for plasma biomarkers (6 mL for Aβ analysis) will be collected into 
appropriately labeled tubes containing dipotassium (K2) EDTA at times specified 
above. 
Samples will be centrifuged at approximately 1700 g for about 10 minutes at 4°C.  
The plasma will be stored in appropriately labeled screw-capped polypropylene 
tubes at approximately -70°C within 1 hour of collection.  Instructions on collection, 
processing, storage and shipment of the sample will be provided in a separate 
laboratory manual. 
7.6 
MRI 
MRI scans will be performed at Screening and Month 18 or in the event of early 
termination.  MRI scans will be read by a central reader prior to inclusion in the 
study to detect any exclusionary conditions such as stroke, hematoma, or intracranial 
tumor and to confirm the presence of hippocampal atrophy.  The screening MRI 
must be performed at least 14 days prior to dosing to allow for the central read and 
interpretation of results prior to dosing.  This brain MRI scan will also serve as the 
subject’s baseline MRI for the study. 
Specific MRI scan sequences for safety and volumetric assessments will be outlined 
in the MRI procedures manual.  Participants will be monitored and data will be 
reacquired if there is subject movement during the scan.  The data will be analyzed 
to determine any new clinical findings and atrophy of whole brain and hippocampus 
(as well as measurement of ventricular volume) to assess changes relative to 
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Brain magnetic resonance imaging (MRI) may include gadolinium contrast if the 
investigator determines that this is necessary for patient care either based on clinical 
signs or the non-contrast MRI.  Gadolinium may also be used when considered the 
standard operating procedure for the study site.  Gadolinium should not be 
administered if the glomerular filtration rate <30 mL/min or equivalent creatinine 
clearance.  However, this decision may be made by the PI on the basis of a change 
in the clinical status or may be done in response to a possible abnormality seen on 
the non-contrast brain MRI. 
An MRI Imaging CRO will be responsible for standardizing the acquisition, training 
the sites on the imaging protocol, ensuring equipment and image QA/QC and for 
overseeing a centralized read of the data.  To ensure proper equipment and image 
QA/QC, the MRI Imaging CRO will have the sites scan a phantom.  Detailed 
procedures for obtaining and processing the MRI, conducting image QA/QC and 
endpoint analysis will be developed in study specific documents and provided as 
appropriate to the investigators, MR technicians, CRO personnel and endpoint 
readers. 
Whole brain, ventricular, and hippocampal volumes will be computed at Screening 
and at Month 18.  Analysis of whole brain, ventricular, and hippocampal volumes 
will be conducted by a centralized reader(s) who will be blinded to subject treatment. 
7.7 
CT SCANS 
A head CT scan may be accepted for evaluation of the eligibility criteria on a case-
by-case basis, as approved by the Sponsor (e.g., when MRI is contraindicated for the 
subject).  The head CT must be suitable for central review and submitted for central 
review based on instructions in the MRI procedures manual. 
Subjects whose screening assessment was based on a CT scan will not undergo a 
follow-up CT scan and will not contribute to the MRI volumetric analyses.      
An Imaging CRO will be responsible for providing guidance on the imaging 
procedure.  Sites will be advised to acquire the CT per their standard clinical 
practice.  Scans will be reviewed by the Imaging CRO central reader.   


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7.8 
FDG-PET 
FDG-PET scans will be performed at Baseline and Months 12 and 18 or in the event 
of early termination in a mild AD dementia subset cohort at select sites in the United 
States and Canada. The Baseline FDG- PET scan must be performed within 7 days 
prior to the baseline visit and +/- 7 days at Months 12 and 18. A central analysis and 
read will be performed on all PET scans. 
Specific FDG-PET acquisition, processing and display guidelines will be outlined 
in the PET Imaging Manual. A blood glucose level will be obtained immediately 
prior to the administration of the FDG-PET dose. The PET scans will be analyzed 
to determine any new clinical findings as well as extent and severity of regional and 
global brain glucose metabolism changes relative to Baseline. 
A PET Imaging CRO will be responsible for standardizing the acquisition, training 
the sites on the imaging protocol, ensuring equipment and image QA/QC and for 
overseeing a centralized read and analysis of the PET study data.  To ensure proper 
equipment and image QA/QC, the PET Imaging CRO will have the sites scan a 
Hoffman phantom.  Detailed procedures for obtaining and processing the PET scans, 
conducting image QA/QC and endpoint analysis will be developed in study specific 
documents and provided as appropriate to the investigators, PET technicians, CRO 
personnel and endpoint readers. 
Extent and severity of brain hypometabolism will be assessed centrally at Baseline, 
Months 12 and 18 by a neuro PET reader(s) who will be blinded to subject treatment. 
7.9 
APOE GENOTYPING 
A 3 ml blood sample will be taken at Baseline for ApoE genotyping.  Results of 
ApoE genotyping will be retained in the trial database, with participants identified 
only by a study participant identification number.  Individual results of ApoE 
genotyping will not be disseminated outside the Sponsor, including the study site, 
except as required by law. 


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7.10 
BLOOD SAMPLING FOR PLASMA STORAGE AND RETENTION 
A 10 mL blood sample will be collected at Baseline and Months 3, 6, 12, 18, and 21 
or Early Termination.   Blood samples will be collected into appropriately labeled 
tubes containing dipotassium (K2) EDTA.  Samples will be centrifuged at 
approximately 1700 g for about 10 minutes at 4°C. The plasma will be stored in 
appropriately labeled screw-capped polypropylene tubes at approximately -70°C 
within 1 hour of collection. 
Samples will be stored for potential future analysis for plasma biomarkers that may 
be identified during the course of the trial. 
7.11 
BLOOD VOLUME 
Total blood sampling volume for the individual participants is approximately 
264 mL. 
Sample Type 
Sample 
Volume (mL) 
Number of Sampling Times 
Total 
Volume 
(mL) 
Screening / 
Baseline 
Treatment 
Non-treatment 
Follow-up 
Routine Laboratory 
13 
2 
6 
1 
117 
Unique Screening Labs 
24 
1 
0 
0 
24 
PK 
4 
1 
4 
1 
24 
Biomarkers (Aβ) 
6 
1 
4 
1 
36 
ApoE Genotyping 
3 
1 
0 
0 
3 
Plasma Storage and 
Retention 
10 
1 
4 
1 
60 
TOTAL (mL) 
 
 
 
 
264 
 
 
 
 


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8.0 
ADVERSE EVENT REPORTING 
8.1 
ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a clinical study 
participant administered a pharmaceutical product.  Study drug treatment does not 
necessarily have a causal relationship with the AE.  An AE, therefore, can be any 
unfavorable change in structure, function or chemistry (including abnormal clinical 
lab results, or ECG findings), symptoms, signs, or diseases temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product, as defined by ICH. 
The criteria for determining whether an abnormal objective test finding should be 
reported as an adverse event are as follows: 
• Test result is associated with accompanying symptoms, and/or 
• Test result requires additional diagnostic testing or medical/surgical 
intervention, and/or 
• Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or 
• Test result is considered to be an adverse event by the investigator or sponsor.  
Repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an 
error does not require reporting as an adverse event. 
8.2 
REPORTING PERIOD 
Adverse event reporting will commence as soon as the study participant has been 
dosed, unless the event is deemed to be related to study procedures.  The study-
related procedure might include discontinuation from or decrease in current therapy, 
a study-specific assessment or scale, or a study-specific procedure.  Events 
associated with such study- specific procedures prior to initial administration of 


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study drug will be tracked as AEs from the time when the study participant signed 
the ICF. 
SAE reporting will commence from the time the participant provides informed 
consent through last subject visit at Month 21.  Any SAE occurring after the 
reporting period must be promptly reported if a causal relationship to study treatment 
is suspected. 
All events, including pre-existing conditions that are not associated with study-
specific procedures, which worsen after the study participant has signed the ICF, but 
occur prior to initial administration of study drug, are not considered AEs and will 
be captured under medical history.  However, worsening of such conditions after 
initial administration of study drug will be designated as AEs. 
8.3 
ASSESSMENT OF SEVERITY 
The following definitions of severity should be used in the evaluation of AEs: 
• Mild: an AE that is easily tolerated and does not interfere with a subject’s usual 
function or daily activities. 
• Moderate: an AE that is sufficiently discomforting so as to interfere to some 
extent with a subject’s usual function or daily activities. 
• Severe: an AE that interferes significantly or prevents a subject’s usual function 
or normal everyday activity. 
The adjective selected should describe the maximum intensity of the adverse event. 
8.4 
ASSESSMENT OF RELATIONSHIP TO STUDY DRUG 
The Investigator’s assessment of causality must be provided for all adverse events 
(serious and non-serious) and recorded in the eCRF.  An Investigator’s causality 
assessment is the determination of whether there exists a reasonable possibility that 
the investigational product caused or contributed to an adverse event.  If the 
Investigator does not know whether or not investigational product caused the event, 
then the event will be handled as “related to investigational product” for reporting 


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purposes, as defined by the Sponsor.  If the investigator's causality assessment is 
"unknown but not related to investigational product", this should be clearly 
documented on study records. 
The following definitions of relationship to study drug should be used to characterize 
the suspected causality of each AE, based on the Principal Investigator 's or licensed 
physician consideration of all available information: 
• Related: There is evidence to suggest a causal relationship between the study 
drug and the AE.   
• 
Not Related: The AE is not reasonably related to the study drug if there is not a 
reasonable possibility that the study drug may have caused the event, i.e., there is no 
evidence or arguments to suggest a causal relationship. 
8.5 
SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) is any AE that is fatal or life-threatening (see below), 
results in persistent or significant disability (see below) or incapacity, requires 
inpatient hospitalization or prolongation of an existing hospitalization, or is a 
congenital anomaly/birth defect. 
Other important medical events that may not result in death, be life-threatening or 
require hospitalization should also be considered SAEs when, based upon 
appropriate medical judgment, they may jeopardize the study participant and may 
require medical or surgical intervention to prevent one of the outcomes listed above.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home or convulsions that do not result in 
inpatient hospitalization. 
8.5.1 
Life Threatening Adverse Event 
A life-threatening AE is any AE that, in the view of the Principal Investigator, places 
the subject at immediate risk of death from the reaction as it occurred.  A life-
threatening AE would not be an AE that, had it occurred in a more serious form, 
might have caused death.  


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8.5.2 
Disability 
Disability is defined as a substantial disruption of a person's ability to conduct 
normal life functions. 
8.5.3 
Unexpected Adverse Event 
An unexpected adverse drug experience is defined as “any adverse drug experience, 
the specificity or severity of which is not consistent with the current IB. For example, 
under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the IB only referred to elevated hepatic enzymes or hepatitis. Similarly, 
cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue 
of greater specificity) if the IB only listed cerebral vascular accidents. Unexpected, 
as used in this definition, refers to an adverse drug experience that has not been 
previously observed (e.g., included in the IB), rather than from the perspective of 
such experience not being anticipated from the pharmacological properties of the 
pharmaceutical product. 
Unexpected adverse events should be reported to the IRB/ Research Ethics Board 
(REB) as per IRB/REB reporting requirements. 
8.6 
DOCUMENTATION OF ADVERSE EVENTS 
The condition of each study subject will be monitored throughout the study. Signs 
and symptoms of possible AEs may be observed by the staff, elicited by asking an 
open or indirect question (e.g., “How have you been feeling?”) or volunteered by the 
subject. All AEs, whether observed by the Investigator or clinical site staff, elicited 
from the subject, or volunteered by the subject, will be recorded. Data will include 
start and end dates, concomitant medications given for AE, Investigator-specified 
severity, relationship to study drug, and action taken. All AEs should be reported to 
the study Sponsor. 
8.7 
REPORTING REQUIREMENTS 
The condition of each study subject will be monitored throughout the study.  Signs 
and symptoms of possible AEs may be observed by the staff, elicited by asking an 


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open or indirect question (e.g., “How have you been feeling?”) or volunteered by the 
subject. All AEs, whether observed by the Investigator or clinical site staff, elicited 
from the subject, or volunteered by the subject, will be recorded on the adverse event 
page(s) of the CRF.  Data will include start and end dates, concomitant medications 
given for AE,  Investigator- specified severity, relationship to study drug, and action 
taken. 
Follow-up of any ongoing AE (including any clinically significant laboratory 
abnormality) should be conducted as follows: 
• If the Investigator determines the AE is not related to the study product or study 
procedures, the AE will be followed until resolution, or 60 days from end of 
study participation. 
• All AEs with a relationship other than not related will be followed until 
resolution, or until the subject is lost to follow-up. 
At the discretion of the Investigator or designated licensed physician and Medical 
Monitor, the length of AE follow-up may be attenuated, with written rationale by 
the Investigator or designated licensed physician. 
8.7.1 
Serious Adverse Events Reporting Requirements 
Knowledge of a SAE occurring or worsening in a subject at any time during the trial 
must be reported within 24 hours to the Safety Monitor.  The site is responsible for 
reporting the event to the relevant IRB/REB in accordance with the IRB or REB’s 
specific requirements for reporting SAEs.  The Principal Investigator or designee 
should not wait to receive additional or follow-up information before an initial 
notification is made to the Sponsor. 
Instructions related to SAE reporting, along with reporting forms and Sponsor 
contact information will be provided by the Sponsor to the Study Site and should be 
maintained in the Study Site File (SSF). 
Reports relative to the subject’s subsequent course must be submitted to the Safety 
Monitor until the event has subsided or, in the case of permanent impairment, until 


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the condition stabilizes. These reports need not be submitted within 24 hours of first 
knowledge of each item of new information, unless the new information results in a 
change in diagnosis or represents a significant worsening of the subject’s condition. 
At any time following the study, the PI or designee should immediately notify the 
Sponsor and the IRB/REB if he/she learns of the occurrence of any malignancy 
involving the participant of a clinical trial or of any congenital anomaly in an 
offspring of a participant. 
 
 


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9.0 
DATA ANALYSIS/STATISTICAL METHODS 
The statistical considerations summarized in the following subsection outline the 
plan for data analysis of this study.  A final and complete Statistical Analysis Plan 
(SAP) will be finalized prior to unblinding the data from the study.  The SAP will 
supersede the protocol. Any deviations from the planned analyses will be described 
and justified in the final integrated study report. 
This trial describes two studies with a common infrastructure in a single protocol. 
Statistical analysis of the clinical efficacy variables will be done for each of the 
studies separately. Statistical analysis of safety and imaging data will be done for 
the study as a whole (combined). 
Continuous variables will be presented showing number of observations available, 
mean, median, minimum, maximum, 1st and 3rd quartiles, and standard deviations 
(or standard errors, depending on the variable) by visit. Categorical variables will be 
presented showing frequencies and percentages by visit. 
All tests will be 2-sided and use an overall study-wise α = 0.05 unless otherwise 
stated. SAS Version 9.1 or later will be used.  Medical dictionary for Regulatory 
Activities. 
(MedDRA) Version 16.0 or later will be used for coding adverse events.  
Medications will be coded using WHO Drug Dictionary (WHODD) Version March 
2009 or later. 
This study is planned using an enrichment strategy, following the draft regulatory 
guidance depicted in the FDA guidance Enrichment Strategies for Clinical Trials to 
Support Approval of Human Drugs and Biological Products (draft guidance, 
December, 2012). This study features a conditional sequential approach to 
hypothesis testing to control alpha, similar to methods using Bauer closed 
procedures, which are referenced in the FDA adaptive design guidance  FDA 
guidance Adaptive Design for Clinical Trials for Drugs and Biologics (draft 
guidance, February 2010) referenced above), and principles for subgroup analyses. 


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This study comprises two independent sub-studies in one main study for purposes 
of independent replication for the co-primary variables: A-Study is composed of the 
first approximately 400 patients randomized; B-Study is composed of the remaining 
approximately 400 patients randomized.  The study as a whole will be analyzed for 
specified inferential purposes.  A-Study and B-Study will be randomized separately. 
A 2-Stage conditional sequence of statistical hypothesis tests, will be used. The 
testing sequence will be as follows: 
1. Stage 1:  concurrent analyses for co-primaries in each of the two independent 
sub-studies: 
• ADAS-cog is analyzed in A-Study and B-Study independently. 
• CDR-sb is analyzed in A-Study and B-Study independently 
2. Stage 2: conditional on significance in all of the first set of analyses: 
• MRI assessment is analyzed in the study (as a whole). 
9.1 
SAMPLE SIZE DETERMINATION 
The primary objective is to evaluate the effect of azeliragon plus SoC on cognition 
and functional outcome by comparing azeliragon plus SoC with placebo plus SoC.  
The co-primary endpoints are change from Baseline on the ADAS-cog total score at 
Month 18 and change from Baseline on the CDR-sb total score at Month 18. The 
study includes AD patients with mild disease as defined by having a baseline MMSE 
of 21 through 26. 
This trial includes two independent sub-studies, each of which is supported by 
randomization independently, because randomization by investigative site is used. 
Each sub-study is powered using alpha = 0.05. 
Approximately 160 subjects (80 per treatment group) will be enrolled and participate 
in the FDG-PET sub-study at select sites in the United States and Canada.   The sample 
size for this sub-study was selected empirically. 


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Sample size calculations are done to power each study (A-study and B-study) 
separately. It is anticipated that each A-study and B-study will randomize 
approximately N=400 each. 
Assuming a standard deviation of the change from Baseline to Month 18 in 
ADAS-cog of 9 (based on Study TTP488-203), using alpha = 0.05, a total sample 
size of 282 patients in balanced allocation (141 patients per group) provides at least 
90% power to detect a difference between treatment groups of 3.5 (based on data 
from mild AD patients in Study TTP488-203) using a 2-sided, 2-sample t-test.  
Assuming a dropout rate of 20% or less, randomization of 354 patients provides 
adequate statistical power for this study to demonstrate superiority of azeliragon plus 
SoC over placebo plus SoC based on the ADAS-cog. 
Assuming a standard deviation of the change from Baseline to Month 18 in CDR-sb 
of 2.4, using alpha = 0.05, a total sample size of 304 patients in balanced allocation 
(152 patients per group) provides at least 90% power to detect a difference between 
treatment groups of 0.9 (based on data from mild AD patients in Study TTP488-203) 
using a 2-sided, 2-sample t-test. Assuming a dropout rate of 20% or less, 
randomization of 380 patients provides adequate statistical power for this study to 
demonstrate superiority of azeliragon plus SoC over placebo plus SoC based on 
CDR-sb. 
9.2 
STATISTICAL HYPOTHESES 
A 2-stage conditional sequence of statistical hypothesis tests, will be used. The 
testing sequence will be as follows: 
• Stage 1: 4 concurrent analyses will be done: 
 A-study analysis of co-primary variables: 
▪ ADAS-cog is analyzed in A-Study. 
▪ CDR-sb is analyzed in A-Study 
 B-study analysis of co-primary variables: 
▪ ADAS-cog is analyzed in B-study. 
▪ CDR-sb is analyzed in B-study 


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• Stage 2: Conditional on statistical significance of both A-study and B-study in 
both co- primary variables, testing will continue: 
 MRI assessment is analyzed in the study (as a whole). 
For simplicity in notation, thresholds for significance are indicated as “p<0.05”; 
however, “0.05” is representative of the alpha allocated to the analysis. The overall 
study-wise alpha is 0.05, but particular analyses may have alpha less than 0.05. 
STAGE 1: 
Hypothesis tests for A-study are as follows: 
The first set of hypotheses to be tested is as follows: 
• H01: µ(ADAS-cog, azeliragon, A-study)= µ(ADAS-cog, P, A-study) 
• H11: µ(ADAS-cog, azeliragon, A-study) ≠ µ(ADAS-cog, P, A-study), 
where µ(ADAS-cog, azeliragon, A-study) and µ(ADAS-cog, P, A-study) denote the 
true mean changes from Baseline at Month 18 on the ADAS-cog total score for the 
A-study azeliragon 5 mg/day added to SoC and placebo added to SoC groups, 
respectively. 
The second set of hypotheses to be tested is as follows: 
• H02: µ(CDR-sb, azeliragon, A-study)= µ(CDR-sb, P, A-study) 
• H12: µ(CDR-sb, azeliragon, A-study) ≠ µ(CDR-sb, P, A-study). 
where µ(CDR-sb, azeliragon, A-study) and µ(CDR-sb, P, A-study) denote the true 
mean changes from Baseline at Month 18 on the CDR-sb score for the A-study AD 
azeliragon 5 mg/day and placebo groups, respectively. 


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Hypothesis tests for B-study are as follows: 
The first set of hypotheses to be tested in B-study (the third set of hypotheses for the 
study as a whole) is as follows: 
• H03: µ
(ADAS-cog, azeliragon, B-study)
= µ
(ADAS-cog, P, B-study) 
• H13: µ
(ADAS-cog, azeliragon, B-study) ≠ µ
(ADAS-cog, P, B-study), 
where µ(ADAS-cog, azeliragon, B-study) and µ(ADAS-cog, P, B-study) denote the 
true mean changes from Baseline at Month 18 on the ADAS-cog total score for the 
B-study azeliragon 5 mg/day added to SoC and placebo added to SoC groups, 
respectively. 
The second set of hypotheses to be tested in B-study (the fourth set of hypotheses 
for the study as a whole) is as follows: 
• H04: µ(CDR-sb, azeliragon, B-study)= µ(CDR-sb, P, B-study) 
• H14: µ(CDR-sb, azeliragon, B-study) ≠ µ(CDR-sb, P, B-study). 
where µ(CDR-sb, azeliragon, B-study) and µ(CDR-sb, P, B-study) denote the true 
mean changes from Baseline at Month 18 on the CDR-sb score for the B-study AD 
azeliragon 5 mg/day and placebo groups, respectively. 
STAGE 2: 
If and only if both hypothesis tests in A-study AD subjects and also B-study AD 
subjects for both co-primary variables (ADAS-cog and CDR-sb) have p<0.05, (i.e., 
p<0.05 for ADAS- cog demonstrating statistical superiority of azeliragon 5 mg 
added to SoC versus placebo added to SoC and also p<0.05 for CDR-sb 
demonstrating statistical superiority of azeliragon 5 mg added to SoC versus placebo 
added to SoC, i.e., statistical significance of the test of the null hypothesis for each 
A-study and B-study independently), testing will proceed to the fifth set of 


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hypotheses to the expansion of the more heterogeneous population of AD subjects 
participating in the study, including all study subjects. 
Consistent with the FDA draft Guidance for Industry: Alzheimer’s Disease: 
Developing Drugs for the Treatment of Early Stage Disease (February, 2012), 
toward the goal of demonstrating disease modification, analysis of MRI data 
(selection and specification will be made prior to database lock) will be done 
conditional on significance of the above named hypothesis tests: 
The next set of hypotheses to be tested is as follows: 
• H05: µ
(MRI, azeliragon, All)
= µ
(MRI, P,All) 
• H15: µ
(MRI, azeliragon, All) ≠ µ
(MRI, P,All), 
where µ(MRI, azeliragon, Alld) and µ(MRI, P,All) denote the true mean changes 
from Baseline at Month 18 on MRI volume measures for all AD azeliragon 5 mg/day 
and placebo groups, respectively. 
It is noted that the specific MRI volume measures and specific statistical 
methodology for the MRI measures will be detailed in the SAP in accordance with 
a discussion with the FDA regarding the evolving scientific knowledge about the 
best correlates of changes in AD with MRI measures. 
9.3 
POPULATIONS OF ANALYSIS 
In accordance with guidance from the International Conference of Harmonization of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 
guideline ICH E9 Statistical Principles for Clinical Trials (1998), the following 
population of analysis will be used for all statistical analysis: 
• The full analysis set (FAS) includes all randomized subjects who receive any 
study medication and have at least one post-Baseline assessment. 


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• The per protocol set (PPS) includes all subjects in the FAS who are not treatment 
failures and who receive at least 6 months of study drug and attend at least 6 
scheduled visits, except for those who are excluded because of major protocol 
violations, where a major protocol violation is one that may affect the 
interpretation of study results (e.g., taking less than 50% of prescribed study 
medication during participation). 
The PPS also includes subjects who are treatment failures at any time during the 
study.  
Final determinations of the PPS will be made at the masked data review meeting 
held in accordance with ICH E9 prior to the lock data. The complete specification 
(made blinded to treatment arm) will be documented in the minutes to the blind data 
review meeting held prior to lock the data. 
• The safety set (SAF) includes all subjects who receive any study medication. 
For the purpose of understanding the influence of dropouts on study conclusions, the 
FAS will be partitioned into subjects who complete (completers) and subjects who 
do not complete (dropouts).  For purposes of this study, a subject is a completer if 
the subject has received treatment for 18 months and has efficacy data for 18 months. 
The FAS will be used for all hypothesis tests of efficacy. Analysis of superiority 
using the PPS will also be done for supportive analyses.  
The SAF will be used for safety analyses. 
9.4 
DISPOSITION, DEMOGRAPHIC, AND BASELINE DATA 
A tabulation of subject disposition will be presented, including the number screened, 
the number randomized in each population group, the number dosed in each 
population group, the number who withdrew prior to completing the study, and 
reasons for withdrawal. 
Demographic and baseline characteristics (disease history, medical history, and prior 
treatments for AD) will be summarized for all randomized patients and for the FAS. 


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A summary will also be provided for baseline-severity categories (ADAS-cog 19 or 
less; ADAS-cog more than 19).  No formal statistical comparisons will be 
performed. 
9.5 
EFFICACY ANALYSIS 
Efficacy evaluation will include the co-primary endpoints (ADAS-cog and 
CDR-sb), key secondary measures, and other efficacy markers. 
A treatment failure is a subject who withdraws from the study due to lack of efficacy 
or due to toxicity, as assessed by a treatment-emergent adverse event that is judged 
associated with study medication.  For purposes of efficacy analysis, a treatment 
failure is considered to have rendered final endpoint data.  The latest on-treatment 
assessment is taken as the (hard) endpoint assessment.  Taking the exit value as an 
endpoint value for a subject who is withdrawn from the study due to lack of efficacy 
is scientifically-based in a progressive disease where it is known that subjects due 
not spontaneously remit. 
Statistical analysis will be done on each A-study and B-study, independently, for the 
co- primary variables: change from baseline in ADAS-cog and change from baseline 
in CDR-sb. sub-study, where A-study includes the first approximately 400 patients 
randomized and B-study includes the remaining approximately 400 patients 
randomized. For all other secondary variables, tertiary variables, and subgroup 
analyses, the study as a whole will be used for inferential purposes. It is noted that 
randomization supports independent analysis of A-Study and B-Study and also 
supports the statistical analysis of all randomized subjects. 
9.5.1 
Efficacy Variables of Analysis 
9.5.1.1 
Primary Efficacy Variables of Analysis 
The primary analysis will include assessment of the following variables of analysis. 
• Mean change from Baseline to Month 18 in ADAS-cog 
• Mean change from Baseline to Month 18 in CDR-sb. 


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Key supportive variables will include mean change from Baseline to Visit in ADAS-
cog and mean change from Baseline to Visit in CDR-sb. 
9.5.1.2 
Key Secondary Variables of Analysis 
The key secondary endpoint will be one of the following (to be determined before 
breaking the blind for study treatment): 
• Change from Baseline in hippocampal volume at Month 18. 
• Change from Baseline in whole brain volume at Month 18. 
• Change from Baseline in ventricular volume at Month 18. 
9.5.1.3 
Other Efficacy Variables of Analysis 
Additional efficacy variables of analysis are as follows: 
• Responder analysis at Months 1, 3, 6, 9, 12, 15 and 18 based on ADAS-cog and 
responder analysis at Months 3, 6, 12, and 18 based on the CDR-sb. 
• The slope of the change over time in ADAS-cog, Mini-Mental State Examination 
(MMSE), and ADCS-ADL scales through Month 18. 
• Time to loss of one global stage on the Clinical Dementia Rating (CDR) score 
through Month 18. 
• Proportion of participants in each CDR global stage at Months 3, 6, 12 and 18. 
• Change from Baseline on the ADAS-cog at Months 1, 3, 6, 9, 12 and 15 and at 
Months 3, 6 and 12 for the CDR-sb. 
• Individual item responses on the Resource Utilization in Dementia Lite (RUD 
Lite) questionnaire and the total caregiver/informant time spent assisting the 
patient based on the RUD Lite at Months 5, 13 and 19. 
• Proportion of participants who enter intermediate or long-term residential care 
(RUD Lite) at Months 6, 12, and 18. 


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• Change from Baseline in the Dementia Quality of Life (DEMQOL) -Proxy total 
score at Months 6, 12, and 18. 
• Change from Baseline in the Neuropsychiatric Inventory (NPI) total score at 
Months 3, 6, 12, and 18. 
• Change from Baseline on the Mini-mental State Examination (MMSE) total 
score at Months 3, 6, 12, and 18. 
• Change from Baseline on the Continuous Oral Word Association Task 
(COWAT) score at Months 3, 6, 12, and 18. 
• Change from Baseline on the Category Fluency Test (CFT) score at Months 3, 
6, 12, and 18. 
• Change from Baseline on the Trail Making Test (Versions A and B) time at 
Months 3, 6, 12 and 18 
• Change from Baseline in the extent of brain glucose hypometabolism at 
Month 18. 
• Change from Baseline in the severity of brain glucose hypometabolism at Month 
18. 
9.5.2 
Statistical Methodology for Primary Analysis 
The primary analysis will use the ITT methodology and a main-effects 
mixed-models for repeated measures (MMRM) methodology. The MMRM will 
utilize an unstructured covariance where the number of parameters is “t(t+1)/2” 
where “t” is the dimension of the covariance matrix, using PROC MIXED in SAS.  
In the unlikely event of lack of convergence, Toeplitz structure will be employed 
where the number of parameters is “t” where “t” is the dimension of the covariance 
matrix. Time is considered as a class variable. Analysis will include treatment, time 
and treatment-by-time interaction as fixed effects, Baseline as covariate, baseline 
stratum as a covariate, and subject as a random effect. Supportive modeling will also 
include MMRM main-effects model with treatment, time, and subject. 


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The primary analysis will be done for each sub-study separately and will use alpha 
= 0.049, which includes an adjustment of 0.001 for interim analyses performed by 
the Independent Data Monitoring Committee (IDMC), thereby preserving the 
overall study-wise alpha = 0.05. 
The primary analysis will also be done on randomization stratification subgroups 
defined by (1) baseline ADAS-cog 19 or less and (2) baseline ADAS-cog more than 
19. 
Multiple imputations (MI) will be used as a supportive analysis with 100 invocations 
(acknowledging that more invocations are needed with more missing data). Monte 
Carlo methods are planned. 
An essential component of the thorough analysis includes an assessment of the 
impact of missing data on study conclusions. As a part of assessing this impact, 
supportive analysis will include an endpoint analysis (reduction to last-observation-
carried-forward, justified in this study based on the monotonic progression of the 
natural course of AD and assuming no more dropouts in the group treated with 
azeliragon plus SoC than in the group treated with placebo plus SoC), a completers 
analysis (observed cases at Month 18), and observed cases by assessment time. 
Interaction terms will be examined in supportive analyses.  In the event of a 
significant interaction term, the impact on analysis conclusion will be examined.  
The primary model will not include interaction terms. A key supportive analysis will 
use the ITT methodology and a main-effects model for ANCOVA adjusting for 
baseline ADAS-cog (CDR-sb) using last-observation-carried-forward (LOCF) 
methods for missing data, justified based on known profiles of ADAS-cog (CDR-sb) 
in AD patients, which is conservative under the assumption that there are not more 
dropouts in the active-treated group than the placebo group. Rank ANCOVA will be 
done as a supportive analysis. 
To ensure robustness of analysis conclusions against missingness, multiple 
imputation methods will also be done to cope with missing data as a key supportive 
analysis using the final on-treatment assessment of treatment failures as non-missing 
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In accordance with the recommendations of the report from the National Academy 
of Science (NAS) panel “The Prevention and Treatment of Missing Data in Clinical 
Trials,” (National Research Council, 2010), missingness is classified as “missing at 
random” (MAR) or “missing not at random” (MNAR).  When subjects are 
withdrawn due to treatment failure, this event is considered in this sensitivity 
analysis to be MNAR, and the endpoint value is taken as the hard endpoint (not 
imputed) in analysis, operationally, the endpoint analysis is the same as LOCF.   Data 
that are missing for other reasons are considered to be MAR, and standard multiple 
imputation methods are planned. 
Descriptive summaries will be produced of the observed values and change from 
Baseline in co-primary variables by treatment group at each individual time point 
and at endpoint (final on-treatment assessment for each subject). 
For statistical analyses, 95% confidence intervals will be produced for the 
least-squares means (LSM) in each treatment group, as well as the LSM differences 
as compared to placebo plus SoC.  For MMRM and ANCOVA, two-sided p-values 
will be displayed for the comparison against placebo plus SoC. 
Because there are limited numbers of subjects per center, there will inadequate 
power to explore impact of the center effect on study conclusion. Descriptive 
statistics by center will be presented. 
The primary analysis controls alpha through the conditional sequence of hypothesis 
testing. No further adjustment for multiplicity is necessary. 
If the PPS differs from the FAS by more than 15%, the analyses will be replicated 
on the PPS.  If the PPS and the FAS do not differ by more than 15%, analysis may 
not be done on the PPS.  Final judgments will be made at the blind data review 
meeting in accordance with ICH E9. 
Methodologies for analysis of MRI and FDG-PET data will be described in the SAP, 
possibly updated in accordance with published findings about relationships between 
changes in MRI and/or FDG-PET data and AD. 


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9.5.3 
Statistical Methodology for Secondary and Other Efficacy Analysis 
Secondary and exploratory endpoints that are measurement variables will use similar 
statistical methodology to the methodology used for primary analysis.  Efficacy 
variables that are proportions will be analyzed using Mantel-Haenszel test, 
controlling for Stratum, if appropriate.  For the analysis of the categories for 
responders, a Cochran-Mantel-Haenszel test will be used. 
Methodologies for variables that are proportions will include construction of 
confidence intervals for each treatment group and for the difference between groups.  
For analysis, Fisher’s exact test will be used for single-population analysis, and a 
Mantel-Haenszel test will be used for analyses combining data across strata. 
Methodologies for time-to-event variables will include construction of 95% 
confidence intervals for each group separately and for the difference between 
groups.  For analysis, a Wilcoxon test will be used for single-population analysis, 
and a van Elteren test will be used for analyses combining data across strata. 
Subgroup analyses will be done as identified in the SAP. 
Responders based on the ADAS-cog total score, will be assessed using cumulative 
percentage plots.  Similarly, responders based on the CDR-sb score will be assessed 
using cumulative percentage plots.  The y-axis will show the cumulative percentage 
of patients who achieved the specific measure of improvement in the ADAS-cog (or 
CDR-sb) total score shown on the x-axis with a separate cumulative percentage 
curve for each treatment group. 
Time to loss of one global stage on the global CDR will include Kaplan-Meier 
curves. Survival estimates for treatment groups will be compared using the logrank 
statistic. Observations will be treated as right censored for participants who complete 
the study without a loss of one stage on the global CDR score or who discontinue 
the study prematurely. 
The proportion of participants who experience loss of one global stage on the CDR 
will be assessed at each Visit using logistic regression with treatment (as a 
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Summary measures from the analysis will include the odds ratio, 95% confidence 
interval for the odds ratio, and p-value for treatment comparison.  Additionally, the 
proportion of participants in each CDR global stage will be presented. 
For change from Baseline in plasma concentrations of Aβ species, an MMRM 
analysis similar to that described for the co-primary endpoints with baseline plasma 
concentrations of Aβ species as a continuous covariate will be performed. 
For change from Baseline in NPI and MMSE, an MMRM analysis similar to that 
described for the co-primary endpoints with baseline NPI, and MMSE, as a 
continuous covariate, respectively, will be performed. 
Individual item responses on the RUD Lite questionnaire and the total 
caregiver/informant time spent assisting the patient based on the RUD Lite 
questionnaire will be summarized by treatment group. 
For change from baseline in DEMQOL-Proxy total score, an ANCOVA analysis 
with Baseline DEMQOL-Proxy as a continuous covariate will be performed. 
If the distribution of any of the above parameters, key secondary, or other secondary 
endpoints does not appear to be normally distributed, the rank analogues will be 
utilized. 
9.5.4 
Subgroup Analyses 
Subgroup analyses will be based on the study as a whole. Subgroup analysis will 
include examination of consistency of efficacy results (ADAS-cog and CDR-sb) 
over subsets determined by demographic and baseline characteristics. The SAP will 
include details for subgroup analysis. 
9.5.5 
Adjustment for Multiple Comparisons 
Multiplicity of the primary efficacy analyses is controlled by using a conditional 
sequence of hypotheses.  The study will be considered to demonstrate statistical 
significance if the primary analysis has a resulting p-value less than 0.05.  No other 
adjustment for multiplicity is required. 


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9.6 
SAFETY ANALYSIS 
The SAF is used for safety analysis.  Adverse events, ECGs, vital signs and safety 
laboratory data will be reviewed and summarized on an ongoing basis during the 
trial to evaluate the safety of participants. 
9.6.1 
Safety Variables of Analysis 
9.6.1.1 
Adverse Events 
Definitions: 
• A treatment-emergent adverse event (TEAE) is an event that is observed or 
reported after administration of study medication that was not present prior to 
study medication administration or an event that represents the exacerbation of 
a pre-existing event. 
• An adverse withdrawal is a subject who withdrew from the study due to an 
adverse event. 
• A serious adverse event (SAE) is an AE that is classified as serious according to 
the criteria specified in the study protocol. 
Adverse events variables of analysis include: 
• Proportions of subjects with TEAEs by Preferred Term and decreasing 
frequency of TEAE 
• Proportions of subjects with TEAEs by System Organ Class and Preferred Term 
• Proportions of subjects with adverse withdrawals 
9.6.1.2 
Vital Signs 
Vitals signs measures of blood pressure and pulse will include the following 
variables of analysis: 
• Mean values and mean changes of values from Baseline to Visit 


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• Proportions of subjects with clinically significant abnormal values or changes in 
vital signs measures. 
• Proportions of subjects with AEs related to vital signs 
9.6.1.3 
Clinical Laboratory 
Clinical Laboratory hematology and clinical chemistry variables of analysis include: 
• Proportions of subjects with TEAVs (shifts from normal status to abnormal 
status) 
• Proportions of subjects meeting DILI criteria per FDA guidance Guidance for 
Industry “Drug-induced liver injury: premarketing clinical evaluation” (CDER, 
CBER, July 2009) 
• Means and mean changes from Baseline to Visit 
• Proportions of subjects with new (post Baseline) clinically significant values 
(Clinical laboratory-related AEs)or changes in laboratory values 
9.6.1.4 
Electrocardiography 
Electrocardiography variables of analyses will include: 
• Proportion of subjects with Corrections to QT intervals will be made by Bazett’s 
method and also by Fridericia’s method. Categorical analysis will be done 
consistent with ICH E14, “Clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs” (October 2005). 
9.6.2 
Statistical Methodology for Safety Analysis 
Adverse events will be coded using MedDRA Version 16.0 or above.  Adverse event 
coding will be done to the lowest level term (LLT).  All treated patients will be 
included in the assessment of safety.  Adverse events will be summarized by 
MedDRA System Organ Class and Preferred Terms.  Separate tabulations will be 


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produced for related AEs (those considered by the Investigator as drug related), 
SAEs, discontinuations due to AEs, and severe events. 
Vital signs, ECG results, and laboratory data will be tabulated for changes over time 
on study.   In addition, TEAV and significant findings will be summarized. 
The following assessments are constructed to provide a view of safety assessments 
after more than one dose of study medication with variable exposure including 
assessments of change to worst value (to examine worse value, minimum and 
maximum values are examined): 
• Baseline 
• First on treatment 
• Last on treatment 
• Last available (includes off-treatment values and safety follow-up assessment 
values) 
• Minimum value 
• Maximum value 
For each post-Baseline assessment, descriptive statistics are provided for the 
assessment value and the change from Baseline to the assessment. 
9.7 
BRAIN MRI 
Brain MRI data will be collected and analyzed for changes over the 18 month 
treatment period for safety or efficacy. The statistical methods will be described in 
the SAP. 
9.8 
PHARMACODYNAMIC DATA 
All participants with at least one dose of study medication will be included in the 
pharmacokinetic and pharmacokinetic/pharmacodynamic analyses, as appropriate.  
For individual endpoints, participants must have at least 1 post-dose 
pharmacodynamic measurement for the given endpoint.  For change from Baseline, 
participants must also have a Baseline value. 


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Plasma Aβ (total, 1-40 and 1-42) concentration and cerebral brain volume 
(hippocampus and whole brain, ventricular) versus time will be tabulated and mean 
concentration or brain volume versus time will be plotted for each treatment group.  
Descriptive statistics for raw and change from baseline values will be generated, as 
appropriate.  Maximum and average change from Baseline values will be calculated 
by treatment group. 
The statistical methods will be described in the SAP. 
9.9 
PHARMACOKINETIC DATA 
Data resulting from blood sampling for trough concentrations of azeliragon will be 
collected and analyzed for changes over the 18 month treatment period. 
Concentration-driven analysis will be planned. The statistical methods will be 
described in the SAP. 
A population pharmacokinetic analysis will be conducted to derive a model relating 
pre-dose steady state concentrations measured at each Visit, to estimates of 
individual clearance.  The relevance of a range of covariates (e.g., age, weight) on 
model parameters will be evaluated. 
Plasma concentrations will be determined to support concentration response 
analyses for selected plasma biomarkers, efficacy and safety data.  Concentration-
response plots will be derived and simple models fitted to the data to explore 
potential relationships.  PK/PD models using either a Bayesian or maximum 
likelihood approach may be utilized to characterize these relationships and estimate 
pharmacokinetic and pharmacodynamic parameters. 
9.10 
DEMQOL AND OTHER QUESTIONNAIRES 
Questionnaires in this study will be scored according to the published guidelines 
provided in validation and documentation for the instruments by the developers. The 
statistical methods will be described in the SAP. 


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9.11 
HANDLING MISSING DATA 
Data are considered to be “on-treatment” if the assessment of collection follows the 
first administration of study medication and if the assessment occurs within 45 days 
following the final administration of study medication, justified based on the long 
half-life of this drug. 
In general, for primary efficacy analysis and for safety analysis, missing data will 
not be imputed. Dates with missing fields will not have days imputed. 
In accordance with the recommendations of the report from the National Academy 
of Science (NAS) panel “The Prevention and Treatment of Missing Data in Clinical 
Trials,” (National Research Council, 2010), sensitivity analyses will be done to 
ensure that study conclusions are robust against missing data.  Last observation 
carried forward (LOCF) and baseline observation carried forward (BOCF) methods 
will be used as appropriate in sensitivity analysis.  Missing data types will be 
examined, and statistical methodologies for appropriate sensitivity analyses will be 
finalized during blind data review as patterns emerge as the study progresses. 
Primary methodologies following the ITT principle are not subject to change. 
A treatment failure is a subject who withdraws from the study due to lack of efficacy 
or due to toxicity, as assessed by a treatment-emergent adverse event that is judged 
associated with study medication (restated for convenience from Section 9.5 
“Efficacy Analysis”). For purposes of efficacy analysis, a treatment failure is 
considered to have rendered final endpoint data. The latest on-treatment assessment 
is taken as the (hard) endpoint assessment. Any method of imputation will not alter 
this assessment. 
Details of methodologies identifying data as missing at random (MAR) or not 
missing at random (NMAR) will be addressed in the SAP.  Statistical methods for 
addressing MAR and NMAR will be described in the SAP. 


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9.12 
DATA MONITORING COMMITTEE 
An external Independent Data Monitoring Committee (IDMC) will be responsible 
for the review of all available safety data at their regularly scheduled meetings during 
the trial. 
The IDMC will consist of at least 3 members, including a neurologist who has 
experience in the treatment of individuals with AD and a senior statistician.  Ad hoc 
members (e.g., experts on RAGE mechanisms or a cardiovascular physician) will be 
available for consultation by the IDMC upon request. 
The IDMC charter will guide operational aspects of the IDMC structure, processes, 
and study stopping rules. 
9.13 
INTERIM ANALYSIS 
Except for the ongoing, blinded medical monitoring of accruing data and except for 
the ongoing review by the IDMC, no interim analysis is planned for this study. 
As a conservative measure, an alpha adjustment is applied to accommodate up to 
10 analyses by the IDMC. Alpha = 0.0001 is apportioned to each of no more than 
10 analyses by the IDMC. 
With the exception of the IDMC, no unblinding is planned in this study for any 
reason other than emergency unblinding for medical imperatives. 
It is emphasized that there is no interim analysis in this study for efficacy. The 
interim analyses described in this section refer to the analyses done by the IDMC for 
safety monitoring only. 
9.14 
DATA MANAGEMENT CONSIDERATIONS 
This study will utilize electronic data capture (EDC) for data capture. The database 
lock will occur for each sub-study (A-Study and B-Study) when the study is declared 
closed, when all subjects have completed the study (last visit of the last subject on-
study). 


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10.0 
QUALITY CONTROL / MONITORING OF THE STUDY 
During study conduct, the Sponsor or its designee will conduct periodic monitoring 
visits to ensure that the protocol and GCPs are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  
Additionally, the study site may be subject quality assurance audits performed by 
the Sponsor, and/or to inspection by the IRB/REB or regulatory authorities. 
 
 


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11.0 
DATA HANDLING AND RECORD KEEPING 
11.1 
CASE REPORT FORMS/ELECTRONIC DATA RECORD 
This study will utilize electronic data capture (EDC) for the data record serving as 
the “Case Report Form (CRF)”.  All required study information must be recorded 
on the appropriate CRF screens/forms using the eCRF Completion Guidelines for 
the study.  The database will house both A-Study and B-Study in a single database, 
but with the delineation of patients who are in A-Study and those who are in B-
Study. The databases for each substudy will be locked separately (hard-lock). 
Quality control measures will progress final data management activities from last-
patient-last-visit to database lock, then unblinding, final analysis, and final reported 
for each sub-study as it completes. The database lock will occur for each sub-study 
(A-Study and B-Study) when the study is declared closed, when all participants have 
completed the study (last visit of the last subject on-study) and the data are fully 
monitored with all queries resolved. 
The PI is responsible for ensuring that the data collected is collected/reported in a 
timely manner and is accurate, complete and legible.  Data will be verified within 
the eCRF by the Study Site and the Study Monitor before being exported.  Any 
changes made during verification will be documented with a full audit trail. 
Any missing or inconsistent data entries will be referred back to the PI or designee, 
using a data query form, and documented for each individual study participant before 
eCRFs are frozen, signed by PI. From that point forward, the database will be 
protected from changes (database lock). 
11.2 
RECORD RETENTION 
For sites in the United States, the PI/Study Site must retain all study records, 
including regulatory documents and individual study participant records, for a period 
of 2 years following the date a marketing application is approved for the drug, for 
the indication for which it is being investigated; or, if no application is to be filed, 
or if the application is not approved, until 2 years after the investigation is 
discontinued, and the FDA is notified or longer if requested by Sponsor (per 21 CFR 
312.62).   


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For sites in Canada, the PI/Study Site must retain all study records, including regulatory 
documents and individual study participant records, for a period of 25 years after the 
date of completion of trial (per FDR C.05.012). 
If the investigator becomes unable for any reason to continue to retain study records 
for the required period (e.g., retirement, relocation, closure of facility), the Sponsor 
should be prospectively notified.  The study records must be transferred to a designee 
acceptable to vTv Therapeutics, such as another investigator, another institution, or 
to vTv Therapeutics.  vTv Therapetuics needs to be notified and approval obtained 
before records may be transferred off site. 
 
 


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12.0 
ETHICS 
12.1 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD 
(REB) 
The study protocol, protocol amendments, informed consent forms, and other 
relevant documents (e.g., recruitment advertisements) will be reviewed and 
approved by the IRB/REB prior to site initiation.  All correspondence with the 
IRB/REB should be retained in the site’s trial file with copies of IRB/REB 
communications forwarded to the Sponsor. 
A protocol amendment may be initiated prior to IRB/REB approval only where the 
change is necessary to eliminate apparent immediate hazards to the participants.  
Should this occur, the investigator must notify the IRB/REB and the Sponsor in 
writing immediately after the implementation of the protocol amendment.  No 
deviations to the protocol are permissible except when necessary to eliminate an 
immediate hazard to study participants.  The investigator shall notify the IRB/REB 
of deviations from the protocol or serious adverse events occurring at the site, in 
accordance with local procedures. 
12.2 
ETHICAL CONDUCT OF THE STUDY 
The study will be conducted in accordance with the Declaration of Helsinki on 
Ethical Principles for Medical Research Involving Human Participants, adopted by 
the General Assembly of the World Medical Association (1996). 
In addition, the study will be conducted in accordance with the protocol, the 
International Conference on Harmonisation guideline on Good Clinical Practice, 
and applicable local regulatory requirements and laws. 
12.3 
SUBJECT INFORMATION AND CONSENT 
Informed consent will be administered in accordance with the requirements of 
21 CFR 50.20-27, FDR C.05.010 and ICH E6 4.8, Principles of Good Clinical 
Practice, as applicable.  Before protocol-specified procedures are carried out, the PI 
and study staff will explain the objectives of the study, study procedures, as well as 


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the risks involved to the study participant, his/her legally authorized representative 
(if applicable) and caregiver/informant prior to their inclusion in the trial. 
Prior to performing any study-specific procedure, each study participant and the 
participant’s caregiver/informant will be required to read and voluntarily sign an 
Institutional Review Board (IRB)/Research Ethics Board (REB)- approved 
informed consent form (ICF), indicating his/her consent to participate (or assent 
[where this is in accordance with local laws, regulations and ethics committee 
policy] in the case of participants who are deemed to be unable to have the cognitive 
ability to provide consent).  This ICF will conform to the requirements of the 
applicable 21 CFR 50.20-27, FDR C.05.010 and ICH E6 Principles of Good Clinical 
Practice (GCP).  The Study Sponsor must agree with the final IRB/REB-approved 
ICF prior to initiation of the study.  Study participants will be provided adequate 
time to review the ICF and if they wish, may take it home to discuss their 
participation in the study with friends, family, and/or a physician.  The original 
signed ICFs must remain in the study participant's file in the Study Site.  Study 
participant will receive a copy of their signed ICF. 
 
 


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13.0 
STUDY TERMINATION CRITERIA 
The study may be terminated prematurely as a result of a regulatory authority 
decision, IRB/REB decision, or at the discretion of the Sponsor.  In addition, the 
Sponsor retains the right to discontinue development of azeliragon at any time. 
Should the study be prematurely terminated, the Sponsor will promptly notify the 
investigator.  Following notification, the investigator must contact all participating 
participants and the hospital pharmacy (if applicable) within 30 days. 
 
 


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14.0 
CONFIDENTIALITY AND PUBLICATION OF STUDY RESULTS 
The information in this and related documents from the Study Sponsor contains trade 
secrets and commercial information that are confidential and may not be disclosed 
unless such disclosure is required by federal or other laws or regulations.  In any 
event, persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
Individual study participant medical information obtained as a result of this study is 
considered confidential, and disclosure to third parties other than those noted below 
is prohibited.  Such medical information may be given to the study participant's 
personal physician or to other appropriate medical personnel responsible for the 
study participant's welfare. 
Data generated as a result of this study are to be available for inspection on request 
of the Sponsor's representative, the IRB/REB, or the local regulatory agency. 
None of the parties involved in the management/conduct/analysis of this study may 
publish any study-related data without the written permission of the Study Sponsor. 
No patent application based on the results of the study may be made by the PI, nor 
may assistance be given to any third party to make such an application, without the 
written authorization of the Study Sponsor. Publication of study results is discussed 
in the Clinical Study Agreement. 
 
 


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REFERENCES 
1. 
Alzheimer’s Association.  2012 Alzheimer’s disease facts and figures.  Alz 
Dementia 2012;8(2):131-168. 
2. 
Arancio O, Zhang HP, Chen X, Lin C, Trinchese F, Puzzo D, et al. RAGE 
potentiates Abeta- induced perturbation of neuronal function in transgenic 
mice. EMBO J. 2004 Oct;23(20):4096-105. 
3. 
Bednar MM, Harrigan EP, Anziano RJ, Camm AJ, Ruskin JN.  The QT 
interval.  Prog Cardiovasc Dis 2001;43(5 Suppl 1):1-45. 
4. 
Berg L. Clinical Dementia Rating (CDR). Psychopharmacol Bull. 
1988;24:637-9. 
5. 
Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, et al. 
Understanding RAGE, the receptor for advanced glycation end products. J Mol 
Med. 2005 Nov;83(11):876-86. 
6. 
Borkowski JG, Benton AL, Spreen O.  Word fluency and brain damage.  
Neuropsychologia 1967;5:135-40. 
7. 
Carrano A, Hoozemans JJM, Van der Vies SM, Rozemuller AJM, Van Horssen 
J, De Vries HE. Amyloid Beta induces oxidative stress-mediated blood-brain 
barrier changes in capillary amyloid angiopathy. Antioxid Redox Signal. 2011 
Sep;15(5):1167-78. 
8. 
Cummings JL, Mega M, Gray K, et al. The Neuropsychiatric Inventory: 
comprehensive assessment of psychopathology in dementia. Neurology 
1994;44:2308-14. 
9. 
Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, et al. RAGE 
mediates amyloid-beta peptide transport across the blood-brain barrier and 
accumulation in brain. Nat Med. 2003 Jul;9(7):907-13. 


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10. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. 
Indiana University School of Medicine (2007). 
"http://medicine.iupui.edu/clinpharm/ddis/clinical- table/" Accessed 
5August2013. 
11. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method 
for grading the cognitive state of participants for the clinician. Journal of 
Psychiatric Research 1975;12:189-98. 
12. Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M et al. An 
inventory to assess activities of daily living for clinical trials in Alzheimer’s 
disease. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc 
Disord. 1997;11 Suppl 2: S33-9. 
13. Guidance for Industry.  Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendation.  DRAFT 
GUIDANCE.   February 2012. 
14. Hartz AMS, Bauer B, Soldner ELB, Wolf A, Boy S, Backhaus R, et al. Amyloid-
β contributes to blood-brain barrier leakage in transgenic human amyloid 
precursor protein mice and in humans with cerebral amyloid angiopathy. Stroke. 
2012 Feb;43(2):514-23. 
15. Kook S-Y, Hong HS, Moon M, Ha CM, Chang S, Mook-Jung I. Aβ₁₋₄₂-RAGE 
interaction disrupts tight junctions of the blood-brain barrier via Ca2+-
calcineurin signaling. J Neurosci. 2012 Jun;32(26):8845-54. 
16. Loonstra AS, Tarlow AR, Sellers AH.  COWAT metanorms across age, 
education, and gender.  Appl Neuropsychol 2001;8:161-6. 
17. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas 
CH, et al. The diagnosis of dementia due to Alzheimer’s disease:  
Recommendations from the National Institute on Aging and the Alzheimer’s 
Association workgroup. Alzheimers Dement. 2011;7(3):263-9. 


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18. Posner, K., et al., The Columbia-Suicide Severity Rating Scale:  Initial validity 
and internal consistency findings from three multisite studies with adolescents 
and adults.  Am J Psychiatry 2011;168: 1266-77. 
19. Reitan R. Validity of the trail making test as an indicator of organic brain 
disease.  Perceptual and Psychomotor Skills 1958;8:271-6. 
20. Rocken C, Kientsch-Engel R, Mansfeld S, et al. Advanced glycation end 
products and receptor for advanced glycation end products in AA amyloidosis. 
Am J Pathol. 2003;162:1213-20. 
21. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. 
American Journal of Psychiatry 1984;141:1356-64. 
22. Schmidt AM, Sahagan B, Nelson RB, Selmer J, Rothlein R, Bell JM. The role 
of RAGE in amyloid-beta peptide-mediated pathology in Alzheimer’s disease. 
Curr Opin Investig Drugs. 2009 Jul;10(7):672-80. 
23. Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al. 
Measurement of health-related quality of life for people with dementia: 
development of a new instrument (DEMQOL) and an evaluation of current 
methodology. Health Technol Assess. 2005;9(10):1-93.,iii-iv 
24. Stern D, Yan SD, Yan SF, Schmidt AM. Receptor for advanced glycation 
endproducts: a multiligand receptor magnifying cell stress in diverse 
pathologic settings. Adv Drug Deliv Rev. 2002;54(12):1615-25. 
25. Tanzi RE, Moir RD, Wagner SL. Clearance of Alzheimer's Abeta peptide: the 
many roads to perdition. Neuron. 2004;43:605-8. 
26. Wimo A, Gustavsson A, Johnsson L, Winblad B, Hsu MA, Gannon B. 
Application of a resource utilization in dementia (RUD) instrument in global 
setting. Alzheimers Dement. 2012; epub 


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27. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, 
Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM. RAGE 
and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 1996 
Aug;382(6593):685–691. 
28. Yan SD, Zhu H, Zhu A, et al. Receptor-dependent cell stress and amyloid 
accumulation in systemic amyloidosis. Nat Med. 2000;6:643-51. 
29. Yan SD, Chen X, Walker DG, Schmidt AM, Arancio O, Lue LF. RAGE: a 
potential target for Abeta-mediated cellular perturbation in Alzheimer’s 
disease. Curr Mol Med. 2007;7(8):735-42. 
30. Yan SD, Bierhaus A, Nawroth PP, Stern DM. RAGE and Alzheimer’s disease: 
a progression factor for amyloid-beta-induced cellular perturbation? J 
Alzheimers Dis. 2009;16(4):833-43. 
 


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APPENDICES 


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APPENDIX 1 
 
CRITERIA FOR SAFETY VALUES OF  
POTENTIAL CLINICAL CONCERN 


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Criteria for Safety Values of Potential Clinical Concern 
Hematology 
Assay 
Lower limit of the normal reference 
range (LLN) 
Upper limit of the normal reference 
range (ULN) 
Hemoglobin 
<0.8 times 
>1.2 times 
Hematocrit 
<0.8 times 
>1.2 times 
RBC 
<0.8 times 
 
Platelets 
<0.5 times 
>1.75 times 
WBC 
<0.6 times 
>1.5 times 
Total Neutrophils (abs) 
<0.8 times 
>1.2 times 
Eosinophils (abs) 
 
>1.2 times 
Monocytes (abs) 
 
>1.2 times 
Basophils (abs) 
 
>1.2 times 
Lymphocytes (abs) 
<0.8 times 
>1.2 times 
 
 
 
Chemistry 
Assay 
Lower limit of the normal reference 
range (LLN) 
Upper limit of the normal reference 
range (ULN) 
Total bilirubin 
 
>1.5 times 
AST 
 
>3 times 
ALT 
 
>3 times 
GGT 
 
>3.0 times 
Alkaline Phosphatase 
 
>3.0 times 
Creatinine 
 
>1.5 times 
BUN 
 
>1.3 times 
Glucose 
<0.6 times 
>1.5 times 
Uric acid 
 
>1.5 times 
Sodium 
<0.95 times 
>1.05 times 
Potassium 
<0.9 times 
>1.1 times 
Calcium 
<0.9 times 
>1.1 times 
Albumin 
<0.8 times 
>1.2 times 
Total protein 
<0.8 times 
>1.2 times 
Bicarbonate 
<0.9 times 
>1.1 times 
Chloride 
<0.9 times 
>1.1 times 
 


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APPENDIX 2 
 
PROHIBITED MEDICATION LIST 


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Prohibited Medication List 
The following medications are NOT ALLOWED as concomitant medications during the study.  
The list is not exhaustive and therefore, the Investigator is asked to contact the Medical Monitor 
and/or the Sponsor for clarification regarding the acceptability of similar agents not mentioned 
here. 
Drugs known to be strong CYP 2C8 inhibitors: NOT ALLOWED 
gemfibrozil 
clopidogrel 
 
 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of 
Medicine (2007). "http://medicine.iupui.edu/clinpharm/ddis/clinical-table/" Accessed 17 Nov 2017. 
 
Guidance for Industry. Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and 
Labeling Recommendation.  DRAFT GUIDANCE.  October 2017. 
 
 

SAP_001.pdf: 
vTv Therapeutics LLC 
                                        TTP488-301 Statistical Analysis Plan 
 
23 March 2018                                                          i                                                                    Confidential  
STATISTICAL ANALYSIS PLAN 
 
 
Title:   
Randomized, double-blind, placebo-controlled, multi-center registration trial to 
evaluate the efficacy and safety of TTP488 in patients with mild Alzheimer’s 
disease receiving acetylcholinesterase inhibitors and/or memantine   
Protocol:   
TTP488-301, Amendment 7, 28 November 2017   
Study Drug:  Azeliragon (TTP488) 
Sponsor:   
vTv Therapeutics LLC (formerly TransTech Pharma, LLC) 
Date:    
23 March 2018 
 
 
 
 


vTv Therapeutics LLC 
Signatures: 
Imogene Dunn, Ph.D. 
SVP, Biometrics and Regulatory Affairs 
vTv Therapeutics LLC 
23 March 2018 
ii 
TTP488-301 Statistical Analysis Plan 
Date 
c? M~cti 2(Jp 
Date 
Confidential 


vTv Therapeutics LLC 
                                        TTP488-301 Statistical Analysis Plan 
 
23 March 2018                                                          iii                                                                    Confidential
 
 
Table of Contents 
1 
Introduction ......................................................................................................... 1 
1.1    Study Objectives ................................................................................................. 2 
1.2    Study Rationale .................................................................................................. 3 
1.3   Subject Population ............................................................................................... 3 
1.4    Randomization .................................................................................................... 3 
1.5   Study Design ....................................................................................................... 4 
1.6    Sample Size and Power Considerations ............................................................. 4 
1.7    Early Stopping, Data Monitoring, and Interim Analysis .................................... 5 
1.8    Conformance to Regulatory Standards ............................................................... 6 
1.9    Modifications from the Statistical Section of the Protocol ................................ 6 
1.9.1    Modification: Elimination of Bazett’s correction for QT-interval. ............ 7 
2 
Statistical Hypotheses ......................................................................................... 8 
3 
Populations of Analysis .................................................................................... 11 
4 
Variables of Analysis ........................................................................................ 12 
4.1    Efficacy Variables ............................................................................................ 12 
4.1.1    Primary Efficacy Variable ........................................................................ 12 
4.1.2    Key Secondary Variables of Analysis (Imaging) ..................................... 12 
4.1.3    Secondary Variables ................................................................................. 12 
4.1.4    Other Efficacy Variables of Analysis ....................................................... 13 
4.1.5    Efficacy Scales .......................................................................................... 14 
4.2    Safety Variables................................................................................................ 17 
4.2.1    Treatment-emergent Adverse Events ........................................................ 17 
4.2.2    The Columbia Suicide Severity Rating Scale (C-SSRS) .......................... 18 
4.2.3    Vital Signs ................................................................................................. 19 
4.2.4    Clinical laboratory assessments ................................................................ 19 
4.2.5    Brain MRI: Safety ..................................................................................... 20 
4.3    Pharmacokinetics Variables ............................................................................. 21 
4.4    Pharmacodynamics Variables .......................................................................... 21 
4.5    Adverse Events of Special Interest ................................................................... 21 
5 
Statistical Methodology .................................................................................... 22 
5.1 Pooling of Investigator Sites ............................................................................. 22 
5.2    Statistical Methodology for Efficacy Analysis................................................. 22 
5.2.1    Statistical Methodology for Primary Efficacy Analysis ........................... 23 
5.2.2    Statistical Methods for Secondary Variables ............................................ 27 
5.2.3    Subgroup Analyses ................................................................................... 28 
5.2.4    MRI and PET Variables ............................................................................ 28 
5.3    Disposition, Demography, and Baseline Characteristics ................................. 29 
5.4    Analysis of Safety Data .................................................................................... 29 


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5.4.1    Adverse Events ......................................................................................... 29 
5.4.2    Vital Signs ................................................................................................. 30 
5.4.3    Routine Clinical Laboratory Measurements ............................................. 30 
5.4.4    Liver Enzyme Function Tests ................................................................... 30 
5.4.5    Electrocardiography .................................................................................. 30 
5.4.6    Methodology for Brain MRI (Safety) Analysis ........................................ 31 
5.5    Pharmacokinetics Analysis ............................................................................... 31 
5.6    Pharmacodynamics Analysis ............................................................................ 32 
5.7    Exploratory Analysis ........................................................................................ 32 
5.8    Concomitant Medications ................................................................................. 32 
6 
Data Conventions .............................................................................................. 33 
6.1    Definition of Baseline ....................................................................................... 33 
6.2    Missing Data ..................................................................................................... 33 
6.3    Dropouts ........................................................................................................... 34 
6.4    Visit Windows .................................................................................................. 34 
6.5    Early Termination Assessments and Follow-up Assessments ......................... 34 
6.6    Unscheduled Assessments ................................................................................ 34 
6.7    Values Below LLQ ........................................................................................... 35 
7 
Analysis Deviations .......................................................................................... 36 
8 
Software ............................................................................................................ 37 
9 
Data Displays .................................................................................................... 38 
10 
Values of Potential Clinical Concern ................................................................ 40 
11 
References ......................................................................................................... 41 
12 
Schedule of Time and Events ........................................................................... 43 


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1 
Introduction 
Alzheimer’s disease (AD) is a neurodegenerative disease and the leading cause of dementia in 
the aging population.  Neuropathological changes in AD consist of the formation and deposition 
of amyloid plaques and neurofibrillary tangles.  The principal components of amyloid plaques 
are aggregated and insoluble forms of amyloid beta (Aβ) peptides ending predominantly at 
amino acid residues 40 and 42.  Furthermore, surrounding the amyloid plaque are astrocytes 
expressing a calgranulin protein, S100b, which is a cytokine associated with chemoattractant 
activity for monocytes and activation of inflammatory cells of the myeloid lineage.  The reactive 
microglia that surrounds plaques increases the expression of pro-inflammatory cytokines and 
complement receptors. 
TTP Translational Technology®, vTv Therapeutics’ proprietary drug discovery engine, was 
employed to develop TTP488, which is an orally bioavailable antagonist of the Receptor for 
Advanced Glycation Endproducts (RAGE). This product is being developed as a potential 
treatment for AD.  
This study is planned using an enrichment strategy, following the draft regulatory guidance 
depicted in the FDA guidance Enrichment Strategies for Clinical Trials to Support Approval of 
Human Drugs and Biological Products (draft guidance, December, 2012).  This study features a 
conditional sequential approach to hypothesis testing to control alpha, using Bauer closed 
procedures, which are referenced in the FDA adaptive design guidance: FDA guidance Adaptive 
Design for Clinical Trials for Drugs and Biologics (draft guidance, February 2010) referenced 
above), and principles for subgroup analyses.  The statistical analysis is planned to conform to 
FDA guidance provided in Draft Guidance Alzheimer’s Disease: Developing Drugs for the 
Treatment of Early Stage Disease (CDER, 2013), review templates provided by the FDA, and 
Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and 
Biological Products (CDER&CBER, 1998). 
The goals of this statistical analysis plan (SAP) are the following: 
• To describe the approach of statistical analysis to support scientifically sound study 
conclusions. 
 
• To conform to regulatory guidance to facilitate the use of the statistical evaluation for 
support in the regulatory review of study results for purposes of product registration. 
 
• To guide the analysis and reporting of study results to enable the production of valid and 
accurate depictions of study data. 
The approach will conform to FDA guidance as described in Guidance for Industry Statistical 
Principles for Clinical Trials (1998).  
This final draft SAP reflects finalization of all attributes of the analysis plan that pertain to or 
affect alpha and key estimation activities, including initial feedback from the FDA.  In 
accordance with ICH E9, the SAP was finalized prior to any unblinding, and following the final 
blind data review meeting (BDRM) when the per-protocol set (PPS) was characterized.  The 


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SAP will be updated, if warranted, based on future feedback from FDA reviewers; any changes 
to the SAP after finalization will be tracked in amendments similar to the process for the study 
protocol. 
Please note that this SAP describes the statistical analyses of two studies with a common 
infrastructure (A-study and B-study).  The statistical analysis will be performed independently as 
two separate studies (the A-study and the B-study) for the co-primary variables: change from 
baseline in ADAS-cog and change from baseline in CDR-sb.  For the key secondary variable 
(and for all other secondary variables), all study subjects in both the A- and B- studies (A-study 
and B-study subjects combined) will be used for inferential purposes.  All clinical efficacy 
variables will be summarized statistically for descriptive purposes for A-study and B-study 
separately (as well as combined).  The randomization process supports the independent analysis 
of the A-study and the B-study, and also supports the statistical analysis of patients from both 
studies (combined) for the key secondary and other secondary variables. Safety analyses will 
also be performed on all patients in both studies. 
1.1    Study Objectives  
The objectives of the primary, key secondary, and secondary endpoints are presented below 
without a hierarchical order of evaluation.  The hierarchical order of the evaluation of the 
endpoints is provided in Section 4.1 (efficacy variables).  The primary objective presented below 
will be evaluated separately for the two studies (A-study and B-study).  The key secondary and 
all other secondary objectives will be evaluated for the combined data from the A-study and B-
study.  
Primary objective: 
• To evaluate the efficacy of azeliragon on cognitive [Alzheimer's Disease Assessment 
Scale-cognitive subscale (ADAS-cog)] and global function [Clinical Dementia Rating 
Scale Sum of Boxes (CDR-sb)] measures in patients with mild AD. 
Key secondary objective: 
• To examine the effect of azeliragon on MRI volumetrics (e.g., whole brain volume, 
ventricular volume, hippocampal volume)  
Secondary objectives: 
• To evaluate the safety and tolerability of 18 months of treatment with azeliragon plus 
standard of care (SoC) relative to placebo plus standard of care. 
• To evaluate the time course of the effect of azeliragon on the cognitive (ADAS-cog) and 
global functional outcome (CDR-sb) measures. 
• To evaluate the efficacy of azeliragon on behavioral symptoms as assessed by the 
Neuropsychiatric Inventory (NPI). 
• To evaluate the efficacy of azeliragon on cognition as assessed by the Mini-Mental State 
Examination (MMSE). 


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• To evaluate the efficacy of azeliragon on the Alzheimer’s Disease Cooperative Study - 
Activities of Daily Living Scale (ADCS-ADL). 
• To evaluate the efficacy of azeliragon on cognition as assessed by the Continuous Oral 
Word Association Task (COWAT), Category Fluency Test (CFT) and Trail Making Test 
(Versions A and B). 
• To evaluate the effect of azeliragon on health status, health care resource utilization, and 
health-related quality of life as assessed by Resource Utilization in Dementia (RUD 
Lite), and Dementia Quality of Life (DEMQOL-proxy) 
• To evaluate the effect of azeliragon on regional and global brain glucose metabolism 
using FDG-PET. 
• To evaluate the effect of azeliragon on plasma Aβ biomarkers. 
• To evaluate azeliragon exposure-response relationships for selected efficacy, safety and 
biomarker endpoints (e.g., ADAS-cog, ADCS-ADL, adverse events, vital signs, plasma 
concentrations of Aβ). 
1.2    Study Rationale 
The primary purpose of this trial is to evaluate the efficacy and safety of azeliragon in patients 
with mild AD.  Prior studies (TTP 488-203) have shown promise for azeliragon in this 
population. 
1.3   Subject Population  
The study population includes mild AD patients (entry MMSE between 21 and 26, inclusive; 
CDR-global score of 0.5 or 1) who have a reliable caregiver/informant with regular contact (i.e., 
10 hours a week as combination of face-to-face visits and telephone contact acceptable) who will 
facilitate the subject’s full participation in the study.   Caregivers/informant must have sufficient 
subject interaction to be able to provide meaningful input into the rating scales administered in 
this study where caregiver/informant input is required, in particular the CDR, and evidence of 
this should be documented in source documentation.  Participants who reside in assisted living 
facilities are permitted, provided they meet caregiver/informant criteria.  Subjects are required to 
be at least 50 years of age. 
1.4    Randomization   
A total of approximately 800 patients will be randomized into this study.  Subjects will be 
enrolled and randomized according to a fixed randomization scheme blocked by study 
investigative site.  Severity of AD will be determined by MMSE (21-26) at screening. ADAS-
cog at Screening will be used as a stratification variable in the randomization scheme: 
• Lower ADAS-cog: Screening ADAS-cog 19 or less. 
• Higher ADAS-cog: Screening ADAS-cog more than 19. 
Randomization will have balanced allocation (1:1) between active plus SoC and placebo plus 
SoC. Dropouts will not be replaced.  


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1.5   Study Design   
This trial is a multi-center, randomized, double-blind, placebo-controlled, parallel-group study 
evaluating the efficacy and safety of 18 months of treatment with azeliragon relative to placebo 
conducted in approximately 800 mild AD patients who are on background standard of care 
(SoC).  Patients will be randomly assigned to 1 dose level (5 mg/day plus SoC) or placebo plus 
SoC in a 1:1 randomization (approximately n=400/group). 
This protocol describes two statistically independent studies with a common infrastructure. 
Statistical analysis for clinical efficacy will be analyzed as two identical separate studies (A-
study and B-study). Analysis for safety and all secondary and exploratory endpoints will be 
analyzed for both the A and B study as a whole (i.e., the two studies combined). 
A-study is conducted at multiple sites in the U.S and Canada.  
B-study is conducted at multiple sites in the U.S., Canada, Ireland, UK, South Africa, New 
Zealand, and Australia.    
The overall structure of the study includes the following periods: 
Screening period:  Screening procedures occur within 60 days of start of study drug 
administration, and they include obtaining informed consent and evaluations to determine 
eligibility for study participation. 
Baseline Study Period (Day -7 — Day 1, pre-dose):  Subjects will have baseline assessments for 
efficacy and safety measures, including vital signs, safety labs, adverse events, 
electrocardiography and concomitant medications, as well as imaging and PK/PD assessments.  
Treatment Period (Day 1 — Month 18):  Subjects are treated with double-blind study 
medication. Efficacy and safety measures are taken.  Blood samples are taken and subjects have 
assessments for safety and PK.    
Follow-up period (Month 21):  Subjects return to the site for final safety assessments including 
vital signs, adverse events, electrocardiography and concomitant medications are taken.  Blood 
draws are taken for safety evaluations and for pharmacokinetics evaluations.  
1.6    Sample Size and Power Considerations  
The protocol (Section 9.1) includes the following statements about sample size and power 
considerations: 
The primary objective is to evaluate the effect of azeliragon plus SoC on cognition and 
functional outcome by comparing azeliragon plus SoC with placebo plus SoC.  The co-
primary endpoints are change from Baseline on the ADAS-cog total score at Month 18 
and change from Baseline on the CDR-sb total score at Month 18.  The study includes 
AD patients with mild disease as defined by having a baseline MMSE of 21 through 26. 


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This trial includes two independent sub-studies, each of which is supported by 
randomization independently, because randomization by investigative site is used. Each 
sub-study is powered using alpha = 0.05. 
Approximately 160 subjects (80 per treatment group) will be enrolled and participate in 
the FDG-PET sub-study.  The sample size for this sub-study was selected empirically. 
Sample size calculations are done to power each study (A-study and B-study) separately.  
It is anticipated that each A-study and B-study will randomize approximately N=400. 
Assuming a standard deviation of the change from Baseline to Month 18 in ADAS-cog of 
9 (based on Study TTP488-203), using alpha = 0.05, a total sample size of 282 patients in 
balanced allocation (141 patients per group) provides at least 90% power to detect a 
difference between treatment groups of 3.5 (based on data from mild AD patients in 
Study TTP488-203) using a 2-sided, 2-sample t-test.  Assuming a dropout rate of 20% or 
less, randomization of 354 patients provides adequate statistical power for this study to 
demonstrate superiority of azeliragon plus SoC over placebo plus SoC based on the 
ADAS-cog. 
Assuming a standard deviation of the change from Baseline to Month 18 in CDR-sb of 
2.4, using alpha = 0.05, a total sample size of 304 patients in balanced allocation (152 
patients per group) provides at least 90% power to detect a difference between treatment 
groups of 0.9 (based on data from mild AD patients in Study TTP488-203) using a 2-
sided, 2-sample t-test.  Assuming a dropout rate of 20% or less, randomization of 380 
patients provides adequate statistical power for this study to demonstrate superiority of 
azeliragon plus SoC over placebo plus SoC based on CDR-sb. 
1.7    Early Stopping, Data Monitoring, and Interim Analysis 
There is no interim analysis in this study, except for medical and safety monitoring by the 
independent data monitoring committee (IDMC).  This study has no plan for early stopping. 
Except for the ongoing, blinded medical monitoring of accruing data and except for the ongoing 
review by the IDMC, no interim analysis is planned for this study. This study has no plan for 
interim analysis. 
As a conservative measure, an alpha adjustment is applied to accommodate up to 10 analyses by 
the IDMC because the safety evaluation will include review of ADAS-cog data from the safety 
perspective.  Alpha = 0.0001 is apportioned to each of no more than 10 analyses by the IDMC 
that includes review of ADAS-cog data, blinded unless there is a data-driven need expressed by 
the IDMC to be unblinded. 
With the exception of the IDMC, no unblinding is planned in this study for any reason other than 
emergency unblinding for medical imperatives. 
It is emphasized that there is no interim analysis in this study for efficacy.  The interim analyses 
described in this section refer to the analyses done by the IDMC for safety monitoring only. 


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1.8    Conformance to Regulatory Standards  
An objective of this SAP is to comply with regulatory standards.  The following guidance 
documents were specifically consulted in the preparation of this SAP: 
• ICH E9: Statistical principles for clinical trials (September 1998); ICH and FDA 
• ICH E9(R1): Estimands and sensitivity analysis in clinical trials (draft; 16 June 2017); 
ICH and FDA. 
• ICH E14: Clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs (October 2005); ICH and FDA 
• E14 Q&A (R3) ICH guideline E14: the clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs (R3)—questions 
and answers (26 January 2016); EMA 
• Guideline on adjustment for baseline covariates in clinical trials (26 February 2015); 
EMA. 
• Guideline on medicinal products for the treatment of Alzheimer’s disease and other 
dementias (24 July 2008); EMA. 
• Good Review Practice: Statistical review template (30 July 2012). Office of Biostatistics; 
CDER; MAPP 6010.4 
• Good Review Practice: Clinical review template (10 December 2010). Office of New 
Drugs; CDER; MAPP 6010.3 
• Guidance: Providing clinical evidence of effectiveness for human drug and biological 
products (May 1998); CDER; CBER.  
• Good Review Practice: Reviewer guidance: Conducting a clinical safety review of a new 
product application and preparing a report on the review (February 2005); CDER.  
• Draft guidance: Developing drugs for the treatment of early stage disease (February 
2013); CDER. 
• Draft guidance: Adaptive design clinical trials for drugs and biologics (February 2010); 
CDER, CBER.  
• Reflection paper on methodological issues in confirmatory clinical trials planned with an 
adaptive design (18 October 2007); EMA 
• Draft guidance: Enrichment strategies for clinical trials to support approval of human 
drugs and biological products (December 2012); CDER, CBER, CDRH. 
• Guidance: Drug-induced liver injury: premarketing clinical evaluation (July 2009); 
CDER, CBER. 
• Guidance: Patient-reported outcome measures: Use in medical product development to 
support labeling claims (December 2009); CDER, CBER, CDRH. 
• ICH and MSSO. (2017, September). MedDRA Introductory Guide Version 20.1.  
The planned statistical analysis of this study is intended to comply with regulatory expectations 
and standards as depicted in the above-listed guidance documents. 
1.9    Modifications from the Statistical Section of the Protocol  
One modification from the Statistical Section of the Protocol is reflected in this SAP, based on 
agreement with the Neurology Products Division of the FDA: 


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(1) Elimination of the use of Bazett’s correction for QT-interval analysis, based on the 
recommendation depicted in ICH E14 Q&A R3 (dated 10 December 2015). 
1.9.1    Modification: Elimination of Bazett’s correction for QT-interval.  
The Q&A, Revision 3 (10 December 2015), published for ICH E14 indicates that Bazett’s 
correction is not informative and discourages its use, and this guideline recommends Fridericia’s 
correction.  
 
 
 


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2 
Statistical Hypotheses 
As depicted in the study protocol, a 2-stage conditional sequence of statistical hypothesis tests, 
will be used. The testing sequence will be as follows: 
• Stage 1:  Four concurrent analyses will be done: 
• A-study analysis of co-primary variables: 
 ADAS-cog is analyzed in A-study. 
 CDR-sb is analyzed in A-study 
• B-study analysis of co-primary variables: 
 ADAS-cog is analyzed in B-study. 
 CDR-sb is analyzed in B-study 
• Stage 2:  Conditional on statistical significance of both A-study and B-study in 
both co- primary variables, testing will continue: 
• MRI assessment is analyzed in the study (as a whole) Stage 2:  
• Stage 3:  Conditional on statistical significance in both stage 1 and stage 2 testing 
will continue: 
• All other secondary endpoints will be evaluated in a hierarchical manner in the 
combined total of subjects in the 2 studies  
For simplicity in notation, thresholds for significance are indicated as “p<0.05”; however, “0.05” 
is representative of the alpha allocated to the analysis. The overall study-wise alpha is 0.05, but 
particular analyses may have alpha less than 0.05.  
STAGE 1: 
Hypothesis tests for A-study are as follows: 
The first set of hypotheses to be tested is as follows: 
• H01: µ(ADAS-cog, azeliragon, A-study)= µ(ADAS-cog, P, A-study) 
• H11: µ(ADAS-cog, azeliragon, A-study) ≠ µ(ADAS-cog, P, A-study), 
where µ(ADAS-cog, azeliragonTTP488, A-study) and µ(ADAS-cog, P, A-study) denote the true mean changes 
from Baseline at Month 18 on the ADAS-cog total score for the A-study azeliragon 5 
mg/day added to SoC and placebo added to SoC groups, respectively. 
The second set of hypotheses to be tested is as follows: 
• H02: µ(CDR-sb, azeliragon, A-study)= µ(CDR-sb, P, A-study) 


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• H12: µ(CDR-sb, azeliragon, A-study) ≠ µ(CDR-sb, P, A-study). 
where µ(CDR-sb, azeliragon, A-study) and µ(CDR-sb, P, A-study) denote the true mean changes from 
Baseline at Month 18 on the CDR-sb score for the A-study azeliragon 5 mg/day and 
placebo groups, respectively. 
Hypothesis tests for B-study are as follows: 
The first set of hypotheses to be tested in B-study (the third set of hypotheses for the 
study as a whole) is as follows: 
• H03: µ
(ADAS-cog, azeliragon, B-study)
= µ
(ADAS-cog, P, B-study) 
• H13: µ
(ADAS-cog, azeliragon, B-study) ≠ µ
(ADAS-cog, P, B-study), 
where µ(ADAS-cog, azeliragon, B-study) and µ(ADAS-cog, P, B-study) denote the true mean changes from 
Baseline at Month 18 on the ADAS-cog total score for the B-study azeliragon 5 mg/day 
added to SoC and placebo added to SoC groups, respectively. 
The second set of hypotheses to be tested in B-study (the fourth set of hypotheses for the 
study as a whole) is as follows: 
• H04: µ(CDR-sb, azeliragon, B-study)= µ(CDR-sb, P, B-study) 
• H14: µ(CDR-sb, azeliragon, B-study) ≠ µ(CDR-sb, P, B-study). 
where µ(CDR-sb, azeliragon, B-study) and µ(CDR-sb, P, B-study) denote the true mean changes from 
Baseline at Month 18 on the CDR-sb score for the B-study azeliragon 5 mg/day and 
placebo groups, respectively. 
STAGE 2: 
If and only if both hypothesis tests in A-study AD subjects and also B-study AD subjects 
for both co-primary variables (ADAS-cog and CDR-sb) have p<0.05 (i.e., p<0.05 for 
ADAS- cog demonstrating statistical superiority of azeliragon 5 mg added to SoC versus 
placebo added to SoC and also p<0.05 for CDR-sb demonstrating statistical superiority of 
azeliragon 5 mg added to SoC versus placebo added to SoC (i.e., statistical significance 
of the test of the null hypothesis for each A-study and B-study independently), testing 
will proceed to the fifth set of hypotheses to the expansion of the population of subjects 
from A-study and B-study combined. 
Consistent with the FDA draft Guidance for Industry: Alzheimer’s Disease: Developing 
Drugs for the Treatment of Early Stage Disease (February, 2012), toward the goal of 
demonstrating disease modification, analysis of MRI data (hippocampal volume as the 
key secondary endpoint) will be done conditional on significance of the above-named 
hypothesis tests: 


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The next set of hypotheses to be tested is as follows: 
• H05: µ
MRI, azeliragon, All)
= µ
(MRI, P,All) 
• H15: µ
MRI, azeliragon, All) ≠ µ
(MRI, P,All), 
where µ(MRI, azeliragon, Alld) and µ(MRI, P,All) denote the true mean changes from Baseline at 
Month 18 on MRI volume measures for all AD azeliragon 5 mg/day and placebo groups, 
respectively. 
STAGE 3: 
If all hypotheses defined in both Stage 1 and Stage 2 demonstrate statistical superiority of 
azeliragon TTP488 5 mg added to SoC versus placebo added to SoC, the secondary 
efficacy endpoints will be tested in hierarchical order.  The order of testing is defined in 
Section 4.1 (efficacy variables).  The outline of the hierarchical testing is: 
• First, the secondary endpoint ranked as #1 will be compared between azeliragon 
TTP488 5 mg added to SoC versus placebo added to SoC in the study as a whole 
(study A and study B combined).  If p<0.05, statistical significance will be 
declared. 
 
• Secondly, if the secondary endpoint ranked as #1 showed a statistically significant 
difference, the secondary endpoint ranked as #2 will be compared between 
azeliragon 5 mg added to SoC versus placebo added to SoC in the study as a 
whole (study A and study B combined).  If p<0.05, statistical significance will be 
declared. 
The hierarchical testing will continue with the consecutive secondary endpoints, as long 
as the previous secondary endpoint is declared as statistically significant. 
 


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3 
Populations of Analysis  
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (1998), the following data sets will be used for all 
statistical analysis: 
• The full analysis set (FAS) includes all randomized subjects who receive any study 
medication and have at least one post-Baseline. 
• The per protocol set (PPS) includes all subjects in the FAS who receive at least 6 months 
of study drug and attend at least 6 scheduled visits, except for those who are excluded 
because of major protocol violations, where a major protocol violation is one that may 
affect the interpretation of study results (e.g., non-compliance with study medication 
requirements as evaluated using TTP488 plasma concentration below the limit of 
quantification at last study visit during 18-month treatment period).  The intended 
criterion of “6 scheduled visits” includes screening and baseline and at least 4 scheduled 
clinic visits after first dose of study medication.  
Final determinations of the PPS will be made at the masked data review meeting 
(BDRM) held in accordance with ICH E9 prior to the lock data.  The complete 
specification (made blinded to treatment arm) will be documented in the minutes to the 
blind data review meeting held prior to lock the data.  
• The safety set (SAF) includes all subjects who receive any study medication. 
For the purpose of understanding the influence of dropouts on study conclusions, the FAS will be 
partitioned into subjects who complete (completers) and subjects who do not complete 
(dropouts).  For purposes of this study, a subject is a completer if the subject has received 
treatment for 18 months and has efficacy data for 18 months (evaluation is made at the endpoint 
level, so if a subject is missing ADAS-cog at Month 18 but has CDR-sb at Month 18, this subject 
is included in analyses for which the data are available). 
It is noted that if the FAS and PPS do not differ by more than 15% in numbers of individuals, 
analysis may be limited to the FAS (ITT analysis), and the PP analysis will not be conducted. 
 
 


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4 
Variables of Analysis  
4.1    Efficacy Variables 
Efficacy evaluation will include the co-primary endpoints (ADAS-cog and CDR-sb), key 
secondary measures, and other efficacy markers.  
4.1.1    Primary Efficacy Variable 
The primary analysis will include assessment of the following variables of analysis.  
• Mean change from Baseline to Month 18 in ADAS-cog 
• Mean change from Baseline to Month 18 in CDR-sb. 
Key supportive variables will include mean change from Baseline to all other Visits in ADAS-
cog and mean change from Baseline to all other Visits in CDR-sb.  Time to threshold worsening 
will be done as supportive analyses for change in ADAS-cog with thresholds of 7 points as an 
indicator of progression, with other cut-points from 1 to 20 as exploratory.   
4.1.2    Key Secondary Variables of Analysis (Imaging) 
The key secondary endpoint is: 
• Change from Baseline in hippocampal volume at Month 18. 
PET variables are considered to be exploratory and will be defined separately. 
4.1.3    Secondary Variables 
The following secondary efficacy endpoints will be evaluated in hierarchical order: 
• Secondary endpoint ranked as #1: The change from baseline to final visit in the ADCS-
ADL scale through Month 18. 
• Secondary endpoint ranked as #2: Change from Baseline in the Neuropsychiatric 
Inventory (NPI) total score at Month 18. 
• Secondary endpoint ranked as #3: The change from baseline to final visit in the 
Mini-Mental State Examination (MMSE) through Month 18. 
• Secondary endpoint ranked as #4: Change from Baseline on the Trail Making Test Version 
A time at Month 18. 
• Secondary endpoint ranked as #5: Change from Baseline on the Trail Making Test Version 
B time at Month 18. 
• Secondary endpoint ranked as #6: Change from Baseline on the Continuous Oral Word 
Association Task (COWAT) score at Month 18. 
• Secondary endpoint ranked as #7: Change from Baseline on the Category Fluency Test 
(CFT) score at Month 18. 


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• Secondary endpoint ranked as # 8: Change from Baseline in the Dementia Quality of Life 
(DEMQOL) -Proxy total score at Month 18. 
4.1.4    Other Efficacy Variables of Analysis 
Additional efficacy variables of analysis are as follows: 
• Responder analysis at Months 3, 6, 9, 12, 15 and 18 based on ADAS-cog (increase from 
baseline of 7 points or more) and responder analysis at Months 3, 6, 12, and 18 based on 
the CDR-sb (increase from baseline of 1 point or more).  It is noted that a responder is a 
subject who has not declined, and thresholds are used for classification of having 
declined. 
 
• Change from Baseline in ventricular volume at Month 18. 
 
• Change from Baseline in whole brain volume at Month 18. 
 
• Time to loss of one global stage on the Clinical Dementia Rating (CDR) score through 
Month 18. 
 
• Change from Baseline on the ADAS-cog at Months 3, 6, 9, 12 and 15 and at Months 3, 6 
and 12 for the CDR-sb and CDR subscale scores. 
 
• Individual item responses on the Resource Utilization in Dementia (RUD) questionnaire 
and the total caregiver time spent assisting the patient based on the RUD at Months 6, 12, 
and 18. 
 
• Proportion of participants who enter intermediate or long-term residential care (RUD) at 
Months 6, 12, and 18. 
 
• Change from Baseline in the Dementia Quality of Life (DEMQOL) - Proxy total score at 
Months 6 and 12. 
 
• Change from Baseline in the Neuropsychiatric Inventory (NPI) total score and subscale 
scores at Months 3, 6 and 12. 
 
• Change from Baseline on the Mini-mental State Examination (MMSE) total score at 
Months 3, 6 and 12. 
 
• Change from Baseline on the Continuous Oral Word Association Task (COWAT) score 
at Months 3, 6 and 12. 
 
• Change from Baseline on the Category Fluency Test (CFT) score at Months 3, 6 and 12. 
 
• Change from Baseline on the Trail Making Test (Versions A and B) time at Months 3, 6 
and 12. 


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• Change from Baseline in the extent of brain glucose hypometabolism at Month 18. 
 
• Change from Baseline in the severity of brain glucose hypometabolism at Month 18 
4.1.5    Efficacy Scales 
The following instruments that are used in this study are subject to statistical analysis: 
4.1.5.1    Alzheimer's Disease Assessment Scale - Cognitive Subscale 70 point (ADAS-
cog):  
• Range: The scale range is 0 to 70 with higher scores indicating greater cognitive 
impairment.  
• Brief description: The ADAS-cog is a structured scale (approximately 40 minutes to 
complete) that evaluates memory, orientation, attention, reasoning, language and 
constructional praxis (Rosen, 1984).  The ADAS-cog scoring range for the version used in 
this study is from 0 to 70.  The ADAS-cog will be conducted at Baseline and at Months 3, 
6, 9, 12, 15 and 18 or in the event of early termination.  The ADAS-cog should always be 
administered prior to other cognitive measures.  
4.1.5.2    Mini Mental State Examination (MMSE):  
• Range: The scale range is 0 to 30 with lower scores indicating greater cognitive 
impairment.  
• Brief description: The MMSE is a brief 30-point test that is used to assess cognition 
(Folstein, 1975).  It is commonly used to screen for dementia.  In the time span of 
about 10 minutes, it samples various functions, including arithmetic, memory and 
orientation.  The MMSE will be administered at Screening, Baseline, and at 
Months 3, 6, 12 and 18 or in the event of early termination.  Participants with scores 
of 21-26 will be eligible for participation in the study. 
4.1.5.3    Controlled Oral Word Association Test (COWAT): 
• Range: The score is the number of correct words.  Lower numbers are associated with 
greater impairment. 
• Brief description: The COWAT is a measure of verbal fluency in which the 
participant is asked to generate orally as many words as possible that begin with the 
letters “F”, “A”, and “S”, excluding proper names and different forms of the same 
word (Borkowski, 1967, Loonstra 2001).  For each letter, the participant is allowed 
one minute to generate the words.   A comparable form of the test includes use of 
“C”, “F” and “L,” which may be used at alternate visits to reduce practice effect due 
to longitudinal testing on this task.   Performance is measured by the total number of 
correct words produced summed across the three letters.  Perseverations (i.e., 


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repetitions of a correct word) and intrusions (i.e., words not beginning with the 
designated letter) are noted.  Although fluency tests are sensitive to language 
dysfunction and deterioration of semantic knowledge, they can also reflect an 
inability to initiate systematic retrieval of information in semantic storage.   
4.1.5.4    Category Fluency Task (CFT):   
• Range: The score is the number of acceptable words produced.  Lower numbers are 
associated with greater impairment. 
 
• Brief description: The Category Fluency Test (CFT) is a measure of the subject’s 
working memory and executive function.  The CFT evaluates the spontaneous 
production of words beginning with a given letter, or of a given category, within 60 
seconds.  In this study, the participant is asked to orally produce as many animals as 
possible in one minute.  Performance is measured by the number of acceptable words 
produced. 
4.1.5.5    Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale (ADCS-
ADL):   
• Range: The scale range is 0-78, with lower scores indicating greater impairment.  
• Brief description: The ADCS-ADL is an activity of daily living inventory developed 
by the ADCS to assess functional performance in participants with AD (Galasko et 
al., 1997).  Informants are queried via a structured interview format as to whether 
participants attempted each item in the inventory during the preceding 4 weeks, as 
well as their level of performance.  The ADCS-ADL will be administered at Baseline, 
and at Months 3, 6, 12 and 18 or in the event of early termination. 
4.1.5.6    Clinical Dementia Rating Scale (CDR):  
• Global CDR Range: 
o 0 = normal; healthy individuals 
o 0.5 = questionable dementia 
o 1 = mild dementia 
o 2 = moderate dementia 
o 3 = severe dementia. 
• CDR sum-of-boxes (CDR-sb) range:  CDR-sb scores range from 0 to 18 with higher 
scores indicating greater cognitive impairment.     
• Brief description: The CDR scale is used as a global measure of dementia and is 
completed by a clinician in the setting of detailed knowledge of the individual patient 
collected from interviews with the patient and caregiver (Berg, 1988).  The CDR 
describes 5 degrees of impairment in performance on each of 6 categories including 
memory, orientation, judgment and problem solving, community affairs, home and 
hobbies, and personal care.  Much of the information will therefore already have been 


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gathered, either as part of normal clinical practice or as part of a research study.  The 
interview takes approximately 40 minutes to administer.   
The scores for each category can also be summed and this is known as the sum of box 
score (CSR-SB).  The CDR will be conducted at Baseline and at Months 3, 6, 12 and 
18 or in the event of early termination.  To avoid patient fatigue, the CDR should be 
performed on a separate visit day than the other cognitive tests.  
4.1.5.7    Neuropsychiatric Inventory (NPI):  
• Range: Scores range from 0-144 with higher scores indicating a greater presence of 
neuropsychiatric symptoms.   
• Brief description: The NPI is a well-validated, reliable, multi-item instrument to 
assess psychopathology in AD based on an interview with the caregiver (Cummings 
et al, 1994, Cummings, 1997).  The interview is also relatively brief (15 minutes).  It 
evaluates both the frequency and severity of 12 behavioral areas including delusions, 
hallucinations, dysphoria (depression) anxiety, agitation/aggression, euphoria, 
disinhibition, irritability, lability, apathy, aberrant motor behavior, appetite and eating 
changes and night-time behaviors.   
Frequency assessments range from 1 (occasionally, less than once per week) to 
4 (very frequently, once or more per day or continuously) as well as severity (1= 
mild, 2 = moderate, 3 = severe).   
Distress is rated by the study partner or caregiver and ranges from 0 (no distress) to 5 
(very severe or extreme).  Distress is captured separately from the total score.  
The overall score and the score for each subscale are the product of severity and 
frequency.  The NPI will be administered at Screening, Baseline, and at Months 3, 6, 
12 and 18 or in the event of early termination. 
4.1.5.8    Resource Utilization in Dementia (RUD):  
• Resource questionnaire with limited statistical evaluation as an instrument.  
• Brief description: The RUD is a validated and reliable questionnaire which assesses 
the health care resource utilization (HCRU) of the patient and caregiver and measures 
the level of formal and informal care (Wimo et al, 2012).  The RUD consists of items 
about caregiver time, caregiver work status, caregiver HCRU (e.g., hospitalization, 
ER visits, health care professional visits and medication), patient living 
accommodation, and patient HCRU.  It takes approximately 15-20 minutes to 
complete and is usually interview administered by any health care professional.  This 
scale will be administered at Baseline and at Months 6, 12 and 18 or in the event of 
early termination.  


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4.1.5.9    Dementia Quality of Life (DEMQOL) – Proxy:  
• Range: The scale range is 31—124, with lower scores indicate greater impairment. 
• Brief description: The DEMQOL-Proxy questionnaire is a validated and reliable 
questionnaire that is interview administered and completed by the caregiver about the 
patient’s health related quality of life (Smith et al, 2005).  It consists of 31 items 
representing 5 domains (daily activities and looking after oneself, health and 
well-being, cognitive functioning, social relationships, and self-concept) and takes 
approximately 20 minutes to complete.  Higher scores indicate better health-related 
quality of life.  This scale will be administered at Baseline and at Months 6, 12 and 18 
or in the event of early termination.  Item 32 is a global quality of life question that 
elicits an overall assessment of the patient’s general quality of life. 
4.1.5.10    Trail-making Tests (TMT) “A” and “B”:  
• Range: 150 seconds maximum for “A” and 300 seconds maximum for “B.” 
• Brief description: The Trail-making tests “A” and “B” score is the number of seconds 
needed to complete the trails with maximum values specified (Reitan, 1958).  Part A 
consists of 25 circles numbered 1 through 25 semi-randomly distributed over a white 
sheet of 8 1/2" X 11" paper.  The participant is instructed to connect the circles with a 
pencil line as quickly as possible in ascending numerical order.  Part B also consists 
of 25 circles, but these circles are either numbered (1 through 13) or contain letters (A 
through L).  Now the participant must connect the circles while alternating between 
numbers and letters in an ascending order (e.g., A to 1; 1 to B; B to 2; 2 to C).  Lower 
scores (seconds) indicate greater cognitive function. 
4.2    Safety Variables 
Safety is monitored in this study by collection of adverse events, vital signs, electrocardiography, 
and clinical laboratory measures.  It is noted that all untoward events or experiences are reported 
as adverse events regardless of whether they are identified by clinical observation, subject 
reporting, physical examination, clinical laboratory test result, electrocardiography, or any other 
examination or test.  It is noted that listings of vital signs, laboratory data, electrocardiograms 
(ECG), and all safety data from all other sources are reviewed by medically qualified individuals 
to ensure that safety signals are identified and reported in the analysis of the safety data from this 
study.  
4.2.1    Treatment-emergent Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 16.0 or above.  Adverse event coding will be done to the lowest level term (LLT).  
Adverse events will be summarized by System Organ Class (SOC) and preferred terms (PT).   
Definitions:  


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• A treatment-emergent adverse event (TEAE) is an event that is observed or reported after 
administration of study medication that was not present prior to study medication 
administration or an event that represents the exacerbation of a pre-existing event.   
• An adverse withdrawal is a subject who withdrew from the study due to an adverse event. 
• A serious adverse event (SAE) is an AE that is classified as serious according to the 
criteria specified in the study protocol. 
Safety and tolerability variables based on adverse events include the following: 
• Proportions of subjects with TEAEs by Preferred Term and decreasing frequency of AEs 
• Proportions of subjects with TEAEs by System Organ Class and Preferred Term 
• Proportions of subjects with related TEAEs 
• Proportions of subjects with severe TEAEs 
• Proportions of subjects who died. 
• Proportions of subjects with treatment-emergent SAEs other than death. 
• Subjects with TEAEs that result in study termination. 
4.2.2    The Columbia Suicide Severity Rating Scale (C-SSRS) 
• Range: The following outcomes are C-SSRS categories and have binary responses 
(yes/no). The categories have been re-ordered from the actual scale to facilitate the 
definitions of the composite and comparative endpoints, and to enable clarity in the 
presentation of the results.  
o Category 1 – Wish to be Dead  
o Category 2 – Non-specific Active Suicidal Thoughts  
o Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent 
to Act  
o Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan  
o Category 5 – Active Suicidal Ideation with Specific Plan and Intent  
o Category 6 – Preparatory Acts or Behavior  
o Category 7 – Aborted Attempt 
o Category 8 – Interrupted Attempt  
o Category 9 – Actual Attempt (non-fatal)  
o Category 10 – Completed Suicide 
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not 
suicide-related) and has a binary response (yes/no).  
The following outcome is a numerical score derived from the C-SSRS categories. The 
score is created at each assessment for each patient and is used for determining treatment 
emergence.  
 


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Suicidal Ideation Score: The maximum suicidal ideation category (1-5 on the C-SSRS) 
present at the assessment. Assign a score of 0 if no ideation is present.  
 
• Brief description: The Columbia Suicide Severity Rating Scale (C-SSRS) is a joint 
interview with the caregiver and patient that systemically assesses suicidal ideation 
and suicidal behavior (Posner et al, 2007).  This scale will be administered at 
Screening Visit to evaluate life time suicide attempt, suicide behaviors, and other 
non-suicidal self-injuries.  Positive responses on the C-SSRS will be mapped to the 
Columbia Classification Algorithm of Suicide Assessment (C-CASA) for 
classification and reporting using a standard algorithm.) 
4.2.3    Vital Signs 
Vital signs measurements consist of blood pressure and pulse rate. Variables of analysis will 
include means, mean changes over time, and proportions of subjects meeting criteria for 
potential clinical concern in vital signs: 
• Mean and mean changes in systolic and diastolic blood pressures  
• Mean and mean changes in pulse 
• Proportions of subjects with treatment-emergent values or changes of potential clinical 
concern. 
4.2.4    Clinical laboratory assessments 
Routine clinical laboratory data will be summarized with descriptive statistics on assessment 
values and change from Baseline.  Routine clinical laboratory data will also be evaluated on the 
basis of laboratory-defined reference ranges and criteria defining potential clinical concern for 
values or changes, as defined in this document (Section 10).  Routinely collected laboratory 
safety data that are not required by the protocol will be considered source data, and will not be 
captured for inclusion into the study database.   
  Definition:  
• A treatment-emergent abnormal value (TEAV) is a laboratory value that is abnormal after 
administration of study medication that was normal prior to study medication 
administration.   
• A TEAV of potential clinical concern is a value or change that meets criteria specified in 
this SAP in Section 10. 
Laboratory analytes in this study include: 
• 
Hematology 
o Hemoglobin 
o Hematocrit 
o Erythrocyte (RBC) count 
o Platelet count 
o Total leukocyte (WBC) count 


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o MCV 
o Leukocyte differential (percent and total) 
 
Total neutrophils  
 
Eosinophils 
 
Monocytes  
 
Basophils 
 
Lymphocytes 
• 
Clinical chemistry 
o BUN 
o Creatinine 
o Glucose 
o HbA1c 
o Calcium 
o Sodium 
o Potassium  
o Chloride 
o Bicarbonate 
o AST 
o ALT 
o GGT 
o LDH 
o Total bilirubin 
o Alkaline phosphatase 
o Uric acid 
o Albumin 
o Total protein 
o Phosphorus 
Safety variables of analysis include: 
• Subjects with TEAVs 
• Subjects with TEAVs of potential clinical concern (based on criteria in this SAP) 
• Subjects with a TEAV in a liver enzyme function test (LFT). 
4.2.5    Brain MRI: Safety 
MRI scans will be performed at Screening and Month 18 or in the event of early termination. 
The primary intent of the MRI assessments was to support eligibility for the trial and key 
secondary objectives of evaluating the effect of TTP488 on MRI brain volumetric measures.    
Variables of analysis will include number (%) of subjects with: 
• Presence of vasogenic edema as categorized as: 
o No vasogenic edema present;  
o Questionable presence of vasogenic edema;  
o Vasogenic edema present, mild severity;  
o Vasogenic edema, moderate severity,  
o Vasogenic edema present, severe severity.   


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• The status of vasogenic edema at Month 18 compared to baseline will be evaluated as 
the number (%) of subjects categorized as vasogenic edema either present or absent 
on prior MRI; if present, further categorized as: 
o Vasogenic edema present and unchanged in size,  
o Vasogenic edema present and increased in size,  
o Vasogenic edema present and decreased in size.     
4.3    Pharmacokinetics Variables 
Blood samples for TTP488 and metabolite (TTP2123, TTP1494, TTP2266) plasma 
concentrations will be collected prior to dosing at Months 3, 6, 12, 18 and 21 or at Early 
Termination. All participants with at least one dose of study medication will be included in the 
pharmacokinetic analysis.   Variable of analysis will be plasma trough concentration at each time 
point.         
4.4    Pharmacodynamics Variables 
Blood samples for plasma biomarkers analysis will be collected prior to dosing on Baseline, 
Months 3, 6, 12, 18, 21 or at Early Termination.    
All participants with at least one dose of study medication will be included in the 
pharmacodynamic analyses.  For individual endpoints, participants must have at least 1 post-dose 
pharmacodynamic measurement for the given endpoint.  For change from Baseline, participants 
must also have a Baseline value.  Variables of analysis will be Plasma Aβ (total, 1-40 and 1-42) 
concentration and change from baseline over time.   
4.5    Adverse Events of Special Interest 
Adverse events related to signs and symptoms of AD potentially pertain to efficacy as well as 
safety of the compound.  Analysis of prior study data suggest the potential abatement of the signs 
and symptoms of AD that are associated with worsening of AD.  Specifically, TEAEs classified 
by MedDRA into the SOC for psychiatric disorders (at the SOC level within the hierarchy of 
MedDRA) and specifically high level group terms (HLGTs) of anxiety disorders and symptoms 
(at the HLGT level within the hierarchy of MedDRA) will be variables of interest for 
comparison. 
Standardized MedDRA queries (SMQs) will be used for dynamic analysis of any TEAE that 
emerges of potential interest. 
 
 


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5 
Statistical Methodology  
General statistical methods will be applied as appropriate for out-patient clinical studies. Safety 
evaluations will rely on descriptive statistics.  Randomization groups will be examined for 
homogeneity between treatment groups.  
Continuous variables will be summarized using mean, median, standard deviation, minimum, 
maximum, and number of subjects available for analysis.  Categorical variables will be 
summarized using frequency, proportion, and number of subjects available for analysis.  
The primary analysis is completely specified in the protocol, and that analysis is the intended 
analysis to be advanced as primary.  Additionally, supportive analyses, sensitivity analyses, and 
secondary analyses will be done with respect to the primary endpoint.  
SAS version 9.3 or later will be used.  
5.1 
Pooling of Investigator Sites 
Blind data review (recommended by ICH E9) has revealed many sites with few subjects 
randomized. Understanding the influence of site effects on analysis conclusions is essential. 
Analysis by site is recommended in ICH E9 for key variables of analysis. Site pools are defined 
as follows: 
• Sites with 12 or more subjects randomized will stand alone 
• Sites with exactly 11 subjects randomized will be pooled together for Pool 11 
• Sites with exactly 10 subjects randomized will be pooled together for Pool 10 
• Sites with exactly 9 subjects randomized will be pooled together for Pool 9 
• Sites with exactly 8 subjects randomized will be pooled together for Pool 8 
• Sites with exactly 7 subjects randomized will be pooled together for Pool 7 
• Sites with exactly 6 subjects randomized will be pooled together for Pool 6 
• Sites with exactly 5 subjects randomized will be pooled together for Pool 5 
• Sites with exactly 4 subjects randomized will be pooled together for Pool 4 
• Sites with exactly 3 subjects randomized will be pooled together for Pool 3 
• Sites with exactly 2 subjects randomized will be pooled together for Pool 2 
• Sites with a single subject randomized will be pooled together for Pool 1. 
Site or site pool will be included in analysis and displays using site or site pool as defined above. 
Forest plots will be generated by site to the extent feasible to describe key results by site. 
5.2    Statistical Methodology for Efficacy Analysis 
Efficacy evaluations will include the co-primary endpoints (ADAS-cog and CDR-sb), key 
secondary endpoint, secondary endpoints and other efficacy variables. 


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The primary analysis of efficacy endpoints will be done on the FAS with supportive and 
sensitivity analyses done to examine robustness against analysis assumptions and handling of 
missing data.   
Statistical analysis will be done on the A-study and the B-study, independently, for the co- 
primary variables: change from baseline in ADAS-cog and change from baseline in CDR-sb. 
The A-study includes the first approximately 400 patients randomized, and the B-study includes 
the remaining approximately 400 patients randomized.  For all other secondary variables and 
subgroup analyses, the study as a whole (A-study and B-study combined) will be used for 
inferential purposes.  It is noted that randomization supports independent analysis of A-study and 
B-study. 
The primary analysis will be done for the A-study and the B-study separately, and each will use 
alpha = 0.049, which includes an adjustment of 0.001 for interim analyses performed by the 
Independent Data Monitoring Committee (IDMC), thereby preserving the overall study-wise 
alpha = 0.05. 
This study is randomized using site randomization; the study randomization also includes a 
randomization stratum for severity of AD using a cut-point of 19 on the ADAS-cog at the time of 
randomization (screening values are used, due to the expectation that a confirming evaluation 
would be done).  Efficacy analyses will be done including randomization stratum as a main 
effect. 
5.2.1    Statistical Methodology for Primary Efficacy Analysis 
The primary analysis will done on change from baseline in ADAS-cog and on change from 
baseline in CDR-sb.  
The primary analysis will use the ITT methodology and a main-effects (for covariates) 
mixed-models for repeated measures (MMRM) methodology. The MMRM will utilize an 
unstructured covariance where the number of parameters is “t(t+1)/2” where “t” is the dimension 
of the covariance matrix, using PROC MIXED in SAS.  In the unlikely event of lack of 
convergence, Toeplitz structure will be employed where the number of parameters is “t” where 
“t” is the dimension of the covariance matrix. Time is considered as a class variable. Analysis 
will include treatment, time, treatment-by-time interaction, Baseline as covariate, and baseline 
stratum as a covariate, and subject as a random effect (acknowledging that subject is a source of 
random variation). This method provides the primary treatment comparison at Month 18. 
Supportive modeling will also include MMRM main-effects model with treatment, time, and 
subject. 
The primary analysis will also be done on randomization stratification subgroups defined by (1) 
baseline ADAS-cog 19 or less and (2) baseline ADAS-cog more than 19. 
Multiple imputations (MI) will be used as an alternative for coping with missing data as 
supportive analyses with 100 invocations (acknowledging that more invocations are needed with 
more missing data). Monte Carlo methods are planned.  
The MI analysis assuming Missing at Random (MAR) will be done as follows:  


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• First, for patients with intermittent missing values, before performing the MI, a monotone 
missingness pattern will be created. Intermittent missing values will be imputed using the 
Markov Chain Monte Carlo (MCMC) methodology which assumes a multivariate normal 
distribution over all variables included in the imputation model. The imputation model 
will be performed by treatment group and will include age, sex, ApoE status, education 
level, body weight (or BMI), baseline stratum, baseline and observed values at Months 3, 
6, 9, 12, 15 and 18. Months 9 and 12 are not included in the model for endpoints which 
were not scheduled to assessed at those visits. The MI procedure in SAS will be used for 
this purpose and this first MI step is planned to be repeated 100 times, creating several 
different datasets with a monotone missing data structure.  A unique seed value will be 
used in the MI procedure and document to allow for replication.  The imputation is based 
on the missing at random (MAR) assumption, i.e. the missing data are assumed to follow 
the same model as the other patients in their respective treatment arm.  
• After this, the remaining missing data will be imputed using a method for monotone 
missingness, also based on the MAR assumption. Thus, for each of the 100 created 
datasets with a monotone missing data pattern, the MI procedure in SAS will used to 
impute missing values based on a sequential procedure reflecting the monotone missing 
data pattern. A seed value of 446786 will be used for this second invocation of the MI 
procedure. Patients with the first missing value occurring at Month 3 will have their 
missing Month 3 value replaced by an imputed value from a regression model by 
treatment group with age, sex, ApoE status, education level, BMI, baseline stratum, and 
baseline as potentially predictive variables.  
• In the next step, patients with the first missing value occurring at Month 6 will have their 
missing Month 6 value replaced by an imputed value from a regression model with 
Month 3 data, in addition to the variables listed above. 
• The same procedure will be repeated for all other visits. 
• The imputed datasets generated with the approach described above do contain only non-
missing values and are used as input in the model for the supportive analysis of the 
primary endpoint. MMRM models similar to what are described above will thus be run 
on each of the generated imputed datasets and the difference between the treatment 
groups at Month 18 will be estimated. The MMRM model will be similar to the primary 
analysis. Finally, the MIANALYZE procedure in SAS will be applied to combine the 
results from these several datasets to derive an overall estimate of the treatment 
difference at Month 18. In addition to the estimates, corresponding 95% confidence 
intervals and p-values will be calculated. 
Another MI analysis will be performed with the assumption that the data in the active treatment 
group are missing not at random (MNAR).  A tipping point-based assumption will be used, i.e. 
the trajectories of the patients in the active treatment group after withdrawal are assumed to be 
worse by an amount of delta.  After the MI using the MAR assumption, as defined above has 
been done, the amount of delta will be added to each imputed value in the active treatment 
group.  Successively harsher deltas will be imposed on the imputed values in the active group, 
starting with an ADAS-cog increment (worsening) of 0.25 points or a CDR-sb increment 


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(worsening) of 0.1 points.  The delta is further increased in the steps of 0.25 points (e.g., 0.50. 
0.75) for ADAS-cog or in the steps of 0.1 points (e.g., 0.2, 0.3) for CDR-sb until the statistical 
significance is lost, i.e., until the p-value becomes more than 0.049.  For the placebo group, the 
MI using MAR assumption will be used. 
Further MI analysis assuming MNAR will be done using the Copy Reference approach.  
Placebo-group based assumption will be used, i.e. the trajectories of the patients are assumed to 
follow the placebo group after the discontinuation.  Methods similar to those described above 
will be used to generate monotone missing data.  After this, the missing data will be imputed 
sequentially for each visit (e.g., Month 3, Month 6).  Only the data from the placebo group will 
be used for the imputation. 
For the ANCOVA models, data from baseline and Month 18 will be used.  Analysis will include 
treatment, baseline stratum as fixed factors and Baseline as covariate.  For the LOCF analysis, 
the last available measurement will be used to impute the Month 18 data in case of missing data. 
Rank analogues (e.g., Wilcoxon analysis, rank ANCOVA, and van Elteren analysis when strata 
are a part of the approach) will be used for additional supportive analyses.  An observed-cases 
analysis will be done by visit. 
An essential component of the thorough analysis includes an assessment of the impact of missing 
data on study conclusions.  As a part of assessing this impact, sensitivity analysis will include an 
endpoint analysis (reduction to last-observation-carried-forward, justified in this study based on 
the monotonic progression of the natural course of AD and assuming no more dropouts in the 
group treated with azeliragon plus SoC than in the group treated with placebo plus SoC), a 
completers analysis (observed cases at Month 18), and observed cases by assessment time. 
Interaction terms will be examined in the supportive analyses.  The primary model will not 
include interaction terms with covariates. In the event of a significant interaction term, the 
impact on analysis conclusion will be examined.  A key sensitivity analysis will use the ITT 
methodology and a main-effects model for ANCOVA adjusting for baseline ADAS-cog (CDR-
sb) using last-observation-carried-forward (LOCF) methods for missing data, justified based on 
known profiles of ADAS-cog (CDR-sb) in AD patients, which is conservative under the 
assumption that there are not more dropouts in the active-treated group than the placebo group.  
Rank ANCOVA will be done as a supportive analysis. 
Additional unplanned sensitivity analyses may be performed. 
Descriptive summaries will be produced of the observed values and change from Baseline in co-
primary variables by treatment group at each individual time point and at endpoint (final on-
treatment assessment for each subject). 
For statistical analyses, 95% confidence intervals will be produced for the least-squares means 
(LSM) in each treatment group, as well as the LSM differences as compared to placebo plus 
SoC.  For MMRM and ANCOVA, two-sided p-values will be displayed for the comparison 
against placebo plus SoC. 


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Because there are limited numbers of subjects per center, there will inadequate power to explore 
impact of the center effect on study conclusion.  Descriptive statistics by center will be 
presented. 
The differences in the least squares means between Azeliragon and placebo, p-values, standard 
errors of the differences, and corresponding 95% confidence intervals for the differences will be 
presented.  In addition, the least-squares means and corresponding 95% confidence intervals will 
be presented for each treatment group.   
5.2.1.1    Responder Analyses 
Survival techniques will be applied to data assessing time to increase in ADAS-cog of 7 points 
(based on meta-analysis published by Vellas, et al; 2007).  For assurance that the results are not 
an artifact of the cut-point, analysis will be done for time to increases of each point from 1 to 20. 
Logrank and Wilcoxon tests will be done as descriptive analyses.  Hazard ratios will be 
examined as descriptive analyses.  
A forest plot will be produced to evaluate the sensitivity to the cut-point of the responder 
analysis. 
5.2.1.2    Other Descriptive Analysis 
Descriptive summaries will be produced of the observed values and change from Baseline in co-
primary variables by treatment group at each individual time point and at endpoint (final on-
treatment assessment for each subject). 
For statistical analyses, 95% confidence intervals will be produced for the least-squares means 
(LSM) in each treatment group, as well as the LSM differences as compared to placebo plus 
SoC.  For MMRM and ANCOVA, two-sided p-values will be displayed for the comparison 
against placebo plus SoC. 
5.2.1.3    Investigator Sites 
Because there are limited numbers of subjects per center, there is inadequate power to explore 
impact of the center effect on study conclusions.  Descriptive statistics by center or center-pool 
will be presented. 
5.2.1.4    Per Protocol Set 
If the PPS differs from the FAS by more than 15%, the analyses will be replicated on the PPS.  If 
the PPS and the FAS do not differ by more than 15%, analysis may not be done on the PPS.   
5.2.1/5    Adjustments for multiplicity 
Multiplicity of the primary efficacy analyses is controlled by using a conditional sequence of 
hypotheses.  The study will be considered to demonstrate statistical significance if the primary 
analysis has a resulting p-value less than 0.049 for both primary endpoints for both A-study and 
B-study.  No other adjustment for multiplicity is required. 


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5.2.2    Statistical Methods for Secondary Variables 
Secondary and exploratory endpoints that are measurement variables will use similar statistical 
methodology to the methodology used for primary analysis.  Stratification for A-study and B-
study will be done as for primary variables.  Efficacy variables that are proportions will be 
analyzed using Mantel-Haenszel test, controlling for Stratum, if appropriate.  For the analysis of 
the categories for responders, a Cochran-Mantel-Haenszel test will be used.  Methodologies for 
variables that are proportions will include construction of confidence intervals for each group 
and for the difference between groups.  For analysis, Fisher’s exact test will be used for single-
population analysis, and a Mantel-Haenszel test will be used for analyses combining data across 
strata.  
Responders based on the ADAS-cog total score, will be assessed using cumulative percentage 
plots.  Similarly, responders based on the CDR-sb score will be assessed using cumulative 
percentage plots.  The y-axis will show the cumulative percentage of patients who achieved the 
specific measure of improvement in the ADAS-cog (or CDR-sb) total score shown on the x-axis 
with a separate cumulative percentage curve for each treatment group. 
The proportion of participants who experience loss of one global stage on the CDR will be 
assessed at each Visit using logistic regression with treatment (as a categorical/class variable), 
and baseline CDR global score (as a continuous variable).  Summary measures from the analysis 
will include the odds ratio, 95% confidence interval for the odds ratio, and p-value for treatment 
comparison.  Additionally, the proportion of participants in each CDR global stage will be 
presented. 
Kaplan-Meier plots will be provided for each time-to-event variable.  For each day, the “survival 
probability” will be computed by the product-limit method.  Time-to-event endpoints may be 
modelled using Cox proportional hazards models with fixed effects for treatment and baseline 
measures as a covariate for supportive purposes.  The estimated hazard ratio between Azeliragon 
and placebo will be presented with associated p-values and 95% confidence intervals.  
Time to loss of one global stage on the global CDR will include Kaplan-Meier curves.  Survival 
estimates for treatment groups will be compared using the logrank statistic.  Observations will be 
treated as right censored for participants who complete the study without a loss of one stage on 
the global CDR score or who discontinue the study prematurely. 
Subgroup analyses will be done as identified subsequently; data-driven subgroup analyses may 
be done as exploratory analyses. 
For change from Baseline in plasma concentrations of Aβ species, an MMRM analysis similar to 
that described for the co-primary endpoints with baseline plasma concentrations of Aβ species as 
a continuous covariate will be performed. Transformation using logarithms may be needed, 
depending on the distribution. 
For change from Baseline in MMSE, an MMRM analysis similar to that described for the 
co-primary endpoints will be performed, with baseline MMSE as a continuous covariate.   


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For change from Baseline in NPI, an MMRM analysis similar to that described for the 
co-primary endpoints will be performed, with baseline NPI as a continuous covariate.   
Individual item responses on the RUD questionnaire and the total caregiver time spent assisting 
the patient based on the RUD questionnaire will be summarized by treatment group. 
For change from baseline in DEMQOL-Proxy total score, an ANCOVA analysis with Baseline 
DEMQOL-Proxy as a continuous covariate will be performed. 
If the distribution of any of the above parameters, key secondary, or other secondary endpoints 
does not appear to be normally distributed, the rank analogues will be utilized.  
5.2.3    Subgroup Analyses 
Subgroups will be defined based on randomization stratification and background or baseline 
characteristics. 
The following subgroup analyses are planned: 
• ApoE status: subjects will be classified according they have 1 or 2 copies of E4 (one 
group) or zero copy of E4 (one group). Efficacy analyses will be done for these 
subgroups. 
o E4=yes 
o E4=no 
 
• Randomization stratification is done on the presenting ADAS-cog value (which is the 
screening assessment, due to the intention for the score to be evaluated for validity based 
on external review of the scoring). Subgroups will be defined by the randomization 
stratum of ADAS-cog 19 or less (one group) or ADAS-cog more than 19 (one group). 
Efficacy analysis will be done for these subgroups: 
o ADAS-cog 19 or less 
o ADAS-cog more than 19 
 
• Years since diagnosis is calculated based on the date of diagnosis of AD. Subjects with 
date of diagnosis within 3 months or those with date of diagnosis more than 5 years have 
questionable status for having declining mild AD on stable medication for AD for at least 
3 months. Efficacy analysis will be done for these subgroups: 
o Years since diagnosis between 3 months and 3 years 
o Years since diagnosis between 3 years and 5 years 
o Years since diagnosis more than 5 years. 
5.2.4    MRI and PET Variables 
For imaging variables, MRI variables are specified; PET variables are considered to be 
exploratory and will be specified separately.  Statistical methodology will include stratification 
for A-study and B-study, acknowledging that the analysis of imaging data is intended to be for 


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the combined studies.  Methodology for MRI will be similar to that for other secondary variables 
of analysis.  Statistical methodology for PET variables will be described in the CSR.  
Statistical methodology will include main-effects ANCOVA on change from baseline (adjusted 
for skull size). Supportive analysis will include Rank ANCOVA.  
5.3    Disposition, Demography, and Baseline Characteristics  
A tabulation of subject disposition will be presented, including the number screened, the number 
randomized in each population group, the number dosed in each population group, the number 
who withdrew prior to completing the study, and reasons for withdrawal. 
Demographic and baseline characteristics (disease history, medical history, and prior treatments 
for AD) will be summarized for all randomized patients and for the FAS.  No formal statistical 
comparisons will be performed.  Summaries of continuous variables will include number of 
patients, mean, median, minimum, maximum, and standard deviation.  Summaries of categorical 
variables will include numbers of patients in each category.  
The variables to be summarized will include: 
• Age, gender, race, and ethnicity 
• Weight, height, BMI 
• Years since diagnosis of AD 
• Baseline MMSE  
• ApoE status 
• Education level 
• Background AD medications (ACHEI, Memantine, Both). 
5.4    Analysis of Safety Data 
5.4.1    Adverse Events 
Adverse events reported in this study will be coded using MedDRA, Version 16.0, or later. 
Coding will be to the lowest level terms (LLT). The verbatim text, the preferred term, and the 
primary system organ class (SOC) will be listed in subject listings.  Summaries that include 
frequencies and proportions of patients reporting AEs will include the preferred terms and the 
SOCs.  Summaries will include TEAEs by severity and by relationship to study medication. 
Adverse event summaries will be constructed displaying AEs in decreasing order of total 
frequency according to the numbers of subjects reporting the AE (not the number of reports).  
• Number (percent) of subjects reporting TEAE by treatment and overall in accordance 
with variables listed in Section 4.1.1.  
Supportive listings will be constructed that includes the subject identification, the treatment 
group, TEAEs, MedDRA terms, seriousness, severity, causality, elapsed time to onset, duration, 
and outcome.  


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Methodology for AESIs will follow the same methodology for TEAEs. 
5.4.2    Vital Signs 
Subjects with vital signs meeting the criteria in Section 10 of this SAP for values of potential 
clinical concern will be flagged and summarized.  Proportions of subjects with vital signs of 
potential clinical concern will be examined for the treatment groups. 
No formal inferential statistics will be applied to the vital signs data. 
For each post-Baseline assessment, descriptive statistics are provided for the assessment value 
and the change from Baseline to the assessment with mean, median, standard deviation, 
minimum, and maximum at each assessment time.  
5.4.3    Routine Clinical Laboratory Measurements 
 Because “exacerbations” of pre-existing abnormalities in laboratory analytes are examined using 
clinical judgment and are reported as TEAEs, additional analysis on TEAVs is limited to 
subjects with values that are normal prior to dosing and abnormal after dosing.  Potentially 
clinically significant abnormalities in laboratory analytes are to be reported as TEAEs and 
summarized as clinical TEAEs. 
Subjects with clinical laboratory data meeting the criteria in Section 10 of this SAP for values of 
potential clinical concern will be flagged and summarized.  Proportions of subjects with clinical 
laboratory values of potential clinical concern will be examined for the treatment groups. 
For each post-Baseline assessment, descriptive statistics are provided for the assessment value 
and the change from Baseline to the assessment with mean, median, standard deviation, 
minimum, and maximum at each assessment time.  
5.4.4    Liver Enzyme Function Tests 
Liver function tests have additional analysis views for this study in accordance with current 
regulatory guidance.  To explore the potential for drug-induced liver injury consistent with 
Guidance for Industry “Drug-induced liver injury: premarketing clinical evaluation” (CDER, 
CBER, July 2009), subjects will be summarized and listed who meet the following criteria: 
(1) Elevations in either AST or ALT of at least 3-times the upper limit of normal, and 
(2) An accompanying abnormal bilirubin of at least 2-times the upper limit of normal.  
5.4.5    Electrocardiography 
The heart rate, QT, PR, and QRS intervals will be recorded at each assessment time.  No formal 
inferential statistics will be applied to the ECG data. 
For each post-Baseline assessment, descriptive statistics are provided for the assessment value 
and the change from Baseline to the assessment with mean, median, standard deviation, 
minimum, and maximum at each assessment time.  


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In addition, the number of subjects with corrected and uncorrected QT values >500 msec will be 
summarized.  Values from individual tracings within the triplicate measurement on Day 1, time 0 
hour that are >500 msec will not be included in the categorical analysis unless the average from 
that triplicate measurement is also >500 msec. 
Electrocardiography data will be summarized by Baseline and Change from Baseline to each 
scheduled assessment time with descriptive statistics.  
Corrections to QT intervals will be made by Fridercia’s method (QTcF).  Categorical analysis 
will be done consistent with ICH E14, “Clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs” (October 2005).  
In accordance with ICH E14, subjects will be categorized and summarized as described above 
according to: 
• Absolute QTc interval prolongation: 
o QTc interval > 450 
o QTc interval > 480 
o QTc interval > 500 
• Change from Baseline in QTc interval: 
o QTc interval increases from Baseline > 30 
o QTc interval increases from Baseline > 60. 
5.4.6    Methodology for Brain MRI (Safety) Analysis 
The primary intent of the MRI assessments was to support eligibility for the trial and key 
secondary objectives of evaluating the effect of TTP488 on MRI brain volumetric measures.   In 
those subjects with MRI assessments safety evaluation was performed by a central 
neuroradiologist to evaluate presence and severity of ARIA-E (vasogenic edema), presence and 
extent of ARIA-H (microhemorrhages), presence of white matter disease, documentation of any 
other MRI abnormalities.   
ARIA-H will be evaluate based on whether microhemorrhages are present, number present, 
status compared to prior MRI, number of new microhemorrhages since previous MRI, number of 
microhemorrhages on previous MRI that have resolved, number of microhemorrhages that have 
increased in size and number that have decreased in size. 
5.5    Pharmacokinetics Analysis 
Data resulting from blood sampling for trough concentrations of TTP488 and metabolites 
(TTP2123, TTP1494, TTP2266) will be collected and analyzed for changes over the 18-month 
treatment period.   
No formal inferential statistics will be applied to the pharmacokinetic data. 


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5.6    Pharmacodynamics Analysis 
Plasma Aβ (total, 1-40 and 1-42) will be analyzed for changes over the 18-month treatment 
period.    
5.7    Exploratory Analysis 
The analyses described in this analysis plan are intended to be done.  It is noted that additional 
analyses may be done for this study.  These additional analyses may or may not be reported. 
5.8    Concomitant Medications 
Concomitant medications will be summarized by drug category and listed. 
 
 


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6 
Data Conventions 
The following analysis conventions will be used in the statistical analysis.  
6.1    Definition of Baseline 
For safety evaluations, the Baseline assessment for all measurements will be the latest available, 
valid measurement taken prior to the initiation study medication, except for electrocardiography 
(ECG) values: The Baseline assessment for ECG include a triplicate assessment with the 
baseline value intended to be the arithmetic mean of the values taken at the Baseline assessment 
that are taken in triplicate. 
6.2    Missing Data 
In general, missing clinical data will not be imputed, except where explicitly defined. In the 
event of study withdrawal, a subject’s final assessment will be used as the endpoint value, if 
applicable.  For Trail Making Test A & B, if the assessment was not done due to cognitive 
reasons, the max score would be imputed.  Note that the reason for “not-done” assessment is 
captured in the eCRF, and the specify field provides reason why.  If the reason relates to 
cognitive reasons, the maximum time for Trails A (150 seconds) or for Trails B (300 seconds) is 
used. 
Data are considered to be “on-treatment” if the assessment or collection follows the first 
administration of study medication and if the assessment occurs within 45 days following the 
final administration of study medication, justified based on the long half-life of this drug.  
Dates with missing fields will not have days imputed. 
In accordance with the recommendations of the report from the National Academy of Science 
(NAS) panel “The Prevention and Treatment of Missing Data in Clinical Trials,” (National 
Research Council, 2010), sensitivity analyses will be done to ensure that study conclusions are 
robust against missing data.  Last observation carried forward (LOCF) and baseline observation 
carried forward (BOCF) methods may be used as appropriate in sensitivity analysis.  Missing 
data types will be examined, and statistical methodologies for appropriate sensitivity analyses 
will be finalized during blind data review as patterns emerge as the study progresses. Primary 
methodologies following the ITT principle are not subject to change. 
The three types of missing data (Rubin, 1976) are considered to examine robustness of analysis 
conclusions against missingness and type of missingness:  
• MCAR (missing completely at random) assumes the event of missingness is independent 
both of observable values and of unobservable values, and the missingness is entirely at 
random. 
• MAR (missing at random) assumes that the missingness can be fully accommodated by 
accounting for variables where data are available.  


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• MNAR (missing not at random) the missingness may be related to the reason the data are 
missing. 
The robustness of analysis conclusions against missingness is managed through supportive and 
sensitivity analyses, employing techniques MAR MI for placebo and MAR MI with delta 
adjustment (jump-to-placebo) for the group randomized to TTP488 (O’Kelly and Ratitch, 
Clinical Trials with Missing Data: A Guide for Practitioners, 2014). 
6.3    Dropouts 
If a subject withdraws from the study, if the date of an adverse event is not available and a 
determination of whether or not the event is treatment emergent cannot be made, by convention 
the event will be considered to be treatment emergent. 
6.4    Visit Windows 
Assessments taken outside of protocol allowable windows will be displayed according to the 
case report form (CRF) assessment recorded by the investigator. 
6.5    Early Termination Assessments and Follow-up Assessments 
When a patient withdraws from the study prematurely for any reason, an early termination (ET) 
visit is to be performed, except in the case when a patient withdraws consent (and the protocol 
specifically states that no further data would be collected).  An ET visit should be “on 
treatment,” and efficacy data collected at the ET visit are suitable for use in statistical analysis. 
Efficacy data from an ET visit will be mapped to a scheduled visit based on the study day of the 
ET visit using the convention that the ET is mapped to the nearest scheduled visit by date. If a 
subject has more than one efficacy value for a visit, the assessment closest to the target day for 
the visit will be used for analysis.  
A follow-up visit is planned for subjects 3 months following the last dose of study medication, 
noting that subjects who roll-over into the open-label extension study will not have the follow-up 
visit, because the last day of dosing for TTP488-301 is one day before the planned first dose of 
medication under TTP488-303 (the protocol for the open-label extension study).  Data collected 
at the follow-up visit are not considered “on treatment,” and the data are not suitable for use in 
statistical analysis (as the data can be tainted by other treatments). 
6.6    Unscheduled Assessments 
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing adverse events) will be included in listings, 
but not summaries.  If more than one laboratory value is available for a given visit, the 
observation identified by the investigator to be the scheduled assessment will be used in 
summaries; all observations will be presented in listings. 
Data from unscheduled assessments will be included in longitudinal data summaries (e.g., 
minimum, maximum over time).  Data planned at scheduled times for which unscheduled 
assessments are taken will not be reflected in by-visit summaries. 


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6.7    Values Below LLQ 
Concentrations for TTP488 or metabolites below the lower limit of quantification (LLQ) for the 
assay will be set to zero, for the purpose of analysis. 
 
 
 


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7 
Analysis Deviations 
All statistical analyses and summary information will be generated according to this analysis 
plan.  Any deviation from this plan will be documented in the clinical study report.  Exploratory 
analyses are permitted per protocol; those analyses will not be considered to be deviations. 
 
 
 
 


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8 
Software 
All analyses will be done using SAS Version 9.3 or later. 
 
 


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9 
Data Displays 
The plans for displaying data will conform to this guideline and also to ICH E3 (Structure and 
Content of clinical Study Reports), and to ICH E9 (Statistical Principles for Clinical Trials). 
The following excerpt from ICH E3 (1996) applies to this SAP: 
“The guidance provided below is detailed and is intended to notify the applicant of virtually 
all of the information that should routinely be provided so that post-submission requests for 
further data clarification and analyses can be reduced as much as possible.  Nonetheless, 
specific requirements for data presentation and/or analysis may depend on specific situations, 
may evolve over time, may vary from drug class to drug class, may differ among regions and 
cannot be described in general terms; it is therefore important to refer to specific clinical 
guidelines and to discuss data presentation and analyses with the reviewing authority, 
whenever possible.  Detailed written guidance on statistical approaches is available from 
some authorities.  
“Each report should consider all of the topics described (unless clearly not relevant) although 
the specific sequence and grouping of topics may be changed if alternatives are more logical 
for a particular study” (p. 2). 
In accordance with FDA and ICH guidance, tables, figures, and key data listings are planned. 
Exploratory and data-driven data displays may also be generated.  
Planned displays will include, but are not limited to, the following: 
• Summary of Accountability (number screened, enrolled, completing, withdrawn, by 
reason; listing of withdrawals with study day and reason) 
• Summary of Demography and Background Data 
• Summary of Adverse Events  
• Summary of Adverse Events by severity and by relatedness 
• Summary of Vital Signs (change over time; criteria of potential clinical concern) 
• Summary of Laboratory Data, including LFTs (change over time, TEAV, and criteria of 
potential clinical concern) 
• Summary of PK Data 
• Summary of Plasma Amyloid-beta Data 
• Summary of Efficacy Data (ADAS-cog, CDR-sb, CDR-global, MMSE, ADCS-ADL, 
NPI) 
• Summary of MRI Data 
• Summary of PET Data 
• Listing of Demography 
• Listing of Dosing  
• Listing of all Adverse Events 
• Listing of all Adverse Events that resulted in Death 
• Listing of all Serious Adverse Events 
• Listing of all Adverse Events resulting in Study Termination 


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• Listing of Treatment-emergent Abnormal Values of Potential Clinical Concern for 
Clinical Laboratory Data 
• Listing of Vital Signs Data 
• Listing of QTc data that meet criteria of potential concern as described in ICH E14 
• Listing of Concentration Data 
• Listing of MRI safety Data 
• Listing of MRI volumetric Data 
• Listing of FDG-PET SUVR Data 
 
In addition to the data summaries and listings described above, the set of displays will include 
clinical laboratory normal ranges (with units) and also a display of the MedDRA mapping 
glossary, which will display the verbatim text as reported by the investigator, the LLT, PT, and 
SOC. 
 
 
 


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10 Values of Potential Clinical Concern 
Parameter 
Threshold (study-specific threshold calculated) 
Hematology 
 
Hemoglobin 
<8.5 g/dL 
Hematocrit 
<25 % 
WBC (Leukocytes) 
<0.6 x LLN (<2.1 10^3/uL) 
Platelets 
<0.5 x LLN (<70 10^3/uL) 
Total Neutrophils (Abs) 
<0.8 x LLN (<0.8 10^3/uL) 
 
Lymphocytes (Abs) 
<0.6 x LLN (<0.6 10^3/uL) 
Chemistry 
 
Total bilirubin 
>2.5 x ULN (>2.7 mg/dL) 
AST 
>3 x ULN (>102 U/L) 
ALT 
>3 x ULN (>123 U/L) 
Alk Phosphatase 
>3 x ULN (>348 U/L) 
Creatinine 
>2 mg/dL 
BUN 
>1.4 x ULN (30.8 mg/dL) 
Glucose 
<70 mg/dL or >270 mg/dL 
Uric acid 
>12 mg/dL 
Sodium 
<125 mmol/L or  >155mmol/L 
Potassium 
<3.0 mmol/L or >6.0 mmol/L 
Bicarbonate 
<16 mmol/L 
Calcium 
<6.0 mg/dL and  >13.0 mg/dL 
Triglycerides 
>750 mg/dL 
Electrocardiogram 
Heart Rate 
<50 bpm and >/=25% decrease from baseline 
>100 bpm and >/=25% increase from baseline 
PR interval 
≥200 msec and ≥25% increase from baseline 
QRS interval 
≥200 msec and ≥25% increase from baseline 
QTc interval 
≥500 msec 
≥30-60 msec increase 
>60 msec increase 
Vitals (sitting)   
SBP 
≥190 mmHg (entry is <180 mmHg)  
Systolic <80 mm Hg 
Decrease from baseline >30 mmHg 
 
DBP 
≥120 mmHg (entry is <105)  
<50 mm Hg 
Parameters not provided with specific thresholds for clinical concern:  RBC count, eosinophils, basophils, monocytes, direct or 
indirect bilirubin (just total as shown above), chloride, albumin, total protein, insulin, total cholesterol, HDL, LDL, urinalysis, 
pulse rate from VS (rely on ECG heart rate). 


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11 References 
• Berg, L. Clinical Dementia rating (CDR). Psychopharmacol Bull. 1988; 24:637-9. 
• Folstein, MF, Folstein, SE; McHugh, PR. Mini-mental State. A practical method for 
grading the cognitive state of participants for the clinician. Journal of Psychiatric 
Research 1975; 12:189-98. 
• Little, RJA, and Rubin, DB. (1987). Statistical analysis with missing data. New York: 
John Wiley and Sons. 
• O’Kelly, M. Ratitch, B., 2014. Clinical Trials with Missing Data: A Guide for 
Practitioners. https://books.google.com/books?isbn=1118762533 
• Rubin,l D.B. (1976, December). Inference and Missing data. Biometrika, Volume 63, 
Issue 3 (Dec., 1976), 581-592.   
• Morris, J.C., Heyman, A., Mohs, R.C., Hughes, J.P., van Belle, G., Fillenbaum, G., 
Mellitis, E.D., Clark, C. “The Consortium to Establish a Registry for Alzheimer’s 
Disease (CERAD). Part 1. Clinical and neuropsychological assessment of Alzheimer’s 
disease.” Neurology 1989; Sep; 39 (9): 1159-65. 
• Reitan R. Validity of the trail making test as an indicator of organic brain disease.  
Perceptual and Psychomotor Skills 1958; 8:271 6. 
• Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. American 
Journal of Psychiatry 1984; 141:1356-64. 
• Vellas, B., Andrieu, S., Canter, C. Dartigues, JF, Gauthier, S. Long term changes in 
ADAS-cog: what is clinically relevant for disease modifying trials in Alzheimer’s. J Nutr 
Health Aging. 2007: 11(4);338-41. 
• ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of 
clinical study reports (E3). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
• ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
clinical trials (E8). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
• ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
• CDER and CBER. (1998, May). Guidance for Industry: Providing clinical evidence of 
effectiveness for human drug and biological products. 
• ICH. (2005, October). ICH Harmonized tripartite guideline: Clinical evaluation of 
QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic 
drugs(E14). 
• International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. 
• CDER and CBER. (2009, July). Guidance for industry: “Drug-induced liver injury: 
premarketing clinical evaluation. 
• CDER and CBER. (2010, February). Draft Guidance: Adaptive design clinical trials for 
drugs and biologics. 
• CDER, Office of New Drugs. (2010, December 12). Manual of policies and procedures: 
Clinical review template. 


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• CDER, Office of Biostatistics. (2012, July 30). Manual of policies and procedures: Good 
Review Practice: Statistical Review Template. 
• CDER, CBER, and CDRH. (2012, December). Draft guidance: Enrichment strategies for 
clinical trials to support approval of human drugs and biological products. 
• CDER. (2013, February). Guidance for industry: “Alzheimer’s disease: Developing drugs 
for the treatment of early stage disease.”  
• ICH. (2015, December). E14 Implementation Working Group: ICH E14 Guideline: The 
clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for 
anon-antiarrhythmic drugs. Questions and Answers (R3).  
• ICH and MSSO. (2017, September). MedDRA Introductory Guide Version 20.1.  
 
 


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12 Schedule of Time and Events  
SCHEDULE OF ACTIVITIES  
 
Protocol Activity 
Screening Baseline 
Treatment 
Early 
Term
Follow-
upa 
Day -60 
to 
Day 0 
Day -7 
to 
Day 0 
Month
0 
Month
1 
Month
2 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Month 
15 
Month 
18 
 
Month 
21 
Study Days 
 
 
1 
30 
60 
90 
180 
270 
360 
450 
540 
 
630 
Window 
 
 
±4d 
±4d 
±4d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
 
± 7d 
Sign informed consent / provide assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Confirmation Formb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Registration/Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Drug, Alcohol, Tobacco Use History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Neuro Exam & Physical 
Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Rosen-Modified Hachinski Ischemic 
Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ApoE genotyping 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Telephone contact 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Brief Neuro & Physical Exams 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Review Concomitant Medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Pressure and Pulse Rate (supine) 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECGd 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Assessment 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study Drug 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Study Drug Dosing 
 
 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
 
 
MMSE 
X 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
Study Days 
 
 
0 
30 
60 
90 
180 
270 
360 
450 
540 
 
630 
Window 
 
 
±4d 
±4d 
±4d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
 
± 7d 
ADAS-cog 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
CDR 
X 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
NPI 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
ADCS-ADL 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
COWAT 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
CFT 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
Trail Making Test (Versions A and B) 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
Columbia Suicide Severity Scale 
(C-SSRS)c 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 


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Protocol Activity 
Screening Baseline 
Treatment 
Early 
Term
Follow-
upa 
Day -60 
to 
Day 0 
Day -7 
to 
Day 0 
Month
0 
Month
1 
Month
2 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Month 
15 
Month 
18 
 
Month 
21 
RUD Lite 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
DEMQOL-proxy 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
FSH (females only), hepatitis, VDRL, 
Thyroid function tests, Vitamin B12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Chemistry (incl HbA1c) 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Brain MRI 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Brain FDG-PET 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
Blood Sample for Plasma Retention 
and Storage 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
Pharmacokinetic Blood Sampling 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
Pharmacodynamic blood sampling 
(Aβ) 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
a 
Follow-up visit required for those participants completing the study but choosing to not participate in an open label 
extension stud y. 
b 
Following completion of Screening visit assessments but prior to scheduling baseline visit, obtain approval from the 
sponsor for the patient to participate in the study. 
c 
C-SSRS is administered to subject jointly with care-giver. 
d 
ECGs at Baseline visit performed in triplicate