Clinical trial NCT02916056
Conditions: Alzheimer's Disease
Keywords: Alzheimer's disease RAGE ADAS-cog CDR-sb
Sponsor: vTv Therapeutics
Start date: 2016-12-01; Completion date: 2018-06-01
Enrollment: 297 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label extension study in patients with mild Alzheimer's disease who have completed participation in the azeliragon Phase 3 (STEADFAST) trial. Patients will receive azeliragon 5 mg/day for up to 2 years.

Detailed description:

Arms: arm 1: Azeliragon (TTP488) 5mg orally once daily for 2 years
Interventions: intervention 1: Azeliragon 5mg
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9Aug2017 
High Point, NC 27265 
Page 1 
vTv THERAPEUTICS LLC 
 4170 MENDENHALL OAKS PKWY 
 HIGH POINT, NC 27265
TITLE PAGE 
CLINICAL TRIAL PROTOCOL
OPEN LABEL EXTENSION STUDY FOR CONTINUED SAFETY AND EFFICACY 
EVALUATION OF AZELIRAGON IN PATIENTS WITH MILD ALZHEIMER'S 
DISEASE  
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:    
TTP488-303 
Clinical Phase: 
Phase 3 
Version and Date: 
AMENDMENT 1 
9AUGUST2017
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 




Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9Aug2017 
High Point, NC 27265 
 
 
 
Page 3 
 
Document Revision History 
Document 
Version Date 
Summary of Changes 
Protocol 
Amendment 1 
09 AUG 2017 
 
Section 4.2 Exclusion Criteria 
o 3.  Clarified that “change” from the 
TTP488-301 Baseline value intended to be 
an “increase”. 
 
Section 4.3.  Added male contraceptive advice for 
fertile, sexually active males. 
 
Section 5.5.  Removed CYP3A4 inhibitors from list 
of prohibited conmeds. 
 
Section 6.1 and Section 7.1.1 and Table 1.  
Revised to allow for vitals to be collected in a 
supine or sitting position. 
 
Section 8.4.  Clarified that adverse event 
assessment of relationship to study drug falls into 
one of two categories:  related / not related. 
 
Appendix 1.  Modified Prohibited Medication List 
to remove CYP3A4 inhibitors. 
 
Editorial Changes: 
o Addition of reference in Section 1.1.1 
Original re-issue 
12 Oct 2016 
 
Editorial changes: 
o Corrected page headers to remove “draft”. 
o Added Trail Making Test (TMT) 
abbreviation 
o Added Reference 6. 
Original Protocol 
23 June 2016 
N/A 
 
 
 
 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9Aug2017 
High Point, NC 27265 
 
 
 
Page 4 
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 in patients 
with mild-to-moderate AD and even greater magnitude of benefit in patients with mild (MMSE 
21-26) AD (ADAS-cog =4.0, p<0.018; CDR-sb =1.0, p=0.02).  Thus, azeliragon has the 
potential to provide effective treatment of AD. 
Objectives: 
The primary objective of this study is: 
• To collect long-term safety and tolerability data. 
 
The secondary objectives of this study are: 
• 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 measures of behavior, cognition, function, 
resource utilization, and quality of life. 
Endpoints: 
Primary Endpoints: 
• Adverse events, clinical safety laboratory tests, ECG, vital signs. 
 
 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9Aug2017 
High Point, NC 27265 
 
 
 
Page 5 
Secondary Endpoints: 
• The slope of change over time in ADAS-cog, CDR-sb, MMSE, ADCS-ADL, and NPI 
scales. 
• Change from Baseline in measures of behavior, cognition, and function. 
Study Design: 
This is an open-label extension study in patients with mild Alzheimer’s disease who have 
completed participation in the azeliragon Phase 3 (STEADFAST) trial.   Patients will receive 
azeliragon 5 mg/day for up to 2 years. 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9 Aug 2017 
High Point, NC 27265 
 
 
 
Page 6 
SCHEDULE OF ACTIVITIES  
Table 1. 
Schedule of Activities 
 
Protocol Activity 
Baseline 
Treatment 
Early 
Term 
Month 18 of 
TTP488-301 
study 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Month 
15 
Month 
18 
Month 
21 
Month 
24 
 
Study Days 
 
90 
180 
270 
360 
450 
540 
630 
720 
 
Window 
 
±14d ±14d ±14d ±14d 
±14d 
±14d 
±14d ±14d 
 
Sign informed consent / 
provide assent   
X* 
 
 
 
 
 
 
 
 
 
Registration  
X* 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
Criteria   
X* 
 
 
 
 
 
 
 
 
 
Body weight   
X 
 
X 
 
X 
 
X 
 
X 
X 
Brief Neuro & Physical 
Exams   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review Concomitant 
Medications   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Pressure and Pulse 
Rate (sitting or supine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECG   
X 
 
X 
 
X 
 
X 
 
X 
X 
Adverse Events Assessment   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Dispensing / 
Accountability 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Dosing   
X* 
 
 
 
 
 
 
 
 
 
MMSE   
X 
 
X 
 
X 
 
X 
 
X 
X 
ADAS-cog   
X 
X 
X 
X 
X 
 
X 
 
X 
X 
CDR  
X 
 
X 
 
X 
 
X 
 
X 
X 
NPI   
X 
 
X 
 
X 
 
X 
 
X 
X 
ADCS-ADL 
X 
 
X 
 
X 
 
X 
 
X 
X 
COWAT 
X 
 
X 
 
X 
 
X 
 
X 
X 
CFT 
X 
 
X 
 
X 
 
X 
 
X 
X 
TMT 
X 
 
X 
 
X 
 
X 
 
X 
X 
Columbia Suicide Severity 
Scale (C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RUD-lite   
X 
 
X 
 
X 
 
X 
 
X 
X 
DEMQOL-proxy   
X 
 
X 
 
X 
 
X 
 
X 
X 
Hematology   
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood Chemistry  
(incl HbA1c)  
X 
 
X 
 
X 
 
X 
 
X 
X 
Pharmacokinetic Blood 
Sampling   
X 
 
X 
 
X 
 
X 
 
X 
X 
Pharmacodynamic blood 
sampling (Aβ)   
X 
 
X 
 
X 
 
X 
 
X 
X 
*procedures unique to OLE.  All other baseline procedures are required TTP488-301 Month 18 procedures and are 
not repeated as part of the TTP488-303 baseline visit. 
 
 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9 Aug 2017 
High Point, NC 27265 
 
 
 
Page 7 
TABLE OF CONTENTS
 
Page 
 
TITLE PAGE ...................................................................................................................................................1 
SIGNATURE CONFIRMATION PAGE ......................................................................................................2 
PROTOCOL SUMMARY ..............................................................................................................................4 
TABLE OF CONTENTS...................................................................................................................................7 
LIST OF TABLES ......................................................................................................................................... 10 
LIST OF ABBREVIATIONS ....................................................................................................................... 11 
1.0 
INTRODUCTION ........................................................................................................................... 13 
1.1 
BACKGROUND AND RATIONALE ............................................................................................. 13 
1.1.1 
Alzheimer’s Disease ......................................................................................................... 13 
1.1.2 
Mechanism of Action ....................................................................................................... 13 
1.1.3 
Clinical Studies ................................................................................................................. 14 
1.1.4 
Dose Selection Rationale .................................................................................................. 17 
1.1.5 
Single Reference Safety Document................................................................................... 19 
2.0 
STUDY OBJECTIVES AND ENDPOINTS.................................................................................. 20 
2.1 
OBJECTIVES ................................................................................................................................... 20 
2.2 
ENDPOINTS ..................................................................................................................................... 20 
3.0 
STUDY DESIGN ............................................................................................................................. 21 
4.0 
SUBJECT SELECTION ................................................................................................................. 22 
4.1 
INCLUSION CRITERIA .................................................................................................................. 22 
4.2 
EXCLUSION CRITERIA ................................................................................................................. 23 
4.3 
CONTRACEPTION REQUIREMENTS AND STUDY PARTICIPANT INSTRUCTION ............ 23 
4.3.1 
Males ................................................................................................................................ 23 
5.0 
STUDY TREATMENTS................................................................................................................. 25 
5.1 
RANDOMIZATION TO STUDY TREATMENT ............................................................................ 25 
5.2 
BREAKING THE BLIND ................................................................................................................ 25 
5.3 
DRUG SUPPLIES ............................................................................................................................. 25 
5.3.1 
Formulation and Packaging .............................................................................................. 25 
5.3.2 
Administration ................................................................................................................... 25 
5.3.3 
Compliance........................................................................................................................ 25 
5.4 
DRUG STORAGE AND DRUG ACCOUNTABILITY .................................................................. 26 
5.5 
CONCOMITANT MEDICATION(S) .............................................................................................. 26 
6.0 
STUDY PROCEDURES ................................................................................................................. 28 
6.1 
STUDY PERIOD .............................................................................................................................. 29 
6.1.1 
Baseline (Month 18 of TTP488-301) ................................................................................ 29 
6.1.2 
Month 3 (± 14 days) ......................................................................................................... 30 
6.1.3 
Month 6 (± 14 days) ......................................................................................................... 30 
6.1.4 
Month 9 (± 14 days) ......................................................................................................... 31 
6.1.5 
Month 12 (± 14 days)........................................................................................................ 31 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9 Aug 2017 
High Point, NC 27265 
 
TABLE OF CONTENTS (continued) 
 
Page 
 
 
 
Page 8 
6.1.6 
Month 15 (± 14 days)........................................................................................................ 32 
6.1.7 
Month 18 (± 14 days)........................................................................................................ 32 
6.1.8 
Month 21 (± 14 days)........................................................................................................ 33 
6.1.9 
Month 24 (± 14 days)........................................................................................................ 33 
6.2 
EARLY TERMINATION ................................................................................................................. 34 
6.3 
SUBJECT WITHDRAWAL ............................................................................................................. 35 
7.0 
ASSESSMENTS .............................................................................................................................. 36 
7.1 
SAFETY AND TOLERABILITY .................................................................................................... 36 
7.1.1 
Vital Signs ........................................................................................................................ 36 
7.1.2 
Electrocardiogram ............................................................................................................. 36 
7.1.3 
Physical Examination ....................................................................................................... 37 
7.1.4 
Neurological Examination ................................................................................................ 37 
7.1.5 
Laboratory ........................................................................................................................ 37 
7.2 
NEUROPSYCHOLOGICAL ASSESSMENTS ................................................................................ 39 
7.2.1 
Cognitive Assessments ..................................................................................................... 40 
7.2.2 
Functional/Global Assessments ........................................................................................ 41 
7.2.3 
Other Assessments ............................................................................................................ 42 
7.3 
SUICIDALITY ASSESSMENTS ..................................................................................................... 43 
7.4 
PLASMA FOR ANALYSIS OF AZELIRAGON AND METABOLITE CONCENTRATIONS ...... 44 
7.5 
PLASMA FOR ANALYSIS OF TOTAL A, A (1-40), A(1-42)................................................. 44 
7.6 
BLOOD VOLUME ........................................................................................................................... 45 
8.0 
ADVERSE EVENT REPORTING ................................................................................................ 46 
8.1 
ADVERSE EVENTS ........................................................................................................................ 46 
8.2 
REPORTING PERIOD ..................................................................................................................... 46 
8.3 
ASSESSMENT OF SEVERITY ....................................................................................................... 47 
8.4 
ASSESSMENT OF RELATIONSHIP TO STUDY DRUG ............................................................. 47 
8.5 
SERIOUS ADVERSE EVENTS ....................................................................................................... 48 
8.5.1 
Life Threatening Adverse Event ....................................................................................... 48 
8.5.2 
Disability .......................................................................................................................... 48 
8.5.3 
Unexpected Adverse Event ............................................................................................... 49 
8.6 
DOCUMENTATION OF ADVERSE EVENTS .............................................................................. 49 
8.7 
REPORTING REQUIREMENTS ..................................................................................................... 49 
8.7.1 
Serious Adverse Events Reporting Requirements ............................................................. 50 
9.0 
DATA ANALYSIS/STATISTICAL METHODS .......................................................................... 51 
9.1 
POPULATIONS OF ANALYSIS ..................................................................................................... 52 
9.2 
DISPOSITION, DEMOGRAPHIC, AND BASELINE DATA ......................................................... 52 
9.3 
SAFETY ANALYSIS ....................................................................................................................... 52 
9.4 
EFFICACY ANALYSIS ................................................................................................................... 53 
9.5 
HANDLING MISSING DATA......................................................................................................... 54 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9 Aug 2017 
High Point, NC 27265 
 
TABLE OF CONTENTS (continued) 
 
Page 
 
 
 
Page 9 
9.6 
DATA MONITORING COMMITTEE............................................................................................. 54 
9.7 
INTERIM ANALYSIS...................................................................................................................... 55 
9.8 
DATA MANAGEMENT CONSIDERATIONS ............................................................................... 55 
10.0 
QUALITY CONTROL / MONITORING OF THE STUDY ....................................................... 55 
11.0 
DATA HANDLING AND RECORD KEEPING.......................................................................... 55 
11.1 
CASE REPORT FORMS/ELECTRONIC DATA RECORD ........................................................... 55 
11.2 
RECORD RETENTION ................................................................................................................... 56 
12.0 
ETHICS ............................................................................................................................................ 56 
12.1 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD (REB) .................... 56 
12.2 
ETHICAL CONDUCT OF THE STUDY......................................................................................... 57 
12.3 
SUBJECT INFORMATION AND CONSENT ................................................................................ 57 
13.0 
STUDY TERMINATION CRITERIA .......................................................................................... 58 
14.0 
CONFIDENTIALITY AND PUBLICATION OF STUDY RESULTS ...................................... 58 
15.0 
REFERENCES ................................................................................................................................ 59 
APPENDICES ................................................................................................................................................ 62 
APPENDIX 1  PROHIBITED MEDICATION LIST ................................................................................ 63 
 
 
 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9 Aug 2017 
High Point, NC 27265 
 
 
 
Page 10 
LIST OF TABLES 
 
Page 
 
Table 1. 
Schedule of Activities ..................................................................................................................6 
Table 2. 
Descriptive Statistics on Trough Concentrations ....................................................................... 18 
 
 
 
 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9 Aug 2017 
High Point, NC 27265 
 
 
 
Page 11 
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 
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 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DEMQOL 
Health-Related Quality of Life for People with Dementia 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders, 4th ed Text Revision 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
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 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9 Aug 2017 
High Point, NC 27265 
 
LIST OF ABBREVIATIONS (continued) 
 
 
Page 12 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMA 
Methylmalonic Acid 
MMSE 
Mini-Mental State Exam 
NASH 
Nonalcoholic Steatohepatitis 
NPI 
Neuropsychiatric Inventory Questionnaire 
PD 
Pharmacodynamic 
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 
TMT 
Trail Making Test 
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 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9 Aug 2017 
High Point, NC 27265 
Page 13 
1.0 
INTRODUCTION 
This Open Label Extension study is designed to collect long term safety and tolerability data of 
azeliragon (TTP488) in participants with mild Alzheimer’s disease (AD) who successfully 
completed the TTP488-301 study. 
1.1 
BACKGROUND AND RATIONALE 
1.1.1 
Alzheimer’s Disease 
Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive loss of 
memory and cognitive function.  AD, 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 triple by the year 2050 (Alzheimer’s Association. 2016). 
1.1.2 
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). 
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 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9 Aug 2017 
High Point, NC 27265 
 
 
 
Page 14 
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. 
Additionally, RAGE is believed to be involved in mediating advanced glycation endproduct 
induced tau hyperphosphorylation (Li et al., 2012).  In vivo, injection of advanced glycation 
endproducts induced tau hyperphosphorylation, memory deterioration, decline of synaptic 
proteins and impairment of long-term potentiation.   These effects are attenuated following 
blockade of the RAGE receptor with a RAGE antibody. 
These data taken together suggest that inhibition of RAGE with an orally available small 
molecule inhibitor presents an attractive therapeutic rationale for the treatment of Alzheimer’s 
disease. 
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 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9 Aug 2017 
High Point, NC 27265 
 
 
 
Page 15 
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 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. 


Azeliragon (TTP488) 
vTv Therapeutics LLC 
TTP488-303 
4170 Mendenhall Oaks Pkwy 
Protocol Amendment 1, 9 Aug 2017 
High Point, NC 27265 
 
 
 
Page 16 
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 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).  There were no deleterious findings 
observed for either the 5-mg/day dose group or the placebo group.  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.  Participants 
receiving 5 mg/day or placebo were re-consented and permitted to continue the study without 
modification. 
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 (predicting a 
negative outcome) 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 


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High Point, NC 27265 
 
 
 
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treatment” defined as data collected within 45 days of the last 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 TTP488-301 Phase 3 study is enrolling 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.   
Patients who successfully complete the TTP488-301 study will be eligible to screen for this 
open label extension study. 
1.1.4 
Dose Selection Rationale 
The azeliragon dose (5 mg daily) for the registration studies (TTP488-301) 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 PK/PD analysis concluded that the optimal trough concentration range 
was 8-15 ng/ml over the 18-month period. 


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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. 
The relative bioavailability of a 5 mg dose of TTP488 administered as a single oral capsule 
under fed conditions (standard FDA high-fat breakfast) compared to the same formulation under 
fasted conditions in healthy volunteers was evaluated in Study TTP488-105.  There was an 
approximately 20% reduction in exposure (Cmax, AUC0-last, and AUC0-72) following 
administration of a single 5 mg dose of TTP488 following a standard FDA high fat breakfast 
compared to dosing in the fasted state.  Fed subjects experienced a greater lag time for 
absorption as compared to fasted subjects (median Tlag of 4 hours versus 1 hour post-dosing, 
respectively); however, the median Tmax was the same between treatment groups (16 hours post-
dosing).  Geometric mean exposure estimates (Cmax, AUC0-last, and AUC0-72) were 
approximately 20% lower for subjects in the fed treatment group as compared to the fasted 
group.  The results of the statistical analysis for bioequivalence in the presence or absence of 
food were consistent with a reduction of azeliragon exposure in the fed state for all parameters 
evaluated (Cmax, AUC0-last, and AUC0-72).  The geometric least-squares mean ratio point 
estimates were approximately 80% for all PK parameters evaluated, with 90% confidence 
intervals that extended below the standard bioequivalence range (80% to 125%). 
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 
The primary objective of this study is: 
• To collect long-term safety and tolerability data. 
 
The secondary objectives of this study are: 
• 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 measures of behavior, cognition, 
function, resource utilization, and quality of life. 
2.2 
ENDPOINTS 
Primary Endpoints: 
• Adverse events, clinical safety laboratory tests, ECG, vital signs. 
Secondary Endpoints: 
• The slope of change over time in ADAS-cog, CDR-sb, MMSE, ADCS-ADL, 
and NPI scales. 
• Change from Baseline in measures of behavior, cognition, and function. 
 
 


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3.0 
STUDY DESIGN 
This is an open-label extension study in patients with mild Alzheimer’s disease who have 
successfully completed participation in the azeliragon Phase 3 TTP488-301 (STEADFAST) 
trial.  Patients will receive azeliragon 5 mg/day for up to 2 years. 
Participants are required to continue to be on SoC of a stable background acetylcholinesterase 
inhibitor therapy and / or memantine 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.   
Behavioral medications (including antidepressants, antipsychotics and anxiolytics) must be on 
stable doses.  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. 
Subjects will participate in approximately 9 outpatient visits including baseline which is the 
same visit at the Month 18 visit in the TTP488-301 study. 
A minimum of three staff members will be required to conduct the protocol at each site.   
• Principal Investigator (PI) – This person is responsible for the clinical evaluation of all 
participants, ensuring enrollment and protocol adherence, and endpoint determinations.  
The PI 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. 
• Non-CDR Rater – This person will meet the educational, clinical and scale experience 
requirements set by the sponsor.  This person can conduct all ratings and assessments 
except the CDR ratings.   
• 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 


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access to the ADAS-cog.  It is important for the CDR rater to remain blinded to ADAS-
cog data and all other scales for that subject.   
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. Successful completion of Study TTP488-301 through the Month 18 Visit without 
ongoing SAEs or history of serious adverse drug reactions during study TTP488-
301.   
2. Patients must enroll in the present study within 7 days of completion of study 
TTP488-301. 
3. 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. 
4. Participants and caregiver/informants who are willing and able to comply with 
scheduled visits, treatment plan, laboratory tests, and other study procedures. 
5. The subject must have a reliable caregiver/informant with regular contact (i.e., 10 
hours a week as a combination of face-to-face visits and telephone contacts are 
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. 
6. 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. 


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7. Subject must be able to ingest oral medications. 
4.2 
EXCLUSION CRITERIA 
Participants presenting with any of the following will be excluded from participation in the 
study. 
1. The subject is felt by the investigator to be unsuitable (on the basis of health, 
compliance, caregiver availability, or for any other reason) for inclusion in the study. 
2. Subjects with serious suicide risk.  If there are “yes” answers on items 4, 5 or on 
any behavioral question of the C-SSRS, a suicide risk assessment must 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. 
3. Subjects demonstrating a QTcF > 480 msec or a >45 msec increase from the 
TTP488-301 Baseline value based on the locally read ECG performed at the 
TTP488-301 Month 18 Visit (TTP488-303 Baseline).  Participants with known 
history of bundle branch block (either right or left) are allowed if absolute QTcF 
value does not exceed 500 msec.  Participants with a functioning pacemaker, 
indicated by an ECG displaying paced rhythm, are allowed with no QTc upper limit. 
4. 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 2-year 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(s) is female and of 
childbearing potential, must agree to use one of the following methods of 


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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. 
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 
TTP488-303 is not a randomized study.  All eligible subjects will receive azeliragon 5 mg / 
day.   
5.2 
BREAKING THE BLIND 
TTP488-303 is an open label study. 
5.3 
DRUG SUPPLIES 
Drug supplies will consist of a 5 mg azeliragon supplied as a Size 2 hard gelatin capsule.  The 
recommended storage condition for the product is room temperature at 15oC to 30oC (59oF to 
86oF). 
5.3.1 
Formulation and Packaging 
Azeliragon will be packaged into child-resistant, high density polyethylene (HDPE) bottles with 
heat induction seal (HIS) closures.   
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 following confirmation of eligibility.  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 treatment period.  The day’s dose of azeliragon 
will be administered in the clinic at each subsequent study visit.  Azeliragon may be 
administered without regard to meals. 
5.3.3 
Compliance 
Participants will bring all unused azeliragon capsules to each study visit.  The number of 
capsules will be counted and documented.  If more than expected are returned, participants will 


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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.  
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.  
Any change in dose or frequency must be captured in the eCRF. 
All Medications taken after the first dose of study medication in the open label extension 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) 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). Exceptions to medications 
that may negatively affect cognitive function are as follows: 


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• Considerations for use of medications that may affect the CNS or cognition 
following enrollment in the open label extension. When 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). Should their use be deemed to be 
chronic (spanning months), discussion with the Sponsor’s medical monitor is 
required.   
The use of following concomitant medications is not allowed: 
• Drugs known to be potent CYP2C8 or any other prohibited concomitant drugs (See 
APPENDIX 1 
 
PROHIBITED MEDICATION LIST for a partial 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 other investigational therapies for Alzheimer’s disease that are being investigated for 
possible disease modification activity (e.g., passive immunotherapies and secretase inhibitors) 
or non-disease modifying purposes are allowed during this study. 
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 proximal 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.   
• Following completion of the cognitive/functional assessments the remainder of study 
visit procedures will be completed.  
• ECGs: obtain prior to blood sampling.  
• 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. 


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6.1 
STUDY PERIOD 
6.1.1 
Baseline (Month 18 of TTP488-301) 
Following completion of the TTP488-301 Month 18 Visit procedures, 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).   
After obtaining consent, the following baseline activities will be completed. 
• Review of inclusion and exclusion criteria 
• If eligible, registration for the TTP488-303 study 
• Dispense study drug if eligible. 
• Subject begins taking study medication in the clinic as soon as baseline procedures are 
completed. 
The TTP488-301 Month 18 assessments will also serve as the Baseline assessments for the 
TTP488-303 Open Label Extension.  The visit procedures that are unique to the TTP488-303 
baseline visit can be completed up to 7 days following the Month 18 visit for the TTP488-301 
study.  The 7 day window will begin on the TTP488-301 Month 18 visit day.  To participate in 
TTP488-303, the subject must be registered and study drug is administered within 7 days of the 
TTP488-301 Month 18 visit day. 
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 to ensure that the patient 
continues to be appropriate for the study.   


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6.1.2 
Month 3 (± 14 days) 
• ADAS-cog. 
• C-SSRS.  
• 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. 
• Vital signs: blood pressure and pulse rate. 
• 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. 
6.1.3 
Month 6 (± 14 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 and pulse rate.  
• Blood sampling for safety laboratory testing including HbA1c. 
• Collect blood samples for PK and PD.  


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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. 
6.1.4 
Month 9 (± 14 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. 
• Vital signs: blood pressure and pulse rate. 
• 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. 
6.1.5 
Month 12 (± 14 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. 


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• Vital signs: blood pressure and pulse rate.  
• Blood 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. 
6.1.6 
Month 15 (± 14 days) 
• 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. 
• Vital signs: blood pressure and pulse rate. 
• 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. 
6.1.7 
Month 18 (± 14 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. 


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• Body weight. 
• ECG. 
• Vital signs: blood pressure  and pulse rate. 
• Blood 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. 
6.1.8 
Month 21 (± 14 days) 
• 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. 
• Vital signs: blood pressure and pulse rate. 
• 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. 
6.1.9 
Month 24 (± 14 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  and pulse rate. 
• Blood sampling for safety laboratory testing including HbA1c. 
• Collect blood samples for PK and PD. 
• Drug accountability. Any discrepancies are recorded in the source. 
• End of study procedures 
6.2 
EARLY TERMINATION 
In the event a subject discontinues participation prior to completion of the Month 24 
visit the following procedures should be performed. 
• ADAS-cog, MMSE, CDR, ADCS-ADL, COWAT, CFT, Trail Making Tests 
(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 and pulse rate. 
• Blood 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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6.3 
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 a final visit, if applicable, 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 based on a specific adverse event profile as recommended by the Sponsor in discussions 
with the PI.  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, 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 
in a sitting or supine position.  Vital signs will be conducted in the same position (sitting or 
supine) at all the study visits and position captured in the source documentation.  Participants 
should be sitting or 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.  Each original recording will be evaluated by the PI or designee following the 
measurement.  The interpretation of results will follow the categories “normal,” “abnormal, 
NCS,” or “abnormal, CS”.  An abnormal measurement may be repeated at the PI or designee 
discretion.  If the abnormal ECG measurements are considered as clinical significant, the 
abnormality will be recorded as AE in the eCRF.   
When assessing eligibility at the Baseline 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 4.  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.  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’s TTP488-301 Month 18 ECG will be reviewed locally in 
order to verify continued eligibility for the study.  If the QTcF is >480 msec based on the local 
QTcF reading, the participant is not eligible.  If the QTcF represents an increase from TTP488-
301 Baseline of > 45 msec, the participant is not eligible. 
At any time during the study, a subject with an absolute QT > 480 msec or an increase from 
baseline in QTcF > 45 msec should prompt a call to the Sponsor’s medical monitor for guidance 
on how to proceed.  


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7.1.3 
Physical Examination 
Brief physical examination will include skin, eyes, oral mucosa, cardiac, and respiratory. A brief 
physical examination will be conducted at all study visits.  Body weight will be also examined 
at the Baseline (Month 18 of TTP488-301), Month 6, Month 12, Month 18, and Month 24 study 
visits. 
7.1.4 
Neurological Examination 
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 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 Baseline 
(Month 18 of TTP488-301), Months 6, 12, 18, and 24 or 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 
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 
 
 
 
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: 
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 


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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, 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 


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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 CDR may be done on a separate proximal visit day to avoid patient fatigue.  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): 
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 Baseline 
(Month 18 of TTP488-301) and at Months 3, 6, 9, 12, 18, and 24 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 Baseline (Month 18 of TTP488-301), and at Months 6, 12, 
18, and 24 or in the event of early termination.  Scores range from 0-30 with lower scores 
indicating greater cognitive impairment.   
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 


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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 (Month 18 of TTP488-301), 
and at Months 6, 12, 18, and 24 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 (Month 18 of TTP488-301), 
and at Months 6, 12, 18, and 24 or in the event of early termination. 
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 (Month 18 of 
TTP488-301), and at Months 6, 12, 18, and 24 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 


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administered at Baseline (Month 18 of TTP488-301), and at Months 6, 12, 18, and 24 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 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 Baseline (Month 18 of TTP488-301) and at Months 6, 12, 18, 
and 24 or in the event of early termination. CDR may be done on a separate proximal visit day 
to avoid patient fatigue. 
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 


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presence of neuropsychiatric symptoms.  The NPI will be administered at Baseline (Month 18 
of TTP488-301), and at Months 6, 12, 18, and 24 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 (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 (Month 18 of TTP488-301) and at Months 6, 12, 18, and 24 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 (Month 18 of TTP488-301) and at Months 6, 12, 18, and 24 or 
in the event of early termination. 
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. 
The C-SSRS will be used to assess suicide ideation or behavior at each study 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, 


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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 at Baseline (Month 18 of 
TTP488-301), Months 6, 12, 18 and 24 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. 
Following blood collection, the tubes will be placed in an ice-water bath (maximum 60 
minutes) until centrifugation.  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. 
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 
(Month 18 of TTP488-301), Months 6, 12, 18, and 24 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 -


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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 
BLOOD VOLUME 
Total blood sampling volume for the individual participants is approximately 106 mL. 
Sample Type 
Sample 
Volume (mL) 
Number of Sampling 
Times 
Total 
Volume 
(mL) 
Routine Laboratory 
16.5 
4 
66 
PK 
4 
4 
16 
Biomarkers (Aβ) 
6 
4 
24 
TOTAL (mL) 
 
 
106 
 
 
 
 


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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 study drug will be tracked as AEs from the time when the study 
participant signed the ICF. 


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SAE reporting will commence from the time the participant provides informed consent through 
last subject visit at Month 24.  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 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. 


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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: A direct cause and effect relationship exists, or is likely to exist, between the 
AE and the study drug in the judgment of the investigator. (i.e., there is evidence or 
arguments to conclude that the study drug caused the adverse event) 
• Not Related: The AE is not related to the study drug, if in the judgment of the 
investigator, 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.  
8.5.2 
Disability 
Disability is defined as a substantial disruption of a person's ability to conduct normal life 
functions. 


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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 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. 


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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 of 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, in consultation with the 
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 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 database lock for the study.  The SAP will supersede the protocol.  Any deviations from 
the planned analyses will be described in the final integrated study report. 
This open-label, single-arm study includes subjects who completed TTP488-301, in which they 
were randomized to receive azeliragon (plus SoC) or placebo (plus SoC). An analysis plan for 
the meta-analysis combining data from TTP488-301 with this study will be done prior to 
database lock for this study. It is intended that the key analysis of results from this open-label 
study be described in the integrated analysis plan, and that the analysis of this study alone be 
described in this protocol.  
SAS Version 9.4 or later will be used.  Medical dictionary for Regulatory Activities (MedDRA) 
Version 18.0 or later will be used for coding adverse events.  Medications will be coded using 
WHO Drug Dictionary (WHODD) Version March 2009 or later. 
Continuous data will be summarized using descriptive statistics (number, mean, median, 
standard deviation, first and third quartiles, minimum, and maximum).  Categorical data will be 
summarized for the enrolled population and also by treatment group according to the 
randomization of TTP488-301 using frequency tables (frequencies and percents). 
Baseline will be the latest available data point prior to the first dose of study medication in this 
study (start of treatment for this protocol). 
Outliers that are detected during the review of the data will be investigated.  Methods for dealing 
with outliers will be defined in the SAP.  In general, missing data will not be imputed, and 
outliers will not be excluded unless they are considered to be erroneous values. 
 


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9.1 
POPULATIONS OF ANALYSIS 
Populations of analysis are defined as follows: 
• The full analysis set (FAS) includes all enrolled patients with on-treatment data.  The 
FAS is used for all efficacy analyses. 
• The per-protocol set (PPS) includes all FAS patients who are not excluded due to a 
significant protocol violation, where a significant protocol violation is one that has the 
potential to affect analysis conclusions.  Final determinations of significant protocol 
violations will be made at the final blind data review meeting in accordance with 
guidance from ICH E9 (Statistical Principles).  
• The safety set (SAF) includes all patients who received at least one dose of study 
medication.  The SAF is used for all safety analyses. 
 
To understand the impact of subjects who withdraw from the study prior to completion, the FAS 
will be partitioned into groups of subjects who complete the study (completers) and subjects 
who do not complete the study (dropouts). 
9.2 
DISPOSITION, DEMOGRAPHIC, AND BASELINE DATA 
A tabulation of subject disposition will be presented, including the number enrolled for the 
single group of enrolled population, the number enrolled by treatment group according to the 
randomized treatment from Study TTP488-301, the number dosed in each population group, the 
number who withdrew prior to completing each part of the study, and reasons for withdrawal. 
Demographic and baseline characteristics (disease history, medical history, and prior 
treatments) will be summarized for all randomized patients and for the FAS.  No formal 
statistical comparisons will be performed. 
9.3 
SAFETY ANALYSIS 
A treatment-emergent adverse event (TEAE) is defined as an AE that was not present at 
baseline, or an exacerbation of a pre-existing AE.  For laboratory data, a treatment-emergent 
abnormal laboratory value (TEAV) represents an abnormal value that was normal at baseline. 


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Safety variables of analysis include the following: 
• Proportions of patients with any TEAEs 
• Proportions of patients with serious TEAEs 
• Proportions of patients with severe TEAE 
• Proportions of patients with TEAEs leading to study drug discontinuation 
• Proportions of patients with TEAEs leading to study withdrawal  
• Proportions of patients with drug-related TEAEs 
• Proportions of patients with TEAVs 
• Proportions of patients meeting DILI criteria 
• Proportions of patients meeting ICH E14 criteria for threshold values or threshold 
changes 
• Mean changes from baseline in vital signs  
• Mean changes from baseline in clinical laboratory measures 
• Mean change from baseline in measures from electrocardiography 
 
Continuous data will be summarized by treatment group using descriptive statistics (number, 
mean, median, standard deviation, first and third quartiles, minimum, and maximum).  
Categorical data will be summarized by treatment group using frequency tables (frequencies 
and percentages). 
9.4 
EFFICACY ANALYSIS 
Efficacy variables will include changes from baseline in scores from questionnaire data and 
cognition and performance assessments. Time to threshold changes will be defined in the SAP 
for the integrated analysis of the data from this study with the data from TTP488-301.  
Continuous data will be summarized by treatment group using descriptive statistics (number, 
mean, median, standard deviation, first and third quartiles, minimum, and maximum).  
Categorical data will be summarized by treatment group using frequency tables (frequencies 
and percentages). 
Baseline will be the latest available data point prior to start of treatment. 


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Outliers that are detected during the review of the data will be investigated.  Methods for dealing 
with outliers will be defined in the SAP.  In general, missing data will not be imputed, and 
outliers will not be excluded unless they are considered to be erroneous values.  Sensitivity 
analyses and exploratory analyses may be done using imputation or excluding outliers to ensure 
robustness of study conclusions. 
9.5 
HANDLING MISSING DATA 
In general, no imputation of values for missing data will be performed, except as otherwise 
described for efficacy evaluation.  Standard clinical monitoring and data management practices 
will be used to ensure the integrity of data.  
Sensitivity analyses will be done to assess the impact of missing data or spurious data on study 
conclusions.  Sensitivity analyses will include methods of imputation, which will be defined in 
the SAP.  Methods of imputation may include favorable imputation (regardless of treatment), 
unfavorable imputation (regardless of treatment), last-observation-carried-forward, and worse-
observation-carried-forward; baseline values will not be carried forward. 
9.6 
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. 
Based on the review of safety data, the IDMC will make recommendations regarding the 
conduct of the study.  These may include amending safety-monitoring procedures, modifying 
the protocol or consent, terminating the study or continuing the study as designed. 
The IDMC charter will specify these and other operational aspects of the IDMC structure, 
processes and study stopping rules. 


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9.7 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 
9.8 
DATA MANAGEMENT CONSIDERATIONS 
This study will utilize electronic data capture (EDC) for data capture. The database lock will 
occur when the study is declared closed, when all subjects have completed the study (last visit 
of the last subject on-study).  
10.0 
QUALITY CONTROL / MONITORING OF THE STUDY 
During study conduct, the Sponsor or its designee will conduct periodic monitoring visits based 
on a risk based approach 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. 
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)”.  The database lock will occur 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). 


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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).   
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 
Therapeutics needs to be notified and approval obtained before records may be transferred off 
site.  
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 


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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 (2013). 
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 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 in the case of participants who are deemed to be unable to have 
the cognitive ability to provide consent [where this is in accordance with local laws, regulations 
and ethics committee policy]).  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. 
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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15.0 
REFERENCES 
1. 
Alzheimer’s Association. 2016 Alzheimer’s Disease Facts and Figures. Alzheimer’s & 
Dementia 2016;12(4). 
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. 
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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. 


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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. Li XH, Lv BL, Xie JZ, Liu J, Zhou XW, Wang JZ.  AGEs induce Alzheimer-like tau  
pathology and memory deficit via RAGE-mediated GSK-3 activation.   Neurobiol 
Aging. 2012 Jul;33(7):1400-10.   
17. Loonstra AS, Tarlow AR, Sellers AH.  COWAT metanorms across age, education, and 
gender.  Appl Neuropsychol 2001;8:161-6. 
18. 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. 
19. 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. 
20. Reitan R. Validity of the trail making test as an indicator of organic brain disease.  
Perceptual and Psychomotor Skills 1958;8:271-6. 
21. 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. 


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22. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. American 
Journal of Psychiatry 1984;141:1356-64. 
23. 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. 
24. 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 
25. 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. 
26. Tanzi RE, Moir RD, Wagner SL. Clearance of Alzheimer's Abeta peptide: the many 
roads to perdition. Neuron. 2004;43:605-8. 
27. 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 
28. 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. 
29. Yan SD, Zhu H, Zhu A, et al. Receptor-dependent cell stress and amyloid accumulation 
in systemic amyloidosis. Nat Med. 2000;6:643-51. 
30. 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. 
31. 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 
 
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 
monteleukast 
pioglitazone 
 
 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of 
Medicine (2007). "http://medicine.iupui.edu/clinpharm/ddis/clinical-table/" Accessed 5Aug2013. 
 
Guidance for Industry. Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and 
Labeling Recommendation.  DRAFT GUIDANCE.  February 2012. 
 
 

SAP_001.pdf: 
vTv Therapeutics LLC 
                                        TTP488-303 Statistical Analysis Plan 
 
21 September 2018   
Confidential 
i 
STATISTICAL ANALYSIS PLAN 
 
 
Title:   
Open label extension study for continued safety and efficacy evaluation of 
azeliragon in patients with mild Alzheimer's disease   
Protocol:   
TTP488-303, Amendment 1, 9 August 2017   
Study Drug:  TTP488 
Sponsor:   
vTv Therapeutics LLC (formerly TransTech Pharma, LLC) 
Date:    
21 September 2018 
 
 
 
 




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                                        TTP488-303 Statistical Analysis Plan 
 
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Table of Contents 
1 
Introduction ......................................................................................................... 1 
1.1  Study Objectives ................................................................................................. 2 
1.2  Study Rationale ................................................................................................... 2 
1.3  Subject Population .............................................................................................. 2 
1.4  Randomization .................................................................................................... 2 
1.5  Study Design ....................................................................................................... 3 
1.6  Sample Size and Power Considerations .............................................................. 3 
1.7  Early Stopping, Data Monitoring, and Interim Analysis .................................... 3 
1.8  Conformance to Regulatory Standards ............................................................... 4 
1.9  Modifications from the Statistical Section of the Protocol ................................. 4 
2 
Statistical Hypotheses ......................................................................................... 5 
3 
Populations of Analysis ...................................................................................... 6 
4 
Variables of Analysis .......................................................................................... 7 
4.1  Efficacy Variables ............................................................................................... 7 
4.1.1 
Primary Efficacy Variable ........................................................................ 7 
4.1.2 
Other Efficacy Variables of Analysis ....................................................... 7 
4.1.3 
Efficacy Scales ......................................................................................... 8 
4.2  Safety Variables ................................................................................................ 11 
4.2.1 
Treatment-emergent Adverse Events ..................................................... 11 
4.2.2 
The Columbia Suicide Severity Rating Scale (C-SSRS) ....................... 12 
4.2.3 
Vital Signs .............................................................................................. 13 
4.2.4 
Clinical laboratory assessments ............................................................. 13 
4.3  Pharmacokinetics and Pharmacodynamics Variables ....................................... 16 
4.4  Adverse Events of Special Interest ................................................................... 16 
5 
Statistical Methodology .................................................................................... 17 
5.1  Statistical Methodology for Efficacy Analysis ................................................. 17 
5.1.1 
Statistical Methodology for Primary Efficacy Analysis ........................ 17 
5.1.2 
Statistical Methods for Secondary Variables ......................................... 18 
5.1.3 
Subgroup Analyses ................................................................................. 19 
5.2  Disposition, Demography, and Baseline Characteristics .................................. 19 
5.3  Analysis of Safety Data .................................................................................... 19 
5.3.1 
Adverse Events ....................................................................................... 19 
5.3.2 
Vital Signs .............................................................................................. 20 
5.3.3 
Routine Clinical Laboratory Measurements .......................................... 20 
5.3.4 
Liver Function Tests ............................................................................... 20 
5.3.5 
Electrocardiography ............................................................................... 21 
5.4  Pharmacokinetics Analysis ............................................................................... 21 
5.4.1 
Methodology for PK Analysis................................................................ 21 
5.5  Exploratory Analysis ........................................................................................ 21 


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5.6  Concomitant Medications ................................................................................. 22 
6 
Data Conventions .............................................................................................. 22 
6.1  Definition of Baseline ....................................................................................... 22 
6.2  Missing Data ..................................................................................................... 22 
6.3  Dropouts ............................................................................................................ 22 
6.4  Visit Windows .................................................................................................. 22 
6.5  Unscheduled Assessments ................................................................................ 22 
6.6  Values Below LLQ ........................................................................................... 23 
7 
Analysis Deviations .......................................................................................... 24 
8 
Software ............................................................................................................ 25 
9 
Data Displays .................................................................................................... 26 
10 
Values of Potential Clinical Concern ................................................................ 27 
11 
References ......................................................................................................... 28 
12 
Schedule of Time and Events ........................................................................... 30 


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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 (azeliragon), 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 the open-label extension study for TTP488-301.  
The goals of this statistical analysis plan (SAP) are the following: 
 To describe the approach of statistical analysis in order 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).  


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1.1 
Study Objectives  
Primary objective: 
 To collect long-term safety and tolerability data. 
Secondary objectives: 
 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 measures of behavior, cognition, function, 
resource utilization, and quality of life. 
1.2 
Study Rationale 
The primary purpose of this trial is to allow participants from TTP488-301 who completed the 
18-month study who may have received either TTP488 or placebo to receive TTP488 open-label.  
1.3 
Subject Population  
The study population includes AD patients who completed TTP488-301 (entry MMSE for 
TTP488-301 was between 21 and 26, inclusive; CDR-global of 0.5 or 1; no requirements were 
imposed for entry into TTP488-303) who have a reliable caregiver 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 must have sufficient subject 
interaction to be able to provide meaningful input into the rating scales administered in this study 
where caregiver 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 criteria. Subjects were required to be at least 50 
years of age to participate in TTP488-301 and TTP488-303. 
1.4 
Randomization   
The open-label extension study was not randomized. 
It is noted that TTP488-301 was randomized, and the randomization scheme for TTP488-301 is 
used to identify what will be called “treatment groups” in this SAP. The completers of TTP488-
301 who are enrollees of TTP488-303 will be designated as  
 Crossing over from placebo to azeliragon or  
 Continuing on azeliragon.  
Randomization in TTP488-301 had balanced allocation (1:1) between active and placebo. 
Dropouts were not allowed to be replaced.  


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1.5 
Study Design   
This is an open-label extension study in patients with mild Alzheimer’s disease who have 
successfully completed participation in the azeliragon Phase 3 TTP488-301 (STEADFAST) trial.  
Patients may receive azeliragon 5 mg/day for up to 2 years. 
Participants were required to continue to be on SoC of a stable background acetylcholinesterase 
inhibitor therapy and / or memantine 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.   
Subjects were expected to participate in approximately 9 outpatient visits including baseline 
which is the same visit at the Month 18 visit in the TTP488-301 study. 
Protocol TTP488-301 included two studies with a common infrastructure (A-study and B-study). 
Participants from either study are allowed to roll over into this open-label extension study. 
A-study is conducted at multiple sites in the US and Canada. B-study is conducted at multiple 
sites in the US, Canada, Ireland, UK, South Africa, New Zealand, and Australia.    
This study was terminated prematurely before participation outside of the US and Canada began; 
therefore, this study is conducted at multiple sites in the US and Canada. 
The overall structure of the study includes the following periods: 
Baseline Study Period: (Month 18 visit of TTP488-301): At the Month 18 visit of TTP488-301, 
subjects who met eligibility requirements were offered enrollment into this open-label extension 
study. Subjects had baseline assessments for efficacy and safety measures, including PK 
assessments.  
Treatment Period: (Day 1 (Month 18 visit of TTP488-301) — Month 24): Subjects were treated 
with open-label azeliragon 5 mg QD. Efficacy and safety measures were taken. Blood samples 
were taken and subjects have assessments for safety and PK.    
1.6 
Sample Size and Power Considerations  
This open-label extension permited enrollment of subjects who completed TTP488-301. The 
total sample size is limited by the enrollment into TTP488-301 and completion of TTP488-301. 
The protocol for TTP488-301 planned for a total of 800 patients to be enrolled. 
No power considerations apply to this open-label study. 
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. 


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1.8 
Conformance to Regulatory Standards  
An objective of this SAP is to comply with regulatory standards.  
The planned statistical analysis of this study is intended to comply with regulatory expectations 
and standards,. 
1.9 
Modifications from the Statistical Section of the Protocol  
There are no modifications from the Statistical Section of the Protocol. 
 
 
 


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2 
Statistical Hypotheses 
There are no formal statistical hypotheses for this open-label study. 
 
 


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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 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, 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).  
Final determinations of the PPS will be made at the final data review meeting 
(DRM) held in accordance with ICH E9 prior to the lock data. 
 The safety set (SAF) includes all patients who received at least one dose of study 
medication.  The SAF is used for all safety analyses. 
 
The FAS is used for efficacy analysis; the SAF will be used for safety analyses. 
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 FAS.   
 


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4 
Variables of Analysis  
4.1 
Efficacy Variables 
Efficacy evaluation will include as efficacy variables of analysis ADAS-cog and CDR-sb (co-
primary variables of analysis), and MMSE, ADCS-ADL, and NPI; other efficacy measure may 
be evaluated using descriptive statistics, including other efficacy markers as identified in 
TTP488-301. It is noted that, although the primary objective of the study is safety and 
tolerability, efficacy evaluation is expected to be informative and useful. This SAP defines the 
primary and supportive variables of analysis to guide the statistical evaluation of the efficacy 
data. 
4.1.1 Primary Efficacy Variable 
The primary analysis will include assessment of the following variables of analysis.  
 Mean change from Baseline in ADAS-cog 
 Mean change from Baseline in CDR-sb. 
.   
4.1.2 Other Efficacy Variables of Analysis 
Additional efficacy variables of analysis are as follows: 
 Individual item responses on the Resource Utilization in Dementia (RUD) questionnaire 
and the total caregiver time spent assisting the patient based on the RUD. 
 Change from Baseline in the Dementia Quality of Life (DEMQOL)-Proxy total score. 
 Change from Baseline in the Neuropsychiatric Inventory (NPI) total score. 
 Change from Baseline on the Mini-mental State Examination (MMSE) total score. 
 
 Change from Baseline in Alzheimer’s Disease Cooperative Study Activities of Daily 
Living Scale (ADCS-ADL) by visit. 
 
 Change from baseline in Continuous Oral Word Association Task (COWAT) by visit. 
 
 Change from Baseline in Category Fluency Test (CFT) by visit. 
 
 Change from baseline in Trail-making Test (TMT) by visit. 


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4.1.3 Efficacy Scales 
The following instruments that are used in this study are subject to statistical analysis: 
4.1.3.1 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.  In TTP488-303, the ADAS-cog will be conducted 
at Months 3, 6, 9, 12, 15, 18, 21 and 24 or in the event of early termination. The 
ADAS-cog should always be administered prior to other cognitive measures.  
4.1.3.2 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.  
In TTP488-303, the MMSE will be administered at Months 6, 12, 18 and 24 or in the 
event of early termination.   
4.1.3.3 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., 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. In 
TTP488-303, the COWAT will be administered at Months 6, 12, 18 and 24 or in the 
event of early termination. 


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4.1.3.4 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. In 
TTP488-303, the CFT will be administered at Months 6, 12, 18 and 24 or in the event of 
early termination. 
4.1.3.5 Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale (ADCS-
ADL):   
 Range: 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. In TTP488-303, the ADCS-ADL will be administered at 
Months 6, 12, 18 and 24 or in the event of early termination. 
4.1.3.6 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 Months 6, 12, 18 and 24 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.  
4.1.3.7 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.  In TTP488-303, the NPI will be administered at Months 6, 12, 18 and 24 or 
in the event of early termination. 
4.1.3.8 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.  In TTP488-303, this scale will be 
administered at Months 6, 12, 18 and 24 or in the event of early termination.  
4.1.3.9 Dementia Quality of Life (DEMQOL) – Proxy:  
 Range: 31—124 with lower scores indicate greater impairment. 


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 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.  In 
TTP488-303, this scale will be administered at Months 6, 12, 18 and 24 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. 
4.1.3.10 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 (eg, A to 1; 1 to B; B to 2; 2 to C). Lower scores (seconds) 
indicate greater cognitive function. In TTP488-303, the TMT will be administered at 
Months 6, 12, 18 and 24 or in the event of early termination. 
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 are reviewed by medically qualified individuals of 
vital signs, laboratory data, electrocardiograms (ECG), and all safety data from all other sources 
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:  
 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.   


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 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 with treatment-emergent SAEs. 
 Subjects with TEAEs that result in study termination. 
 
4.2.2 The Columbia Suicide Severity Rating Scale (C-SSRS) 
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.) .  In TTP488-303, the C-
SSRS will be conducted at Months 3, 6, 9, 12, 15, 18, 21 and 24 or in the event of early 
termination. 
 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).  
 


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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.  
 
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.  
 
Endpoints:  
 
Composite endpoints based on the above categories are defined below.  
o Suicidal ideation: A “yes” answer at any time during treatment to any one of the five 
suicidal ideation questions (Categories 1-5) on the C-SSRS.  
 
o Suicidal behavior: A “yes” answer at any time during treatment to any one of the five 
suicidal behavior questions (Categories 6-10) on the C-SSRS.  
 
o Suicidal ideation or behavior: A “yes” answer at any time during treatment to any one 
of the ten suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS.  
Comparative endpoints of interest are defined below. “Treatment emergence” is used for 
outcomes that include events that first emerge or worsen. “Emergence” is used for outcomes 
that include events that first emerge. 
 
4.2.3 Vital Signs 
Vital signs measurements consist of blood pressure and pulse rate. .  In TTP488-303, the vital 
signs will be conducted at Months 3, 6, 9, 12, 15, 18, 21 and 24 or in the event of early 
termination. 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 clinically important 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. In TTP488-303, the clinical laboratory blood samples will be collected at 
Months 6, 12, 18 and 24 or in the event of early termination.  
  Definition:  


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 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 
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 
 


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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 function test (LFT) 
 
 


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4.3 
Pharmacokinetics and Pharmacodynamics Variables 
Blood samples for pharmacokinetic (PK) analysis will be collected prior to dosing at Baseline 
(Month 18 of TTP488-301), Months 6, 12, 18 and 24 or at Early Termination. 
Blood samples for plasma Aβ (total, 1-40 and 1-42) biomarkers analysis will be collected prior to 
dosing on Baseline (Month 18 of TTP488-301), Months 6, 12, 18, and 24 or at Early 
Termination.   
4.4 
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. 
 
 


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5 
Statistical Methodology  
General statistical methods will be applied as appropriate for out-patient, open-label clinical 
studies. Safety evaluations will rely on descriptive statistics. Randomization groups from 
TTP488-301 will be examined to delineate between subjects who received placebo during 
TTP488-301 and those who received TTP488 during TTP488-301. For the purpose of this SAP, 
these groups will be considered “treatment groups” acknowledging that all subjects receive open-
label azeliragon in this study. 
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.  
Baseline will be the latest available data point prior to start of treatment in TTP488-303. 
Data displays will include the following designations for treatment groups: 
 Subjects randomized to azeliragon in TTP488-301 
 Subjects randomized to placebo in TTP488-301 
 All subjects. 
 
SAS Version 9.4 or later will be used.  Medical dictionary for Regulatory Activities (MedDRA) 
Version 18.0 or later will be used for coding adverse events.  Medications will be coded using 
WHO Drug Dictionary (WHODD) Version March 2009 or later. 
5.1 
Statistical Methodology for Efficacy Analysis 
Efficacy evaluation will include the co-primary variables of analysis (ADAS-cog and CDR-sb), 
key secondary measures, and other efficacy markers. 
Statistical analysis will be considered descriptive analysis. No alpha is allocated for this study. 
5.1.1 Statistical Methodology for Primary Efficacy Analysis 
The primary descriptive analysis will be done on change from baseline in ADAS-cog and on 
change from baseline in CDR-sb.  
Analysis of covariance (ANCOVA) will be done to compare those patients who were 
randomized to azeliragon in TTP488-301 with those who were randomized to placebo. The 
ANCOVA will include baseline measure as a covariate and treatment arm from TTP488-301; a 
main-effects model will be used.  
Descriptive analysis will be applied to those patients who were treated with placebo in TTP488-
301 to compare the profile during TTP488-301 with that of the profile in TTP488-303.  


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Descriptive statistics will be applied to the total patient population without regard for prior 
treatment. 
Analyses will include data from the 18-month period from TTP488-301 with continuation for the 
available visit data from TTP488-303.  
Additional supportive analyses will be done for which data displays are not planned. 
Descriptive summaries will be produced of the observed values and change from Baseline in 
efficacy 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. 
5.1.2 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.   
Subgroup analyses may 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 ANCOVA 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 MMSE, an ANCOVA analysis similar to that described for the 
co-primary endpoints will be performed, with baseline MMSE as a continuous covariate.   
For change from Baseline in ADCS-ADL, an ANCOVA analysis similar to that described for the 
co-primary variables of interest will be performed, with baseline ADCS-ADL as a continuous 
covariate. 
For change from Baseline in NPI, an ANCOVA 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.  


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5.1.3 Subgroup Analyses 
Subgroups may be defined post-hoc.  
5.2 
Disposition, Demography, and Baseline Characteristics  
A tabulation of subject disposition will be presented, including the number 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 enrolled 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 
 MMSE category (mild or moderate) 
 MMSE, ADAS-cog, CDR-sb, CDR-global, ADCS-ADL 
 ApoE status 
 Education level 
 Background AD medications (ACHEI, Memantine, Both). 
5.3 
Analysis of Safety Data 
5.3.1 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 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).  


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 Number (percent) of subjects reporting TEAE by treatment and overall in accordance 
with variables listed in Section 4.2.1.  
Supportive listings will be constructed that includes the subject identification, the treatment 
group (based on randomization from TTP488-301 and the pooled group of enrollees from 
TTP488-303), TEAEs, MedDRA terms, seriousness, severity, causality, elapsed time to onset, 
duration, and outcome.  
Methodology for AESIs will follow the same methodology for TEAEs. 
5.3.2 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.  
 
5.3.3 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.  
 
5.3.4 Liver 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 


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(2) An accompanying abnormal bilirubin of at least 2-times the upper limit of normal.  
5.3.5 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.  
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 Fridericia’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 
Pharmacokinetics Analysis 
5.4.1 Methodology for PK Analysis 
Data resulting from blood sampling for trough concentrations of azeliragon and its metabolites 
TTP1494, TTP2266, and TTP2123 will be collected and analyzed using descriptive statistical 
methods.    
No formal inferential statistics will be applied to the pharmacokinetic data. Potential 
relationships between azeliragon concentrations and treatment effects may be examined.  
5.5 
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. 


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5.6 
Concomitant Medications 
Concomitant medications will be summarized by drug category and listed. 
6 
Data Conventions 
The following analysis conventions will be used in the statistical analysis.  
6.1 
Definition of Baseline 
Two baselines will be used in this study: (1) the latest assessment prior to the first dose of 
double-blind study drug, and (2) the latest assessment prior to the first dose of open-label study 
drug. For safety evaluations, the Baseline assessment for all measurements will be the latest 
available, valid measurement taken prior to the initiation of study medication in TTP488-303.  
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. 
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 
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 


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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. 
6.6 
Values Below LLQ 
Concentrations for TTP488 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 9.4 or later. 
 
 


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9 
Data Displays 
The plans for displaying data will be appropriate for open-label extension studies.  
Planned displays will include, but are not limited to, the following: 
 Summary of Accountability (number 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 PD Data 
 Summary of Efficacy Data (ADAS-cog, CDR-sb, CDR-global, MMSE, ADCS-ADL, 
NPI) 
 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 
 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 azeliragon, TTP1494, TTP2266, TTP2123 Concentration Data 
 Listing of plasma Aβ (total, 1-40 and 1-42) 
 
 
 
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. Biometrikia, Volume 63, 
Issue 3 (Dec., 1976), 581-592.   
 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. 
 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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 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. 
 


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12 Schedule of Time and Events  
SCHEDULE OF ACTIVITIES  
 
Protocol Activity 
Baseline 
Treatment 
Early 
Term 
 
Month 18 of 
TTP488-301 
study 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Month 
15 
Month 
18 
Month 
21 
Month 
24 
 
Study Days 
 
90 
180 
270 
360 
450 
540 
630 
720 
 
Window 
 
±14d ±14d ±14d 
±14d 
±14d 
±14d 
±14d 
±14d 
 
Sign informed consent / 
provide assent   
X* 
 
 
 
 
 
 
 
 
 
Registration  
X* 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
Criteria   
X* 
 
 
 
 
 
 
 
 
 
Body weight   
X 
 
X 
 
X 
 
X 
 
X 
X 
Brief Neuro & Physical 
Exams   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review Concomitant 
Medications   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Pressure and Pulse Rate 
(sitting or supine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECG   
X 
 
X 
 
X 
 
X 
 
X 
X 
Adverse Events Assessment   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Dispensing / 
Accountability 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Dosing   
X* 
 
 
 
 
 
 
 
 
 
MMSE   
X 
 
X 
 
X 
 
X 
 
X 
X 
ADAS-cog   
X 
X 
X 
X 
X 
 
X 
 
X 
X 
CDR  
X 
 
X 
 
X 
 
X 
 
X 
X 
NPI   
X 
 
X 
 
X 
 
X 
 
X 
X 
ADCS-ADL 
X 
 
X 
 
X 
 
X 
 
X 
X 
COWAT 
X 
 
X 
 
X 
 
X 
 
X 
X 
CFT 
X 
 
X 
 
X 
 
X 
 
X 
X 
TMT 
X 
 
X 
 
X 
 
X 
 
X 
X 
Columbia Suicide Severity 
Scale (C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RUD-lite   
X 
 
X 
 
X 
 
X 
 
X 
X 
DEMQOL-proxy   
X 
 
X 
 
X 
 
X 
 
X 
X 
Hematology   
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood Chemistry  
(incl HbA1c)  
X 
 
X 
 
X 
 
X 
 
X 
X 
Pharmacokinetic Blood 
Sampling   
X 
 
X 
 
X 
 
X 
 
X 
X 
Pharmacodynamic blood 
sampling (Aβ)   
X 
 
X 
 
X 
 
X 
 
X 
X 
*procedures unique to OLE.  All other baseline procedures are required TTP488-301 Month 18 procedures and are 
not repeated as part of the TTP488-303 baseline visit.