Conditions: Alzheimer Disease
Keywords: Receptor for Advanced Glycation Endproducts (RAGE) ADAS-cog CDR-sb
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 43
Healthy volunteers: no

Brief summary:
This is a study to evaluate the efficacy and safety of azeliragon in patients with mild Alzheimer's disease and impaired glucose tolerance. Patients will receive either azeliragon or placebo with a patient's participation lasting approximately 9 months (in Part 1) or 21 months (in Part 2).

Detailed description:

Arms:
arm 1: Azeliragon 5mg capsule administered orally, once daily for 6 months (Part 1) or 18 months (Part 2) arm 2: Matching placebo capsule administered orally, once daily for 6 months (Part 1) or 18 months (Part 2)

Interventions: intervention 1: Azeliragon intervention 2: Placebo
Intervention descriptions: intervention 1: Azeliragon 5 mg capsule administered orally, once daily intervention 2: Matching placebo capsule administered orally, once daily

Protocol document:
Prot_000.pdf: 
 
 
 
 
vTv THERAPEUTICS LLC 
 4170 MENDENHALL OAKS PKWY 
 HIGH POINT, NC 27265 
 
 
TITLE PAGE 
 
CLINICAL TRIAL PROTOCOL  
 
 
RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, MULTICENTER 
STUDIES TO EVALUATE THE SAFETY AND EFFICACY OF AZELIRAGON AS A 
TREATMENT FOR SUBJECTS WITH MILD ALZHEIMER’S DISEASE AND 
IMPAIRED GLUCOSE TOLERANCE 
 
 
Investigational Product:     
TTP488 
Investigational Product Name:    
azeliragon 
US IND Number:     
 
IND 68,445 
Health Canada File Number: 
TBD 
EudraCT Number:  
 
NA 
Protocol and Study Number:    
TTP488-305 
Clinical Phase: 
 
 
Phase 2/3 
Version and Date: 
 
 
29 APRIL 2019 
 
 
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
1


 
SIGNATURE CONFIRMATION PAGE 
 
 
 
 
Investigational Product: 
Azeliragon (TTP488)  
Study Number: 
 
TTP488-305 
Protocol Title:  
RANDOMIZED, DOUBLE-BLIND, PLACEBO 
CONTROLLED, MULTICENTER STUDIES TO 
EVALUATE THE SAFETY AND EFFICACY OF 
AZELIRAGON AS A TREATMENT FOR SUBJECTS WITH 
MILD ALZHEIMER’S DISEASE AND IMPAIRED 
GLUCOSE TOLERANCE 
Protocol Dated: 
29 APRIL 2019 
 
 
I have reviewed and approved of the protocol listed above. 
 
 
Louis Kirby, M.D. 
 
 
________________________________________________ 
 
Responsible Medical Officer  
 
 
 
 
Signature  
 
 
Date 
vTv Therapeutics LLC 
 
 
Imogene Dunn, Ph.D. 
 
 
________________________________________________ 
 
Senior Vice President, Biometrics and Regulatory Affairs 
 
Signature  
 
 
Date 
vTv Therapeutics LLC 
 
 
Aaron Burstein, Pharm.D. 
 
 
________________________________________________ 
 
Senior Vice President, Clinical Development  
 
 
Signature  
 
 
Date 
vTv Therapeutics LLC  
 
04-29-2019
04-29-2019
04-29-2019
2


Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
 
 
High Point, NC 27265 
 
 
 
Page 3 
Document Revision History 
Document 
Version Date 
Summary of Changes 
Original Protocol 
29 April 2019 
N/A 
 
 
 
 
3


Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
 
 
High Point, NC 27265 
 
 
 
Page 4 
PROTOCOL SYNOPSIS 
Study Number:  TTP488-305 
Phase:  2/3 
 
Title of Study: 
Randomized, double-blind, placebo-controlled, multicenter studies to evaluate the safety and efficacy of 
azeliragon as a treatment for subjects with mild Alzheimer’s disease and impaired glucose tolerance 
Objectives: 
PART 1 
The primary objective of this study is: 
 
To evaluate the impact of 6 months of treatment with oral azeliragon on cognitive performance 
The secondary objectives of this study are: 
 
To evaluate the efficacy of azeliragon treatment on measures of function and activities of daily 
living  
 
To evaluate the efficacy of azeliragon treatment on complications of diabetes 
 
To evaluate the safety and tolerability of 6 months of azeliragon treatment  
 
To evaluate the effect of azeliragon treatment on biomarkers and markers of inflammation  
 
PART 2 
The primary objective of this study is: 
 
To evaluate the efficacy of 18 months of treatment with oral azeliragon on cognition and global 
function  
The secondary objectives of this study are: 
 
To evaluate the safety and tolerability of azeliragon treatment. 
 
To evaluate the efficacy of azeliragon treatment on activities of daily living, behavior, and 
quality of life 
 
To evaluate the efficacy of azeliragon treatment on complications of diabetes 
 
To evaluate the effect of azeliragon treatment on biomarkers and markers of inflammation 
Endpoints 
PART 1 
Primary Endpoint: 
 
Change from Baseline in the ADAS-cog14 at Month 6 
Secondary Endpoints: 
 
Change from Baseline in the CDR-sb at Month 6 
 
Change from Baseline in the FAQ at Month 6 
 
Change from Baseline in the Amsterdam-IADL at Month 6 
 
Change from Baseline in eGFR at Month 6 
 
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Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
 
 
High Point, NC 27265 
 
 
 
Page 5 
Study Number:  TTP488-305 
Phase:  2/3 
 
Safety Endpoints: 
 
Adverse events, clinical laboratory tests, vital signs, 12-lead ECG, C-SSRS  
PART 2 
Co-Primary Endpoints: 
 
Change from Baseline in the ADAS-cog14 at Month 18 
 
Change from Baseline in CDR-sb at Month 18 
Secondary Endpoints: 
 
Responder status at Months 6, 12, and 18 based on the ADAS-cog14 
 
Change from Baseline in FAQ score at Month 18 
 
Change from Baseline in Amsterdam-IADL score at Month 18 
 
Change from Baseline in MMSE score at Month 18 
 
Change from Baseline in eGFR at Month 18 
 
Change from Baseline in whole brain volume at Month 18 
Safety Endpoints: 
 
Adverse events, clinical safety laboratory tests, ECG, vital signs, C-SSRS 
Exploratory Endpoints:   
 
Change from Baseline at Month 18 for measures of behavior and quality of life (NPI, DEMQOL-
proxy) 
 
Change from Baseline at Months 3, 6, and 12 for the primary and secondary measurements:  
ADAS-cog14, FAQ, Amsterdam-IADL, CDR-sb, MMSE, NPI, DEMQOL-proxy. 
 
Change from Baseline in plasma concentrations of Aβ species at Month 18 
 
Change from Baseline in brain MRI (hippocampal, ventricular) volumetric measures at Month 18
Study Design: 
TTP488-305 is a protocol that consists of two sequential, multi-center, randomized, double-blind, 
placebo-controlled, parallel group studies to evaluate the safety and efficacy of oral azeliragon 5 mg/day 
relative to placebo in approximately 300 subjects (100 Part 1, 200 Part 2) with mild AD (screening MMSE 
21-26, baseline MMSE 19-27 and ADAS-cog14 score of ≥10) and impaired glucose tolerance (Screening 
HbA1c 6.5% -9.5%, inclusive).  Eligible participants will be randomly assigned to azeliragon or placebo 
in a 1:1 randomization for a double-blind dosing period of 6 months (Part 1) or 18 months (Part 2).  The 
Part 1 and Part 2 studies will have independently randomized, unique study populations. 
 
The Part 1, 6-month, double-blind treatment portion of the study will include 5 clinic visits.  The primary 
objective of the Part 1 portion is to evaluate the efficacy of 6 months of oral azeliragon on a measure of 
cognition (ADAScog14).  Secondary objectives of Part 1 will be to evaluate the efficacy of 6 months of 
oral azeliragon on multiple measures of function to inform selection of a functional endpoint to serve as 
co-primary in Part 2, as well as the sample size required to adequately power the study to detect treatment 
effect on cognitive and functional measures in the study population.  Upon completion of Part 1, a 
subject’s participation is considered complete and they will not be permitted to participate in Part 2.   
 
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Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
 
 
High Point, NC 27265 
 
 
 
Page 6 
Study Number:  TTP488-305 
Phase:  2/3 
 
The Part 2, 18-month, double-blind treatment portion of the study will include 9 clinic visits.  Part 2 will 
enroll 200 subjects who will be randomized to receive oral azeliragon 5 mg/day or placebo in a 1:1 
randomization.    
Study Drug, Doses and Mode of Administration: 
Azeliragon and matching placebo will be administered orally once daily.   
 
5 mg azeliragon 
 
Placebo  
Number of Study Participants Planned:  
Part 1: 
100 subjects in 2 treatment groups (approximately 50 subjects per arm) 
Part 2: 
200 subjects in 2 treatment groups (approximately 100 subjects per arm) 
Subject Selection 
Subject eligibility must 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.   
 
Inclusion Criteria 
1. 
Evidence of a personally signed and dated informed consent document indicating that the subject (or 
a legally authorized representative) and caregiver/informant has been informed of all pertinent 
aspects of the study.  Participants must be able to provide consent or assent (where this is in 
accordance with local laws, regulations and ethics committee policy) and consent/assent must be 
re-evaluated during the study at regular intervals. 
2. 
Male or female subjects aged 50-85 years (inclusive) at Screening Visit. 
3. 
Female subjects must be of non-child-bearing potential.  Male subjects with female partners of 
childbearing potential must agree to acceptable birth control for the duration of the study and for 
90 days thereafter. 
4. 
If on pharmacological treatment for diabetes, must be on stable dose for at least 60 days prior to 
screening and remain stable through Baseline.  There should be expectation that treatment and dose 
will remain stable during the study period.   
5. 
Clinical diagnosis of probable Alzheimer’s disease, consistent with the criteria from the 2011 
National Institute on Aging and Alzheimer’s Association workgroup [McKhann 2011], for at least 
2 months prior to Screening.  Evidence of progression must be documented in source documentation 
at the time of screening based on review of prior medical records and/or information gathered from 
the subject or caregiver/informant(s).   
6. 
Mini-Mental State Exam (MMSE) score of 21-26 inclusive at Screening and 19-27 at Baseline.   
7. 
CDR global score of 0.5 or 1 at Screening and Baseline. 
8. 
ADAS-cog14 score of ≥ 10 at Screening and Baseline.  
 
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Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
 
 
High Point, NC 27265 
 
 
 
Page 7 
Study Number:  TTP488-305 
Phase:  2/3 
 
9. 
Participant must be on a stable dose of a background cholinesterase inhibitor and/or memantine 
(approved by relevant health authority where trial is being conducted) at least 60 days prior to 
Screening and remain stable through Baseline.  There must be agreement not to change the treatment 
or dose during the study period unless the investigator judges that the dose needs to be reduced or 
stopped due to a safety and/or tolerability reason. 
10. Hemoglobin A1c (HbA1c) 6.5% - 9.5%, inclusive, at Screening. 
11. Body mass index (BMI) 19.0 – 37.0 kg/m2, inclusive, at Screening Visit and Baseline Visit. 
12. Body weight at least 45.0 kg at Screening Visit and Baseline Visit. 
13. Participants and caregiver/informants who are willing and able to comply with scheduled visits, 
treatment plan, laboratory tests, and other study procedures. 
14. The subject must have a reliable caregiver/informant with regular contact (i.e., 10 hours a week as 
combination of face-to-face visits and telephone contact acceptable) who will facilitate the subject’s 
full participation in the study.  Caregiver/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, 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. 
15. 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. 
16. Subject must be able to ingest oral medications. 
 
Exclusion Criteria 
Participants presenting with any of the following will be excluded from participation in the study. 
1. 
Current evidence or history of neurological or any other illness that could contribute to dementia 
including, but not limited to, other neurocognitive disorders (e.g., Lewy body disease, fronto-
temporal dementia, Parkinson disease), HIV cognitive impairment, head injury with loss of 
consciousness proximate to the onset of dementia, vitamin B12 deficiency (see Exclusion 3, below), 
or thyroid disease (unless adequately treated for at least 3 months with normalization of laboratory 
values). 
2. 
Participants from a family with known autosomal dominant AD associated with mutations in APP, 
PS1 or PS2 genes or strongly suspected, but not yet identified mutations in APP, PS1 or PS2 genes, 
or Down’s syndrome.  Individuals from families with any number of late onset AD affected family 
members may participate in this study. 
3. 
Vitamin B12 levels lower than laboratory reported normal limits (and remains below on repeat 
testing).  Participants may be enrolled following the initiation of B12 therapy for 4 weeks prior to 
dosing and confirmed within normal limits upon repeat. 
4. 
Evidence of neurologic deficits from a previous stroke or MRI changes consistent with multi-infarct 
dementia.  Diagnosis or any history of cerebrovascular stroke, severe carotid stenosis, cerebral 
hemorrhage, intracranial tumor, subarachnoid hemorrhage that, as determined by the investigator, 
could either contribute to the patient’s current cognitive or functional status, impair his/her ability to 
fully participate in the trial or that may impact his/her status during the course of the trial. 
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Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
 
 
High Point, NC 27265 
 
 
 
Page 8 
Study Number:  TTP488-305 
Phase:  2/3 
 
5. 
Specific exclusionary brain MRI findings (as identified on the central MRI read) as determined by 
the investigator that could either significantly contribute to the patient’s current cognitive or 
functional decline, impair his/her ability to fully participate in the trial or that may impact his/her 
status during the course of the trial.  In any case, the following are exclusionary: 
a. 10 or more microhemorrhages, as identified by the central reading report. 
b. Grade three deep white matter changes (diffuse involvement of entire region) on the central 
reading report.   
6. History of schizophrenia or late onset (after age 40) bipolar disorder.  Current or recent (within 6 
months prior to Screening) clinically relevant or unstable psychiatric disorder (e.g., major depressive 
disorder) that, per the investigator’s judgment, could significantly contribute to the patient’s current 
cognitive or functional decline, impair his/her ability to fully participate in the trial, or may impact 
his/her status during the course of the trial. 
7. Serious suicide risk per the following criteria: 
a. Suicidal ideation associated with intent and/or plan within the previous year as indicated by a 
“yes” answer on Items 4 or 5 of the C-SSRS; 
b. History of suicidal behavior within the previous 10 years as indicated by a “yes” answer to any 
of the suicidal behavior items of the C-SSRS with a behavior occurring within the previous 
10 years; 
c. Lifetime history of serious or recurrent suicidal behavior (serious is defined as actual 
lethality/medical damage score > 2 on Screening C-SSRS)  
8. History of cancer within the last 5 years except adequately treated cervical carcinoma in-situ, 
cutaneous basal cell or squamous cell cancer, or non-progressive prostate cancer not requiring 
current treatment. 
9. Participants with poorly controlled hypertension with or without existing therapy (ex: systolic≥140 
mmHg or diastolic ≥90 mmHg with repeated measures) at Screening or Baseline.  Subjects with 
repeated measures of systolic≥140 mmHg or diastolic ≥90 mmHg at Screening will be allowed to 
participate with management of blood pressure below the exclusionary levels with introduction of 
an allowable medication and the subject has been on the drug for 4 weeks prior to Baseline.  Subjects 
with repeated measures of systolic ≥140 mmHg or diastolic ≥90 mmHg at Baseline will be excluded. 
10. Participants with evidence or history of severe drug allergies (such as resulting in dyspnea or severe 
rash) or allergy to any constituents of the study drug as formulated. 
11. Known history or current evidence of moderate to severe substance use disorder according to DSM-5 
criteria within 1 year prior to Screening or a positive result on the drug screening test (unless due to 
a permitted concomitant medication [e.g., a benzodiazepine as a sleep aid]). 
12. Subjects with pulmonary hypertension are excluded. 
13. Previous participation and dosing in another clinical trial for Alzheimer’s disease as follows: 
a. Exposure to putative disease modifying therapies within 1 year before Screening Visit is 
exclusionary, unless placebo treatment assignment is documented. 
b. Exposure to symptomatic therapy within 90 days (or five half-lives, whichever is longer) before 
Screening Visit is exclusionary. 
Any clinical trial (Alzheimer’s or non-Alzheimer’s) study visit within 90 days before the Screening 
Visit is exclusionary regardless of treatment assignment. 
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Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
 
 
High Point, NC 27265 
 
 
 
Page 9 
Study Number:  TTP488-305 
Phase:  2/3 
 
14. 
Participants who are taking or are expected to use drugs known to be strong CYP2C8 
inhibitors. 
15. 
Participants receiving systemic steroids.  Topical corticosteroid application to the skin is 
allowed, as are localized corticosteroid injections if administered no more than once every 6 
months during the last year and are expected to be administered no more frequently during 
the study.  Use of inhaled, intranasal or otic steroids are not excluded.  
16. 
Participants receiving medications that may negatively affect cognitive function (e.g., 
antidepressants, antipsychotics, sedatives/anxiolytics) unless such medications have been 
taken at a stable dose for at least 4 weeks prior to enrollment (i.e., in the investigator’s 
judgment, efficacy and tolerability have been optimized) and are expected to continue on a 
stable dose for the duration of the trial. 
17. 
Prescription medical food (i.e., Axona) intended for the dietary management of the metabolic 
processes associated with Alzheimer’s disease. 
18. 
Participants may not donate blood within 8 weeks prior to enrollment and for 6 months after 
the last administration of study drug. 
19. 
History of clinically significant or current unstable cardiac disease as determined by the PI 
and in consultation with the Sponsor.  Examples of cardiac disease that would be exclusionary 
include 2nd degree or greater heart block without a pacemaker, sick sinus syndrome, 
ventricular tachycardia or fibrillation, sustained supraventricular tachycardia, symptomatic 
bradycardia, congenital long QT interval syndrome, atrial fibrillation, clinically significant 
angina/coronary artery disease, myocardial infarction in the past year, congestive heart 
failure, cardiomyopathy, myocarditis, left ventricular hypertrophy, valvular heart disease 
requiring treatment or life style modification. Subjects with atrial fibrillation on anticoagulant 
therapy and who have had no thromboembolic events or other referable cardiac events in the 
preceding 1 year are considered stable and may be screened.  
20. 
Participants demonstrating QTcF > 470 msec on Screening 12-lead ECG (confirmed with a 
repeat measure).  Participants with known history of bundle branch block (either right or left) 
are allowed if QTcF value does not exceed 500 msec.  Participants with a functioning 
pacemaker, indicated by an ECG displaying paced rhythm, are allowed with no QTcF upper 
limit. 
21. 
History of diabetic ketoacidosis within the last year. 
22. 
History of  more than one severe episode of hypoglycemia that required assistance by a third 
party within the past year. 
23. 
History of chronic pancreatitis. 
24. 
Current clinically significant hepatic disease or elevated LFTs ≥ 2 times the upper limit of 
normal (ULN) at Screening. 
25. 
Stage 4 kidney disease (estimated GFR < 30 mL/min/1.73 m2, as calculated by the CKD-EPI 
equation [Levey 2009]). 
26. 
Any laboratory value not already specified above that is outside the laboratory reference 
range and considered by the Principal Investigator, or appropriately qualified designee, to be 
a clinically significant abnormality. 
27. 
Use of insulin therapy. 
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Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
 
 
High Point, NC 27265 
 
 
 
Page 10 
Study Number:  TTP488-305 
Phase:  2/3 
 
28. 
Any other medical condition or reason that, in the opinion of the Principal Investigator or 
appropriately qualified designee, makes the subject unsuitable to participate in this clinical 
trial. 
 
Eligibility for randomization will be reviewed and approved by an independent Randomization 
Authorization Committee.  The remit of this committee will be to ensure each patient deemed by the 
Investigator to be eligible for the trial meets key eligibility criteria and is suitable for participation in the 
study.    
10


Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
 
 
High Point, NC 27265 
 
 
 
Page 11 
Study Number:  TTP488-305 
Phase:  2/3 
 
Statistical Methods: 
Population of Analysis: 
The following population of analysis will be used for all statistical analysis: 
 
The full analysis set (FAS) includes all randomized subjects who receive any study medication 
and have at least one post-Baseline assessment. 
 
The per protocol set (PPS) includes all subjects in the FAS, except for those who are excluded 
because of major protocol violations, where a major protocol violation is one that may affect the 
interpretation of study results (e.g., taking less than 50% of prescribed study medication during 
participation). 
 
The safety set (SAF) includes all subjects who receive any study medication. 
The FAS will be used for all hypothesis tests of efficacy. The PPS is used for supportive efficacy analysis. 
The SAF will be used for safety analyses. 
Sample size considerations for Part 1:  
Assuming a standard deviation of the change from Baseline to Month 6 in ADAS-cog14 of 4, using alpha 
= 0.05, a total sample size of approximately 82 subjects in balanced allocation (41 subjects per group) 
provides at least 90% power to detect a difference between treatment groups of 2.9 using a 2-sided, 
2-sample t-test.  Assuming a dropout rate of 18% or less, randomization of 100 subjects provides adequate 
statistical power for Part 1 to demonstrate superiority of azeliragon over placebo based on the 
ADAS-cog14. 
Sample size considerations for Part 2:  
Assuming a standard deviation of the change from Baseline to Month 18 in ADAS-cog14 of 7.5, using 
alpha = 0.049, a total sample size of 120 subjects in balanced allocation (60 subjects per group) provides 
at least 90% power to detect a difference between treatment groups of 4.5 using a 2-sided, 2-sample t-test.  
Assuming a dropout rate of 25% or less, randomization of 160 subjects provides adequate statistical power 
for Part 2 to demonstrate superiority of azeliragon over placebo based on the ADAS-cog14. 
Statistical methods: 
The primary analysis will use the intent-to-treat (ITT) methodology and a main-effects model for analysis 
of covariance with baseline ADAS-cog14 as a covariate on change from baseline to endpoint in 
ADAS-cog14 using multiple-imputation methods for coping with missing data. The primary analysis will 
be supported by a mixed-models repeated measures (MMRM) analysis with adjustment for baseline 
ADAS-cog14 measures.  Similar methodology will be used for the functional endpoints (CDR-sb, FAQ, 
Amsterdam IADL). The primary analysis will also be supported by ANCOVA using last-observation-
carried-forward (LOCF) methods, and also an observed cases analysis (no imputation, no deletion) will 
be done. The supportive MMRM analysis will include treatment, time and treatment-by-time interaction 
as fixed effects, baseline as covariate and subject as a random effect.  Supportive modeling will also 
include MMRM main-effects model with treatment, time, and subject. The same statistical methodology 
will be applied to the functional endpoints. A conditional sequence of statistical hypotheses will be used 
to control alpha with the ADAS-cog14 being tested first, and conditional on statistical significance, testing 
will proceed to CDR.  
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Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
 
 
High Point, NC 27265 
 
 
 
Page 12 
Study Number:  TTP488-305 
Phase:  2/3 
 
Descriptive summaries will be produced of the observed values and change from baseline in co-primary 
variables by treatment group at each individual time point and at endpoint (final on-treatment assessment 
for each subject).   
In accordance with FDA guidance on adaptive studies, the planned features of the confirmatory phase 
(Part 2) are pre-specified. The features subject to modification informed by the learning phase of the study 
(Part 1) are: 
 
Primary endpoint for Part 2 
 
Sample size for Part 2 
 
Study duration for Part 2 
 
Eligibility for Part 2 
 
Dose of study drug for Part 2 
 
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4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 13 
Table 1. 
Part 1 Schedule of Activities 
Protocol Activity 
Screening 
Baseline 
Treatment Perioda 
Follow-upb 
Day -60 to 
Day -1 
Day -7 to 
Day 1 
Day 1c 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 / 
ET 
3 months 
after last 
dose 
Study Days 
-60 to -1 
-7 to 1 
1 
30 
60 
90 
120 
150 
180 or ET 
270 
Window 
 
 
 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
Sign informed consent / provide 
assentd 
X 
 
 
 
 
 
 
 
 
 
Assessment of continued 
consent/assent 
 
X 
 
 
 
X 
 
 
X 
X 
Assign Screening ID 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
Medical History/Surgical History / 
Drug, Alcohol, Tobacco Use History 
X 
 
 
 
 
 
 
 
 
 
Complete Neuro Exam & Physical 
Exam 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
ApoE genotyping 
 
X 
 
 
 
 
 
 
 
 
Telephone Contact 
 
 
 
X 
X 
 
X 
X 
 
 
Body weight 
X 
X 
 
 
 
X 
 
 
X 
X 
BMI calculation 
X 
 
 
 
 
 
 
 
 
 
Brief Neuro & Physical Exams 
 
X 
 
 
 
X 
 
 
X 
X 
Review Concomitant Medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood Pressure and Pulse Rate 
(supine) e 
X 
Xe 
 
 
 
X 
 
 
X 
X 
12 Lead ECGe 
Xf 
Xe 
 
 
 
X 
 
 
X 
X 
Adverse Events Assessment 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
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Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
Table 1. 
Part 1 Schedule of Activities (continued) 
 
 
Page 14 
Protocol Activity 
Screening 
Baseline 
Treatment Perioda 
Follow-upb 
Day -60 to 
Day -1 
Day -7 to 
Day 1 
Day 1c 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 / 
ET 
3 months 
after last 
dose 
Study Days 
-60 to -1 
-7 to 1 
1 
30 
60 
90 
120 
150 
180 or ET 
270 
Window 
 
 
 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
Dispense / Return Study Drug / 
Drug Accountability 
 
 
X 
 
 
X 
 
 
X 
 
Study Drug Dosinga,c 
 
 
X 





 
MMSEg 
X 
X 
 


X
 
 
Xh
X 
ADAS-cog14g 
X 
X 
 


X 
 
 
Xh 
X 
CDRg 
X 
X 
 
 
 
X 
 
 
Xh 
X 
FAQ 
 
X 
 
 
 
X 
 
 
Xh 
X 
Amsterdam-IADL 
 
X 
 
 
 
X 
 
 
Xh 
X 
Columbia Suicide Severity Scale 
(C-SSRS)i 
X 
X 
 
 
 
X 
 
 
X 
X 
Fasting Central Lab Blood and 
Urine Collectionj 
X 
X 
 
 
 
X 
 
 
X 
X 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
Provide meal/snackk 
X 
X 
 
 
 
X 
 
 
X 
X 
Blood glucose measurementl 
X 
X 
 
 
 
X 
 
 
X 
X 
Brain MRIm 
X 
 
 
 
 
 
 
 
 
 
Blood Sample for PK, PD and 
Plasma Retention and Storage 
 
X 
 
 
 
X 
 
 
X 
X 
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Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
Table 1. 
Part 1 Schedule of Activities (continued) 
 
 
Page 15 
a 
Participants will receive azeliragon 5 mg once daily, or matching placebo during the treatment period. 
b 
Follow-up visit required for all participants who dosed with study medication.  A Follow-up Visit should be completed 3 months after a subject completes Month 6 for those participants who 
complete the study; or at least 45 days after the last dose of study drug if the subject discontinues the study prior to Month 6.     
c 
Subject begins taking study medication in the clinic as soon as baseline procedures are completed, and eligibility confirmed.  Date of first dose is noted as Day 1.  
d 
Where assent is in accordance with local laws, regulations and ethics committee policy. 
e 
Vitals and ECG will be measured in triplicate at Baseline and as single values at all other times.  An average of the three measurements for ECG and blood pressure will be used 
for eligibility determination. 
f 
ECG at Screening visit repeated if QTc > 470 msec. 
g 
Neuropsychological assessments are not to be performed with fasted participant; ensure participant has been fed and meets blood glucose measurement requirements prior to 
any neuropsychological assessments. 
h 
Neuropsychological assessments are performed at the Early Termination Visit only when the visit is within 30 days of the last dose of study drug. 
i 
C-SSRS is administered to subject jointly with caregiver. 
j 
Blood Chemistry sample is collected in a fasted state (8-hour fast). 
k 
Provide a low carbohydrate/high protein meal or snack after fasting blood samples are drawn and before any neuropsychological assessments are performed.   
l 
Blood glucose measurement is an in-office point of care measurement after an appropriate period following the meal/snack, and prior to neuropsychological assessments are 
performed.   
m CT scan may be utilized for subjects with contraindication to MRI.  MRI or CT should be done at least 14 days prior to the baseline visit to allow time for MRI report to support 
eligibility decision. 
 
15


Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 16 
Table 2. 
Part 2 Schedule of Activities 
Protocol Activity 
Screening 
Baseline 
Treatment Perioda 
Follow-
upb 
Day -60 to 
Day -1 
Day -7 to 
Day 1 
Day 1c 
Month 1
Month 2
Month 3
Month 6
Month 9
Month 12 Month 15
Month 18 
/ET 
3 months 
after last 
dose 
Study Days 
-60 to -1 
-7 to 1 
1 
30 
60 
90 
180 
270 
360 
450 
540 or ET
630 
Window 
 
 
 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
± 7d 
Sign informed consent / 
provide assentd 
X 
 
 
 
 
 
 
 
 
 
 
 
Assessment of continued 
consent/assent 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Assign Screening ID 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Medical History / Surgical 
History / Drug, Alcohol, 
Tobacco Use History 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Neuro Exam & 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
ApoE genotyping 
 
X 
 
 
 
 
 
 
 
 
 
 
Telephone contact 
 
 
 
X 
X 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
BMI calculation 
X 
 
 
 
 
 
 
 
 
 
 
 
Brief Neuro & Physical Exams 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Review Concomitant 
Medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Pressure and Pulse Rate 
(supine) 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
16


Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
Table 2. 
Part 2 Schedule of Activities (continued) 
 
 
Page 17 
Protocol Activity 
Screening 
Baseline 
Treatment Perioda 
Follow-
upb 
Day -60 to 
Day -1 
Day -7 to 
Day 1 
Day 1c 
Month 1
Month 2
Month 3
Month 6
Month 9
Month 12 Month 15
Month 18 
/ET 
3 months 
after last 
dose 
Study Days 
-60 to -1 
-7 to 1 
1 
30 
60 
90 
180 
270 
360 
450 
540 or ET
630 
Window 
 
 
 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
± 7d 
12 Lead ECGe 
Xf 
Xe 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Assessment 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense / Return Study Drug / 
Drug Accountability 
 

X 
 
 
X
X 
X
X 
X 
X 
 
Study Drug Dosinga,c 
 
 
X


 

 
 
 
 
MMSEg 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Xh 
X 
ADAS-cog14g 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Xh 
X 
CDRg 
X 
X 
 
 
 
X 
X 
 
X 
 
Xh 
X 
FAQ 
 
X 
 
 
 
X 
X 
 
X 
 
Xh 
X 
Amsterdam-IADL 
 
X 
 
 
 
X 
X 
 
X 
 
Xh 
X 
NPI 
 
X 
 
 
 
X 
X 
 
X 
 
Xh 
X 
DEMQOL-proxy 
 
X 
 
 
 
X 
X 
 
X 
 
Xh 
X 
Columbia Suicide Severity 
Scale (C-SSRS)i 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Fasting Central Lab Blood and 
Urine Collectionj 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Provide meal/snackk 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Blood glucose measurementl 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Brain MRIm 
X 
 
 
 
 
 
 
 
 
 
X 
 
Blood Sample for PK, PD, and 
Plasma Retention and Storage 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
17


Azeliragon 
 
 
vTv Therapeutics LLC 
 
 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
Table 2. 
Part 2 Schedule of Activities (continued) 
 
 
Page 18 
a 
Participants will receive azeliragon 5 mg once daily, or matching placebo during the treatment period. 
b 
Follow-up visit required for all participants who dosed with study medication.  A Follow-up Visit should be completed 3 months after a subject completes Month 18 for those participants who 
complete the study; or at least 45 days after the last dose of study drug if the subject discontinues the study prior to Month 18.    
c 
Subject begins taking study medication in the clinic as soon as baseline procedures are completed, and eligibility confirmed.  Date of first dose is noted as Day 1.  
d 
Where assent is in accordance with local laws, regulations and ethics committee policy. 
e 
Vitals and ECG will be measured in triplicate at Baseline and as single values at all other times.  An average of the three measurements for ECG and blood pressure will be used 
for eligibility determination. 
f 
ECG at Screening visit repeated if QTc > 470 msec. 
g 
Neuropsychological assessments are not to be performed with fasted participant; ensure participant has been fed and meets blood glucose measurement requirements prior to 
any neuropsychological assessments. 
h 
Neuropsychological assessments are performed at the Early Termination Visit only when the visit is within 30 days of the last dose of study drug. 
i 
C-SSRS is administered to subject jointly with caregiver. 
j 
Blood Chemistry sample is collected in a fasted state (8-hour fast). 
k 
Provide a low carbohydrate/high protein meal or snack after fasting blood samples are drawn and before any neuropsychological assessments are performed.   
l 
Blood glucose measurement is an in-office point of care measurement after an appropriate period following the meal/snack, and prior to neuropsychological assessments are 
performed.   
m CT scan may be utilized for subjects with contraindication to MRI.  MRI or CT should be done at least 14 days prior to the baseline visit to allow time for MRI report to support 
eligibility decision. 
 
18


Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 19 
TABLE OF CONTENTS 
 
Page 
 
TITLE PAGE ............................................................................................................................................................ 1 
SIGNATURE CONFIRMATION PAGE ................................................................................................................. 2 
PROTOCOL SYNOPSIS ......................................................................................................................................... 4 
LIST OF TABLES .................................................................................................................................................. 23 
LIST OF FIGURES ................................................................................................................................................ 23 
LIST OF ABBREVIATIONS ................................................................................................................................. 24 
1.0 
INTRODUCTION .............................................................................................................................. 26 
1.1 
BACKGROUND AND RATIONALE ................................................................................................ 26 
1.1.1 
Dementia and Diabetes ....................................................................................................... 26 
1.1.2 
Mechanism of Action .......................................................................................................... 27 
1.1.3 
Clinical Studies ................................................................................................................... 28 
1.1.4 
Dose Selection Rationale .................................................................................................... 34 
1.1.5 
Single Reference Safety Document ..................................................................................... 35 
2.0 
STUDY OBJECTIVES AND ENDPOINTS .................................................................................... 36 
2.1 
OBJECTIVES ...................................................................................................................................... 36 
2.1.1 
Part 1 ................................................................................................................................... 36 
2.1.2 
Part 2 ................................................................................................................................... 36 
2.2 
ENDPOINTS ....................................................................................................................................... 37 
2.2.1 
Part 1 ................................................................................................................................... 37 
2.2.2 
Part 2 ................................................................................................................................... 37 
3.0 
STUDY DESIGN ................................................................................................................................ 39 
4.0 
SUBJECT SELECTION ................................................................................................................... 41 
4.1 
INCLUSION CRITERIA ..................................................................................................................... 41 
4.2 
EXCLUSION CRITERIA .................................................................................................................... 42 
4.3 
CONTRACEPTION REQUIREMENTS AND STUDY PARTICIPANT INSTRUCTION ............... 47 
4.3.1 
Males ................................................................................................................................... 47 
4.3.2 
Females ............................................................................................................................... 47 
5.0 
STUDY TREATMENTS ................................................................................................................... 48 
5.1 
PROCESS FOR RANDOMIZATION TO STUDY TREATMENT ................................................... 48 
5.2 
PROCESS FOR EMERGENCY BREAKING THE BLIND .............................................................. 48 
5.3 
DRUG SUPPLIES ............................................................................................................................... 48 
5.3.1 
Formulation and Packaging ................................................................................................. 48 
5.3.2 
Administration ..................................................................................................................... 49 
5.3.3 
Compliance .......................................................................................................................... 49 
5.3.4 
Drug Storage and Drug Accountability ............................................................................... 49 
5.4 
CONCOMITANT MEDICATION(S) ................................................................................................. 49 
6.0 
STUDY PROCEDURES .................................................................................................................... 53 
6.1 
SCREENING / Part 1 and Part 2.......................................................................................................... 54 
19


Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
TABLE OF CONTENTS (continued) 
 
Page 
 
 
 
Page 20 
6.2 
PART 1 STUDY PERIOD ................................................................................................................... 57 
6.2.1 
Part 1 / Baseline (approximately Day -7-Day 1) ................................................................. 57 
6.2.2 
Part 1 / Month 1 Telephone Contact (Day 30 ± 7 days) ...................................................... 59 
6.2.3 
Part 1 / Month 2 Telephone Contact (Day 60± 7 days) ....................................................... 59 
6.2.4 
Part 1 / Month 3 Clinic Visit (Day 90 ± 7 days) ................................................................. 59 
6.2.5 
Part 1 / Month 4 Telephone Contact (Day 120 ± 7 days) .................................................... 61 
6.2.6 
Part 1 / Month 5 Telephone Contact (Day 150 ± 7 days) .................................................... 61 
6.2.7 
Part 1 / Month 6 Clinic Visit (Day 180 ± 7 days) ............................................................... 61 
6.2.8 
Part 1 / Follow-Up Visit ...................................................................................................... 62 
6.2.9 
Part 1 / Early Termination ................................................................................................... 64 
6.3 
PART 2 STUDY PERIOD ................................................................................................................... 65 
6.3.1 
Part 2 / Baseline (approximately Day -7-Day 1) ................................................................. 65 
6.3.2 
Part 2 / Month 1 Telephone Contact (Day 30 ± 7 days) ...................................................... 67 
6.3.3 
Part 2 / Month 2 Telephone Contact (Day 60 ± 7 days) ...................................................... 67 
6.3.4 
Part 2 / Month 3 Clinic Visit (Day 90 ± 7 days) ................................................................. 67 
6.3.5 
Part 2 / Month 6 Clinic Visit (Day 180 ± 7 days) ............................................................... 69 
6.3.6 
Part 2 / Month 9 Clinic Visit (Day 270 ± 7 days) ............................................................... 70 
6.3.7 
Part 2/ Month 12 Clinic Visit (Day 360 ± 7 days) .............................................................. 71 
6.3.8 
Part 2 / Month 15 Clinic Visit (Day 450 ± 7 days) ............................................................. 72 
6.3.9 
Part 2 / Month 18 Clinic Visit (Day 540 ± 7 days) ............................................................. 74 
6.3.10 
Part 2 / Follow-Up Visit ...................................................................................................... 75 
6.3.11 
Part 2 / Early Termination ................................................................................................... 76 
6.4 
SUBJECT WITHDRAWAL ................................................................................................................ 77 
7.0 
ASSESSMENTS ................................................................................................................................. 79 
7.1 
SAFETY AND TOLERABILITY ....................................................................................................... 79 
7.1.1 
Body Measurements ........................................................................................................... 79 
7.1.2 
Vital Signs ........................................................................................................................... 79 
7.1.3 
Electrocardiogram ............................................................................................................... 79 
7.1.4 
Physical Examination.......................................................................................................... 80 
7.1.5 
Neurological Examination .................................................................................................. 80 
7.1.6 
Laboratory ........................................................................................................................... 81 
7.2 
NEUROPSYCHOLOGICAL ASSESSMENTS .................................................................................. 84 
7.2.1 
Cognitive Assessments ....................................................................................................... 84 
7.2.2 
Functional/Global Assessments .......................................................................................... 85 
7.2.3 
Other Assessments .............................................................................................................. 86 
7.3 
SUICIDALITY ASSESSMENTS ........................................................................................................ 87 
7.4 
PLASMA FOR ANALYSIS OF AZELIRAGON AND METABOLITE CONCENTRATIONS ........ 88 
7.5 
PLASMA FOR ANALYSIS OF TOTAL A, A (1-40), A(1-42) ................................................... 88 
7.6 
MRI ...................................................................................................................................................... 88 
7.7 
CT SCANS ........................................................................................................................................... 89 
7.8 
APOE GENOTYPING ........................................................................................................................ 90 
7.9 
BLOOD SAMPLING FOR STORAGE AND RETENTION .............................................................. 90 
7.10 
BLOOD VOLUME .............................................................................................................................. 91 
20


Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
TABLE OF CONTENTS (continued) 
 
Page 
 
 
 
Page 21 
8.0 
ADVERSE EVENT REPORTING ................................................................................................... 92 
8.1 
ADVERSE EVENTS ........................................................................................................................... 92 
8.2 
REPORTING PERIOD ........................................................................................................................ 92 
8.3 
ASSESSMENT OF SEVERITY .......................................................................................................... 93 
8.4 
ASSESSMENT OF RELATIONSHIP TO STUDY DRUG ................................................................ 93 
8.5 
SERIOUS ADVERSE EVENTS ......................................................................................................... 94 
8.5.1 
Life Threatening Adverse Event ......................................................................................... 94 
8.5.2 
Disability ............................................................................................................................. 94 
8.5.3 
Unexpected Adverse Event ................................................................................................. 95 
8.6 
DOCUMENTATION OF ADVERSE EVENTS ................................................................................. 95 
8.7 
REPORTING REQUIREMENTS ........................................................................................................ 95 
8.7.1 
Serious Adverse Events Reporting Requirements ............................................................... 96 
9.0 
DATA ANALYSIS/STATISTICAL METHODS ............................................................................ 97 
9.1 
POTENTIAL ADAPTIVE FEATURES ............................................................................................. 97 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................... 98 
9.3 
RANDOMIZATION AND BLINDING ............................................................................................. 99 
9.3.1 
RANDOMIZATION........................................................................................................... 99 
9.3.2 
BREAKING THE BLIND .................................................................................................. 99 
9.4 
STATISTICAL HYPOTHESES ....................................................................................................... 100 
9.5 
POPULATIONS OF ANALYSIS ...................................................................................................... 101 
9.6 
DISPOSITION, DEMOGRAPHIC, AND BASELINE DATA ......................................................... 102 
9.7 
EFFICACY ANALYSIS .................................................................................................................... 102 
9.7.1 
Efficacy Variables of Analysis .......................................................................................... 103 
9.7.2 
Statistical Methodology for Primary Analysis .................................................................. 104 
9.7.3 
Statistical Methodology for Secondary and Other Efficacy Analysis ............................... 107 
9.7.4 
Subgroup Analyses ........................................................................................................... 107 
9.7.5 
Adjustment for Multiple Comparisons.............................................................................. 108 
9.8 
SAFETY ANALYSIS ........................................................................................................................ 108 
9.8.1 
Safety Variables of Analysis ............................................................................................. 108 
9.8.2 
Statistical Methodology for Safety Analysis ..................................................................... 110 
9.9 
PHARMACODYNAMIC DATA ...................................................................................................... 110 
9.10 
PHARMACOKINETIC DATA .......................................................................................................... 110 
9.11 
QUESTIONNAIRES ......................................................................................................................... 111 
9.12 
HANDLING MISSING DATA ......................................................................................................... 111 
9.13 
DATA MONITORING COMMITTEE ............................................................................................. 112 
9.14 
INTERIM ANALYSIS ...................................................................................................................... 112 
9.15 
DATA MANAGEMENT CONSIDERATIONS ............................................................................... 113 
10.0 
QUALITY CONTROL / MONITORING OF THE STUDY ....................................................... 114 
21


Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
TABLE OF CONTENTS (continued) 
 
Page 
 
 
 
Page 22 
11.0 
DATA HANDLING AND RECORD KEEPING .......................................................................... 115 
11.1 
CASE REPORT FORMS/ELECTRONIC DATA RECORD ............................................................ 115 
11.2 
RECORD RETENTION .................................................................................................................... 115 
12.0 
ETHICS ............................................................................................................................................ 117 
12.1 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD (REB) ..................... 117 
12.2 
ETHICAL CONDUCT OF THE STUDY ......................................................................................... 117 
12.3 
SUBJECT INFORMATION AND CONSENT ................................................................................. 117 
13.0 
STUDY TERMINATION CRITERIA ........................................................................................... 119 
14.0 
CONFIDENTIALITY AND PUBLICATION OF STUDY RESULTS ....................................... 120 
15.0 
REFERENCES ................................................................................................................................. 121 
APPENDICES ...................................................................................................................................................... 125 
 
 
22


Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 23 
LIST OF TABLES 
 
Page 
 
Table 1. 
Part 1 Schedule of Activities ............................................................................................................. 13 
Table 2. 
Part 2 Schedule of Activities ............................................................................................................. 16 
Table 3. 
Descriptive Statistics on Trough Concentrations .............................................................................. 34 
Table 4. 
Part 1 Blood Sampling Volumes ....................................................................................................... 91 
Table 5. 
Part 2 Blood Sampling Volumes ....................................................................................................... 91 
 
 
 
 
LIST OF FIGURES 
 
 
Figure 1. 
Change from Baseline in ADAS-cog:  Comparison of Placebo-treated patients with HbA1c at 
Baseline ≥ 6.5% and HbA1c < 6.5%  (TTP488-301 A-Study [Target Analysis Set]) ...................... 30 
Figure 2. 
Change from Baseline in ADAS-cog:  Type 2 Diabetic Subgroup (TTP488-301 [Target Analysis 
Set]) ................................................................................................................................................... 31 
Figure 3. 
Changes in Inflammatory Biomarker Profile:  Type 2 Diabetic Subgroup (TTP488-301 A-Study 
[FAS completers]) ............................................................................................................................. 33 
 
 
 
23


Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 24 
LIST OF ABBREVIATIONS 
 
 
Aβ 
Aβ peptide fragment of the amyloid precursor protein 
AD 
Alzheimer’s Disease 
ADAS-cog14 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale - 14 Item 
AE 
Adverse Event 
AGE 
Advanced Glycation Endproduct 
A-IADL 
Amsterdam Instrumental Activities of Daily Living questionnaire 
ALT 
Alanine Aminotransferase 
APP 
Amyloid Precursor Protein 
AST 
Aspartate Aminotransferase 
BBB 
Bundle branch block 
BMI 
Body mass index 
BUN 
Blood Urea Nitrogen 
CDR 
Clinical Dementia Rating Scale 
CDR-SB 
Clinical Dementia Rating Scale-Sum of Boxes 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CT 
Computed Tomography 
DEMQOL 
Health-Related Quality of Life for People with Dementia 
DILI 
Drug Induced Liver Injury 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, 4th ed Text Revision 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
FAQ 
Functional Assessment Questionnaire 
FAS 
Full analysis set 
FDR 
Food and Drug Regulations 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyltransferase 
HbA1c 
Hemoglobin A1c 
HDPE 
High density polyethylene 
HIS 
Heat induction seal 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate Dehydrogenase 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMA 
Methylmalonic Acid 
MMSE 
Mini-Mental State Exam 
MRI 
Magnetic Resonance Imaging 
NASH 
Nonalcoholic Steatohepatitis 
NPI 
Neuropsychiatric Inventory Questionnaire 
PD 
Pharmacodynamic 
PI 
Principal Investigator 
24


Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
LIST OF ABBREVIATIONS (continued) 
 
 
Page 25 
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 
SoC 
Standard of care 
SUVR 
Standardized uptake value ratio 
T2DM 
Type 2 diabetes 
TAS 
Target analysis set 
TEAE 
Treatment-Emergent Adverse Event 
TEAV 
Treatment-Emergent Abnormal Value 
TSH 
Thyroid Stimulating Hormone 
TTP488 
Azeliragon 
UA 
Urinalysis 
ULN 
Upper Limit of Normal 
QD 
Taken Once Daily 
QTcF 
QT interval calculated using Fridericia’s correction factor 
WHODD 
WHO Drug Dictionary 
 
 
 
25


Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 26 
1.0 
INTRODUCTION 
These studies are designed to evaluate the safety and efficacy of azeliragon as a 
treatment for subjects with mild Alzheimer’s disease and impaired glucose 
tolerance. 
1.1 
BACKGROUND AND RATIONALE 
1.1.1 
Dementia and Diabetes 
Worldwide there are currently approximately 35.6 million people with 
dementia.(Alzheimer’s Association 2016)  There is an estimated 98 million people 
(65-79 years-old) who have diabetes.(International Diabetes Federation 2017)  In 
the absence of a treatment that slows or halts the progression of cognitive and 
functional decline, AD often seriously impacts patients and their families as well as 
the healthcare economy.  This is true in the AD population generally, but also among 
those with both AD and diabetes. 
Numerous studies have suggested a link between type 2 diabetes and cognitive 
decline, mild cognitive impairment, and dementia.(Dhananjayan 2018)  Type 2 
diabetes may be present in up to 35% of people with Alzheimer’s disease.(Janson 
2004)  Recently, a linear correlation between circulating HbA1c levels and cognitive 
decline has been observed in the English Longitudinal Study of Ageing.(Zheng 
2018)  It is also estimated that, in the United States, nearly 40 percent of Medicare 
beneficiaries age 65 and older with dementia also have diabetes.(Alzheimer’s 
Association. 2018)  Given the prevalence of type 2 diabetes and dementia in the most 
rapidly-growing segment of the population, there is a significant unmet medical 
need. 
An overproduction of amyloid beta (Aβ) has been implicated as the leading 
mechanistic factor in AD pathology. Aβ is known to bind to the receptor for 
advanced glycation endproducts (RAGE), an immunoglobulin supergene family 
member expressed on multiple cell types in the brain and the periphery.(Yan 1996, 
Stern 2002)  RAGE is expressed at low levels in many healthy tissues (except skin 
and mucus membranes) and is prominently expressed on endothelial cells and 
microglia of the neurovascular compartment.  RAGE ligands include Aβ, S100b, 
HMGB1, and Advanced Glycation Endproducts (AGEs).  Increases in the 
26


Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 27 
concentration of RAGE ligands induce RAGE expression.  RAGE-ligand 
interactions lead to sustained inflammatory states that play a role in chronic diseases, 
including diabetes, inflammation, and AD.(Stern 2002, Bierhaus 2005)  RAGE has 
been proposed to contribute to AD pathology by: promoting inflammation, vascular 
leakage, and influx of peripheral Aβ into brain; mediating Aβ induced oxidative 
stress and Aβ- mediated neuronal death.(Dean 2003, Carrano 2011, Hartz 2012, 
Kook 2012)  Additionally, RAGE is believed to be involved in mediating advanced 
glycation endproduct-induced tau hyperphosphorylation.(Li 2012) In AD, increases 
in RAGE protein and percentage of RAGE‐expressing microglia parallel the severity 
of disease.(Yan 1996) 
AGEs accumulate in tissues of people with type 2 diabetes playing a major role in 
worsening of complications of type 2 diabetes, such as retinopathy, neuropathy and 
nephropathy.  When the concentration of RAGE ligands (e.g., AGEs) increase, more 
RAGE expression is induced.(Bierhaus 2005)  Furthermore, AGE accumulation 
parallels the development of cognitive impairment and dementia in individuals with 
type 2 diabetes.(Dhananjayan 2018) 
1.1.2 
Mechanism of Action 
Azeliragon is an orally bioavailable inhibitor of the receptor for advanced glycation 
endproducts (RAGE) being developed by vTv.   
In transgenic mouse models of AD, azeliragon is associated with less 
neuroinflammation (TNF-. TGF-. IL-1) and Aβ deposition in the brain, 
improvement in cerebral blood flow and glucose uptake in the brain, and 
preservation of cognitive / behavioral performance compared to control animals.  
Azeliragon has also been shown, in animal models of type 2 diabetes, to reduce 
inflammatory markers with improvement in wound healing (endothelial cell 
extension), diabetic retinopathy (microvascular trees comparable to control) and 
nephropathy (improved sclerotic lesions).   
Recent exploratory analyses of azeliragon from the STEADFAST Phase 3 studies 
provide preliminary clinical evidence that patients with increased concentrations of 
RAGE ligands may benefit from azeliragon.   
27


Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 28 
These data taken together suggest that inhibition of RAGE with an orally available 
small molecule inhibitor, such as azeliragon, presents an attractive therapeutic 
rationale for the treatment of Alzheimer’s dementia in patients with impaired 
glucose tolerance.  
1.1.3 
Clinical Studies 
The azeliragon clinical development program to date consists of eight Phase 1 
studies in the USA, three Phase 2 studies in North America (US and Canada), two 
Phase 3 studies (operationally conducted under one protocol) and an open-label 
extension study conducted globally, described in the Investigator’s Brochure. 
vTv recently completed two Phase 3 studies (under protocol TTP488-301, 
STEADFAST A-Study and STEADFAST B-Study) examining the effect of 
azeliragon on both cognitive (i.e., ADAS-cog11) and functional (i.e., CDR-sb) 
outcomes in patients with mild dementia of the Alzheimer’s disease type.  The trial 
was a randomized, double-blind, placebo-controlled trial in 880 participants with 
probable mild AD, MMSE 21-26 at screening, CDR 0.5 or 1, receiving stable 
standard of care (acetylcholinesterase inhibitor and/or memantine) evaluating the 
efficacy and safety of 18 months of treatment with azeliragon 5 mg/day relative to 
placebo.  The clinical trial design included two separate, identical studies (A-Study 
and B-Study) operationally conducted under a single protocol.  Each study was 
independently powered to evaluate efficacy with respect to co-primary endpoints of 
ADAS cog11 and CDR-sb and were randomized separately.  Patients were 
randomized 1:1 (site-based randomization) to azeliragon (5 mg/day) or placebo.  The 
A-Study was conducted in North America (US and Canada).  The B-Study was 
global, conducted in North America (US and Canada), Ireland, UK, South Africa, 
Australia and New Zealand.    
Topline results from the STEADFAST A-Study failed to demonstrate a beneficial 
effect of azeliragon on the protocol specified primary endpoints. As a result, the 
ongoing studies (including the B-Study) were terminated, databases locked, and data 
analyzed. Although the STEADFAST A-Study and B-Study did not achieve 
statistical significance on either of the co-primary endpoints, important results were 
obtained through post-hoc subgroup analysis that warrant additional investigation.  
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Further examination of the data showed clear differences in rate of placebo decline 
in ADAS-cog between the STEADFAST study (3 points in 18 months), the 
azeliragon Phase 2b study (10 points in 18 months) and that published for other 
similar studies (6 points in 18 months [Thomas 2016]), which may explain the lack 
of detectable effect in the STEADFAST study (the study was powered to detect a 4 
point difference in change from baseline between active and placebo at 18 months, 
assuming a placebo decline of approximately 6 points over 18 months).  It is 
hypothesized that subjects with higher expression of RAGE would present more 
inflammation and neurodegeneration and decline at a faster rate.   
It has been demonstrated that advanced glycation endproducts accumulate in tissues 
of patients with diabetes with expression of RAGE increasing in response to injury 
and increases in ligand concentrations, including AGEs.  This interaction of AGEs, 
and other ligands of RAGE, leads to sustained cellular damage and inflammation 
thus contributing to complications of diabetes including retinopathy, neuropathy and 
nephropathy.  Further it has been shown that accumulation of AGEs parallels the 
development of cognitive impairment and dementia in patients with diabetes.   Thus, 
patients with diabetes represent a sub-group expected to have increased 
concentration of RAGE ligands, increased expression of the RAGE receptor, have 
the potential to decline at a more rapid rate and thereby likely to respond to an 
antagonist of RAGE.   
A comparison of placebo-treated subjects in the diabetic subgroup (defined as 
HbA1c ≥ 6.5%) and the non-diabetic (HbA1c < 6.5%) complement of the target 
analysis set (subjects with evidence of cognitive impairment at Baseline [ADAScog 
≥ 10]) is provided in Figure 1.  Interestingly, the data show a clear difference in the 
rate of cognitive decline between the placebo subjects with diabetes and the placebo 
subjects without diabetes.  The diabetic, placebo-treated subjects had numerically 
greater decline from baseline in the ADAS-cog when compared with the non-
diabetic, placebo treated subjects.  These data further support the hypothesis that 
subjects with presumed higher expression of RAGE present more inflammation and 
neurodegeneration and decline at a faster rate.   
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Figure 1. 
Change 
from 
Baseline 
in 
ADAS-cog: 
 
Comparison 
of 
Placebo-treated patients with HbA1c at Baseline ≥ 6.5% and 
HbA1c < 6.5%  (TTP488-301 A-Study [Target Analysis Set]) 
 
*p values are relative to each population’s Baseline.  
A subpopulation of STEADFAST participants with probable Alzheimer’s disease 
and type 2 diabetes was evaluated during post hoc, exploratory, subgroup analyses 
of the STEADFAST Study.  Patients with type 2 diabetes were selected because they 
are known to have increased levels of AGEs; and increased levels of AGEs are 
known to induce RAGE expression.  Therefore, HbA1c was chosen as a surrogate 
for identifying individuals with elevated levels of AGEs and high RAGE expression.  
Based on the hypothesis that subjects with presumed increased expression of RAGE 
would demonstrate enhanced effects from a RAGE antagonist, the subgroup was 
defined as those STEADFAST participants with Baseline HbA1c ≥ 6.5%.  The 
objective of the subgroup analysis was to determine if a differential response to 
azeliragon was observed in patients with increased HbA1c. 
Twenty-four subjects (17 azeliragon and 7 placebo) in the STEADFAST A-study 
dataset were identified as the Target Analysis Set (TAS).  The TAS represents the 
intended subject population for future studies and is defined as subjects with HbA1c 
≥ 6.5% at Baseline and evidence of cognitive impairment at Baseline (ADAS-cog ≥ 
10).  Twenty-six subjects (13 azeliragon and 13 placebo) in the STEADFAST B-
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study were identified as the TAS with Baseline HbA1c ≥ 6.5% and ADAS-cog ≥ 10.  
Unfortunately, the B-study was terminated by the sponsor and limited data are 
available beyond Month 9 for this subgroup.  Figure 2 displays the Change from 
Baseline in ADAS-cog11 for the A-Study and B-Study in the TAS.   
Figure 2. 
Change from Baseline in ADAS-cog:  Type 2 Diabetic Subgroup (TTP488-
301 [Target Analysis Set]) 
 
Results from the A-Study that completed the 18-month treatment period as planned, 
show a clear delineation between azeliragon and placebo groups in ADAS-cog 
throughout the duration of the study; separation achieves nominal statistical 
significance at multiple timepoints throughout treatment.  The azeliragon-treated 
group (n=17) demonstrated a 3.8-point benefit on ADAS-cog relative to the placebo 
group (n=7) at Month 6, which was nominally statistically significant (p = 0.009).  
The azeliragon-treated group went on to demonstrate a 6.1-point benefit on ADAS-
cog relative to the placebo group at Month 18, which was nominally statistically 
significant (p = 0.018). 
Results from the B-Study that terminated after approximately 12 months of 
treatment, show numerical values on ADAS-cog change from baseline favoring 
azeliragon.  The azeliragon-treated group (n=13) demonstrated a 1.9-point benefit 
on ADAS-cog relative to the placebo group (n=13) at Month 6.  The azeliragon-
treated group went on to demonstrate a 3.6-point benefit on ADAS-cog relative to 
the placebo group at Month 12.   
Change from Baseline in CDR-sb was evaluated for the A-Study and B-Study in the 
TAS.  Results from the A-Study that completed the 18-month treatment period as 
planned, show a clear delineation between azeliragon and placebo groups in 
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CDR-sb.  The azeliragon-treated group (n=17) demonstrated a 1.7-point benefit on 
CDR-sb relative to the placebo group (n=7) at Month 18 (p = 0.05).   
CDR-sb results from the B-Study are difficult to interpret.  The planned study 
duration of 18 months was intended to allow sufficient time to see decline in the 
functional measure.  Unfortunately, the B-study was terminated prematurely by the 
sponsor and limited data are available beyond Month 6 for the B Study type 2 
diabetic subgroup.  In the B-Study at Month 12, the azeliragon-treated group (n=13) 
demonstrated a 1.5-point change from Baseline while the placebo-treated group 
(n=13) had a 0.8-point change from Baseline.  The inherent variability of the 
CDR-sb measure combined with the small sample size and shorter study duration 
for subjects in the B study has limited the interpretation of the functional endpoint 
in the B-Study.   
The subgroup analysis of the STEADFAST Study showed cognitive benefit of 
azeliragon treatment in the subset of patients with probable AD and type 2 diabetes 
(as determined by HbA1c ≥ 6.5%).  In support of the biological hypothesis for 
pursuing further development in patients with Alzheimer’s dementia and type 2 
diabetes, analyses were performed on changes in brain volumetric MRI, brain FDG 
PET, plasma RAGE related inflammatory markers, and glycemic control in patients 
that completed the 18-month study.  The brain volumetric MRI data show favorable 
trends for less whole brain atrophy and less ventricular enlargement in the 
azeliragon-treated subgroup with HBA1c ≥6.5%.  FDG PET data (standardized 
uptake value ratio [SUVR] for the mean composite region defined as unweighted 
combination of frontal, anterior/posterior cingulate, lateral parietal, lateral temporal 
and hippocampus) show trends for smaller decrements in glucose uptake (SUVR) in 
the azeliragon-treated subgroup with HBA1c ≥6.5%.  Acknowledging the small 
sample sizes in the subgroup, the treatment differences in the type 2 diabetic 
subgroup (HbA1c ≥6.5%) are more robust than the overall study population. 
Furthermore, a decrease in several plasma inflammatory biomarkers was observed 
in the type 2 diabetic subgroup patients treated with azeliragon in the A-Study. The 
biomarker panel data (Figure 3) show significant decreases from Baseline to Month 
18 in the azeliragon group in IL-6, IL 12, INF, CD40L, MIP-1, IL-2 and TNF, 
and FGF-2; the data also show strong trends toward a decrease in IL 13, TGF, 
MCP-3 MPC-1 and CSF2 in the azeliragon group.  These inflammatory biomarkers 
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are those associated with RAGE activation and are contributors to the 
neuroinflammation signaling pathway.  The decrease in several plasma 
inflammatory biomarkers in the azeliragon-treated group provides further biological 
evidence of a treatment response in this subpopulation. 
Figure 3. 
Changes in Inflammatory Biomarker Profile:  Type 2 Diabetic 
Subgroup (TTP488-301 A-Study [FAS completers]) 
 
 
The observed cognitive benefit of azeliragon in a subgroup of AD patients with 
co-existing type 2 diabetes is supported by biological evidence of response including 
MRI, FDG-PET, and biomarker data.  Furthermore, the subgroup findings are 
consistent with the biology of RAGE and the mechanism of action of azeliragon.  It 
is biologically plausible that blocking RAGE-ligand interactions in this population, 
with azeliragon, can result in a robust beneficial effect.  These results warrant further 
investigation to confirm azeliragon is a potential therapeutic approach for the 
treatment of patients with Alzheimer’s disease and impaired glucose tolerance.   
The present study has been designed to evaluate the efficacy of azeliragon in subjects 
with mild Alzheimer’s disease and impaired glucose tolerance, defined as HbA1c 
≥6.5%. 
*nominal p<0.05 Wilcoxon 
test
%Change from Baseline at Month 
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1.1.4 
Dose Selection Rationale 
The azeliragon dose (5 mg daily) for the current study 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) and the Phase 3 study 
(TTP488-301). 
The decision to advance a 5mg dose into Phase 3 was based on 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 3. 
Table 3. 
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 the choice of cut-points, analysis 
included the following cuts: 
 
Tertile 
 
Quartile 
 
Quintile 
 
Decile 
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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. 
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 effect of food on the pharmacokinetics of azeliragon was evaluated in the 
TTP488-105 study.  There was an approximately 20% reduction in exposure (Cmax, 
AUC0-last, and AUC0-72) following administration of a single 5 mg dose of azeliragon 
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).  
Therefore, azeliragon may be administered without regard to food. 
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 
2.1.1 
Part 1 
Primary objective: 
The primary objective of this study is to evaluate the impact of 6 months of treatment 
with oral azeliragon on cognitive performance. 
Secondary objectives: 
 
To evaluate the efficacy of azeliragon treatment on measures of function and 
activities of daily living 
 
To evaluate the efficacy of azeliragon treatment on complications of diabetes 
 
To evaluate the safety and tolerability of 6 months of azeliragon treatment 
 
To evaluate the effect of azeliragon treatment on biomarkers and markers of 
inflammation 
2.1.2 
Part 2 
Primary objective: 
The primary objective of this study is to evaluate the efficacy of 18 months of 
treatment with oral azeliragon on cognition and global function. 
Secondary objectives: 
 
To evaluate the safety and tolerability of azeliragon treatment 
 
To evaluate the efficacy of azeliragon treatment on activities of daily living, 
behavior, and quality of life 
 
To evaluate the efficacy of azeliragon treatment on complications of diabetes 
 
To evaluate the effect of azeliragon treatment on biomarkers and markers of 
inflammation 
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2.2 
ENDPOINTS 
2.2.1 
Part 1 
Primary Endpoint: 
 Change from Baseline in the ADAS-cog14 at Month 6 
Secondary Endpoints: 
 Change from Baseline in the CDR-sb at Month 6 
 Change from Baseline in the FAQ at Month 6 
 Change from Baseline in the Amsterdam-IADL at Month 6 
 Change from Baseline in eGFR at Month 6 
Safety Endpoints: 
 Adverse events, clinical laboratory tests, vital signs, 12-lead ECG, C-SSRS 
2.2.2 
Part 2 
Co-Primary Endpoints: 
 Change from Baseline in the ADAS-cog14 at Month 18 
 Change from Baseline in CDR-sb at Month 18 
Secondary Endpoints: 
 Responder status at Months 6, 12, and 18 based on the ADAS-cog14 
 Change from Baseline in FAQ score at Month 18 
 Change from Baseline in Amsterdam-IADL score at Month 18 
 Change from Baseline in MMSE score at Month 18 
 Change from Baseline in eGFR at Month 18 
 Change from Baseline in whole brain volume at Month 18 
Safety Endpoints: 
Adverse events, clinical safety laboratory tests, ECG, vital signs, C-SSRS 
 
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Exploratory Endpoints: 
 Change from Baseline at Month 18 for measures of behavior and quality of life 
(NPI, DEMQOL-proxy) 
 Change from Baseline at Months 3, 6, and 12 for the primary and secondary 
measurements:  ADAS-cog14, FAQ, Amsterdam-IADL, CDR-sb, MMSE, NPI, 
DEMQOL-proxy 
 Change from Baseline in plasma concentrations of Aβ species at Month 18 
 Change from Baseline in brain MRI (hippocampal, ventricular) volumetric 
measures at Month 18 
 
 
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3.0 
STUDY DESIGN 
TTP488-305 is a protocol that consists of two sequential, multi-center, randomized, 
double-blind, placebo-controlled, parallel group studies to evaluate the safety and 
efficacy of oral azeliragon 5 mg/day relative to placebo in approximately 
300 subjects (100 Part 1, 200 Part 2) with mild Alzheimer’s disease (screening 
MMSE 21-26, baseline MMSE 19-27 and ADAS-cog14 score of ≥ 10) and impaired 
glucose tolerance (Screening HbA1c 6.5% -9.5%, inclusive).  Eligible participants 
will be randomly assigned to azeliragon or placebo in a 1:1 randomization for a 
double-blind dosing period of 6 months (Part 1) or 18 months (Part 2).  The Part 1 
and Part 2 studies will have independently randomized, unique study populations. 
The Part 1, 6-month, double-blind treatment portion of the study will include 5 clinic 
visits.  The primary objective of the Part 1 portion is to evaluate the efficacy of 
6 months of oral azeliragon on a measure of cognition (ADAS-cog14).  Secondary 
objectives of Part 1 will be to evaluate the efficacy of 6 months of oral azeliragon 
on multiple measures of function to inform selection of a functional endpoint to 
serve as co-primary in Part 2, as well as the sample size required to adequately power 
the study to detect treatment effect on cognitive and functional measures in the study 
population.  Upon completion of Part 1, a subject’s participation is considered 
complete and they will not be permitted to participate in Part 2.  The Schedule of 
Activities for Part 1 is described in Table 1. 
The Part 2, 18-month, double-blind treatment portion of the study will include 
9 clinic visits.  Part 2 will enroll 200 subjects who will be randomized to receive oral 
azeliragon 5 mg/day or placebo in a 1:1 randomization.   The Schedule of Activities 
for Part 2 is described in Table 2. 
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 subject eligibility, enrollment and 
protocol adherence, endpoint determinations, and medical decisions related to 
the study.  The PI will supervise project personnel and ensure that raters 
maintain a high level of skill and accuracy in conducting assessments.  The PI 
may not serve as the CDR Rater. 
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 
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.  If s/he is responsible for study oversight and other study 
assessments, s/he may not serve as the CDR Rater.   
 
Non-CDR Rater – This person will meet the education, clinical and scale 
experience requirements set by the sponsor.  This person can conduct all 
ratings and assessments, once qualified by the rater training staff, except for 
the CDR.  If appropriately qualified, the PI or Study Coordinator may also 
fulfill this role. 
 
CDR Rater – This person will render the CDR rating based on clinical 
assessment of participant and caregiver / study partner, using scale worksheets 
provided by the Sponsor, but without access to the ADAS-cog or any other 
study assessments, including adverse events and laboratory data.  Neither the 
PI nor the Study Coordinator responsible for study oversight may fulfill this 
role. 
 
 
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4.0 
SUBJECT SELECTION 
4.1 
INCLUSION CRITERIA 
Subject eligibility must be reviewed and documented by an appropriately qualified 
member of the Principal Investigator’s (PI's) study team before participants are 
included in the study.   
1. Evidence of a personally signed and dated informed consent document 
indicating that the subject (or a legally authorized representative) and 
caregiver/informant has been informed of all pertinent aspects of the study.  
Participants must be able to provide consent or assent (where this is in 
accordance with local laws, regulations and ethics committee policy) and 
consent/assent must be re-evaluated during the study at regular intervals. 
2. Male or female subjects aged 50-85 years (inclusive) at Screening Visit. 
3. Female subjects must be of non-childbearing potential.  Male subjects with 
female partners of child bearing potential must agree to acceptable birth control 
for the duration of the study and for 90 days thereafter. 
4. If on pharmacological treatment for diabetes, must be on  stable dose for at least 
60 days prior to screening and remain stable through Baseline.  There should be 
expectation that treatment and dose will remain stable during the study period.   
5. Clinical diagnosis of probable Alzheimer’s disease, consistent with the criteria 
from the 2011 National Institute on Aging and Alzheimer’s Association 
workgroup [McKhann 2011], for at least 2 months prior to Screening.  Evidence 
of progression must be documented in source documentation at the time of 
screening based on review of prior medical records and/or information gathered 
from the subject or caregiver/informant(s).   
6. Mini-Mental State Exam (MMSE) score of 21-26 inclusive at Screening and 
19-27 at Baseline.   
7. CDR global score of 0.5 or 1 at Screening and Baseline. 
8. ADAS-cog14 score of ≥10 at Screening and Baseline.  
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9. Participant must be on a stable dose of a background cholinesterase inhibitor 
and/or memantine (approved by relevant health authority where trial is being 
conducted) at least 60 days prior to Screening and remain stable through 
Baseline.  There must be agreement not to change the treatment or dose during 
the study period unless the investigator judges that the dose needs to be reduced 
or stopped due to a safety and/or tolerability reason. 
10. Hemoglobin A1c (HbA1c) 6.5% - 9.5%, inclusive, at Screening. 
11. Body mass index (BMI) 19.0 – 37.0 kg/m2, inclusive, at Screening Visit and 
Baseline Visit. 
12. Body weight at least 45.0 kg at Screening Visit and Baseline Visit. 
13. Participants and caregiver/informants who are willing and able to comply with 
scheduled visits, treatment plan, laboratory tests, and other study procedures. 
14. The subject must have a reliable caregiver/informant with regular contact (i.e., 
10 hours a week as combination of face-to-face visits and telephone contact 
acceptable) who will facilitate the subject’s full participation in the study.  
Caregiver/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, 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. 
15. 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. 
16. 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. Current evidence or history of neurological or any other illness that could 
contribute to dementia including, but not limited to, other neurocognitive 
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disorders (e.g., Lewy body disease, fronto-temporal dementia, Parkinson 
disease), HIV cognitive impairment, head injury with loss of consciousness 
proximate to the onset of dementia, vitamin B12 deficiency (see Exclusion 3, 
below) or thyroid disease (unless adequately treated for at least 3 months with 
normalization of laboratory values). 
2. Participants from a family with known autosomal dominant AD associated with 
mutations in APP, PS1 or PS2 genes or strongly suspected, but not yet identified 
mutations in APP, PS1 or PS2 genes, or Down’s syndrome.  Individuals from 
families with any number of late onset AD affected family members may 
participate in this study. 
3. Vitamin B12 levels lower than laboratory reported normal limits (and remains 
below on repeat testing).  Participants may be enrolled following the initiation 
of B12 therapy for 4 weeks prior to dosing and confirmed within normal limits 
upon repeat. 
4. Evidence of neurologic deficits from a previous stroke or MRI changes 
consistent with multi-infarct dementia.  Diagnosis or any history of 
cerebrovascular stroke, severe carotid stenosis, cerebral hemorrhage, intracranial 
tumor, subarachnoid hemorrhage that, as determined by the investigator, could 
either contribute to the patient’s current cognitive or functional status, impair 
his/her ability to fully participate in the trial or that may impact his/her status 
during the course of the trial. 
5. Specific exclusionary brain MRI findings (as identified on the central MRI read) 
as determined by the investigator that could either significantly contribute to the 
patient’s current cognitive or functional decline, impair his/her ability to fully 
participate in the trial or that may impact his/her status during the course of the 
trial.  In any case, the following are exclusionary: 
a) 10 or more microhemorrhages as identified by the central reading report. 
b) Grade three deep white matter changes (diffuse involvement of entire region) 
on the central reading report.   
6. History of schizophrenia or late onset (after age 40) bipolar disorder.  Current or 
recent (within 6 months prior to Screening) clinically relevant or unstable 
psychiatric disorder (e.g., major depressive disorder) that, per the investigator’s 
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judgment, could significantly contribute to the patient’s current cognitive or 
functional decline, impair his/her ability to fully participate in the trial, or may 
impact his/her status during the course of the trial. 
7. Serious suicide risk per the following criteria: 
a) Suicidal ideation associated with intent and/or plan within the previous year 
as indicated by a “yes” answer on Items 4 or 5 of the C-SSRS; 
b) History of suicidal behavior within the previous 10 years as indicated by a 
“yes” answer to any of the suicidal behavior items of the C-SSRS with a 
behavior occurring within the previous 10 years; 
c) Lifetime history of serious or recurrent suicidal behavior (serious is defined 
as actual lethality/medical damage score > 2 on Screening C-SSRS)  
8. History of cancer within the last 5 years except adequately treated cervical 
carcinoma in-situ, cutaneous basal cell or squamous cell cancer, or non-
progressive prostate cancer not requiring current treatment. 
9. Participants with poorly controlled hypertension with or without existing therapy 
(ex: systolic≥140 mmHg or diastolic ≥90 mmHg with repeated measures) at 
Screening or Baseline.  Subjects with repeated measures of systolic≥140 mmHg 
or diastolic ≥90 mmHg at Screening will be allowed to participate with 
management of blood pressure below the exclusionary levels with introduction 
of an allowable medication and the subject has been on the drug for 4 weeks 
prior to Baseline.  Subjects with repeated measures of systolic≥140 mmHg or 
diastolic ≥90 mmHg at Baseline will be excluded. 
10. Participants with evidence or history of severe drug allergies (such as resulting 
in dyspnea or severe rash) or allergy to any constituents of the study drug as 
formulated. 
11. Known history or current evidence of moderate to severe substance use disorder 
according to DSM-5 criteria within 1 year prior to Screening or a positive result 
on the drug screening test (unless due to a permitted concomitant medication 
[e.g., a benzodiazepine as a sleep aid]). 
12. Subjects with pulmonary hypertension are excluded. 
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13. Previous participation and dosing in another clinical trial for Alzheimer’s disease 
as follows: 
a. Exposure to putative disease modifying therapies within 1 year before 
Screening Visit is exclusionary, unless placebo treatment assignment is 
documented. 
b. Exposure to symptomatic therapy within 90 days (or five half-lives, 
whichever is longer) before Screening Visit is exclusionary. 
Any clinical trial (Alzheimer’s or non-Alzheimer’s) study visit within 90 days 
before the Screening Visit is exclusionary regardless of treatment assignment. 
14. Participants who are taking or are expected to use drugs known to be strong 
CYP2C8 inhibitors. 
15. Participants receiving systemic steroids.  Topical corticosteroid application to 
the skin is allowed, as are localized corticosteroid injections if administered no 
more than once every 6 months during the last year and are expected to be 
administered no more frequently during the study.  Use of inhaled, intranasal or 
otic steroids are not excluded.  
16. Participants receiving medications that may negatively affect cognitive function 
(e.g., antidepressants, antipsychotics, sedatives/anxiolytics) unless such 
medications have been taken at a stable dose for at least 4 weeks prior to 
enrollment (i.e., in the investigator’s judgment, efficacy and tolerability have 
been optimized) and are expected to continue on a stable dose for the duration 
of the trial. 
17. Prescription medical food (i.e., Axona) intended for the dietary management of 
the metabolic processes associated with Alzheimer’s disease. 
18. Participants may not donate blood within 8 weeks prior to enrollment and for 
6 months after the last administration of study drug. 
19. History of clinically significant or current unstable cardiac disease as determined 
by the PI and in consultation with the Sponsor.  Examples of cardiac disease that 
would be exclusionary include 2nd degree or greater heart block without a 
pacemaker, sick sinus syndrome, ventricular tachycardia or fibrillation, 
sustained supraventricular tachycardia, symptomatic bradycardia, congenital 
long QT interval syndrome, atrial fibrillation, clinically significant 
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angina/coronary artery disease, myocardial infarction in the past year, congestive 
heart failure, cardiomyopathy, myocarditis, left ventricular hypertrophy, 
valvular heart disease requiring treatment or life style modification. Subjects 
with atrial fibrillation on anticoagulant therapy and who have had no 
thromboembolic events or other referable cardiac events in the preceding 1 year 
are considered stable and may be screened.  
20. Participants demonstrating QTcF > 470 msec on Screening 12-lead ECG 
(confirmed with a repeat measure).  Participants with known history of bundle 
branch block (either right or left) are allowed if QTcF value does not exceed 
500 msec.  Participants with a functioning pacemaker, indicated by an ECG 
displaying paced rhythm, are allowed with no QTcF upper limit. 
21. History of diabetic ketoacidosis within the last year. 
22. History of more than one severe episode of hypoglycemia that required 
assistance by a third party within the past year. 
23. History of chronic pancreatitis. 
24. Current clinically significant hepatic disease or elevated LFTs ≥ 2 times the 
upper limit of normal (ULN) at Screening. 
25. Stage 4 kidney disease (estimated GFR < 30 mL/min/1.73 m2, as calculated by 
the CKD-EPI equation [Levey 2009]). 
26. Any laboratory value not already specified above that is outside the laboratory 
reference range and considered by the Principal Investigator, or appropriately 
qualified designee, to be a clinically significant abnormality. 
27. Use of insulin therapy. 
28. Any other medical condition or reason that, in the opinion of the Principal 
Investigator or appropriately qualified designee, makes the subject unsuitable to 
participate in this clinical trial. 
Eligibility for randomization will be reviewed and approved by an independent 
Randomization Authorization Committee.  The remit of this committee will be to 
ensure each patient deemed by the Investigator to be eligible for the trial meets key 
eligibility criteria and is suitable for participation in the study.    
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4.3 
CONTRACEPTION REQUIREMENTS AND STUDY PARTICIPANT 
INSTRUCTION 
4.3.1 
Males 
A fertile male study participant, whose sexual partner is female and of childbearing 
potential, must agree to use one of the following methods of contraception for the 
duration of the study (from the first dose until 90 days after the final dose of the 
study medication):  abstinence, use of condom plus their female partners must use 
another form of contraception including implants, injectables, combined oral 
contraceptives, barrier contraception methods, spermicides, intrauterine devices 
(IUDs), transdermal contraceptives, and intravaginal contraception rings. The male 
study participant should also agree to no sperm donation for 90 days after the final 
dose of study medication. 
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. 
4.3.2 
Females 
Only females of non-child bearing potential are allowed in the study.  Screening 
laboratory FSH values will be obtained on all females to confirm post-menopausal 
status for those females who are not surgically sterile.  No additional birth control is 
required. 
 
 
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5.0 
STUDY TREATMENTS 
5.1 
PROCESS FOR RANDOMIZATION TO STUDY TREATMENT 
Subjects will be screened by Investigators or qualified designees to assess eligibility 
for randomization into the study.  An interactive voice response system (IVRS)/ 
interactive web response system (IWRS) will be used for assignment of treatment. 
Subjects will be enrolled and randomized according to a fixed randomization scheme 
blocked by study investigative site.  Randomization will have balanced allocation 
(1:1) between azeliragon and placebo.  Dropouts will not be replaced. 
5.2 
PROCESS FOR EMERGENCY BREAKING THE BLIND 
The study will be double-blind.  At the initiation of the study, the study site will be 
instructed on the electronic process for breaking the blind.  Blinding should only be 
broken in emergency situations when knowledge of the treatment assignments is 
necessary for subject safety.  Upon breaking the blind, the reason must be 
documented in the electronic data capture system. The sponsor or representative 
should be consulted prior to breaking the blind except in emergent circumstances.  
5.3 
DRUG SUPPLIES 
Drug supplies will consist of a 5 mg and matching placebo formulation supplied as 
a Size 2 hard gelatin capsule in a double-blind fashion.  The recommended storage 
condition for the product is room temperature at 15oC to 30oC (59oF to 86oF). 
5.3.1 
Formulation and Packaging 
Azeliragon and matching placebo capsules will be packaged into child-resistant, 
high density polyethylene (HDPE) bottles with heat induction seal (HIS) closures.  
Supplies will be packaged in a blinded fashion.  All doses and formulations are 
identical in appearance and packaging. 
Storage conditions and participant dosing instructions will be listed on the 
packaging. 
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5.3.2 
Administration 
Treatment will begin in the clinic at the baseline visit immediately following 
randomization. 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 study medication will be administered in the 
clinic at the end of each subsequent study visit.  Study medication may be 
administered without regard to meals. 
5.3.3 
Compliance 
Participants will bring all unused azeliragon/placebo capsules to each study visit.  
The number of capsules will be counted and documented.  If more than expected are 
returned, participants will be asked to account for missed doses.  If the number of 
capsules is less than expected, participants will be asked to account for the missing 
capsules (e.g., capsules that are lost vs. excessive dosing of study medication). 
Caregivers/Informants will be instructed to assist with monitoring dosing 
compliance.  Dosing compliance < 90% or > 100% for a 3-month period will be 
documented as a protocol deviation. 
5.3.4 
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. 
5.4 
CONCOMITANT MEDICATION(S) 
All participants will be questioned about concomitant medication and supplements 
at each study visit.  Concomitant medications (including over the counter 
medications and supplements) taken during the study must be recorded with 
indication, daily dose, and start and stop dates of administration.  During the study, 
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participants should be instructed to review new prescriptions and over-the-counter 
preparations with the investigator prior to taking any medications. All new 
medications should be discussed with the investigator and recorded on the Case 
Report Form (CRF).  If the medication is started because of an adverse event (AE) 
or medical history indication, this event should be reported on the appropriate CRF. 
 
Medications taken within 60 days prior to screening must be documented as a 
prior medication.   
 
All past medications/therapies for dementia, regardless of timing relative to 
screening, must be recorded.   
 
Medications taken after the first dose of study medication must be documented 
as concomitant medications. 
The following are specific considerations with regard to use of concomitant 
medications.  Any additional questions regarding medications should be addressed 
to the Sponsor’s medical monitor. 
Anti-diabetic therapy: 
 
Participants on anti-diabetic therapy must be on a stable dose for at least 
60 days prior to Screening and remain stable through Baseline.  There should 
be expectation that treatment and dose will remain stable for the duration of 
the trial.   
 
Participants using insulin therapy are excluded from study participation. 
Treatment for dementia: 
 
All participants must be on a stable dose of background therapy (cholinesterase 
inhibitor and/or memantine) at least 60 days prior to Screening and remain 
stable through Baseline.  There must be agreement to continue at the stable 
treatment and dose for the duration of the trial.   
 
Dose reductions of background therapy are permitted during the course of the 
trial (e.g., due to safety/tolerability or to conform with local standard of care).   
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 
Dose increases of background cholinesterase inhibitor and/or memantine 
during the course of the trial will be considered major protocol deviations. 
Medications that may affect behavior or cognitive function (e.g., antidepressants, 
antipsychotics, sedatives/anxiolytics) must be at a stable dose (i.e., in the 
investigators judgment, efficacy and tolerability have been optimized) for at least 
4 weeks prior to randomization and are expected to continue on a stable dose for the 
duration of the trial. (Dose adjustments are permitted however participants must 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: 
 
Participants may receive pre-medication (e.g., sedative or anxiolytic) for the 
MRI or CT scan assessment.  This medication should not be administered 
within 5 half-lives preceding any efficacy assessments. 
 
Considerations for use of medications that may affect the CNS or cognition 
following randomization. Generally, medications that affect cognition are not 
allowed. In such case that there is an acute need for use of a medication that 
may negatively affect 
cognition 
or the CNS in general (e.g., 
sedatives/anxiolytics, antipsychotics, opiates), their use should be transient (no 
more than 4 weeks), must be stable for at least one week prior to any cognitive 
assessments, and discussed with the sponsor’s medical monitor prior to use (or 
as soon as possible following discovery of their use). Chronic use of these 
medications is not permitted. Should their use be deemed to be chronic 
(spanning months), discussion with the Sponsor’s medical monitor is required 
regarding continued participation in the trial.  
The use of following concomitant medications is not allowed: 
 
Drugs known to be strong CYP2C8 inhibitors (See APPENDIX 2 for a list). 
 
Any use of steroid treatment. Allowable exceptions: a) topical, otic, nasal or 
inhaled corticosteroid applications to the skin, and b) localized corticosteroid 
injections, no more than once every 6 months. 
 
Prescription medical food (i.e. Axona) intended for the dietary management of 
the metabolic processes associated with Alzheimer’s disease. 
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 
No investigational therapies for any indication within 30 days or 5 half-lives 
(whichever is longer) before Screening Visit, will be permitted.  Also, no 
investigational therapies for any indication will be permitted during study 
participation.   
 
Insulin therapy 
 
 
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6.0 
STUDY PROCEDURES 
 
Study participants must arrive at clinic visits following an overnight (8 hour) 
fast to collect clinical lab samples in a fasted state.  A separate clinic visit 
within the protocol-allowed visit window may also be utilized for collecting 
fasting clinical lab samples. 
 
Anti-diabetic medication, if normally taken in the morning, should be withheld 
the morning of clinic visits and taken at the same time as the meal or snack. 
 
Following fasted blood sampling, the subject must consume a low 
carbohydrate / high protein meal or snack prior to the rest of the study 
procedures, if performed on the same day.  The time of finishing the 
meal/snack must be documented in the source documents. 
 
An on-site point of care blood glucose measurement must be obtained prior to 
neuropsychological assessments and documented in the source documents.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject (again) and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
Cognitive/functional assessments must be performed following the meal/snack 
and blood glucose measurement, during a study visit.   
 
It is required that cognitive/functional assessments be performed with the 
subject in the following order:  MMSE, ADAS-cog, patient portion of the 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.   
 
Dosing should occur in the clinic on study visit days from the newly dispensed 
study medication supply.  If the subject has already dosed with study drug on 
the clinic day, they should not be dosed in the clinic. The study drug will be 
dispensed and the subject instructed to dose at home the following day 
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according to their usual schedule. This will be documented in source 
documents and be listed as a minor protocol deviation. 
6.1 
SCREENING / Part 1 and Part 2 
For logistical purposes, up to 60 days will be allowed for screening to confirm that 
participants meet all selection criteria for the study.  It is strongly encouraged that 
the screening period is minimized to the shortest possible duration whenever 
possible.  The investigator (or an appropriate delegate at the investigator site) will 
obtain informed consent from each subject, caregiver/informant, and when 
appropriate, legally authorized representative in accordance with Subject 
Information and Informed Consent/Assent (where this is in accordance with local 
laws, regulations and ethics committee policy).  The screening assessments may be 
separated out into more than one visit if required.  Refer to the Schedule of Events 
for a tabular presentation for screening activities (Table 1, Table 2). 
The following activities will be completed: 
 
Complete informed consent/assent process (where this is in accordance with 
local laws, regulations and ethics committee policy) resulting in a signed 
ICF(s) by the appropriate parties. 
 
Assign screening identification number. 
 
Fasting blood and urine specimens for safety laboratory tests (serum 
chemistry, hematology, UA) will be collected, in addition to the following: 
 
Plasma glucose and HbA1c 
 
Hepatitis screens (including hepatitis B surface antigen, hepatitis B core 
antibody, hepatitis B surface antibody, and hepatitis C antibody) 
 
Thyroid function (T3, T4, and TSH) 
 
Vitamin B12 
 
Serum FSH concentrations in all female participants to confirm post- 
menopausal status and eligibility regarding non-child bearing potential 
 
Urine drug screen 
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 
Provide subject with a meal/snack. 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE. 
 
ADAS-cog14. 
 
CDR (calculation of both global score and sum of boxes score ). 
 
Columbia Suicide Severity Scale (C-SSRS). 
 
Demographic information (i.e., sex, date of birth, race/ethnicity). 
 
Complete medical and surgical history, including family medical history of 
dementia. 
 
History of prior participation and dosing in a clinical trial. 
 
Record and review all prior medications for Alzheimer’s disease. 
 
Record and review concomitant medications and any discontinued medication 
in the 60 days prior to the Screening visit. 
 
History of drug, alcohol and tobacco use. 
 
Complete physical and neurological exams. 
 
Height, body weight, and body mass index (BMI) calculation. 
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest. 
 
Single 12-lead electrocardiogram (ECG) after 5 minutes rest.  Repeat ECG if 
QTcF > 470 msec. 
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 
Review of inclusion and exclusion criteria. 
 
Brain MRI should be performed at least 14 days prior to Month 0/Day 1 dosing 
to allow time for central read; the MRI may also include gadolinium contrast 
if determined to be appropriate by the investigator. For subjects with a 
contraindication to MRI scanning (e.g. pacemaker), a CT scan will fulfill the 
requirements for assessing subject eligibility.  Use of contrast is allowed upon 
investigator discretion. 
Re-screening of a Participant 
Participants who had been screened and failed to join the study based on the 
following reasons are allowed to re-screen if the subject is beyond the original 
60-day screening window.  A re-screening subject must receive a new screening ID.   
Participants do not have to repeat the MRI if dosing occurs within 90 days from the 
initial screening MRI. 
 
Participants with Vitamin B12 below the normal limits at initial screening. 
 
Participants must subsequently have been taking Vitamin B12 for at least 
4 weeks after initial screen failure and have repeat B12 level within the normal 
range.   
 
Participants who are not on a stable dose of anti-diabetic therapy for at least 
60 days prior to Screening may rescreen once they have reached at least 
60 days of stable dosing. 
 
Participants who are not on a stable dose of dementia therapy for at least 
60 days prior to Screening may rescreen once they have reached at least 
60 days of stable dosing. 
 
Hypertension discovered at screening that is subsequently actively managed 
and the blood pressure values are within acceptable limits. 
 
Subjects who have a Screening CDR global of 0 or an MMSE score >26 may 
rescreen upon approval of the sponsor’s medical monitor. Screening CDR 
global scores greater than 1 or MMSE scores less than 21 may not rescreen. 
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The time to rescreen a subject is up to the investigator but in any case, may not 
be within 3 months with no upper time limit. They may rescreen only once. 
Subjects who score out of range are considered a screen fail, even if they are 
planning to rescreen.    
 
Subjects who did not complete the screening procedures within the protocol-
specified 60-day window may rescreen. 
 
Subjects who have a Screening HbA1c outside of the eligible range may re-test 
HbA1c during the screening period and re-assess eligibility.  If the 60-day 
Screening period elapses, the subject may re-screen with a new Screening ID 
6.2 
PART 1 STUDY PERIOD 
6.2.1 
Part 1 / Baseline (approximately Day -7-Day 1) 
 
Assessment of continued consent / assent (where applicable). 
 
Fasting clinical laboratories: 
 
Collect blood sample for plasma retention and storage. 
 
Blood sample for ApoE genotyping. 
 
Blood and urine sampling for safety labs including HbA1c. 
 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE, ADAS-cog14, CDR, FAQ, Amsterdam-IADL. 
 
C-SSRS. 
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 
Brief physical and neurologic examination. 
 
Update concomitant medications. 
 
Body weight. 
 
Assess baseline symptoms/adverse events. 
 
12-lead electrocardiogram (ECG) after 5 minutes rest.  Perform triplicate 
measures and use the average QTcF for inclusion. 
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest.  Perform 
triplicate measures and use the average blood pressure readings for inclusion. 
 
Review of inclusion and exclusion criteria including the results of Screening 
laboratories and Screening MRI scan, and confirm continued eligibility 
Day 1 
At the conclusion of the Baseline visit, the following procedures are performed if 
the subject is confirmed eligible:  
 
Randomize subject if eligible. 
 
Dispense study drug if eligible. 
 
Subject takes first dose of study medication in the clinic under observation and 
time of dosing recorded. 
If the baseline assessments are performed on more than one day, up to 7 days are 
allowed for completion of baseline procedures prior to subject randomization and 
dosing.  The 7-day window will begin on the day that the first baseline assessment 
is performed and ends on the day when the subject is randomized, and study drug is 
administered. 
If it is necessary to extend the 7-day period for any other reason (e.g., schedule 
conflicts, patient/caregiver/informant illness, inclement weather) the Sponsor should 
be contacted for approval and the visit window may be extended up to 7 days.  In 
this case, re-review of the inclusion/exclusion criteria and concomitant medications 
should occur within 7 days prior to the first dose to ensure that the patient continues 
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to be appropriate for the study.  Other baseline procedures may be repeated at the 
discretion of the Investigator but are not required.  The 60-day period from screening 
to first dose remains in effect.  Should the overall screening time exceed 60 days, 
re-screening is required. 
6.2.2 
Part 1 / Month 1 Telephone Contact (Day 30 ± 7 days)  
 
Telephone contact with subject and caregiver (separate or combined). 
 
Review and record new concomitant medications. 
 
Assess symptoms/adverse events by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
 
Assess drug compliance with the question “Have you been taking your 
medication every day as instructed?” 
6.2.3 
Part 1 / Month 2 Telephone Contact (Day 60± 7 days)  
 
Telephone contact with subject and caregiver (separate or combined). 
 
Review and record new concomitant medications. 
 
Assess symptoms/adverse events by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
 
Assess drug compliance with the question “Have you been taking your 
medication every day as instructed?” 
 
Provide subject and caregiver with instructions for next visit (e.g., date, 
requirement for fasting blood samples, hold dosing on morning of visit, return 
used study drug bottles). 
6.2.4 
Part 1 / Month 3 Clinic Visit (Day 90 ± 7 days) 
 
Assessment of continued consent / assent (where applicable). 
 
Fasting blood and urine sampling for safety labs, including HbA1c. 
 
Collect blood sample for plasma retention and storage. 
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 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE, ADAS-cog14, CDR-sb, FAQ, Amsterdam-IADL. 
 
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. 
 
Body weight. 
 
12-lead electrocardiogram (ECG) after 5 minutes rest.   
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest. 
 
Return study drug. 
 
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 daily dose of study medication in the clinic. 
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 61 
6.2.5 
Part 1 / Month 4 Telephone Contact (Day 120 ± 7 days) 
 
Telephone contact with subject and caregiver (separate or combined). 
 
Review and record new concomitant medications. 
 
Assess symptoms/adverse events by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
 
Assess drug compliance with the question “Have you been taking your 
medication every day as instructed?” 
6.2.6 
Part 1 / Month 5 Telephone Contact (Day 150 ± 7 days) 
 
Telephone contact with subject and caregiver (separate or combined). 
 
Review and record new concomitant medications. 
 
Assess symptoms/adverse events by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
 
Assess drug compliance with the question “Have you been taking your 
medication every day as instructed?” 
 
Provide subject and caregiver with instructions for next visit (e.g., date, 
requirement for fasting blood samples, hold dosing on morning of visit, return 
used study drug bottles). 
6.2.7 
Part 1 / Month 6 Clinic Visit (Day 180 ± 7 days) 
 
Assessment of continued consent / assent (where applicable). 
 
Fasting blood and urine sampling for safety labs, including HbA1c. 
 
Collect blood sample for plasma retention and storage. 
 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 62 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE, ADAS-cog14, CDR-sb, FAQ, Amsterdam-IADL. 
 
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. 
 
Body weight. 
 
12-lead electrocardiogram (ECG) after 5 minutes rest. 
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest. 
 
Return study drug. 
 
Drug accountability. Any discrepancies are recorded in the source. 
6.2.8 
Part 1 / Follow-Up Visit  
A Follow-up Visit will be completed 3 months [90 ± 7 days] after a subject 
completes Month 6 for those participants who complete the study; or at least 45 days 
after the last dose of study drug, if the subject discontinues the study prior to 
Month 6.   
If a subject does not complete a follow up visit, the reason and efforts to contact 
subjects for follow-up should be documented in the source and EDC.  An Early 
Termination Visit does not satisfy the requirements for a Follow-Up Visit. 
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vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
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At any point, if a participant withdraws consent, no further evaluations should be 
performed, and no additional data should be collected.   
 
Assessment of continued consent / assent (where applicable). 
 
Fasting blood and urine sampling for safety labs, including HbA1c. 
 
Collect blood sample for plasma retention and storage. 
 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE, ADAS-cog14, CDR-sb, FAQ, Amsterdam-IADL. 
 
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. 
 
Body weight. 
 
12-lead electrocardiogram (ECG) after 5 minutes rest. 
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest. 
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 64 
6.2.9 
Part 1 / Early Termination 
In the event a subject discontinues participation prior to completion of the Month 6 
Visit and less than 45 days have elapsed since the subject’s last dose of study drug, 
the Early Termination Visit should be completed, performing the study procedures 
as follows.  In all cases, a Follow-up Visit (as described in Section 6.2.8) should be 
performed approximately 3 months after the last dose of study drug.  However, if a 
participant withdraws consent prior to early termination, no further evaluations 
should be performed, and no additional data should be collected.   
 
Assessment of continued consent / assent (where applicable). 
 
Fasting blood and urine sampling for safety labs, including HbA1c. 
 
Collect blood sample for plasma retention and storage. 
 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE, ADAS-cog14, CDR-sb, FAQ, Amsterdam-IADL. 
 
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. 
 
Body weight. 
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 65 
 
12-lead electrocardiogram (ECG) after 5 minutes rest. 
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest. 
 
Return study drug. 
 
Drug accountability. Any discrepancies are recorded in the source. 
6.3 
PART 2 STUDY PERIOD 
6.3.1 
Part 2 / Baseline (approximately Day -7-Day 1) 
 
Assessment of continued consent / assent (where applicable). 
 
Fasting clinical laboratories: 
 
Collect blood sample for plasma retention and storage. 
 
Blood sample for ApoE genotyping. 
 
Blood and urine sampling for safety labs, including HbA1c. 
 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE, 
ADAS-cog14, 
CDR, 
FAQ, 
Amsterdam-IADL, 
NPI, 
DEMQOL-proxy. 
 
C-SSRS. 
 
Brief physical and neurologic examination. 
 
Update concomitant medications. 
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 66 
 
Body weight. 
 
Assess baseline symptoms/adverse events. 
 
12-lead electrocardiogram (ECG) after 5 minutes rest.  Perform triplicate 
measures and use the average QTcF for inclusion. 
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest.  Perform 
triplicate measures and use the average blood pressure readings for inclusion. 
 
Review of inclusion and exclusion criteria including the results of Screening 
laboratories and Screening MRI scan, and confirm continued eligibility. 
Day 1 
At the conclusion of the Baseline visit, the following procedures are performed if 
the subject is confirmed eligible:  
 
Randomize subject if eligible. 
 
Dispense study drug if eligible. 
 
Subject takes first dose of study medication in the clinic under observation 
with time of dosing recorded. 
If the baseline assessments are performed on more than one day, up to 7 days are 
allowed for completion of baseline procedures prior to subject randomization and 
dosing.  The 7-day window will begin on the day that the first baseline assessment 
is performed and ends on the day when the subject is randomized, and study drug is 
administered. 
If it is necessary to extend the 7-day period for any other reason (e.g., schedule 
conflicts, patient/caregiver/informant illness, inclement weather) the Sponsor should 
be contacted for approval and the visit window may be extended up to 7 days.  In 
this case, re-review of the inclusion/exclusion criteria and concomitant medications 
should occur within 7 days prior to the first dose to ensure that the patient continues 
to be appropriate for the study.  Other baseline procedures may be repeated at the 
discretion of the Investigator but are not required.  The 60-day period from screening 
to first dose remains in effect.  Should the overall screening time exceed 60 days, 
re-screening is required. 
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Azeliragon (TTP488) 
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4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
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6.3.2 
Part 2 / Month 1 Telephone Contact (Day 30 ± 7 days) 
 
Telephone contact with subject and caregiver (separate or combined). 
 
Review and record new concomitant medications. 
 
Assess symptoms/adverse events by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
 
Assess drug compliance with the question “Have you been taking your 
medication every day as instructed?” 
6.3.3 
Part 2 / Month 2 Telephone Contact (Day 60 ± 7 days) 
 
Telephone contact with subject and caregiver (separate or combined). 
 
Review and record new concomitant medications. 
 
Assess symptoms/adverse events by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
 
Assess drug compliance with the question “Have you been taking your 
medication every day as instructed?” 
 
Provide subject and caregiver with instructions for next visit (e.g., date, 
requirement for fasting blood samples, hold dosing on morning of visit, return 
used study drug bottles). 
6.3.4 
Part 2 / Month 3 Clinic Visit (Day 90 ± 7 days) 
 
Assessment of continued consent / assent (where applicable). 
 
Fasting blood and urine sampling for safety labs, including HbA1c. 
 
Collect blood sample for plasma retention and storage. 
 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 68 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE, 
ADAS-cog14, 
CDR-sb, 
FAQ, 
Amsterdam-IADL, 
NPI, 
DEMQOL-proxy. 
 
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. 
 
Body weight. 
 
12-lead electrocardiogram (ECG) after 5 minutes rest. 
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest. 
 
Return study drug 
 
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 daily dose of study medication in the 
clinic. 
 
Provide subject and caregiver with instructions for next visit (e.g., date, 
requirement for fasting blood samples, hold dosing on morning of visit, return 
used study drug bottles). 
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 69 
6.3.5 
Part 2 / Month 6 Clinic Visit (Day 180 ± 7 days) 
 
Assessment of continued consent / assent (where applicable). 
 
Fasting blood and urine sampling for safety labs, including HbA1c. 
 
Collect blood sample for plasma retention and storage. 
 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE, 
ADAS-cog14, 
CDR-sb, 
FAQ, 
Amsterdam-IADL, 
NPI, 
DEMQOL-proxy. 
 
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. 
 
Body weight. 
 
12-lead electrocardiogram (ECG) after 5 minutes rest. 
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest. 
 
Return study drug. 
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 70 
 
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 daily dose of study medication in the 
clinic. 
 
Provide subject and caregiver with instructions for next visit (e.g., date, 
requirement for fasting blood samples, hold dosing on morning of visit, return 
used study drug bottles). 
6.3.6 
Part 2 / Month 9 Clinic Visit (Day 270 ± 7 days) 
 
Assessment of continued consent / assent (where applicable). 
 
Fasting blood and urine sampling for safety labs, including HbA1c. 
 
Collect blood sample for plasma retention and storage. 
 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE, ADAS-cog14. 
 
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?” 
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 71 
 
Brief physical and neurologic examination. 
 
Body weight. 
 
12-lead electrocardiogram (ECG) after 5 minutes rest.   
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest. 
 
Return study drug. 
 
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 daily dose of study medication in the 
clinic. 
 
Provide subject and caregiver with instructions for next visit (e.g., date, 
requirement for fasting blood samples, hold dosing on morning of visit, return 
used study drug bottles). 
6.3.7 
Part 2/ Month 12 Clinic Visit (Day 360 ± 7 days) 
 
Assessment of continued consent / assent (where applicable). 
 
Fasting blood and urine sampling for safety labs, including HbA1c. 
 
Collect blood sample for plasma retention and storage. 
 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
71


Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 72 
 
MMSE, 
ADAS-cog14, 
CDR-sb, 
FAQ, 
Amsterdam-IADL, 
NPI, 
DEMQOL-proxy. 
 
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. 
 
Body weight. 
 
12-lead electrocardiogram (ECG) after 5 minutes rest. 
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest. 
 
Return study drug. 
 
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 daily dose of study medication in the 
clinic. 
 
Provide subject and caregiver with instructions for next visit (e.g., date, 
requirement for fasting blood samples, hold dosing on morning of visit, return 
used study drug bottles). 
6.3.8 
Part 2 / Month 15 Clinic Visit (Day 450 ± 7 days) 
 
Assessment of continued consent / assent (where applicable). 
 
Fasting blood and urine sampling for safety labs, including HbA1c. 
 
Collect blood sample for plasma retention and storage. 
 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 73 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE, ADAS-cog14. 
 
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. 
 
Body weight. 
 
12-lead electrocardiogram (ECG) after 5 minutes rest. 
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest. 
 
Return study drug. 
 
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 daily dose of study medication in the 
clinic. 
 
Provide subject and caregiver with instructions for next visit (e.g., date, 
requirement for fasting blood samples, hold dosing on morning of visit, return 
used study drug bottles). 
 
 
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 74 
6.3.9 
Part 2 / Month 18 Clinic Visit (Day 540 ± 7 days) 
 
Assessment of continued consent / assent (where applicable). 
 
Fasting blood and urine sampling for safety labs, including HbA1c. 
 
Collect blood sample for plasma retention and storage. 
 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE, 
ADAS-cog14, 
CDR-sb, 
FAQ, 
Amsterdam-IADL, 
NPI, 
DEMQOL-proxy. 
 
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. 
 
Body weight. 
 
12-lead electrocardiogram (ECG) after 5 minutes rest. 
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest. 
 
Return study drug. 
 
Drug accountability. Any discrepancies are recorded in the source. 
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 75 
 
Brain MRI.  For subjects with a contraindication to MRI scanning (e.g., 
pacemaker), no brain MRI is required for this visit. 
6.3.10 
Part 2 / Follow-Up Visit  
A Follow-up Visit will be completed 3 months [90 ± 7 days] after a subject 
completes Month 18 for those participants who complete the study; or at least 
45 days after the last dose of study drug if the subject discontinues the study prior to 
Month 18.   
If a subject does not complete a follow up visit, the reason should be documented in 
the source and EDC.  An Early Termination visit does not satisfy the requirement 
for a Follow-Up Visit. 
At any point, if a participant withdraws consent, no further evaluations should be 
performed, and no additional data should be collected.   
 
Assessment of continued consent / assent (where applicable). 
 
Fasting blood and urine sampling for safety labs, including HbA1c. 
 
Collect blood sample for plasma retention and storage. 
 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE, 
ADAS-cog14, 
CDR-sb, 
FAQ, 
Amsterdam-IADL, 
NPI, 
DEMQOL-proxy. 
 
C-SSRS. 
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 76 
 
Review and record new concomitant medications. 
 
Assess symptoms/adverse events by asking the participants to respond to a 
non-leading question such as “How have you been feeling?” 
 
Brief physical and neurologic examination. 
 
Body weight. 
 
12-lead electrocardiogram (ECG) after 5 minutes rest. 
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest. 
6.3.11 
Part 2 / Early Termination 
In the event a subject discontinues participation prior to completion of the Month 18 
Visit and less than 45 days have elapsed since the subject’s last dose of study drug, 
the Early Termination Visit should be completed performing the study procedures 
as follows.  In all cases, a Follow-up Visit (as described in Section 6.3.10) should be 
performed approximately 3 months after the last dose of study drug.  However, if a 
participant withdraws consent prior to early termination, no further evaluations 
should be performed, and no additional data should be collected.   
 
Assessment of continued consent / assent (where applicable). 
 
Fasting blood and urine sampling for safety labs, including HbA1c. 
 
Collect blood sample for plasma retention and storage. 
 
Collect blood samples for PK and PD. 
 
Provide subject with a meal/snack. 
 
Check blood sugar, using point of care device, after an appropriate time.   
 
If subject is hypoglycemic (<90mg/dL), feed the subject again and 
re-check blood sugar prior to neuropsychological assessments.  
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Azeliragon (TTP488) 
vTv Therapeutics LLC 
 
4170 Mendenhall Oaks Pkwy 
TTP488-305 
High Point, NC 27265 
 
 
 
Page 77 
 
If 
subject 
is 
hyperglycemic 
(>300mg/dL), 
reschedule 
the 
neuropsychological assessments for a proximal day within the visit 
window. 
 
MMSE, 
ADAS-cog14, 
CDR-sb, 
FAQ, 
Amsterdam-IADL, 
NPI, 
DEMQOL-proxy. 
 
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. 
 
Body weight. 
 
12-lead electrocardiogram (ECG) after 5 minutes rest. 
 
Vital signs: blood pressure (supine), pulse rate after 5 minutes rest. 
 
Return study drug. 
 
Drug accountability. Any discrepancies are recorded in the source. 
 
Brain MRI.  For subjects with a contraindication to MRI scanning (e.g., 
pacemaker), no brain MRI is required for this visit. 
6.4 
SUBJECT WITHDRAWAL 
Participants may withdraw from the study at any time at their own request or the 
request of their study partner, caregiver/informant/guardian, or they may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety, 
behavioral, compliance, or administrative reasons.  If a participant does not return 
for a scheduled visit, every effort should be made to contact the participant including 
certified letter, return receipt requested.  The investigator should inquire about the 
reason for withdrawal, request that the participant return all unused investigational 
product(s), request that the participant return for any remaining clinic visits.  
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If the participant withdraws from the study and joins another clinical study or does 
not wish to complete the remaining clinic visits, an Early Termination and/or 
Follow-up Visit should be performed as follows: 
 
An Early Termination should be performed if less than 45 days have elapsed 
since the subject’s last dose of study drug.   
 
A Follow-up Visit should be performed when ≥ 45 days have elapsed since the 
subject’s last dose of study drug. 
Continued follow-up with the participant may be required if there are any unresolved 
adverse events (refer to Section 8.7). 
If the participant withdraws from the study, and also withdraws consent for 
disclosure of future information, no further evaluations should be performed, and no 
additional data should be collected.  The Sponsor may retain and continue to use any 
data collected before such withdrawal of consent.  An individual patient enrolled in 
the trial may be discontinued from dosing (and continue in the study) based on a 
specific adverse event profile as recommended by either the IDMC and/or the 
Sponsor in discussions with the PI.  The IDMC or the Sponsor may temporarily stop 
dosing of enrolled subjects and/or additional enrollment of new patients at any time 
and may permanently terminate the study at any time. 
Any emergent medical condition or safety finding that, in the opinion of the 
Investigator, may jeopardize the participant’s safety if he/she continues dosing will 
be sufficient reason to discontinue dosing (temporarily or permanently), while the 
participant continues in 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.  Once 
resolved, the Investigator and Medical Monitor may discuss if it would be 
appropriate to re-start dosing. 
 
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7.0 
ASSESSMENTS 
7.1 
SAFETY AND TOLERABILITY 
7.1.1 
Body Measurements 
Height (cm) will be measured at the Screening Visit, without shoes. 
Body weight (kg) will be measured on the same scale without shoes, coats, or 
sweaters. 
BMI will be calculated as body weight (kg) / height (m) 2.   
7.1.2 
Vital Signs 
Vital signs measurements will consist of blood pressure and pulse rate while the 
participant is supine.  Vital signs will be conducted at all the study visits.  Participant 
should have been supine at least 5 minutes prior to vital signs determination.  At 
Baseline, pre-dose measurements will be performed in triplicate; all other vital signs 
readings (at time points shown in the Schedule of Activities) will be a single 
measurement.  The baseline triplicate readings for blood pressure will be averaged 
for eligibility determination. 
7.1.3 
Electrocardiogram 
12–lead ECG should be recorded after participants have been resting at least 
5 minutes in the supine position.  Digital ECG tracings will be performed using 
equipment from and analyzed by a central ECG laboratory.  The cardiologist reading 
the ECGs will be blinded regarding study drug assignment.  All standard intervals 
will be measured. 
When assessing eligibility at the Screening visit, the presence of BBB (either left or 
right) is allowable as long as the absolute QTcF value does not exceed 500 msec and 
the subject does not have any other cardiac exclusions as described in exclusion 
criterion 19.  When an ECG displays a paced rhythm indicating a functioning 
pacemaker is present, there is no upper QTcF limit as long as there are no related 
cardiac exclusions (reference exclusion criterion 20).  Note: If there is no known 
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history of BBB (either right or left), the discovery of such should prompt further 
investigation prior to proceeding with screening.  
At the Baseline visit, the participant will have an ECG obtained (in triplicate) in 
order to verify continued eligibility for the study.  If the QTcF is >470 msec is 
determined based on the average of the 3 QTcFs obtained from the local reading, a 
subject should not be dosed, pending central reading of the ECG.   
When the site receives the Baseline Visit Central ECG Laboratory reading(s), if 
QTcF is confirmed as exclusionary (using the criteria immediately above), the 
subject should be excluded. If the central reading does not confirm the exclusion, 
the patient may be dosed as soon as convenient/possible.  If a patient was dosed 
based on local reading that determined to be acceptable (using the criteria above) 
and the central reading is nevertheless determined to be exclusionary, the site should 
contact the Sponsor for guidance on how to proceed. 
At any time during the study, a subject with any of the above ECG values should 
prompt a call to the Sponsor for guidance on how to proceed.  
7.1.4 
Physical Examination 
Complete physical examination will include skin, eyes, ears, nose and throat, 
cardiac, respiratory, abdomen, and extremities.  Complete physical examination will 
be conducted at the Screening visit.  Brief physical examination will include skin, 
eyes, oral mucosa, cardiac, and respiratory, and a directed exam related to any 
reported AEs.  A brief physical examination will be conducted at all the study visits.  
Body weight will be also examined at all study visits. 
Clinically relevant findings noted at Screening will be considered medical history.  
Any treatment emergent new finding on brief physical examination will be 
documented as an adverse event.    
7.1.5 
Neurological Examination 
Complete neurological examination will include cortical function, meningeal 
irritation assessment, cranial nerves, motor and sensory function, coordination, deep 
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tendon reflexes, stance and gait.  Complete neurological examination will be 
conducted at Screening. 
Brief neurological examination will include meningeal irritation assessment, cranial 
nerves, motor and sensory function, coordination, deep tendon reflexes, stance and 
gait.  Brief neurological examination will be conducted at all the study visits. 
Clinically relevant findings noted at Screening will be considered medical history.  
Any treatment emergent new finding on brief neurological examination will be 
documented as an adverse event.    
7.1.6 
Laboratory 
7.1.6.1 
Standard Safety Laboratory Tests 
Unless noted otherwise, safety laboratory tests will be performed in the fasted state, 
according to the Schedule of Activities in Table 1 and Table 2.  All routine laboratory 
tests will be analyzed by a central laboratory that will provide instructions and 
supplies. 
 
Hematology 
Chemistry 
Urinalysis 
Otherc 
Hemoglobin 
Hematocrit RBC count 
Platelet count WBC count 
MCV 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
BUN and Creatinine 
Plasma Glucose (fasting) 
Calcium 
Sodium  
Potassium  
Chloride 
Total CO2 (Bicarbonate) 
AST 
ALT 
GGT  
LDH 
Total Bilirubin  
Alkaline phosphatase  
Uric acid 
Albumin 
Total protein 
HbA1c 
Insulin 
eGFR calculation
pH 
Glucose (qual) Protein 
(qual) Blood (qual) 
Ketones Nitrites 
Leukocyte esterase 
Microscopya 
FSHb 
Urine drug screen  
T3, T4, TSH  
Vitamin B12 
Hepatitis B, C 
a 
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.  
b 
Females. 
c 
At screening. 
 
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 
Hepatitis screens include hepatitis B surface antigen, hepatitis B core antibody, 
hepatitis B surface antibody, and hepatitis C antibody.  
 
Minimum requirement for urine drug testing includes: cocaine, THC, opiates, 
benzodiazepines and amphetamines. 
7.1.6.2 
Assessment of Blood Glucose Using Point of Care Device 
An on-site point of care blood glucose measurement must be obtained prior to 
neuropsychological assessments.  The point of care blood glucose measurement 
should be obtained after an appropriate time following the low carbohydrate / high 
protein meal or snack (e.g., 30-60 minutes).  The blood glucose measurement 
obtained using the point of care device will only be documented in the source 
documents and used to determine if it is appropriate to proceed with 
neuropsychological assessments.   
The blood glucose measurement from the central laboratory will be the measurement 
included in the study database. 
7.1.6.3 
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.) 
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b. Participants with pre-existing AST or ALT baseline values above the normal 
range who subsequently present with AST or ALT ≥2 times the baseline values 
and ≥3 times the upper limit of normal concurrent with a total bilirubin ≥2 times 
the upper limit of normal with no evidence of 1) hemolysis,  2) cholestasis 
(elevated  alkaline phosphatase ≥2 times the upper limit of normal or not 
available) or 3) Gilbert’s Syndrome (common benign condition associated with 
intermittent elevations of primarily indirect, unconjugated, bilirubin to about 2 X 
upper limit of normal.) 
Increases defined above should be confirmed with repeat testing within 48 to 
72 hours.   In addition to repeating AST and ALT, laboratory tests should include 
albumin, amylase, creatine kinase, total bilirubin, direct and indirect bilirubin, 
gamma-glutamyl transferase (GGT), international normalized ratio (INR) and 
alkaline phosphatase.  Symptoms should be assessed.  The medical monitor should 
be contacted to discuss the patient’s condition. 
Close observation should be immediately initiated if symptoms persist and/or repeat 
testing confirm the abnormalities described above.  Evaluation should include 
repeating laboratory tests (two or three time weekly; frequency may decrease to once 
a week or less if abnormalities stabilize or trial drug is discontinued and the subject 
is asymptomatic), and a detailed medical history and physical assessment.  A 
detailed history, including relevant information, such as history of symptoms or 
concurrent illnesses, concomitant medication use (including review of 
acetaminophen use and herbal/dietary supplements), alcohol consumption, 
recreational drug use and special diets.  Additionally, family history, sexual history, 
travel history, history of contact with a jaundiced subject, surgery, blood transfusion, 
history of liver or allergic disease, and work exposure, should be collected.  Ruling 
out acute hepatitis A, B, C, D, and E infection, autoimmune or alcoholic hepatitis, 
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. 
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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.   
If a participant presents at any visit with any condition that, in the opinion of the 
investigator, 
may 
jeopardize 
the 
accurate 
evaluation 
of 
participant’s 
neuropsychological function, participants should not receive neuropsychological 
tests, and reserve an additional visit to evaluate function within the allowance of the 
visit window.   
Neuropsychological assessments must not be performed if the patient is fasting; 
neuropsychological assessments should be performed following the meal/snack and 
blood glucose measurement, during a study visit.  The same rater should follow a 
particular participant for any given assessment for the duration of the study 
whenever possible.  The scales are to be administered to the subject in the following 
order when they occur at the same visit:  MMSE, ADAS-cog, CDR (patient portion), 
C-SSRS.  All neuropsychological assessments must be performed by a trained rater.   
 
Non-CDR Rater – This person will meet the education, clinical and scale 
experience requirements set by the sponsor.  This person can conduct all ratings 
and assessments, once qualified by the rater training staff, except for the CDR.  
If appropriately qualified, the PI or Study Coordinator may also fulfill this role. 
 
CDR Rater – This person will render the CDR rating based on clinical 
assessment of participant and caregiver / study partner, using scale worksheets 
provided by the Sponsor, but without access to the ADAS-cog or any other study 
assessments.  Neither the PI nor the Study Coordinator responsible for study 
oversight may fulfill this role. 
7.2.1 
Cognitive Assessments 
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 
according to the Schedule of Activities in Table 1 and Table 2.  Scores range from 
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0-30 with lower scores indicating greater cognitive impairment.  Participants with 
scores of 21-26 at Screening and scores of 19-27 at Baseline will be eligible for 
participation in the study.  The MMSE must always be administered in a fed state. 
Alzheimer's Disease Assessment Scale - Cognitive Subscale 90 point 
(ADAS-cog14):  The 14-Item Alzheimer’s Disease Assessment Scale - Cognitive 
Subscale (ADAS-cog14) is a structured scale (approximately 45 minutes to 
complete) that evaluates memory, orientation, attention, reasoning, language, 
constructional praxis, delayed recall, digit cancellation, and maze-completion.  The 
ADAS-cog14 scoring range is from 0 to 90, with higher scores indicating greater 
cognitive impairment (Mohs et al. 1997).  The ADAS-cog will be administered 
according to the Schedule of Activities in Table 1 and Table 2.  Participants with 
scores of ≥10 at Screening and Baseline will be eligible for participation in the 
study.  The ADAS-cog must always be administered when the subject is in a fed 
state. 
7.2.2 
Functional/Global Assessments 
Functional Activities Questionnaire (FAQ):  The FAQ is an inventory of 
instrumental activities of daily living developed by (Pfeffer 1982).  The FAQ is 
administered by asking the informant to rate patient’s ability (0-3) on 10 different 
activities of daily living.  The total FAQ score ranges from 0 to 30, with higher 
scores indicating greater functional loss.  The FAQ will be administered according 
to the Schedule of Activities in Table 1 and Table 2.   
Amsterdam-Instrumental Activities of Daily Living Questionnaire (A-IADL):  The 
A-IADL is an adaptive questionnaire designed to assess impairments in instrumental 
activities of daily living in early dementia.(Sikkes 2013)  The questionnaire is 
completed by a caregiver / informant.  The original questionnaire consists of 70 
items in seven categories and the administration time is approximately 20-25 
minutes. The A-IADL total score is calculated using an item response theory method 
of scoring and lower scores indicate greater functional impairment.  The A-IADL 
will be administered according to the Schedule of Activities in Table 1 and Table 2. 
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 caregiver (first) and patient 
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(second).(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.  The interview 
takes approximately 40 minutes to administer. 
CDR global ratings are 0 for cognitively unimpaired 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 (CDR-SB).  Sum of box scores range from 0 to 18 
with higher scores indicating greater cognitive impairment. 
The CDR will be administered according to the Schedule of Activities in Table 1 
and Table 2 and the subject must in a fed state. 
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 1994)  The interview is also relatively brief (15 minutes).  It 
evaluates both the frequency and severity of 12 behavioral areas including delusions, 
hallucinations, dysphoria (depression) anxiety, agitation/aggression, euphoria, 
disinhibition, irritability, lability, apathy, aberrant motor behavior, appetite and 
eating changes and night-time behaviors. 
Frequency assessments range from 1 (occasionally, less than once per week) to 
4 (very frequently, once or more per day or continuously) as well as severity (1= 
mild, 2 = moderate, 3 = severe).  Distress is rated by the study partner or caregiver 
and ranges from 0 (no distress) to 5 (very severe or extreme).  The overall score and 
the score for each subscale are the product of severity and frequency.  Scores range 
from 0-144 with higher scores indicating a greater presence of neuropsychiatric 
symptoms.  The NPI will be administered according to the Schedule of Activities in 
Table 2.   
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 2005)  It 
consists of 31 items representing 5 domains (daily activities and looking after 
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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 according to 
the Schedule of Activities in Table 2.   
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 2011)  This scale will be administered at Screening Visit to 
evaluate life time suicide attempt, suicide behaviors, and other non-suicidal 
self-injuries.  The CSSRS must be administered by a certified rater.  Positive 
responses on the C-SSRS will be mapped to the Columbia Classification Algorithm 
of Suicide Assessment (C-CASA) for classification and reporting using a standard 
algorithm. 
At the Screening and Baseline Visit, the C-SSRS will be used to detect possible 
suicidality prior to dosing.  If the patient’s responses indicate: (1) the subject may 
have had suicide ideation associated with actual intent and/or plan in the past year, 
(2) any history of suicidal behavior in the past 10 years, (3) any lifetime history of 
recurrent suicidal behavior the subject should be excluded.  In the event that the 
subject answers “Yes” to the suicidal ideation items 4 or 5 of the C-SSRS or a history 
of suicidal behavior within the previous 10 years as indicated by a “yes” answer to 
any of the suicidal behavior items of the C-SSRS at the screening or baseline visit, 
that subject will not be eligible for inclusion in the study.  
Following dosing, the C-SSRS will be used to assess suicide ideation or behavior at 
each study visit.  Following dosing (after the Baseline / Randomization visit), if there 
are “yes” answers on items 4, 5 or on any behavioral question of the C-SSRS, a 
professional suicide risk assessment must 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 an independent, 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.  Neither the PI nor any member 
of the PI staff may conduct this interview.  A change from baseline to a yes on any 
of these items will also constitute an AE and must be documented as such.  
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7.4 
PLASMA FOR ANALYSIS OF AZELIRAGON AND METABOLITE 
CONCENTRATIONS 
Blood samples for pharmacokinetic (PK) analysis of azeliragon and metabolite 
concentrations will be collected according to the Schedule of Activities in Table 1 
and Table 2. 
All PK Blood samples to provide plasma for pharmacokinetic analysis will be 
collected, processed, stored, and shipped according the lab manual instructions. 
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 according to the 
Schedule of Activities in Table 1 and Table 2. 
Blood samples for plasma biomarkers will be collected, processed, stored, and 
shipped according the lab manual instructions. 
7.6 
MRI 
MRI scans will be performed at Screening in Part 1 and at Screening and Month 18 
/ Early Termination in Part 2.  MRI scans will be read by a central reader prior to 
inclusion in the study to detect any exclusionary conditions such as stroke, 
hematoma, or intracranial tumor.  The screening MRI should be performed at least 
14 days prior to dosing to allow for the central read and interpretation of results prior 
to dosing.  A local read is not required.  Outside or prior MRI scans will not suffice 
for inclusion. 
Specific MRI scan sequences required for safety and/or volumetric assessments will 
be outlined in the MRI procedures manual.  Participants will be monitored, and 
images will be reacquired if there is subject movement during the scan.  Volume, 
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surface area, and thickness values for all Freesurfer-generated regions will be 
assessed.   
Brain magnetic resonance imaging (MRI) may include gadolinium contrast if the 
investigator determines that this is necessary for patient care either based on clinical 
signs or findings on the non-contrast MRI.  Gadolinium may also be used when 
considered the standard operating procedure for the study site.  Gadolinium should 
not be administered if the glomerular filtration rate <30 mL/min or equivalent 
creatinine clearance.  However, this decision may be made by the PI on the basis of 
a change in the clinical status or may be done in response to a possible abnormality 
seen on the non-contrast brain MRI. 
An MRI Imaging CRO will be responsible for standardizing the acquisition, training 
the MRI sites on the imaging protocol, ensuring equipment and image QA/QC and 
for overseeing a centralized read of the data.  To ensure proper equipment and image 
QA/QC, the MRI Imaging CRO will have the MRI sites scan a phantom.  Detailed 
procedures for obtaining and processing the MRI, conducting image QA/QC and 
endpoint analysis will be developed in study specific documents and provided as 
appropriate to the investigators, MR technicians, CRO personnel and endpoint 
readers. 
Analysis of whole brain, ventricular, and hippocampal volumes will be conducted 
by a centralized reader(s) who will be blinded to subject treatment. 
7.7 
CT SCANS 
A head CT scan may be accepted for evaluation of the eligibility criteria on a case-
by-case basis, as approved by the Sponsor (e.g., when MRI is contraindicated for the 
subject).  The head CT must be suitable for central review and submitted for central 
review based on instructions in the MRI procedures manual. 
Subjects whose screening assessment was based on a CT scan will not undergo a 
follow-up CT scan (Part 2 only) and will not contribute to the MRI volumetric 
analyses (Part 2 only).      
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An Imaging CRO will be responsible for providing guidance on the imaging 
procedure.  Sites will be advised to acquire the CT per their standard clinical 
practice.  Scans will be reviewed by the Imaging CRO central reader.   
7.8 
APOE GENOTYPING 
A blood sample will be taken at Baseline for ApoE genotyping.  Results of ApoE 
genotyping will be retained in the trial database, with participants identified only by 
a study participant identification number.  Individual results of ApoE genotyping 
will not be disseminated outside the Sponsor, including the study site, except as 
required by law. 
7.9 
BLOOD SAMPLING FOR STORAGE AND RETENTION 
A blood sample will be collected according to the Schedule of Activities in Table 1 
and Table 2.   Blood samples for whole blood and plasma storage/retention will be 
collected, processed, stored, and shipped according the lab manual instructions. 
Samples will be stored for up to 2 years following study closure for potential future 
analysis for plasma biomarkers associated with AGEs, RAGE expression, or RAGE 
antagonist response that may be identified during the course of the trial. 
Instructions on collection, processing, storage and shipment of the sample will be 
provided in a separate laboratory manual. 
 
 
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7.10 
BLOOD VOLUME 
Total blood sampling volume for the individual participants is approximated below 
for Part 1 (Table 4) and Part 2 (Table 5) participants. 
Table 4. 
Part 1 Blood Sampling Volumes 
Sample Type 
Sample 
Volume (mL) 
Number of Sampling Times 
Total 
Volume 
(mL) 
Screening / 
Baseline
Treatment 
Non-treatment 
Follow-up 
Routine Laboratory 
12 
2
2
1 
60
Unique Screening Labs 
12 
1
0
0 
12
PK 
5 
1
2
1 
20
Biomarkers (Aβ) 
10 
1 
2 
1 
40 
ApoE Genotyping 
3 
1
0
0 
3
Plasma Storage and 
Retention 
10 
1 
2 
1 
40 
TOTAL (mL) 
 
 
175
 
 
 
Table 5. 
Part 2 Blood Sampling Volumes 
Sample Type 
Sample 
Volume (mL) 
Number of Sampling Times 
Total 
Volume 
(mL) 
Screening / 
Baseline
Treatment 
Non-treatment 
Follow-up 
Routine Laboratory 
12 
2
6
1 
108
Unique Screening Labs 
12 
1
0
0 
12
PK 
5 
1
6
1 
40
Biomarkers (Aβ) 
10 
1 
6 
1 
80 
ApoE Genotyping 
3 
1
0
0 
3
Plasma Storage and 
Retention 
10 
1 
6 
1 
80 
TOTAL (mL) 
 
 
323
 
 
 
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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.  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: There is evidence to suggest a causal relationship between the study 
drug and the AE.   
 
Not Related: The AE is not reasonably related to the study drug if there is not 
a reasonable possibility that the study drug may have caused the event, i.e., 
there is no evidence or arguments to suggest a causal relationship. 
8.5 
SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) is any AE that is fatal or life-threatening (see below), 
results in persistent or significant disability (see below) or incapacity, requires 
inpatient hospitalization or prolongation of an existing hospitalization, or is a 
congenital anomaly/birth defect. 
Other important medical events that may not result in death, be life-threatening or 
require hospitalization should also be considered SAEs when, based upon 
appropriate medical judgment, they may jeopardize the study participant and may 
require medical or surgical intervention to prevent one of the outcomes listed above.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home or convulsions that do not result in 
inpatient hospitalization. 
8.5.1 
Life Threatening Adverse Event 
A life-threatening AE is any AE that, in the view of the Principal Investigator, places 
the subject at immediate risk of death from the reaction as it occurred.  A 
life-threatening AE would not be an AE that, had it occurred in a more serious form, 
might have caused death.  
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 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.  All AEs should be reported to the study Sponsor. 
8.7 
REPORTING REQUIREMENTS 
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, declared stable, or 
until the end of study participation. 
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 
All AEs with a relationship of related will be followed until resolution, 
declared stable, or until the subject is lost to follow-up. 
At the discretion of the Investigator or designated licensed physician and Medical 
Monitor, the length of AE follow-up may be attenuated, with written rationale by 
the Investigator or designated licensed physician. 
8.7.1 
Serious Adverse Events Reporting Requirements 
Knowledge of a SAE occurring or worsening in a subject at any time during the trial 
must be reported within 24 hours to the Sponsor / Sponsor Representative.  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 death or 
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 this section describe the protocol-
defined plan for data analysis of this study.  A final and complete Statistical Analysis 
Plan (SAP) will be finalized prior to unblinding the data from the learning stage of 
the study (Part 1), possibly updated prior to unblinding the confirmatory stage of the 
study (Part 2). The SAP will supersede the protocol. Any deviations from the 
planned analyses will be described and justified in the final integrated study report. 
This trial describes two studies (learning stage and confirming stage) with a common 
infrastructure in a single protocol. Statistical analysis of the clinical efficacy 
variables will be done for each of the study studies separately. Analysis of MRI 
volumetric data only applies to part 2 of the study. Statistical evaluation of adverse 
events will be done by each part separately and also integrated for the study as a 
whole. Statistical analysis of safety measures that are collected by visit will be done 
for the study as a whole (combined). 
Continuous variables will be presented showing number of observations available, 
mean, median, minimum, maximum, 1st and 3rd quartiles, and standard deviations 
(or standard errors, depending on the variable) by visit. Categorical variables will be 
presented showing frequencies and percentages by visit. 
All tests will be 2-sided and use an overall study-wise α = 0.05 unless otherwise 
stated. SAS Version 9.4 or later will be used.  Medical dictionary for Regulatory 
Activities (MedDRA) Version 21.0 or later will be used for coding adverse events.  
Medications will be coded using WHO Drug Dictionary (WHODD) Version 
March 2018 or later. 
This study features a conditional sequential approach to hypothesis testing to control 
alpha, similar to methods using Bauer closed procedures. 
9.1 
POTENTIAL ADAPTIVE FEATURES 
This study is planned to conform to regulatory guidance depicted in the FDA 
guidance Adaptive Designs for Clinical Trials of Drugs and Biologics (draft 
guidance, September 2018). 
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Part 1 of the study will inform the selection of a functional endpoint to serve as 
co-primary in Part 2, as well as the sample size required to adequately power the 
study to detect treatment effect on cognitive and functional measures in the study 
population.   
Consistent with the FDA draft guidance on adaptive designs, it is acknowledged that 
interim analysis is common in trials, and it includes blinded analysis or unblinded 
analysis. In this study, however, Part 1 is intended to be completed, the database 
locked, and the analysis done as a final analysis, thereby avoiding the need for the 
interim analysis.  
The planned features of the confirmatory phase (Part 2) that will be subject to 
modification informed by the learning phase (Part 1) of the study are: 
 
Primary endpoint(s) for Part 2 
 
Sample size for Part 2 
 
Study duration for Part 2 
 
Eligibility criteria for Part 2 
 
Dose of study drug for Part 2 
9.2 
SAMPLE SIZE DETERMINATION 
Sample size considerations for Part 1:  
Assuming a standard deviation of the change from Baseline to Month 6 in 
ADAS-cog14 of 4, using alpha = 0.05, a total sample size of approximately 
82 subjects in balanced allocation (41 subjects per group) provides at least 90% 
power to detect a difference between treatment groups of 2.9 using a 2-sided, 
2-sample t-test.  Assuming a dropout rate of 18% or less, randomization of 
100 subjects provides adequate statistical power for Part 1 to demonstrate superiority 
of azeliragon over placebo based on the ADAS-cog14. 
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Sample size considerations for Part 2:  
Assuming a standard deviation of the change from Baseline to Month 18 in 
ADAS-cog14 of 7.5, using alpha = 0.049 (to include an adjustment for potential 
alpha inflation due to the independent data monitoring committee reviews), a total 
sample size of 120 subjects in balanced allocation (60 subjects per group) provides 
at least 90% power to detect a difference between treatment groups of 4.5 using a 
2-sided, 2-sample t-test.  Assuming a dropout rate of 25% or less, randomization of 
160 subjects provides adequate statistical power for Part 2 to demonstrate superiority 
of azeliragon over placebo based on the ADAS-cog14. 
9.3 
RANDOMIZATION AND BLINDING 
9.3.1 
RANDOMIZATION 
This protocol includes two independent randomizations for the two stages of the 
adaptive study.  
Subjects will be screened by Investigators or qualified designees to assess eligibility 
for randomization into the study.  An interactive voice response system (IVRS)/ 
interactive web response system (IWRS) will be used for assignment of treatment. 
For each stage of the study, subjects will be enrolled and randomized according to a 
fixed randomization scheme blocked by study investigative site. There is no other 
stratification in the randomization scheme for either stage of the study.  
Randomization will have balanced allocation (1:1) between azeliragon and placebo.  
Dropouts will not be replaced. 
A randomization plan will be developed to guide the programming and security of 
the randomization scheme for this study. 
9.3.2 
BREAKING THE BLIND 
The study will be double-blind.  At the initiation of the study, the study site will be 
instructed on the electronic process for breaking the blind.  Blinding should only be 
broken in emergency situations when knowledge of the treatment assignments is 
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necessary for subject safety.  Upon breaking the blind, the reason must be 
documented in the electronic data capture system. The sponsor or representative 
should be consulted prior to breaking the blind except in emergency circumstances.  
9.4 
STATISTICAL HYPOTHESES 
The learning stage has a single primary endpoint while the confirming stage of the 
study has two co-primary endpoints. The conditional sequence of hypothesis tests 
applies to both, acknowledging that the imaging endpoints will not exist for the 
learning stage of the study. 
For each stage of this adaptive study, a 2-stage conditional sequence of statistical 
hypothesis tests will be used. The testing sequence will be as follows: 
The first set of hypotheses to be tested is as follows: 
 
H01: The mean change in ADAS-cog14 in the active group active group is 
equal to that of the placebo group. 
 
H11: The mean change in ADAS-cog14 in the active group is not equal (is 
superior) to that of the placebo group. 
Conditional on statistical significance, testing will proceed: 
 
H02: The mean change in CDR-sb in the active group is equal to that of the 
placebo group. 
 
H12: The mean change in CDR-sb in the active group is not equal (is superior) 
to that of the placebo group. 
Conditional on statistical significance, testing will proceed: 
 
H03: The mean change in FAQ in the active group is equal to that of the placebo 
group. 
 
H13: The mean change in FAQ in the active group is not equal (is superior) to 
that of the placebo group. 
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Conditional on statistical significance within the confirmatory stage, testing will 
proceed: 
 
H02: The mean change in MRI variable of analysis in the active group is equal 
to that of the placebo group. 
 
H12: The mean change in MRI variable of analysis in the active group is not 
equal (is superior) to that of the placebo group. 
9.5 
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 masked data review meeting 
held in accordance with ICH E9 prior to the lock data. The complete specification 
(made blinded to treatment arm) will be documented in the minutes to the blind data 
review meeting held prior to lock the data. 
 
The safety set (SAF) includes all subjects who receive any study medication. 
For the purpose of understanding the influence of dropouts on study conclusions, the 
FAS will be partitioned into subjects who complete (completers) and subjects who 
do not complete (dropouts).   
The FAS will be used for all hypothesis tests of efficacy. Analysis of superiority 
using the PPS will also be done for supportive analyses. If the PPS does not differ 
from the FAS by at least 15%, the PPS is considered optional. 
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The SAF will be used for safety analyses. 
9.6 
DISPOSITION, DEMOGRAPHIC, AND BASELINE DATA 
A tabulation of subject disposition will be presented, including the number screened, 
the number randomized in each population group, the number dosed in each 
population group, the number who withdrew prior to completing the study, and 
reasons for withdrawal. 
Demographic and baseline characteristics will be summarized for all randomized 
patients and for the FAS.  Variables of interest include the following: 
 
Age 
 
Sex, 
 
Race, 
 
Ethnicity 
 
Medical history 
 
Prior AD medication 
 
Height/weight/BMI 
 
Education level 
 
ApoE4-carrier status 
 
Years since diagnosis of AD 
 
Years since diagnosis of diabetes or HbA1c evaluation of 6.5% or more 
Additionally, baseline characteristics will be compared for efficacy measures of 
MMSE, ADAS-cog14, CDR-sb, FAQ, Amsterdam IADL, ApoE4-carrier status, 
HbA1c.  No formal statistical comparisons will be performed. 
9.7 
EFFICACY ANALYSIS 
Efficacy evaluation will include the primary (ADAS-cog14 for Part 1) and 
co-primary endpoints (ADAS-cog14 and CDR-sb) for Part 2, key secondary 
measures, and other efficacy markers. 
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Statistical analysis will be done on each stage of the study, independently, for the 
primary / co- primary variables: change from baseline in ADAS-cog14 and change 
from baseline in CDR-sb. For all other secondary variables, and subgroup analyses, 
the study as a whole will be used for inferential purposes.  
9.7.1 
Efficacy Variables of Analysis 
9.7.1.1 
Primary Efficacy Variables of Analysis 
The primary analysis will include assessment of the following variables of analysis. 
Learning stage (Part 1) 
 
Mean change from Baseline to Month 6 in ADAS-cog14 
Confirm stage (Part 2) 
 
Mean change from Baseline to Month 18 in ADAS-cog14 
 
Mean change from Baseline to Month 18 in CDR-sb 
Supportive variables will include mean change from Baseline to Visit in ADAS-
cog14 and mean change from Baseline to Visit in CDR-sb. 
9.7.1.2 
Secondary Variables of Analysis 
Part 1 secondary variables of analysis will include. 
 
Mean change from baseline in CDR-sb at Month 6. 
 
Mean change from baseline in the FAQ at Month 6. 
 
Mean change from baseline in the Amsterdam-IADL at Month 6. 
 
Mean change from baseline in eGFR at Month 6. 
Part 2 will include the following secondary variables of analysis: 
 
Time to decline (to support responder analysis) where the specification of 
decline will be included in the SAP. 
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 
Mean change from baseline in FAQ score at Month 18 
 
Mean change from baseline in Amsterdam-IADL score at Month 18 
 
Mean change from baseline in MMSE score at Month 18 
 
Mean change from baseline in eGFR at Month 18. 
 
Mean change from baseline in whole brain volume at Month 18. 
9.7.1.3 
Other Efficacy Variables of Analysis 
Additional efficacy variables of analysis are as follows: 
 
Mean change from Baseline in hippocampal volume at Month 18. 
 
Mean change from Baseline in ventricular volume at Month 18. 
 
Mean change from Baseline in NPI 
 
Mean change from Baseline in DEMQOL. 
9.7.2 
Statistical Methodology for Primary Analysis 
The primary analysis will use the ITT methodology and a main-effects 
mixed-models for repeated measures (MMRM) methodology. The MMRM will 
utilize an unstructured covariance where the number of parameters is “t(t+1)/2” 
where “t” is the dimension of the covariance matrix, using PROC MIXED in SAS.  
In the unlikely event of lack of convergence, Toeplitz structure will be employed 
where the number of parameters is “t” where “t” is the dimension of the covariance 
matrix. Time is considered as a class variable. Analysis will include treatment, time 
and treatment-by-time interaction as fixed effects, Baseline as covariate, and subject 
as a random effect. Supportive modeling will also include MMRM main-effects 
model with treatment, time, and subject. 
Model assumptions will be evaluated. If the parametric assumptions are evaluated 
as inappropriate or violated, rank analogues will be advanced. 
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The primary analysis will be done for each stage separately.  Part 1 will use 
alpha = 0.0499, which includes an adjustment of 0.0001 for interim analyses 
performed by the Independent Data Monitoring Committee (IDMC).  The alpha 
adjustment for the IDMC for Part 1 is considered to be negligible, hence, the stated 
alpha for Part 1 is 0.05 for the 100-patient, 6-month trial.  Part 2 will use 
alpha = 0.049, which includes an adjustment of 0.001 for interim analyses performed 
by the Independent Data Monitoring Committee (IDMC), thereby preserving the 
overall study-wise alpha = 0.05.  The alpha adjustment of 0.001 is considered to be 
appropriate for the 200-patient, 18-month study. 
Multiple imputations (MI) will be used as a supportive analysis with 100 invocations 
(acknowledging that more invocations are needed with more missing data). Monte 
Carlo methods are planned. 
An essential component of the thorough analysis includes an assessment of the 
impact of missing data on study conclusions. As a part of assessing this impact, 
supportive analysis will include: 
 
an endpoint analysis (reduction to last-observation-carried-forward, justified 
in this study based on the monotonic progression of the natural course of AD 
and assuming no more dropouts in the group treated with azeliragon than in 
the group treated with placebo) 
 
a completers analysis (observed cases at endpoint) 
 
observed cases by assessment time. 
Interaction terms will be examined in supportive analyses.  In the event of a 
significant interaction term, the impact on analysis conclusion will be examined.  
The primary model will not include interaction terms. A key supportive analysis will 
use the ITT methodology and a main-effects model for ANCOVA adjusting for 
baseline ADAS-cog14 (CDR-sb) using last-observation-carried-forward (LOCF) 
methods for missing data, justified based on known profiles of ADAS-cog14 
(CDR-sb) in AD patients, which is conservative under the assumption that there are 
not more dropouts in the active-treated group than the placebo group. Rank 
ANCOVA will be done as a supportive analysis. 
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To ensure robustness of analysis conclusions against missingness, multiple 
imputation methods will also be done to cope with missing data as a key supportive 
analysis using the final on-treatment assessment of treatment failures as non-missing 
data at endpoint. 
In accordance with the recommendations of the report from the National Academy 
of Science (NAS) panel “The Prevention and Treatment of Missing Data in Clinical 
Trials,” (National Research Council, 2010), missingness is classified as “missing at 
random” (MAR) or “missing not at random” (MNAR).  When subjects are 
withdrawn due to treatment failure, this event is considered in this sensitivity 
analysis to be MNAR, and the endpoint value is taken as the hard endpoint (not 
imputed) in analysis, operationally, the endpoint analysis is the same as LOCF.   Data 
that are missing for other reasons are considered to be MAR, and standard multiple 
imputation methods are planned. 
Descriptive summaries will be produced of the observed values and change from 
Baseline in co-primary variables by treatment group at each individual time point 
and at endpoint (final on-treatment assessment for each subject). 
For statistical analyses, 95% confidence intervals will be produced for the 
least-squares means (LSM) in each treatment group, as well as the LSM differences 
as compared to placebo.  For MMRM and ANCOVA, two-sided p-values will be 
displayed for the comparison against placebo. 
Because there are limited numbers of subjects per center, there will inadequate 
power to explore impact of the center effect on study conclusion. Descriptive 
statistics by center will be presented. 
The primary analysis controls alpha through the conditional sequence of hypothesis 
testing. No further adjustment for multiplicity is necessary. 
If the PPS differs from the FAS by more than 15%, the analyses will be replicated 
on the PPS.  If the PPS and the FAS do not differ by more than 15%, analysis may 
not be done on the PPS.  Final judgments will be made at the blind data review 
meeting in accordance with ICH E9. 
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9.7.3 
Statistical Methodology for Secondary and Other Efficacy Analysis 
Secondary and exploratory endpoints that are measurement variables will use similar 
statistical methodology to the methodology used for primary analysis.  Efficacy 
variables that are proportions will be analyzed using Mantel-Haenszel test.  For the 
analysis of the categories for responders, a Cochran-Mantel-Haenszel test will be 
used. 
Methodologies for variables that are proportions will include construction of 
confidence intervals for each treatment group and for the difference between groups.  
For analysis, Fisher’s exact test will be used for single-population analysis, and a 
Mantel-Haenszel test will be used for analyses combining data across strata. 
Methodologies for time-to-event variables will include construction of 95% 
confidence intervals for each group separately and for the difference between 
groups.  For analysis, a Wilcoxon test will be used for single-population analysis, 
and a van Elteren test will be used for analyses combining data across strata. 
Subgroup analyses will be done as identified in the SAP. 
Responders based on the ADAS-cog14 total score will be described using 
Kaplan-Meier curves using the specification of responder (lack of decline) provided 
in the SAP.   Also, a graphical representation will be defined where the y-axis will 
show the cumulative percentage of patients who achieved the specific measure of 
improvement in the ADAS-cog14 total score shown on the x-axis with a separate 
cumulative percentage curve for each treatment group. 
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 
advanced. 
9.7.4 
Subgroup Analyses 
The SAP will include details for subgroup analysis. 
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9.7.5 
Adjustment for Multiple Comparisons 
Multiplicity of the primary efficacy analyses is controlled by using a conditional 
sequence of hypotheses.  The study will be considered to demonstrate statistical 
significance if the primary analysis has a resulting p-value less than 0.05.  No other 
adjustment for multiplicity is required. 
9.8 
SAFETY ANALYSIS 
The SAF is used for safety analysis.  Adverse events, ECGs, vital signs and safety 
laboratory data will be reviewed and summarized on an ongoing basis during the 
trial to evaluate the safety of participants. 
9.8.1 
Safety Variables of Analysis 
9.8.1.1 
Adverse Events 
Definitions: 
 
A treatment-emergent adverse event (TEAE) is an event that is observed or 
reported after administration of study medication that was not present prior to 
study medication administration or an event that represents the exacerbation of 
a pre-existing event. 
 
An adverse withdrawal is a subject who withdrew from the study due to an 
adverse event. 
 
A serious adverse event (SAE) is an AE that is classified as serious according 
to the criteria specified in the study protocol. 
Adverse events variables of analysis include: 
 
Proportions of subjects with TEAEs by Preferred Term and decreasing 
frequency of TEAE 
 
Proportions of subjects with TEAEs by System Organ Class and Preferred 
Term 
 
Proportions of subjects with adverse withdrawals 
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9.8.1.2 
Vital Signs 
Vitals signs measures of blood pressure and pulse will include the following 
variables of analysis: 
 
Mean values and mean changes of values from Baseline to Visit 
 
Proportions of subjects with abnormal values or changes in vital signs 
measures of potential clinical concern. 
 
Proportions of subjects with AEs related to vital signs 
9.8.1.3 
Clinical Laboratory 
Clinical Laboratory hematology and clinical chemistry variables of analysis 
include: 
 
Proportions of subjects with TEAVs (shifts from normal status to abnormal 
status) 
 
Proportions of subjects meeting DILI criteria per FDA guidance, Guidance for 
Industry “Drug-induced liver injury: premarketing clinical evaluation” 
(CDER, CBER, July 2009) 
 
Means and mean changes from Baseline to Visit 
 
Proportions of subjects with new (post Baseline) values (Clinical laboratory-
related AEs) or changes in laboratory values of potential clinical concern 
9.8.1.4 
Electrocardiography 
Electrocardiography variables of analyses will include: 
 
Proportion of subjects with Corrections to QT intervals will be made by 
Fridericia’s method. Categorical analysis will be done consistent with ICH 
E14, “Clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs” (October 2005). 
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9.8.2 
Statistical Methodology for Safety Analysis 
Adverse events will be coded using MedDRA Version 21.0 or above.  Adverse event 
coding will be done to the lowest level term (LLT).  All treated patients will be 
included in the assessment of safety.  Adverse events will be summarized by 
MedDRA System Organ Class and Preferred Terms.  Separate tabulations will be 
produced for related AEs (those considered by the Investigator as drug related), 
SAEs, discontinuations due to AEs, and severe events. 
Vital signs, ECG results, and laboratory data will be tabulated for changes over time 
on study.   In addition, TEAV and significant findings will be summarized. 
For each post-Baseline assessment, descriptive statistics are provided for the 
assessment value and the change from Baseline to the assessment. 
9.9 
PHARMACODYNAMIC DATA 
All participants with at least one dose of study medication will be included in the 
pharmacodynamic analyses, as appropriate.  For individual endpoints, participants 
must have at least 1 post-dose pharmacodynamic measurement for the given 
endpoint.  For change from Baseline, participants must also have a Baseline value. 
Plasma Aβ (total, 1-40 and 1-42) concentration and cerebral brain volume 
(hippocampus and whole brain, ventricular) versus time will be tabulated and mean 
concentration or brain volume versus time will be plotted for each treatment group.  
Descriptive statistics for raw and change from baseline values will be generated, as 
appropriate.  Maximum and average change from Baseline values will be calculated 
by treatment group. 
The statistical methods will be described in the SAP. 
9.10 
PHARMACOKINETIC DATA 
Data resulting from blood sampling for trough concentrations of azeliragon will be 
collected and summarized descriptively. Concentration-driven analysis of the 
relationship between azeliragon  (and potentially metabolite concentrations) and 
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efficacy/safety may be performed. The statistical methods will be described in the 
SAP. 
9.11 
QUESTIONNAIRES 
Questionnaires include cognitive assessment, functional assessments, behavioral 
assessments, and assessments of quality of life. Questionnaires in this study will be 
scored according to the published guidelines provided in validation and 
documentation for the instruments by the developers. The statistical methods will be 
described in the SAP. 
9.12 
HANDLING MISSING DATA 
Data are considered to be “on-treatment” if the assessment of collection follows the 
first administration of study medication and if the assessment occurs within 45 days 
following the final administration of study medication, justified based on the long 
half-life of this drug. 
In general, for primary efficacy analysis and for safety analysis, missing data will 
not be imputed. Dates with missing fields will not have days imputed. 
In accordance with the recommendations of the report from the National Academy 
of Science (NAS) panel “The Prevention and Treatment of Missing Data in Clinical 
Trials,” (National Research Council, 2010), sensitivity analyses will be done to 
ensure that study conclusions are robust against missing data.  Last observation 
carried forward (LOCF) and baseline observation carried forward (BOCF) methods 
will be used as appropriate in sensitivity analysis.  Missing data types will be 
examined, and statistical methodologies for appropriate sensitivity analyses will be 
finalized during blind data review as patterns emerge as the study progresses. 
Primary methodologies following the ITT principle are not subject to change. 
Details of methodologies identifying data as missing at random (MAR) or not 
missing at random (NMAR) will be addressed in the SAP.  Statistical methods for 
addressing MAR and NMAR will be described in the SAP. 
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9.13 
DATA MONITORING COMMITTEE 
An external Independent Data Monitoring Committee (IDMC) will be responsible 
for the review of all available safety data at their regularly scheduled meetings during 
the trial. 
The IDMC will consist of at least 3 members, including a neurologist who has 
experience in the treatment of individuals with AD and a senior statistician.  Ad hoc 
members (e.g., experts on RAGE mechanisms or a cardiovascular physician) will be 
available for consultation by the IDMC upon request. 
The IDMC will initially be provided with data displays in accordance with the IDMC 
charter.   
Blinded summary IDMC reports will also be distributed to all participating sites for 
local IRB/REB submission, where applicable.  The IDMC will meet in person or by 
conference call on a quarterly basis.  The IDMC charter will specify these and other 
operational aspects of the IDMC structure, processes and study stopping rules. 
9.14 
INTERIM ANALYSIS 
Except for the ongoing, blinded medical monitoring of accruing data and except for 
the ongoing review by the IDMC, no interim analysis is planned for Part 1 or Part 2. 
Although this study has an adaptive design, and sample size re-estimation for Part 2 
of the study is a potential feature for revaluation, the analysis of Part 1 to be used for 
the re-estimation is to be done as a final analysis following the database lock, hence, 
the analysis will not be an interim analysis. It is acknowledged that a blinded analysis 
is considered an interim analysis in accordance with the draft guidance from the 
FDA on adaptive designs, and no interim analysis is intended for this study. 
As a conservative measure, an alpha adjustment is applied to accommodate analyses 
by the IDMC because the safety evaluation will include review of ADAS-cog14 data 
from the safety perspective. Alpha = 0.0001 is divided among no more than 4 interim 
analyses in the 100-subject, 6-month trial (for an alpha adjustment of 0.0001, which 
is considered to be negligible, so alpha=0.05 is available for the final analysis); for 
Part 2, alpha = 0.0001 is apportioned to each of no more than 10 analyses by the 
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IDMC that includes review of ADAS-cog14 data, blinded unless there is a 
data-driven need expressed by the IDMC to be unblinded. 
With the possible exception of the IDMC, no unblinding is planned in this study for 
any reason other than emergency unblinding for medical imperatives. 
It is emphasized that there is no interim analysis in this study for efficacy. The 
interim analyses described in this section refer to the analyses done by the IDMC for 
safety monitoring only. 
9.15 
DATA MANAGEMENT CONSIDERATIONS 
This study will utilize electronic data capture (EDC) for data capture. The database 
lock will occur when each Part of the study is declared closed, when all subjects 
have completed the study part (last visit of the last subject on-study). 
 
 
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10.0 
QUALITY CONTROL / MONITORING OF THE STUDY 
During study conduct, the Sponsor or its designee will conduct periodic monitoring 
visits to ensure that the protocol and GCPs are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  
Additionally, the study site may be subject to quality assurance audits performed by 
the Sponsor, and/or to inspection by the IRB/REB or regulatory authorities. 
 
 
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11.0 
DATA HANDLING AND RECORD KEEPING 
11.1 
CASE REPORT FORMS/ELECTRONIC DATA RECORD 
This study will utilize electronic data capture (EDC) for the data record serving as 
the “Case Report Form (CRF)”.  All required study information must be recorded 
on the appropriate CRF screens/forms using the eCRF Completion Guidelines for 
the study.  Quality control measures will progress final data management activities 
from last-patient-last-visit to database lock, then unblinding, final analysis, and final 
reported for each part of the study. 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 and signed by the PI. From that point forward, the database will 
be protected from changes (database lock). 
11.2 
RECORD RETENTION 
For sites in the United States, the PI/Study Site must retain all study records, 
including regulatory documents and individual study participant records, for a period 
of 2 years following the date a marketing application is approved for the drug, for 
the indication for which it is being investigated; or, if no application is to be filed, 
or if the application is not approved, until 2 years after the investigation is 
discontinued, and the FDA is notified or longer if requested by Sponsor (per 21 CFR 
312.62).   
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). 
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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. 
 
 
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12.0 
ETHICS 
12.1 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD 
(REB) 
The study protocol, protocol amendments, informed consent forms, and other 
relevant documents (e.g., recruitment advertisements) will be reviewed and 
approved by the IRB/REB prior to site initiation.  All correspondence with the 
IRB/REB should be retained in the site’s trial file with copies of IRB/REB 
communications forwarded to the Sponsor. 
A protocol amendment may be implemented prior to IRB/REB approval only where 
the change is necessary to eliminate apparent immediate hazards to the participants.  
Should this occur, the investigator must notify the IRB/REB and the Sponsor in 
writing immediately after the implementation of the protocol amendment.  No 
deviations to the protocol are permissible except when necessary to eliminate an 
immediate hazard to study participants.  The investigator shall notify the IRB/REB 
of deviations from the protocol or serious adverse events occurring at the site, in 
accordance with local procedures. 
12.2 
ETHICAL CONDUCT OF THE STUDY 
The study will be conducted in accordance with the Declaration of Helsinki on 
Ethical Principles for Medical Research Involving Human Participants, adopted by 
the General Assembly of the World Medical Association (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 
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the risks involved to the study participant, his/her legally authorized representative 
(if applicable) and caregiver/informant prior to their inclusion in the trial. 
Prior to performing any study-specific procedure, each study participant and the 
participant’s caregiver/informant will be required to read and voluntarily sign an 
Institutional Review Board (IRB)/Research Ethics Board (REB) - approved 
informed consent form (ICF), indicating his/her consent to participate (or assent 
[where this is in accordance with local laws, regulations and ethics committee 
policy] in the case of participants who are deemed to be unable to have the cognitive 
ability to provide consent).  This ICF will conform to the requirements of the 
applicable 21 CFR 50.20-27, FDR C.05.010 and ICH E6 Principles of Good Clinical 
Practice (GCP).  The Study Sponsor must agree with the final IRB/REB-approved 
ICF prior to initiation of the study.  Study participants will be provided adequate 
time to review the ICF and if they wish, may take it home to discuss their 
participation in the study with friends, family, and/or a physician.  The original 
signed ICFs must remain in the study participant's file in the Study Site.  Study 
participant will receive a copy of their signed ICF. 
Continued consent / assent will be evaluated at each study visit for the duration of 
the study. 
 
 
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13.0 
STUDY TERMINATION CRITERIA 
The study may be terminated prematurely as a result of a regulatory authority 
decision, IRB/REB decision, or at the discretion of the Sponsor.  In addition, the 
Sponsor retains the right to discontinue development of azeliragon at any time. 
Should the study be prematurely terminated, the Sponsor will promptly notify the 
investigator.  Following notification, the investigator must contact all participating 
participants and the hospital pharmacy (if applicable) within 30 days. 
 
 
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14.0 
CONFIDENTIALITY AND PUBLICATION OF STUDY RESULTS 
The information in this and related documents from the Study Sponsor contains trade 
secrets and commercial information that are confidential and may not be disclosed 
unless such disclosure is required by federal or other laws or regulations.  In any 
event, persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
Individual study participant medical information obtained as a result of this study is 
considered confidential, and disclosure to third parties other than those noted below 
is prohibited.  Such medical information may be given to the study participant's 
personal physician or to other appropriate medical personnel responsible for the 
study participant's welfare. 
Data generated as a result of this study are to be available for inspection on request 
of the Sponsor's representative, the IRB/REB, or the local regulatory agency. 
None of the parties involved in the management/conduct/analysis of this study may 
publish any study-related data without the written permission of the Study Sponsor. 
No patent application based on the results of the study may be made by the PI, nor 
may assistance be given to any third party to make such an application, without the 
written authorization of the Study Sponsor. Publication of study results is discussed 
in the Clinical Study Agreement. 
 
 
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15.0 
REFERENCES 
1. 
Alzheimer’s Association. 2016 Alzheimer’s Disease Facts and Figures. 
Alzheimer’s & Dementia 2016;12(4):459-509. 
2. 
Alzheimer’s Association. 2018 Alzheimer’s Disease Facts and Figures. 
Alzheimers Dement 2018;14(3):367-429. 
3. 
Berg L. Clinical Dementia Rating (CDR). Psychopharmacol Bull. 
1988;24:637-9. 
4. 
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 (Berl) 2005;83(11):876-886. 
5. 
Carrano A, Hoozemans JJ, van der Vies SM, Rozemuller AJ, van Horssen J, 
de Vries HE. Amyloid Beta induces oxidative stress-mediated blood-brain 
barrier changes in capillary amyloid angiopathy. Antioxid Redox Signal 
2011;15(5):1167-1178. 
6. 
Cummings JL, Mega M, Gray K, et al. The Neuropsychiatric Inventory: 
comprehensive assessment of psychopathology in dementia. Neurology 
1994;44:2308-14. 
7. 
Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, et al. 
RAGE mediates amyloid-beta peptide transport across the blood-brain barrier 
and accumulation in brain. Nat Med 2003;9(7):907-913. 
8. 
Dhananjayan et al.  Advance Glycation, Diabetes and Dementia.  2018.  
https://doi.org/10.1016/B978‐0‐12‐809454‐9.00009‐3. 
9. 
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. 
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10. 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. 
11. Guidance for Industry.  Clinical Drug Interaction Studies — Study Design, Data 
Analysis, and Clinical Implications Guidance for Industry DRAFT 
GUIDANCE.  October 2017. 
12. Hartz AM, Bauer B, Soldner EL, Wolf A, Boy S, Backhaus R, et al. Amyloid- 
beta contributes to blood-brain barrier leakage in transgenic human amyloid 
precursor protein mice and in humans with cerebral amyloid angiopathy. Stroke 
2012;43(2):514-523. 
13. International Diabetes Federation. IDF Diabetes Atlas, 8th edn. Brussels, 
Belgium: International Diabetes Federation, 2017.  
14. Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC.  Increased 
Risk of Type 2 Diabetes in Alzheimer Disease.  Diabetes Feb 2004, 53 (2) 474-
481; DOI: 10.2337/diabetes.53.2.474. 
15. Kook SY, Hong HS, Moon M, Ha CM, Chang S, Mook-Jung I. Abeta(1)(-
)(4)(2)-RAGE interaction disrupts tight junctions of the blood-brain barrier via 
Ca(2)(+)-calcineurin signaling. J Neurosci 2012;32(26):8845-8854. 
16. Levey AS, Stevens LA, et al. A New Equation to Estimate Glomerular 
Filtration Rate. Ann Intern Med. 2009; 150:604-612. 
17. 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;33(7):1400-1410. 
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. 
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19. Mohs RC, Knopman D, Petersen RC, Ferris SH, Ernesto C, Grundman M, 
Sano M, Bieliauskas L, Geldmacher D, Clark C, Thal LJ.  Development of 
cognitive instruments for use in clinical trials of antidementia drugs: additions 
to the Alzheimer's Disease Assessment Scale that broaden its scope. The 
Alzheimer's Disease Cooperative Study.  Alzheimer Dis Assoc Disord. 
1997;11 Suppl 2:S13-21. 
20. Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S. Measurement of 
functional activities in older adults in the community. J Gerontol 1982; 37: 
323-9. 
21. 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. 
22. Sikkes SA, Knol DL, Pijnenburg YA, de Lange-de Klerk ES, Uitdehaag BM, 
Scheltens P. Validation of the Amsterdam IADL Questionnaire- _, a new tool 
to 
measure 
instrumental 
activities 
of 
daily 
living 
in 
dementia. 
Neuroepidemiology 2013;41:35–41. 
23. Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al. 
Measurement of health-related quality of life for people with dementia: 
development of a new instrument (DEMQOL) and an evaluation of current 
methodology. Health Technol Assess. 2005;9(10):1-93.,iii-iv 
24. Stern D, Yan SD, Yan SF, Schmidt AM. Receptor for advanced glycation 
endproducts: a multiligand receptor magnifying cell stress in diverse pathologic 
settings. Adv Drug Deliv Rev 2002;54(12):1615-1625. 
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25. Thomas RG. et al. Longitudinal decline in mild-to-moderate Alzheimer's 
disease: Analyses of placebo data from clinical trials Alzheimer's & Dementia: 
The Journal of the Alzheimer's Association.  2016. Volume 12, Issue 5, 598 – 
603. 
26. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, et al. RAGE and amyloid- 
beta peptide neurotoxicity in Alzheimer's disease. Nature 1996;382(6593):685- 
691. 
27. Zheng F, Yan L, Yang Z, Zhong B, Xie W.  HbA1c, diabetes and cognitive 
decline: the English Longitudinal Study of Ageing.  Diabetologia. 2018 
Apr;61(4):839-848. Epub 2018 Jan 25. 
 
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APPENDICES 
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APPENDIX 1 
 
CRITERIA FOR SAFETY VALUES OF  
POTENTIAL CLINICAL CONCERN 
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Criteria for Safety Values of Potential Clinical Concern 
Hematology 
Assay 
Lower limit of the normal reference 
range (LLN) 
Upper limit of the normal reference 
range (ULN) 
Hemoglobin 
<0.8 times 
>1.2 times 
Hematocrit 
<0.8 times 
>1.2 times 
RBC 
<0.8 times 
 
Platelets 
<0.5 times 
>1.75 times 
WBC 
<0.6 times 
>1.5 times 
Total Neutrophils (abs) 
<0.8 times 
>1.2 times 
Eosinophils (abs) 
 
>1.2 times 
Monocytes (abs) 
 
>1.2 times 
Basophils (abs) 
 
>1.2 times 
Lymphocytes (abs) 
<0.8 times 
>1.2 times 
 
 
 
Chemistry 
Assay 
Lower limit of the normal reference 
range (LLN) 
Upper limit of the normal reference 
range (ULN) 
Total bilirubin 
 
>1.5 times 
AST 
 
>3 times 
ALT 
 
>3 times 
GGT 
 
>3.0 times 
Alkaline Phosphatase 
 
>3.0 times 
Creatinine 
 
>1.5 times 
BUN 
 
>1.3 times 
Glucose 
<0.6 times 
>1.5 times 
Uric acid 
 
>1.5 times 
Sodium 
<0.95 times 
>1.05 times 
Potassium 
<0.9 times 
>1.1 times 
Calcium 
<0.9 times 
>1.1 times 
Albumin 
<0.8 times 
>1.2 times 
Total protein 
<0.8 times 
>1.2 times 
Bicarbonate 
<0.9 times 
>1.1 times 
Chloride 
<0.9 times 
>1.1 times 
 
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APPENDIX 2 
 
PROHIBITED MEDICATION LIST 
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Prohibited Medication List 
The following medications are NOT ALLOWED as concomitant medications during the study.  
The list is not exhaustive and therefore, the Investigator is asked to contact the Medical Monitor 
and/or the Sponsor for clarification regarding the acceptability of similar agents not mentioned 
here. 
Drugs known to be strong CYP 2C8 inhibitors: NOT ALLOWED 
gemfibrozil 
clopidogrel 
 
 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of 
Medicine (2007). "http://medicine.iupui.edu/clinpharm/ddis/clinical-table/" Accessed 17 Nov 2017. 
 
Clinical Drug Interaction Studies — Study Design, Data Analysis, and Clinical Implications Guidance for Industry 
DRAFT GUIDANCE.  October 2017. 
 
 
129

SAP_001.pdf: 
vTv Therapeutics LLC 
 
TTP488-305 Part 1 Statistical Analysis Plan 
 
08 Dec 2020  
Confidential 
1 
STATISTICAL ANALYSIS PLAN 
(SAP for Part 1) 
 
 
Title:  
Randomized, double-blind, placebo controlled, multicenter studies to evaluate the 
safety and efficacy of azeliragon as a treatment for subjects with mild 
Alzheimer’s disease and impaired glucose tolerance 
Protocol:  
TTP488-305, 29 April 2019  
Study Drug:  TTP488 (azeliragon) 
Sponsor:  
vTv Therapeutics LLC  
Date:   
08 December 2020 
 
 
 
 


vTv Therapeutics LLC 
 
TTP488-305 Part 1 Statistical Analysis Plan 
 
08 Dec 2020  
Confidential 
2 
Randomized, double-blind, placebo controlled, multicenter studies to evaluate the safety 
and efficacy of azeliragon as a treatment for subjects with mild Alzheimer’s disease and 
impaired glucose tolerance 
 
Prepared by: 
 
________________________________________________________________ 
Jessie Nicodemus Johnson, Ph.D.            
 
 
Date 
Senior Statistician, Consultant 
Pentara Corporation, Inc 
 
 
 
 
 
 
 
Approved By: 
 
 
 
________________________________________________________________ 
Suzanne Hendrix, PhD 
 
 
 
 
 
Date 
CEO, Consultant Statistician TTP488-305 
Pentara Corporation, Inc 
 
 
 
 
________________________________________________________________ 
Aaron Burstein, PharmD 
 
 
 
 
 
Date 
SVP Clinical Development 
vTv Therapeutics LLC 
 
 
12/09/2020
12/09/2020
12/09/2020


vTv Therapeutics LLC 
 
TTP488-305 Part 1 Statistical Analysis Plan 
 
08 Dec 2020  
Confidential 
3 
Table of Contents 
1 
Introduction ......................................................................................................... 5 
1.1  Study Objectives ................................................................................................. 6 
1.2  Study Rationale ................................................................................................... 6 
1.3  Subject Population .............................................................................................. 6 
1.4  Randomization .................................................................................................... 7 
1.5  Study Design ....................................................................................................... 7 
1.6  Sample Size and Power Considerations .............................................................. 8 
1.7  Early Stopping, Data Monitoring, and Interim Analysis .................................... 9 
1.8  Conformance to Regulatory Standards ............................................................. 10 
1.9  Modifications from the Statistical Section of the Protocol ............................... 12 
1.10  Adaptive Study.................................................................................................. 12 
2 
Statistical Hypotheses ....................................................................................... 12 
3 
Estimand Specification ..................................................................................... 14 
4 
Populations of Analysis .................................................................................... 15 
5 
Variables of Analysis ........................................................................................ 16 
5.1  Efficacy Variables ............................................................................................. 16 
5.1.1 
Primary Efficacy Variable ...................................................................... 16 
5.1.2 
Secondary Variables of Analysis ........................................................... 16 
5.1.3 
Exploratory Variable .............................................................................. 16 
5.1.4 
Proof of Concept .................................................................................... 16 
5.1.5 
Efficacy Scales ....................................................................................... 17 
5.2  Safety Variables ................................................................................................ 19 
5.2.1 
Treatment-emergent Adverse Events ..................................................... 19 
5.2.2 
The Columbia Suicide Severity Rating Scale (C-SSRS) ....................... 20 
5.2.3 
Vital Signs .............................................................................................. 21 
5.2.4 
ECG ........................................................................................................ 21 
5.2.5 
Clinical laboratory assessments ............................................................. 21 
5.3  Pharmacokinetics and Pharmacodynamics Variables ....................................... 23 
5.4  Adverse Events of Special Interest ................................................................... 23 
6 
Statistical Methodology .................................................................................... 23 
6.1  Pooling of Investigator Sites ............................................................................. 23 
6.2  Statistical Methodology for Efficacy Analysis ................................................. 23 
6.3  Per Protocol Set................................................................................................. 24 
6.4  Adjustments for multiplicity ............................................................................. 24 
6.5  Subgroup Analyses ........................................................................................... 24 
6.5.1 
Investigator Sites .................................................................................... 24 
6.5.2 
Covariate and Categorical Interaction Analyses .................................... 25 
6.6  Statistical Methodology for Primary Efficacy Analysis ................................... 25 
6.6.1 
PK ........................................................................................................... 26 
6.6.2 
Missing Data .......................................................................................... 26 
6.7  Statistical Methodology for Secondary Analysis .............................................. 26 
6.8  Disposition, Demography, and Baseline Characteristics .................................. 27 


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6.9  Analysis of Safety Data .................................................................................... 28 
6.9.1 
Adverse Events ....................................................................................... 28 
6.9.2 
Vital Signs .............................................................................................. 28 
6.9.3 
APOE genotyping .................................................................................. 28 
6.9.4 
Routine Clinical Laboratory Measurements .......................................... 28 
6.9.5 
Electrocardiography ............................................................................... 29 
6.10  Pharmacokinetics Analysis ............................................................................... 30 
6.11  Pharmacodynamic Analysis .............................................................................. 30 
6.12  Concomitant Medications ................................................................................. 30 
7 
COVID-19 Data and Analysis Conventions ..................................................... 31 
8 
Data Conventions .............................................................................................. 32 
8.1  Definition of Baseline ....................................................................................... 32 
8.2  Missing Data ..................................................................................................... 32 
8.3  Dropouts ............................................................................................................ 33 
8.4  Visit Windows .................................................................................................. 33 
8.5  Early Termination Assessments and Follow-up Assessments .......................... 33 
8.6  Unscheduled Assessments ................................................................................ 33 
8.7  Values Below LLQ ........................................................................................... 33 
8.8  Analysis Deviations .......................................................................................... 34 
9 
Software ............................................................................................................ 35 
10 
Data Displays .................................................................................................... 36 
11 
Values of Potential Clinical Concern ................................................................ 37 
12 
References ......................................................................................................... 38 
13 
Schedule of Time and Events ........................................................................... 40 
 


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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®, TransTech’s (now vTv Therapeutics) proprietary drug 
discovery engine, was employed to develop TTP488, which is an orally bioavailable antagonist 
of the Receptor for Advanced Glycation Endproducts (RAGE). This product is being developed 
as a potential treatment for AD.  
These studies are designed to evaluate the safety and efficacy of azeliragon as a treatment for 
subjects with mild Alzheimer’s disease and impaired glucose tolerance. 
This study is planned with an enrichment strategy, following the draft regulatory guidance 
depicted in the FDA guidance Enrichment Strategies for Clinical Trials to Support 
Determination of Effectiveness of Human Drugs and Biological Products (March 2019). The 
statistical analysis is planned to conform to FDA guidance provided in Draft Guidance Early 
Alzheimer’s Disease: Developing Drugs for Treatment (February 2018), review templates 
provided by the FDA, and Guidance for Industry: Providing Clinical Evidence of Effectiveness 
for Human Drug and Biological Products (CDER&CBER, 1998). 
The goals of this statistical analysis plan (SAP) are the following: 
 To describe the approach of statistical analysis in order to support scientifically sound 
study conclusions for Part 1 of TTP488-305. 
 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  
The primary objective of this study is: 
 To evaluate the impact of 6 months of treatment with oral azeliragon on cognitive 
performance 
 
The secondary objectives of this study are: 
 To evaluate the efficacy of azeliragon treatment on measures of function and activities 
of daily living 
 To evaluate the efficacy of azeliragon treatment on complications of diabetes 
 To evaluate the safety and tolerability of 6 months of azeliragon treatment  
 To evaluate the effect of azeliragon treatment on biomarkers and markers of 
inflammation 
 
 
1.2 
Study Rationale 
Analysis of study TTP488-301 demonstrated potential beneficial effects of azeliragon that 
increased with higher baseline HbA1c value. This finding is consistent with the hypothesis that 
the TTP488-301 RAGE antagonist may have beneficial effects in patients who have 
overexpression of RAGE.   HbA1c is being used as a marker for increased RAGE expression 
because research has shown a correlation of increased HbA1c with increased RAGE in a group 
of diabetic elderly patients with MCI (as well as a correlation of increased RAGE with increased 
AGEs).  Further, patients with diabetes and HbA1c have increased AGE accumulation where 
AGEs bind to RAGE and promote increased expression of RAGE. (Gorska-Ciebiada 2015) 
 
This study is an adaptive learn-and-confirm study to confirm TTP488-301 diabetes subgroup 
findings at 6 months (in Part 1) as well as use the information in Part 1 to refine the protocol for 
Part 2.  
1.3 
Subject Population  
The study population includes subjects with a clinical diagnosis of probable mild AD (screening 
MMSE between 21 and 26, inclusive; baseline MMSE between 19 and 27, inclusive; CDR-
global of 0.5 or 1 at screening and baseline; ADAS-cog14 score of at least 10 at screening and 
baseline) and screening HbA1c of 6.5% - 9.5%.  The study population includes subjects 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, A-IADL, and FAQ and evidence of this should be documented in source 


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documentation. Participants who reside in assisted living facilities are permitted provided that 
they meet caregiver criteria. Subjects are between 50 and 85 years of age, inclusive. 
1.4 
Randomization  
A total of 100 subjects were originally planned to be randomized into Part 1 of this study, but the 
total enrolled was 43 due to a slow enrollment and sponsor decision to stop enrollment due to the 
additive impact of the COVID pandemic on enrollment rates . Subjects were enrolled and 
randomized according to a fixed randomization scheme blocked by study investigative site.  
Randomization is intended to have balanced allocation (1:1) between active and placebo. 
Dropouts will not be replaced.  
1.5 
Study Design  
TTP488-305 is a protocol that consists of two sequential, multi-center, randomized, double-blind, 
placebo-controlled, parallel group studies operationally conducted under a single protocol.   The 
purpose of the study is to evaluate the safety and efficacy of 5 mg/day oral azeliragon relative to 
placebo in subjects with mild Alzheimer’s disease (screening MMSE 21-26, baseline MMSE 19-
27 and ADAS-cog14 score of ≥ 10) and impaired glucose tolerance (Screening HbA1c 6.5% -
9.5%, inclusive). Eligible participants will be randomly assigned to azeliragon or placebo in a 1:1 
randomization for a double-blind dosing period of 6 months (Part 1) or 18 months (Part 2). The 
Part 1 and Part 2 studies will have independently randomized, unique study populations. 
The Part 1, 6-month, double-blind treatment portion of the study will include 5 clinic visits. The 
primary objective of the Part 1 portion is to evaluate the efficacy of 6 months of oral azeliragon on 
a measure of cognition (ADAS-cog14). Secondary objectives of Part 1 will be to evaluate the 
efficacy of 6 months of oral azeliragon on multiple measures of function (CDR, Amsterdam-IADL, 
FAQ) to inform selection of a functional endpoint to serve as co-primary in Part 2. Additionally, 
Part 1 will be used to inform the sample size required to adequately power Part 2 of this study. The 
Schedule of Activities for Part 1 is described in Section 14 of this SAP. 
Part 1 is conducted at multiple sites in the U.S and Canada.   
The overall structure of the study includes the following periods: 
Screening period: Screening procedures occur within 60 days of start of study drug 
administration, and they include obtaining informed consent and evaluations to determine 
eligibility for study participation. 
Baseline Study Period: (Day -7 — Day 1, pre-dose): Subjects will have baseline assessments for 
efficacy and safety measures, including imaging and PK assessments.  
Treatment Period: (Day 1 — Month 6): Subjects are treated with double-blind study medication. 
Efficacy and safety measures are taken. Blood samples are taken and subjects have assessments 
for safety and PK.   


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Follow-up period: (Month 9): Subjects return to the site for final safety assessments including 
vital signs, adverse events, electrocardiography and concomitant medications are taken. Blood 
draws are taken for safety evaluations and for pharmacokinetics evaluations.  
1.6 
Sample Size and Power Considerations  
Original Sample size considerations for Part 1 (from protocol):  
Assuming a standard deviation of the change from Baseline to Month 6 in 
ADAS-cog14 of 4, using alpha = 0.05, a total sample size of approximately 82 subjects 
in balanced allocation (41 subjects per group) provides at least 90% power to detect a 
difference between treatment groups of 2.9 using a 2-sided, 2-sample t-test.   Assuming 
a dropout rate of 18% or less, randomization of 100 subjects provides adequate 
statistical power for Part 1 to demonstrate superiority of azeliragon over placebo based 
on the ADAS-cog14. (Section 9.2). 
Recalculated power considerations for Part 1: 
ADAS-Cog: Estimates and standard deviations were drawn from a model that fit 
change in ADAS-Cog11 over time using the data from the STEADFAST A-study and 
B-study combined (N=880). The model utilized all individuals in the study. Estimates 
were drawn at an HbA1C of 7.2 (average from present TTP488-305 study; Part 1). 
The estimates of standard deviation and effect size for the change from baseline in 
ADAS-Cog was 3.4 and -1.54 respectively. Given a sample size of 43, a two-sided 
alpha of 0.05 would result in 30% power to detect a significant effect. If we observe 
the estimated effect size and standard deviation at the given sample size in Part 1 of 
the current study (TTP-305) we would expect to observe a p-value of 0.144 which 
could be considered evidence of a trend.  
Previous studies (Siemers et al 2016) suggest that mean to standard deviation ratio 
between ADAS-Cog 11 and 14 are similar, therefore it is expected that the estimates 
drawn using ADAS-Cog11 will be applicable to ADAS-Cog14 data. 
Cognitive Composite: The association of treatment was also tested using a composite 
that was derived from STEADFAST A and B studies. Composites allow the global 
assessment of multiple aspects of disease as well as exclusion of items that do not 
contribute to progression and thus add noise to the data. The composite is composed of 
the ADAS-Cog comprehension, word finding difficulty, and remembering test 
instructions variables. The composite will be calculated by summing the within visit z-
scores for each item across individuals. Z-scores are calculated by subtracting the 
individual item score at visit x from the baseline mean item score and dividing this 
value by the item standard deviation at baseline.  
The ADAS-Cog variables included in the model were chosen using PLS regression 
where treatment status at 6 months was the outcome variable and ADAS-Cog 11 and 
CDR-SB individual items were predictor variables. The PLS was modeled using 


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STEADFAST study B as this dataset showed a smaller ADAS-Cog effect with 
treatment.  
PLS estimates and standard deviations were drawn from the STEADFAST data (A-
study and B-study combined) as above for ADAS-cog. The model fit change in PLS 
over time with estimates drawn at an HbA1C of 7.2. The estimates of standard 
deviation and effect size for the change from baseline were -0.92 and 1.5, 
respectively. Given a sample size of 43, an alpha of 0.05 would result in 49% power 
to detect a significant effect. If we observe the estimated effect size and sd at the 
given sample size in the present study (Part 1) we would expect to observe a p-value 
of 0.052 indicating that the composite is somewhat more sensitive to treatment effects 
than the ADAS-cog 11. 
Modified Cognitive Composite: The STEADFAST analysis indicates that a portion of 
the observed change may be due to age-related cognitive decline.  To assess this, a 
modified composite that incorporated aspects associated with cognitive decline due to 
aging, specifically trail making test (TMT A/B) and Controlled Oral Word 
Association Test (COWAT) was generated.   As these variables are not available in 
ELEVAGE, historic data (ADNI) was used to identify the best surrogate for each. All 
surrogates were found to be within ADAS-Cog individual items. Word finding 
difficulty was found to be a suitable surrogate for TMTA, while delayed word recall 
and ideational praxis were surrogates for TMTB (r=0.5, 0.6, and 0.6 respectively). 
The COWAT surrogates were orientation and word recognition (r=0.5 at 12 months). 
(delayed recall, ideational praxis, orientation, and word recognition).  
The model fit change in PLS over time with estimates drawn at an HbA1C of 7.2. The 
estimates of standard deviation and effect size for the change from baseline were -
1.73 and 2.9, respectively. Given a sample size of 43, a two-sided alpha of 0.05 
would result in 47% power to detect a significant effect. If we observe the estimated 
effect size and sd at the given sample size in the present study (Part 1) we would 
expect to observe a p-value of 0.059 indicating that the composite is somewhat more 
sensitive to treatment effects than the ADAS-cog 11. 
1.7 
Early Stopping, Data Monitoring, and Interim Analysis 
There will be no interim analyses.  
An adjustment for alpha is included in the original protocol, as a conservative measure to 
accommodate unblinded evaluations by the independent data monitoring committee (IDMC). The 
alpha adjustment is applied to accommodate up to 10 analyses by the IDMC because the safety 
evaluation will include review of ADAS-Cog data from the safety perspective. Alpha = 0.0001 is 
apportioned to each of no more than 10 analyses by the IDMC that includes review of ADAS-
Cog data. 
There will be two database locks: one for the double-blind treatment period, and one for the 
follow-up period.  Final analysis will be performed on the interim database after all subjects 
complete the treatment period (Month 6 or Early Termination) and all Treatment Period data is 
locked.  The final database lock will occur after all Follow-up Visits are complete. 


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1.8 
Conformance to Regulatory Standards  
An objective of this SAP is to comply with regulatory standards. The following guidance 
documents were specifically consulted in the preparation of this SAP: 
 ICH E9: Statistical principles for clinical trials (September 1998); ICH and FDA 
 ICH E9(R1): Estimands and sensitivity analysis in clinical trials (draft; October  2017); 
ICH and FDA. 
 ICH E14: Clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs (October 2012); ICH and FDA 
 E14 Q&A (R3) ICH guideline E14: the clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs (R3)—questions 
and answers (26 January 2016); EMA 
 Guideline on adjustment for baseline covariates in clinical trials (26 February 2015); 
EMA. 
 Guideline on the clinical investigation of medicines for the treatment of Alzheimer’s 
disease (Feb 2018); EMA. 
 Good Review Practice: Statistical review template (30 July 2012). Office of Biostatistics; 
CDER; MAPP 6010.4 
 Good Review Practice: Clinical review template (10 December 2010). Office of New 
Drugs; CDER; MAPP 6010.3 
 Guidance: Providing clinical evidence of effectiveness for human drug and biological 
products (May 1998); CDER; CBER.  
 Draft Guidance: Demonstrating Substantial Evidence of Effectiveness for Human Drug 
and Biological Products (Draft, December 2019); CDER, CBER. 
 Good Review Practice: Reviewer guidance: Conducting a clinical safety review of a new 
product application and preparing a report on the review (February 2005); CDER.  
 Draft guidance: Early Alzheimer’s Disease:  Developing drugs for treatment (February 
2018); CDER, CBER. 
 Draft guidance: Adaptive designs for clinical trials of drugs and biologics (November 
2019); CDER, CBER.  
 Reflection paper on methodological issues in confirmatory clinical trials planned with an 
adaptive design (18 October 2007); EMA 
 Draft guidance: Enrichment strategies for clinical trials to support Determination of 
effectiveness of human drugs and biological products (March 2019); CDER, CBER. 
 Guidance: Drug-induced liver injury: premarketing clinical evaluation (July 2009); 
CDER, CBER. 
 Guidance: Patient-reported outcome measures: Use in medical product development to 
support labeling claims (December 2009); CDER, CBER, CDRH. 
 ICH and MSSO. (March 2019). MedDRA Introductory Guide Version 22.0.  
 FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review 
Boards. March 2020 . Updated on September 2020. 


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 FDA Guidance: Statistical Considerations for Clinical Trials During the COVID-19 
Public Health Emergency Guidance for Industry. June 2020; CDER, CBER, CDRH, 
CVM. 
The planned statistical analysis of this study is intended to comply with regulatory expectations 
and standards as depicted in the above-listed guidance documents. 
 
 


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1.9 
Modifications from the Statistical Section of the Protocol  
The power calculation was updated from the protocol and the composite score analysis was 
added. Secondary variables (MMSE and biomarkers) and exploratory assessment of 
ADAScog11 progression were added. In addition, the statistical analysis plan adds more detail 
and analyses and supersedes the statistical section of the protocol. 
1.10 Adaptive Study 
This study is an adaptive trial, which includes 2 studies under the same protocol. This SAP is 
focused on Part 1 of this adaptive study.  
 
This SAP conforms to standards set forth in Adaptive Designs for Clinical Trials of Drugs and 
Biologics Guidance for Industry (CDER, CBER, November 2019). The intention of the adaptive 
nature of this protocol is to leverage potential advantages related to statistical analysis as 
depicted in the FDA final guidance. 
 
2 
Statistical Hypotheses 
Part 1 has a single primary endpoint (ADAS-Cog14). 
The testing sequence will be as follows for strict significance, however proof of concept will be 
attained by significance in any of the outcomes below (Figure 1): 
The first set of hypotheses to be tested is as follows: 
H01: The mean change in ADAS-cog14 in the active group is equal to that of the placebo 
group*. 
H11: The mean change in ADAS-cog14 in the active group is not equal (is superior) to that 
of the placebo group*.  
Conditional on statistical significance, testing will proceed hierarchically: 
H02: The mean change in A-IADL in the active group is equal to that of the placebo group. 
H12: The mean change in A-IADL in the active group is not equal (is superior) to that of the 
placebo group§. 
Conditional on statistical significance, testing will proceed: 
H03: The mean change in CDR-sb in the active group is equal to that of the placebo group. 
H13: The mean change in CDR-sb in the active group is not equal (is superior) to that of the 
placebo group§. 


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Conditional on statistical significance, testing will proceed: 
H04: The mean change in FAQ in the active group is equal to that of the placebo group. 
H14: The mean change in FAQ in the active group is not equal (is superior) to that of the 
placebo group§. 
H05: The mean change in the cognitive composites or GST in the active group is equal to that 
of the placebo group. 
H15: The mean change in the cognitive composites or GST in the active group is not equal 
(is superior) to that of the placebo group. 
* ADAS-Cog will also be run using LZCF.  If neither of these are significant, the 
cognitive composites and global statistical test (GST) will be assessed for significance to 
demonstrate proof of concept. It is acknowledged that the present study is underpowered 
to replicate the clinically meaningful effect size observed in the STEADFAST combined 
A- and B-study diabetes subgroup. Therefore, if the observed effect size (treatment 
difference) or percent slowing (treatment difference divided by the placebo change) is 
equal to or greater than the corresponding values from the STEADFAST pooled analysis 
(-0.92; -61%), this will be considered proof of concept. Lack of strict statistical 
significance is expected with this range of effect size due to the small n, but this result, in 
the context of the consistency of the effect seen in STEADFAST Part A with the 
STEADFAST Part B data would provide proof of concept for this compound. 
     § All secondary variables will also be run using LZCF.  
 


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3 
Estimand Specification 
This SAP is constructed to conform to regulatory guidance. In particular, this section is included 
as recommended by ICH E9 (R1) Addendum on estimands and sensitivity analysis in clinical 
trials to the guideline on statistical principles for clinical trials (30 August 2017).  
In accordance with ICH E9 Addendum, the specification of the estimand is included in this SAP 
with the 4 attributes detailed in ICH E9 Addendum, Section A.3.1: 
A. The Population, that is, the subjects targeted by the scientific question: 
For this study, the population consists of subjects with AD and HbA1c of 6.5% - 9.5% 
who meet eligibility requirements for the study, receive double-blind medication, and 
have at least one valid post-baseline measure of ADAS-cog(14). 
B. The variable (or endpoint) to be obtained for each patient, that is required to address the 
scientific question: 
For this study, the primary endpoint is Change in ADAS-cog(14). 
C. The specification of how to account for intercurrent events to reflect the scientific 
question of interest: 
Due to the small sample size intercurrent events will not be accounted for in this analysis. 
 
D. The population-level summary for the variable that provides, as required, a basis for a 
comparison between treatment conditions: 
For this study, the population-level summary for the variable is the least-squares mean 
(LSM) of the treatment difference in mean change from baseline in ADAS-cog(14). 


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4 
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 will be used for all 
statistical analysis: 
 The full analysis set (FAS) includes all randomized subjects, whether or not they receive 
any study medication, and who 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 masked data review meeting held in 
accordance with ICH E9 prior to the lock data. The complete specification (made blinded 
to treatment arm) will be documented in the minutes to the blind data review meeting held 
prior to lock the data. 
 The safety set (SAF) includes all subjects who receive any study medication. 
The FAS will be used for all hypothesis tests of efficacy. Analysis of superiority using the PPS 
will also be done for supportive analyses. If the PPS does not differ from the FAS by at least 15%, 
the PPS is considered optional. 
The SAF will be used for safety analyses. 
 
 


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5 
Variables of Analysis  
5.1 
Efficacy Variables 
Efficacy evaluation will include the primary endpoint (ADAS-cog14 for Part 1), secondary 
measures, and other efficacy markers. 
Statistical analysis will be done on each primary and secondary variable independently. 
5.1.1 Primary Efficacy Variable 
The primary analysis will include assessment of the following variables. 
 
Mean change from Baseline to Month 6 in ADAS-cog14* 
5.1.2 Secondary Variables of Analysis  
 
Mean change from baseline in the Amsterdam-IADL at Month 6. 
 
Mean change from baseline in CDR-sb at Month 6. 
 
Mean change from baseline in the FAQ at Month 6. 
 
Mean change from baseline in the MMSE at Month 6. 
 
Mean change of treatment on biomarkers and markers of inflammation 
5.1.3 Exploratory Variable 
 
Mean change from baseline in ADAS-cog11 at Month 6. 
5.1.4 Proof of Concept 
 Mean change from baseline in Cognitive Composite at Month 6 
 Mean change from baseline in Modified Cognitive Composite at Month 6 
 Mean change from baseline in GST at Month 6 
 *If the ADAS-Cog is not significant (P > 0.05) the cognitive composites and global 
statistical test (GST) will be assessed for significance to demonstrate proof of concept. No 
correction will be performed for these comparisons since they are all testing the overall 
effect of treatment on progression of disease and are expected to be highly correlated. 
 


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5.1.5 Efficacy Scales 
Generation of instrument total scores will be calculated from individual items.  The following 
instruments that are used in this study are subject to statistical analysis: 
5.1.5.1 Alzheimer's Disease Assessment Scale - Cognitive Subscale 90 point (ADAS-cog):  
 Range: The scale range is 0 to 90 with higher scores indicating greater cognitive 
impairment.  
 Brief description: The 14-Item Alzheimer’s Disease Assessment Scale - Cognitive 
Subscale (ADAS-cog14) is a structured scale (approximately 45 minutes to complete) 
that evaluates memory, orientation, attention, reasoning, language, constructional praxis, 
delayed recall, digit cancellation, and maze-completion. The ADAS-cog14 scoring range 
is from 0 to 90, with higher scores indicating greater cognitive impairment (Mohs et al. 
1997). The ADAS-Cog should always be administered prior to other cognitive measures. 
The ADAS-Cog will be administered at Screening, Baseline, Months 3 and 6 or in the 
event of early termination. Participants must have scores of ≥10 at Screening and 
Baseline to be eligible for participation in the study.  
5.1.5.2 Mini Mental State Examination (MMSE):  
 Range: The scale range is 0 to 30 with lower scores indicating greater cognitive 
impairment.  
 Brief description: The MMSE is a brief 30-point test that is used to assess cognition 
(Folstein, 1975). It is commonly used to screen for dementia. In the time span of about 
10 minutes, it samples various functions, including arithmetic, memory and orientation. 
The MMSE will be administered at Screening, Baseline, Months 3 and 6 or in the event 
of early termination. Participants must have scores of 21-26 at Screening and 19-27 at 
Baseline to be eligible for participation in the study.  
 
5.1.5.3 Functional Activities Questionnaire (FAQ): 
 Range: The score ranges from 0 to 30. Higher scores are associated with greater 
impairment. 
 Brief description: The FAQ is an inventory of instrumental activities of daily living 
developed by (Pfeffer 1982). The FAQ is administered by asking the informant to rate 
patient’s ability (0-3) on 10 different activities of daily living.  The FAQ will be 
administered at Screening, Baseline, Months 3 and 6 or in the event of early termination.  
5.1.5.4 Amsterdam-Instrumental Activities of Daily Living Questionnaire (A-IADL):  
 Range: scoring range from 20 to 80, with lower scores indicating greater impairment. 
 Brief description: The A-IADL is an adaptive questionnaire designed to assess 
impairments in instrumental activities of daily living in early dementia.(Sikkes 2013) The 
questionnaire is completed by a caregiver / informant. The original questionnaire consists 
of 70 items in seven categories and the administration time is approximately 20-25 


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minutes. The A-IADL total score is calculated using an item response theory method of 
scoring (Embretson and Reise 2000, Reise and Waller).  Higher scores indicate greater 
functional impairment. The A-IADL will be administered at Screening, Baseline, 
Months 3 and 6 or in the event of early termination.  
 
5.1.5.5 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 
gathered, either as part of normal clinical practice or as part of a research study. The 
interview takes approximately 40 minutes to administer.  
The scores for each category can also be summed and this is known as the sum of box 
score (CSR-SB). The CDR will be conducted at Baseline and at Months 3 and 6 or in the 
event of early termination. To avoid patient fatigue, the CDR may be performed on a 
separate, but proximate, visit day than the other cognitive tests.  
5.1.5.6 Global Statistical Test (GST):  
A GST allows assessment of a global change in disease status/trajectory by standardizing 
and then combining measures. The GST will be a combination of 3 z-scores  (ADAS-
COG, CDR-SB, and A-IADL) with standardization calculated using the baseline mean 
and standard deviation for each score. The GST will be calculated for each subject at 
each timepoint by averaging the three z-scores and this GST will then be analyzed as a 
new outcome by calculating change from baseline to each visit.  
5.1.5.7 Cognitive Composite:  
Composites allow the global assessment of multiple aspects of disease as well as 
exclusion of items that do not contribute to progression and thus add noise to the data. 
The cognitive composite is composed of the ADAS-Cog comprehension, word finding 


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difficulty, and remembering test instructions variables. The composite will be calculated 
at each timepoint by summing the within visit z-scores for each item across individuals. 
Z-scores are calculated by subtracting the individual item score at visit x from the mean 
item score at visit x and dividing this value by the item standard deviation at visit x.  
5.1.5.8 Modified Cognitive Composite:  
The modified composite incorporates the cognitive composite variables as well as aspects 
associated with cognitive decline due to aging, specifically trail making test (TMT A/B) 
and Controlled Oral Word Association Test (COWAT). As these variables are not 
available in ELEVAGE; historic data (ADNI) was used to identify the best surrogate for 
each. All surrogates were found to be within ADAS-Cog individual items. Word finding 
difficulty was found to be a suitable surrogate for TMTA, while delayed word recall and 
ideational praxis were surrogates for TMTB (r=0.5, 0.6, and 0.6 respectively). The 
COWAT surrogates were orientation and word recognition (r=0.5 at 12 months).   
5.1.5.9 Biomarker:  
Blood for plasma biomarkers will be collected at baseline as well as months 3, 6, and 
follow-up.  
5.2 
Safety Variables 
Safety is monitored in this study by collection of adverse events, vital signs, electrocardiography, 
C-SSRS, 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 including 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.  
5.2.1 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.  
 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 


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 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 
 
5.2.2 The Columbia Suicide Severity Rating Scale (C-SSRS) 
 Range: The following outcomes are C-SSRS categories and have binary responses 
(yes/no). The categories have been re-ordered from the actual scale to facilitate the 
definitions of the composite and comparative endpoints, and to enable clarity in the 
presentation of the results.  
o Category 1 – Wish to be Dead  
o Category 2 – Non-specific Active Suicidal Thoughts  
o Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without 
Intent to Act  
o Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan  
o Category 5 – Active Suicidal Ideation with Specific Plan and Intent  
o Category 6 – Preparatory Acts or Behavior  
o Category 7 – Aborted Attempt 
o  Category 8 – Interrupted Attempt  
o Category 9 – Actual Attempt (non-fatal)  
o Category 10 – Completed Suicide 
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not 
suicide-related) and has a binary response (yes/no).  
 
The following outcome is a numerical score derived from the C-SSRS categories. The score 
is created at each assessment for each patient and is used for determining treatment 
emergence.  
 
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.  


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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. 
 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 lifetime 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.)  
5.2.3 Vital Signs 
Vital signs measurements consist of blood pressure and pulse rate. Variables of analysis will 
include means, mean changes over time, and proportions of subjects meeting criteria for 
potential clinical concern in vital signs: 
 Mean and mean changes in systolic and diastolic blood pressures  
 Mean and mean changes in pulse 
 Proportions of subjects with treatment-emergent values or changes of potential clinical 
concern. 
5.2.4  ECG 
12-lead ECGs are obtained at the Screening, Baseline, Month 3, Month 6/ET, and Follow-up 
visits. Triplicate measurements are obtained at Baseline; all other study visits collect single 
measurements.  
 
ECG results will be obtained from the Central Reader.  Interpretation of results as normal, 
abnormal not clinically significant or abnormal clinically significant will also be collected from 
the investigator or designee.  
5.2.5 Clinical laboratory assessments 
Routine clinical laboratory data, including eGFR, 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.  
 Definition:  
 A treatment-emergent abnormal value (TEAV) is a laboratory value that is abnormal after 
administration of study medication that was normal prior to study medication 
administration.  


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 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 
o Phosphorus 
 
Safety variables of analysis include: 
 Subjects with TEAVs 
 Subjects with TEAVs of potential clinical concern (based on criteria in this SAP) 
 Subjects with a TEAV in a liver function test (LFT) 
 


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5.3 
Pharmacokinetics and Pharmacodynamics Variables 
Blood samples for pharmacokinetic (PK) analysis will be collected prior to dosing at Baseline, 
Months 3, 6, and at Early Termination. 
All participants with at least one dose of study medication will be included in the 
pharmacokinetic and pharmacokinetic/pharmacodynamic analyses, as appropriate.  
5.4 
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. Descriptive analysis will include TEAEs classified by MedDRA into the 
SOC for psychiatric disorders (at the SOC level within the hierarchy of MedDRA) and high level 
group terms (HLGTs) of anxiety disorders and symptoms (at the HLGT level within the 
hierarchy of MedDRA). 
Standardized MedDRA queries (SMQs) will be used for dynamic analysis of any TEAE that 
emerges of potential interest. 
Conditions associated with substance abuse are included in the SOC Psychiatric Disorders in 
high level term (HLT) “Substance-related disorders,” which will be used for identification of 
terms pertaining to substance abuse. Variables of interest will include incidence estimates for 
each treatment group for the HLT and PTs within the HLT. It is noted that terms that refer to a 
person as a “drug abuser” would be captured in the SOC Social Circumstances, which is not 
intended for contributing to variables of analysis. 
6 
Statistical Methodology 
General statistical methods will be applied as appropriate for out-patient clinical studies. Safety 
evaluations will rely on descriptive statistics. Randomization groups will be examined for 
homogeneity between treatment groups.  
Continuous variables will be summarized using mean, median, standard deviation, minimum, 
maximum, and number of subjects available for analysis. Categorical variables will be 
summarized using frequency, proportion, and number of subjects available for analysis.  
SAS version 9.3 or later will be used.  
6.1 
Pooling of Investigator Sites 
Pooled sites will not be included in the model due to small N overall.    
 
6.2 
Statistical Methodology for Efficacy Analysis 
The primary analysis will use the ITT methodology and a mixed-model measures (MMRM) 
methodology with a random slope and intercept for each individual. The MMRM will utilize an 


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unstructured covariance with only one parameter for the correlation between the slope and 
intercept. Time (ADY) is considered as a continuous variable. Analysis will include baseline risk 
score, treatment, time, as well as HbA1C by treatment, treatment-by-time, baseline by treatment, 
and baseline by time interactions as fixed effects. Subject will be included as a random effect. 
Baseline visit will be included in the model. Baseline risk score is derived from the historic 
STEADFAST data and calculated as a linear calculation of:  
age*-0.03582 + hba1c*-0.2335 + mmsebl*-0.2683 + base*-0.09342 
First the baseline risk score will be subtracted from the change score for each individual. Then the 
mean baseline value of the risk adjusted change score will be calculated separately for each 
treatment group. Finally, the risk adjusted change scores for each individual will have their group 
mean added back in to ensure an average score of 0 at baseline for each group. This adjusted 
change score will be used in the model in place of change from baseline. Model assumptions will 
be evaluated. If the parametric assumptions are evaluated as inappropriate or violated, rank 
analogues will be advanced.  
6.3 
Per Protocol Set 
If the PPS differs from the FAS by more than 15%, the analyses will be replicated on the PPS. If 
the PPS and the FAS do not differ by more than 15%, analysis may not be done on the PPS. 
Final judgments will be made at the blind data review meeting in accordance with ICH E9. 
6.4 
Adjustments for multiplicity 
Multiplicity of the primary efficacy analyses is controlled by using a conditional sequence of 
hypotheses. The study will be considered to demonstrate statistical significance if the primary 
analysis has a resulting p-value less than 0.049 for both primary endpoints for both A-study and 
B-study. No other adjustment for multiplicity is required. 
 
 
6.5 
Subgroup Analyses 
6.5.1 Investigator Sites 
Blind data review (recommended by ICH E9) may reveal many sites with few subjects 
randomized. Understanding the influence of site effects on analysis conclusions is essential and 
analyses to explore this are recommended in ICH E9 for key variables of analysis. A forest plot 
will be generated excluding each site one at a time to assess the impact of site for all efficacy 
measures.  


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6.5.2 Covariate and Categorical Interaction Analyses 
The following variables will be assessed for interactions with the primary efficacy variable and 
time using the MMRM as described above: 
 baseline score (for outcome being analyzed) 
 baseline MMSE 
 baseline HbA1C (continuous)  
 ApoE4(carrier/non-carrier; discrete) 
 ApoE4(number of E4 alleles; discrete) 
6.6 
Statistical Methodology for Primary Efficacy Analysis 
We will use alpha = 0.0499, which includes an adjustment of 0.0001 for interim analyses 
performed by the Independent Data Monitoring Committee (IDMC).  
In addition to the primary MMRM model, a last z-score carried forward (LZCF), will be run for 
the primary variable. Z-scores will be calculated for each timepoint.  For individuals with 
missing data the last z-score will be carried forward. Let Z be the imputed z-score, while x is the 
last observation at timepoint t1 and µ and σ are the mean and standard deviation of the next 
timepoint (t2) for which the data is missing. 
Zt2=(xt1 - µt2)/σt2 
Z-scores imputed relative to the group mean and standard deviation at each timepoint, will better 
preserve the slope of each arm and thus is more robust to differences in dropout rate across 
treatment. The model using LZCF will be the primary analysis for the GST and the composite 
scores..  
Descriptive summaries will be produced of the observed values and change from Baseline in 
ADAS-cog14 by treatment group at each individual time point and at endpoint (final on-treatment 
assessment for each subject). 
For statistical analyses, 95% confidence intervals will be produced for the least-squares means 
(LSM) in each treatment group, as well as the LSM differences as compared to placebo. For 
MMRM and ANCOVA, two-sided p-values will be displayed for the comparison against placebo. 
The primary analysis controls alpha through the conditional sequence of hypothesis testing. No 
further adjustment for multiplicity is necessary. 
If the PPS differs from the FAS by more than 15%, the analyses will be replicated on the PPS. If 
the PPS and the FAS do not differ by more than 15%, analysis may not be done on the PPS. Final 
judgments will be made at the blind data review meeting in accordance with ICH E9. 


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6.6.1 PK 
The trough PK concentration data collected prior to each dose will be used in a concentration 
response relationship analysis to assess correlation with each outcome which will mirror the 
primary analysis but replace the treatment variable with PK concentration. 
6.6.2 Missing Data 
An essential component of the thorough analysis includes an assessment of the impact of missing 
data on study conclusions. As a part of assessing this impact, supportive analysis will include: 
 observed cases by assessment time. 
To ensure robustness of analysis conclusions against missingness, multiple imputation methods 
will also be done to cope with missing data as a key supportive analysis using the final on-treatment 
assessment of treatment failures as non-missing data at endpoint.  Multiple imputations (MI) will 
be used as a supportive analysis with 100 invocations (acknowledging that more invocations are 
needed with more missing data). Monte Carlo methods are planned. 
In accordance with the recommendations of the report from the National Academy of Science 
(NAS) panel “The Prevention and Treatment of Missing Data in Clinical Trials,” (National 
Research Council, 2010), missingness is classified as “missing at random” (MAR) or “missing not 
at random” (MNAR). When subjects are withdrawn due to treatment failure, this event is 
considered in this sensitivity analysis to be MNAR, and the endpoint value is taken as the hard 
endpoint (imputed for progression over time) in analysis.  Data that are missing for other reasons 
are considered to be MAR, and standard multiple imputation methods are planned. 
6.7 
Statistical Methodology for Secondary Analysis 
Secondary and exploratory endpoints that are measurement variables will use similar statistical 
methodology to the methodology used for primary analysis and will also use similar figures as 
those described in the associated TOC. Efficacy variables that are proportions will be analyzed 
using Mantel-Haenszel test. For the analysis of the categories for responders, a Cochran-Mantel-
Haenszel test will be used. 
Secondary endpoints will be performed using LZCF as described above.  Composite and GST 
scores will only be run as LZCF.  
Methodologies for variables that are categorical and summarized with proportions will include 
construction of confidence intervals for each treatment group and for the difference between 
groups. For analysis, Fisher’s exact test will be used for single-population analysis, and a Mantel-
Haenszel test will be used for analyses combining data across strata. 
Methodologies for time-to-event variables will include construction of 95% confidence intervals 
for each group separately and for the difference between groups. For analysis, a Wilcoxon test will 
be used for single-population analysis. 


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 A graphical representation will be defined where the y-axis will show the cumulative percentage 
of subjects who achieved the specific measure of improvement or worsening in the ADAS-cog14 
total score shown on the x-axis with a separate cumulative percentage curve for each treatment 
group. 
6.8 
Disposition, Demography, and Baseline Characteristics  
A tabulation of subject disposition will be presented, including the number screened, the number 
randomized in each population group, the number dosed in each population group, the number 
who withdrew prior to completing the study, and reasons for withdrawal. 
Demographic and baseline characteristics (disease history, medical history, and prior treatments 
for AD) will be summarized for all randomized subjects and for the FAS. No formal statistical 
comparisons will be performed. Summaries of continuous variables will include number of 
subjects, mean, median, minimum, maximum, and standard deviation. Summaries of categorical 
variables will include numbers of subjects in each category.  
The variables to be summarized will include: 
 Age, gender, race, and ethnicity 
 Weight, height, BMI 
 Years since diagnosis of AD 
 Education level 
 Previous medication for AD (AChEI, Memantine) 
 Hypertension Y/N 
 Diabetic medication type (ATC4 classification) 
 Acetylcholinesterase inhibitor usage (Y/N) 
 Memantine usage (Y/N) 
 Acetylcholinesterase inhibitor usage (Y/N) and Memantine usage (Y/N) 
Summaries will be provided overall and stratified by treatment group. 
Additionally, baseline characteristics will be compared for efficacy measures of MMSE, ADAS-
Cog14, CDR-sb, FAQ, Amsterdam IADL, HbA1c. No formal statistical comparisons will be 
performed. 


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6.9 
Analysis of Safety Data 
6.9.1 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 subjects reporting AEs will include the preferred terms and the SOCs. Summaries 
will include TEAEs by severity and by relationship to study medication. 
Adverse event summaries will be constructed displaying AEs in decreasing order of total 
frequency according to the numbers of subjects reporting the AE (not the number of reports).  
 Number (percent) of subjects reporting TEAE by treatment and overall in accordance 
with variables listed in Section 4.1.1.  
Supportive listings will be constructed that includes the subject identification, the treatment 
group, TEAEs, MedDRA terms, seriousness, severity, causality, elapsed time to onset, duration, 
and outcome.  
Methodology for AESIs will follow the same methodology for TEAEs. 
6.9.2 Vital Signs 
Subjects with vital signs meeting the criteria in Section 10 of this SAP for values of potential 
clinical concern will be identified 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.  
6.9.3 APOE genotyping 
APoE4 promotes the accumulation of β-amyloid proteins that are the cause of the 
characteristic plaques seen in the brains of AD subjects. The ApoE genes have consistently been 
associated with risk of AD dementia and will be 
assessed as indicated in Table 1. The genotypes will be designated as 2/2, 2/3, 3/3, 3/4, or 
4/4. Data will be summarized by treatment group. 
 
6.9.4 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 


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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 identified 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. 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 
(2) An accompanying abnormal bilirubin.  
6.9.5 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 Fridercia’s method (QTcF). Categorical analysis 
will be done consistent with ICH E14, “Clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs” (October 2005).  
In accordance with ICH E14, subjects will be categorized and summarized as described above 
according to: 
 Absolute QTc interval prolongation: 
o QTc interval > 450 
o QTc interval > 480 
o QTc interval > 500 
 Change from Baseline in QTc interval: 
o QTc interval increases from Baseline > 30 
o QTc interval increases from Baseline > 60. 


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6.10 Pharmacokinetics Analysis 
Data resulting from blood sampling for trough concentrations of TTP488 and metabolites will be 
analyzed descriptively.  
No formal inferential statistics will be applied to the pharmacokinetic data. 
6.11 Pharmacodynamic Analysis 
Plasma inflammatory biomarker change from baseline to 3 and 6 months will be evaluated using 
an MMRM containing terms for baseline value, treatment, time, and treatment-by-time 
interaction. Analysis will be done separately for each biomarker.    
6.12 Concomitant Medications 
Concomitant medications will be summarized by drug category and listed.  Summaries will also 
be prepared for individuals taking medications for the treatment of hypertension and diabetes. 
Hypertension summaries will be stratified by Y/N while diabetes summaries will be stratified 
according to type of medication classified under the concomitant medications ATC4 variable. 
Use of these medications in addition to, Acetylcholinesterase and Memantine usage at baseline 
will be included in baseline tables.  Summaries will be provided overall and stratified by 
treatment group. 
 
 


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7 
COVID-19 Data and Analysis Conventions 
Regulatory guidance was issued by the FDA and the EMA to acknowledge the potential impact 
of the COVID-19 pandemic on clinical trials, including missed visits or evaluations done in a 
manner different from the original intention of the protocol. This SAP includes recommended 
plans for coping with statistics and data issues related to COVID-19. 
 
From the FDA guidance, the following excerpt applies to this SAP: 
 
Sponsors should describe in appropriate sections of the clinical study report (or in a 
separate study-specific document):  
1. Contingency measures implemented to manage study conduct during disruption 
of the study as a result of COVID-19 control measures.  
2.  A listing of all participants affected by the COVID-19 related study disruption by 
unique subject number identifier and by investigational site, and a description of 
how the individual’s participation was altered.  
3. Analyses and corresponding discussions that address the impact of implemented 
contingency measures (e.g., trial participant discontinuation from investigational product 
and/or study, alternative procedures used to collect critical safety and/or efficacy data) on 
the safety and efficacy results reported for the study.  
 
Robust efforts by sponsors, investigators, and IRBs/IECs to maintain the safety of trial 
participants and study data integrity are expected, and such efforts should be documented. 
As stated above, FDA recognizes that protocol modifications may be required, including 
unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 control 
measures. Efforts to minimize impacts on trial integrity, and to document the reasons for 
protocol deviations, will be important. 
 
The following modifications to the primary analysis are intended to reflect the original analysis 
plan accommodating emergency modifications to visit schedules: 
 
 Visits were intended to result in the primary endpoint evaluation at Month 6. Due to 
COVID-19, the endpoint visit may be later than Month 6. Three approaches will be used:  
o In the primary analysis, the Month 6 value can be predicted from earlier or later 
time points. Multiple imputation methods will be employed to predict all missing 
Month 6 visits, based on available time points for each patient.  
o Supportive analysis will be done using MMRM, which copes with extra data or 
mis-timed data.  
o Supportive analysis will also be done using the latest on-treatment value 
available, regardless of whether it is earlier or later than Month 6. 
 Homogeneity analysis will be done comparing results prior to COVID-19 with those after 
impact of COVID-19 started. COVID-19 impact start date will be 13 March 2020. 
 
 
 


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8 
Data Conventions 
The following analysis conventions will be used in the statistical analysis.  
8.1 
Definition of Baseline 
For safety evaluations, the Baseline assessment for all measurements will be the latest available, 
valid measurement taken prior to the initiation study medication, except for electrocardiography 
(ECG) values: The Baseline assessment for ECG include a triplicate assessment with the 
baseline value intended to be the arithmetic mean of the values taken at the Baseline assessment 
that are taken in triplicate. Baseline values for efficacy outcomes will be the average of screening 
and baseline visits where available. For the GST, the z-scores at each visit will be calculated 
using the mean over all patients of the average of screening and baseline, and using the standard 
deviation pooled across screening and baseline. 
8.2 
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. 
Data are considered to be “on-treatment” if the assessment or collection follows the first 
administration of study medication and if the assessment occurs within 45 days following the 
final administration of study medication, justified based on the long half-life of this drug.  
Dates with missing fields will not have days imputed. 
In accordance with the recommendations of the report from the National Academy of Science 
(NAS) panel “The Prevention and Treatment of Missing Data in Clinical Trials,” (National 
Research Council, 2010), sensitivity analyses will be done to ensure that study conclusions are 
robust against missing data. Last observation carried forward (LOCF) and baseline observation 
carried forward (BOCF) methods will be used as appropriate in sensitivity analysis. Missing data 
types will be examined, and statistical methodologies for appropriate sensitivity analyses will be 
finalized during blind data review as patterns emerge as the study progresses. Primary 
methodologies following the ITT principle are not subject to change. 
The three types of missing data (Rubin, 1976) are considered to examine robustness of analysis 
conclusions against missingness and type of missingness:  
 MCAR (missing completely at random) assumes the event of missingness is independent 
both of observable values and of unobservable values, and the missingness is entirely at 
random. 
 MAR (missing at random) assumes that the missingness can be fully accommodated by 
accounting for variables where data are available.  
 MNAR (missing not at random) the missingness may be related to the reason the data are 
missing. 


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The robustness of analysis conclusions against missingness is managed through supportive and 
sensitivity analyses, employing techniques MAR MI for placebo and MAR MI with delta 
adjustment (jump-to-placebo) for the group randomized to TTP488 (O’Kelly and Ratitch, 
Clinical Trials with Missing Data: A Guide for Practitioners, 2014). 
8.3 
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. 
8.4 
Visit Windows 
Assessments taken outside of protocol allowable windows will be displayed according to the 
case report form (CRF) assessment recorded by the investigator. 
8.5 
Early Termination Assessments and Follow-up Assessments 
When a patient withdraws from the study prematurely for any reason, an early termination (ET) 
visit is to be performed, except in the case when a patient withdraws consent (and the protocol 
specifically states that no further data would be collected). An ET visit should be “on treatment,” 
and efficacy data collected at the ET visit are suitable for use in statistical analysis. Any data 
collected 45 or more days after last dose of investigational product (IP)_will be considered “off 
treatment”. 
8.6 
Unscheduled Assessments 
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing adverse events) will be included in listings, 
but not summaries. If more than one laboratory value is available for a given visit, the 
observation identified by the investigator to be the scheduled assessment will be used in 
summaries; all observations will be presented in listings. 
Data from unscheduled assessments will be included in longitudinal data summaries (e.g., 
minimum, maximum over time). Data planned at scheduled times for which unscheduled 
assessments are taken will not be reflected in by-visit summaries. 
8.7 
Values Below LLQ 
Concentrations for TTP488 and metabolites below the lower limit of quantification (LLQ) for 
the assay will be set to zero for the purpose of analysis. 
 
 


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8.8 
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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9 
Software 
All analyses will be done using SAS Version 9.3 or later. 
 
 


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36 
10 Data Displays 
The plans for displaying data will conform to this guideline and also to ICH E3 (Structure and 
Content of clinical Study Reports), and to ICH E9 (Statistical Principles for Clinical Trials). 
The following excerpt from ICH E3 (1996) applies to this SAP: 
“The guidance provided below is detailed and is intended to notify the applicant of virtually 
all of the information that should routinely be provided so that post-submission requests for 
further data clarification and analyses can be reduced as much as possible. Nonetheless, 
specific requirements for data presentation and/or analysis may depend on specific situations, 
may evolve over time, may vary from drug class to drug class, may differ among regions and 
cannot be described in general terms; it is therefore important to refer to specific clinical 
guidelines and to discuss data presentation and analyses with the reviewing authority, 
whenever possible. Detailed written guidance on statistical approaches is available from 
some authorities.  
“Each report should consider all of the topics described (unless clearly not relevant) although 
the specific sequence and grouping of topics may be changed if alternatives are more logical 
for a particular study” (p. 2). 
In accordance with FDA and ICH guidance, tables, figures, and key data listings are planned. 
Exploratory and data-driven data displays may also be generated.  
 
In addition to the data summaries and listings, 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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11 Values of Potential Clinical Concern 
Criteria for Safety Values of Potential Clinical Concern 
Hematology 
Assay 
Lower limit of the normal reference 
range (LLN) 
Upper limit of the normal reference 
range (ULN) 
Hemoglobin 
<0.8 times 
>1.2 times 
Hematocrit 
<0.8 times 
>1.2 times 
RBC 
<0.8 times 
 
Platelets 
<0.5 times 
>1.75 times 
WBC 
<0.6 times 
>1.5 times 
Total Neutrophils (abs) 
<0.8 times 
>1.2 times 
Eosinophils (abs) 
 
>1.2 times 
Monocytes (abs) 
 
>1.2 times 
Basophils (abs) 
 
>1.2 times 
Lymphocytes (abs) 
<0.8 times 
>1.2 times 
Chemistry 
Assay 
Lower limit of the normal reference 
range (LLN) 
Upper limit of the normal reference 
range (ULN) 
Total bilirubin 
 
>1.5 times 
AST 
 
>3 times 
ALT 
 
>3 times 
GGT 
 
>3.0 times 
Alkaline Phosphatase 
 
>3.0 times 
Creatinine 
 
>1.5 times 
BUN 
 
>1.3 times 
Glucose 
<0.6 times 
>1.5 times 
Uric acid 
 
>1.5 times 
Sodium 
<0.95 times 
>1.05 times 
Potassium 
<0.9 times 
>1.1 times 
Calcium 
<0.9 times 
>1.1 times 
Albumin 
<0.8 times 
>1.2 times 
Total protein 
<0.8 times 
>1.2 times 
Bicarbonate 
<0.9 times 
>1.1 times 
Chloride 
<0.9 times 
>1.1 times 
 
 


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12 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 E9: Statistical principles for clinical trials (September 1998); ICH and FDA 
 ICH E9(R1): Estimands and sensitivity analysis in clinical trials (draft; October  2017); 
ICH and FDA. 
 ICH E14: Clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs (October 2012); ICH and FDA 
 E14 Q&A (R3) ICH guideline E14: the clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs (R3)—questions 
and answers (26 January 2016); EMA 
 Guideline on adjustment for baseline covariates in clinical trials (26 February 2015); 
EMA. 
 Guideline on the clinical investigation of medicines for the treatment of Alzheimer’s 
disease (Feb 2018); EMA. 
 Good Review Practice: Statistical review template (30 July 2012). Office of Biostatistics; 
CDER; MAPP 6010.4 
 Good Review Practice: Clinical review template (10 December 2010). Office of New 
Drugs; CDER; MAPP 6010.3 
 Guidance: Providing clinical evidence of effectiveness for human drug and biological 
products (May 1998); CDER; CBER.  
 Draft Guidance: Demonstrating Substantial Evidence of Effectiveness for Human Drug 
and Biological Products (Draft, December 2019); CDER, CBER. 
 Good Review Practice: Reviewer guidance: Conducting a clinical safety review of a new 
product application and preparing a report on the review (February 2005); CDER.  
 Draft guidance: Early Alzheimer’s Disease:  Developing drugs for treatment (February 
2018); CDER, CBER. 
 Draft guidance: Adaptive designs for clinical trials of drugs and biologics (November 
2019); CDER, CBER.  
 Reflection paper on methodological issues in confirmatory clinical trials planned with an 
adaptive design (18 October 2007); EMA 
 Draft guidance: Enrichment strategies for clinical trials to support Determination of 
effectiveness of human drugs and biological products (March 2019); CDER, CBER. 
 Guidance: Drug-induced liver injury: premarketing clinical evaluation (July 2009); 
CDER, CBER. 
 Guidance: Patient-reported outcome measures: Use in medical product development to 
support labeling claims (December 2009); CDER, CBER, CDRH. 


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 ICH and MSSO. (March 2019). MedDRA Introductory Guide Version 22.0.  
  FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review 
Boards. March 2020 . Updated on September 2020. 
 FDA Guidance: Statistical Considerations for Clinical Trials During the COVID-19 
Public Health Emergency Guidance for Industry. June 2020; CDER, CBER, CDRH, 
CVM. 
 
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. 
 Mohs RC, Knopman D, Petersen RC, Ferris SH, Ernesto C, Grundman M, Sano M, 
Bieliauskas L, Geldmacher D, Clark C, Thal LJ. Development of cognitive instruments 
for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease 
Assessment Scale that broaden its scope. The Alzheimer's Disease Cooperative Study. 
Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S13-21.  
 Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S. Measurement of functional 
activities in older adults in the community. J Gerontol 1982; 37: 323-9. 
 Sikkes SA, Knol DL, Pijnenburg YA, de Lange-de Klerk ES, Uitdehaag BM, Scheltens 
P. Validation of the Amsterdam IADL Questionnaire- _, a new tool to measure 
instrumental activities of daily living in dementia. Neuroepidemiology 2013;41:35–41. 
 FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review 
Boards. March 2020 . Updated on June 3, 2020. 
 Gorska-Ciebiada M, Saryusz-Wolska M, Borkowska A, Ciebiada M and Loba J (2015) 
C-reactive protein, advanced glycation end products, and their receptor in type 2 diabetic, 
elderly patients with  mild cognitive impairment.  Front. Aging Neurosci. 7:209.  doi: 
10.3389/fnagi.2015.00209 
 Siemers ER, Sundell KL, Carlson C, Case M, Sethuraman G, Liu-Seifert H, Dowsett SA, 
Pontecorvo MJ, Dean RA, Demattos R. Phase 3 solanezumab trials: Secondary outcomes 
in mild Alzheimer’s disease patients. Alzheimers and Dementia 2016; 12:110-120. 
 
Reise SP and Waller NG. Item response theory and clinical measurement. Annual Review of 
Clinical Psychologists. 2009:27-48. 
 
Embretson SE and Reise SP. Item response theory for psychologists. Ed. Erlbaum, Mahwah NJ 
(2000). 
 
 


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13 Schedule of Time and Events  
SCHEDULE OF ACTIVITIES  
 
Part 1 Schedule of Activities 
Protocol Activity 
Screening Baseline 
Treatment Perioda 
Follow-
upb 
Day -60 to 
Day -1 
Day -7 to 
Day 1 
Day 
1c 
Month 
1 
Month 
2 
Month 
3 
Month 
4 
Month 
5 
Month 
6 / ET 
3 
months 
after 
last dose 
Study Days 
-60 to -1 
-7 to 1 
1 
30 
60 
90 
120 
150 
180 or 
ET 
270 
Window 
 
 
 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
Sign informed consent 
/ provide assentd 
X 
 
 
 
 
 
 
 
 
 
Assessment of 
continued 
consent/assent 
 
X 
 
 
 
X 
 
 
X 
X 
Assign Screening ID 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Criteria 
X 
X 
X 
 
 
 
 
 
 
 
Medical 
History/Surgical 
History / Drug, 
Alcohol, Tobacco Use 
History 
X 
 
 
 
 
 
 
 
 
 
Complete Neuro 
Exam & Physical 
Exam 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
ApoE genotyping 
 
X 
 
 
 
 
 
 
 
 
Telephone Contact 
 
 
 
X 
X 
 
X 
X 
 
 
Body weight 
X 
X 
 
 
 
X 
 
 
X 
X 
BMI calculation 
X 
 
 
 
 
 
 
 
 
 
Brief Neuro & 
Physical Exams 
 
X 
 
 
 
X 
 
 
X 
X 
Review Concomitant 
Medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood Pressure and 
Pulse Rate (supine) e 
X 
Xe 
 
 
 
X 
 
 
X 
X 
12 Lead ECGe 
Xf 
Xe 
 
 
 
X 
 
 
X 
X 


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Protocol Activity 
Screening Baseline 
Treatment Perioda 
Follow-
upb 
Day -60 to 
Day -1 
Day -7 to 
Day 1 
Day 
1c 
Month 
1 
Month 
2 
Month 
3 
Month 
4 
Month 
5 
Month 
6 / ET 
3 
months 
after 
last dose 
Study Days 
-60 to -1 
-7 to 1 
1 
30 
60 
90 
120 
150 
180 or 
ET 
270 
Window 
 
 
 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
Adverse Events 
Assessment 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Dispense / Return 
Study Drug / Drug 
Accountability 
 
 
X 
 
 
X 
 
 
X 
 
Study Drug Dosinga,c 
 
 
X 






 
MMSEg 
X 
X 
 


X
 
 
Xh
X 
ADAS-cog14g 
X 
X 
 


X 
 
 
Xh 
X 
CDRg 
X 
X 
 
 
 
X 
 
 
Xh 
X 
FAQ 
 
X 
 
 
 
X 
 
 
Xh 
X 
Amsterdam-IADL 
 
X 
 
 
 
X 
 
 
Xh 
X 
Columbia Suicide 
Severity Scale 
(C-SSRS)i 
X 
X 
 
 
 
X 
 
 
X 
X 
Fasting Central Lab 
Blood and Urine 
Collectionj 
X 
X 
 
 
 
X 
 
 
X 
X 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
Provide meal/snackk 
X 
X 
 
 
 
X 
 
 
X 
X 
Blood glucose 
measurementl 
X 
X 
 
 
 
X 
 
 
X 
X 
Brain MRIm 
X 
 
 
 
 
 
 
 
 
 
Blood Sample for PK, 
PD and Plasma 
Retention and Storage 
 
X 
 
 
 
X 
 
 
X 
X 
a 
Participants will receive azeliragon 5 mg once daily, or matching placebo during the treatment period. 
b 
Follow-up visit required for all participants who dosed with study medication. A Follow-up Visit should be completed 3 
months after a subject completes Month 6 for those participants who complete the study; or at least 45 days after the last dose of 
study drug if the subject discontinues the study prior to Month 6.   
c 
Subject begins taking study medication in the clinic as soon as baseline procedures are completed, and eligibility 
confirmed. Date of first dose is noted as Day 1.  
d 
Where assent is in accordance with local laws, regulations and ethics committee policy. 
e 
Vitals and ECG will be measured in triplicate at Baseline and as single values at all other times. An average of 
the three measurements for ECG and blood pressure will be used for eligibility determination. 
f 
ECG at Screening visit repeated if QTc > 470 msec. 
g 
Neuropsychological assessments are not to be performed with fasted participant; ensure participant has been fed 
and meets blood glucose measurement requirements prior to any neuropsychological assessments. 
h 
Neuropsychological assessments are performed at the Early Termination Visit only when the visit is within 30 
days of the last dose of study drug. 


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42 
i 
C-SSRS is administered to subject jointly with caregiver. 
j 
Blood Chemistry sample is collected in a fasted state (8-hour fast). 
k 
Provide a low carbohydrate/high protein meal or snack after fasting blood samples are drawn and before any 
neuropsychological assessments are performed.  
l 
Blood glucose measurement is an in-office point of care measurement after an appropriate period following the 
meal/snack, and prior to neuropsychological assessments are performed.  
m CT scan may be utilized for subjects with contraindication to MRI. MRI or CT should be done at least 14 days 
prior to the baseline visit to allow time for MRI report to support eligibility decision. 
 
 


ADAS‐Cog14
A‐IADL
CDR‐Sb
MMSE
GST and 
Cognitive
Composites
Post‐hoc Analyses
(p‐value reported as nominal)
Prove Proof of 
Concept Non‐
regulatory 
Endpoint
Significant Finding (p<0.05)
Non‐Significant 
Finding (p>0.05)
Figure 1. Statistical Hypothesis Schematic
FAQ
Success: 
Positive 
for 
Functional 
/ global
Endpoint 
Positive 
Study
Success: 
Positive 
for 
Functional
Success: 
Positive 
for 
Cognition