Clinical trial NCT05074498
Conditions: Alzheimer's Disease
Keywords: TB006 pharmacokinetics pharmacodynamics immunogenicity mild to severe Alzheimer's Disease
Sponsor: TrueBinding, Inc.
Start date: 2021-10-08; Completion date: 2022-10-13
Enrollment: 154 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Part 1 of this study will be conducted to determine the safety, tolerability, and pharmacokinetic (PK) profile of multiple doses of TB006, as well as the maximum tolerated dose of TB006, and to assess the immunogenicity of TB006 (production of anti-TB006 antibody). Part 2 of this study will be conducted to determine the clinical efficacy of TB006 in participants with mild to severe Alzheimer's Disease.

Detailed description:

Arms: arm 1: Participants will be randomized to 1 of 3 ascending dose groups to receive a total of 5 once-weekly doses of TB006, infused over 1 hour. arm 2: Participants will be randomized to receive 5 once-weekly doses of matching placebo. arm 3: Participants will receive the highest safe and well-tolerated dose identified in Part 1, infused over 1 hour. Randomization will be stratified according to severity at Baseline (mild versus moderate Alzheimer's Disease). arm 4: Participants will be randomized to receive matching placebo. Randomization will be stratified according to severity at Baseline (mild versus moderate Alzheimer's Disease).
Interventions: intervention 1: TB006 intervention 2: Placebo
Intervention descriptions: intervention 1: intravenous infusion intervention 2: intravenous infusion

Protocol documents:
SAP_002.pdf: 
Statistical Analysis Plan: TB006AD2102 
Study Title: 
A Seamless Phase 1b/2a Double-blind, Randomized, Multiple 
dose, Multi-center, Sequential Dose-escalation Study to Assess 
the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics 
and Efficacy of TB006 in Patients with Mild to Severe 
Alzheimer’s Disease 
Study Number: 
TB006AD2102 
Study Phase:  
Phase 1b/2a 
Sponsor: 
TrueBinding, Inc. 
300 Lincoln Center Drive 
Suite 200 
Foster City, CA 
94404 
Version:  
Final 2.0 
NCT Number: 
NCT05074498 
Date: 
11Apr2022 
Confidentiality Statement 
This document contains confidential and proprietary information, and is not to be distributed 
to any third party. 


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1. TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS .........................................................................................................2 
LIST OF TABLES ...........................................................................................................................4 
LIST OF FIGURES .........................................................................................................................4 
LIST OF APPENDICES ..................................................................................................................4 
2. 
SIGNATURE PAGE ................................................................................................................5 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...........................................6 
4. 
INTRODUCTION ..................................................................................................................10 
5. 
TRIAL OBJECTIVES ............................................................................................................10 
5.1. 
Primary Objectives.............................................................................................................10 
5.2. 
Secondary Objectives.........................................................................................................10 
 
 
6. 
STUDY DESIGN CONSIDERATIONS ................................................................................11 
6.1. 
Study Design ......................................................................................................................11 
6.1.1. Justification of Sample Size ...............................................................................................14 
6.2. 
Efficacy Endpoints .............................................................................................................14 
6.3. 
Safety Endpoints ................................................................................................................14 
6.4. 
Pharmacokinetic Endpoints ...............................................................................................15 
6.5. 
Pharmacodynamic Endpoints .............................................................................................16 
6.6. 
Other Drug Related Endpoints ...........................................................................................16 
7. 
STUDY POPULATIONS .......................................................................................................16 
7.1. 
Analysis Populations ..........................................................................................................16 
7.1.1. Full Analysis Set (FAS) .....................................................................................................16 
7.1.2. Safety Analysis Set (SAS) .................................................................................................16 
7.1.3. Pharmacokinetic Analysis Set (PKS).................................................................................16 
7.1.4. Pharmacodynamic Analysis Set (PDS) ..............................................................................16 
7.1.5. Efficacy Analysis Set – Part 2 (EAS2) ..............................................................................17 
7.2. 
Subgroups ..........................................................................................................................17 
8. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL .........17 
9. 
OVERALL STATISTICAL CONSIDERATIONS ................................................................17 
9.1. 
General Conventions ..........................................................................................................17 
9.2. 
Baseline definition .............................................................................................................18 
9.3. 
Handling of PK Concentration Values Below Lower Limit of Quantification .................18 
9.4. 
Handling of Missing Data ..................................................................................................19 
9.4.1. Partial Dates .......................................................................................................................19 
9.4.2. Missing Value Imputation for Efficacy Endpoints – Part 2 ...............................................20 
9.5. 
MMRM Method .................................................................................................................20 
9.6. 
Seriousness, Relationship and Severity of AEs .................................................................20 


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9.7. 
Visit Windows/Unscheduled Visits ...................................................................................21 
10. STATISTICAL ANALYSIS METHODS ..............................................................................21 
10.1. Subject Disposition ............................................................................................................21 
10.2. Demographics and Baseline Characteristics ......................................................................22 
10.3. Medical History And Viral Serology .................................................................................23 
10.4. Prior and Concomitant Medications and Procedures .........................................................23 
10.5. Pharmacokinetics ...............................................................................................................24 
10.6. Pharmacodynamics ............................................................................................................26 
10.7. Treatment Compliance and Exposure ................................................................................26 
11. EFFICACY PARAMETERS ..................................................................................................27 
11.1. Primary Analysis ................................................................................................................27 
11.2. Secondary Analysis ............................................................................................................27 
11.2.1. Change from Baseline at Day 36 on the Clinical Dementia Rating Scale – Sum of 
Boxes Total Score ............................................................................................................27 
11.2.2. Responder on the Clinical Dementia Rating Scale at Days 36 and 104 ............................27 
11.2.3. Change from baseline Cognitive Drug Research System Battery at Days 36 and 
104 ...................................................................................................................................28 
11.2.4. Change from baseline MMSE total score at Days 36 and 104 ..........................................28 
11.2.5. Change from baseline NPI total score at Days 36 and 104 ................................................28 
11.3. Sensitivity Analysis ...........................................................................................................28 
 
11.4.1. Change From Baseline Through End of Study – Cognition Parameters ...........................28 
11.5. Interim Analysis .................................................................................................................29 
11.6. Subgroup Analyses ............................................................................................................29 
12. SAFETY AND TOLERABILITY ..........................................................................................30 
12.1. Adverse Events ..................................................................................................................30 
12.2. Laboratory Results .............................................................................................................31 
12.3. Electrocardiogram (12-Lead) .............................................................................................33 
12.4. Vital Signs ..........................................................................................................................35 
12.5. Columbia Suicide Severity Rating Scale ...........................................................................35 
13. OTHER RELEVANT DATA ANALYSES/SUMMARIES ..................................................36 
13.1. Hospitalizations and Clinical Unit Confinement ...............................................................36 
13.2. Physical and Neurological Examinations ..........................................................................36 


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13.3. Immunogenicity analysis ...................................................................................................37 
14. REFERENCES .......................................................................................................................37 
15. APPENDICES ........................................................................................................................38 
 
LIST OF TABLES 
Table 1. 
Handling of Partial Dates .......................................................................................19 
Table 2.  
CTCAE Grades ......................................................................................................31 
Table 3.  
ECG Measurements ...............................................................................................34 
Table 4.  
Vital Sign Tests Performed ....................................................................................35 
 
LIST OF FIGURES 
Figure 1 
Study Design and Treatment Schema for Part 1 and Part 2 ...................................12 
Figure 2. 
Study Design and Treatment Schema – Interleave with Study TB006HV1101 ....13 
 
LIST OF APPENDICES 
Appendix I: 
Schedule of Assessments and Procedures..............................................................38 
Appendix II: Summary of Efficacy Analyses .............................................................................47 
Appendix III: Summary of Laboratory Assays Performed ...........................................................48 
Appendix IV: Potentially Clinically Important Values.................................................................50 
 
 
 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
2. SIGNATURE PAGE 
lb TrueBinding 
11Apr2022 
Study Title: 
A Seamless Phase I b/2a Double-blind, Randomized, Multiple 
dose, Multi-center, Sequential Dose-escalation Study to Assess 
the Safety, Tolerability, Phaimacokinetics, Pha1macodynamics 
and Efficacy of TB006 in Patients with Mild to Severe 
Alzheimer's Disease 
Stud Number: 
TB006AD2 l 02 
Prepai·ed by: 
DocuSigned by: 
{J 
Signer Name: 
L
Signing Reason: I am the author of this document 
Signing Time: 12-Apr-2022 I 03:33:33 EDT 
053E504EECB249B9B7E731AE1A775A71 
PhD 
Principal Biostatistician, Biostatistics 
MMS Holdings 
liiiiy: 
{J 
Signer Name: - -
L
Signing Reason: I have reviewed this document 
Signing Time: 12-Apr-2022 I 03:48:33 EDT 
R 
· 
db 
CAD557FFFDB24E87ADA80676AEB4ABC2 
ev1ewe 
y: 
MCom 
Senior Biostatistician II, Biostatistics 
MMS Holdings 
liiii: 
{J 
Signer Name:- -
L
Signing Reason: I approve this document 
Signing Time: 12-Apr-2022 110:07:35 PDT 
A 
db 
A3EA3B5AE6694A04A3393E173E8742D8 
pprove 
y: 
Confidential 
PhaimD 
Clinical Development Lead 
TrneBinding, Inc. 
Date: ----------
Date: ________ _ 
Date: ----------
Page 5 of 50 


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3. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACR 
Assessment/Collection/Result 
AD 
Alzheimer’s Disease 
ADA 
Anti-Drug Antibody 
ADL 
Activities of Daily Living 
AE 
Adverse Events 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
Anti-HBc 
IgM Hepatitis B Core Antibody 
Anti-HCV 
Hepatitis C Antibody 
ApoE4 
Apolipoprotein E4 
AR(1) 
Auto-regressive 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC0–6 
Area under the concentration time curve from time zero to the 6-hour 
post end of infusion timepoint 
AUC0–last 
Area Under the Concentration-Time Curve from Zero Time to the Last 
Measurable Time Point 
AUCtau 
Area Under the Concentration-Time Curve over a Dosing Interval 
  
 
BLQ 
Below the Lower Limit of Quantification 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CDER 
Center for Drug Evaluation and Research 
CDR 
Cognitive Drug Research 
CDRS 
Clinical Dementia Rating Scale 
CFB 
Change from Baseline 
CI 
Confidence Interval 
CL 
Total Clearance 
cm 
Centimeter 
Cmax 
Maximum Observed Plasma Concentration 


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CMH 
Cochran Mantel-Haenszel 
COVID 
Coronavirus Disease 
CPK 
Creatine Phosphokinase 
CSF 
Cerebrospinal Fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Concentration at the End of a Dosing Interval 
D 
Day 
DBP 
Diastolic Blood Pressure 
DSM 5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
E/D 
Early Discontinuation  
EAS2 
Part 2 – Efficacy Analysis Set 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Forms 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating Hormone 
 
 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B Surface Antigen 
hCG 
Human Chorionic-Gonatropin 
HDL 
High-Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
IgM anti HBc 
Immunoglobulin M Antibody to Hepatitis B Core Antibody 
IV 
Intravenously 
Kg 
Kilogram 
KR 
Kenward-Roger 
LDL 
Low-Density Lipoprotein 
LS 
Least Square 


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MAD 
Multiple Ascending Dose 
MAR 
Missing at random 
MCH 
Mean Corpuscular Hemoglobin 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
MMSE 
Mini-Mental State Examination 
 
 
NCA 
Non-Compartmental Analysis 
 
 
 
 
NINCDS-ADRDA 
National Institute of Neurological and Communicative Disorders and 
Stroke – Alzheimer’s Disease and Related Disorders Association 
NPI 
Neuropsychiatric Inventory 
PCI 
Potentially Clinically Important 
PCS 
Potentially Clinically Significant 
PD 
Pharmacodynamics 
PDS 
Pharmacodynamic Analysis Set 
 
 
PK 
Pharmacokinetic 
PKS 
Pharmacokinetic Analysis Set 
PT 
Preferred Term 
QTcB 
QT Corrected Interval Using Bazett equation 
QTcF 
QT Corrected Interval Using Fridericia's  Formula 
qw 
Weekly 
RBC 
Red Blood Cell  
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 


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SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
t½ 
Terminal Elimination Phase Half Life 
TBL 
Total Bilirubin 
TEAE 
Treatment-Emergent Adverse Event 
tmax 
Time at Which Maximum Plasma Concentration Occurs 
TOEPH 
Heterogeneous Toeplitz  
TSH 
Thyroid-Stimulating Hormone 
ULN 
Upper Limit of Normal 
UN 
Unstructured 
Vz 
Volume of Distribution 
WHO DD 
World Health Organization-Drug Dictionary 
 
 


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4. INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the framework for the reporting, 
summarization and statistical analysis methodology of the safety, tolerability, pharmacokinetic 
(PK), pharmacodynamics (PD) and efficacy endpoints measured throughout the study. It is based 
on Protocol TB006AD2102 Amendment 2.0 dated 15 October 2021. 
 
5. TRIAL OBJECTIVES 
5.1. PRIMARY OBJECTIVES 
The study is planned to conduct in two different parts, and primary objectives for Part 1 are as 
listed: 
x To determine the safety and tolerability of multiple doses of TB006 
x To determine the PK profile of multiple doses of TB006 
x To determine the maximum tolerated dose of multiple doses of TB006 
x To assess the immunogenicity of TB006 (production of anti-TB006 antibody) 
The primary objective for Part 2 is as follows: 
x To determine the clinical efficacy of TB006 in patients with mild to severe 
Alzheimer’s disease (AD) 
5.2. SECONDARY OBJECTIVES 
There is no secondary objective planned for Part 1 of the study.  
The following are the secondary objectives for the Part 2 of the study: 
x To determine the clinical efficacy of TB006 in patients with mild to severe AD 
x To determine the safety and tolerability of multiple doses of TB006 
x To determine the PK following multiple doses of TB006 
 
 


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6. STUDY DESIGN CONSIDERATIONS 
6.1. STUDY DESIGN 
This is a seamless, two-part Phase 1b/Phase 2a, multi-center, randomized, double-blind, placebo-
controlled study. Part 1 is a multiple ascending dose (MAD) escalation study to evaluate the 
safety, tolerability, PK, PD, and efficacy of TB006 in patients with AD. Part 2 is a multi-center, 
randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy of 
TB006 after 1 month of treatment. The total study duration for each patient will be up to 
approximately 19 weeks. 
Patients will receive a total of 5 doses, given in qw intervals. In Part 1, the planned starting dose 
in Group 1 will be 140 mg qw for 5 weeks. Subsequent planned doses are 420 and 1,000 mg qw 
for Groups 2 and 3, respectively. The planned dose in Part 2 will be the highest safe and well-
tolerated dose from Part 1. All doses are infused IV over 1 hour. Part 1 will interleave with the 
single ascending dose (SAD) study (Study TB006HV1101). Each group in Part 1 will commence 
after the safety, tolerability, and PK of the single dose equivalent to the combined total of 5 qw 
doses planned in this study has been established. Explicitly, dosing in Group 1 (140 mg qw) will 
commence when the safety and tolerability of the 700 mg single dose in the SAD study has been 
established. Groups 2 (420 mg qw) and 3 (1000 mg qw) will begin after a review of the available 
safety, tolerability, and PK data from the previous group; and after the 2,100 and 5,000 mg single 
dose, respectively, has been administered. Dose levels may be adjusted depending on the safety, 
tolerability, and available PK of doses in the SAD study and previous groups in this study. 
Patients will be enrolled across all active centers into each dose group sequentially. 
In Part 1, 8 patients will be enrolled into each dose group; 6 patients in each group will be 
randomized to active TB006 treatment, and 2 patients to placebo. 
Dose escalation decisions will use safety, tolerability, and available PK data through the first 
dose administered to the last patient in each group and a minimum of 14 days from the respective 
dose group that has been dosed in the SAD study (Protocol number TB006HV1101). Data will 
be reviewed by a blinded Safety Review Committee (SRC). 
Part 2 will commence after the last patient in Part 1 has received their first dose. The planned 
dose in Part 2 will be 1,000 mg qw × 5 doses, but may be adjusted depending on the safety and 
tolerability of the doses in Part 1. Patients will be randomized to active TB006 or placebo (1:1) 
and will follow the same dosing schedule and procedures (with some exceptions – see Part 2 
schedule of assessment) as in Part 1. Randomization in Part 2 will be stratified according to 
baseline patient severity, with mild AD patients [Mini-Mental State Examination (MMSE) 21-
24] and moderate-severe AD patients (MMSE ≤ 20) in each stratum. 
This is an outpatient study. Patients will return to the clinic for screening and baseline 
procedures, on dosing days, and on follow-up visits. Patients will have the option of checking 
into the clinic and staying overnight on Day -2 or Day -1, as well as on days prior to the other 
dosing days. 
Assessments for safety and tolerability, efficacy, PK, and PD are performed throughout the 
study. If a patient reports any adverse events (AEs), they may be required to return to the clinical 


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unit at the discretion of the investigator for additional assessments. All AEs must be followed to 
adequate resolution. 
Figure 1 
Study Design and Treatment Schema for Part 1 and Part 2 
 
* Study drug administration 
Note: Visit days and procedures will occur during a window of ± 2 days from Day 1 to End of Treatment. 
D = Day; IV = intravenously, qw = weekly. 
PART l 
(Groups 1 - 3) 
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Figure 2. 
Study Design and Treatment Schema – Interleave with Study TB006HV1101 
 
Dosing in Group 1 (140 mg TB006/placebo aww) will commence when the safety and tolerability of the 700 mg single dose in the SAD study has been established. Groups 2 
(420 mg TB006/placebo qw) and 3 (1,000 mg TB006/placebo qw) will begin after a review of the available safety, tolerability and PK data from the previous group; and after the 
2,100 and 5,000 mg, respectively, have been administered. 
* Study drug administration 
Note: Visit days and procedures will occur during a window of ± 2 days from Day 1 to End of Treatment 
D = Day; IV = intravenously; PK = pharmacokinetic; qw = weekly; SAD = single ascending dose. 
 
jTB006HVIIOl j 
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6.1.1. JUSTIFICATION OF SAMPLE SIZE 
In Part 1, patients will be recruited sequentially in separate increasing dose groups, with each 
group randomizing 6 patients to a specific dose of TB006 and 2 randomized to placebo. If all 3 
planned dose levels are investigated, the study will recruit approximately 24 patients in total (18 
receiving TB006 treatment at the different dose levels, and 6 receiving placebo). 
In Part 2, patients will be randomized to TB006 or placebo in a 1:1 ratio so that approximately 
58 patients will be randomized to each group. Randomization in Part 2 will be stratified 
according to baseline patient severity, with mild AD patients (MMSE 21-24) and moderate-
severe AD patients (MMSE ≤ 20) in each stratum. Patients enrolled at the same TB006 dose 
level in Part 1, as well as all placebo patients, will be included in the efficacy analyses in Part 2. 
Thus, the number of patients in each group for the primary efficacy analysis will be 
approximately 64. 
Assuming that the standard deviation (SD) of change from baseline (CFB) Clinical Dementia 
Rating Scale (CDRS) - Sum of Boxes at Day 104 is 0.5, a total of 128 patients will provide 80% 
power to detect a mean CFB difference of 0.25 at Day 104 using a 2-sided, 2 sample t-test at the 
5% level of significance. 
6.2. EFFICACY ENDPOINTS 
For Part 1, there is no efficacy endpoint planned for primary and secondary analysis, but 
following endpoints is planned for exploratory analysis: 
x CFB through end of study on the CDRS – Sum of Boxes total score 
x CFB through end of study on the Cognitive Drug Research (CDR) System Battery Score, 
composite scores, and individual task measures 
x CFB through end of study on the MMSE score 
x CFB through end of study on the Neuropsychiatric Inventory (NPI) score 
For Part 2, the planned primary efficacy endpoint is: 
x CFB through Day 104 on the CDRS – Sum of Boxes total score. 
And the associated secondary endpoints are as under: 
x CFB through Day 36 on the CDRS – Sum of Boxes total score 
x Proportion of responders on the CDRS – Sum of Boxes at Days 36 and 104 
x CFB to Days 36 and 104 on the CDR System Battery, composite scores, and individual 
task measures 
x CFB to Days 36 and 104 on the MMSE score 
x CFB to Days 36 and 104 on the NPI score 
6.3. SAFETY ENDPOINTS 
The safety endpoints for Part 1 and Part 2 of the study will be recorded and reported throughout 
the safety reporting period. The safety reporting period is from Day 1 (start of TB006 infusion) 
through Day 104. Safety endpoints for both protocol parts of this study include: 
x Incidence of AEs and serious adverse events (SAEs)  


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x Clinical Safety Laboratory Assessments  
x Vital Signs  
x Electrocardiograms  
x Suicidal Ideation and Behavior Risk Monitoring 
x Physical and Neurological Examinations 
The safety endpoints listed above will be reported as primary endpoints for Part 1 of the study 
and as secondary endpoints for Part 2 of the study. 
6.4. PHARMACOKINETIC ENDPOINTS 
The PK analysis will be performed using PK parameters derived by non-compartmental analysis 
(NCA) using the TB006 plasma concentration time data. The PK parameters will be estimated 
using actual sampling time relative to the start of infusion. 
For Part 1 of the study, the PK analysis will be performed as primary endpoint and includes, but 
not limited to: 
x 
Area under the concentration time curve from time zero to the 6-hour post end of infusion 
timepoint (AUC0-6) (Days 1, 8, and 29) 
x Area under the concentration time curve over a dosing interval (AUCtau) (Days 1 and 29) 
x Area under the concentration-time curve from zero time to the last measurable time point 
(AUC0 –last) (Day 29) 
x Maximum observed plasma concentration (Cmax) (Days 1, 8, and 29) 
x Time at which maximum plasma concentration occurs (tmax) (Days 1, 8, and 29) 
x Concentration at the end of a dosing interval (Ctrough) (Days 8, 15, 22, 29, and 36) 
x Terminal elimination phase half-life (t½) (Day 29 only) 
x Total clearance (CL), calculated as dose/AUCtau. (Day 29 only) 
x Volume of distribution (Vz), calculated as dose/kel × AUCtau, where kel is the apparent 
elimination rate-constant, computed by log linear regression of the terminal log linear 
segment of the plasma concentration versus time curve (Day 29 only). 
The extent of CSF distribution as estimated by TB006 CSF concentrations on Day 36 will also 
be determined. 
For Part 2 of the study, the PK analysis will be performed as secondary endpoint and will 
include: 
x Maximum observed plasma concentration (Cmax) (Days 1, 8, and 29) 
x 
Concentration at the end of a dosing interval (Ctrough) (Days 29 and 36) 
x Area under the concentration-time curve from zero time to the last measurable time point 
(AUC0 –last) (Day 29) 
x 
Terminal elimination phase half-life (t½) (Day 29 only) 
Note that no CSF will be collected in Part 2 of the study. 


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6.5. PHARMACODYNAMIC ENDPOINTS 
6.6. OTHER DRUG RELATED ENDPOINTS 
Apart from above analysis, following other drug related assessment will also be performed for 
Part 1, secondary analysis, of the study. 
x Assessment of maximum tolerable dose 
x Detection of anti-TB006 antibodies (from PK plasma sampling) 
 
7. STUDY POPULATIONS 
7.1. ANALYSIS POPULATIONS 
7.1.1. FULL ANALYSIS SET (FAS) 
The Full Analysis Set (FAS) includes all subjects who are randomized to study drug. The FAS 
will be used for the analysis of disposition and protocol deviations. 
7.1.2. SAFETY ANALYSIS SET (SAS) 
The Safety Analysis Set (SAS) includes all subjects in the FAS who received at least one dose of 
study drug. Subjects in this analysis set will be analyzed according to the study drug they 
actually received. The FAS and the SAS will be the same if all randomized patients are dosed 
with study drug. The SAS will be used for all analyses, except for disposition, protocol 
deviations, PK and PD.  
7.1.3. PHARMACOKINETIC ANALYSIS SET (PKS) 
The Pharmacokinetic Analysis Set (PKS) includes all subjects who received assigned dose of 
TB006 and have at least one post-dose blood sample with measurable TB006 concentrations. 
The PKS will be used for all PK analyses. 
7.1.4. PHARMACODYNAMIC ANALYSIS SET (PDS) 
The Pharmacodynamic Analysis Set (PDS) includes all subjects who received assigned dose of 
TB006 or placebo and have at least one post-dose evaluable PD assessment. The PDS will be 
used for all PD and efficacy analyses. 


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7.1.5. EFFICACY ANALYSIS SET – PART 2 (EAS2) 
The Part 2 – Efficacy Analysis Set (EAS2) includes all subjects who received assigned dose of 
TB006 in Part 2 and the subjects enrolled at the same TB006 dose level in Part 1, as well as all 
placebo patients will be included and have at least one post-dose evaluable PD assessment across 
subject. The EAS2 will be used for all efficacy analysis planned for Part 2 of the study. 
7.2. SUBGROUPS 
The dispositions, efficacy, PK/PD, biomarker, and immunogenicity analysis for Part 2 will be 
presented for overall and baseline patient severity: mild AD patients (MMSE 21-24) and 
moderate-severe AD patients (MMSE ≤ 20). 
 
8. CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL 
The following analyses described in this SAP are not mentioned in the study protocol: 
x Assessment of dose proportionality (see Section 10.5: Pharmacokinetics). 
 
9. OVERALL STATISTICAL CONSIDERATIONS 
9.1. GENERAL CONVENTIONS 
Summary statistics will be presented for categorical data as number and percentage [n (%)] 
where the percentage is displayed to one decimal point (e.g., 98.1). 
Descriptive statistics will be presented for continuous data with applicable decimal precision as 
follows in relation to the source data (indicated as N), with a maximum of three decimals to be 
displayed: 
x Number (n). 
x Mean, (N+1). 
x SD, (N+2). 
x Median, (N+1). 
x Minimum, (N+0). 
x Maximum, (N+0). 


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Study day is calculated relative to the first dose of study drug infusion and will thus in most 
cases coincide with the visit naming (e.g., Day 1 will be on study day = 1, Day 15 will be on 
study day = 15 etc.) 
x If the current assessment/collection/result (ACR) date is on or after first dose of study 
drug infusion: 
Study Day = (Current ACR Date – First dose of Study Drug infusion Date) + 1 
x If the current ACR date is before first dose of study drug infusion: 
Study Day = (Current ACR Date – First dose of Study Drug Infusion Date) 
Study day will not be calculated if either the current ACR or the first dose of study drug infusion 
date is incomplete or missing. 
All the tables in Part 1, will be displayed by treatment groups (i.e., TB006 140 mg qw, TB006 
420 mg qw, TB006 1000 mg qw, and Pooled placebo).  
The dispositions, efficacy, PK/PD, biomarker, and immunogenicity analysis for Part 2 will be 
classified by treatment groups (i.e., TB006 and Placebo) and baseline AD severity stratifications 
[i.e. mild AD (MMSE 21-24) and moderate-severe AD (MMSE ≤ 20)]. For efficacy tables of 
Part 2, the subjects enrolled at the same TB006 dose level in Part 1, as well as all placebo 
patients will be included.  
For all baseline, safety and efficacy assessments, the subjects will be tabulated using the actually 
received treatment. For example, if there is a subject who is planned to receive TB006 but 
accidentally gets treated with one of the other regimens, the subject will be tabulated under the 
other regimen actually received.  
The tables and listing for both protocol parts will be presented separately. The detailed layout 
will be presented in mock shell. 
9.2. BASELINE DEFINITION 
Baseline is defined as the last available value prior to the subject receiving first dose of study 
drug infusion (i.e., Day 1). If the potential Baseline ACR is on Day 1 (and time is not recorded), 
it is assumed that the ACR occurred before the start of first dose of study drug infusion. 
CFB is calculated as: 
 
CFB = Observed value – Baseline Value 
Percentage change from Baseline (CFB%) is calculated as: 
 
CFB% = (CFB ÷ Baseline Value) × 100 
9.3. HANDLING OF PK CONCENTRATION VALUES BELOW LOWER LIMIT OF QUANTIFICATION 
For PK concentrations, values that are below the lower limit of quantification (BLQ) the 
following handling measures will be applied: 


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• 
For NCA, pre-dose concentrations prior to the first dose of TB006 that are BLQ will be 
set to zero. Post-dose concentrations that are BLQ and occur before the first quantifiable 
concentration will also be treated as zero. Post-dose concentrations that are BLQ but 
occur after the first quantifiable concentration will be treated as missing. 
• 
For summaiy statistics, BLQ concentrations will be treated as zero. 
• 
fu listing presentation these values will be mai·ked/footnoted as being BLQ. 
9.4. HANDLING OF MISSING DATA 
No fo1mal imputation of missing data is planned for Pait I of the study. There are however a few 
handling conventions and asslllllptions applicable to pa1iial/missing data points which ai·e 
described in the following subsections. 
9.4.1. PARTIAL DATES 
Although pa1iial dates will not be 'filled up' in this study, some asslllllptions will be made in 
regai·ds paiiial dates for background calculation/classification purposes as appropriate (for AEs, 
prior/concomitant medications etc.) 
Table 1. 
Handling of Partial Dates 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date 
D 
M and Y same as M and Y of first dose 
Date of first dose of study drug 
ofstudydmg 
M and/or Y not same as date of first 
First day of month 
dose of study drug 
D andM 
Y same as Y of first dose of study chug 
Date of first dose of study drug 
Y prior to Y of first dose of study drug 
Date of screening date 
but same as Y of screening date 
D, MandY 
None - date completely missing 
Date of first dose of study drug 
Stop date 
D 
M and Y same as M and Y of last dose 
Date of last dose of study chug 
of study chug 
M and/or Y not same as date of last 
Use last day of month 
dose of studv drug 
D andM 
Y same as Y oflast dose of study chug 
Date of last dose of study chug 
Y not same as Y of last dose of study 
Dec31 
drug 
D, M andY 
None - date completely missing 
No imputation, but assume ongoing 
D = day, M = month, Y = year 
Note: In all cases, if an estimated sta1t date is after a complete stop date, use the first day of the stop date month. 
Similarly, if the estimated stop date is before a complete or imputed sta1t date, use the last day of the strut 
day month. 
In all cases, if it cannot be determined if the AB/medication occmred prior to or after the first dose of study 
chug infusion, the AE should be defined as treatment emergent, and medication will be considered as 
concomitant medication. 
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9.4.2. MISSING VALUE IMPUTATION FOR EFFICACY ENDPOINTS – PART 2 
Apart from handling conventions and assumptions applicable to partial/missing data points 
mentioned above, there will be additional imputation for missing efficacy assessments listed 
under: 
x CDRS – Sum of Boxes total score 
x MMSE score  
x NPI score 
For these imputations, the missingness will be considered as missing at random (MAR). There 
will be no imputation for individual missing values, but missing data will be imputed implicitly 
using Mixed Model Repeated Measures (MMRM).  
The MMRM analysis will be performed for above listed efficacy endpoints as described in 
Section 9.5.  
9.5. MMRM METHOD 
The primary and secondary efficacy endpoints associated with efficacy assessments listed in 
Section 9.4.2 will be analyzed using a MMRM model. The model will include treatment group, 
visit, stratification factor (MMSE ≤ 20 and 21-24), and treatment by visit as fixed effects and 
associated baseline assessment as covariate. The model will use visit as repeated component in 
the model. 
An unstructured (UN) covariance structure will be applied for the MMRM. In the event the UN 
covariance matrix results in non-convergence of the model, then the Heterogeneous Toeplitz 
(TOEPH) and auto regressive [i.e. AR(1)] covariance structures will be used, respectively, with 
separate subject random effect. The Kenward-Roger (KR) approximation will be used to 
estimate denominator degrees of freedom. 
The least square (LS) mean for CFB and associated 95% confidence interval (CI), and standard 
error will be presented for each treatment group. 
The MMRM model will utilize all available data values for respective efficacy assessments. 
9.6. SERIOUSNESS, RELATIONSHIP AND SEVERITY OF AES 
Missing seriousness, severity and relationship of AEs that have been queried and remain missing 
after such, will be treated ‘worst case’ for presentation filtering purposes as follows: 
x Missing seriousness: Will be considered as serious and included in the SAE displays. 
x Missing relationship: Will be considered as related and included in the related AE 
displays. 
x Missing severity: 
o If subject has died, will be considered as Grade 5 severity across all associated 
displays. 


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o If subject has not died but subject had intervention indicated for the AE, will be 
considered as Grade 4 severity across all associated displays. 
o If none of the previous conditions are met, will be considered as Grade 3 severity 
across all associated displays. 
9.7. VISIT WINDOWS/UNSCHEDULED VISITS 
No mapping/renaming of visits (unscheduled or otherwise) will be done for this study. That is, 
only regular scheduled visit data will be used for summarization in tables. However, all collected 
data will be listed. 
Unscheduled visits will be considered eligible for Baseline values. Unscheduled visit results will 
also be considered eligible for testing of potentially clinically significant (PCS) values 
(laboratory, Electrocardiogram (ECG) and vital signs). 
 
10. STATISTICAL ANALYSIS METHODS 
10.1. SUBJECT DISPOSITION 
The following disposition related items are planned to be listed using the protocol part and 
analysis set indicated in parentheses: 
x Screening failures (Part 1 – All subjects) 
x Screening failures (Part 2 – All subjects) 
x Randomized subjects (Part 1 – FAS) 
x Randomized subjects (Part 2 – FAS) 
x Unblinded subjects, if any (Part 1 – FAS) 
x Unblinded subjects, if any (Part 2 – FAS) 
x Inclusion/Exclusion violations (Part 1 – FAS) 
x Inclusion/Exclusion violations (Part 2 – FAS) 
x Subject completion/discontinuation information (Part 1 – FAS) 
x Subject completion/discontinuation information (Part 2 – FAS) 
x Subject analysis set inclusions (Part 1 – FAS) 
x Subject analysis set inclusions (Part 2 – FAS) 
x Subject deviations (Part 1 – FAS) 
x Subject deviations (Part 2 – FAS) 
The following disposition related items are planned to be tabulated using summary and 
descriptive statistics as applicable, by treatment groups and baseline AD severity stratifications 
(for Part 2 only), using the protocol part and analysis set indicated in parentheses: 


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x Subject completion/discontinuation information (Part 1 – All subjects). Including 
breakdown by reason for subject discontinuation. 
x Subject completion/discontinuation information (Part 2 – All subjects). Including 
breakdown by reason for subject discontinuation. 
x Subject analysis set inclusions (Part 1 – All subjects). Including reason for exclusion 
from analysis set, if required. 
x Subject analysis set inclusions (Part 2 – All subjects). Including reason for exclusion 
from analysis set, if required. 
x Subject deviations (Part 1 – FAS). 
x Subject deviations (Part 2 – FAS). 
The data for these presentations are obtained from the following electronic Case Report Forms 
(eCRFs): 
x Informed Consent 
x Screen Failure 
x Inclusion Exclusion Criteria 
x Randomization 
x End of Study 
10.2. DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
The following demographics and baseline characteristic items will be listed using SAS for both 
protocol parts: 
x Subject demographics: 
o Age 
o Sex 
o Race 
o Ethnicity 
x Baseline vital characteristics: 
o Height (cm) 
o Weight (kg) 
o BMI (kg/m2) 
x Substance usage, including checking for: 
o Tobacco/nicotine use 
o Alcohol use 
o Drug use 


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The above demographic, baseline characteristics and substance use items are planned to be 
tabulated using summary and descriptive statistics as applicable, by treatment groups for SAS. 
The data for these presentations will be obtained from the following eCRFs: 
x Demography 
x Physical Examination (for baseline height/weight) 
x 
Medical History (for substance usage medical history) 
x 
Drug and Alcohol Screening 
The following items will be derived: 
x Body mass index (BMI) at Baseline: 
Baseline BMI = Baseline weight (kg) ÷ [Baseline height (m)]2 
10.3. MEDICAL HISTORY AND VIRAL SEROLOGY 
The medical history terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 22.1, Sep 2019. 
The following medical history and viral serology baseline characteristic items will be listed using 
SAS for both protocol parts: 
x Medical history: 
o Medical conditions or allergies reported 
x Viral serology 
o HBsAg 
o IgM anti HBc 
o anti HCV 
o HIV 
x COVID-19 status 
The above medical history is planned to be tabulated using summary statistics, by treatment 
groups using SAS. 
The data for these presentations will be obtained from the following eCRFs and external data: 
x Medical History 
x Viral Serology 
x Laboratory Data 
10.4. PRIOR AND CONCOMITANT MEDICATIONS AND PROCEDURES 
A prior medication or procedure is defined as having started and ended prior to first dose of 
study drug infusion. Conversely, a concomitant medication or procedure is defined as either 
having started prior to first dose of study drug infusion and ended on/after first dose of study 


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drug infusion, is ongoing at Baseline or, having started on/after first dose of study drug infusion. 
Medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
Global Sep 2019 B3/C3 format. 
Listings of prior and concomitant medications/procedures will be presented for both protocol 
parts as recorded in the eCRF (SAS). 
Summary tables by WHO-DD Anatomical Therapeutic Chemical (ATC) level 3 and preferred 
name will be presented, by treatment groups on the following items: 
x Prior medications/procedures (Part 1 – SAS). 
x Prior medications/procedures (Part 2 – SAS). 
x Concomitant medications/procedures (Part 1 – SAS) 
x Concomitant medications/procedures (Part 2 – SAS) 
The data for these presentations will be obtained from the Concomitant Medications Details 
eCRF. 
The Prior/Concomitant status will be derived using the medication start and stop dates as per 
definition provided at the start of this section. For partial dates see Section 9.4.1. 
10.5. PHARMACOKINETICS 
The following PK listings are planned for presentation (PKS) for both protocol parts: 
x TB006 plasma concentration levels 
x TB006 CSF concentration level (Part 1 only)  
x Pharmacokinetic parameters of plasma TB006 
x Dose-normalized plasma exposure PK parameters (AUCs and Cmax) – (Part 1 only). 
The following descriptive summary tables are planned to be presented for subjects who received 
TB006 (PKS), by treatment groups and baseline AD severity stratifications (for Part 2 only): 
x Plasma concentration of TB006 at each time points 
x CSF concentration of TB006 at each time points (Part 1 only) 
x Plasma PK parameters 
x Dose-normalized exposure PK parameters (AUCs and Cmax) (Part 1 only, Days 1, 8, and 
29, as applicable) 
x Power model slope estimate for dose proportionality assessment (including 95% CI) (Part 
1 only) 
Figures of the following PK items are planned for presentation (PKS) for both protocol parts: 
x Overlaid individual plasma concentration versus time plots (linear and semi-logarithmic 
scale) by treatment groups 


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x Overlaid mean plasma concentration versus time plots, presented by treatment groups 
(linear scale with and without SD) 
x Overlaid mean plasma concentration versus time plots, presented by treatment groups 
(semi-logarithmic scale with and without SD) 
x Boxplots of dose-normalized PK parameters (AUCs and Cmax), grouped by treatment 
groups grouped within each figure (Part 1 only, Days 1, 8, and 29, as applicable) 
x Scatterplots of PK parameters (AUCs and Cmax), versus dose (as part of power model 
results), by treatment groups (Part 1 only, Days 1, 8 and 29, as applicable) 
Assessment of dose proportionality will be performed by PK Day (Day 1, 8, and 29, as 
applicable) and will not be based strictly on statistical rule criteria but rather, several factors will 
be taken into account when assessing dose proportionality, such as: 
x Power model results (e.g., the slope estimate and the width of the 95% CIs) 
x Graphical evaluation (box plots of dose normalized AUCs and Cmax) 
x Descriptive statistics by treatment groups of dose-normalized PK parameters 
Evaluations of the dose proportionality of these parameters will include using the Power Model 
if there will be at least 3 dose levels available. A statistical linear relationship between the ln-
transformed PK parameters and the ln-transformed dose will be fitted by using a mixed model 
with ln-transformed dose as a covariate and random effect for intercept and subject. Here, (ln-) 
stands for natural logarithm. Additional predictors may be included in the model. The general 
form of the Power Model is described as: 
Ln(Y) = β0 + β Ln(Dose) + ε 
Where, Y represents the PK parameter (AUCs and Cmax), and β0 is constant. This approach is 
usually referred to as a power model because after exponentiation: 
Y = α (Dose)β 
Note that β = 1 would correspond to perfect dose proportionality. 
The following example SAS® code can be utilized and modified as needed: 
Proc Mixed Data = <Dataset>; 
 Class <subjectnum> 
 Model <lnY> = <lnDose> / ddfm=kr; 
 Random <intercept> /  subject = <subjectnum>  type=UN; 
 Estimate ‘Logdose  - 1 unit’ <lndose> 1/cl  alpha=0.05; 
 ods output estimates = <estimate>; 
Run; 
Where <Dataset> is the input dataset, <subjectnum> is the subject number, <LnY> is Ln(Y) (Y 
being the PK parameter in question, <LnDose> is Ln(Dose), <intercept> is the intercept and 
<estimate> is the output dataset containing the estimate. 
The data for these presentations will be obtained from the external PK laboratory data and eCRF. 


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Descriptive summary tables of biomarker levels from both plasma and CSF (for Part 1 only) 
collection will be presented, by treatment groups and baseline AD severity stratifications (for 
Part 2 only), using PDS for both protocol parts, including CFB and CFB% through end of study. 
The relationship between dose, Day 29 plasma TB006 PK exposure parameters (AUCtau and 
Cmax), Day 36 CSF TB006 concentration and PD biomarkers listed in Section 10.6 will be 
assessed graphically. Scatter plots of CFB and CFB% will be presented next to another in grid 
format for PD endpoint values versus TB006 AUCtau and Cmax. The PD endpoints will be for 
timepoints Day 36 and end of study. The main measure of interest for consideration will be the 
CFB of PD biomarkers. 
The data for these presentations will be obtained from the external laboratory data and eCRF. 
10.7. TREATMENT COMPLIANCE AND EXPOSURE 
A listing of subject exposure to all the doses of TB006 will be presented including the date/time 
of dose and dose level exposed to (SAS) for both protocol parts separately. Also, the treatment 
compliance information will be listed. 
A table containing summary statistics of dose level exposure, by treatment groups will also be 
presented using SAS. 
Treatment compliance is defined as the number of IV doses (including partial doses, active and 
placebo) actually received divided by the number of doses expected (× 100) over the time period 
defined by the first infusion date and the last dose date. 
Descriptive statistics for treatment compliance and the number and percentage of subjects with at 
least 80% compliant will be presented using SAS. 
The data for these presentations will be obtained from the Study drug infusion eCRF. 
 


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11.  EFFICACY PARAMETERS 
All the efficacy analysis planned for Part 1 will be performed using PDS and efficacy analysis 
planned for Part 2 will be performed using EAS2. The EAS2 include all PDS subjects of Part 2, 
placebo subjects of Part 1 and subjects with same dose level in Part 1 pooled together. 
11.1. PRIMARY ANALYSIS 
There is no primary efficacy analysis planned for Part 1.  
For Part 2, the CFB through Day 104 on the CDRS – Sum of Boxes total score is primary 
efficacy endpoint, and it will be analyzed using MMRM with treatment group, randomization 
strata (MMSE ≤ 20 and 21-24), visit, and treatment group (treated vs. placebo) by visit 
interaction as fixed effects and a baseline CDRS - Sum of Boxes score as a covariate. The LS 
mean difference, the 95% CI of the difference, and the p-value will be presented as well as the 
descriptive statistics. 
11.2. SECONDARY ANALYSIS 
There is no secondary efficacy analysis planned for Part 1.  
For Part 2, the following secondary analysis are planned. 
11.2.1. 
CHANGE FROM BASELINE AT DAY 36 ON THE CLINICAL DEMENTIA RATING SCALE – 
SUM OF BOXES TOTAL SCORE 
The secondary efficacy endpoint, CFB at Day 36 on the CDRS – Sum of Boxes, and will be 
analyzed and reported as described for the primary analysis in Section 11.1. 
Also, the summary statistics will be tabulated for CDRS individual scores, sum of box total score 
and Global CDRS score by treatment groups and baseline AD severity stratifications. 
11.2.2. 
RESPONDER ON THE CLINICAL DEMENTIA RATING SCALE AT DAYS 36 AND 104 
A responder is defined as at least 1-point improvement from baseline on the Sum of Boxes score. 
The patients with missing data will be included in the denominator and treated as a non-
responder.  
The proportion of the responders between treatment groups will be tested using the Cochran 
Mantel-Haenszel (CMH) test, adjusting for randomization strata (MMSE ≤ 20 and 21-24) and 
the common risk difference and the 95% CI will be presented.  
Also, the number and percentages of responders over time will be tabulated by treatment groups 
and baseline AD severity stratifications. 
The CDRS individual scores, sum of box total score, Global CDRS score and responder status 
will be listed as well. 


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11.2.3. 
CHANGE FROM BASELINE COGNITIVE DRUG RESEARCH SYSTEM BATTERY AT DAYS 36 
AND 104 
This endpoint is analyzed separately, and detail of analysis is described in CDR system battery 
SAP [5]. 
11.2.4. 
CHANGE FROM BASELINE MMSE TOTAL SCORE AT DAYS 36 AND 104 
The secondary efficacy endpoint, CFB at Day 36 and Day 104 on the MMSE total score will be 
analyzed using MMRM with treatment group, visit, and treatment group by visit interaction as 
fixed effects and a corresponding MMSE total baseline score as a covariate. The LS mean 
difference, the 95% CI of the difference, and the p-value will be presented as well as the 
descriptive statistics. 
Also, the summary statistics will be tabulated for MMSE score by treatment groups and baseline 
AD severity stratifications. 
The MMSE scores will be listed as well. 
11.2.5. 
CHANGE FROM BASELINE NPI TOTAL SCORE AT DAYS 36 AND 104 
The secondary efficacy endpoint, CFB at Day 36 and Day 104 on the NPI total score will be 
analyzed using MMRM with treatment group, randomization strata (MMSE ≤ 20 and 21-24), 
visit, and treatment group by visit interaction as fixed effects and a corresponding NPI total 
baseline score as a covariate. The LS mean difference, the 95% CI of the difference, and the p-
value will be presented as well as the descriptive statistics. 
Also, the summary statistics will be tabulated for NPI by treatment groups and baseline AD 
severity stratifications. 
The individual and composite NPI scores will be listed as well. 
11.3. SENSITIVITY ANALYSIS 
Not applicable for either part of this study.  
  
11.4.1. 
CHANGE FROM BASELINE THROUGH END OF STUDY – COGNITION PARAMETERS 
The observed and change/shift from baseline in results from the cognition parameters - CDRS 
individual scores, sum of box total score, Global CDRS score, Responders for CDRS-sum of 
boxes total score, MMSE score, and NPI total score will be summarized by treatment groups 
using continuous and categorical descriptive statistics. 
The assessment associated with cognition parameters - CDR system battery, will be analyzed 
separately, and detail of analysis is described in CDR system battery SAP [5]. 


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11.5. INTERIM ANALYSIS 
No formal interim analysis planned for this study. 
A SRC will meet for each dose cohort before continuing to the next dose cohort. 
11.6. SUBGROUP ANALYSES 
The subgroup analysis for Part 2 will be performed as described in Section 7.2. 


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12. SAFETY AND TOLERABILITY 
12.1. ADVERSE EVENTS 
The following AE definitions are applicable to both protocol parts of this study: 
x AE reporting period: Defined from start of first dose of study drug infusion on Day 1 up 
to and including End of Study. 
x AE: Any untoward medical occurrence in a subject. 
x Treatment-emergent AE (TEAE): Defined as any AE that started on or after first dose of 
study drug infusion within the studies’ AE reporting period.  
x SAE: Defined as any AE that is indicated as serious on the AEs Details eCRF, as per 
investigator’s assessment. 
x Related AE: Defined as any AE that is indicated as related to study drug on the AEs 
Details eCRF, as per investigator’s assessment. 
x AE leading to discontinuation: Defined as any AE that has an “other action taken” 
indicated as “withdrawn from study" on the AEs Details eCRF. 
All AEs will be coded using the MedDRA version 22.1, Sep 2019. The following AE items will 
be listed separately for each protocol parts using the SAS: 
x All AEs 
x AEs leading to study discontinuation 
x Serious AEs 
x AEs leading to death (if applicable) 
The following items are planned to be presented in summary tables showing event incidence and 
corresponding subject count, experiencing said AE/AE type using the SAS, by treatment groups 
using SAS: 
x AE overview, including row items for frequency of subjects [n(%)] experiencing: 
o At least one AE 
o AEs by toxicity grade 
 Grade 1 
 Grade 2 
 Grade 3 
 Grade 4 
 Grade 5 
o Serious AEs 


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o Related AEs 
o Non-related AEs 
o AEs leading to study discontinuation 
o AEs leading to death 
• 
AEs by system organ class (SOC) and prefeITed te1m (PT) 
• 
AEs by descending incidence of PT 
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• 
AEs by toxicity grade (Common Te1minology Criteria for Adverse Events [CTCAE] 
grading) 
• 
Related AEs by SOC and PT 
• 
Related AEs by descending incidence of PT. 
• 
Serious AEs 
• 
AEs resulting in death 
• 
AEs leading to study discontinuation 
Only TEAEs will be used for summarization of all tables, but for listing all AEs will be counted. 
The TEAE status will be derived using the AE start and stop dates as per definition provided at 
the start of this section. For partial dates see Section 9.4.1. 
The data for these presentations will be obtained from the Adverse Events Details eCRF. 
AE assignment to CTCAE toxicity grades is explained in Table 2 below. 
Table 2. 
CTCAE Grades 
G1·ade 
Grade Descriotion 
Grade Details 
Grade 1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate 
Minimal, local, or non-invasive intervention indicated, limiting age-
appropriate instrnmental ADL* 
Grade 3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting selfcare ADL * 
Grade 4 
Life-threatening 
Life-threatening consequences: w-gent intervention indicated 
Grade 5 
Fatal 
Death related to AE 
ADL: activities of daily living. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
** Self-care ADL refer to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
12.2.LABORATORY RESULTS 
fu the context of this study the difference between potentially clinically impo1tant (PCI) and PCS 
results are defined as follows: 
Confidential 
Page 31 of SO 


TB006 
 
Statistical Analysis Plan: TB006AD2102 
11Apr2022 
 
 
 
Confidential 
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x A PCS result is defined as an abnormal laboratory assay result marked as clinically 
significant in the Investigator’s opinion. 
x A PCI result is defined as a laboratory assay result that meets criteria tested against as 
used by the local laboratory for identifying as PCI. 
The following subject safety laboratory result items are planned to be listed using the SAS for 
both protocol parts: 
x Chemistry 
x Hematology 
x Urinalysis 
x Drug and Alcohol Screening 
x Abnormal results 
x PCS results 
x PCI results 
The following local laboratory result items are planned for table presentation, by treatment 
groups for each applicable visit using the SAS: 
x Chemistry:   
o CFB with descriptive statistics 
o Shift from Baseline with summary statistics 
x Hematology:   
o CFB with descriptive statistics 
o Shift from Baseline with summary statistics 
x Urinalysis: 
o CFB with descriptive statistics for numeric results 
o Qualitative summary of Urinalysis 
x PCI laboratory results as tested against local laboratory criteria set (see Appendix IV: 
Potentially Clinically Important Values for list of criteria) 
x Marked abnormalities, including the following criteria: 
o Alanine aminotransferase (ALT) > 1.5 x upper limit of normal (ULN) 
o Bilirubin > 1.5 x ULN (where if fractioned, direct bilirubin >= 35%) 
o ALT or aspartate aminotransferase (AST) > 3 x ULN and total bilirubin (TBL) > 2 
x ULN and alkaline phosphatase (ALP) > 1.5 x ULN (Hy’s law) 
A list of local laboratory assays planned to be performed can be found in Appendix III:Appendix 
III:Summary of Laboratory Assays Performed. The planned timings of laboratory sample 
collection are given in Appendix I: Schedule of Assessments and Procedures. 


TB006 
 
Statistical Analysis Plan: TB006AD2102 
11Apr2022 
 
 
 
Confidential 
Page 33 of 50 
The following ECG listings will be presented for both protocol parts using the SAS: 
x Quantitative results containing all the measurements listed in Table 3. 
x Potentially clinically significant results. 
The following ECG summary tables are planned, by treatment groups using the SAS: 
x CFB with descriptive statistics on all the measurements listed in Table 3. 
x Categorical Outliers and marked abnormalities, including the following criteria: 
For marked abnormalities: 
o QTcB > 450 (msec) for male subjects. 
o QTcB > 470 (msec) for female subjects. 
o Increase in QTcB from baseline ≥ 60 (msec). 
o Increase in heart rate CFB% ≥ 30% AND observed heart rate > 90 (bpm). 
For categorical outliers: 
o QTcB > 500 (msec). 
o Increase in QTcB from baseline ≥ 30 (msec) and < 60 (msec). 
o Increase in QTcB from baseline ≥ 60 (msec). 
x Time-matched, placebo-adjusted QTcB CFB for all post-dose timepoints ≤ 24 hours. 
The following figures are planned for presentation ECG parameter QTcB for both parts of study 
by treatment groups using the SAS: 
x Mean observed values after study drug infusion on dosing days (by dose group) 
x Mean observed values over time (excluding post-dose assessments on dosing days) 
x Mean CFB after study drug infusion on dosing days (by dose group) 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
• 
Mean CFB over time (excluding post-dose assessments on dosing days) 
lb TrueBinding 
11Apr2022 
• 
Placebo-con ected mean CFB in QTcB with 90% CI whiskers across post-dose timepoints 
up to 24 hours (by dose group) 
A time-matched analysis of change in QTcB will be graphically explored. The mean CFB in 
QTcB versus placebo will be plotted at the different timepoints :S 24 hours post-dose, along with 
90% 2-sided CI. The upper limit of the 90% CI should be below the 10 (msec) bound as 
provided by the International Conference on Haim onization (ICH) E14 guideline to be deemed 
as having no QTc prolongation effect. Due to the small number of subjects planned per coho1t, 
subjects from the different coho1ts will be pooled into active treatment and placebo. If any upper 
limits are observed above the 10 (msec) mark from the pooled plot, fmt her exploration by coho1t 
may be explored. The estimates and 90% CI will be obtained through an analysis of covariance 
(ANCOV A), using baseline QTcB as covai·iate and treatment (pooled active and placebo) as 
effect. 
The following example SAS® code can be utilized and modified as needed: 
Proc GLM Dat a = <Dat a s e t>; 
By <Tmpt>; 
Cla ss <TRT>; 
Model <CFB> = <TRT> <Bas eVal> / soluti on; 
LSmeans <TRT> / diff cl Al pha = 0 . 1 pdiff; 
ods output LSMeanDiffCL = <e stmt>; 
Run; 
Quit; 
Where <Dataset> is the input dataset, <Tmpt> is the timepoint, <TRT> if is the treatment group, 
<Base Val> is the baseline value and <estmt> is the output set containing the estimate and 
con esponding 90% CI. 
The data for these presentations will obtained from the following eCRFs: 
• 
12-Lead Electrocardiogram Details. 
• 
Vital Signs (for hea1t rate). 
Table 3 below gives the ECG measurements to be assessed. 
Table 3. 
ECG Measurements 
Measurement 
QT interval (msec) 
QT, con-ected with Bazett's formula 
(QTcB) interval (msec) 
QRS interval (msec) 
PR interval (msec) 
Herut Rate (HR) (bpm) 
The planned timings of these ECG are given in Appendix I: Schedule of Assessments and 
Procedures. 
Confidential 
Page 34 of SO 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
12.4. VITAL SIGNS 
lb TrueBinding 
11Apr2022 
Listings will be presented on the following vital sign items separately for both protocol pm.ts 
using the SAS: 
• 
Quantitative results on all the tests listed in Table 4. 
• 
Potentially clinically significant results (Refer marked abno1malities listed under). 
The following vital sign tables ru.·e planned to be presented, by treatment groups using the SAS: 
• 
CFB with descriptive statistics on all the tests listed in Table 4. 
• 
Mru.·ked abno1malities including the following criteria: 
o Decrease in systolic blood pressure (SBP) of ~ 25 (mmHg) versus baseline 
( orthostatic hypotension). 
o Decrease in diastolic blood pressure (DBP) of ~ 15 (mmHg) versus baseline 
( orthostatic hypotension). 
o fucrease/decrease in SBP of ~ 20 (mmHg) versus baseline. 
o fucrease/decrease in DBP of~ 10 (mmHg) versus baseline. 
o fucrease/Decrease in Weight of~ 7% versus baseline. 
o fucrease/Decrease in Hea1t Rate by 15 bpm. 
The data for these presentations will be obtained from the following eCRFs: 
• 
Vital Signs. 
• 
Physical Examination (for weight). 
Table 4 below gives the vital sign tests to be perfo1med. 
Table 4. 
Vital Sign Tests Performed 
Test 
Pulse (bpm) 
Pulse oximetry, SPO2 (%) 
Respiratory rate (b1pm) 
Supine DBP (mmHg) 
Supine SBP (mmHg) 
Temperature (0C) 
Weight (kg) 
The planned timings for the vital signs measurements are given in Appendix I: Schedule of 
Assessments and Procedures. 
12.5.COLUMBIA SUICIDE SEVERITY RATING SCALE 
The Columbia Suicide Severity Rating Scale (C-SSRS) will be listed for both protocol pa1ts 
separately using the SAS. 
Confidential 
Page 35 of SO 


TB006 
 
Statistical Analysis Plan: TB006AD2102 
11Apr2022 
 
 
 
Confidential 
Page 36 of 50 
The information for these presentations will be obtained from the following eCRFs: 
x C-SSRS Screening  
x C-SSRS Since Last Visit  
The C-SSRS responses over time will be tabulated using count and percent by treatment groups 
throughout the study, using SAS. 
 
13. OTHER RELEVANT DATA ANALYSES/SUMMARIES 
13.1. HOSPITALIZATIONS AND CLINICAL UNIT CONFINEMENT 
A combined listing on the following items will be presented using the SAS separately for both 
protocol parts: 
x Hospitalizations 
x Clinical unit confinement 
The information for these presentations will be obtained from the following eCRFs: 
x Adverse Events Details eCRF 
x Clinical Unit Confinement 
Duration per hospital stay is calculated in days as: 
Hospitalization Duration (days) = (Discharge Date – Admission Date) + 1  
Duration of clinical unit confinement is calculated in days as: 
Clinical Unit Confinement Duration (days) = (Discharge Date – Admission Date) + 1   
It should be noted that the above duration definitions consider part of a day to count as a whole 
day.  
13.2. PHYSICAL AND NEUROLOGICAL EXAMINATIONS 
A listing of physical and neurological examination findings for both protocol parts will be 
presented separately using the SAS. 
The information for the listing will be obtained from the following eCRFs: 
x Physical and Neurological Examination 
x Physical and Neurological Exam Abnormalities 
It should be noted that weight will be presented and summarized alongside the vital signs (see 
Section 12.4 for details), and height will be presented alongside demographics and baseline 
characteristics (see Section 10.2 for details). 
Body systems to assess include: 


TB006 
 
Statistical Analysis Plan: TB006AD2102 
11Apr2022 
 
 
 
Confidential 
Page 37 of 50 
x Cardiovascular 
x Respiratory 
x Gastrointestinal 
x Neurological (Mental status, Motor and Sensory Skills, Hearing and Speech, Vision, 
Coordination, Balance)  
13.3. IMMUNOGENICITY ANALYSIS 
To assess the immunogenicity of TB006, the presence of anti TB006 antibodies, and associated 
titer values will be listed by patient and time point for both protocol parts using SAS. 
The anti-drug antibody titer values will be summarized descriptively for all subjects, by 
treatment groups and baseline AD severity stratifications (for Part 2 only), using SAS. Also, the 
status of anti-drug antibody will be tabulated by treatment groups and baseline AD severity 
stratifications (for Part 2 only), using SAS. 
 
14. REFERENCES 
1. ICH E3: Structure and Content of Clinical Study Reports, CDER, FDA (1996). 
2. ICH E9: Statistical Principles for Clinical Trials, CDER, FDA (1998). 
3. TB006AD2102_MAD_Protocol_V3_Am2_Docusign_15Oct2021. 
4. TB006AD2102_eCRF_Specification_v2.0_09NOV2021_Final 
5. TRU212572_CDR_System_Statistical_Analysis_Plan_V2.0_13_Jan_2022.


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
15.APPENDICES 
Appendix I: SCHEDULE OF ASSESSMENTS AND PROCEDURES 
Table 5. 
Part 1 - Schedule of Activities 
N 
Study Drug Administration Pe1iod 
1:.1) 
I 
.5 Q 
N 
., 
= 0 
-
.. 
M 
0 
r--
I 
I 
in 
.. 
0\ 
.. 
-
., 
\Q 
M 
M 
f") 
I,,, 00 
Q 
Q 
.... 
I 
00 -
I 
M 
I 
I 
\Q 
Q 
M 
Q 
I -
\Q 
M 
f") 
M 
Q 
f") 
<.J 
M 
O'I 
Q 
Q 
M 
Q 
Q 
00 
I 
Q 
Q 
-
f") 
Q 
Q 
Q 
Q 
General and Safety Assessments 
Informed consent 
X 
Eligibility criteria 
X 
X 
Medical history" 
(includes substance 
X 
X 
X 
usage) 
Demography 
X 
Physical and 
nemological 
X 
X 
X 
examination 
Randomization 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
.0 
Q 
e 
\Q 
Q -
r.l 
Q 
X 
X 
X 
X 
X 
Notes 
lb TrueBinding 
l 1Apr2022 
Recheck eligibility before 
randomization and/or first dose of 
studydmg 
Medical occruTences that begin 
before the sta1t of study dtug but 
after obtaining infonned consent 
will be recorded on the Medical 
Histo1y/CruTent Medical Conditions 
section of the CRF, not the AE 
section 
Physical examination will include 
height (screening only) and weight 
measmements; see also Section 
8.2.1 of Protocol 
Pre-dose, then 2 and 6 homs after 
the end of the study dtug infusion 
on Dl, D8, D15, D22, D29; 
othe1w ise once on the days 
indicated; see Section 8.2.2 of 
Protocol for vital signs assessments 
I 
Confidential 
Page 38 of 50 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
lb TrueBinding 
l 1Apr2022 
Table 5. Part 1 - Schedule of Activities 
12-lead ECG 
AE monitoring 
Prior/concornitant 
medication review 
C-SSRS 
Clinical unit 
confinement 
Outpatient visit 
Confidential 
X 
X 
X 
X 
X 
.. -
I 
Q 
X 
X 
X 
X 
.. .... 
Q 
X 
.. 
\C 
I 
M 
Q 
00 
Q 
X 
Study Drug Administration Pe1iod 
Notes 
M -
I 
O'I 
Q 
in -
Q 
X 
0 
M 
I 
\C 
5 
.. 
M 
M 
Q 
X 
r--
M I 
f") 
M 
Q 
X 
.. 
\C 
8 
Dl, D8, D15, D22, D29: pre-dose, 
then 2 and 6 hours after end of study 
dmg infusion 
X 
X 
X 
X 
D -1, D36, D64, D104, EID: 
time-matched with Dl, D8, D15, 
D22, D29 pre-dose to the extent 
possible 
All AEs and SAEs will be collected 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
from the time of the first study dmg 
XXXXXXXXXXXXX X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
administration until D104. 
At least 6 hours following study 
dmg adrninistration on dosing days; 
discharge from the clinical unit v.•ill 
be at the discretion of the 
investigator provided there are no 
safety concerns identified from 
review of the clinical data. 
Optional overnight confinement 
from either D -2 or D -1 and on 
days prior to other dosing days (D7, 
D14, D21, D28) 
If the patient is not overnight 
X 
X 
X 
X 
confined on D -1 (see above), the 
D -1 visit will be an outpatient visit 
Page 39 of50 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
Table 5. Part 1 - Schedule of Activities 
Site to contact patient 
Viral serology (HBsAg, 
IGM anti-HBc, 
anti-HCV, HIV) and 
COVID-19 
Urine alcohol 
Dmg screening 
Clinical laboratory tests 
(clinical chemistry, 
hematology, urinalysis) 
MMSE 
Clinical Dementia 
Rating scale 
Cognitive Dmg 
Research Dementia 
Rating batte1-y'1 
NPI 
assessment 
Study dmg IV infusion 
Confidential 
N 
1::.1) 
I 
.!: o 
N 
E 
I 
00 
Q 
c., N 
c,) 
I 
Q 
X 
X 
X 
X 
X 
X 
" -
I 
Q 
X 
X 
X 
.. -
Q 
" 
\C 
I 
N 
Q 
X 
00 
Q 
X 
Study Drug Administration Pe1iod 
M -
I 
O'I 
Q 
X 
in -
Q 
0 
N 
I 
\C 
5 
X 
" 
N 
0\ 
N 
N 
Q 
Q 
X 
X 
Central Laboratory Assessments 
X 
X 
X 
" 
\C 
8 
X 
X 
X 
X 
X 
Pharmacodynamic Assessments: Cognition Testing, MRI, Blood Samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Tt·eatment 
X 
X 
X I I X I I X 
Notes 
lb TrueBinding 
l 1Apr2022 
Investigator or designee to 
telephone the patient betv.•een D2-6, 
D9-13, Dl6-20, D23-27, andD30-
34 
Locally perfonned at site 
Fluid biomarkers will be detennined 
in plasma 
Page 40 of SO 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
Table 5. Part 1 - Schedule of Activities 
r 
Blood sample for PK 
assessment 
Blood sample for ApoE4 
genotyping 
Blood sample for ADA 
assessment 
Lumbar puncture for 
CSF collectione 
N 
1::.1) 
I 
C Q 
·= 0 .... 
00 
""' 
c., N 
00 
I 
Q 
X 
N 
I 
Q 
" -
I 
Q 
X 
.. -
Q 
X 
X 
Study Drug Administration Pe1iod 
" 
M 
in 
0 
" 
r--
0\ 
" 
\C 
00 -
N 
N 
N 
\C 
I 
I 
I 
I 
N 
Q 
I -
\C 
N 
N 
Q 
Q 
O'I 
Q -
Q 
N 
Q 
Q 
Q 
Q 
Q 
Q 
Phannacokinetics 
X 
X 
X 
Pha1·macokinetics and Pha1·macodynamics 
X 
X 
X 
Q 
\C -
Q 
Q 
X 
X 
X 
.0 
Q 
X 
Notes 
lb TrueBinding 
l 1Apr2022 
Pre-dose, end of infusion, then 1, 2, 
4, and 6 homs after the end of 
infusion on Dl, DS, and D29; single 
time point on other days 
Optional ApoE4 sampling is 
collected at screening but can be 
taken at any visit until the last study 
visit (Section 8.7 of Protocol) 
ADA assessment is performed on 
blood sample collected for PK 
assessments; D 1 and DS assessment 
is performed on the pre-dose sample 
Lumbar puncture indicated for D-1 
can be perfo1med any time between 
D-8 and D-1 
CSF biomarkers, and TB006 levels 
will be detennined in CSF 
---- AD = Alzheimer's Disease; ADA = anti-dtug antibody; AE = adverse event; anti-HCV = hepatitis C vims antibody; 
~
ein E4; COVID = coronavims disease; CRF = case repo1t form; C-SSRS = Columbia Suicide Severity Rating Scale; CSF = cerebrospinal 
fluid; D = Day; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; ECG = electrocardiogram; EID = Early Discontinuation; 
HBsAg = hepatitis B surface antigen; lgM anti-HBc = illllllunoglobulin M antibody to hepatitis B core antibody; IV = intravenous(ly); MMSE = Mini-Mental 
State Examination; 
NINCDS-ADRDA = National Institute ofNemological and Communicative Disorders and Stroke -
Alzheimer's Disease and Related Disorders Association; NPI = Nemopsychiatric Inventory; PD = pharmacodynamic(s); 
PK = phannacokinetic(s); SAE = serious adverse event. 
a 
Visit days and procedures are allowed a window of± 2 days from Day 1 to End of Treatment. 
b 
Applicable only for patients who discontinue early from the study. 
Confidential 
Page 41 of 50 


TB006 
 
Statistical Analysis Plan: TB006AD2102 
11Apr2022 
Confidential 
Page 42 of 50 
c 
The medical history assessed at the screening visit should include prior AD treatment assessment(s). Establishing the clinical diagnosis of AD should include 
use of criteria from the DSM-5 – Criteria for Major Neurocognitive Disorder (previously dementia) (Section 10.4 of Protocol, Appendix 4) and the 
NINCDS-ADRDA (Note: ADRDA is now the Alzheimer’s Association) (Section 10.5 or Protocol, Appendix 5). 
d The Cognitive Drug Research battery is to be performed twice during the screening visit in both Part 1 and Part 2. 
e The lumbar puncture procedure is optional. 
 
 
lb TrueS.nding 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
Table 6. Part 2 - Schedule of Activities 
Informed consent 
Eligibility criteria 
Medical history" 
(includes substance 
usage) 
Demography 
Physical and 
nemological 
examination 
Randomization 
Vital signs 
Confidential 
N 
1:.1) 
I 
.: o 
N 
,s 
I 
00 
Q 
<.J 
N 
c,) 
I 
Q 
X 
X 
X 
X 
X 
X 
X 
., -
I 
Q 
X 
X 
X 
X 
X 
.. .... 
Q 
X 
.. 
\C 
I 
N 
Q 
00 
Q 
X 
Study Drug Administration Pe1·iod 
.... 
I 
0\ 
Q 
in -
Q 
N 
N 
Q 
t--
N 
I 
M 
N 
Q °' 
N 
Q 
General and Safety Assessments 
X 
X 
X 
.. 
\C 
8 
X 
X 
X 
X 
X 
X 
X 
Notes 
lb TrueBinding 
l 1Apr2022 
Recheck eligibility before 
randomization and/or first dose of 
study drug 
Medical occtmences that begin 
before the stait of study drug but 
after obtaining informed consent 
will be recorded on the Medical 
History/Cun-ent Medical 
Conditions section of the CRF, not 
the AE section 
Physical examination will include 
height (screening only) and weight 
measmements; see also Section 
8.2.1 of Protocol. 
Pre-dose, then 2 and 6 homs after 
the end of the study dmg infusion 
on Dl, D8, D15, D22, D29; 
othe1wise once on the days 
indicated; see Section 8.2.2 of 
Protocol for vital signs assessments 
Page 43 of SO 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
Table 6. Part 2 - Schedule of Activities 
12-lead ECG 
AE monitoring 
N 
1:.1) 
I 
.: o 
N 
,s 
I 
00 
Q 
<.J 
N 
c,) 
I 
Q 
X 
., -
I 
Q 
X 
.. .... 
Q 
X 
X 
.. 
\C 
I 
N 
Q 
00 
Q 
X 
X 
X 
Study Drug Administration Pe1·iod 
.... 
I 
0\ 
Q 
X 
in -
Q 
X 
X 
N 
N 
Q 
X 
X 
X 
t--
N 
I 
M 
N 
Q 
X 
°' 
N 
Q 
X 
X 
.. 
\C 8 
X 
X 
X 
X 
Notes 
lb TrueBinding 
l 1Apr2022 
Dl, D8, Dl5, D22, D29: pre-dose, 
then after end of study dmg 
infusion 
X 
X 
D -1, D36, Dl04, EID: 
time-matched with Dl, D8, Dl5, 
D22, D29 pre-dose to the extent 
possible 
X 
X 
All AEs and SAEs will be 
collected from the time of the first 
study dmg administration until 
Dl04. 
Prior/concornitant 
medication review 
X 
X 
X 
XXXXXXXXXXXXX X 
C-SSRS 
Clinical unit 
confinement 
Outpatient visit 
Confidential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
At least 6 hours following study 
dmg administration on dosing 
days; discharge from the clinical 
unit will be at the discretion of the 
investigator provided there are no 
safety concerns identified from 
review of the clinical data. 
Optional overnight confinement 
from either D -2 or D -1 and on 
days prior to other dosing days 
(D7, Dl4, D21, D28) 
If the patient is not overnight 
X 
X 
X 
X 
confined on D -1 ( see above), the 
D -1 visit will be an outpatient visit 
Page 44 of50 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
Table 6. Part 2 - Schedule of Activities 
Site to contact patient 
Viral serology (HBsAg, 
IGM anti-HBc, 
anti-HCV, HIV) and 
COVID-19 
Urine alcohol 
Dmg screening 
Clinical laboratory tests 
(clinical chemistry, 
hematology, urinalysis) 
MMSE 
Clinical Dementia 
Rating scale 
Cognitive Dmg 
Research System 
battery" 
NPI 
assessment 
Study dmg IV infusion 
Confidential 
N 
1::.1) 
I 
.!: o 
N 
E 
I 
00 
Q 
c., N 
c,) 
I 
Q 
X 
X 
X 
X 
X 
X 
" -
I 
Q 
X 
X 
X 
" -
Q 
" 
\C 
I 
N 
Q 
X 
00 
Q 
X 
Study Drug Administration Pe1·iod 
-
I 
0\ 
Q 
X 
in -
Q 
X 
N 
°' 
N 
N 
Q 
Q 
X 
X 
Central Laborato1·y Assessments 
X 
X 
X 
" 
\C 
8 
X 
X 
X 
X 
X 
Pha1·macodynamic Assessments: Cognition Testing, MRI, Blood Samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Treatment 
X 
X 
X I I X I I X 
Notes 
lb TrueBinding 
l 1Apr2022 
Investigator or designee to 
telephone the patient between 
D2-6, D9-13, D16-20, D23-27, and 
D30-34 
Locally performed at site 
Fluid biomarkers will be 
detemlined in plasma 
Page 45 of SO 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
Table 6. Part 2 - Schedule of Activities 
lb TrueBinding 
l 1Apr2022 
N 
Study Drug Administration Pe1·iod 
Notes 
Blood sample for PK 
assessment 
Blood sample for ADA 
assessment 
Blood sample for ApoE4 
genotyping 
1::.1) 
I 
C Q 
·= 0 .... 
00 
""' 
c., N 
00 
I 
Q 
X 
N 
I 
Q 
" -
I 
Q 
" -
Q 
X 
X 
" 
\C 
00 -
I 
N 
Q 
I 
Q 
0\ 
Q 
in 
Q 
N 
i'--
°' 
N 
N 
M 
\0 
I 
Q 
-
N 
M 
N 
Q -
Q 
N 
Q 
M 
Q 
Q 
Q 
Ph1u·macokinetics 
X 
" 
.,, 
\C 
Q 
0 
M 
\C -
r.i'.l 
Q 
Q 
Q 
Pre-dose and the end of infusion on 
X 
X 
X 
X 
Dl and D29; single sample on 
X 
X 
other days 
ADA assessment is perfonned on 
blood sample collected for PK 
assessments; D 1 assessment is 
perfo1med on the pre-dose sample 
Optional ApoE4 sampling is 
collected at screening but can be 
taken at any visit until the last 
study visit (Section 8.7 of Protocol) 
AD = Alzheimer's Disease; ADA = anti-dtug antibody; AE = adverse event; anti-HCV = hepatitis C vims antibody; 
ApoE4 = apo 1poprotein E4; COVID = coronavirns disease; CRF = case repo1t f01m; C-SSRS = Columbia Suicide Severity Rating Scale; D = Day; 
DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; ECG = electrocardiogram; EID = Early Discontinuation; HBsAg = hepatitis B 
surface antigen; IgM anti-HBc = immunoglobulin M antibody to hepatitis B core antibody; IV = intravenous(ly); MMSE = Mini-Mental State Examination; 
NINCDS-ADRDA = National Institute of Neurological and Collllllunicative Disorders and Stroke - Alzheimer's Disease 
an Re at 
DISor ers Association; NPI = Neuropsychiatric Invento1y; 
PD= phannacodynamic(s); 
PK = phannacokinetic(s); SAE = serious adverse event. 
a 
Visit days and procedures are allowed a window of± 2 days from Day 1 to End of Treatinent. 
b 
Applicable only for patients who discontinue early from the study. 
c 
The medical history assessed at the screening visit should include prior AD treatment assessment(s). Establishing the clinical diagnosis of AD should include 
use of criteria from the DSM-5 - Criteria for Major Neurocognitive Disorder (previously dementia) (Section 10.3 of Protocol, Appendix 4) and the 
NINCDS-ADRDA (Note: ADRDA is now the Alzheimer's Association) (Section 10.4 of Protocol, Appendix 5). 
d 
The Cognitive Drug Research batte1y is to be perfonned twice during the screening visit in both Pait 1 and Pait 2. 
Confidential 
Page 46 of50 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
Appendix II: SUMMARY OF EFFICACY ANALYSES 
Statistical Method 
CDRS - Sum of Boxes total 
EAS2 
MMRM 
score 
CDRS - Proportion of 
EAS2 
CMH 
respondent 
MMSEscore 
EAS2 
MMRM 
NP/score 
EAS2 
MMRM 
CDRS 
EAS2 
Descriptive statistics 
CDRS - Proportion of 
EAS2 
Descriptive statistics 
respondent 
MMSEscore 
EAS2 
Descriptive statistics 
NP/score 
EAS2 
Descriptive statistics 
Confidential 
Part 2 
Part 2 
Part 2 
Part 2 
Part 2 
Part 2 
Part 2 
Part 2 
lb TrueBinding 
l 1Apr2022 
Interpretation 
Prima,y analysis 
Seconda,y 
analysis 
Seconda,y 
analysis 
Seconda,y 
analysis 
Seconda,y 
analysis 
Seconda,y 
analysis 
Seconda,y 
analysis 
Seconda,y 
analysis 
Page 47 of SO 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
lb TrueBinding 
l 1Apr2022 
Appendix III: SUMMARY OF LABORATORY AsSAYS PERFORMED 
Laboratory Category 
Assay Grouping 
Assay 
Chemist,y 
Electrolytes 
Glucose 
Potassium 
Sodium 
Calcium 
Renal Function 
Blood Urea Nitrogen (BUN) 
Creatinine 
Liwr Function 
Alanine Aminotransferase (ALT) 
Aspartate Aminotransferase (AST) 
Albumin 
Creatine Phosphokinase (CPK) 
Alkaline phosphatase 
Total Bilirnbin 
Direct Bilirnbin 
Total Protein 
Lipid Profile 
Total Cholesterol 
High-density Lipoprotein (HDL) Cholesterol 
Low-density Lipoprotein (LDL) Cholesterol 
Triglycerides 
Thyroid-stimulating Honnone (TSH) 
Hemoglobin Ale (HbAlc) 
Hematology 
RBCindices 
Platelet count 
Red Blood Cell (RBC) count / Etythrocytes 
Hemoglobin 
Hematocrit 
Ety. Mean Corpuscular volume (MCV) 
Ety. Mean Corpuscular Hemoglobin (MCH) 
Leukocytes 
White Blood Cell (WBC) Count 
Neutrophils Absolute 
with differential 
Neutrophils Percent 
Lymphocytes Absolute 
Lymphocytes Percent 
Monocytes Absolute 
Monocytes Percent 
Eosinophils Absolute 
Eosinophils Percent 
Reticulocytes Absolute 
Reticulocytes Percent 
Basophils Absolute 
Basophils Percent 
Urinalysis (dipstick) 
Specific Gravity 
pH 
Glucose 
Protein 
Confidential 
Page 48 of SO 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
Laboratory Category 
Assay Grouping 
Other Screening Tests 
Viral serology 
Non-childbearing potential only 
Plasma Alcohol and Urine Blood 
Screen 
WOCBP 
Confidential 
Assay 
Occult Blood 
Ketones 
Bilirubin 
Urobilinogen 
Nitrite 
lb TrueBinding 
l 1Apr2022 
Leukocyte esterase 
Microscopic examination if blood or protein is 
abnonnal 
Hepatitis B sw-face antigen (HBsAg) 
IgM Hepatitis B core antibody (anti-HBc) 
Hepatitis C antibody (Anti-HCV) 
Human immunodeficiency virus (HIV) 
COVID19 
Follicle-stimulating Honnone (FSH) 
Estradiol 
Alcohol 
Optiates 
Methadone 
Buprenorphine 
Methamphetamine 
Cocaine 
Amphetamines 
Highly sensitive human chorionic-gonatropin 
(hCG) pregnancy test 
Page 49 of SO 


TB006 
Statistical Analysis Plan: TB006AD2 l 02 
Appendix IV: POTENTIALLY CLINICALLY IMPORTANT VALUES 
lb TrueBinding 
l 1Apr2022 
The following table contains a list of ranges used by the laboratory to flag critical laborato1y 
values which will also be used in this study to identify any potentially clinically impo1tant values 
within the table and listings presentations. If a planned laboratory assay does not have applicable 
PCI criteria limits, that assay is not included in the below table. 
PC/ Criteria Value Limits 
Laboratory Cateeory 
Assay 
Unit 
Lower 
Uvner 
Chemishy 
Albumin 
f!/dL 
2.0 
6.0 
Alkaline Phosvhatase 
IUIL 
NA 
200 
Alanine Aminotransferase 
JUIL 
NA 
150 
Asvartate Aminotransferase 
IUIL 
NA 
150 
Bilirubin 
mf!/dL 
NA 
2.50 
Blood Urea Nih'Of!en 
mf!ldL 
NA 
30.0 
Calcium 
mf!/dL 
7.0 
13.5 
Glucose 
mf!ldL 
40 
250 
Potassium 
mmol/L 
3.2 
6.0 
Sodium 
mmol/L 
130 
150 
Hematology 
Hematocrit (Female) 
% 
24.0 
54.0 
Hematocrit (Male) 
% 
24.0 
60.0 
Hemof!lobin (Female) 
f!/dL 
8.0 
18.0 
Hemof!lobin (Male) 
f!ldL 
8.0 
20.0 
Lymvhocvtes 
01\3/uL 
0.50 
NA 
Neutrovhils 
01\3/uL 
1.00 
NA 
Platelets 
01\3/uL 
75 
750 
Leukocytes 
01\3/uL 
2.5 
25.0 
Other Screening Tests 
Human immunodeficiency virus (HIV) 
Positive 
COVID19 
Positive 
Optiates 
Positive 
Methadone 
Positive 
Bupreno,phine 
Positive 
Methamphetamine 
Positive 
Cocaine 
Positive 
Amphetamines 
Positive 
Confidential 
Page 50 of SO 


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TB006 
 
Statistical Analysis Plan: TB006AD2102 
14Nov2022 
Confidential  
 
Page 1 of 6 
 
ADDENDUM TO STATISTICAL ANALYSIS PLAN: TB006AD2102  
FINAL VERSION 2.0 DATED 11 APRIL 2022 
 
Study Title: 
A Seamless Phase 1b/2a Double-blind, Randomized, 
Multiple dose, Multi-center, Sequential Dose-
escalation Study to Assess the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of 
TB006 in Patients with Mild to Severe 
 
 
Study Number: 
TB006AD2102 
Study Phase: 
Phase 1b/2a 
Sponsor: 
TrueBinding, Inc. 
300 Lincoln Center Drive  
Suite 200 
Foster City, CA, 94404 
 
Addendum Version: 
Final ver 1.0 
NCT Number: 
NCT05074498 
Date: 
14Nov2022 
 
 
 
Confidentiality Statement 
This document contains confidential and proprietary information, and is not to 
be distributed to any third party. 
 


TB006 
 
Statistical Analysis Plan: TB006AD2102 
14Nov2022 
Confidential  
 
Page 2 of 6 
 
Table of Contents 
Addendum to Statistical Analysis Plan: TB006AD2102 Final Version 2.0 dated 11 april 2022 ... 1 
1. Signature Page .......................................................................................................................... 3 
2. Purpose ...................................................................................................................................... 4 
3. Descriptions of Changes in Study Conduct and Analysis Planned in Protocol and Statistical 
Analysis Plan ............................................................................................................................ 5 
4. References ................................................................................................................................. 6 
 


TB006 
 
Statistical Analysis Plan: TB006AD2102 
14Nov2022 
Confidential  
 
Page 3 of 6 
 
1. 
SIGNATURE PAGE 
Study Title: 
A Seamless Phase 1b/2a Double-blind, Randomized, 
Multiple dose, Multi-center, Sequential Dose-escalation 
Study to Assess the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Efficacy of 
TB006 in Patients with Mild to Severe 
Study Number: 
TB006AD2102 
 
 
 
Prepared by:  
 
Date: 
 
, PhD 
Principal Biostatistician, Biometrics 
MMS Holdings, Inc 
 
 
 
Reviewed by: 
           Date: 
 
Senior Biostatistician II, Biometrics 
MMS Holdings, Inc 
 
 
 
Approved by:
 
Date: 
 
 PharmD 
Clinical Development Lead 
TrueBinding, Inc. 
 
 
 
 


TB006 
 
Statistical Analysis Plan: TB006AD2102 
14Nov2022 
Confidential  
 
Page 4 of 6 
 
2. 
PURPOSE 
The Statistical Analysis Plan (SAP) version 2.0 dated 11 April 2022 need to clarify the definition 
of Efficacy Analysis Set-Part 2 (EAS2). The EAS2 is defined in SAP as:  
The Part 2  Efficacy Analysis Set (EAS2) includes all subjects who received assigned 
dose of TB006 in Part 2 and the subjects enrolled at the same TB006 dose level in Part 1, 
as well as all placebo patients will be included and have at least one post-dose evaluable 
PD assessment across subject. 
Here PD assessment  can be mistaken to refer to plasma or imaging biomarkers and hence the 
definition for EAS2 is clarified in addendum SAP to replace 
updated definition is as under: 
The Part 2  Efficacy Analysis Set (EAS2) includes all subjects who received assigned 
dose of TB006 in Part 2 and the subjects enrolled at the same TB006 dose level in Part 1, 
as well as all placebo patients will be included and have at least one post-dose evaluable 
efficacy assessment across subject. 


TB006 
 
Statistical Analysis Plan: TB006AD2102 
14Nov2022 
Confidential  
 
Page 5 of 6 
 
3. 
DESCRIPTIONS OF CHANGES IN STUDY CONDUCT AND 
ANALYSIS PLANNED IN PROTOCOL AND STATISTICAL 
ANALYSIS PLAN 
This change will only impact the analysis population definition in SAP version 2.0 dated 11 
April 2022, Section 7.1.5. 
 


TB006 
 
Statistical Analysis Plan: TB006AD2102 
14Nov2022 
Confidential  
 
Page 6 of 6 
 
4. 
REFERENCES  
1. TrueBinding TB006AD2102 Statistical Analysis Plan Version 2.0 Final signed, dated 11 
April 2022. 

Prot_000.pdf: 
Compound: TB006 
Protocol TB006AD2102 
T rneBinding, Inc. 
Protocol Date and Version: 15 Oct 2021; v 3.0 
CLINICAL PROTOCOL 
Protocol Title: 
A Seamless Phase 1 b/2a Double-blind, Randomized, Multiple 
dose, Multi-center, Sequential Dose-escalation Study to Assess 
the Safety, Tolerability, Phannacokinetics, Phaim acodynamics 
and Efficacy of TB006 in Patients with Mild to Severe 
Alzheimer's Disease 
Protocol Number: 
TB006AD2102 
Amendment: 
2.0 
Compound: 
TB006 
Study Phase: 
Phase 1b/2a 
Short Title: 
A Phase 1 b/2a, multi-dose, multi-center study to assess the 
safety, tolerability, phaimacokinetics, phaim acodynamics, and 
efficacy ofTB006 in patients with Alzheimer's Disease. 
Sponsor 
Sponsor Name: 
TrneBinding, Inc. 
Legal 
300 Lincoln Center Drive 
Registered 
Suite 200 
Address: 
Foster City, CA 
94404 
Protocol 
Name: 
, PhaimD 
Approver Function: 
Clinical Development Lead, TrneBinding, Inc. 
Regulatory Agency 
Not applicable 
Identifier Number 
Protocol Date: 
Document Version 
Date 
Original (v 1.0) 
25 Mar 2021 
Amendment 1.0 (v 2.0) 
02 Aug 2021 
Amendment 2.0 (v 3.0) 
15 Oct 2021 
CONFIDENTIALITY NOTICE 
The info1mation contained in this protocol and all other infonnation relevant to TB006 are the 
confidential and proprietaiy infonnation of T me Binding, Inc. and, except as may be required by 
federal, state, or local laws or regulation, may not be disclosed to others without the prior written 
pe1mission of TrneBinding, Inc. 
CONFIDENTIAL 
NCT Number: NCT05074498 
This NCT number has been applied to the document for 
purposes of posting on Clinicaltrials.gov 
Page 1 of 101 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
SPONSOR SIGNATORY: 
TB006AD2102 
T rneBinding, Inc. 
A Seamless Phase 1 b/2a Double-blind, Randomized, Multiple dose, Multi-center, Sequential 
Dose-escalation Study to Assess the Safety, Tolerability, Pha1macokinetics, Phannacodynamics 
and Efficacy ofTB006 in Patients with Mild to Severe Alzheimer's Disease 
I, the undersigned, have approved of the clinical trial protocol with the date of 15 Oct 2021. 
Name and Title 
PhaimD 
Clinical Development Lead 
TrneBinding, Inc 
300 Lincoln Center Drive 
Suite 200 
Foster City, CA 
94404 
CONFIDENTIAL 
Signature and Date 
DocuSigned by: 
V 
Signer Name: 
Signing Reas.on: I approve thie, document 
Signing lime: 15-Oct-2021I 16:22:13 EDT 
1OE33B247CD84 B92A681 F9ED03BD2773 
Page 2 of 101 


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL
Page 3 of 101 
INVESTIGATOR AGREEMENT
TB006AD2102: 
A Seamless Phase 1b/2a Double-blind, Randomized, Multiple dose, Multi-center, Sequential 
Dose-escalation Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics 
and Efficacy of TB006 in Patients with Mild to Severe Alzheimer’s Disease 
I have read the protocol, including all appendices, and I agree that it contains all the necessary 
information for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein, in compliance with current Good Clinical Practice (GCP) standards as defined 
by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) Guideline for GCP, all applicable national, state, and local laws and 
regulations, and the applicable Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) and other institutional requirements.  
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by TrueBinding, Inc. or specified designees. 
I will discuss the material with them to ensure that they are fully informed about TB006, 
understand this study, and are able to comply. 
______________________________
__________________________ 
Principal Investigator (printed) 
Signature 
______________________________ 
Date


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL
Page 4 of 101 
TABLE OF CONTENTS 
1
PROTOCOL SUMMARY ...........................................................................................13
1.1
Synopsis ..........................................................................................................................13
1.2
Schema ............................................................................................................................18
1.3
Schedule of Activities (SoA) ..........................................................................................20
2
INTRODUCTION ........................................................................................................31
2.1
Study Rationale ...............................................................................................................31
2.2
Background .....................................................................................................................31
2.2.1
Disease Background........................................................................................................31
2.2.2
Truebinding, Inc. Investigational Product Background: TB006 .....................................32
2.3
Benefit/Risk Assessment ................................................................................................33
2.3.1
Risk Assessment .............................................................................................................33
2.3.2
Benefit Assessment .........................................................................................................34
2.3.3
Overall Benefit Risk Conclusion ....................................................................................34
3
OBJECTIVES AND ENDPOINTS .............................................................................35
4
STUDY DESIGN...........................................................................................................38
4.1
Overall Design ................................................................................................................38
4.1.1
Study Duration for Participation .....................................................................................39
4.1.2
Number of Participants ...................................................................................................39
4.1.3
Replacement of Patients ..................................................................................................39
4.1.4
Number of Sites ..............................................................................................................39
4.2
Scientific Rationale for Study Design ............................................................................39
4.3
Justification for Dose ......................................................................................................40
4.4
End of Study ...................................................................................................................42
5
STUDY POPULATION ...............................................................................................43
5.1
Inclusion Criteria ............................................................................................................43
5.2
Exclusion Criteria ...........................................................................................................45
5.3
Lifestyle Considerations .................................................................................................46
5.3.1
Meals and Dietary Restrictions .......................................................................................46
5.3.2
Alcohol ............................................................................................................................46
5.3.3
Activity ...........................................................................................................................46
5.4
Screen Failures ................................................................................................................46
6
STUDY DRUG ..............................................................................................................48
6.1
Study Drug Administered ...............................................................................................48
6.2
Dose Modification ..........................................................................................................49
6.2.1
Dose Escalation and Stopping Considerations ...............................................................49
6.3
Preparation, Handling, Storage, and Accountability ......................................................49
6.4
Measures to Minimize Bias: Randomization and Blinding ............................................50
6.4.1
Randomization ................................................................................................................50
6.4.2
Blinding...........................................................................................................................50


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL
Page 5 of 101 
6.5
Study Intervention Compliance ......................................................................................51
6.6
Prior and Concomitant Therapy......................................................................................51
6.7
Study Drug After the End of the Study...........................................................................52
7
DISCONTINUATION OF STUDY DRUG AND PATIENT 
DISSCONTINUATION/WITHDRAWAL .................................................................53
7.1
Liver Injury .....................................................................................................................54
7.2
Cardiac Changes .............................................................................................................54
7.3
Lost to Follow up............................................................................................................54
8
STUDY ASSESSMENTS AND PROCEDURES.......................................................55
8.1
General Study Periods ....................................................................................................55
8.1.1
Screening, Enrollment and/or Randomization ................................................................55
8.1.2
Study Drug Administration and Follow-up Period.........................................................55
8.2
Safety Assessments .........................................................................................................55
8.2.1
Physical and Neurological Examinations .......................................................................56
8.2.2
Vital Signs.......................................................................................................................56
8.2.3
Electrocardiograms .........................................................................................................56
8.2.4
Clinical Safety Laboratory Assessments ........................................................................57
8.2.5
Suicidal Ideation and Behavior Risk Monitoring ...........................................................58
8.3
Adverse Events and Serious Adverse Events .................................................................59
8.3.1
Time Period and Frequency for Collecting Adverse Events and 
Serious Adverse Events Information ..............................................................................59
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events..............................................................................................................................59
8.3.3
Follow-up of Adverse Events and Serious Adverse Events ...........................................60
8.3.4
Regulatory Reporting Requirements for Serious Adverse Events ..................................60
8.3.5
Disease-related Events and/or Disease-related Outcomes not 
Qualifying as Adverse Events or Serious Adverse Events.............................................60
8.4
Treatment of Overdose ...................................................................................................61
8.5
Pharmacokinetics ............................................................................................................61
8.6
Pharmacodynamics .........................................................................................................62
8.6.1
Blood Samples for Biomarker Assessments ...................................................................62
8.6.2
Lumbar Puncture (Part 1 only) .......................................................................................62
8.6.3
Cognition Testing............................................................................................................62
8.6.4
Magnetic Resonance Imaging.........................................................................................64
8.6.5
Positron Emission Tomography ......................................................................................64
8.7
Pharmacogenetics ...........................................................................................................64
8.8
Immunogenicity Assessments.........................................................................................65
8.9
Total Volume of Blood Sampling ...................................................................................65
9
STATISTICAL CONSIDERATIONS........................................................................67
9.1
Statistical Hypotheses .....................................................................................................67
9.2
Sample Size Determination ............................................................................................67
9.3
Populations for Analyses ................................................................................................67
9.4
Statistical Analyses .........................................................................................................68


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL
Page 6 of 101 
9.4.1
General Considerations ...................................................................................................68
9.4.2
Part 1 Primary Endpoints................................................................................................68
9.4.3
Part 1 Exploratory Endpoints..........................................................................................69
9.4.4
Part 1 Other Analyses .....................................................................................................69
9.4.5
Part 2 Primary and Secondary Endpoints .......................................................................69
9.4.6
Part 2 Exploratory Endpoints..........................................................................................70
9.5
Interim Analysis ..............................................................................................................70
9.6
Safety Review Committee ..............................................................................................71
9.7
Handling of Missing Data...............................................................................................71
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ....................................................................................................72
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................72
10.1.1 
Regulatory and Ethical Considerations...........................................................................72
10.1.2 
Financial Disclosure........................................................................................................72
10.1.3 
Informed Consent Process ..............................................................................................72
10.1.4 
Data Protection................................................................................................................74
10.1.5 
Data Quality Assurance ..................................................................................................74
10.1.6 
Source Documents ..........................................................................................................75
10.1.7 
Protocol Deviations .........................................................................................................76
10.1.8 
Study and Site Start Closure ...........................................................................................76
10.1.9 
Publication Policy...........................................................................................................77
10.2
Appendix 2: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................78
10.2.1 
Definition of AE .............................................................................................................78
10.2.2 
Definition of Serious Adverse Event ..............................................................................79
10.2.3 
Recording and Follow-Up of AE and/or SAE................................................................80
10.2.4
Reporting of Serious Adverse Events.............................................................................83
10.2.5 
National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0...........................................................................................83
10.3
Appendix 3: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................85
10.3.1 
Rechallenge Following Liver Chemistry Events that are Possibly 
Related to Study Drug .....................................................................................................87
10.3.2 
Restart Following Transient Resolving Liver Chemistry Events 
Not Related to Study Drug ..............................................................................................88
10.4
Appendix 4: Diagnostic and Statistical Manual of Mental 
Disorders Fifth Edition Criteria for Major Neurocognitive 
Disorder (previously dementia) ......................................................................................90
10.5
Appendix 5: National Institute of Neurological and 
Communicative Disorders and Stroke – Alzheimer’s Disease and 
Related Disorder Association (NINCDS-ADRDA) – Criteria for 
Diagnosis of Probable Alzheimer’s Disease...................................................................91
10.6
Appendix 6: Protocol Amendment History ....................................................................92


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL
Page 7 of 101 
11
References ....................................................................................................................100


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL
Page 8 of 101 
LIST OF TABLES
Table 1.
Part 1 - Schedule of Activities ........................................................................... 20
Table 2.
Part 2 - Schedule of Activities ........................................................................... 26
Table 3.
Objectives and Endpoints .................................................................................. 35
Table 4.
Study Intervention(s) Administered .................................................................. 48
Table 5.
Protocol-required Clinical Safety Laboratory Assessments .............................. 58
Table 6.
Summary of Blood Sample Volumes for Part 1 ................................................ 65
Table 7.
Summary of Blood Sample Volumes for Part 2 ................................................ 66
Table 8.
Windows for PK Sample Collection ................................................................. 76
Table 9.
Phase 1 Liver Chemistry Stopping Criteria and Follow-up Assessments ......... 85


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL
Page 9 of 101 
LIST OF FIGURES
Figure 1. 
Study Design and Treatment Schema for Part 1 and 2 ..................................... 18
Figure 2.
Study Design and Treatment Schema – Interleave with Study TB006HV1101 19


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL
Page 10 of 101 
LIST OF ABBREVIATIONS 
AD
Alzheimer’s disease
ADL
activities of daily living
AE
adverse event
ALT
alanine aminotransferase
anti-HCV
hepatitis C virus antibody 
ApoE4
apolipoprotein E4 
AST
aspartate aminotransferase 
AUC
area under the curve 
AUC0–tau
area under the concentration-time curve from zero time to end of 
dosing period 
AUC0-  
area under the concentration-
at steady state
BMI
body mass index
CFR
Code of Federal Regulation 
CIOMS 
Council for International Organizations of Medical Sciences  
CL
Total clearance 
Cmax
maximum observed plasma concentration 
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials 
COVID 
coronavirus disease 
CPK
creatine phosphokinase
CRF
Case Report Form
CSF
cerebrospinal fluid
C-SSRS
Columbia Suicide Severity Rating Scale 
CT
computed tomography 
Ctrough
concentration at the end of a dosing interval
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug-induced liver injury 
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DRE
disease-related event
E/D
early discontinuation
ECG
electrocardiogram


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL
Page 11 of 101 
eCRF 
electronic Case Report Form
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle stimulating hormone  
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBsAg
hepatitis B surface antigen
HED
human equivalent dose
HRT
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
IEC
Independent Ethics Committee 
IgG4 
immunoglobulin G4
IgM anti-HBc
immunoglobulin M antibody to hepatitis B core antibody 
INR
international normalized ratio 
IRB
Institutional Review Board
IV
Intravenous(ly) 
IWRS 
Interactive Web Response System 
MAD
multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model for repeated measures 
MMSE
Mini-Mental State Examination 
NCI
National Cancer Institute 
NINCDS-ADRDA
National Institute of Neurological and Communicative Disorders and 
Stroke – Alzheimer’s Disease and Related Disorders Association 
NOAEL
no observed adverse effect level
NPI
neuropsychiatric inventory 
NPI-D
neuropsychiatric inventory caregiver distress


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL
Page 12 of 101 
PD 
pharmacodynamic(s) 
PDS
PD analysis set
PI
principal investigator
PK
pharmacokinetic(s)
PKS
PK analysis set
PT
preferred term
QTcB
QT interval corrected using Bazett’s formula
QTcF
QT interval corrected using Fridericia’s formula 
qw
weekly 
S228P
point mutation in human IgG4 at serine 228 to proline 
SAD 
single ascending dose 
SAE
serious adverse event 
SAP
statistical analysis plan
SAS
safety analysis set
SoA
schedule of activities 
SOC 
system organ class 
SRC
Safety Review Committee 
SUSAR
suspected unexpected serious adverse reaction 
t½
terminal elimination phase half-life 
tmax 
time at which maximum plasma concentration occurs 
ULN 
upper limit of normal 
US
United States
Vd
Volume of distribution
WOCBP
woman of childbearing potential


Compound: TB006 
Protocol TB006AD2102 
T rneBinding, Inc. 
Protocol Date and Version: 15 Oct 2021; v 3.0 
1 PROTOCOLSUMMARY 
1.1 Synopsis 
Protocol Title: 
A Seamless Phase 1 b/2a Double-blind, Randomized, Multiple dose, Multi-center, Sequential 
Dose-escalation Study to Assess the Safety, Tolerability, Phaim acokinetics, Phaim acodynamics 
and Efficacy ofTB006 in Patients with Mild to Severe Alzheimer's Disease 
Short Title: 
A Phase 1 b/2a, multi-dose, multi-center study to assess the safety, tolerability, phaimacokinetics, 
phannacodynamics, and efficacy of TB006 in patients with Alzheimer's Disease. 
Rationale: 
The TB006 nonclinical pha1macology program establishes its potential as a therapeutic agent for 
AD by neutralizing Gal-3, which regulates the production and accumulation of AP and tau 
proteins and is overexpressed in AD. The preclinical data have shown evidence of addressing 
underlying disease pathology and improving cognition. 
The preclinical safety profile of TB006 further suppo11s the clinical investigation of TB006. 
This is a seamless, two-part Phase 1 b/2a combined MAD and proof of concept study in patients 
with AD. Paii l of the study will evaluate the safety, tolerability, PK, PD and efficacy of qw 
doses of TB006, administered as an IV infusion over 1 how-. Paii l of this study will be 
conducted in parallel with the Phase 1 SAD study (Protocol number TB006HV1101). Each dose 
level in this study will staii after the safety, tolerability, and PK of the single dose equivalent to 
the combined total of the 5 qw doses has been established. In Pa11 2 of this study, emollment will 
continue at the highest tolerated dose from Paii l . Part 2 will assess the efficacy of TB006 on 
cognition using the Clinical Dementia Rating scale - Sum of Boxes as the primary endpoint. 
Patients emolled at the saine dose level in Part 1, as well as all placebo patients, will be included 
in the efficacy analyses in Paii 2. Randomization in Pait 2 will be stratified according to patient 
severity. 
Objectives and Endpoints: 
OBJECTIVES -PART 1 
ENDPOINTS 
Primary 
• To dete1mine the safety and 
• Safety endpoints, including the incidence of 
tolerability of multiple doses of 
AEs and SAEs, clinical laboratory 
TB006 
pai·aineters, vital signs, ECGs, C-SSRS, and 
physical and nemological examinations, until 
Day 104 after the first TB006 dosing 
• To dete1mine the PK profile of 
• PK pai·ameters derived by noncompa1imental 
multiple doses ofTB006 
analysis using the TB006 plasma 
CONFIDENTIAL 
Page 13 of 101 


Compound: TB006 
Protocol TB006AD2102 
T rneBinding, Inc. 
Protocol Date and Version: 15 Oct 2021; v 3.0 
• 
To detennine the maximum tolerated 
dose of multiple doses of TB006 
• 
To assess the immunogenicity of 
TB006 (production of anti-TB006 
antibody) 
concentrntion-time data, including, but not 
limited to and as appropriate: 
o AUCtau: area under the concentrntion-time 
curve over a dosing interval 
o 
Cmax: maximum observed plasma 
concentration 
o tmax: time at which maximum plasma 
concentration occurs 
o 
C1roug1i: concentrntion at the end of a 
dosing interval 
o 
t½: tenninal elimination phase half-life 
o CL: total clearance 
o V d: volume of distribution 
• 
Extent of CSF disti·ibution as estimated by 
TB006 CSF concentrations 
• 
Safety endpoints as above 
• 
Detection of anti-TB006 antibodies 
• 
Change from baseline through end of study 
on the Clinical Dementia Rating scale - Sum 
of Boxes total score 
• 
Change from baseline through end of study 
on the Cognitive Drng Research system 
battery score, composite scores and individual 
task measures 
• 
Change from baseline through end of study 
on the MMSE score 
• 
Change from baseline through end of study 
on the NPI score 
• 
• 
CONFIDENTIAL 
Page 14 of 101 


Compound: TB006 
Protocol TB006AD2102 
T rneBinding, Inc. 
Protocol Date and Version: 15 Oct 2021; v 3.0 
OBJECTIVES - PART 2 
Primary 
• 
To detennine the clinical efficacy of 
TB006 in patients with mild to severe 
AD 
Secondary 
• 
To detennine the clinical efficacy of 
TB006 in patients with mild to severe 
AD 
• 
To detennine the safety and 
tolerability of multiple doses of TB006 
• 
To detennine the PK following 
multiple doses of TB006 
ENDPOINTS 
• 
Change from baseline through Day 104 on the 
Clinical Dementia Rating scale - Sum of 
Boxes total score 
• 
Change from baseline through Day 36 on the 
Clinical Dementia Rating scale - Sum of 
Boxes total score 
• 
Propo1iion of responders on the Clinical 
Dementia Rating scale - Sum of Boxes at 
Days 36 and 104 
• 
Change from baseline to Days 36 and 104 on 
the Cognitive Drng Research System Batte1y , 
composite scores and individual task 
measures 
• 
Change from baseline to Days 36 and 104 on 
the MMSE score 
• 
Change from baseline to Days 36 and 104 on 
the NPI score 
• 
Safety endpoints, including the incidence of 
AEs and SAEs, clinical laborato1y parameters, 
vital signs, ECGs, C-SSRS, and physical and 
neurological examinations, until Day 104 after 
the first TB006 dosing 
• 
PK parameters including, but not liinited to, 
by Ct.rough, Cmax, and t½. 
CONFIDENTIAL 
Page 15 of 101 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Examination; 
NPI = Neuropsychiatric Inventory; 
PK = phannacokinetic(s); SAE = senous a verse even. 
Overall Design: 
T rneBinding, Inc. 
This is a seamless, two-pali Phase 1 b/Phase 2a, multi-center, randomized, double-blind, 
placebo-controlled study. Paii 1 is a-MAD escalation study to evaluate the safety, tolerability, 
PK, PD, and efficacy of TB006 in patients with AD. Pa1i 2 is a multi-center, randomized, 
double-blind, placebo-controlled, pai·allel-group study to evaluate the efficacy of TB006 after 
1 month of ti·eatment. The total study duration for each patient will be up to approximately 
19 weeks. 
Patients will receive a total of 5 doses, given in qw intervals. In Paii 1, the planned staiting dose 
in Group 1 will be 140 mg qw for 5 weeks. Subsequent planned doses ai·e 420 and 1,000 mg qw 
for Groups 2 and 3, respectively. The planned dose in Paii 2 will be the highest safe and 
well-tolerated dose from Paii 1. All doses ai·e infused IV over 1 hour. Paii 1 will interleave with 
the SAD study (Study TB006HV1101). Each group in Pa1i 1 will commence after the safety, 
tolerability, and PK of the single dose equivalent to the combined total of 5 qw doses planned in 
this study has been established (minimum of 14 days from last patient dosing). Explicitly, dosing 
in Group 1 (140 mg qw) will commence when the safety and tolerability of the 700 mg single 
dose in the SAD study has been established. Groups 2 ( 420 mg qw) and 3 (1,000 mg qw) will 
begin after a review of the available safety, tolerability and PK data from the previous group; and 
after the 2,100 and 5,000 mg single dose, respectively, has been administered. Dose levels may 
be adjusted depending on the safety, tolerability, and PK of doses in the SAD study and previous 
groups in this study. Patients will be emolled across all active centers into each dose group 
sequentially. 
In Paii 1, 8 patients will be emolled into each dose group; 6 patients in each group will be 
randomized to active TB006 ti·eatment, and 2 patients to placebo. 
Dose escalation decisions will use safety, tolerability and available PK data through the first dose 
administered to the last patient in each group and a minimum of 14 days from the respective dose 
group in the SAD study (Protocol number TB006HV1101). Data will be reviewed by a blinded 
SRC. 
Paii 2 will commence after the last patient in Paii 1 has received their first dose. The planned 
dose in Paii 2 will be 1,000 mg qw x 5 doses, but may be adjusted depending on the safety and 
tolerability of the doses in Pait 1. Patients will be randomized to active TB006 or placebo (1: 1) 
and will follow the same dosing schedule and procedures (with some exceptions - see Pait 2 
SoA) as in Paii 1. Randomization in Pali 2 will be sti·atified according to baseline patient 
CONFIDENTIAL 
Page 16 of 101 


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL
Page 17 of 101 
severity, with mild AD patients (MMSE 21-24) and moderate-severe AD patient
in each strata.
This is an outpatient study. Patients will return to the clinic for screening and baseline 
procedures, on dosing days, and on follow-up visits. Patients will have the option of checking 
into the clinic and staying overnight on Day -2 or Day -1, as well as on days prior to the other 
dosing days. 
Assessments for safety and tolerability, efficacy, PK, and PD are performed throughout the 
study. If a patient reports any AEs, they may be required to return to the clinical unit at the 
discretion of the investigator for additional assessments. All AEs must be followed to adequate 
resolution. 
Disclosure Statement: This is a randomized, placebo-controlled, sequential and parallel group 
treatment study that is patient and investigator blinded. 
Number of Participants: 
In Part 1, 8 patients will be enrolled into each dose group, thus a total of approximately 
24 patients will be randomized in this portion of the study. In Part 2, 116 patients will be 
enrolled, 58 into active TB006 treatment and 58 to placebo. 
Dose Groups and Duration: 
In Part 1, three dose groups are planned, each representing one dose level of TB006 or placebo. 
In Part 2, two groups (active TB006 and placebo) are planned. 
Each patient will be screened for eligibility up to 28 days prior to first dosing, and study 
assessments will be performed up to 104 days after first dosing. The total study duration for each 
patient will therefore be up to approximately 19 weeks. 
Data Monitoring/Other Committee: In Part 1 only 


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL
Page 18 of 101 
1.2 Schema 
Figure 1. 
Study Design and Treatment Schema for Part 1 and 2
* Study drug administration
Note: Visit days and procedures will occur during a window of ± 2 days from Day 1 to End of Treatment.
D  Day; IV  
ekly.
PART l 
(Groups 1- 31 
0-28 
0-1 01• 
os• 
0 15" 022• 029" 
036 
043 
064 
0104 
Group 1 
I Se,e,,,;ro,. I I I I I I 
I 
I 
J40mgqwTll006 
(n-6) Placebo IV 
(n=2) 
I 
Dose escolor,on dec1s1on occursajrer losrpatrent rece,ves 
first dose in this group 
0·28 
O·l 
01• 
08' 
015* 022• 029' 
036 
043 
064 
0104 
Group2 
420 mg qw T6006 
(n 6) Placebo IV 
(n 2) 
I Screening I I I I I I 
I 
I 
-----i Oose1r.,calation decision occm$u{tef Jhst {)l)l;e,,, receives 
l r,,sr dose in a,;s group 
~------~ D-28 
D-1 
Dl* 
os• 
0 1s• 
022• 029• 
036 
043 
D64 
Group3 
1000mg(lwl~006 
(n=61 Placebo IV 
(n=2) 
I Screening I I I I I I 
I 
I 
£nrollme111 ;r, (Jur I 2 begir1$ when last 
putienl enrolled I eceives fir st dose 
0-28 
0-1 
D1* 
D36 
D104 
D43 
D64 
0104 
Part2 
I Screening I I I I I I I 
1000mgqwTB006 
>---~-+--+---+--+---+---<---+-----+-----+--------i 
PART2 
(n °8) Placebo IV 
(n- 58) 
= intravenously, qw = we 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Figure 2. 
Study Design and Treatment Schema - Interleave with Study TB006HV1101 
ITB006HVI IOI I 
I TB006AD2 I 02 I 
~-~
0-42 
CH 01• 
014 
.,..., 1 I . 
I 
tOf!le 18006/ 11-=
5""'"'=""'"--+--+------+------------l 
Placebo IV 
I ""'"''"'""'"' .... ~, 
0 7S 
07S 
S.000n'l8l0006/ 1-S."''""""'"'"""--+--+------+------------l 
....... I . I 
f"MebolV 
I 
014 
T rneBinding, Inc. 
0104 
0 104 
0104 
034 
I 
... 
I 
0104 
-tDosing in Group 1 (140 mg TB006/placebo qw) w-ill collllllence when the safety and tolerability of the 700 mg single dose in the SAD study has been established. Groups 2 
( 420 mg TB006/placeho qw) and 3 (1,000 mg TB006/placeho qw) will begin after a review of the available safety, tolerability and PK data from the previous group; and after the 
2,100 and 5,000 mg, respectively, have been administered. 
* Study dmg administration 
Note: Visit days and procedw-es will occw- dw-ing a window of± 2 days from Day 1 to End of Treatment 
D = Day; IV= intravenously; PK = phannacokinetic; qw = weekly; SAD = severe Alzheimer's Disease. 
CONFIDENTIAL 
Page 19 of 101 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
1.3 Schedule of Activities (SoA) 
Table 1. 
Part 1 - Schedule of Activities 
.. 
i:J) f",l 
·= Q 
M 
" 
= 0 
.... 
I 
I 
.... 
.. 
Q0 
Q 
Q -
I 
Q 
N 
<.J N 
Q 
00 
I 
Q 
Informed consent 
X 
Eligibility criteria 
X 
X 
Medical history" 
(includes substance 
X 
X 
X 
usage) 
Demography 
X 
Physical and 
new-ological 
X 
X 
examination 
Randomization 
X 
CONFIDENTIAL 
Q0 
Q 
T rneBinding, Inc. 
I 
Study Drug Administration Period 
Notes 
0 
r--
" 
t"') 
...,. 
.. 
" 
" 
oi-i 
N 
M 
N 
0'I 
t"') 
...,. 
.0 
.... 
I 
I 
I 
IC 
...,. 
0 
Q 
I 
.... 
IC 
N 
t"') 
N 
0 
t"') 
IC 
.... 
---
0\ 
Q 
.... 
Q 
N 
Q 
t"') 
Q 
Q 
Q 
Q 
Q 
Q 
Q 
General and Safety Assessments 
I 
Recheck eligibility before 
randomization and/or first dose of 
study drug 
Medical occurrences that begin 
before the sta1t of study drng but 
after obtaining infonned consent 
will be recorded on the Medical 
History/CmTent Medical Conditions 
section of the CRF, not the AE 
section 
Physical examination will include 
X 
X 
X 
height (screening only) and weight 
measm·ements; see also 
Section 8.2.1 
Page 20 of 101 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Table 1. 
Part 1 - Schedule of Activities 
.. 
i:J) f",l 
·= Q 
M 
" 
= 0 
.... 
I 
I 
t .... 
.. 
Q 
Q -
I 
""' Q0 
Q 
N 
<.J N 
Q 
00 
I 
Q 
Vital signs 
X 
X 
X 
12-lead ECG 
X 
X 
X 
AE monitoring 
X 
X 
Prior/ concomitant 
X 
X 
X 
X 
X 
medication review 
C-SSRS 
X 
X 
CONFIDENTIAL 
Q0 
Q 
X 
X 
X 
X 
X 
T rneBinding, Inc. 
I 
Study Drug Administration Period 
Notes 
0 
r--
" 
" 
...,. 
.. 
" 
t"') 
oi-i 
N 
M 
N 
0'I 
«-;> 
" 
...,. 
.0 
.... 
I 
I 
IC 
...,. 
0 
Q 
I 
.... 
IC 
N 
t"') 
N 
0 
t"') 
IC 
.... 
---
0\ 
Q 
.... 
Q 
N 
Q 
t"') 
Q 
Q 
Q 
Q 
Q 
Q 
Q 
Pre-dose, then 2 and 6 hours after 
the end of the study dmg infusion 
X 
X 
X 
X 
X 
X 
X 
on Dl , D8, Dl5, D22, D29; 
othe1wise once on the days 
indicated; see Section 8.2.2 for vital 
signs assessments 
Dl , D8, Dl 5, D22, D29: pre-dose, 
then 2 and 6 hours after end of study 
dmg infusion 
X 
X 
X 
X 
X 
X 
X 
D -1, D36, D64, Dl04, EID: 
time-matched with Dl, D8, Dl5, 
D22, D29 pre-dose to the extent 
possible 
All AEs and SAEs will be collected 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
from the time of the first study dmg 
administration until D 104. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 21 of 101 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Table 1. 
Part 1 - Schedule of Activities 
.. 
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·= Q 
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= 0 
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Q 
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<.J N 
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00 
I 
Q 
Clinical unit 
confinement 
X 
X 
X 
Outpatient visit 
X 
Site to contact patient 
X 
Viral serology (HBsAg, 
IGM anti-HBc, 
X 
anti-HCV, HIV) and 
COVID-19 
Urine alcohol 
X 
X 
Drug screening 
X 
X 
CONFIDENTIAL 
Q0 
Q 
X 
T rneBinding, Inc. 
I 
Study Drug Administration Period 
Notes 
0 
r--
" 
" 
...,. 
.. 
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At least 6 how-s following study 
drug administration on dosing days; 
discharge from the clinical unit will 
be at the discretion of the 
investigator provided there are no 
X 
X 
X 
safety concerns identified from 
review of the clinical data. 
Optional overnight confinement 
from either D -2 or D -1 and on 
days prior to other dosing days (D7, 
Dl4, D21, D28) 
If the patient is not overnight 
X 
X 
X 
X 
confined on D -1 ( see above), the 
D -1 visit will be an outpatient visit 
Investigator or designee to 
X 
X 
X 
X 
telephone the patient between D2-6, 
D9-13, Dl6-20, D23-27, and D30-
34 
Central Laboratory Assessments 
I 
X 
X 
Locally performed at site 
X 
X 
Page 22 of 101 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Table 1. 
Part 1 - Schedule of Activities 
Clinical laboratory tests 
( clinical chernistry, 
hematology, urinalysis) 
.. 
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X 
X 
X 
Pharmacodynamic Assessments: Cognition Testing, MRI, Blood Samples 
MMSE 
Clinical Dementia 
Rating scale 
Cognitive Drug 
Research Dementia 
Rating battery' 
NPI 
assessment 
Study drug IV infusion 
CONFIDENTIAL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Treatment 
X 
X 
X 
X 
X 
Page 23 of 101 
T rneBinding, Inc. 
Notes 
Fluid biomarkers will be detennined 
in plasma 


Compound: TB006 
Protocol TB006AD2102 
T rneBinding, Inc. 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Table 1. 
Part 1 - Schedule of Activities 
.. 
Study Drug Administration Period 
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Blood sample for PK 
assessment 
X 
X 
X 
X 
Blood sample for ApoE4 
X 
genotyping 
I 
Pharmacokinetics and Pha1·macodynamics 
Blood sample for ADA 
assessment 
Lumbar puncture for 
CSF collectione 
X 
X 
X 
X 
X 
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Notes 
Pre-dose, end of infusion, then 1, 2, 
4, and 6 hours after the end of 
infusion on Dl, D8, and D29; single 
time point on other days 
Optional ApoE4 sampling is 
collected at screening but can be 
taken at any visit until the last study 
visit (Section 8.7) 
ADA assessment is performed on 
blood sample collected for PK 
assessments; D 1 and D8 assessment 
is perfonned on the pre-dose sample 
Lumbar puncture indicated for D-1 
can be performed any time betv.re.en 
D-8 and D-1 
CSF biomarkers, and TB006 levels 
will be detennined in CSF 
AD = Alzheimer's Disease; ADA = anti-dtug antibody; AE = adverse event; anti-HCV = hepatitis C vims antibody; 
ApoE4 = apohpoprotein E4; COVID = coronavirus disease; CRF = case report form; C-SSRS = Columbia Suicide Severity Rating Scale; CSF = cerebrospmal 
fluid; D = Day; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; ECG = electrocardiogram; EID = Early Discontinuation; 
HBsAg = hepatitis B surface anti<>en; I<> 
anti-HBc = immunoglobulin M antibody to hepatitis B core antibody; IV = intravenous(ly); MMSE = Mini-Mental 
State Examination; 
NINCDS-ADRDA = National Institute of Neurological and Communicative Disorders and Stroke -
Alzheimer's Disease an Re ate Disor ers Association; NPI = Neuropsychiati·ic Inventory; PD = phannacodynamic(s); 
PK = pharmacokinetic(s); SAE = serious adverse event. 
a 
Visit days and procedures are allowed a window of± 2 days from Day 1 to End ofTreatinent. 
CONFIDENTIAL 
Page 24 of 101 
I 
I 
I 


Compound: TB006 
TrueBinding, Inc. 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0
CONFIDENTIAL
Page 25 of 101 
b 
Applicable only for patients who discontinue early from the study. 
c 
The medical history assessed at the screening visit should include prior AD treatment assessment(s). Establishing the clinical diagnosis of AD should include 
use of criteria from the DSM-5 – Criteria for Major Neurocognitive Disorder (previously dementia) (Section, 10.4, Appendix 4) and the NINCDS-ADRDA 
(Note: ADRDA is now the Alzheimer’s Association) (Section 10.5, Appendix 5). 
d The Cognitive Drug Research battery is to be performed twice during the screening visit in both Part 1 and Part 2. 
e The lumbar puncture procedure is optional. 
f 
 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Table 2. 
Part 2 - Schedule of Activities 
.. 
1:.1) f",l 
·= Q 
N 
" 
= 0 
.... 
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I 
I 
.. 
I,,, Q0 
Q 
Q -
I 
Q 
N 
<.J N 
Q 
00 
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Informed consent 
X 
Eligibility criteria 
X 
X 
Medical history" 
(includes substance 
X 
X 
X 
usage) 
Demography 
X 
Physical and 
neurological 
X 
X 
examination 
Randomization 
X 
Vital signs 
X 
X 
X 
CONFIDENTIAL 
Q0 
Q 
X 
T rneBinding, Inc. 
I 
Study Drug Administration Period 
Notes 
0 
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.. 
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N 
" 
N 
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-
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Q 
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r'l 
Q 
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Q 
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Q 
Q 
General and Safety Assessments 
I 
Recheck eligibility before 
randomization and/or first dose of 
studydrng 
Medical occun-ences that begin 
before the start of study drng but 
after obtaining informed consent 
will be recorded on the Medical 
Histo1y/Ctment Medical 
Conditions section of the CRF, not 
the AE section 
Physical examination will include 
X 
X 
X 
height (screening only) and weight 
measurements; se.e also 
Section 8.2.1 
Pre-dose, then 2 and 6 hours after 
the end of the study drng infusion 
X 
X 
X 
X 
X 
X 
X 
on Dl, D8, Dl5, D22, D29; 
othe1wise once on the days 
indicated; see Section 8.2.2 for 
vital signs assessments 
Page 26 of 101 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Table 2. 
Part 2 - Schedule of Activities 
.. 
i:J) f",l 
·= Q 
r-1 
" 
= 0 
.... 
t .... 
I 
I 
.. 
Q 
Q 
""' 00 
-
I 
Q 
N 
<.J N 
Q 
00 
I 
Q 
12-lead ECG 
X 
X 
X 
AE monitoring 
X 
X 
Prior/ concomitant 
X 
X 
X 
X 
X 
medication review 
C-SSRS 
X 
X 
Clinical unit 
confinement 
X 
X 
X 
CONFIDENTIAL 
00 
Q 
X 
X 
X 
X 
X 
T rneBinding, Inc. 
I 
Study Drug Administration Period 
Notes 
0 
r--
.. 
:::l 
oi-i 
N 
" 
N 
0\ 
.. 
.0 
N 
Q 
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.... 
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N 
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Q 
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i:..l 
Q 
Q 
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Q 
Dl, D8, Dl5, D22, D29: pre-dose, 
then after end of study chug 
infusion 
X 
X 
X 
X 
X 
X 
D -1, D36, Dl04, EID: 
time-matched with Dl, D8, Dl5, 
D22, D29 pre-dose to the extent 
possible 
All AEs and SAEs will be 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
collected from the time of the first 
study drng administration until 
Dl04. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
At least 6 hours following study 
dmg adrninistration on dosing 
days; discharge from the clinical 
unit will be at the discretion of the 
investigator provided there are no 
X 
X 
X 
safety concerns identified from 
review of the clinical data. 
Optional overnight confinement 
from either D -2 or D -1 and on 
days prior to other dosing days 
(D7, Dl4, D2 1, D28) 
Page 27 of 101 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Table 2. 
Part 2 - Schedule of Activities 
.. 
i:J) f",l 
·= Q 
r-1 
" 
= 0 
.... 
t .... 
I 
I 
.. 
Q 
Q 
""' 00 
-
I 
Q 
N 
<.J N 
Q 
00 
I 
Q 
Outpatient visit 
X 
Site to contact patient 
X 
Viral serology (HBsAg, 
IGM anti-HBc, 
X 
anti-HCV, HIV) and 
COVID-19 
Urine alcohol 
X 
X 
Drug screening 
X 
X 
Clinical laboratory tests 
( clinical chemistry, 
X 
X 
hematology, urinalysis) 
00 
Q 
X 
Study Drug Administration Period 
0 
r--
.. 
:::l 
oi-i 
N 
" 
N 
0\ 
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X 
X 
X 
X 
X 
X 
X 
X 
Central Laborato1-y Assessments 
X 
X 
X 
X 
X 
X 
X 
X 
Pha1·macodynamic Assessments: Cognition Testing, MRI, Blood Samples 
MMSE 
X 
X 
X 
X 
X 
X 
X 
Clinical Dementia 
X 
X 
X 
X 
X 
X 
Rating scale 
Cognitive Drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research System 
battery'1 
NPI 
X 
X 
X 
X 
X 
CONFIDENTIAL 
Page 28 of 101 
T rneBinding, Inc. 
I 
Notes 
If the patient is not ovemight 
confined on D -1 (see above), the 
D -1 visit will be an outpatient visit 
Investigator or designee to 
telephone the patient between 
D2-6, D9-13, D16-20, D23-27, and 
D30-34 
I 
Locally performed at site 
I 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Table 2. 
Part 2 - Schedule of Activities 
assessment 
y 
s 
Blood sample for PK 
assessment 
Blood sample for ADA 
assessment 
Blood sample for ApoE4 
genotyping 
.. 
i:J) f",l 
·= Q 
= .s 
t 
""' 00 
<.J N 
00 
I 
Q 
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r-1 
" .... 
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I 
.. 
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00 
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T rneBinding, Inc. 
Study Drug Administration Period 
Notes 
0 
r--
.. 
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N 
" 
N 
0\ 
N 
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.... 
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N 
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Q\ 
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Q 
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X 
Q 
ff') 
Q 
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ff') 
-
Q 
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.0 
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..._ 
i:..l 
Fluid biomarkers will be 
detennined in plasma 
Pre-dose and the end of infusion on 
X 
X 
X 
X 
D 1 and D29; single sample on 
X 
X 
other days 
ADA assessment is performed on 
blood sample collected for PK 
assessments; D 1 assessment is 
perfonned on the pre-dose sample 
Optional ApoE4 sampling is 
collected at screening but can be 
taken at any visit until the last 
study visit (Section 8.7) 
AD= Alzheimer's Disease; ADA= anti-dtug antibody; AE = adverse event; anti-HCV = hepatitis C vims antibody; 
ApoE4 = apo 1poprotein E4; COVID = coronavirus disease; CRF = case report form; C-SSRS = Columbia Suicide Severity Rating Scale; CSF = cerebrospinal 
fluid; D = Day; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; ECG= electrocardiogram; EID= Eady Discontinuation; 
HBsAg = hepatitis B surface antioen; lo 
anti-HBc = immunoglobulin M antibody to hepatitis B core antibody; IV= intravenous(ly); MMSE = Mini-Mental 
State Examination; 
NINCDS-ADRDA = National Institute of Neurological and Communicative Disorders and Stroke -
Alzheimer's Disease an 
e ate 
ISor ers ssociation; NPI = Neuropsychiati·ic Inventory; 
PD= phannacodynamic(s); 
PK = phannacokinetic(s); SAE = serious adverse event. 
CONFIDENTIAL 
Page 29 of 101 


Compound: TB006 
TrueBinding, Inc. 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0
CONFIDENTIAL
Page 30 of 101 
a 
Visit days and procedures are allowed a window of ± 2 days from Day 1 to End of Treatment. 
b 
Applicable only for patients who discontinue early from the study. 
c 
The medical history assessed at the screening visit should include prior AD treatment assessment(s). Establishing the clinical diagnosis of AD should include 
use of criteria from the DSM-5 – Criteria for Major Neurocognitive Disorder (previously dementia) (Section, 10.3, Appendix 4) and the NINCDS-ADRDA 
(Note: ADRDA is now the Alzheimer’s Association) (Section 10.4, Appendix 5). 
d 
The Cognitive Drug Research battery is to be performed twice during the screening visit in both Part 1 and Part 2.
e 
 


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL 
Page 31 of 101 
2 INTRODUCTION 
TB006 is a humanized IgG4 (S228P) type monoclonal antibody, being developed by 
TrueBinding, Inc. for the treatment of AD. 
2.1
Study Rationale
The TB006 nonclinical pharmacology program establishes its potential as a therapeutic agent for 
AD by neutralizing Gal-
proteins and is overexpressed in AD. The preclinical data have shown evidence of addressing 
underlying disease pathology and improving cognition. 
The preclinical safety profile of TB006 further supports the clinical investigation of TB006. 
This is a two-part Phase 1b/2a combined MAD and proof of concept study in patients with AD. 
Part 1 of the study will evaluate the safety, tolerability, PK, PD and efficacy of TB006, 
administered qw as an IV infusion over 1 hour. Part 1 of this study will be conducted in parallel 
with the Phase 1 SAD study (Protocol number TB006HV1101). Each dose level in this study 
will start after the safety, tolerability, and PK of the single dose equivalent to the combined total 
of the 5 qw doses has been established. In Part 2 of this study, enrollment will continue at the 
highest tolerated dose from Part 1. Part 2 will assess the efficacy of TB006 on cognition using 
the Clinical Dementia Rating scale – Sum of Boxes as the primary endpoint. Patients enrolled at 
the same dose level in Part 1, as well as all placebo patients, will be included in the efficacy 
analyses in Part 2. Randomization in Part 2 will be stratified according to patient severity. 
This study will characterize TB006 safety, tolerability, plasma and CSF PK, and efficacy. In 
, as well as cognition, using the Clinical Dementia Rating Scale, the MMSE, the 
Cognitive Drug Research system battery, and the NPI, will be evaluated. 
 
 
 
2.2 Background 
2.2.1 Disease Background 
AD is a chronic progressive neurodegenerative disorder and is the leading cause of dementia 
among older adults. In the US, AD is one of the leading causes of death, ranking sixth among US 
adults and fifth among adults aged 65 years or older (CDC, 2020). 
The most common and thoroughly investigated hypotheses proposed to explain the 
pathophysiology of AD are the amyloid hypothesis and tau hypothesis. Considerable evidence 
and tau initiate the disease cascade. Abnormal tau accumulates 
to form neurofibrillary tangles inside nerve bodies, where they destroy cell structure and interfere 
with neuronal function and communication. Eventually, cell death and brain atrophy result. 


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL 
Page 32 of 101 
Other factors that may also contribute to AD include insufficient blood and nutrient delivery of 
the vascular system to the brain and neuroinflammation which damages neurons in the brain. 
Drug development in the dementia arena has been highly active in the past 20 years. There are 
approximately 5 compounds with market approval, all of which aim to improve the symptoms of 
dementia. These “symptomatic” treatments may improve cognition in the short term but have no 
effect on the progression of the disease. More recently, therapies with large molecule antibodies 
have explored the impact of targeting the underlying pathology such as amyloid or damaged tau. 
These treatments seek to modify the course of the disease by slowing disease progression. 
Although some of these compounds have shown efficacy in patient subtypes and have 
demonstrated an acceptable safety and tolerability profile in clinical studies (Panza et al, 2019; 
Van Dyck, 2017), none have met their primary endpoint; ergo none have been approved for 
marketing. Therefore, an urgent unmet medical need remains for the treatment of AD. 
Key to the success of drug development in this patient population is the need to identify patients 
early in the course of their disease for treatment intervention. Patients with advanced 
symptomatic disease have significant demyelination, neuronal cell loss, and loss of volume. 
Early identification measures include advanced imaging, most notably MRI, CSF testing for the 
NIA, 2020; Risacher and 
Saykin, 2013).
2.2.2 Truebinding, Inc. Investigational Product Background: TB006 
Galectins are a ubiquitous group of proteins found in a variety of cells and tissues and are 
involved in numerous metabolic processes and functions. At least 15 galectin isotypes have been 
identified in epithelial cells of the respiratory system, digestive tract, urinary tract, skin, 
cardiovascular system, liver, immune cells, and in the CNS. Gal-3 plays an important role in 
different pathogenic conditions, including in neuroinflammatory and neurodegenerative 
disorders such as multiple sclerosis, AD, Parkinson’s disease, and Huntington’s disease. In 
addition, Gal-3 also plays a protective role due to its anti apoptotic effect in target cells. In vivo 
data from several investigators suggest that Gal-3 may be an important therapeutic target in 
pathological conditions including the disorders of the CNS. 
TB006 is a humanized IgG4 (S228P) type monoclonal antibody that is highly specific and has 
high affinity to human Gal-3. It has demonstrated the potential to treat neurodegenerative 
disorders such as AD and traumatic brain injury, with an apparent wide safety margin, in 
preclinical models.
Detailed information can be found in the TB006 IB (see latest available version of IB). 


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL 
Page 33 of 101 
2.3 Benefit/Risk Assessment 
Based on preclinical pharmacology data and nonclinical toxicity studies with TB006, the overall 
benefit/risk profile favors clinical development of TB006 for treatment of AD. 
More detailed information about the known and expected benefits and risks of TB006 based on 
data from the preclinical program may be found in the IB. 
2.3.1 Risk Assessment
A standard battery of toxicology studies was conducted with TB006. The pivotal safety 
assessment was a 1 month GLP toxicology study in cynomolgus monkeys. Doses ranged from 
10 to 200 mg/kg, and evaluation included clinical and laboratory observations, a 5 week recovery 
period, and full histopathology. No treatment related adverse findings were observed. Mild 
lymphoid hyperplasia occurred in males at the 10, 100, and 200 mg/kg dose levels, but based on 
mild severity, lack of dose dependency and historical test facility data from similar studies in 
cynomolgus monkeys, this finding was considered a species specific mild, reactive immune 
response and not an adverse toxicological finding. It is likely an immunogenicity reaction. No 
other findings were observed in this or any of the other toxicology studies. 
TB006 is a first in class monoclonal antibody, therefore there are no known class adverse effects 
or risks to report from clinical studies. In general, risks associated with other monoclonal 
antibodies include allergic reactions such as hives or itching, flu like symptoms such as chills, 
fatigue, fever, and muscle aches and pains, nausea and vomiting, skin rashes and decreases in 
blood pressure. These effects have not been observed in preclinical studies to date. Other 
marketed IgG4 humanized monoclonal antibodies, such as natalizumab, eculizumab, and 
pembrolizumab, are used clinically. These antibodies largely target the immune system. There 
appears to be a spectrum of target-related negative effects when the total antibody dose gets too 
high. This pattern is not evident with TB006 in the preclinical toxicology profile, but will be 
closely observed in Phase 1 studies. 
When performed correctly and according to industry standards, venipuncture complications are 
rare. However, even when properly performed, complications can include fainting, dizziness, 
hematoma, nerve injury, and arterial puncture or laceration. Blood draws and administration of 
the IV infusion in this study will be performed adequately trained medical staff to minimize any 
risk to patients. 
Risks associated with a lumbar puncture can include headache, pain or numbness, bleeding, 
infection, puncture pain, and herniation. The lumbar puncture procedure will be performed by 
medical staff experienced with the technique and using aseptic techniques to minimize any risk 
to patients.
MR images are performed without the use of ionizing radiation, so patients are not exposed to 
the harmful effects of ionizing radiation. AEs for MRI scans are very rare. Millions of MRI scans 
are performed in the US every year, and the FDA receives around 300 AE reports for MRI 
scanners and coils each year from manufacturers, distributors, user facilities, and patients. The 
majority of these reports describe heating and/or burns (thermal injuries). To produce good 


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL 
Page 34 of 101 
quality images, patients must generally remain very still throughout the entire MRI procedure. 
The MRI procedure will be performed by medical staff experienced with the equipment and the 
technique to minimize any risk to patients.
The safety assessments to be performed in this study, including clinical chemistry, hematology 
and urinalysis analyses, vital signs, ECGs, physical and neurological examinations, and 
assessments of AEs, SAEs, and C-SSRS are standard evaluations to ensure patient safety in this 
clinical study.
2.3.2
Benefit Assessment 
TB006 is a humanized IgG4 (S228P) type monoclonal antibody that is highly specific and has 
high affinity to human Gal-3. It has demonstrated efficacy in preclinical models of 
neurodegenerative disorders such as AD and traumatic brain injury, and results are consistent 
with or superior to other compounds that have advanced into late-stage clinical studies. Thus, 
there is potential for TB006 to be effective in these disorders. The preclinical safety profile of 
TB006 supports the further investigation of TB006 in clinical studies. 
Understanding that this therapy may have no clinical benefits to patients themselves, patients in 
this study will contribute to the process of developing new therapies in an area of unmet need. 
Patients will undergo clinical evaluations/assessments associated with study procedures (eg, 
safety laboratory tests, vital sign and ECG measurements, and physical and neurological 
examinations), which would be a potential benefit for their own health awareness.
During confinement in the clinic, meals and access to forms of entertainment will be provided to 
patients. Patient expenses for time, travel, and other costs will be offset by a monetary 
compensation, consistent with standards for such study participations and after approval from the 
IRB to ensure that no coercion or undue influence are imposed on patients. 
2.3.3 Overall Benefit Risk Conclusion 
The above benefit risk assessment supports the conduct of this clinical study. 
The preclinical data on TB006 to date suggests a wide margin of safety and minimal risk of 
adverse effects. The risks associated with study procedures, including lumbar puncture and blood 
draws, are also very low. Any potential adverse effects associated with the study drug and 
procedures are further minimized by intense safety monitoring and medical oversight by the 
investigator and study staff. Therefore, the potential risks identified in association with TB006 
are justified by the anticipated benefits that may be afforded to patients with AD, if TB006 is 
successfully developed. 
This study will be the second clinical study conducted with TB006. This study will be conducted 
in parallel and combined with the Phase 1 SAD study (Protocol number TB006HV1101). Each 
group in this study will commence after the safety, tolerability, and available PK of the single 
dose equivalent to the combined total of 5 qw doses planned in this study has been established. 


Compound: TB006 
Protocol TB006AD2102 
T rneBinding, Inc. 
Protocol Date and Version: 15 Oct 2021; v 3.0 
3 
OBJECTIVES AND ENDPOINTS 
Table 3. 
Objectives and Endpoints 
OBJECTIVES -PART 1 
Primary 
• 
To detennine the safety and 
tolerability of multiple doses of 
TB006 
• 
To determine the PK profile of 
multiple doses ofTB006 
ENDPOINTS 
• 
Safety endpoints, including the incidence of 
AEs and SAEs, clinical laboratory 
parameters, vital signs, ECGs, C-SSRS, and 
physical and neurological examinations, until 
Day 104 after the first TB006 dosing 
• 
PK parameters derived by noncompartmental 
analysis using the TB006 plasma 
concentrntion-time data, including, but not 
limited to and as appropriate: 
o AUCtau: area under the concentrntion-time 
curve over a dosing interval 
o 
Cmax: maximum observed plasma 
concentration 
o tmax: time at which maximum plasma 
concentration occurs 
o 
C1roug1i: concentrntion at the end of a 
dosing interval 
o 
t½: tenninal elimination phase half-life 
o CL: total clearance 
o V d: volume of distribution 
• 
Extent of CSF disti·ibution as estimated by 
TB006 CSF concentrations 
• 
To detennine the maximum tolerated 
• 
Safety endpoints as above 
dose of multiple doses of TB006 
• 
To assess the immunogenicity of 
• 
Detection of anti-TB006 antibodies 
TB006 (production of anti-TB006 
antibody) 
CONFIDENTIAL 
• 
Change from baseline through end of study 
on the Clinical Dementia Rating scale - Sum 
of Boxes total score 
Page 35 of 101 


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Protocol Date and Version: 15 Oct 2021; v 3.0 
OBJECTIVES - PART 2 
Primary 
• To detennine the clinical efficacy of 
TB006 in patients with mild to severe 
AD 
Secondary 
• To detennine the clinical efficacy of 
TB006 in patients with mild to severe 
AD 
• 
Change from baseline through end of study 
on the Cognitive Drng Research system 
battery score, composite scores and individual 
task measmes 
• 
Change from baseline through end of study 
on the MMSE score 
• 
Change from baseline through end of study 
on the NPI score 
ENDPOINTS 
• Change from baseline through Day 104 on the 
Clinical Dementia Rating scale - Sum of 
Boxes total score 
• Change from baseline through Day 36 on the 
Clinical Dementia Rating scale - Sum of 
Boxes total score 
• Propo1iion of responders on the Clinical 
Dementia Rating scale - Sum of Boxes at 
Days 36 and 104 
• Change from baseline to Days 36 and 104 on 
the Cognitive Drng Research System Batte1y , 
composite scores and individual task 
measm·es 
• Change from baseline to Days 36 and 104 on 
the MMSE score 
• Change from baseline to Days 36 and 104 on 
the NPI score 
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Compound: TB006 
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Protocol Date and Version: 15 Oct 2021; v 3.0 
• 
To detennine the safety and 
tolerability of multiple doses of TB006 
• 
To detennine the PK following 
multiple doses of TB006 
• 
Safety endpoints, including the incidence of 
AEs and SAEs, clinical laborato1y parameters, 
vital signs, ECGs, C-SSRS, and physical and 
neurological examinations, until Day 104 after 
the first TB006 dosing 
• 
PK parameters including, but not limited to, 
by Ctrough, Cma.x, and t½. 
AD = Alzheimer's Disease; AEs = adverse events· C-SSRS = Columbia Suicide Severity Rating Scale; 
CSF = cerebros inal fluid; D = Da ; ECG = electrocardio 
MMSE = Mini Mental State 
Examination; 
NPI = Neuropsychiatric Inventory; 
PK= phannacokinetic(s); SAE= serious adverse event. 
CONFIDENTIAL 
Page 37 of 101 


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4 STUDY DESIGN 
4.1 Overall Design 
This is a seamless, two-part, Phase 1b/2a, multi-center, randomized, double-blind, placebo-
controlled, MAD escalation study to evaluate the safety, tolerability, PK, PD and efficacy of 
TB006 in patients with AD. The total study duration for each patient will be up to approximately 
19 weeks. 
Patients will receive a total of 5 doses, given in qw intervals. In Part 1, the planned starting dose 
in Group 1 will be 140 mg qw for 5 weeks. Subsequent planned doses are 420 and 1,000 mg qw 
for Groups 2 and 3, respectively (the dosing group schedule is presented in Table 4). The 
planned dose in Part 2 will be the highest safe and well-tolerated dose from Part 1. All doses are 
infused IV over 1 hour. Part 1 will interleave with the SAD study (Study TB006HV1101). Each 
group in Part 1 will commence after the safety, tolerability, and PK of the single dose equivalent 
to the combined total of 5 qw doses planned in this study has been established (minimum of 
14 days from last patient dosing). Explicitly, dosing in Group 1 (140 mg qw) will commence 
when the safety and tolerability of the 700 mg single dose in the SAD study has been established. 
Groups 2 (420 mg qw) and 3 (700 mg qw) will begin after a review of the available safety, 
tolerability, and PK data from the previous group; and after the 2,100 and 5,000 mg single dose, 
respectively, has been administered. Dose levels may be adjusted depending on the safety, 
tolerability, and available PK of doses in the SAD study and previous groups in this study. 
Patients will be enrolled across all active centers into each dose group sequentially. 
In Part 1, 8 patients will be enrolled into each dose group (see Section 6.4.1 for details of 
randomization within each dose group). 
Dose escalation decisions will use safety, tolerability, and available PK data through the first 
dose administered to the last patient in each group and a minimum of 14 days from the respective 
dose group that has been dosed in the SAD study (Protocol number TB006HV1101). Data will 
be reviewed by a blinded SRC. Dose escalation and stopping rules are described in Section 6.2.1 
and details on the SRC are described in Section 9.6.  
Part 2 will commence after the last patient in Part 1 has received their first dose. The planned 
dose in Part 2 will be 1,000 mg qw × 5 doses, but may be adjusted depending on the safety and 
tolerability of the doses in Part 1. Patients will be randomized to active TB006 or placebo (1:1) 
and will follow the same dosing schedule and procedures (with some exceptions – see SoA) as in 
Part 1. Randomization in Part 2 will be stratified according to baseline patient severity, with mild 
AD patients (MMSE 21-24) and moderate-
 
This is an outpatient study. Patients will return to the clinic for screening and baseline 
procedures, on dosing days, and on follow-up visits. Patients will have the option of checking 
into the clinic and staying overnight on Day -2 or Day -1, as well as on days prior to the other 
dosing days. 


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Study assessments will be conducted, and patients will be dosed according to the SoA (Table 1 
and Table 2). Assessments for safety and tolerability, efficacy, PK, and PD are performed 
throughout the study (see Section 8). If a patient reports any AEs, they may be required to return 
to the clinical unit at the discretion of the investigator for additional assessments. All AEs must 
be followed to adequate resolution. 
4.1.1 Study Duration for Participation  
Each patient will be screened for eligibility up to 28 days prior to dosing, and study assessments 
will be performed up to 104 days after the first dose. The total study duration for each patient 
will therefore be up to approximately 19 weeks. 
4.1.2 Number of Participants  
In Part 1, 8 patients will be enrolled into each dose group, thus a total of approximately 
24 patients will be randomized in this portion of the study (see Section 6.4.2 for details on 
randomization). In Part 2, 116 patients will be enrolled; 58 into active TB006 treatment and 58 to 
placebo. 
The sample size determination is presented in Section 9.2. 
4.1.3 Replacement of Patients  
Patients who discontinue early from Part 1 of the study may be replaced, depending on when the 
discontinuation occurs. Replacement patients will receive the same treatment to which the 
discontinued patient was assigned. Patients who discontinue from Part 2 of the study will not be 
replaced. 
4.1.4 Number of Sites 
There are approximately 12 to 15 sites in this multi-center study, all in the US. 
4.2
Scientific Rationale for Study Design
This is a seamless, two-part, Phase 1b/2a combined MAD and proof of concept study to assess 
the safety, tolerability, efficacy, PK, and PD of TB006 in AD patients. 
An AD patient population is included in the study to determine the safety and tolerability of 
TB006 in the patient population that is being pursued for development. A mild to severe patient 
population is the tentative population of interest because they have the greatest medical need of 
the AD population and afford a large opportunity for improvement. TB006 may do more than 
simply halt disease progression. If it can improve cognition, the mild to severe population is 
where it is most likely to be detected. Patients with significant comorbidities are excluded to 
avoid confounding the interpretation of safety data.
Randomization will be used in this study to avoid bias in the assignment of patients to treatment, 
to prevent introducing bias into evaluations, to increase the likelihood that known and unknown 
patient attributes (eg, demographics and baseline characteristics) are balanced across dose 
groups, and to ensure the validity of statistical comparisons across treatment groups. 


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In Part 1, 8 patients per dose group (6 patients randomized to TB006 and 2 patients to placebo) 
are considered adequate to evaluate initial safety and PK in AD patients, and to support dose 
escalation decisions. In Part 2, patients will be randomized to TB006 or placebo in a 1:1 ratio 
-24]) so that approximately 58 patients are 
assigned to each group. Part 2 will assess the efficacy of TB006 on cognition using the Clinical 
Dementia Rating Scale – Sum of Boxes as the primary endpoint. Patients enrolled at the same 
dose level in Part 1, as well as all placebo patients, will be included in the efficacy analyses in 
Part 2. 
Dose escalation decisions in Part 1, as well as dose selection for Part 2, will use safety, 
tolerability, and available PK data through the first dose administered to the last patient in each 
group and single dose safety and tolerability data from the SAD study (Protocol number 
TB006HV1101). 
All clinical and laboratory assessments are standard measurements commonly used in Phase 1 
studies to ensure patient safety. 
Serial sampling to evaluate the repeat-dose PK profile of TB006 will be applied in Part 1 of this 
study, sparse sampling will be used in Part 2.  
The interleave design with the SAD study is to ensure an efficient completion of the Phase 1 
studies, while ensuring that safety and tolerability at the exposures in this study are adequately 
established in the SAD study. 
as well as nonspecific 
biomarkers such as 
, are being collected and measured to assess target binding and 
target engagement. Patients will perform a battery of cognition tests, including the MMSE, the 
Cognitive Dementia Rating Scale, the Cognitive Drug Research system battery, and the NPI 
throughout the study to assess cognition. 
 
 
The rationale for the selection of doses in this study is described in Section 4.3. 
4.3 Justification for Dose 
The selection of doses in the SAD study was made after a careful assessment of the preclinical 
pharmacology and toxicology data while allowing for cautious escalation to the highest safe 
exposures or the maximum tolerated dose (FDA, 2005). The doses planned for this study are 
tentative and may be adjusted based on safety, tolerability, and available PK data from the SAD 
study and the previous group(s) in this study. The intent is to maintain the safety margins as 
described here.
The preclinical safety of TB006 was explored in a definitive 1 month GLP toxicology study in 
cynomolgus monkeys. Doses used in this study were 10, 30, 100, and 200 mg/kg, administered 
qw for 5 doses. Mild lymphoid hyperplasia occurred in males at the 10, 100, and 200 mg/kg dose 
levels, but based on mild severity, lack of dose dependency and historical test facility data from 


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Page 41 of 101 
similar studies in cynomolgus monkeys, this finding was considered a species specific mild, 
reactive immune response and not an adverse toxicologic finding. No other adverse effects 
occurred, and so the NOAEL in cynomolgus monkeys dosed once qw for 4 weeks was 
200 mg/kg. The mean Day 29 exposures associated with this dose were Cmax and AUC0- of 
 
Using a body surface area calculation and a 10 × safety factor, the maximum recommended safe 
starting dose would be 6.4 mg/kg, ~440 mg in a 70 kg person in the SAD study. Consideration, 
however, was given to preclinical efficacy data, where activity was demonstrated at a dose level 
of 10 mg/kg in mice. The HED conversion of this dose was approximately 70 mg in a 70 kg 
person. Subsequent planned doses in the SAD study were 200, 700, 2,100 and 5,000 mg. At the 
highest dose, a predicted safety margin from the NOAEL was estimated to be 8-fold on Cmax and 
a 6-fold margin on AUC0- based on early PK projections. Planned doses are to be modified 
based on safety and tolerability and PK (to retain these margins).  
If TB006 behaves like other IgG4 antibodies, the half-life will likely be longer than the 
approximate 10 to12 days observed in monkeys. Qw dosing will result in accumulation. Despite 
this, the safety and tolerability of a single dose is a conservative approach to estimating the 
safety and tolerability of the same dose divided into qw administration for 1 month. In addition, a 
similar conservative approach can be applied to establishing initial safety margin estimates by 
using one compartment simulations derived from monkey toxicokinetic data. The highest 
 8-fold on 
the Cmax and 6-fold on the AUC from the NOAEL in the 1 month toxicology study. The lowest 
esults in a safety margin of nearly 60- and 30-fold 
on the Cmax and AUC, respectively. Using the HED conversion from the 200 mg/kg dose level in 
monkeys, the margins from the NOAEL range from ~30-fold at the lowest dose to ~5-fold at the 
highest dose for a 70 kg person. 
The mid dose of 420 mg qw enables a cautious escalation between doses. Evidence of 
intolerance or other safety signals, or PK differences that result in reductions in safety margins 
from the SAD study or previous doses in this study, may necessitate a change in planned doses. 
While TB006 is a first in class anti-Gal-3 antibody, a wider array of approved IgG4 human 
monoclonal antibodies have been used clinically. Most of these target the immune system, and 
there appears to be a spectrum of negative effects, largely immune-mediated, when the total 
antibody dose gets too high. These and all other toxicities will be closely monitored. Dose 
escalation will either be modified or will cease when evidence of toxicity appears. 
The proposed dose range covers a potentially efficacious dose to a projected supratherapeutic 
dose. Successful safety, tolerability and PK characterization of a wide dose range will enable 
efficient drug development. Traditionally, MAD studies employ the planned clinical dosing 
interval, and patients are dosed to steady state to determine steady state PK and safety. The 
projected half-life of TB006 is expected to enable monthly dosing in later clinical studies. The 
qw dosing schedule used in this study will enable a determination of multiple dose PK and 
provide an estimate of repeat dose safety and tolerability. 


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4.4 End of Study 
End of Study (Individual Patient): A patient is considered to have completed the study if 
he/she has completed all study visits through the Day 104 assessments as shown in the SoA 
(Table 1 and Table 2). 
End of Study (End of Trial): The end of the study is defined as the date of the last visit of the 
last patient in the study or last scheduled procedure shown in the SoA (Table 1 and Table 2) for 
the last patient in the study. 


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5 STUDY POPULATION 
Before any study specific activities/procedures, the appropriate written informed consent must be 
obtained (see Section 10.1.3) [Appendix 1]). Prospective approval of protocol deviations to 
recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not 
permitted. 
5.1 Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply:
1.
2.
2, inclusive.
3. MMSE score of 24 or less.
4. Must be ambulatory.
5. Clinical diagnosis of AD consistent with the following:
a.
Probable AD, according to NINCDS-ADRDA (Section 10.5 [Appendix 5])
b. Meets the DSM 5 – Criteria for Major Neurocognitive Disorder (previously
dementia) (Section 10.4 [Appendix 4])
6. Contraceptive use by men should be consistent with local regulations regarding the
methods of contraception for those participating in clinical studies.
a.
Male patients:
Male patients are eligible to participate if they agree to the following from the
first day of dosing through 6 months following the last dose of study drug:
Refrain from donating sperm
PLUS, either:
Be abstinent from heterosexual intercourse as their preferred and usual
lifestyle (abstinent on a long term and persistent basis) and agree to remain
abstinent unless partner is not a WOCBP
OR
Must agree to use contraception/barrier as detailed below:
o
Agree to use a male condom and female partner use of an additional
highly effective contraceptive method with a failure rate of < 1% per year
when having sexual intercourse with a WOCBP who is not currently
pregnant.
b. Females must be of non-childbearing potential defined as:
At least 12 months post-menopausal
Surgically sterile, resulting from but not limited to tubal ligation,
hysterectomy, and oophorectomy.
Documented infertility from other causes, such as endometriosis or uterine
fibroids.


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The investigator is responsible for review of medical history, menstrual
history, and recent sexual activity to decrease the risk for inclusion of a
woman with an early undetected pregnancy.
7. Patients or caregiver has the ability to understand the purpose and risks of the study and
provide signed and dated informed consent as described in Section 10.1.3 (Appendix 1)
which includes compliance with the requirements and restrictions listed in the ICF and in
this protocol. Patients whose caregiver signs the informed consent must provide their
assent.
8. May or may not be receiving 1 or more of the currently marketed cognition enhancing
AD medications, including, but not limited to donepezil, memantine, rivastigmine, and
galantamine. If receiving, it must be the same medication and dose the past 2 months
prior to screening.
9. Either currently or previously (in pre AD condition) literate and capable of reading,
writing, and communicating effectively with others.


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5.2 Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply:
1. Any medical or neurological condition other than AD that in the opinion of the
investigator could be a contributing cause of the patient's dementia (eg, medication use,
vitamin B12 deficiency, abnormal thyroid function, stroke or other cerebrovascular
condition, diffuse Lewy body disease, head trauma).
2. History within the past 6 months or evidence of clinically significant psychiatric illness
(eg, major depression, schizophrenia, or bipolar affective disorder).
3. Diagnosis of a dementia-related CNS disease other than AD (eg, Parkinson’s Disease,
Huntington’s Disease, frontotemporal dementia, multi-infarct dementia, dementia with
Lewy bodies, normal pressure hydrocephalus).
4. Identification of other known cause of dementia or any other clinically significant
contributing co-morbid pathologies at screening MRI, in the opinion of the investigator.
5. Participation in any other drug, biologic, device, or clinical study or treatment with any
investigational drug or approved therapy for investigational use within 30 days (or 5 half
lives, whichever is longer) prior to screening, and/or participation in any other clinical
study involving experimental medications for AD within the 60 days (or 5 half lives,
whichever is longer) prior to screening.
6. Any contraindications to having a brain MRI eg, pacemaker; non-MRI-compatible
aneurysm clips, artificial heart valves, or other metal foreign body; claustrophobia).
7. Any untreated or unstable clinically significant medical condition (ie, hypertension,
diabetes, chronic obstructive pulmonary disorder, asthma, depression, etc) as judged by
the investigator.
8. Any clinically significant findings in medical examination, including physical
examination, 12-
patients).
9.
10. Abnormalities in lumbar spine previously known or determined by a screening lumbar
X-ray (if conducted).
11. History of clinically significant back pain, back pathology, and/or back injury (eg,
degenerative disease, spinal deformity, or spinal surgery) that may predispose patient to
complications or technical difficulty with lumbar puncture.
12. Evidence or history of significant active bleeding or coagulation disorder or use of
non-steroidal anti-inflammatory drugs or other drugs that affect coagulation or platelet
function within 14 days prior to lumbar catheter insertion.
13. Allergy to lidocaine (Xylocaine®) or its derivatives.
14. Medical or surgical conditions for which lumbar puncture is contraindicated.


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15. Loss of more than 100 mL blood (eg, a blood donation) within 2 months before first 
study drug administration, or has received any blood, plasma, or platelet transfusions 
within 3 months before Day 1, or plans to donate blood during the study or within 
3 months after the study. 
16. Recent (1-month) history of a positive COVID-19 test result or disease symptoms of 
COVID-19 disease such as shortness of breath, cough, rhinorrhea, and sore throat, etc. 
17. Known history of, or a positive test result for, HBsAg, IgM anti HBc, anti HCV, or HIV 
types 1 or 2 at screening. Patients with a documented history of treatment for Hepatitis C 
are otherwise eligible to participate. 
18. Regular alcohol consumption within 6 months prior to the study defined as: an average 
8 g of alcohol: a half pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) 
measure of spirits. 
19. Meets DSM-5 criteria for moderate or severe substance use disorder within the past 
12 months, or has a positive test for substances of abuse, or has used substances, 
including but not limited to opiates, methadone, buprenorphine, methamphetamine, 
cocaine, amphetamines recreationally within the past 12 months. 
20. Unable to complete this study for other reasons or the investigator believes that he or she 
should be excluded. 
5.3 Lifestyle Considerations 
5.3.1 Meals and Dietary Restrictions
No fasting or other dietary restrictions, including caffeine, are applicable. Dietary restrictions 
may apply to patients undergoing PET scans, depending on the requirements of the facility. 
These restrictions could include reduced carbohydrate intake for up to 24 hours and fasting for 
6 hours prior to the procedure.
5.3.2 Alcohol
Moderate alcohol consumption (up to 2 units/day [males] and 1 unit/day [females]) is allowed 
throughout the study. One unit is equivalent to 8 g of alcohol: a half pint ( 240 mL) of beer, 
1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. 
5.3.3 Activity 
Patients will abstain from strenuous exercise for 24 hours before each blood collection for 
clinical laboratory tests. Patients may participate in light recreational activities during the study 
(eg, moderate exercise such as walking or bicycling).
5.4 Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients to meet the CONSORT publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 


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demography, screen failure details, eligibility criteria, medical history, prior therapies, and any 
SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened if they have the potential to be included. Rescreened patients should be assigned the 
same patient number as for the initial screening. Informed consent is required before patients can 
be rescreened. See Section 10.1.3 (Appendix 1) for Informed Consent Process details. 




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6.2 Dose Modification 
All planned dose levels may be adjusted upon review of the available PK and safety data from 
the SAD and Part 1 of this study as referenced previously. Every effort will be made to achieve 
the safety margins described in Section 4.3 through the highest dose. In addition, safety, 
tolerability and available PK data from this study will be taken into consideration for the second 
and third dose levels of Part 1, and the selected dose in Part 2. Lastly, dose groups in Part 1 may 
be added or removed from the planned design based on emerging data. 
6.2.1 Dose Escalation and Stopping Considerations 
While concrete dose escalation stopping criteria will not be included, the following variables (at 
a minimum) will be taken into account by the SRC at the protocol-specified time points for these 
decisions, and when events arise during the course of study treatment: 
Number and frequency of treatment-related AEs characterized as moderate or severe in
severity
Number and frequency of treatment-related SAEs
Discontinuation due to AEs
Emergent cardiovascular events, such as QTc increases or vital sign changes
Liver function enzyme increases
6.3 Preparation, Handling, Storage, and Accountability 
The investigator or designee must document that appropriate temperature conditions have
been maintained during transit and storage for all study drug received and any
discrepancies are reported and resolved before use of the study drug.
Only patients enrolled in the study may receive study drug and only authorized site staff
may supply or administer study drug. All study drug must be stored in a secure,
environmentally controlled, and monitored (manual or automated) area in accordance
with the labeled storage conditions with access limited to the investigator and authorized
site staff.
The investigator, institution, or the head of the medical institution (where applicable) is
responsible for study drug accountability, reconciliation, and record maintenance (ie,
receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study drugs are
provided in the Pharmacy Manual.


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6.4 Measures to Minimize Bias: Randomization and Blinding 
6.4.1
Randomization 
All patients will be centrally assigned to randomized study drug using an IWRS. Before the 
study is initiated, the log in information and directions for the IWRS will be provided to each 
site.
In Part 1, 8 patients will be enrolled into each dose group; 6 patients in each group will be 
randomized to active TB006 treatment, and 2 patients to placebo (with 3 dose groups planned, 
for a total of 18 patients receiving TB006 treatment at different dose levels, and a total of 
6 patients receiving placebo). In Part 2, 116 patients will be randomized to active TB006 or 
placebo (1:1) and will follow the same dosing schedule and procedures (with some exceptions – 
see SoA) as in Part 1. Randomization in Part 2 will be stratified according to baseline patient 
severity, with mild AD patients (MMSE 21-24) and moderate-severe AD patients (MMSE  20) 
in each strata. 
On Day 1, patients will be assigned a unique number (randomization number) in ascending 
numerical order as patients are enrolled. Once a randomization number has been assigned, it 
must not be re assigned. The randomization number encodes the patient’s assignment to either 
active TB006 treatment or placebo, according to the randomization schedule generated prior to 
the study. Each patient will receive blinded study drug, labeled with his/her unique 
randomization number. 
6.4.2 Blinding 
In Part 1, in each dose group, 6 patients will be randomized to active TB006 treatment, and 
2 patients to placebo. In Part 2, 58 patients will be randomized to active TB006 treatment, and 
58 patients to placebo. Investigators will remain blinded to each patient’s assigned study drug 
throughout the course of the study. In order to maintain this blind, an unblinded pharmacist will 
be responsible for the reconstitution and dispensation of all study drug. Active study drug and 
placebo are made to be identical in appearance. Refer to the Dose Preparation Manual for further 
details on dose preparation and blinding. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study drug records at the site(s) to verify that randomization/dispensing has been performed 
accurately. 
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a patient’s treatment 
assignment is warranted. Patient safety must always be the first consideration in making such a 
determination. If the investigator decides that unblinding is warranted, the investigator should 
make every effort to contact the sponsor prior to unblinding a patient’s treatment assignment 
unless this could delay emergency treatment of the patient. If a patient’s treatment assignment is 
unblinded, the sponsor must be notified within 24 hours after breaking the blind. The date and 
reason that the blind was broken must be recorded in the source documentation and CRF, as 
applicable. 


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6.5 Study Intervention Compliance 
When the individual dose for a patient is prepared from a bulk supply, the preparation of the dose 
will be confirmed by a second member of the study site staff. 
The investigator is responsible for study drug administration. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. The 
dose of study drug and study patient identification will be confirmed at the time of dosing by a 
second member of the study site staff. 
6.6 Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of screening or receives 
during the study must be recorded along with:
 Reason for use 
 Dates of administration including start and end dates 
Dosage information including dose and frequency
The Medical/Scientific Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
The use of 1 or more of the currently marketed cognition enhancing AD medications, including, 
but not limited to donepezil, memantine, rivastigmine, and galantamine, are allowed in this 
study. Patients should not be considered for inclusion if dose changes or changes in medication 
are anticipated during the course of the study. 
Other medications to treat stable, chronic medical conditions are acceptable as long as they had 
been started more than 30 days before screening and their chronic use is anticipated. In general, 
patients receiving other monoclonal antibodies on a chronic basis are not acceptable, as are 
medications used on an acute (ie, < 2 weeks) basis. Examples include:
 Anti-infectives/antibiotics 
 Corticosteroids
 Opioid analgesics
 Anxiolytics (for acute anxiety)
 Muscle relaxants
2 grams/day, is permitted for use any time during the 
study.
Any questions or uncertainties about concomitant medication may be discussed with the 
Medical/Scientific Monitor. 


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6.7 Study Drug After the End of the Study 
There will be no post-study access to the study drug for any of the patients. 


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7 DISCONTINUATION OF STUDY DRUG AND PATIENT 
DISSCONTINUATION/WITHDRAWAL 
A patient may stop study drug or withdraw from the study at any time for any reason or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. 
Reasons for removal from study drug and/or from the study include any of the following: 
Liver injury (see Section 7.1 below)]
Cardiac changes (see Section 7.2 below)
Adverse events
Pregnancy
Protocol deviation
If the patient meets an exclusion criterion (either newly developed or not previously
recognized) that poses a greater risk to the patient with continued participation
If, in the investigator’s opinion, continuation of the study would be harmful to the
patient’s well being
Sponsor decision
Patient request to discontinue study drug or withdraw consent for study participation
Death
Lost to follow-up
At the time of discontinuing from the study, if possible, an E/D visit should be conducted, as 
shown in the SoA (Table 1 and Table 2). See Table 1 and Table 2 for data to be collected at the 
time of study discontinuation. 
Every effort should be made by the site to follow the patient and maintain scheduled safety visits 
through the Day 104 visit if at all possible, even for patients who voluntarily withdraw their 
consent. 
If the patient withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the site study records.


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7.1 Liver Injury 
Discontinuation of study drug for abnormal liver function should be considered by the 
investigator when a patient meets one of the conditions outlined in Section 10.3 (Appendix 3) or 
if the investigator believes that it is in best interest of the patient. 
7.2
Cardiac Changes
A patient who meets the below criteria based on the average of triplicate ECG readings will be 
withdrawn from the study: 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QTcB or QTcF after study drug infusion), the investigator or qualified designee will determine 
if the patient can continue in the study and if any change in patient management is needed. This 
review of the ECG printed at the time of collection must be documented. Any new clinically 
relevant finding should be reported as an AE. 
7.3 Lost to Follow up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:
The site must attempt to contact the patient and reschedule the missed visit as soon as
possible and counsel the patient on the importance of maintaining the assigned visit
schedule and ascertain whether or not the patient wishes to and/or should continue in the
study.
Before a patient is deemed lost to follow up, the investigator or designee must make
every effort to regain contact with the patient or caregiver (where possible, 3 telephone
calls and, if necessary, a certified letter to the patient’s last known mailing address or
local equivalent methods). These contact attempts should be documented in the patient’s
medical record.
Should the patient continue to be unreachable, he/she will be considered to have
withdrawn from the study.
Discontinuation of specific sites or of the study as a whole are handled in Section 10.1.8. 


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8 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Table 1 and Table 2).
Protocol waivers or exemptions are not allowed. Specifications related to protocol
deviations are presented in Section 10.1.7.
Immediate safety concerns should be discussed with the sponsor immediately upon
occurrence or awareness to determine if the patient should continue or discontinue study
drug.
Adherence to the study design requirements, including those specified in the SoA
(Table 1 and Table 2), is essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential
patients meet all eligibility criteria. The investigator will maintain a screening log to
record details of all patients screened and to confirm eligibility or record reasons for
screening failure, as applicable.
Procedures conducted as part of the patient’s routine clinical management (eg, blood
count) and obtained before signing of the ICF may be utilized for screening purposes,
provided the procedures met the protocol-specified criteria and were performed within
the time frame defined in the SoA (Table 1 and Table 2).
The maximum amount of blood collected from each patient over the duration of the
study, including any extra assessments that may be required, will not exceed 250 mL (see
Table 6 and Table 7). Repeat or unscheduled samples may be taken for safety reasons or
for technical issues with the samples.
8.1 General Study Periods 
8.1.1 Screening, Enrollment and/or Randomization 
Screening will occur between Day -28 and Day -2. The purpose of the screening period is to 
obtain informed consent and to establish protocol eligibility. Informed consent will be obtained 
after the study has been fully explained to each patient and before the conduct of any screening 
procedures or assessments. Procedures to be followed when obtaining informed consent are 
detailed in Section 10.1.3 (Appendix 1). 
Screening assessments are performed as outlined in the SoA (Table 1 and Table 2). 
8.1.2 Study Drug Administration and Follow-up Period
Following randomization, patients will receive study drug as an IV infusion at qw intervals, for 
5 doses. Study assessments will be performed up to Day 104 as outlined in the SoA (Table 1 and 
Table 2). 
8.2 Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1 and Table 2).


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8.2.1 Physical and Neurological Examinations 
A complete physical examination will include, at a minimum, assessments of the
cardiovascular, respiratory, gastrointestinal and neurological systems.
The neurological examination will assess mental status, motor and sensory skills, hearing
and speech, vision, coordination, and balance.
Height and weight will also be measured and recorded. Height will only be measured at
screening.
Investigators should pay special attention to clinical signs related to previous serious
illnesses.
8.2.2 Vital Signs 
Oral temperature, pulse rate, respiratory rate, and blood pressure will be assessed as
indicated in the SoA (Table 1 and Table 2).
Blood pressure and pulse measurements will be assessed with a completely automated
device. Manual techniques will be used only if an automated device is not available.
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest
with the patient in a quiet setting without distractions (eg, television, cell phones). Blood
pressure measurements will be taken with the patient in the sitting position.
Vital signs will be taken before blood collection for laboratory tests, if that is scheduled
for the same time point.
8.2.3 Electrocardiograms 
12-lead ECG measurements will be obtained as outlined in the SoA (Table 1 and Table 2)
using an ECG machine that automatically calculates the heart rate and measures PR,
QRS, QT, and QTc intervals (triplicate measurements will be obtained at all-time points,
except at the screening visit where a single measurement will be obtained). Refer to
Section 7.2 for QTc withdrawal criteria and any additional QTc readings that may be
necessary.
At each time point at which triplicate ECG are required, 3 individual ECG tracings
should be obtained at 2-minute intervals.
On non-dosing days, effort should be made to perform 12-lead ECGs time-matched with
the pre-dose time point on dosing days.
The PI or designated site physician will review and assess all ECGs as Normal,
Abnormal, or Not Evaluable. Once signed, the original ECG tracing will be retained with
the patient’s source documents. At the request of the sponsor, a copy of the original ECG
will be made available to the sponsor.
On Part 1 only, ECGs will be transferred electronically to an ECG central reader for
analysis according to the study-specific recommendations included in the ECG manual.
The central ECG reader will review machine reads and provide corrected values as
specified in the manual. The following parameters will be recorded: PR interval, RR
interval, QRS complex/duration, QT interval, QTc, heart rate, and clinical interpretation.


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The results from the central reader will be captured in the study database, together with
the investigator assessment of the ECG.
In Part 2, only the machine readings and investigator interpretations will be recorded in
the study database.
8.2.4 Clinical Safety Laboratory Assessments 
The tests detailed in Table 5 will be performed by the central laboratory; see the SoA
(Table 1 and Table 2) for the timing and frequency.
Protocol-specific requirements for inclusion or exclusion of patients are detailed in
Section 5 of the protocol.
Additional tests may be performed at any time during the study as determined necessary
by the investigator or required by local regulations.
The investigator must review the laboratory report and document this review. The
investigator should consider documenting any clinically relevant changes as AEs in the
CRF. The laboratory reports must be filed with the source documents. Clinically
significant abnormal laboratory findings are those that are not associated with the
underlying disease, unless judged by the investigator to be more severe than expected for
the patient's condition.
All laboratory tests with values considered clinically significantly abnormal during
participation in the study should be repeated at appropriate intervals until the values
return to normal or baseline or are no longer considered clinically significant by the
investigator or Medical/Scientific Monitor.
If such values do not return to normal/baseline within a period of time judged reasonable
by the investigator, the etiology should be identified and the sponsor notified.
All protocol-required laboratory assessments, as defined in this section, must be
conducted in accordance with the laboratory manual and the SoA (Table 1 and Table 2).
If laboratory values from non-protocol specified laboratory assessments performed at the
institution’s local laboratory require a change in patient management or are considered
clinically significant by the investigator (eg, SAE, or AE, or dose modification), then the
results must be recorded in the CRF.


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Table 5. 
Protocol-required Clinical Safety Laboratory Assessments
Hematology
Clinical Chemistry
Urinalysis 
Platelet count 
RBC count
Hemoglobin 
Hematocrit 
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
BUN
Creatinine
CPK 
Glucose (nonfasting) 
Potassium 
Sodium 
Calcium 
AST/SGOT 
ALT/SGPT 
Alkaline phosphatase 
Total and direct bilirubin 
Total protein 
Albumin 
Total cholesterol 
HDL 
LDL 
Triglycerides 
TSH 
HbA1c 
Specific gravity 
pH, glucose, protein, blood, 
ketones, bilirubin, urobilinogen, 
nitrite, leukocyte esterase by 
dipstick 
Microscopic examination (if 
blood or protein is abnormal) 
Other Screening Tests  
Urine alcohol and drug screen (including but not limited to opiates, methadone, buprenorphine, 
methamphetamine, cocaine, and amphetamines) 
Viral serology (HBsAg, IgM anti-HBc, anti-HCV, HIV) and COVID-19 
The results of each test must be entered into the CRF. 
ALT 
-HCV 
hepatitis C virus antibody; AST
aspartate aminotransferase; 
BUN  blood urea nitrogen; COVID  coronavirus disease; CPK  creatine phosphokinase; CRF  case report 
form; HbA1c  hemoglobin A1c; HBsAg  hepatitis B surface antigen; hCG  human chorionic gonadotropin; 
HDL  high-density lipoprotein; IgM anti-HBc  immunoglobulin M antibody to hepatitis B core antibody; 
LDL  low-density lipoprotein; MCH 
RBC  red blood cell; SGOT  Serum Glutamic-Oxaloacetic Transaminase; SGPT  Serum Glutamic-Pyruvic 
Transaminase; TSH
thyroid-stimulating hormone; WBC
 white blood cell. 
8.2.5 Suicidal Ideation and Behavior Risk Monitoring 
The C-SSRS is a prospective semi-structured interview comprised of the following areas of 
assessment: Ideation, Intensity of Ideation, Behavior, and Lethality. It has been used extensively 
in global clinical studies (academic and industry sponsored) and in a range of therapeutic areas, 
disorders and indications, including psychiatry, neurology, obesity, urology and endocrinology 
and is FDA-approved. It has been used to determine eligibility to enroll at screening and at every 
follow-up visit to prospectively monitor suicidality during the study. The C-SSRS was developed 
for use in clinical studies and can be administered by non-mental health professionals with 
training. All C-SSRS raters for this study will have a certificate that verifies training completion 
and allows them to rate in this study.


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There are 2 versions of the C-SSRS. The “Past 6 months” version of the C-SSRS will be 
completed at screening and the “Since Last Visit” version will be completed at all remaining 
visits according to the SoA (Table 1 and Table 2). The “Since Last Visit” version will also be 
completed at any unscheduled clinic visits. 
8.3 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Section 10.2 (Appendix 2).
AE(s) will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study drug or study procedures, or that caused 
the patient to discontinue the study (see Section 7).
8.3.1 Time Period and Frequency for Collecting Adverse Events and Serious Adverse 
Events Information 
All AEs and SAEs will be collected from the time of the first study drug administration until 
Day 104. Medical occurrences that begin before the start of study drug but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions section of 
the CRF, not the AE section. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.2 (Appendix 2). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
The investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and he/she considers the event to be reasonably 
related to the study drug or study participation, the investigator must promptly notify the 
sponsor. 
8.3.2 Method of Detecting Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.2 
(Appendix 2).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.


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8.3.3 Follow-up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is given in Section 10.2 (Appendix 2).
8.3.4 Regulatory Reporting Requirements for Serious Adverse Events
Notification by the investigator to the sponsor of an SAE is essential so that legal
obligations and ethical responsibilities towards the safety of patients and the safety of a
study drug under clinical investigation are met.
The sponsor has a legal responsibility to notify the FDA about new safety information of
a study drug under clinical investigation. The sponsor will comply with regulatory
requirements relating to safety reporting to the FDA, IRB/IEC, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other
specific safety information (eg, summary or listing of SAEs) from the sponsor will
review and then file it along with the IB and will notify the IRB/IEC, if appropriate
according to local requirements.
8.3.5 Disease-related Events and/or Disease-related Outcomes not Qualifying as 
Adverse Events or Serious Adverse Events 
The following DREs are common in patients with AD and can be serious/life threatening: 
Anxiety and psychosis
Dysphagia and other eating disorders
Exacerbation of AD
Injuries from falls
Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the 
event may meet the definition of an SAE. These events will be recorded in the patient’s CRF 
when reported. These DREs will be monitored by the SRC on a routine basis. 
NOTE: However, if either of the following conditions applies, then the event must be recorded 
and reported as an SAE (instead of a DRE): 
The event is, in the investigator’s opinion, of greater severity, frequency, or duration than
expected for the individual patient.
OR 


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The investigator considers that there is a reasonable possibility that the event was related
to study drug.
8.4 
Treatment of Overdose 
For this study, any dose of study drug greater than the planned doses of study drug indicated in 
this protocol, will be considered an overdose. There is no recommendation for a specific 
treatment for an overdose. 
In the event of an overdose, the investigator should: 
Contact the Medical/Scientific Monitor immediately.
Closely monitor the patient for any AE/SAE and laboratory abnormalities until TB006
can no longer be detected systemically until the next scheduled dose.
Obtain a plasma sample for PK analysis according to the protocol schedule unless
otherwise advised by the Medical/Scientific Monitor.
Document the quantity of the excess dose as well as the duration of the overdose in the
CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical/Scientific Monitor based on the clinical evaluation of the patient. 
8.5 
Pharmacokinetics 
Whole blood samples of approximately 5 mL will be collected for measurement of
plasma concentrations of TB006 as specified in the SoA (Table 1 and Table 2).
Additional samples may be collected at additional time points during the study if
warranted and agreed upon between the investigator and the sponsor. The timing of
sampling may be altered during the course of the study based on newly available data (eg,
to obtain data closer to the time of peak plasma concentrations) to ensure appropriate
monitoring.
Instructions for the collection and handling of biological samples will be provided by the
sponsor. The actual date and time (24-hour clock time) of each sample will be recorded.
Samples will be used to evaluate the PK of TB006. Each plasma sample will be divided
into 2 aliquots (1 each for PK and a back-up). Samples collected for analyses of plasma
TB006 concentration may also be used to evaluate safety or efficacy aspects related to
concerns arising during or after the study.
Other than ApoE4 genetic testing from a sample at the Screening visit, genetic analyses
will not be performed on these plasma samples. Patient confidentiality will be
maintained. At visits during which whole blood samples for the determination of multiple
aspects of TB006 will be taken, 1 sample of sufficient volume can be used.


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Lumbar puncture procedure will be performed at the time points as specified in the SoA
(Part 1 only) (Table 1) to obtain CSF samples for measurement of concentrations of
TB006. The lumbar procedure is optional for participating patients.
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the sponsor 
and site study files but will not constitute a protocol amendment. The IRB/IEC will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment of the 
ICF.
8.6 
Pharmacodynamics 
8.6.1 Blood Samples for Biomarker Assessments
Venous blood samples of approximately 5 mL will be collected for measurement of plasma 
, and other relevant biomarkers at the time points 
specified in the SoA (Table 1 and Table 2). 
8.6.2 Lumbar Puncture (Part 1 only) 
Lumbar puncture procedure (optional for participating patients) will be performed at the time 
points as specified in the SoA (Table 1
, and other relevant biomarkers. 
8.6.3 Cognition Testing 
Patients will perform a battery of cognition tests, including the MMSE, the Clinical Dementia 
Rating Scale, the Cognitive Drug Research system battery, and the NPI throughout the study to 
assess cognition. Tests, with the exception of the Cognitive Drug Research system battery will be 
performed by paper only. The Cognitive Drug Research system battery will be performed using 
an electronic device. 
8.6.3.1 Clinical Dementia Rating Scale 
Clinical Dementia Rating Scale is a global assessment instrument that yields global score and a 
sum of boxes score. The Clinical Dementia Rating Scale is derived from a semi-structured 
interview with the participant and an appropriate informant, and it rates impairment in 
6 categories (memory, orientation, judgment and problem solving, community affairs, home and 
hobbies, and personal care) on a 5-point scale for which 0  no impairment, 0.5  questionable 
impairment, and 1, 2, and 3  mild, moderate, and severe impairment, respectively. From the 
6 individual category ratings, or box scores, the Clinical Dementia Rating Scale – Global Score 
is established by clinical scoring rules, for which the Clinical Dementia Rating of 0  no 
dementia and Clinical Dementia Rating of 0.5, 1, 2, or 3  questionable, mild, moderate, or 
severe dementia, respectively (Morris, 1993). The Clinical Dementia Rating Scale – Sum of 
boxes score is a detailed quantitative general index that provides more information than the 
Clinical Dementia Rating Scale – Global Score in participants with early (prodromal to mild) 


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dementia (Coley et al, 2011; Cedarbaum et al, 2013). In particular, the Clinical Dementia Rating 
Scale – Sum of Boxes has been proposed for use in longitudinal assessment of dementia and is 
widely used in AD studies as a global measure of disease progression (Williams et al, 2013).
8.6.3.2 Mini-mental State Examination
The MMSE is a brief 30-point questionnaire used to assess cognitive impairment with lower 
scores indicating greater impairment. The MMSE assesses 11 categories of cognition including 
orientation to time, memory, attention, concentration, naming, repetition, comprehension, and 
the ability to create a sentence and to copy 2 intersecting polygons. The total scores on the scale 
ranges from 0 to 30 with lower scores indicating greater impairment.
The MMSE will be administered at the time points indicated in the SoA (Table 1 and Table 2). 
The MMSE will be administered by a trained member of the investigational team. At each site, 
the same individual, whenever possible, will perform the MMSE evaluation on a specific patient 
throughout the study. The screening MMSE will be used for purposes of determining patient 
eligibility and does not need to be reconciled with the baseline MMSE score.
8.6.3.3 Cognitive Drug Research System 
The Cognitive Drug Research system is an automated battery amenable to measurement of 
cognitive deficits in patients with AD. It consists of performance tasks measuring attention, 
working memory, episodic memory and executive function. It contains 11 tests and is performed 
on a tablet-like device. The average duration of the battery is approximately 25 minutes. 
The Cognitive Drug Research system is performed at the time points listed in the SoA (Table 1 
and Table 2). Two training sessions will be conducted at least 30 minutes apart during the 
screening period to allow patients to become familiar with the procedure, reduce test anxiety, 
reduce learning effects, and produce a stable baseline assessment. 
8.6.3.4 Neuropsychiatric Inventory
The NPI is a rater-administered, fully structured interview in which all questions are provided 
and read verbatim. The sole source of information is the interview with a caregiver who knows 
the patient well. This study uses the NPI version with 10 behavioral domains: delusions, 
hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, 
apathy/indifference, disinhibition, irritability/lability, and aberrant motor behavior. 
The NPI total score is calculated by adding the scores of the domains (each domain scores ranges 
from 0 to 12). The NPI total score ranges from 0 to 120 with higher scores indicating greater 
behavioral impairment. 
The NPI-D scores in each of the domains are not included in the NPI total score. The NPI-D total 
score is calculated by adding the scores of caregiver distress in each of the domains (score ranges 
from 0 to 5 in each domain). The NPI-D total score ranges from 0 to 50 with higher scores 
indicating greater distress. 


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The NPI will be administered at the time points indicated in the SoA (Table 1 and Table 2). The 
NPI will be administered by an independent, trained, and certified member of the investigational 
team. At each site, the same individual, whenever possible, will perform the NPI evaluation on a 
specific patient throughout the study. 
8.7 
Pharmacogenetics 
A 2 ml sample of blood will be taken for ApoE4 genotyping at screening from patients who give 
separate written informed consent for this optional research. If this sample is not taken at 
screening, it may be taken at any visit until the last study visit. 
 
 A general analysis of deoxyribonucleic acid will 
not be employed. However, other targeted analyses of genetic polymorphisms in AD may be 
conducted.  
Instructions for collection, processing, labelling, storing and shipping samples are detailed in the 
Laboratory Manual.


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8.8 
Immunogenicity Assessments 
T rneBinding, Inc. 
Antibodies to TB006 will be evaluated in plasma samples collected from all patients at the time 
points according to the SoA (Table 1 and Table 2). These samples will be tested by the sponsor 
or sponsor's designee. 
Anti-TB006 antibodies will be detennined on plasma samples collected for plasma PK 
determinations, and no additional blood samples need to be obtained. 
Plasma samples will be screened for antibodies binding to TB006 and the titer of confnmed 
positive samples will be repo1ied. Other analyses may be perfo1med to verify the stability of 
antibodies to TB006 and/or fmiher characterize the immunogenicity ofTB006. 
The detection and characterization of antibodies to TB006 will be perfo1med using a validated 
assay method by or under the supervision of the sponsor. All samples collected for detection of 
antibodies to study diug will also be evaluated for TB006 plasma concentration to enable 
interpretation of the antibody data. Antibodies may be farther characterized and/or evaluated for 
their ability to neutralize the activity of the study diug(s). 
8.9 
Total Volume of Blood Sampling 
Table 6 and Table 7 presents the number of blood samples and the total volume of blood that will 
be collected throughout the study (Paiis 1 and 2). 
Table 6. Summary of Blood Sample Volumes for Part 1 
Approximate 
Sample Volume 
Approximate 
per Collection 
Number of Collection Time 
Total Volume 
(mL) 
Points 
Collected (mL) 
Clinical laborato1y tests• 
12.5 
6 
12.5x6 = 75 
Viral serology 
3.5 
1 
3.5Xl = 3.5 
PK and/or ADA blood sampling 
5 
22 
5x22 = 110 
Phanna.cogenetic sampling ( optional) 
2 
1 
2 
PD blood sampling 
6 
3 
6x3 = 18 
Total Blood Volume Estimate 
208.50 
ADA= anti-dtug antibody; PD= phannacodyna1nic(s); PK= phannacokinetic(s). 
a 
12.5 mL sample for hematology, clinical chetnistty, and includes serum pregnancy test where this is 
perfonned at the same time point. 
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Table 7. Summary of Blood Sample Volumes for Part 2 
Approximate 
Sample Volume 
per Collection 
(mL) 
Clinical laborato1y tests• 
12.5 
Viral serology 
3.5 
PK and/or ADA blood sampling 
5 
Phanna.cogenetic sampling ( optional) 
2 
PD blood sampling 
6 
Total Blood Volume Estimate 
Number of Collection Time 
Points 
6 
I 
8 
I 
3 
ADA = anti-dtug antibody; PD = phannacodyna1nic(s); PK = phannacokinetic(s). 
T rneBinding, Inc. 
Approximate 
Total Volume 
Collected (mL) 
12.5x6 = 75 
3.5xl = 3.5 
5x8 = 40 
2 
6x3 = 18 
138.50 
a 
12.5 mL sample for hematology, clinical chetnistty, and includes serum pregnancy test where this is 
perfonned at the same time point. 
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9 STATISTICAL CONSIDERATIONS 
9.1 Statistical Hypotheses 
The primary endpoint in Part 2 is the change from baseline Clinical Dementia Rating Scale – 
Sum of Boxes score at through Day 104. The primary null hypothesis to be tested is as follow: 
H0: There is no difference between TB006 group and placebo group in change from
baseline Clinical Dementia Rating Scale – Sum of Boxes score at through Day 104.
9.2
Sample Size Determination
In Part 1, patients will be recruited sequentially in separate increasing dose groups, with each 
group randomizing 6 patients to a specific dose of TB006 and 2 randomized to placebo. If all 
3 planned dose levels are investigated, the study will recruit approximately 24 patients in total 
(18 receiving TB006 treatment at the different dose levels, and 6 receiving placebo). 
In Part 2, patients will be randomized to TB006 or placebo in a 1:1 ratio so that approximately 
58 patients will be randomized to each group. Randomization in Part 2 will be stratified 
according to baseline patient severity, with mild AD patients (MMSE 21-24) and 
moderate-
dose level in Part 1, as well as all placebo patients, will be included in the efficacy analyses in 
Part 2. Thus, the number of patients in each group for the primary efficacy analysis will be 
approximately 64. 
Assuming that the standard deviation of change from baseline Clinical Dementia Rating 
Scale – Sum of Boxes at Day 104 is 0.5, a total of 128 patients will provide 80% power to detect 
a mean change from baseline difference of 0.25 at Day 104 using a 2-sided, 2 sample t-test at the 
5% level of significance. 
9.3
Populations for Analyses
For the purposes of analysis, the following analysis sets are defined: 
Full analysis set (FAS)
All patients who are randomly assigned to study drug 
Safety analysis set (SAS)
All patients randomly assigned to study drug and who take at 
least 1 dose of study drug. Patients will be analyzed according to 
the study drug they actually received
PK analysis set (PKS)
All patients who received at least 1 dose of TB006 and have at 
least 1 post-dose blood sample with measurable TB006 
concentrations 
PD analysis set (PDS)
All patients who received blinded study drug and have at least 
1 post-dose evaluable PD assessment
The FAS will be used for the analysis of disposition and protocol deviations. The SAS will be 
used for all other analyses, except specifically for PK and PD. The FAS and the SAS will be the 


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same if all randomized patients are dosed with study drug. The PKS will be used for all PK 
analyses and the PDS will be used for all PD and efficacy analyses. 
9.4
Statistical Analyses
The SAP will be finalized prior to database lock and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints including primary, secondary, and 
exploratory endpoints. 
9.4.1 General Considerations
Descriptive statistics will be used to summarize the results of the study. Continuous variables 
will be summarized by reporting the number of observations, mean, standard deviation, median, 
minimum, and maximum. For the PK parameters and plasma concentrations, geometric mean 
and coefficient of variation will also be presented. Categorical/discrete variables will be 
summarized using frequency tables showing the number and percentage of patients within a 
particular category. All summaries will be presented by dose group and treatment group. 
Baseline values will be taken as the most recent assessment prior to dosing, reported during 
screening and up to and including Day 1. 
9.4.2 Part 1 Primary Endpoints 
9.4.2.1 Safety and Tolerability 
All AEs will be coded using the most recent version of MedDRA. The incidence of AEs will be 
summarized by SOC and PT. Similar summaries will be produced for AEs by severity, SAEs, 
treatment related AEs, and AEs leading to discontinuation. AEs are collected from the first dose 
of study drug, thus all AEs are considered treatment emergent AEs.
The ECG results will be presented by visit, summarizing the continuous measurements based on 
the average of triplicate values, including the QT, QTc, QRS, RR, PR intervals, as well as 
change from baseline values, and clinically significant changes in heart rate and rhythm.
Reported values and change from baseline values of hematology, clinical chemistry and 
urinalysis (and the determinations relevant to the normal ranges and appropriate clinically 
significant or CTCAE toxicity gradings) will be summarized by laboratory test for each 
assessment day, using appropriate descriptive statistics.
Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and oral 
temperature) will be summarized by assessment day showing absolute values, change from 
baseline values, and clinically significant changes (including orthostasis) using appropriate 
descriptive statistics.  
Physical and neurological examinations will be summarized by assessment day showing shift 
from baseline.


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The C-SSRS assessments will be presented in a by-subject listing. 
9.4.2.2 Pharmacokinetics 
Plasma and available CSF TB006 concentrations over time will be presented, showing both 
individual and mean concentrations. Plasma PK parameters will also be calculated and presented 
descriptively. Plasma PK parameters of interest may include Cmax, tmax, Ctrough, AUCtau, CL, and 
Vd. 
Additional PK analysis using a population PK approach may be used but will be reported 
separately from the clinical study report. 
9.4.2.3 Immunogenicity 
The presence of anti TB006 antibodies will be listed by patient and time point. Analyses will be 
performed using appropriate descriptive statistics to summarize the results. 
 
 
9.4.4 Part 1 Other Analyses 
The patient disposition showing numbers randomized, treated, completed, treatment 
discontinuation, and discontinued from the study will be summarized. For those patients who 
discontinued the study or the study treatment prematurely, the reason for discontinuation will be 
summarized.
All patient data will be reviewed for the occurrence of protocol deviations. Summaries will be 
presented showing the numbers of patients with each class and type of deviation. 
Demographic variables to be summarized will include age, gender, race, ethnicity, height, 
weight, and BMI. 
Baseline characteristics to be summarized will include medical history and viral serology. Prior 
and concomitant medications will be summarized showing the number and percentage of patients 
taking each medication. Medications will be coded using the World Health Organization Drug 
Dictionary preferred name. 
9.4.5 Part 2 Primary and Secondary Endpoints 
Patients enrolled at the same TB006 dose level in Part 1, as well as all placebo patients, will be 
included in the efficacy analyses in Part 2. 


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The primary efficacy endpoint in Part 2, Clinical Dementia Rating Scale – Sum of Boxes change 
from baseline through Day 104 will be analyzed using MMRM with treatment group, 
randomization strata (MMSE  20 and 21-24), visit, and treatment group by visit interaction as 
fixed effects and a baseline Clinical Dementia Rating Scale - Sum of Boxes score as a covariate. 
The least square mean difference, the 95% confidence interval of the difference, and the p-value 
will be presented as well as the descriptive statistics.  
The key secondary efficacy endpoint is the change from baseline through Day 36 on the Clinical 
Dementia Rating Scale – Sum of Boxes, and will be analyzed using the MMRM as previously 
described. Other secondary efficacy endpoints include change from baseline Cognitive Drug 
Research System battery at Days 36 and 104, change from baseline MMSE total score at 
Days 36 and 104, change from baseline NPI total score at Days 36 and 104, and a responder 
analysis on the Clinical Dementia Rating Scale at Days 36 and 104. A responder is defined as a 
1-point improvement on the Sum of Boxes score. The patients with missing data will be included
in the denominator and treated as a non-responder. The secondary endpoints except for the
responder analysis will be analyzed similarly using the MMRM with treatment group,
randomization strata (MMSE  20 and 21-24), visit, and treatment group by visit interaction as
fixed effects and a corresponding baseline score as a covariate. The proportion of the responders
between treatment groups will be tested using the Cochran Mantel-Haenszel test, adjusting for
randomization strata (MMSE  20 and 21-24) and the common risk difference and the 95%
confidence interval will be presented.
Safety endpoints including AEs, clinical laboratory tests, vital signs, ECGs, C-SSRS, and 
physical and neurological examination results will be presented as described in Section 9.4.5. 
The available noncompartmental PK parameters (eg, Cmax and Ctrough) will be summarized 
descriptively.
 
9.5 Interim Analysis 
No interim analysis is planned for this study. 


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9.6 Safety Review Committee 
An SRC will be involved in the conduct of this study. The SRC will be comprised of the PI and 
sponsor representatives including the Medical/Scientific Monitor, pharmacokineticist, statistician 
and others as deemed necessary. The SRC will review safety and available PK data on each 
accruing dose group after the last patient in each group has received their first dose. Safety, 
tolerability, and available PK data when the last patient in each group receives the first dose of 
study drug, will be used for dose escalation decisions. Also, each group in this study will 
commence after the safety, tolerability, and PK of the single dose equivalent to the combined 
total of 5 qw doses planned in the SAD study (Study TB006HV1101) has been established 
(minimum of 14 days from last patient dosing). Data will be reviewed by a blinded SRC. A 
decision will be made by the committee to either continue dosing for the next group at the 
planned dose level, continue at a modified dosing schedule, or to discontinue any dose escalation 
(and discontinue the study). 
Safety reasons that could halt dose escalation are discussed in Section 6.2.1. 
As needed, details of the responsibilities and organization of the SRC will be provided in a 
separate document.
9.7 Handling of Missing Data 
All data will be handled as available. No specific approaches will be utilized to impute missing 
data apart from possibly in cases of missing dates, severity or relationship for AEs, where a 
worst case may be assumed.
Full details of the handling of missing data including the missing individual items in the 
cognition tests, will be provided in the SAP.


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CIOMS international ethical guidelines
Applicable ICH GCP guidelines
Applicable laws and regulations
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, patient 
recruitment advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. 
The investigator will be responsible for the following: 
Providing written summaries of the status of the study to the IRB/IEC annually or more
frequently in accordance with the requirements, policies, and procedures established by
the IRB/IEC.
Notifying the IRB/IEC of SAEs or other significant safety findings as required by
IRB/IEC procedures.
Providing oversight of the conduct of the study at the site and adherence to requirements
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical
studies (if applicable), and all other applicable local regulations.
10.1.2 Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information, as requested, to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1-year after completion of the study.
10.1.3 Informed Consent Process
An initial sample ICF is provided for the investigator to prepare the informed consent
document to be used at his or her site. Updates to the sample ICF are to be communicated
formally in writing from the sponsor Study Manager to the investigator. The written


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informed consent form is to be prepared in the language(s) of the potential patient 
population.
 The investigator or his/her representative will explain the nature of the study to the 
patient or his/her legally authorized representative and answer all questions regarding the 
study.
 Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective patient, to the patient’s participation 
in the clinical study will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center. 
 The source document must include a statement that written informed consent was 
obtained before the patient was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.
 Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study if the ICF is revised. 
 The original signed ICF is to be retained in accordance with institutional policy, and a 
copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative. 
 The investigator is also responsible for asking the patient if the patient has a primary care 
physician and if the patient agrees to have his/her primary care physician informed of the 
patient’s participation in the clinical study unless it is a local requirement. The 
investigator will then inform the primary care physician. If the patient agrees to such 
notification, the investigator is to inform the patient’s primary care physician of the 
patient’s participation in the clinical study. If the patient does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the patient’s medical record. 
 If a patient is unable to read, or if a legally acceptable representative is unable to read, an 
impartial witness should be present during the entire informed consent discussion. After 
the written ICF and any other written information to be provided to patients is read and 
explained to the patient or the patient’s legally acceptable representative, and after the 
patient or the patient’s legally acceptable representative has orally consented to the 
patient’s participation in the study and, if capable of doing so, has signed and personally 
dated the ICF, the witness should sign and personally date the consent form. By signing 
the consent form, the witness attests that the information in the consent form and any 
other written information was accurately explained to, and apparently understood by, the 
patient or the patient’s legally acceptable representative, and that informed consent was 
freely given by the patient or the patient’s legally acceptable representative (Refer to ICH 
GCP guideline, Section 4.8.9). 


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Patients who are rescreened are required to sign a new ICF.
10.1.4 Data Protection 
Patients will be assigned a unique identifier by the sponsor. Any patient records or
datasets that are transferred to the sponsor will contain the identifier only; patient names
or any information that would make the patient identifiable will not be transferred.
The patient must be informed that his/her personal study-related data will be used by the
sponsor in accordance with local data protection law. The level of disclosure must also be
explained to the patient who will be required to give consent for their data to be used as
described in the informed consent.
The patient must be informed that his/her medical records may be examined by Clinical
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
The investigator must ensure that the patient’s confidentiality is maintained for
documents submitted to the sponsor.
For SAEs reported to the sponsor, patients are to be identified by their unique patient
identification number, initials (for faxed reports, in accordance with local laws and
regulations), and age (in accordance with local laws and regulations).
Documents that are not submitted to the sponsor (eg, signed ICFs) are to be kept in
confidence by the investigator, except as described below.
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the
investigator and institution permit authorized representatives of the company, of the
regulatory agency(ies), and the IRB/IEC direct access to review the patient’s original
medical records for verification of study related procedures and data. Direct access
includes examining, analyzing, verifying, and reproducing any records and reports that
are important to the evaluation of the study.
The investigator is obligated to inform and obtain the consent of the patient to permit
such individuals to have access to his/her study related records, including personal
information.
10.1.5 Data Quality Assurance 
All patient data relating to the study will be recorded on printed or eCRFs unless
transmitted to the sponsor or designee electronically (eg, laboratory data). The
investigator is responsible for verifying that data entries are accurate and correct by
physically or electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and
regulatory agency inspections, and provide direct access to source data documents.


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Monitoring details describing strategy (eg, risk-based initiatives in operations and quality,
such as Risk Management and Mitigation Strategies and Analytical Risk based
Monitoring), methods, responsibilities, and requirements, including handling of
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring)
are provided in the Monitoring Plan.
The sponsor or designee is responsible for the data management of this study including
quality checking of the data.
The sponsor assumes accountability for actions delegated to other individuals (eg,
Contract Research Organizations).
Study monitors will perform ongoing source data verification to confirm that data entered
into the CRF by authorized site personnel are accurate, complete, and verifiable from
source documents; that the safety and rights of patients are being protected; and that the
study is being conducted in accordance with the currently approved protocol and any
other study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study
must be retained by the investigator for at least 2 years after the last marketing approval
in an ICH region or at least 2 years have elapsed since the formal discontinuation of
clinical development of the study drug (eg, via notification of the FDA or local regulatory
authority), unless local regulations or institutional policies require a longer retention
period. No records may be destroyed during the retention period without the written
approval of the sponsor. No records may be transferred to another location or party
without written notification to the sponsor.
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected
for audit by representatives from (sponsor’s) Global Research and Development
Compliance and Audit function (or designees). Inspection of site facilities (eg, pharmacy,
protocol required therapy storage areas, laboratories) and review of study-related records
will occur to evaluate the study conduct and compliance with the protocol, ICH GCP, and
applicable regulatory requirements.
Retention of study documents will be governed by the Clinical Trial Agreement.
All written information and other material to be used by patients and investigative staff
must use vocabulary and language that are clearly understood.
10.1.6 Source Documents
Source documents provide evidence for the existence of the patient and substantiate the
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source
documents must be consistent with the source documents or the discrepancies must be
explained. The investigator may need to request previous medical records or transfer
records, depending on the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the Site Trial Binder or other
site communication.


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10.1.7 Protocol Deviations 
There will be no exemptions (a prospective approved deviation) from the inclusion or exclusion 
criteria. 
The investigator should not deviate from the protocol, except where necessary for patient safety. 
If other unexpected circumstances arise that will require deviation from protocol-specified 
procedures, the investigator should consult with the Medical/Scientific Monitor to determine the 
appropriate course of action. 
The investigator and study staff should adhere to the time points for all procedures to the extent 
possible. However, circumstances that result in delays are understandable. If delays are 
 10 min for vital signs) or result in a compromised ability to interpret data (ie, 
ECG delays that prohibit time-matched comparisons), these will be considered protocol 
deviations. 
Every attempt will be made to collect each PK blood sample at the designated time point, and the 
actual time of each blood sample will be recorded on the source document and eCRF. However, 
blood samples not collected within the interval specified for the scheduled sample time below 
(Table 8) should be recorded in the source documents. 
Table 8. 
Windows for PK Sample Collection 
Time Window 
Nominal Sampling Time 
No more than 0.5 hours pre-dose ± 0.5 minutes
Pre-dose (0 hours) on D1, D8, and D29
± 0.25 hours 
End of study drug infusion, 1 and 2 hours after the end of study 
drug infusion on D1, D8, and D29 
± 0.75 hours 
4 and 6 hours after the end of study drug infusion on D1, D8, 
and D29
D
 Day
The Significant Protocol Deviation eCRF is to be completed for deviations that are identified by 
the sponsor before study start 
10.1.8 Study and Site Start Closure
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 


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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC
or local health authorities, the sponsor's procedures, or GCP guidelines.
Inadequate recruitment of patients by the investigator.
Discontinuation of further study drug development.
If the study is prematurely terminated or suspended, the sponsor will promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator will promptly inform the patient and must ensure 
appropriate patient therapy and/or follow-up. 
10.1.9 Publication Policy 
Data from this study are the property of the sponsor, TrueBinding, Inc. Data may not be
disclosed by the investigator(s) to any external source without the permission of
TrueBinding, Inc.
If an investigator wishes to present or publish data in the public domain, the investigator
must agree to seek approval from the sponsor before submitting any manuscript or
abstract for publication or presentation. This allows the sponsor to protect proprietary
information and to provide comments.
The sponsor will comply with the requirements for publication of study results. In
accordance with standard editorial and ethical practice, the sponsor will generally support
publication of multicenter studies only in their entirety and not as individual site data. In
this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 


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10.2 Appendix 2: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.2.1 Definition of AE 
AE Definition 
• 
An adverse event (AE) is any untoward medical occmTence in a patient or clinical 
study patient, temporally associated with the use of study drng, whether or not 
considered related to the study diug. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnonnal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study diug. 
Events Meeting the AE Definition 
• 
Any abno1m al laboratory test results (hematology, clinical chemistiy, or minalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measmements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
• 
Any new condition detected or diagnosed after study diug adininisti·ation even though 
it may have been present before the stait of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected diug-diug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study di11g 
or a concomitant medication. Overdose per se will not be repoited as an AE/serious AE 
(SAE) unless it is an intentional overdose taken with possible suicidaVself-ha1ming 
intent. Such overdoses should be repo1ted regardless of sequela. 
Events 
Meeting the AE Definition 
• 
Any clinically significant abnonnal laborato1y findings or other abnonnal safety 
assessments that ai·e associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the patient's condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient's 
condition. 
• 
Medical or smgical procedme (eg, endoscopy, appendectomy): the condition that leads 
to the procedme is the AE. 
• 
Situations in which an untowai·d medical occmTence did not occm (social and/or 
convenience adinission to a hospital). 
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• 
Anticipated day-to-day fluctuations of pre-existing disease( s) or condition( s) present or 
detected at the sta1i of the study that do not worsen. 
10.2.2 Definition of Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met ( eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. 
Results in death 
b. 
Is life threatening 
The te1m 'life threatening' in the definition of 'serious' refers to an event in which the patient 
was at risk of death at the time of the event. It does not refer to an event that hypothetically 
inight have caused death if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician's office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether "hospitalization" 
occmTed or was necessaiy, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. 
Results in persistent or significant disability/incapacity 
• The te1m disability means a substantial disrnption of a person's ability to conduct 
nonnal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diaiThea, influenza, 
and accidental trauma ( eg, sprained ankle) that may interfere with or prevent eve1yday 
life functions but do not constitute a substantial disrnption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other medically important serious event: 
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• 
Medical or scientific judgment should be exercised in deciding whether SAE repo1ting 
is appropriate in other situations such as impo1tant medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
sen ous. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drng dependency or diug abuse. 
10.2.3 Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation ( eg, hospital progress notes, laborato1y reports, and diagnostics repo1ts) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE infonnation in the case repo1t fonn 
(CRF). 
• 
It is not acceptable for the investigator to send photocopies of the patient's medical records 
in lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for ce1tain cases are requested. In 
this case, all patient identifiers, with the exception of the patient number, will be redacted 
on the copies of the medical records before submission. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical infonnation. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
• 
The investigator must assign the following AE attributes: 
o AE diagnosis or syndi·ome(s), if known (if not known, signs or symptoms); 
o Dates of onset and resolution (if resolved); 
o Severity (or toxicity defined below); 
o Assessment of relatedness to study drng or other protocol-required therapies and 
o Action taken.If AE severity changes, record each change as a single event. 
• 
The following should be considered when recoding SAEs: 
o Death is an outcome of an event. The event that results in the death should be recorded 
and reported on both an SAE and CRF. 
o For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. 
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Protocol Date and Version: 15 Oct 2021; v 3.0 
Assessment of Severity 
T rneBinding, Inc. 
The investigator will make an assessment of severity for each AE and SAE repo1ted during the 
study per the NCI CTCAE version 5.0 (see Section 10.2.5). Toxicities that are not specified in 
NCI CTCAE will be defined as follows: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instmmental ADL ( eg, preparing meals, shopping for groceries or clothes, 
using the telephone, managing money). 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL ( eg, bathing, dressing and undressing, feeding self, using the toilet, taking 
medications). 
An AE that is assessed as severe should not be confused with an SAE. Severe is a catego1y 
utilized for rating the severity of an event; and both AEs and SAEs can be assessed as 
severe. An event is defined as 'serious' when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
• 
Grade 4: Life-threatening consequences; mgent inte1vention indicated. 
• 
Grade 5: Death related to AE. 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study drng and each 
occU1Tence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be rnled 
out. 
• 
The investigator will use clinical judgment to detennine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study diug adininistration, will 
be considered and investigated. 
• 
The investigator will also consult the IB in his/her assessment. 
• 
For each AE/SAE, the investigator !!!!!.U. document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occU1Ted and the investigator has minimal 
infonnation to include in the initial repo1t . However, it is very important that the 
investigator always makes an assessment of causality for every event before the initial 
transmission of the SAE data. 
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Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
T rneBinding, Inc. 
• 
The investigator may change his/her opinion of causality in light of follow-up infonnation 
and send an SAE follow-up repo1t with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when detennining regulato1y repo1ting 
requirements. 
• 
Causality assessments are defined below: 
o Causality assessments that indicate the event is "Not Drng Related": 
• 
Um-elated: The event is related to an etiology other than the study drng 
administration (the alternative etiology must be documented in the patient's 
medical record). 
• 
Unlikely: The event is unlikely to be related to the study diug and likely to be 
related to factors other than study diug. 
o Causality assessments that indicate the event is "Drng Related": 
Possible: There is an association between the event and the administration of study 
diug and there is a plausible mechanism for the event to be related to the study 
diug; but there may also be alternative etiology, such as characteristics of the 
patient's clinical status or underlying disease. 
• 
Probable: There is an association between the event and the adininistration of study 
diug and there is a plausible mechanism for the event to be related to the study 
diug, and the event could not be reasonably explained by known characteristics of 
the patient's clinical status or an alternative etiology is not apparent. 
• 
Definite: There is an association between the event and the adininistration of study 
diug and there is a plausible mechanism for the event to be related to the study di11g 
and causes other than the study diug have been rnled out and/or the event re-appeared 
on re-exposure to the study diug. 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perfonn or an ange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested to elucidate 
the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• 
If a patient dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor with a copy of any post-moliem 
findings including histopathology. 
• 
New or updated infonnation will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the infonnation. 
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Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
10.2.4 Reporting of Serious Adverse Events 
SAE Reporting to via an Electronic Data Collection Tool 
T rneBinding, Inc. 
• 
The primaiy mechanism for repo1i ing an SAE will be the electronic data collection 
tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool in order to repo1i the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study patient or receives updated data 
on a previously repo1ied SAE after the electronic data collection tool has been taken 
off-line, then the site can repo1i this infonnation on a paper SAE f01m or to the 
MedicaVScientific Monitor by telephone. 
• 
Conta.cts for SAE repo1iing are noted below. 
10.2.5 National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 
The NCI CTCAE is a descriptive tenninology which can be utilized for AE repo1iing. A grading 
(severity) scale is provided for each AE te1m. 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or noninvasive inte1vention indicated; limiting 
age-appropriate instrumental ADL *. 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-cai·e ADL**. 
• 
Grade 4: Life-threatening consequences; urgent inte1vention indicated. 
• 
Grade 5: Death related to AE. 
*Instrumental ADL refer to prepai·ing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Published date of version 5.0: 27 Nov 2017, available here: 
CONFIDENTIAL 
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https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf 
from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
T rneBinding, Inc. 
10.3 Appendix 3: Liver Safety: Suggested Actions and Follow-up 
Assessments 
Phase 1 liver chemistry stopping criteria define liver injury, evaluate liver event etiology, and are 
considered in dose escalation decisions. 
Table 9. 
Phase 1 Liver Chemistry Stopping Criteria and Follow-up Assessments 
Liver Chemistry Stopping Criteria 
Alanine aminotransferase (ALT) 
3 x upper limit of n01m al (ULN) 
ALT-absolute 
If ALT~ 3 x ULN AND bilirnbin 2 x ULN (> 35% direct bilirnbin) or 
international n01m alized ratio (INR) > 1.5, repo1t as a serious adverse event 
(SAE)a,b 
See additional actions and follow-up assessments below 
Required Actions and Follow-up Assessments 
Actions 
Follow-Up Assessments 
• Immediately discontinue study drng 
• Viral hepatitis serology 
• Repo1t the event to the sponsor within 
• 
Obtain INR and recheck with each liver 
24 hours 
chemistiy assessment until the 
• Complete the liver event case report fo1m 
transaminases values show downward 
(CRF), and complete an SAE data 
trend 
collection tool if the event also met the 
• Sernm creatine phosphokinase (CPK) 
criteria for an SAEb 
and lactate dehydrogenase (LDH) 
• Perfo1m liver function follow-up 
• Fractionate bilirnbin, if total bilirnbin 
assessments 
~ 2 x ULN 
• Monitor the patient until liver function test • Complete blood count with differential to 
abno1m alities resolve, stabilize, or return 
assess eosinophilia 
to baseline (see MONITORING) 
• Record the appearance or worsening of 
MONITORING: 
clinical symptoms of liver injmy , or 
If ALT 
3 x ULN AND bilirubin 
hypersensitivity, on the AE CRF 
~2 x ULN or INR > 1.5 
• Record use of concomitant medications 
• Repeat liver function tests (include ALT, 
(including acetaminophen, herbal 
aspaitate ti·ansaminase [AST], alkaline 
remedies, and other over-the-counter 
phosphatase, bilirnbin and INR) and 
medications) on the concomitant 
perfo1m liver function follow-up 
medications CRF 
assessments within 24 hours. 
• Record alcohol use on the liver event 
• Monitor patient twice weekly until liver 
alcohol intake CRF 
function test abno1malities resolve, 
If ALT 
3 x ULN AND bilirubin 
stabilize, or return to baseline. 
2 x ULN or INR > 1.5: 
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A specialist or hepatology consultation is
recommended.
If ALT  3 × ULN AND bilirubin 
< 2 × ULN and INR  1.5: 
Repeat liver function tests (include ALT,
AST, alkaline phosphatase, bilirubin and
INR) and perform liver function follow-up
assessments within 24 to 72 hours
Monitor patients weekly until liver
function abnormalities resolve, stabilize, or
return to baseline
Anti-nuclear antibody, anti-smooth
muscle antibody, Type 1 anti-liver
kidney microsomal antibodies, and
quantitative total immunoglobulin G
(IgG) or gamma globulins
Serum acetaminophen adduct high
performance liquid chromatography
assay (quantifies potential acetaminophen
contribution to liver injury in patients
with definite or likely acetaminophen use
in the preceding week [James et al,
2009])
Liver imaging (ultrasound, magnetic
resonance, or computerized tomography)
and/or liver biopsy to evaluate liver
disease; complete liver imaging and/or
liver biopsy CRFs
a 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study drug if ALT  3 × ULN and bilirubin  2 × ULN. Additionally, if 
serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary 
bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury.  
b 
All events of ALT  3 × ULN and bilirubin  2 × 
 35% direct bilirubin) or ALT  3 × ULN and INR 
1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding
studies of hepatic impairment or cirrhosis). The INR stated threshold value will not apply to patients
receiving anticoagulants.
c 
Includes: Hepatitis A immunoglobulin M (IgM) antibody; hepatitis B surface antigen and hepatitis B core 
antibody; hepatitis C RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or 
if unavailable, heterophile antibody or monospot testing); and hepatitis E IgM antibody.  


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Protocol Date and Version: 15 Oct 2021; v 3.0 
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Page 87 of 101 
A patient who met liver chemistry stopping criteria cannot restart study drug unless all of the 
following conditions are met: 
TrueBinding Inc. approval is granted (as described below)
Institutional Review Board/Independent Ethics Committee (IRB/IEC) approval is
obtained
Separate ICF for study drug restart/rechallenge is signed by the patient
If TrueBinding Inc. approval to restart/rechallenge the patient with study drug is not granted, 
then the patient must permanently discontinue study drug and may continue in the study for 
protocol-specified follow-up assessments. 
10.3.1 Rechallenge Following Liver Chemistry Events that are Possibly Related to 
Study Drug 
Following study drug-induced liver injury, rechallenge is associated with 13% mortality
across all study drugs in prospective studies (Andrade et al, 2009). Clinical outcomes
vary with nearly 50% fatality with halothane readministered within 1 month of the initial
injury. However, some interventions seldom result in recurrent liver injury or fatality.
Risk factors for a fatal rechallenge outcome include:
o
Hypersensitivity with initial liver injury (eg, fever, rash, eosinophilia) 
(Andrade et al, 2009)
o
 2 × 
 35% of
total)
o
Ongoing severe liver injury defined by ALT  3 × ULN AND bilirubin  2 × ULN
 35% 
 1.5
o
SAE or fatality previously observed with rechallenges (Hunt, 2010; Papay et al, 2009)
o
Evidence of drug-related preclinical liability (eg, reactive metabolites, mitochondrial
impairment) (Hunt, 2010)
Rechallenge refers to resuming study drug following drug-induced liver injury (DILI).
Because of the risks associated with rechallenge after DILI, this should only be
considered if there is compelling evidence of benefit from a critical or life-saving
medicine, there is no alternative approved medicine available, and a benefit/risk
assessment of rechallenge is considered to be favorable.
Approval by the sponsor for rechallenge with study drug can be considered when:
o
The Principal investigator requests consideration of rechallenge with study drug or a
patient who is receiving compelling benefit with study drug that exceeds risk and for
whom no effective alternative therapy is available.
o
IRB/IEC approval for rechallenge with study drug has been obtained.


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Protocol Date and Version: 15 Oct 2021; v 3.0 
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If the rechallenge is approved by the sponsor in writing:
The patient must be provided with a clear description of the possible benefits and risks of
study drug administration including the possibility of recurrent, more severe liver injury
or death.
The patient must provide signed informed consent specifically for the rechallenge with
study drug. Documentation of informed consent must be recorded in the study file.
Study drug must be administered at the dose specified by the sponsor.
Patients approved by the sponsor for rechallenge with study drug must return to the clinic
twice a week for liver chemistry tests until stable liver chemistry tests have been
demonstrated and then standard laboratory monitoring may resume as per protocol.
If the patient meets protocol-defined liver chemistry stopping criteria after study drug
rechallenge, study drug should be permanently discontinued.
The sponsor and the IRB/IEC, must be informed of the outcome for the patient following
study drug rechallenge.
The sponsor must be notified of any adverse events.
AND/OR
10.3.2 Restart Following Transient Resolving Liver Chemistry Events Not Related to 
Study Drug 
Restart refers to resuming study drug following liver chemistry events for which there are
clear underlying causes (other than DILI) (eg, biliary obstruction, pancreatic events,
hypotension, acute viral hepatitis). Furthermore, there should be no evidence of alcoholic
hepatitis or hypersensitivity.
Approval by the sponsor for study drug restart can be considered when:
o
The investigator requests consideration for study drug restart if liver chemistry events
have a clear underlying cause (eg, biliary obstruction, pancreatic events, hypotension,
acute viral hepatitis) and liver chemistry tests have improved to normal or are within
1.5 × baseline and ALT < 3 × ULN.
o
Possible DILI has been excluded by the investigator and the study team. This includes
the absence of markers of hypersensitivity (otherwise unexplained fever, rash,
eosinophilia). Where a study drug has an identified genetic marker associated with
liver injury (eg, lapatinib, abacavir, and amoxicillin/clavulanate), the presence of the
marker should be excluded. If study drug-related liver injury cannot be excluded, the
guidance on rechallenge in the previous part of this Appendix will apply.
o
There is no evidence of alcoholic hepatitis.
o
IRB/IEC approval of study drug restart has been obtained.


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If restart of study drug is approved by the sponsor in writing: 
The patient must be provided with a clear description of the possible benefits and risks of
study drug administration including the possibility of recurrent, more severe liver injury
or death.
The patient must provide signed informed consent specifically for the restart of study
drug. Documentation of informed consent must be recorded in the study file.
Study drug must be administered at the dose specified by the sponsor.
Patients approved by the sponsor for restart of study drug must return to the clinic twice a
week for liver chemistry tests until stable liver chemistry tests have been demonstrated
and then standard laboratory monitoring may resume as per protocol.
If the patient meets protocol-defined liver chemistry stopping criteria after study drug
restart, study drug should be permanently discontinued.
The sponsor, and the IRB/IEC, must be informed of the outcome for the patient following
study drug restart.
The sponsor must be notified of any adverse events.


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Protocol Date and Version: 15 Oct 2021; v 3.0 
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10.4 Appendix 4: Diagnostic and Statistical Manual of Mental Disorders 
Fifth Edition Criteria for Major Neurocognitive Disorder (previously 
dementia) 
Evidence of significant cognitive decline from a previous level of performance in one or
more of the following domains:
Learning and memory
Language
Executive function
Perceptual-motor
Social cognition
The cognitive deficits interfere with independence in everyday activities. At a minimum,
assistance should be required with complex instrumental activities of daily living, such as
paying bills or managing medications.
o
The deficits do not occur exclusively during the course of a delirium.
o
The disturbance is not better accounted for by another Axis I disorder (eg, Major
Depressive Disorder, Schizophrenia).


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Protocol Date and Version: 15 Oct 2021; v 3.0 
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10.5 Appendix 5: National Institute of Neurological and Communicative 
Disorders and Stroke – Alzheimer’s Disease and Related Disorder 
Association (NINCDS-ADRDA) – Criteria for Diagnosis of Probable 
Alzheimer’s Disease 
Criteria for Diagnosis of Probable Alzheimer’s Disease:
o
Dementia established by clinical examination and documented by a standard test of
cognitive function (eg, mini-mental state examination, Blessed Dementia Scale, etc.) and
confirmed by neuropsychological tests;
o
Significant deficiencies in 2 or more areas of cognition, for example, word
comprehension and task-completion ability;
o
Progressive deterioration of memory and other cognitive functions;
o
No loss of consciousness;
o
Onset from age 40 to 90, typically after 65;
o
No other diseases or disorders that could account for the loss of memory and cognition.
Diagnosis of Probably Alzheimer’s Disease is Supported by:
o
Progressive deterioration of specific cognitive functions: language (aphasia), motor skills
(apraxia), and perception (agnosia);
o
Impaired activities of daily living and altered patterns of behavior;
o
A family history of similar problems, particularly if confirmed by neurological testing;
o
The following laboratory results:
-- Cerebrospinal fluid (lumbar puncture test);
-- Normal electroencephalogram test of brain activity;
-- Evidence of cerebral atrophy in a series of computed tomography (CT) scans.
Other Features Consistent with Alzheimer’s Disease:
o
Plateaus in the course of illness progression;
o
CT findings normal for the person’s age;
o
Associated symptoms including depression, insomnia, incontinence, delusions,
hallucinations, weight loss, sex problems, and significant verbal, emotional, and physical
outbursts;
o
Other neurological abnormalities, especially in advanced disease, including increased
muscle tone and a shuffling gait.
Features that Decrease the Likelihood of Alzheimer’s Disease:
o
Sudden onset;
o
Such early symptoms as seizures, gait problems, and loss of vision and coordination.


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Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
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10.6 Appendix 6: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table and the rationale for these changes are 
detailed below.
Amendment 2.0 
The rationale for updates to the TB006AD2102 protocol are detailed below. 
Overall Rationale for the Amendment 
Objectives and Endpoints 
1. Updated primary endpoint analysis from “Clinical Dementia Rating scale change from
baseline through Day 36” to “Clinical Dementia Rating scale change from baseline through
Day 104.”
Rationale: To prioritize the durability of effect through end of patient follow-up as well as
the effect at the end of the treatment period.
Study Population
2. Inclusion criteria “6” related to contraceptive use in men has been updated to state that males
must agree to use protocol defined contraceptive methods from the first day of dosing
through 6 months following the last dose of study drug.
Rationale: It has been determined that the contraceptive use timeframe of 90 days from last
dose of study drug is not effective for this study. This change has been incorporated to bring
the protocol document and requirement for male contraception into alignment with the
current Investigators Brochure.
3. Change COVID-19 exclusion criterion from 3-month history of positivity to 1-month history
of positivity.
Rationale: Isolation beyond one month presents a minimum risk of spreading the infection
and a minimum risk of re-emergence of symptoms that could confound the assessment of the
safety profile.
Study Assessments and Procedures
4. Change the dose escalation pattern between dose Groups in Part 1 and between Group 3 in
Part 1 to Part 2 from “available safety and PK follow-up 14 days after the last patient
receives their last dose in each group” to “available safety and PK follow-up after the last
patient in each dose group receives their first dose.”


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Protocol Date and Version: 15 Oct 2021; v 3.0 
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Rationale: The safety and tolerability of single doses up to 5,000 mg is established in the 
healthy volunteer SAD study (Protocol TB006HV1101). The dose levels used in this study 
are also used in the SAD study, however in this study the total dose is administered in 
5 weekly divided doses.  Therefore, projected exposures (both Cmax and AUC) in this study 
will be lower at each dose level than that at the equivalent doses used in the SAD study. In 
addition, enrollment will be at a rate (approximately 1 patient/site/month; 4 sites participating 
in Part 1) that will enable accumulation of a considerable amount of safety and tolerability 
data when the last patient in enrolled. These data, combined with the safety and tolerability 
data from the SAD study, provides sufficient information to make informed dose escalation 
decisions and, although a change from the original protocol, presents a minimum amount of 
risk to patients. 
5. Urine alcohol and drug screening test were separated on the Schedule of Activities.
Rationale: This is a procedural change. The urine alcohol test will be performed by the local
laboratory.
6. Increase frequency of MMSE and Clinical Dementia Rating scale assessments.
Rationale: To assess for efficacy at an early timepoint (during the treatment period).
Note: The Clinical Dementia Rating scale was erroneously scheduled at weekly intervals
during the treatment period. This was corrected.
7. Added “hemoglobin” to laboratory assessments in Table 5, Protocol-required Clinical Safety
Laboratory Assessments.
Rationale: Omission was an oversight in original protocol.
8. In the Suicide Ideation and Behavior Risk Monitoring portion of the study and the C-SSRS
assessment. The C-SSRS assessment is provided to subjects through 2 versions, the
“Lifetime” version at screening and then the “Since Last Visit” version on all remaining
visits according to the Schedule of Events. The C-SSRS version provided at screening has
been updated from the “Lifetime” version to the “Past 6 months” version.
Rationale: Asking patients to recall a “lifetime” occurrence in this patient population is not
necessary or relevant in a mild to severe AD patient population.
9. Changed the Lumbar Puncture procedure to “optional”.
Rationale: Acquisition of CSF data (TB006 concentrations, CSF biomarkers) is not germane
to the assessment of TB006 efficacy and tends to discourage AD patients from participating.
Nonetheless, acquisition of partial data will be informative for subsequent drug development.


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
T rneBinding, Inc. 
10. Added MRI and PET scan on Day 36. Allowed procedures window of± 3 days for 
MRI/PET. 
Rationale: To assess the effect at an earlier timepoint. Procedure window allows flexibility 
for patient and study staff. 
Administrative Changes 
11. Removed Prinicpal Investigator name on Investigator agreement page. 
Rationale: This study is multi-site study, removing the Principal Investigator name allows, 
thus removing the the name on the page will change per site. 
Summary of Changes: 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
• Updated Title page to align 
• Administrntive update 
with protocol version 
Investigator 
• Removed '-
• This is a multi-site study thus 
Agreement 
-
'and replaced with 
there will be more than one 
"Principal Investigator" 
investigator 
Section 1.1, Synopsis, • Updated primaiy endpoint 
Objectives and 
Change from baseline on the 
Endpoints - Pali 2 
Clinical Dementia Rating 
• Endpoints were updated to 
scale - Sum of Boxes total 
prioritize not only the efficacy 
score from "through 
ofti·eatment at the end of dosing 
Day 36" to "through 
but the durability of effect 
Day 104". 
through end of patient follow-up 
• Updated secondary endpoint 
Change from baseline on the 
Clinical Dementia Rating 
scale - Sum of Boxes total 
score from "through 
Day 104" to "through 
Day 36" 
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Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Section 1.1, Synopsis, • Revised sentence relating to 
Overall Design 
review of safety, PK, and 
tolerablility data to include 
that safety, tolerability and 
PK data would be reviewed 
after the 2,100 mg and 
5,000 mg single dose, 
respectively, had been 
administered" 
Section 1.2, Schema, 
• Updated schema to include 
Figure 1 and Figure 2 
new dosing regimen for the 
MAD study 
Section 1.3, Schedule 
Table 1 
of Activities 
• Added an MMSE 
assessment at Day 15 visit 
• Added a Clinical Dementia 
Rating scale at Day 15 visit 
• Lumber puncture was 
updated to "optional" 
Table 2 
• Added an MMSE 
assessment at Day 15 visit 
• Removed a Clinical 
Dementia Rating scale 
assessment at the Day 8 visit 
and the Day 22 visit 
Table 1 and 2 
• Sepai·ated out the urine 
alcohol tests from the drng 
screening tests 
• Added an additional 
assessment for MRI and 
PET at Day 36 and added a 
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T rneBinding, Inc. 
• To provide additional clarity on 
when safety data would be 
reviewed 
• To align with the new dosing 
regimen 
• Updated MMSE and Clinical 
Dementia Rating scale in the 
Schedule of Activities tables to 
assess and detect efficacy at an 
early timepoint 
• Acquisition of CSF data (TB006 
concentrations, CSF biomarkers) 
is not gennane to the assessment 
of TB006 efficacy and tends to 
discourage AD patients from 
paiiicipating 
• To evaluate to assess and detect 
efficacy at an early timepoint 
• The Clinical Dementia Rating 
scale was en oneously scheduled 
at weekly intervals during the 
treatment period 
• Tests will be perfonned by 
different laboratories and ai·e 
sepai·ate tests. Updated for 
clarity 
• To assess efficacy at an eai·lier 
timepoint and expanding the 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Section 3, Objectives 
and Endpoints 
CONFIDENTIAL 
window for the assessment 
of± 3 days 
• In Paii 2, updated prima1y 
endpoint Change from 
baseline on the Clinical 
Dementia Rating scale -
Sum of Boxes total score 
from "through Day 36" to 
"through Day 104" 
• In Paii 2, updated secondaiy 
endpoint Change from 
baseline on the Clinical 
Dementia Rating scale -
Sum of Boxes total score 
from "through Day 104" to 
"through Day 36" 
• 
• 
• 
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procedure window "alllows" 
flexibility for patient and study 
staff 
• Endpoints were updated to 
prioritize not only the efficacy 
ofti·eatment at the end of dosing 
but the durability of effect 
through end of patient follow-up 
• 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Section 4.1, Overall 
• Edited sentence to add that 
Design 
text was refening to Pait 1 
• Dose escalation decisions 
were changed from using 
available safety and PK 
follow-up "14 days after the 
last patient receives their 
last dose in each group" to 
"available safety and PK 
follow-up after the last 
patient in each dose group 
receives their first dose" 
• Revised to state that Pait 2 
would comment "after the 
last patient in Pali 1 had 
received their first dose" 
instead of "at least 14 days 
after the last patient in Pait 1 
received their first dose" 
Section 4.2, Scientific • Updated dosing escalation 
Rationale for Study 
Design 
Section 4.4, End of 
• Revised the te1m "End of 
Study 
Study'' to "End of Study 
(End of Trial) 
Section 5 .1, Inclusion • Male contraceptive use was 
Criteria 
updated contraceptive use 
from the first day of dose 
through 90 days after dosing 
to 6 months after dosing 
Section 5.2, Exclusion • Updated recent history of a 
Criteria 
positive COVID-19 test 
from 3 months to 1 month 
• Defined the abbreviation of 
"qw" to weekly and 
removed abbreviation 
CONFIDENTIAL 
Page 97 of 101 
T rneBinding, Inc. 
• Administrntive change for 
clarity 
• Sufficient data from the SAD 
study provides sufficient 
info1mation to make info1med 
dose escalation decisions and, 
although a change from the 
original protocol, presents a 
minimum amount of risk to 
patients 
• To align with overall study 
design 
• Administrative change for 
clarity 
• This change has been 
incorporated to bring the 
protocol document and 
requirement for male 
contraception into alignment 
with the cmTent Investigators 
Brochure 
• Isolation beyond 1 month 
presents minimal risk of 
spreading infection 
• Minor edit for readability 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Section 8.2.4, Clinical • Added "hemoglobin" to 
Safety Laboratory 
Table 5 
Assessments 
Section 8.2.5, Suicide • Replaced the "Lifetime" 
Ideation and Behavior 
version of the C-SSRS with 
Risk Monitoring 
the "Past 6 months" version 
of the C-SSRS 
Section 8.5, 
• Lumbar puncture was 
Phannacokinetics 
updated to "optional" 
Section 8.6.2, Lumbar • Assessment was changed to 
Puncture 
"optional" 
Section 9 .1, Statistical • Updated the primary 
Hypotheses 
endpoint in Pait 2 from 
change from baseline 
Clinical Dementia Rating 
Scale - Sum of Boxes score 
"at Day 36" to "through 
Day 104" 
• Update also applied to the 
null hypothesis. 
Section 9 .2, Sample 
• Updated the primary 
Size Detennination 
efficacy endpoint for change 
from baseline Clinical 
Dementia Rating Scale -
Sum of Boxes at "Day 36" 
to "Day 104" 
CONFIDENTIAL 
Page 98 of 101 
T rneBinding, Inc. 
• Omission was an oversight in 
the original protocol 
• To more align the protocol 
document with the appropriate 
assessments for the patient 
population 
• Acquisition of CSF data is not 
ge1mane to the study. Partial 
info1mation will be infonnative 
for subsequent drng 
development 
• Acquisition of CSF data is not 
ge1mane to the study. Partial 
info1mation will be infonnative 
for subsequent drng 
development 
• To align with updates to 
objectives and endpoints in 
Section 3 
• To align with updates to 
objectives and endpoints in 
Section 3 


Compound: TB006 
Protocol TB006AD2102 
Protocol Date and Version: 15 Oct 2021; v 3.0 
Section 9.4.5, Pait 2 
• Updated the primary 
Primary and 
efficacy endpoint in Pait 2 
Seconda1y Endpoints 
from Clinical Dementia 
Rating Scale - Sum of 
Boxes change from baseline 
"at Day 36" to "through 
Day 104" 
• Updated the key seconda1y 
efficacy endpoint to the 
change from baseline on the 
Clinical Dementia Rating 
Scale - Sum of Boxes 
"through Day 104" to 
"through Day 36" 
Section 9.4.6, Pait 2 
• Revised sentence to include 
Explorato1y 
Day 36 as well as Day 64 
Endpoints 
and text for analyses were 
changed from Analysis of 
Covai·iance to MMRM and 
added the additional 
compai·isons including "with 
treatment group visit, and 
treatment group by visit 
interaction as fixed effects" 
Section 9.6, Safety 
• Revised the text to indicate 
Review Committee 
that the SRC will review 
after the "last patient in each 
group has received their first 
dose" to align with the new 
dosing regimen 
CONFIDENTIAL 
Page 99 of 101 
T rneBinding, Inc. 
• To align with updates to 
objectives and endpoints in 
Section 3 
• To align with changes to the 
endpoints in the objectives and 
endpoints table 
• To align with changes to dose 
escalation decisions in the 
Overall Study Design 


Compound: TB006
TrueBinding, Inc. 
Protocol TB006AD2102
Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL 
Page 100 of 101 
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Protocol Date and Version: 15 Oct 2021; v 3.0 
CONFIDENTIAL 
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