Clinical trial NCT03751007
Conditions: Diabetes type1
Sponsor: Precigen Actobio T1D, LLC
Start date: 2018-10-24; Completion date: 2021-10-13
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to assess the safety and tolerability of different doses of AG019 administered alone or in combination with teplizumab in participants with recent-onset type 1 diabetes (T1D).

Detailed description:
This Phase 1b/2a, multi-center study will be conducted in participants with clinical recent-onset type 1 diabetes (T1D).

The primary objective of this study is to assess the safety and tolerability of different doses of AG019 alone as well as AG019 in combination with teplizumab. The secondary objectives of this study are: to obtain pharmacodynamic (PD) data of AG019 alone as well as AG019 in combination with teplizumab; and to determine the potential presence of AG019 in systemic circulation (safety - systemic exposure) and the presence of L. lactis bacteria in fecal excretion (local exposure): Pharmacokinetic (PK) profile.

This study consists of 2 phases:

Phase 1b: this open-label part of the study will investigate the safety and tolerability of 2 different doses of AG019 in 2 age groups (18-40 years of age and 12-17 years of age).

Phase 2a: this randomized, double-blind part of the study will investigate the safety and tolerability of AG019, in combination with teplizumab, in 2 age groups (18-40 years of age and 12-17 years of age).

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None
Interventions: intervention 1: AG019 - Low Dose intervention 2: Teplizumab intervention 3: Placebo-AG019 intervention 4: Placebo-Teplizumab intervention 5: AG019 - High Dose intervention 6: AG019 - High Dose
Intervention descriptions: intervention 1: Solid, orally administered capsule - 2 capsules per day for 1 day (single dose) or 8 weeks (repeat dose) intervention 2: Daily IV infusions of Teplizumab during the first 12 days of AG019 treatment. Total cumulative dose is approximately 17mg (dose calculation based on body surface area). intervention 3: Formulated identically to AG019 with the active ingredient removed. intervention 4: Formulated identically to teplizumab with the active ingredient removed. intervention 5: Solid, orally administered capsule - 6 capsules per day for 1 day (single dose) or 8 weeks intervention 6: Solid, orally administered capsule - 6 capsules per day for 8 weeks.

Protocol documents:
Prot_000.pdf: 
Precigen ActoBio T1D, LLC 
Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
This document contains confidential information.  It is intended solely for the use of the principal investigator, co-
investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory bodies. 
AG019-T1D-101 CSP Final 9.0 11-Jun-2020 
Page 1/93 
Clinical Study Protocol 
Protocol Title: 
A prospective, multi-center, Phase 1b/2a study to assess the safety and 
tolerability of different doses of AG019 administered alone or in 
association with teplizumab in patients with clinical recent-onset Type 1 
Diabetes Mellitus (T1D). 
Investigational Drug: 
AG019 
Protocol Number: 
AG019-T1D-101 
EudraCT Number: 
IND number: 
2017-002871-24 
18000 
Sponsor: 
Precigen ActoBio T1D, LLC 
20374 Seneca Meadows Parkway 
Germantown, MD 20876 
USA 
Sponsor Signatory: 
Name and Title: 
_________________________ 
Signature 
Protocol Date: 
Final 9.0 11-Jun-2020 
GCP STATEMENT 
This trial will be conducted in compliance with this protocol, Good Clinical Practices and applicable regulatory requirements. 


Precigen ActoBio T1D, LLC 
Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
This document contains confidential information.  It is intended solely for the use of the principal investigator, co-
investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
bodies. 
AG019-T1D-101 CSP Final 9.0 11-Jun-2020 
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Table of Contents 
1.
INTRODUCTION AND STUDY RATIONALE ................................................................................. 24 
1.1. 
Background ............................................................................................................................ 24 
Non-clinical Studies .............................................................................................................. 25 
Effects in humans .................................................................................................................. 25 
1.2. 
Rationale .................................................................................................................................. 26 
2.
Objectives ............................................................................................................................................... 27 
2.1. 
Primary Objective ................................................................................................................... 27 
2.2. 
Secondary Objectives ........................................................................................................... 27 
3.
Study Design ......................................................................................................................................... 27 
3.1. 
General information ............................................................................................................... 27 
3.2. 
Phase 1b portion .................................................................................................................... 28 
3.3. 
Phase 2a portion ................................................................................................................... 29 
3.4. 
Rationale for the study design ........................................................................................... 30 
4.
Study Population .................................................................................................................................. 33 
4.1. 
Sample Size ............................................................................................................................. 33 
4.2. 
Inclusion Criteria ..................................................................................................................... 33 
4.3. 
Exclusion Criteria ................................................................................................................... 35 
4.4. 
Controlling Enrolment .......................................................................................................... 36 
4.5. 
Removal of Patients ............................................................................................................... 37 
4.6. 
Special considerations ......................................................................................................... 38 
5.
Study Treatment .................................................................................................................................. 38 
5.1. 
Treatments .............................................................................................................................. 38 
5.1.1 
AG019 ....................................................................................................................................... 38 
5.1.2 
Teplizumab ............................................................................................................................. 39 
5.1.3 
T1D therapy during the study ............................................................................................. 40 
5.1.4 
Other concomitant therapy ................................................................................................ 40 
5.2. 
Description of the cohorts ....................................................................................................41 
5.2.1 
AG019 Cohorts .........................................................................................................................41 
5.2.2 
Combination Cohorts ........................................................................................................... 42 
5.3. 
Identity of Investigational Medicinal Product .................................................................. 43 
5.3.1 
AG019 ........................................................................................................................................ 43 
5.3.2 
Teplizumab .............................................................................................................................. 44 


Precigen ActoBio T1D, LLC 
Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
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5.4. 
Labelling, Packaging and Storage ..................................................................................... 44 
5.5. 
Investigational Medicinal Product Administration ......................................................... 44 
5.6. 
Placebo/Comparator ............................................................................................................ 45 
5.7. 
Study Drug Accountability .................................................................................................. 45 
5.8. 
Return and destruction of study drug .............................................................................. 46 
5.9. 
Method of Assigning Patients to Treatment .................................................................. 46 
5.10. 
Blinding .................................................................................................................................... 46 
6.
Assessments .......................................................................................................................................... 47 
6.1. 
General assessments ............................................................................................................ 47 
6.2. 
Safety Assessments ............................................................................................................. 48 
6.3. 
Laboratory Assessments ..................................................................................................... 48 
6.3.1 
General considerations ....................................................................................................... 48 
6.3.2 
Local lab assessments ......................................................................................................... 49 
6.3.3 
Central lab assessments ..................................................................................................... 50 
6.3.3.1 Pharmacokinetic Assessments .......................................................................................... 50 
6.3.3.2 Mechanistic Assessments ................................................................................................... 50 
6.3.3.3 Metabolic outcome assessments ...................................................................................... 51 
6.4. 
Other assessments ............................................................................................................... 52 
6.4.1 
Electronic Patient Reported Outcomes (ePRO) ............................................................ 52 
6.4.2 
Continuous Glucose Monitoring (CGM) .......................................................................... 53 
7.
Study Procedures ................................................................................................................................ 53 
7.1. 
Visit Schedule ........................................................................................................................ 53 
7.2. 
Single Dose Patients ............................................................................................................ 53 
7.2.1 
Screening Visit (Day -28 – Day 0) ..................................................................................... 53 
7.2.2 
Treatment Visit (Day 1) ......................................................................................................... 54 
7.2.3 
End of Study visit (Day 4) .................................................................................................... 54 
7.3. 
Repeat Dose Patients .......................................................................................................... 55 
7.3.1 
Screening Visit (Day -28 – Day 0) ..................................................................................... 55 
7.3.2 
Baseline Visit (Day 1 – start of active treatment) ........................................................... 55 
7.3.3 
Visits during active treatment phase ............................................................................... 56 
7.3.3.1 For all patients in AG019 cohorts and Combination Cohorts .................................... 56 
7.3.3.2 Additional visits for patients in Combination Cohorts ................................................. 59 


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Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
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7.3.3.3 Additional feces sampling (at home) on Days 58, 60, 62 and 64 (only for repeat 
dose patients in AG019 Cohorts 2 and 4 and for patients in the combination 
cohorts) .................................................................................................................................... 59 
7.3.4 
Visits after the active treatment phase ........................................................................... 60 
7.3.4.1 Day 90 follow-up visit........................................................................................................... 60 
7.3.4.2 Day 180 follow-up visit ......................................................................................................... 60 
7.3.4.3 Day 270 follow-up visit ........................................................................................................ 60 
7.3.4.4 Day 360 follow-up visit (End of Study).............................................................................. 61 
7.4. 
Unscheduled visits ................................................................................................................. 61 
8.
Adverse Event Reporting .................................................................................................................. 62 
8.1. 
Adverse Event Definition .................................................................................................... 62 
8.2. 
Assessing Severity of Adverse Events ............................................................................ 62 
8.2.1 
Grading of Hypoglycemic and Hyperglycemic Events ............................................... 63 
8.3. 
Assessing Relationship to Study Treatment .................................................................. 64 
8.4. 
Recording of Adverse Events ............................................................................................ 64 
8.5. 
Adverse Event Follow-up Period ...................................................................................... 65 
8.6. 
Serious Adverse Event Definition ..................................................................................... 65 
8.7. 
Reporting of Serious Adverse Events .............................................................................. 66 
8.8. 
Serious Adverse Event Follow-up Period ........................................................................ 67 
8.9. 
Regulatory Reporting of Adverse Events ........................................................................ 67 
8.10. 
Expected adverse events .................................................................................................... 67 
8.10.1 AG019........................................................................................................................................67 
8.10.2 Teplizumab ............................................................................................................................. 68 
8.10.2.1 Hematologic ........................................................................................................................... 68 
8.10.2.2 
Cytokine Release Syndrome ............................................................................... 68 
8.10.2.3 
Lymphoproliferative Disease ............................................................................... 69 
8.10.2.4 
Anti-idiotype Responses ....................................................................................... 69 
8.10.2.5 
Infection ..................................................................................................................... 69 
8.10.2.6 
Rash .............................................................................................................................70 
9.
Data Management ................................................................................................................................70 
10.
Statistical Methods ................................................................................................................................ 71 
10.1. 
Study Endpoints....................................................................................................................... 71 
10.2. 
Sample Size Consideration .................................................................................................. 71 


Precigen ActoBio T1D, LLC 
Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
This document contains confidential information.  It is intended solely for the use of the principal investigator, co-
investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
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10.3. 
Definitions of Study Populations for Analysis ................................................................. 72 
10.3.1 The Safety (SAF) Analysis Set ............................................................................................. 72 
10.3.2 The Pharmacokinetic (PK) Analysis Set ............................................................................ 72 
10.3.3 The Pharmacodynamic (PD) Analysis Set ........................................................................ 72 
10.4. 
Baseline Characteristics and Demographic Variables ................................................. 72 
10.5. 
Pharmacokinetic Analysis .................................................................................................... 72 
10.6. 
Pharmacodynamic analysis ................................................................................................. 73 
10.7. 
Safety Analysis ........................................................................................................................ 73 
10.8. 
Interim Analysis ....................................................................................................................... 73 
10.9. 
Reporting of Deviations to Original SAP .......................................................................... 74 
11.
Ethics ........................................................................................................................................................ 74 
11.1. 
Good Clinical Practice ........................................................................................................... 74 
11.2. 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) ................. 74 
11.3. 
Patient Information and Informed Consent ..................................................................... 74 
11.4. 
Data Safety Monitoring Board and Medical Monitor .................................................... 75 
11.4.1 
Medical Monitor ...................................................................................................................... 75 
11.4.2 DSMB.........................................................................................................................................75 
11.4.3 Study/Treatment Stopping Criteria ................................................................................... 77 
11.4.3.1 Criteria for premature study termination ......................................................................... 77 
11.4.3.2 Criteria for suspension of enrollment ............................................................................... 77 
11.4.3.3 Criteria for adjusting AG019 treatment ............................................................................. 78 
11.4.3.4 Criteria for discontinuation of AG019 treatment in a single patient ......................... 78 
11.4.3.5 Teplizumab Withholding in an Individual Patient During the 12-Day Treatment 
Period 79 
11.4.3.6 Further Evaluation after Withholding Teplizumab Infusions ...................................... 80 
11.5. 
Financial Disclosure by Principal Investigators ............................................................. 80 
12.
Study Management and Administration ......................................................................................... 81 
12.1. 
Curriculum vitae ...................................................................................................................... 81 
12.2. 
Protocol Modifications .......................................................................................................... 81 
12.3. 
Data Quality Control and Quality Assurance .................................................................. 81 
12.4. 
Monitoring ................................................................................................................................ 81 
12.5. 
Audit and Inspection ............................................................................................................ 82 
12.6. 
Source Documents ............................................................................................................... 82 


Precigen ActoBio T1D, LLC 
Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
This document contains confidential information.  It is intended solely for the use of the principal investigator, co-
investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
bodies. 
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12.7. 
Electronic Data Capture ...................................................................................................... 82 
12.8. 
Premature Termination of the Study ................................................................................ 82 
12.9. 
Study Report ........................................................................................................................... 82 
12.10. Finance, Insurance and Publication ................................................................................. 83 
12.11. 
Archiving and Data Retention ............................................................................................ 83 
12.12. Confidentiality ........................................................................................................................ 83 
List of Figures 
Figure 1Study Design 


Precigen ActoBio T1D, LLC 
Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
This document contains confidential information.  It is intended solely for the use of the principal investigator, co-
investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
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List of Abbreviations 
ADA 
American Diabetes Association 
AE 
adverse event 
AG019 
genetically modified Lactococcus lactis strain sAGX0407 
ALT 
alaninne aminotransferase 
ALP 
alkaline phosphatase 
APC 
antigen presenting cell 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BCG 
Bacillus Calmette-Guérin 
BID 
bis in die (twice daily) 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CA 
competent authority 
CBC 
complete blood count 
CCR6 
Chemokine receptor type 6 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
CFU 
colony forming units 
CGM 
continous glucose monitor 
CMV 
cytomegalovirus 
CO2 
carbon dioxide 
CRA 
clinical research associate 
(e)CRF
(electronic) Case Report Form 
CRO 
contract research organization 
CRP 
C-reactive protein
CRS 
cytokine release syndrome 
CS 
clinically significant 
CTCAE 
common terminology criteria for adverse events 
DC 
dendritic cell 
DP 
drug product 
DS 
drug substance 
DSMB 
Data Safety Monitoring Board 
EBV 
Eppstein-Barr Virus 
ECG 
electrocardiogram 
ELISA 
enzyme-linked immunosorbent assay 
eGFR 
estimated glomerular filtration rate 
ePRO 
electronic patient reported outcomes 
EU 
European Union 
FDA 
Food and Drug Administration 
Fc 
crystallizable fragment 
FcR 
Fc receptor 
Foxp3 
Forkhead box p3 


Precigen ActoBio T1D, LLC 
Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
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investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
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FPG 
fasting plasma glucose 
GAD65 
glutamic acid decarboxylase 65 
GALT 
gut-associated lymphoid tissue 
GCP 
Good Clinical Practices 
GI 
gastrointestinal 
GM 
genetically modified 
Hb 
hemoglobin 
HBV 
Hepatitis B virus 
Hct 
hematocrit 
HCV 
Hepatitis C virus 
HDL 
high density lipoproteins 
hIL-10 
human interleukin-10 
HIV 
human immunodeficiency virus 
hPINS 
human proinsulin 
HPMC 
hydroxypropylmethylcellulose 
i.e.
id est 
IA-2 
insulinoma-associated protein 2 
IAA 
insulin autoantibody 
IB 
investigator's brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IgG 
immunoglobulin G 
IL 
interleukin 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
intravenous 
kcal 
kilocalories 
L. lactis
Lactococcus lactis 
LDH 
lactate dehydrogenase 
LDL 
low density lipoproteins 
mM 
milliMolar 
mAb 
monoclonal antibody 
MCC 
microcrystalline cellulose 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
medical dictionary for regulatory activities 
MHC 
major histocompatibility complex 
MM 
Medical Monitor 
MMTT 
mixed meal tolerance test 


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Clinical Study Protocol AG019-T1D-101 
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investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
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MoA 
mode of action 
NCI 
Natoional Cancer Institute 
NCS 
non-clinically significant 
NOD 
nonobese diabetic 
NSAID 
non-steroidal anti-inflammatory drugs 
OKT3 
Orthoclone Kung T3 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PMN 
polymorphonuclear neutrophils 
qPCR 
quantitative real-time polymerase chain reaction 
RBC 
red blood cell 
RDW 
red blood cell distribution width 
REB 
research ethics board 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
sAGX0407 
Lactococcus lactis strain sAGX0407, genetically engineered to produce human proinsulin 
and human interleukin-10 
SAP 
statistical analysis plan 
SD 
standard deviation 
SEM 
Standard error of the mean 
SUSAR 
suspected unexpected serious adverse reaction 
T1D 
type 1 diabetes mellitus 
TB 
tuberculosis 
TCR 
T cell receptor 
TEAE 
treatment-emergent adverse event 
Teff (cell) 
effector T (cell) 
TGF 
transforming growth factor 
TID 
ter in die (three times daily) 
Treg (cell) 
regulatory T (cell) 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
VLDL 
very low density lipoproteins 
WBC 
white blood cell 
WHO 
World Health Orgnization 
ZnT8 
zinc transporter 8 


Precigen ActoBio T1D, LLC 
Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
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investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
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1. INTRODUCTION AND STUDY RATIONALE
1.1.Background
Approximately 10-15 million people worldwide suffer from T1D, the most common metabolic disorder 
in infancy and adolescence, affecting 167,000 children in the US alone. The SEARCH for Diabetes in 
Youth study estimated that, in 2009, 18,436 children in the US were newly diagnosed with T1D 
(Hamman et al., 2014). Recent data shows that the prevalence of T1D in children in the US increased 
by 21.1% between 2001 and 2009 (Hamman et al., 2014). It is reported that global incidence of T1D is 
increasing by 3% every year (Egro, 2013).  
T1D is an autoimmune disease that results from a progressive T cell mediated destruction of the 
insulin-producing β-cells in the islets of Langerhans in the pancreas, in genetically susceptible 
individuals (Knip, 2002). The absolute loss of β-cells, and therefore insulin production, results in 
increased glucose levels in urine and blood (i.e., glycosuria and hyperglycemia). This leads to chronic 
hyperglycemia which instigates micro- and macrovascular complications (van Belle et al., 2011).  
Patients with T1D require lifelong treatment with insulin. Untreated or poorly controlled T1D can lead 
to blindness, kidney failure, nerve damage, and cardiovascular complications such as coronary heart 
disease, stroke, and accelerated atherosclerosis (American Diabetes Association, 2014). Moreover, 
long term management requires a multidisciplinary approach that includes physicians, nurses, 
dieticians, and other specialists. T1D-associated healthcare costs in the US reach $14 billion annually 
(Atkinson et al., 2014). 
Immune intervention for recent-onset T1D aims to prevent or reverse the disease by blocking 
autoimmunity, thereby preserving or restoring β-cell mass and function and decreasing the likelihood 
of both hypoglycemia and the long-term complications associated with T1D.  
Antigens may behave as immunogens that provoke an adaptive immune response or as tolerogens 
that induce a state of specific immunological unresponsiveness (immune tolerance) to subsequent 
challenging doses of the antigen. Several factors determine the immunogenic versus tolerogenic 
capacity of an antigen, including its molecular form, the nature of antigen presenting cells (APCs), the 
dose, the route of administration and local response environment (Anderton et al., 1999).  
The gut-associated lymphoid tissue (GALT) is the largest immune organ in the body and is the primary 
route by which individuals are exposed to antigens. Tolerance induction is the default immune 
pathway in the gut. Oral tolerance is the active process by which the immune system does not respond 
to an orally administered antigen. One of the major mechanisms of oral tolerance is the induction of 
antigen-specific regulatory T (Treg) cells, a process that is related to the gut dendritic cells (DCs) and 
linked to both transforming growth factor (TGF)-β and retinoic acid (Commins, 2015). 
Treg cells have the capacity to induce or re-install tolerance to autoantigens while minimizing 
detrimental effects on host defense. Treg cell expansion can be achieved using cytokines. Activating or 
expanding antigen-specific Treg cells may achieve the same therapeutic effect as broad spectrum 
immunosuppression without the associated toxicity. In an autoimmune disease such as T1D, 
antigen-specific restoration of tolerance should be targeted (Cabrera et al., 2012).  
A number of studies in T1D animal models have demonstrated a pathogenic and/or beneficial role for 
these cytokines as well as their therapeutic potential in T1D (Nepom et al., 2013).     


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The effect of IL-10 on T1D has been studied in animal models. One study has shown that systemic 
overexpression of IL-10 in nonobese diabetic (NOD) mice, using a viral vector, significantly ameliorated 
T1D in a dose dependent manner (Goudy et al., 2003). The IL-10 therapy dramatically increased the 
percentage of CD4+CD25+ Treg cells. This study demonstrated the potential for immunomodulatory 
gene therapy to prevent autoimmune diseases, including T1D, and implicates IL-10 as a molecule 
capable of increasing the percentages of Treg cells in vivo. 
AG019 consists of the biologically contained food-grade lactic acid bacteria L. lactis, strain sAGX0407, 
genetically engineered for the in situ expression and secretion of hPINS and hIL-10. Through oral 
administration of AG019, the GM L. lactis sAGX0407 bacteria will be introduced orally into the patient’s 
GI tract (distal ileum and entire colon), where they will reside for a limited period of time. During their 
residency in the GI tract, the engineered bacteria will produce and deliver therapeutic concentrations 
of hIL-10 and hPINS locally, without systemic exposure, with the aim of inducing long term tolerance 
to β-cell antigens. 
AG019 will be administered in association with a treatment with teplizumab, a humanized anti-CD3 
mAb. This mAb primarily targets the CD3/ T cell receptor (TCR) complex, a molecule complex 
associated with antigen recognition, which is found on the cell membrane of mature T lymphocytes 
and which is associated with T cell activation. 
Non-clinical Studies 
Proof-of-concept studies have demonstrated that intestinal co-delivery of hPINS and hIL-10 using GM 
L. lactis, in association with a short term, low dose treatment with a surrogate hamster anti-mouse
CD3 mAb, reverses T1D in NOD mice via induction of forkhead box P3 (Foxp3)+ Treg cells (Takiishi et
al., 2012; Takiishi et al., 2017).
The non-clinical studies have focused on determining the Mode of Action (MoA), establishing PD data, 
obtaining PK data, investigating the toxicology and safety pharmacology, and evaluating the safety 
profile of AG019 in association with teplizumab. 
More detailed information about these non-clinical studies is contained in the Investigator’s Brochure 
for AG019.  
Effects in humans 
To date, AG019 alone as well as AG019 in association with teplizumab have not been studied in 
humans.  
Teplizumab has been studied extensively in more than 800 patients with recent-onset T1D. These 
studies have enabled the identification of a safe dose regimen. Furthermore, this teplizumab 
treatment regimen preserved insulin production and reduced the use of exogenous insulin in some 
patients with new-onset T1D. (Herold et al., 2005; Herold et al., 2009; Sherry et al., 2011; Hagopian et 
al., 2013; Herold et al., 2013; Tooley et al., 2016). 


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1.2.Rationale 
Currently, no disease curing or modifying treatments are available for T1D. There is a high unmet need 
to develop effective treatments for T1D patients. 
T1D is a cell-mediated autoimmune disorder resulting in the absolute destruction of the pancreatic 
insulin-producing β-cells. The disease is immune-mediated and thought to be caused by a combination 
of genetic and environmental factors that ultimately leads to loss of insulin secreting β-cells in 
pancreatic islets and high levels of blood glucose. High blood glucose levels and autoimmunity cause 
acute complications, such as ketoacidosis, as well as a wide variety of late complications. Although 
current insulin products achieve satisfactory glycemic control in the majority of patients, barriers such 
as reaching glycemic goals, fear of hypoglycemia, and the complexity and demands of day-to-day 
management (insulin dose adjustment, self-monitoring of blood) have an enormous impact on patient 
quality of life.   
Although patients with T1D have a life-long dependency on injections of exogenous insulin to meet 
metabolic demands, this cannot mimic the physiologically regulated hormone response of a normal 
β-cell population. Insulin supplementation does not reverse the β-cell destructive process and is by 
itself not without life-threatening risks. Insufficient insulin levels can put the patient in a hyperglycemic 
state, which can ultimately result in diabetic ketoacidosis, causing nausea, vomiting, dry mouth, 
shortness of breath, and a fruity breath smell. On the other hand, insulin overdose can cause 
dangerous hypoglycemia where blurred vision, sudden mood changes, nervousness, pale skin, 
headache, shaking, and a loss of consciousness can occur. In addition, insulin replacement is an 
intensive therapy requiring continuous monitoring of blood glucose levels, adapting insulin injections 
accordingly and following a strict diet. 
Nonclinical studies performed to date by IA have confirmed that intestinal delivery of hIL-10 and hPINS 
by GM L. lactis, in association with a short-term treatment with systemic anti-CD3 mAb, reverted 
diabetes in NOD mice and increased frequencies of local Treg cells, which not only accumulated in the 
pancreatic islets, but also suppressed immune response in an autoantigen-specific way. Initial blood 
glucose concentrations and insulin autoantibody (IAA) positivity were predictors of stable reversal of 
hyperglycemia (Takiishi et al., 2012; Takiishi et al., 2017). Cured mice remained responsive to disease-
unrelated antigens; which argues against excessive immunosuppression. Treatment success of the 
co-administration was significantly superior to monotherapy of either L. lactis sAGX0407 or anti-CD3 
mAb alone. Though the exact mechanisms are not yet fully understood, studies suggest that the anti-
CD3 mAb specifically depletes effector T (Teff) cells, and also induces the migration of chemokine 
receptor type 6 (CCR6)+ T cells from the peripheral circulation and the secondary lymphoid organs to 
the GI tract, where they secrete IL-10 (Waldron-Lynch et al., 2012). This results in an accumulation of 
tolerance promoting IL-10 secreting CD4+CD25highCCR6+Foxp3 Treg cells in the GI mucosal tissues, 
which is an attractive target for antigen-specific modulation through topical delivery of antigen (hPINS) 
and the tolerance inducing cytokine (hIL-10) secreted by L. lactis sAGX0407. These phenomena appear 
to be very effective in installing stable and long term antigen specific tolerance. 
Given the positive results obtained in the NOD mouse model, the Sponsor believes that co-delivery of 
a Treg cell enhancer and an antigen implicated in β-cell autoimmunity will be able to reverse T1D in 
humans, and that the effectiveness will be increased upon association with anti-CD3 mAb. 


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2. OBJECTIVES
2.1.Primary Objective
The primary objective of this study is to assess the safety and tolerability of different doses of AG019 
alone as well as AG019 in association with teplizumab. 
2.2.Secondary Objectives 
The secondary objectives of this study are: 
•
to obtain PD data of AG019 alone as well as AG019 in association with teplizumab,
•
to determine the potential presence of AG019 or its secreted proteins in systemic circulation
(safety – systemic exposure) and the presence of L. lactis bacteria in fecal excretion (local
exposure): PK profile.
3. STUDY DESIGN
3.1.General information
This Phase 1b/2a, multi-center study will be conducted in patients with clinical recent-onset T1D. 
A maximum of 8 single dose patients and a maximum of 48 evaluable repeat dose patients will be 
enrolled in clinical sites in the US and Belgium.  
This study will consist of 2 phases: 
•
Phase 1b: this open label part of the study will investigate the safety and tolerability of 2
different doses of AG019, in 2 age groups (18-40 years of age, further referred to as adults,
and 12-17 years of age, further referred to as pediatrics, respectively), administered as single
or repeat doses. Patients will be enrolled in 4 sequential cohorts (AG019 cohorts).
•
Phase 2a: this randomized, double blind part of the study will investigate the safety and
tolerability of AG019, in association with teplizumab, in 2 age groups (18-40 years of age and
12-17 years of age respectively), in comparison with placebo. Patients will be enrolled in 2
cohorts (combination cohorts).
In all AG019 cohorts (see Section 5.2), 2 single dose patients will be enrolled prior to the enrollment of 
the repeat dose patients, and patients will be enrolled sequentially into 2 descending age groups (adult 
cohorts, 18-40y, and pediatric cohorts, 12-17y). The single dose patients will be followed up for a total 
of 4 days, after which they will have completed their participation in the study. 
All repeat dose patients in all cohorts described below will be followed up for a total of 12 months (8 
weeks of treatment plus 10 months of post-treatment follow-up). After the 12-month follow-up visit 
the patients will have completed their participation in the study. 


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The treating Investigator and MM will review the eCRF-reported safety related data (including clinical 
data, local lab results and safety related data transcribed from the patient’s diary into the eCRF) at 
defined study time points. The specific role and responsibilities of the MM are outlined in Section 11.4. 
A DSMB will be established and will review the eCRF-reported safety related data for all enrolled 
patients at specified time points (including safety related data transcribed from the patient’s diary into 
the eCRF). The specific role and responsibilities of the DSMB are outlined in Section 11.4 and in the 
DSMB charter. 
In addition to the scheduled clinic visits, all patients will be asked to keep a diary for collection of 
information relating to the study drug intake, concomitant medication intake, occurrence of adverse 
events including hypoglycemic and hyperglycemic events, and insulin use. 
During the study, all patients will receive appropriate diabetic therapy according to current ADA or 
equivalent guidelines (Section 5.1.3). 
3.2.Phase 1b portion 
The Phase 1b open-label portion of the study will enroll 4 sequential AG019 cohorts evaluating the 
safety of AG019 administered orally for 8 weeks. In each of these 4 cohorts, enrollment of up to 6 
repeat dose patients4 will be preceded by enrollment of 2 single dose patients as outlined below. 
•
AG019 Cohort 1: 2 capsules per day, patients 18-40y
o
Single dose: 2 patients
o
Repeat dose: up to 6 patients
•
AG019 Cohort 2: 6 capsules per day, patients 18-40y
o
Single dose: 2 patients
o
Repeat dose: up to 6 patients
•
AG019 Cohort 3: 2 capsules per day, patients 12-17y
o
Single dose: 2 patients
o
Repeat dose: up to 6 patients
•
AG019 Cohort 4: 6 capsules per day, patients 12-17y
o
Single dose: 2 patients
o
Repeat dose: up to 6 patients
Within each of these cohorts, patients will be enrolled as follows: 
•
Treatment of single dose patient 1

Data review after the Day 4 follow-up visit (treating Investigator and MM)
4 4 repeat dose patients will be enrolled per AG019 cohort. In addition, both single dose patients in each AG019 
cohort will be offered the option of being re-enrolled as repeat dose patients in the same AG019 cohort, provided 
that no safety concerns have been identified during their participation as a single dose patient. Therefore, if both 
single dose patients agree to be re-enrolled as repeat dose patients, the maximum number of repeat dose patients 
will be 6. 


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•
Treatment of single dose patient 2

Data review after the Day 4 follow-up visit (treating Investigator and MM)
•
Treatment of repeat dose patient 1

Data review after the Day 7 follow-up visit (treating Investigator and MM)
•
Treatment of repeat dose patient 2

Data review after the Day 7 follow-up visit (treating Investigator and MM)
•
Treatment of the remaining repeat dose patients

Data review after the Day 7 follow-up visit of the last patient (DSMB – review of all
available data from all patients enrolled into all cohorts)
Once all repeat dose patients in a cohort have had their Day 7 follow-up visit, the DSMB will review all 
available data from all patients enrolled into all cohorts. If no safety concerns are identified, the DSMB 
will formulate a recommendation to the sponsor on opening the next cohort(s) for treatment. 
3.3.Phase 2a portion 
The Phase 2a double-blind portion of the study will evaluate 2 cohorts of patients administered AG019 
daily for 8 weeks5, in association with daily IV infusions of teplizumab for the first 12 days of the 8-
week treatment period (combination cohorts).  
•
Combination Cohort 1: 12 patients (18-40y) to receive AG019 (6 capsules per day5, 8 weeks)
plus teplizumab (daily infusions, 12 days), or matching placebo capsules and placebo infusions
•
Combination Cohort 2: 12 patients (12-17y) to receive AG019 (6 capsules per day5, 8 weeks)
plus teplizumab (daily infusions, 12 days), or matching placebo capsules and placebo infusions
Within each of these combination cohorts, the first 2 enrolled patients will be treated with active 
treatment (AG019 plus teplizumab) in an open label fashion. Patients 3-12 will be randomized (4:1) to 
receive active treatment or placebo in a double-blind fashion. Therefore enrollment will be done as 
follows: 
•
Treatment of patient 1: Treatment with AG019 plus teplizumab

Data review of all data collected up to the Day 12 follow up visit (the last day of
teplizumab infusion) (treating Investigator and MM)
•
Treatment of patient 2: Treatment with AG019 plus teplizumab

Data review of all data collected up to the Day 12 follow up visit (the last day of
teplizumab infusion) (DSMB – review of all available data from all patients enrolled
into all cohorts)
•
Treatment of patients 3-12: randomization (4:1) to double Active Treatment or double
Placebo.
5 The dose of AG019 to be administered in the Phase 2a portion of the study is not yet known and will be determined 
by the results of the Phase 1b portion of the study. If the AG019 cohorts reveal safety concerns associated with the 
6-capsule treatment, the DSMB will recommend lowering the AG019 dose in all ongoing AG019 and combination
cohorts.


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The overall enrollment plan is outlined in Figure 1. 
3.4.Rationale for the study design 
The ActoBiotics® platform, consisting of GM L. lactis bacteria, has been used to deliver therapeutic 
proteins and peptides, including bioactive cytokines and antigens, to mucosal tissues in several 
preclinical and clinical studies (Steidler et al., 2000; Steidler et al., 2003; Braat et al., 2006; Rottiers et 
al., 2009; Coulie, 2013; Limaye et al., 2013; Coulie, 2014; Robert et al., 2014).  
Through oral administration of AG019, the GM L. lactis sAGX0407 bacteria will be introduced into the 
patient’s GI tract (distal ileum and entire colon), where they will reside for a limited period of time. 
The residence time of the bacteria is transient and determined by the intestinal transit rate. During 
their residency in the GI tract, the engineered bacteria will produce and deliver therapeutic 
concentrations of hIL-10 and hPINS locally, without systemic exposure, with the aim of inducing long 
term tolerance to β-cell antigens. 
The Sponsor has already demonstrated in nonclinical and clinical studies that the ActoBiotics® 
platform has an excellent safety profile. XXXX
XXX 


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XXX 
More details about the nonclinical studies are described in the AG019 Investigator Brochure. 
AG019 has not been tested in human patients to date, neither as standalone treatment nor in 
combination with teplizumab. Therefore the Sponsor has designed the study in such a way that the 
safety of AG019 alone as well as in combination with teplizumab can be investigated while keeping 
potential risks for the patients to a minimum. The following measures have been taken to allow for 
minimal risks for the patients in this study: 
•
The safety of AG019 alone will first be evaluated before opening the combination cohorts.
•
A dose escalation was built into the AG019 cohorts, allowing to evaluate the safety profile of
low dose AG019 before evaluating the safety of a higher dose of AG019
•
In each AG019 cohort, 2 single dose patients will be enrolled in a staggered way, and their data
will be reviewed, before opening treatment of the repeat dose patients.
•
A significant portion of recent-onset T1D patients are children. It is therefore important to
include this population already in the early stages of development. Measures have been taken, 
to enable the Sponsor to thoroughly investigate the safety of AG019 alone as well as in
association with teplizumab in adults, before opening the corresponding pediatric AG019 and
combination cohorts for treatment.
•
A DSMB and medical monitor will be heavily involved in each review and decision step, as
outlined in the enrollment plan, before proceeding to the next cohort
•
An extensive set of study stopping criteria and dose adjustment/stopping criteria has been
generated.


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Figure 1: Overall enrollment plan. 


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4. STUDY POPULATION
The study population will consist of adults and children who have clinical recent-onset diagnosis of 
type 1 diabetes mellitus. 
Screening for eligible patients will be performed within 28 days prior to the first administration of study 
drug. 
4.1.Sample Size 
A maximum of 48 patients will be enrolled in clinical sites in US and Belgium.  
In total, 8 single dose patients and up to 48 repeat dose patients6 will be enrolled. 
Patients who discontinue after entry into the treatment phase may be replaced if approved by the 
Sponsor. Details about the different cohorts are outlined in Section 5.2. 
4.2.Inclusion Criteria 
The below tables provide an overview of all inclusion and exclusion criteria which are required to be 
met for: 
•
AG019 cohorts: column ‘AC’
•
Combination cohorts: column ‘CC’
6 4 repeat dose patients will be enrolled per AG019 cohort. In addition, both single dose patients in each AG019 
cohort will be offered the option of being re-enrolled as repeat dose patients, provided that no safety concerns have 
been identified during their participation as a single dose patient. Therefore, if both single dose patients agree to be 
re-enrolled as repeat dose patients, the maximum number of repeat dose patients per AG019 cohort will be 6. 


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Inclusion Criteria 
AC 
CC 
Male or non-pregnant, non-lactating females, 18-40 (both inclusive) years of age or ≥ 12-
17 (both inclusive) years of age7:  
•
Females of child bearing potential must have a negative serum pregnancy test
at the screening visit, and, if heterosexually active, must
•
use a hormonal (oral, implantable or injectable) method of birth control
which remains the same in both nature and dose throughout the study; or
•
have documentation of placement of an intrauterine device or
intrauterine system; or
•
use a barrier method of contraception (i.e.; condom or occlusive cap
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal
foam/gel/film/cream/suppository).
•
Females unable to bear children must have documentation of such in the case
report form (i.e., tubal ligation, hysterectomy, or post-menopausal [defined as
a minimum of one year since the last menstrual period]).
•
Males must agree to not conceive a child during their participation in the study
and must agree to use a barrier method of birth control throughout the study
(i.e.; condom or occlusive cap [diaphragm or cervical/vault caps] with
spermicidal foam/gel/film/cream/suppository), or must have documentation of 
sterilization (with the appropriate post-vasectomy documentation of the
absence of sperm in the ejaculate).
X 
X 
Diagnosis of diabetes according to the ADA recommended criteria: 
•
FPG concentration (after 8 or more hours of no caloric intake) ≥126 mg/dL*, or
•
Plasma glucose concentration ≥200 mg/dL 2 hours after ingesting a 75-g oral
glucose load in the morning after an overnight fast of at least 8 hours*, or
•
Symptoms of hyperglycemia (e.g., polyuria, polydipsia, polyphagia) and a
random (casual, non-fasting) plasma glucose concentration ≥200 mg/dL
*In absence of unequivocal hyperglycemia, result to be confirmed by repeat testing
X 
X 
Evidence of auto-antibodies to at least 1 of the following β-cell autoantigens: insulin°, IA-
2, GAD65, ZnT8 
If evidence of autoantibody positivity is documented in the patient’s medical file, the 
assessment does not need to be repeated as part of eligibility verification 
°Insulin autoantibody positivity should be assessed within 10 days following initiation of 
exogenous insulin treatment.  
X 
X 
Stimulated C-peptide measured during 4h Mixed Meal tolerance Test (MMTT) > 0.2 
nmol/L (note: this inclusion criterion does not apply to single dose patients) 
X 
X 
The first administration of AG019 should occur no later than 150 days post diagnosis. 
X 
X 
Body weight ≥ 33kg 
X 
X 
Willing and medically able to postpone live vaccine immunizations for at least 8 weeks 
after randomization 
X 
7 Age-dependent enrolment in each cohort needs to be considered when evaluating this inclusion criterion. 


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Inclusion Criteria 
AC 
CC 
Ability and willingness of patient to participate fully in all aspects of this clinical study 
X 
X 
Written informed consent obtained and documented (patient, parent, guardian as 
applicable) 
X 
X 
Willingness to use a continuous glucose monitoring device and willingness to comply 
with the protocol defined glucose monitoring (note: this inclusion criterion does not 
apply to single dose patients) 
X 
X 
•
Total bilirubin ≤1.0 x upper limit of normal (ULN)
•
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤1.5 x ULN
•
≥1,000 lymphocytes/µL
•
≥1,000 polymorphonuclear neutrophils (PMN)/µL
•
≥100,000 platelets/µL
•
Hgb ≥10 g/dL
•
Serum Creatinin ≤1.5 x ULN
•
eGFR ≥60 mL/min/1.73m²
•
INR ≤0.1 above upper limit of normal
•
Absence of clinically significant age appropriate abnormalities on all other lab
values, except for abnormalities directly attributable to T1D.
X 
X 
4.3.Exclusion Criteria 
The below table provides an overview of all exclusion criteria which are required to be met for: 
•
AG019 cohorts: column ‘AC’
•
Combination cohorts: column ‘CC’
Exclusion criteria 
AC 
CC 
Previous history of serious cytokine release syndrome to teplizumab or other humanized 
anti-CD3 monoclonal antibodies with no or minimal capacity to bind Fc receptors. 
X 
Current use of any systemic antibiotics, except for the following: XXX
X 
X 
Use of immunosuppressive or immunomodulatory therapies, including systemic steroids 
within 1 month prior to randomization 
X 
X 
Participation in another investigational drug trial within 12 weeks prior to the first study 
drug intake and during participation in this study 
X 
X 
History of recurrent infections, other autoimmune diseases, cardiac disease, malignancy, 
or any other (chronic) medical condition which, in the investigator’s opinion, could 
compromise participant safety 
X 
X 


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Exclusion criteria 
AC 
CC 
Documented history of human immunodeficiency virus (HIV), Hepatitis Virus Type C 
(HCV), Hepatitis Virus Type B (HBV) infection 
X 
X 
Evidence of active infection with Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) 
X 
X 
Positive result of SARS-Cov2 PCR test at screening or within 3 days before randomization 
X 
Untreated hypothyroidism or active Graves’ disease 
X 
Evidence of any active infection with the exception of superficial skin infections 
X 
Vaccination 
with 
live 
virus 
or 
organism 
within 
8 
weeks 
prior 
to 
randomization (vaccination with killed virus within 2 weeks prior to randomization 
should be avoided as vaccine immunity may be compromised; however it is not 
exclusionary) 
X 
Evidence of active or latent tuberculosis (TB). All patients must be evaluated for TB; 
including history of TB or possible previous contact with TB. Appropriate screening tests 
(e.g. TST, TSPOT, QuantiFeron, or other appropriate tests) should be performed in all 
patients unless vaccinated with BCG. 
X 
X 
Administration of anti-CD3 antibody in past year 
X 
X 
Current therapy with any other anti-diabetic agents other than insulin (MDI, CSII or 
analogue). Current or planned therapy with experimental (i.e., unapproved) insulin. 
Patients on therapy for type 2 diabetes (e.g. metformin) should stop their therapy in 
order to be eligible for study participation. 
X 
X 
Use of medications known to influence glucose tolerance 
X 
X 
Daily use of systemic non-steroidal anti-inflammatory agents 
X 
X 
Compromised GI mucosal integrity or motility, not attributable to T1D (i.e., recent 
diarrhea, gluten sensitive enteropathy, inflammatory bowel disease, irritable bowel 
syndrome), or current use of medications known to influence GI motility 
X 
X 
Inability to swallow size 1 capsules. If needed, this may be verified by asking the patients 
to swallow one placebo capsule with water. 
X 
X 
Alcohol or illicit drug consumption, which in the opinion of the investigator, may 
interfere with the patient’s ability to comply with the study procedures 
X 
X 
Active psychiatric problems, which in the opinion of the investigator, may interfere with 
the patient’s ability to comply with study procedures 
X 
X 
4.4.Controlling Enrolment 
Due to the design of the study, the enrolment plan, the regular MM/DSMB review and the fact that 
this is a multicentre study, controlling enrolment will be a critical factor for the success of this trial. 
Enrolment will be controlled by using the interactive web response system (Interactive Response 
Technology, IRT) in both Phase 1b and Phase 2a portions of this trial. All patients will require 


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registration in IRT. Details on the use of the IRT system, for registration of patients or for randomization 
of patients, will be outlined in the IRT manual. 
4.5.Removal of Patients 
In accordance with the Declaration of Helsinki, patients have the right to withdraw from the study at 
any time for any reason. The Investigator and Sponsor also have the right to withdraw patients from 
the study. Patients may be removed from the study for the following reasons: 
•
Adverse reactions
•
Clinical sepsis regardless of the cause
•
At the request of the Investigator, MM, DSMB or Sponsor, whether for administrative or other
reasons
•
Protocol violation or unreliable behavior
•
Termination of the study by the Sponsor
The date of and the reason for discontinuation will be recorded in the electronic case report form 
(eCRF).  
Patients who withdraw from the study after receiving the first dose of IMP for reasons other than 
safety or tolerability may be replaced: 
•
Patients who withdraw before the Day 180 follow-up visit (primary end point) may be replaced 
upon consultation with the coordinating investigator and sponsor
•
Patients who withdraw after the Day 180 follow-up visit will not be replaced
If a patient discontinues, all end of study visit procedures should be conducted. 
If a patient is removed from the study, the date of the last dose of IMP and all observations collected 
up to the time of termination will be recorded on the eCRF along with the reason for termination. 
Scheduled safety evaluations and follow-up examinations (see Visit Schedule, Appendix A) will be 
conducted, if possible.  
When a patient fails to return for scheduled assessments, the following efforts should at a minimum 
be made to contact him/her to determine a reason for the failure to return: 3 phone attempts, 
including the date and time, should be documented in the patient’s source documents. If there is no 
response to the phone calls, a certified letter should be sent to the patient. After these efforts have 
been exhausted, a patient should be identified as lost to follow-up in the eCRF. 
Patients enrolled into the Combination Cohorts who are excluded prior to receiving the first dose of 
IMP (teplizumab and AG019 or corresponding placebos) due to any of the criteria mentioned in Section 
11.4.3.5 will be replaced. Replacement of patients will be done through the IRT. Details of this 
procedure are outlined in the IRT manual. 


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4.6.Special considerations 
As this is a First In Human study, no participating patient is allowed to donate any sperm or egg cells 
during their participation in the study and for 12 months thereafter. 
5. STUDY TREATMENT
5.1.Treatments
5.1.1AG019 
Single dose patients will be treated with (2 or 6 capsules of) AG019. 
All patients in the repeat dose cohorts, and all patients in the combination cohorts who are randomized 
to study treatment, will be treated for 8 weeks with AG019 with one of the doses listed in Table 2: 
Table 2: AG019 dosing regimens for repeat dose patients 
Dose 
Number of capsules 
Total daily dose 
Treatment duration 
Low dose AG019 
2 (1 morning, 1 evening) 
XXX 
8 weeks 
High dose AG019 
6 (3 morning, 3 evening) 
XXX 
8 weeks 
The total treatment duration for repeat dose patients is 8 weeks or 56 days. Patients will be required 
to take AG019 for 56 days, even if the Day 56 follow-up visit is not scheduled on Day 56 (there is a 2-
day visit window on the Day 56 follow-up visit). 
•
If the Day 56 follow-up visit is scheduled on Day 54 or Day 55, patients will take their remaining 
AG019 home again and will continue to take AG019 until the evening dose on Day 56. The
patients will then take their remaining AG019 back to the site on Day 90 for final accountability
•
If the Day 56 follow-up visit is scheduled on Day 57 or Day 58, patients should be instructed to
take AG019 until the evening dose on Day 56.
The daily dose of AG019 to be used in the Phase 2a portion of the study (combination cohorts) is not 
yet known and will be determined by the results of the Phase 1b portion of the study (AG019 cohorts). 
Based upon the data obtained in the nonclinical studies, the Sponsor anticipates that a 6-capsule 
regimen will be administered in the combination cohorts. Following rules will apply: 
•
If the DSMB concludes that no safety concerns are associated with the high dose of AG019 (6
capsules per day) in the Phase 1b portion of the study (AG019 cohorts), the patients enrolled


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in the Phase 2a portion of the study (combination cohorts) will take the high dose of AG019 
for 8 weeks.  
•
If the DSMB concludes that safety concerns are associated with the high dose of AG019 (6
capsules per day) in the Phase 1b portion of the study (AG019 cohorts) and that no safety
concerns are associated with the low dose of AG019 (2 capsules per day), the DSMB will
recommend lowering the AG019 dose in all ongoing and planned (AG019 and) combination
cohorts .
If, at any time during the study, safety concerns associated with the high dose of AG019 are identified, 
the DSMB will recommend lowering the daily dose of AG019 in all ongoing and planned AG019 cohorts, 
as well as in all ongoing and planned combination cohorts. 
XXX
5.1.2Teplizumab 
All patients in the combination cohorts who are randomized to study treatment, as well as the first 2 
patients in the combination cohorts who are treated in open label, will be treated for 12 days with 
teplizumab (daily IV infusions) according to the below schedule, in addition to their AG019 treatment: 
XXX 
XXX
The parameters used to calculate the daily dosing of study drug will be based on the height and weight 
at Day 1. The total cumulative average dose will be 9034 µg/m² or approximately ~17 mg for each 
patient. This total dose is the same as that used in previous trials in a 14 day regimen (Sherry et al., 
2011; Hagopian et al., 2013; Herold et al., 2013; Herold et al., 2013) with the change that the protocol 


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has been shortened XXX
5.1.3T1D therapy during the study 
During the study, all patients will receive appropriate diabetic therapy according to current ADA or 
equivalent guidelines. Treatment with commercially available insulin (multiple dose insulin injection 
therapy, continuous subcutaneous insulin infusion therapy or analogue therapies) is allowed. 
Treatment with other forms of commercially available insulin therapy, or treatment with experimental 
insulin, is not allowed during this study. 
In accordance with ADA recommendations, preprandial glucose level target should be 4.4-7.2 mmol/L 
(80-130 mg/dL) and peak post prandial (1-2h after meal) glucose level target should be <10 mmol/L 
(<180 mg/dL). 
5.1.4Other concomitant therapy 
Any concomitant therapy used by the patient at any time following ICF signature must be recorded in 
the eCRF through the end of the short term follow-up must be recorded on the eCRF. In addition, for 
any SAEs that require medication for treatment, those medications must be recorded on the 
concomitant medications page. The medication name, dosage, frequency, route of administration, 
start and stop dates, and indication for use must be recorded. The medical monitor should be notified 
in advance of (or as soon as possible after) any instances in which prohibited therapies are 
administered. The MM will subsequently advise on actions to be taken, if any. 
Prohibited therapy during the entire treatment period includes any antibiotic treatment known to 
affect the viability of L. lactis sAGX0407 (see Appendix B), β-cell stimulants, immunosuppressive or 
immunomodulatory therapies, including systemic steroids, other investigational drug(s), vaccination 
with live virus or organism, anti-CD3 antibody, any anti-diabetic agents other than insulin, medications 
known to influence glucose tolerance and daily use of non-steroidal anti-inflammatory agents. 
For patients enrolled in the combination cohorts, premedication with ibuprofen or similar non-
steroidal anti-inflammatory drugs (NSAID) and with an antihistamine is recommended and may be 
useful in patients who develop rashes during teplizumab administration. 
As paracetamol may induce false positive signals of hyperglycemia by the continuous glucose 
monitoring devices, its use for reasons other than the reasons mentioned in the previous paragraph 
should be avoided as much as possible throughout the study. 


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5.2.Description of the cohorts 
The enrollment plan is presented in Figure 1 and is described below. 
5.2.1AG019 Cohorts 
A total of 8 single dose patients and up to 24 repeat dose patients8 will be enrolled sequentially into 
the following AG019 cohorts: 
•
AG019 Cohort 1: 2 capsules per day, patients 18-40y
o
Single dose: 2 patients
o
Repeat dose: up to 6 patients8
•
AG019 Cohort 2: 6 capsules per day, patients 18-40y
o
Single dose: 2 patients
o
Repeat dose: up to 6 patients8
•
AG019 Cohort 3: 2 capsules per day, patients 12-17y
o
Single dose: 2 patients
o
Repeat dose: up to 6 patients8
•
AG019 Cohort 4: 6 capsules per day, patients 12-17y
o
Single dose: 2 patients
o
Repeat dose: up to 6 patients8
A total of 2 single dose patients and up to 6 repeat dose patients8 will be enrolled in each open label 
safety cohort, designed to investigate the safety profile of AG019 administered alone.  
Single dose patients 
In a first stage, 2 single dose patients will be enrolled in a staggered way. Each of these patients will be 
treated for 1 day with AG019 (number of capsules of AG019 will correspond to the cohort these 
patients have been enrolled into). These patients will be followed up for a total of 4 days (Treatment 
day [Day 1] plus 3 additional days), after which they will have completed their study participation (Day 
4).  
After study completion of each single dose patient, the treating Investigator and MM will review the 
collected data, and if no safety concerns are identified, treatment of the next patient (i.e., the second 
single dose patient or the first repeat dose patient) can begin.  
Each single dose patient will be offered the option of being re-enrolled as repeat dose patient, provided 
that no safety concerns have been identified during their participation as a single dose patient. A wash-
8 4 repeat dose patients will be enrolled per AG019 cohort. In addition, both single dose patients in each AG019 
cohort will be offered the option of being re-enrolled as repeat dose patients, provided that no safety concerns have 
been identified during their participation as a single dose patient. Therefore, if both single dose patients agree to be 
re-enrolled as repeat dose patients, the maximum number of repeat dose patients per cohort will be 6. 


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out period of 7 days will be required before the single-dose patients can be re-enrolled as repeat dose 
patients, to ensure that no AG019 bacteria are present in their GI tract at the time of re-enrollment. In 
addition, these patients cannot be enrolled as staggered patients into the repeat dose group. 
If a single dose patient wishes to be re-enrolled as repeat dose patient, all inclusion and exclusion 
criteria applicable to repeat dose patients should be met (including those criteria that do not apply to 
single dose patients).  
Repeat dose patients 
A minimum of 4 repeat dose patients will be enrolled per AG019 cohort. In addition, both single dose 
patients in each AG019 cohort will be offered the option of being re-enrolled as repeat dose patients 
in the same AG19 cohort, provided that no safety concerns have been identified during their 
participation as a single dose patient. Therefore, if both single dose patients agree to be re-enrolled as 
repeat dose patients, the maximum number of repeat dose patients will be 6. 
Each of these repeat dose patients will be treated daily for 8 weeks with AG019. The first 2 repeat dose 
patients will be enrolled in a staggered way. 
•
After treatment of the first patient, the data collected up to the Day 7 follow-up visit will be
reviewed by the treating Investigator and MM, and if no concerns are identified, the second
patient will be treated.
•
After the Day 7 follow-up visit of this second patient, the collected data will be reviewed by
the treating Investigator and MM, and if no concerns are identified, the remaining patients will 
be treated.
Once all repeat dose patients in a cohort have had their Day 7 follow-up visit, the DSMB will review all 
available data from all enrolled patients in all cohorts. If no safety concerns are identified, the DSMB 
will formulate a recommendation to the sponsor on opening the next cohort(s) for treatment, 
according to the enrollment schedule outlined in Figure 1. Detailed guidelines on the 
recommendations to be formulated by the DSMB will be described in the DSMB Charter. A brief 
summary of these guidelines is included in Section 11.4.2. 
All Repeat dose patients in all AG019 cohorts will be followed up for a total of 12 months (8 weeks of 
treatment plus 10 months of post-treatment follow-up). After the 12-month follow-up visit (Day 360) 
the patients will have completed their participation in the study. 
5.2.2Combination Cohorts 
The Phase 2a double-blind portion of the study will evaluate 2 cohorts (“combination cohorts”) of 12 
patients. Each patient will be administered 6 capsules daily 9 of AG019 (or placebo) for 8 weeks, in 
association with daily IV infusions of teplizumab for the first 12 days of the 8-week treatment period.  
9 The dose of AG019 to be administered in the Phase 2a portion of the study is not yet known and will be determined 
by the results of the Phase 1b portion of the study. If the AG019 cohorts reveal safety concerns associated with the 
6-capsule treatment, the DSMB will recommend lowering the AG019 dose in all AG019 and combination cohorts.


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•
Combination Cohort 1: 12 patients 18-40y to receive AG019 (6 capsules per day9, 8 weeks)
plus teplizumab (daily infusions, 12 days), or matching placebo capsules and placebo infusions
•
Combination Cohort 2: 12 patients 12-17y to receive AG019 (6 capsules per day9, 8 weeks)
plus teplizumab (daily infusions, 12 days), or matching placebo capsules and placebo infusions
Within each of these combination cohorts, the first 2 enrolled patients will be treated with active 
treatment (AG019 plus teplizumab) in an open label fashion. Patients 3-12 will be randomized (4:1) to 
receive (double) active treatment or (double) placebo in a double-blind fashion. Therefore enrollment 
will be done as follows: 
•
Treatment of patient 1: Treatment with AG019 plus teplizumab

Data review of all data collected up to the Day 12 follow up visit (the last day of
teplizumab infusion) (treating Investigator and MM)
•
Treatment of patient 2: Treatment with AG019 plus teplizumab

Data review of all data collected up to the Day 12 follow up visit (the last day of
teplizumab infusion) (DSMB – review of all available data from all patients in all
cohorts)
•
Treatment of patients 3-12: randomization (4:1) to double active treatment or double placebo.
All patients in all Combination cohorts will be followed up for a total of 12 months (8 weeks of 
treatment plus 10 months of post-treatment follow-up). After the 12-month follow-up visit (Day 360) 
the patients will have completed their participation in the study. 
5.3.Identity of Investigational Medicinal Product 
5.3.1AG019 
The clinical formulation of AG019 DS consists of live GM L. lactis bacteria, genetically modified to 
secrete hIL-10 and hPINS. The bulk DS is a slightly yellow, lyophilized powder.  
The oral IMP consists of solid, XXX capsules filled with AG019 DS and XXX.  
XXX.  
XXX


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5.3.2Teplizumab 
The formulation of teplizumab consists of: 
XXX 
XXX
5.4.Labelling, Packaging and Storage 
XXX
5.5.Investigational Medicinal Product Administration 
XXX
Detailed instructions for dose preparation and dispensing to patients will be provided to the 
clinical site by the Sponsor or its designee. 


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Total bilirubin, AST, ALT, LDH, Complete Blood Count (CBC), and INR will be evaluated to verify the 
need to withhold teplizumab (or placebo) infusion prior to each (potential) teplizumab administration, 
as described in Appendix A. The drug infusion withholding criteria presented in Section 11.4.3.5 should 
be evaluated. 
5.6.Placebo/Comparator 
XXX
AG019 placebo and teplizumab placebo will be packaged identically to their active counterparts 
and will be matched for size, color and taste (as applicable), to prevent possible breaches in the 
blinding. 
Administration of placebo will be identical to administration of its respective active treatment. 
5.7.Study Drug Accountability 
The Investigator or his/her designee is responsible for ensuring adequate accountability of all used and 
unused study drug (AG019, teplizumab and their corresponding placebos). This includes 
acknowledgement of receipt of each shipment of study drug (quantity and condition), patient 
dispensing records and returned or destroyed study drug. Dispensing records will document quantities 
received. Quantities dispensed to patients will be documented, including lot number, date dispensed, 
patient identification number, patient initials and the initials of the person dispensing the study drug. 
Throughout the course of the study, the Sponsor or its designee will perform study drug accountability 
and provide instructions for adequate study drug disposal. Study drug accountability records must be 
readily available for audit by the Sponsor or its designee and for inspection by regulatory authorities 
at any time. 
The Investigator will not allow study drug to be given to any patient not included in the study or any 
unauthorized person. 
It is the responsibility of the site personnel to maintain adequate study drug dispensing records. 
AG019 (or corresponding placebo) compliance will be reviewed by the study staff at every follow-up 
visit during the active treatment period. Each patient will be instructed to return all used and unused 
study drug at each visit during the active treatment period and at the end of the treatment phase. A 
count of the used and unused capsules will be performed to assess compliance. 
Teplizumab (or corresponding placebo) accountability and compliance will be verified at every follow-
up visit by the site staff. Adequate documentation of receipt, dispensing and return will be maintained 
by the site staff. 


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5.8.Return and destruction of study drug 
All patients are required to return all empty medication blisters, partially used blisters and unused 
blisters to the study site upon completion of treatment or in case of withdrawal. If a patient is lost to 
follow-up during the treatment phase, the site should make every reasonable effort to obtain the used, 
partially used and unused blisters. 
Unused AG019 capsules will be destroyed by a dedicated drug destruction facility. Local destruction 
by the site is not allowed unless mandated by the site’s local procedures. If unused, used and partially 
used study drug is destroyed on site, this can only be done after IMP accountability has been 
performed by the Sponsor or its designee. 
Materials used for teplizumab infusions, as well as empty teplizumab vials, can be destroyed locally by 
the sites. All materials and vials are to be treated as hazardous medical waste per the site’s Standard 
Operating Procedures. 
Unused teplizumab vials will be destroyed by a dedicated drug destruction facility. Local destruction 
by the site is not allowed unless mandated by the site’s local procedures. If unused, used and partially 
used study drug is destroyed on site, this can only be done after IMP accountability has been 
performed by the Sponsor or its designee. 
5.9.Method of Assigning Patients to Treatment 
In the AG019 cohorts, all patients (single dose and repeat dose) will be treated with AG019. 
Registration of every patient will be required through the IRT (see Section 4.4). 
In the combination cohorts, the first 2 patients will be treated with AG019 + teplizumab. The remaining 
10 patients in each combination cohort will be randomized (4:1) to study drug or placebo. Patients 
randomized to receive study drug will be treated with AG019 + teplizumab, patients randomized to 
receive placebo will be treated with AG019-placebo and teplizumab-placebo. Randomization will be 
done through the IRT. 
During the screening and treatment phase, every study visit for every patient will need to be registered 
in the IRT. Details about the functionality and use of the IRT are found in the IRT manual. 
5.10.Blinding 
For the randomized patients in the combination cohorts, blinding will be accomplished by arranging 
for AG019 and placebo components as well as teplizumab and placebo components to have identical 
packaging. IMP will be delivered in a blinded fashion, as outlined in the Pharmacy Manual. All study 
personnel at the site, the patient and the Sponsor (except for the clinical supply manager) will be 
blinded to treatment allocation in the randomized portion of the combination cohorts for the first 6 
months of the study. Once all patients in all combination cohorts have completed their 6-month follow-
up visit (Day 180), unblinding will be done and all data will be analyzed and reported. After completion 
of the full 12 months follow-up all additional data will be analyzed and reported separately. 


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The identity of IMP assigned to patient numbers or to individual boxes of IMP can be accessed through 
IRT. When it is medically indicated, the Investigator may contact the MM and Sponsor to discuss the 
possibility of breaking the blind for a patient. A patient’s treatment assignment should only be 
unblinded when knowledge of the treatment is essential for the further management of the patient 
(i.e., medical emergency).  In the absence of a medical emergency, breaking the code should not be 
considered.  
For emergency blind-break procedures, contact the MM or his/her designee at the contact numbers 
provided in the Study Manual. The reason and date/time of the unblinding and the name of the 
individual who broke the blind must be appropriately documented in the patient’s medical record or 
source documents and in the eCRF.   
6. ASSESSMENTS
At predefined time points, all participating patients will undergo a series of assessments in order to 
evaluate the safety and tolerability of AG019 alone as well as the safety and tolerability of AG019 co-
administered with teplizumab. Additional assessments will be done in order to evaluate the 
pharmacodynamics activity and the pharmacokinetic profile of AG019 alone as well as the safety and 
tolerability of AG019 co-administered with teplizumab. 
XXX
6.1.General assessments 
General assessments for this study will include: 
•
Informed Consent: Before study procedures are performed, patients will be informed about
the study and required to sign and date the IRB/IEC approved ICF. For patients <18 years of
age, assent of the patient will be obtained, as well as consent from the parents and/or legally
acceptable representative. Details about informed consent procedure are listed in Section
11.3.
•
Inclusion/exclusion criteria: As part of the screening visit, all inclusion and exclusion criteria
listed in Section 4 will be verified.
•
Medical History and demographic data:
o
the medical history comprises a general medical history (including history of alcohol
abuse, illicit drug abuse and smoking history), relevant T1D related medical history
(including date of diabetes diagnosis, relevant glycaemia levels, autoantibody
positivity, current insulin use and start date of insulin therapy as applicable) and
medication history
o
Demographic data will include age, ethnicity and year of birth
•
Physical examination including visual inspection of skin, examination of eyes, ears and throat,
auscultation of heart, lungs and abdomen, and percussion/palpation of abdomen. Other
assessments may be performed at the discretion of the investigator. Clinically significant
abnormalities will be recorded in the eCRF.
•
Vital signs including height (collected at screening only), weight, sitting blood pressure, heart
rate, respiratory rate and body temperature.


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•
12-lead electrocardiogram (ECG): To monitor the heart function of the study participants, the
investigator will perform a 12-lead ECG and will determine whether the result of this test is
normal or not. Abnormal test results will be recorded as adverse events.
•
Placement of a continuous glucose monitoring (CGM) device: Once all in/exclusion criteria
are verified, the investigator will train the patient on the placement of the CGM device during
the baseline visit. The CGM device will be placed, so the patient will know how to do this at
home. The placement of the CGM, as well as the first CGM reading, will be done prior to
administration of the first dose of study drug(s). The Sponsor will supply the CGM devices.
•
Tuberculosis test: As part of the eligibility verification, all patients will undergo a test to
determine whether the patient shows signs of active or latent tuberculosis. The decision on
the type of test to be used is left to the discretion of the investigator, and could include e.g.
TST, TSPOT, QuantiFeron or other appropriate tests.
•
Concomitant medications: At every visit, the investigator will obtain information about
concomitant medications the patient is taking (including dose, frequency, route of
administration, start and stop dates)
6.2.Safety Assessments 
Safety will be assessed by collecting and recording Adverse Events (AEs) and laboratory assessments 
and the presence of L. lactis sAGX0407 in whole blood.   
The study will utilize local laboratories for safety assessments. The clinical laboratory will indicate 
laboratory values out of normal ranges. The Investigator must assess all abnormal clinical laboratory 
results for clinical significance in a timely fashion. A notation of ‘clinically significant’ (CS) or ‘non-
clinically significant’ (NCS) with initials and date will be documented on the respective laboratory 
report next to any abnormal value. An abnormal clinical laboratory value will be considered and 
documented as an AE, if in the opinion of the Investigator, it is clinically significant. The Investigator 
will follow proper adverse event reporting procedures. 
For details on the data to be collected for adverse events, please refer to Section 8. 
XXX
6.3.Laboratory Assessments 
6.3.1General considerations 
Throughout the study, blood samples will be collected at regular intervals, as described in the 
Visit schedule   
XXX 


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XXX
6.3.2Local lab assessments 
Parameters to be analysed will include: 
•
Hematology: complete blood count: Red Blood Cell (RBC) count, haemoglobin, haematocrit,
mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular
haemoglobin concentration (MCHC), RBC distribution width (RDW), white blood cell (WBC)
count, differential count, platelet count
•
Serum Chemistry: blood glucose, sodium, potassium, chloride, calcium, CO2/bicarbonate
•
Liver function tests: alkaline phosphatase (ALP), AST, ALT, lactate dehydrogenase (LDH), total
protein, albumin, total bilirubin
•
Pregnancy tests for women of childbearing potential: serum (at screening), urine (at other
visits – the Sponsor can provide urine dip sticks if needed)
•
Coagulation tests: INR
•
Inflammatory: C-reactive protein (CRP)
Following additional blood parameters will be analysed at screening, and if no concerns are identified, 
these parameters will not require analysis at follow-up visits: 
•
Kidney function tests: uric acid, urea/blood urea nitrogen (BUN), creatinine, estimated
glomerular filtration rate (eGFR)
•
Cardiovascular tests: total cholesterol, triglycerides, high density lipoproteins (HDL), low
density lipoproteins (LDL), very low density lipoproteins (VLDL - optional)
•
Thyroid stimulating hormone (TSH)
Total bilirubin, AST, ALT, LDH, Complete Blood Count (CBC), and INR will be evaluated to verify the 
need to withhold teplizumab (or placebo) infusion before each (potential) teplizumab administration, 
as described in the Visit Schedule The drug infusion withholding criteria presented in Section 
11.4.3.5 should be evaluated. 
In addition to the above lab assessments to be analysed by the site’s local lab, EBV/CMV/HCV/HBV/HIV 
monitoring assessments will be done. Potential reactivation will be assessed at regular intervals by 
viral serologies (IgG/IgM) and/or polymerase chain reaction (PCR) for viral load.  
As part of the eligibility verification, the presence of one or more autoantibodies against beta cell 
antigens will be verified. If documentation of autoantibody positivity is found in the patient’s medical 
file, the assessment does not have to be repeated at screening. 
As part of the eligibility verification, all new patients will be tested for SARS-Cov2 at screening and 
within 3 days before the start of teplizumab/placebo infusions. 


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6.3.3Central lab assessments 
6.3.3.1Pharmacokinetic Assessments 
Following parameters will be assessed for analysis of systemic and local exposure to L. lactis: 
•
Presence of live L. lactis clinical strain bacteria in whole blood,XXX
•
Measurable serum levels of hIL-10 and hPINS, XXX
•
Presence of L. lactis clinical strain bacteria in fecal excretion, XXX
Throughout the study, blood and feces samples will be collected at regular intervals for analysis by the 
central laboratory, as described in the Visit schedule.  
•
Blood sample collection for PK analysis, collected form all repeat dose patients in all AG019
cohorts and the combination cohorts
•
Feces sample collection for PK analysis, collected from all repeat dose patients in AG019
Cohorts 2 and 4, and from all patients in the combination cohorts
Blood and feces samples for PK assessments will be analyzed by a central lab. 
Details on sample collection, labeling, storage, shipment and analysis are described in the central lab 
manual.  
The Site will train the patients on how to collect feces samples. All stool samples will be collected and 
labeled with patient number, and date and time of sample collection.  
6.3.3.2Mechanistic Assessments 
The pharmacodynamic activity of the IMP will be assessed by measurement of biomarkers in blood 
and serum samples. Relevant parameters will be assessed, including immune markers for effect, 
relevant T1D parameters and relevant cytokines.  
Throughout the study, blood samples will be collected at regular intervals for analysis by the 
central laboratory, as described in the Visit schedule. Samples intended for mechanistic 
assessments will be collected from all repeat dose patients in AG019 Cohorts 2 and 4, and from all 
patients in the combination cohorts 
All collected samples will be analyzed by a central lab. Details on sample collection, labeling, storage, 
shipment and analysis are described in the central lab manual. 


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6.3.3.3Metabolic outcome assessments 
Throughout the study, following metabolic outcome assessments will be performed at regular 
intervals as described in the Visit schedule. Blood samples collected as part of these assessments will 
be analysed by a central lab: 
•
Insulin dose adjusted HbA1C (IDAA1c = HbA1c (%) + [4 x insulin dose (U/Kg/24h)]): insulin dose
adjusted measurement of glycemic control
•
4h mixed meal tolerance test (MMTT): measure of C-peptide levels, C-peptide area under the
curve (AUC) and blood glucose levels after mixed meal stimulation
Details on collection, processing, storage and shipment will be provided in the central lab manual. 
6.3.3.3.1Mixed Meal Tolerance Test 
The MMTT is a liquid meal that is ingested in the fasting state with timed measurements. Also this test 
is meant to assess the potential participant’s insulin production capability. This assessment will be 
conducted within 21 days of randomization (except for the single dose patients) and at predefined 
follow-up visits as outlined in the visit schedule. In order for the results to be meaningful, it is important 
for the participant to follow certain dietary and lifestyle guidelines in the days preceding the test. A 
high carbohydrate diet must be followed for the three days leading up to the test.  
The test should be rescheduled if the participant has a blood glucose (measured on his/her home 
meter) less than 70 mg/dL (3.85 mmol/L) or greater than 200 mg/dL (11.1 mmol/L).  
The participant is required to fast starting the night before the test, and is instructed to consume only 
water for at least ten hours preceding the test. Long-acting insulin or Basal rates (insulin pump users) 
will continue as normal. The use of rapid-acting insulin is acceptable up to 2 hours before the MMTT 
and the use of short-acting insulin up to 6 hours before the MMTT to correct hyperglycemia. 
Mixed Meal Dose: The test meal (Boost High Protein) is given at a dose of 6 mL per kilogram body 
weight. Maximum dose is 360 mL. Boost High Protein is supplied in 8 fluid ounce containers. The 
Sponsor will supply the test meals. 
The MMTT takes approximately four hours to complete, and must be scheduled in the morning (i.e. 
must be started before 10 AM). It is important to carefully review the eligibility criteria with the 
participant before starting the test, since if certain criteria have been violated the test will need to be 
rescheduled for another date.  
Procedure: Mixed Meal Dose  
Step 1. Ensure the patient is currently fasting 
Step 2. Prepping Participant for MMTT  
a.
The MMTT must begin between 7:00 - 10:00 a.m. for proper interpretation.
b.
Obtain the weight of the participant and calculate Boost High Protein meal size = 6 mL/kg, up
to 360 mL, 1lb = 0.45 kg


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c.
The MMTT test uses a standard oral mixed meal formula (Boost High Protein) composed of
liquid sucrose, soy protein, casein, and soy oil. The test meal is given at a dose of 6 kcal/kg
body weight, at 1 kcal/mL to a maximum of 360 kcal.
d.
The participant should remain sitting or resting in bed quietly throughout the test.
Note: The participant can engage in quiet, non-strenuous activities such as reading, playing
cards, watching TV and may walk to the bathroom between blood draws if necessary (but
should otherwise remain in resting position until the test is completed).
It is recommended that participants not be asked to answer questions for the purpose of
completing case report forms during the MMTT.
e.
Place an IV line into an antecubital vein, using an intracatheter/butterfly needle (usually 20 or
22 gauge depending upon the size of the participant). Note: The intracatheter may be kept
patent between samples with a slow saline drip or heparinized saline solution (as per the
guidelines of your institution) in a 20 mL syringe, injecting about 2-3 mL after each blood draw.
f.
Before the procedure, fill several 3 mL syringes with luer-lock tips with 1 mL normal saline
solution to flush the adapter after each blood draw. This is only necessary if the blood sampling
is more than 3 minutes apart.
Step 3. Obtain baseline samples: 
a.
The first sample should be taken at least 10 minutes after establishing the line(s) and when
participant is calm and relaxed (if possible, depending on age) - this is the “-10 minute” sample
b.
The second sample should be taken just prior to drinking the Boost High Protein - this is the “0
minute” sample
c.
Meal consumption - Start the clock at the beginning of the drink. The dose of Boost High
Protein must be completely consumed within five (5) minutes.
d.
Obtain post-meal blood samples.
e.
Samples are taken at 15, 30, 60, 90, 120, 150, 180, 210 and 240 minutes
f.
A timer should be turned on at 0 min
g.
The actual start time for each blood draw should be recorded in the patient’s source
documents and on the Requisition form
h.
Upon completion of the test, the participant should have a snack, for example peanut butter
or cheese crackers, coffee, milk or ginger ale.
6.4.Other assessments 
6.4.1Electronic Patient Reported Outcomes (ePRO) 
All patients (except for the single dose patients) will be asked to keep an electronic diary. The diaries 
will contain following information: 


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•
Safety related information (all experienced adverse events and serious adverse events,
including signs of clinical sepsis and known risks associated with the use of anti-CD3 mAb or
with T1D glycemic control)
•
Occurrence of hypoglycemic events including all relevant information for standard
classification (these will be captured separately from other safety related information)
•
Deviations from planned study drug intake (e.g. missed doses or incorrect doses taken)
•
Changes in concomitant medication intake
•
Insulin requirements: Daily
The electronic diaries will be kept from the day of signing the informed consent until the patient is 
withdrawn or completes the study. 
A site research coordinator will train the patients on how to complete the electronic diary. 
The research coordinator will review these diaries at every follow-up visit to verify that they have been 
completed properly and consistently. If needed, the patients will be re-trained on the completion of 
the diary. All relevant data reported in the diaries will be translated into the eCRF by the research 
coordinator.  
6.4.2Continuous Glucose Monitoring (CGM) 
All study patients (except for the single dose patients) will receive a XXX CGM device for the entire 
duration of their study participation. The investigator will train the patients on how to place the CGM 
device and will provide written instructions to the patient. The data generated by the device will be 
downloaded at every site visit. The devices will store data for up to 30 days. 
7. STUDY PROCEDURES
7.1.Visit Schedule
The schedule of assessments, evaluations and laboratory studies is presented in XX. A 
summary of procedures to be performed per visit is given below. 
7.2.Single Dose Patients 
7.2.1Screening Visit (Day -28 – Day 0) 
Following screening observations and procedures will be completed within 28 days prior to 
randomization: 
•
Signed and dated ICF
•
Assessment against inclusion and exclusion criteria
•
Medical history


Precigen ActoBio T1D, LLC 
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•
Demographic Data
•
Physical Exam
•
Vital signs
•
12-lead ECG
•
Serum pregnancy test (in females of childbearing potential)
•
Blood sampling for local lab (hematology, chemistry, specific screening blood analysis and
autoantibodies testing)
•
Infectious diseases (EBV, CMV, HIV, HCV, HBV)
•
Tuberculosis test
•
Drugs of abuse test
•
Record concomitant medications
•
Record adverse events
•
Register patient in IRT
o
Registration in IRT should be done as soon as eligibility is confirmed and ICF is signed.
Ideally this should be done before the Day 1 visit (start of treatment visit).
7.2.2Treatment Visit (Day 1) 
Prior to the first intake of AG019, following observations and procedures will be completed: 
•
Register visit in IRT
•
Physical Exam
•
Vital Signs
•
Urine pregnancy test (in women of childbearing potential)
•
Record Adverse events
•
Record concomitant medications
•
Administer morning dose of AG019
For Single Dose patients, it is recommended to schedule the Day 1 visit on a Monday, Tuesday or Friday, 
to avoid having to schedule the Day 4 visit (end of study visit) on a weekend day. 
7.2.3End of Study visit (Day 4) 
Following observations and procedures will be completed: 
•
Physical exam
•
Vital signs
•
12-lead ECG (only if there is suspicion of cardiac problems)
•
Urine pregnancy test (in women of childbearing potential)
•
Blood sampling for local lab
•
Record Adverse events
•
Record concomitant medications
•
IMP accountability


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7.3.Repeat Dose Patients 
7.3.1Screening Visit (Day -28 – Day 0) 
Following screening observations and procedures will be completed within 28 days prior to 
randomization: 
•
Signed and dated ICF
•
Assessment against inclusion and exclusion criteria
•
Medical history
•
Demographic Data
•
Physical Exam
•
Vital signs
•
12-lead ECG
•
Serum pregnancy test (in females of childbearing potential)
•
Blood sampling for local lab (hematology, full chemistry, specific screening blood analysis,
infectious disease, autoantibodies)
•
SARS-Cov2 PCR test (only applicable for patients in the combination cohorts)
•
Blood sampling for mechanistic assessments (only for repeat dose patients in AG019 Cohorts
2 and 4 and for patients in the combination cohorts)
•
Blood sampling for central lab (HbA1c)
•
Blood sample for central lab PK
•
Feces collection for central lab PK10 (only for repeat dose patients in AG019 Cohorts 2 and 4
and for patients in the combination cohorts)
•
Tuberculosis test
•
Mixed Meal Tolerance Test (MMTT) for C-peptide and glucose assessments
•
Drugs of abuse test
•
Record concomitant medications
•
Record adverse events
•
ePRO preparation / explanation
•
Assessment of insulin use and hypoglycemic events
•
Register patient in IRT
o
Registration in IRT should be done as soon as eligibility is confirmed and ICF is signed
to allow for timely shipment of study drug. Ideally this should be done at least 1 week
before the Day 1 visit (start of treatment visit).
7.3.2Baseline Visit (Day 1 – start of active treatment) 
Prior to the first administration of IMP, following observations and procedures will be completed: 
10 Sites should make every reasonable effort to collect feces during the screening visit. If feces cannot be collected 
during the screening visit, patients will be asked to collect feces between the Screening visit and the Day 1 visit, 
according to the instructions provided by the site and the collection materials provided by the central lab. 


Precigen ActoBio T1D, LLC 
Clinical Study Protocol AG019-T1D-101 
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investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
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•
SARS-Cov2 PCR test (only applicable for patients in the combination cohorts, to be taken within 
3 days before the first teplizumab/placebo infusion)
•
Register visit in IRT
•
Physical Exam
•
Vital Signs
•
Urine pregnancy test (in women of childbearing potential)
•
Blood sampling for mechanistic assessments (only for repeat dose patients in AG019 Cohorts
2 and 4 and for patients in the combination cohorts)
•
Record concomitant medications
•
Record adverse events
•
Placement of CGM device, training of patient on how to place the CGM device at home
•
ePRO review including insulin use and hypoglycemic events
•
Blood sampling for local lab (hematology, full chemistry, INR)
•
Evaluation of drug infusion withholding criteria (only for Combination Cohorts)
•
Administer first dose of AG019/placebo (for combination cohorts, randomized treatment
should be respected)
•
First teplizumab/placebo (randomized treatment should be respected)
For patients enrolled in the Repeat Dose AG019 cohorts, it is recommended to schedule the Day 1 visit 
on a Friday, to avoid having to schedule follow-up visits on weekend days. 
For patients enrolled in the Combination cohorts, it is recommended to schedule the Day 1 visit on a 
Monday, to avoid study drug infusions in 2 consecutive weekends. 
7.3.3Visits during active treatment phase 
7.3.3.1For all patients in AG019 cohorts and Combination Cohorts 
7.3.3.1.1Day 4 follow-up visit 
Following observations and procedures will be completed: 
•
Register visit in IRT
•
Physical Exam
•
Vital Signs
•
Urine pregnancy test (in women of childbearing potential)
•
Blood sampling for local lab (hematology, full chemistry, INR)
•
Record concomitant medications
•
Record adverse events
•
Study drug accountability
•
ePRO review including insulin use and hypoglycemic events
•
CGM readings/download
•
Evaluation of drug infusion withholding criteria (only for Combination Cohorts)
•
Teplizumab/placebo (randomized treatment should be respected) infusion
7.3.3.1.2Day 7 follow-up visit 


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Following observations and procedures will be completed: 
•
Register visit in IRT
•
Physical Exam
•
Vital Signs
•
Urine pregnancy test (in women of childbearing potential)
•
Blood sampling for local lab (hematology, full chemistry, INR)
•
Record concomitant medications
•
Record adverse events
•
ePRO review including insulin use and hypoglycemic events
•
CGM readings/download
•
Evaluation of drug infusion withholding criteria (only for Combination Cohorts)
•
Teplizumab/placebo (randomized treatment should be respected) infusion
•
Study drug accountability
7.3.3.1.3Day 12 follow-up visit 
Following observations and procedures will be completed: 
•
Register visit in IRT
•
Physical Exam
•
Vital Signs
•
Urine pregnancy test (in women of childbearing potential)
•
Blood sampling for local lab (hematology, full chemistry, INR)
•
Record concomitant medications
•
Record adverse events
•
Infectious disease monitoring (PCR)
•
Blood sample for central lab PK
•
Blood sample for mechanistic assessments (only for repeat dose patients in AG019 Cohorts 2
and 4 and for patients in the combination cohorts)
•
ePRO review including insulin use and hypoglycemic events
•
CGM readings/download
•
Evaluation of drug infusion withholding criteria (only for Combination Cohorts)
•
Teplizumab/placebo (randomized treatment should be respected) infusion including blood
sample for safety labs and evaluation of drug infusion withholding criteria (only for
Combination Cohorts)
•
Study drug accountability
7.3.3.1.4Day 28 follow-up visit 
Following observations and procedures will be completed: 


Precigen ActoBio T1D, LLC 
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investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
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•
Register visit in IRT
•
Physical Exam
•
Vital Signs
•
Urine pregnancy test (in women of childbearing potential)
•
Blood sampling for local lab (hematology, chemistry)
•
Record concomitant medications
•
Record adverse events
•
Infectious disease monitoring (PCR)
•
ePRO review including insulin use and hypoglycemic events
•
CGM readings/download
•
AG019/placebo dispensing (for combination cohorts, randomized treatment should be
respected)
•
AG019 drug accountability
7.3.3.1.5Day 56 follow-up visit (End of Treatment) 
Following observations and procedures will be completed: 
•
Physical Exam
•
Vital Signs
•
12-lead ECG
•
Urine pregnancy test (in women of childbearing potential)
•
Blood sampling for local lab (hematology, chemistry)
•
Blood sampling for mechanistic assessments (only for repeat dose patients in AG019 Cohorts
2 and 4 and for patients in the combination cohorts)
•
Blood sampling for central lab (HbA1c)
•
Blood sample for central lab PK
•
Feces collection for central lab PK (only for repeat dose patients in AG019 Cohorts 2 and 4 and
for patients in the combination cohorts)
•
Record concomitant medications
•
Record adverse events
•
Infectious disease monitoring (PCR)
•
AG019 drug accountability
•
ePRO review including insulin use and hypoglycemic events
•
CGM readings/download


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7.3.3.2Additional visits for patients in Combination Cohorts 
For patients in the Combination cohorts, additional follow-up visits for teplizumab infusions will take 
place on Day 2, Day 3, Day 5, Day 6, Day 8, Day 9, Day 10 and Day 11. During each of these visits, 
following observations and procedures will be completed: 
•
Register visit in IRT
•
Record concomitant medications
•
Record adverse events
•
Teplizumab infusion including blood sample for safety labs and evaluation of teplizumab
infusion withholding criteria
7.3.3.3Additional feces sampling (at home) on Days 58, 60, 62 and 64 
(only for repeat dose patients in AG019 Cohorts 2 and 4 and for 
patients in the combination cohorts) 
After the Day 56 follow-up visit, patients in AG019 Cohorts 2 and 4 and in the combination cohorts will 
be asked to collect additional feces samples every other day until Day 64. The samples will be collected 
and kept in the patient’s freezer, and will be handed over to the site personnel during the next follow-
up visit. Sites can arrange for a courier to pick up the collected samples from the patient’s home after 
Day 64, if the patient does not want to store the feces samples in his/her freezer until the next site 
visit (Day 90). 
Details on collection, labelling and storage of the samples will be explained verbally and in writing to 
the patients.  
A 2-day visit window is allowed for the Day 56 visit. The first feces sample will be collected in the 
hospital on the Day 56 follow-up visit, regardless on which day this visit takes place. If it is not possible 
to collect a feces sample at the site, the sample collection equipment will be given to the patient and 
a sample will be collected at home, ideally on the same day. Subsequent samples will be collected 
every 2 days following this visit, as described in the below table. 
EOT visit date 
First sample 
Second 
sample 
Third sample 
Fourth sample Fifth sample 
D54 
D54 
D56 
D58 
D60 
D62 
D55 
D55 
D57 
D59 
D61 
D63 
D56 
D56 
D58 
D60 
D62 
D64 
D57 
D57 
D59 
D61 
D63 
D65 
D58 
D58 
D60 
D62 
D64 
D66 


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7.3.4Visits after the active treatment phase 
7.3.4.1Day 90 follow-up visit 
Following observations and procedures will be completed: 
•
Physical Exam
•
Vital Signs
•
Urine pregnancy test (in women of childbearing potential)
•
Blood sampling for local lab (hematology, chemistry)
•
Infectious disease monitoring (PCR)
•
Blood sampling for mechanistic assessments (only for repeat dose patients in AG019 Cohorts
2 and 4 and for patients in the combination cohorts)
•
Blood sampling for central lab (HbA1c)
•
Blood sample for central lab PK
•
Mixed Meal Tolerance Test (MMTT)
•
Record concomitant medications
•
Record adverse events
•
ePRO review including insulin use and hypoglycemic events
•
CGM readings/download
7.3.4.2Day 180 follow-up visit 
Following observations and procedures will be completed: 
•
Physical Exam
•
Vital Signs
•
Urine pregnancy test (in women of childbearing potential)
•
Blood sampling for local lab (hematology, chemistry)
•
Blood sampling for mechanistic assessments (only for repeat dose patients in AG019 Cohorts
2 and 4 and for patients in the combination cohorts)
•
Blood sampling for central lab (HbA1c)
•
Mixed Meal Tolerance Test (MMTT)
•
Record concomitant medications
•
Record adverse events
•
ePRO review including insulin use and hypoglycemic events
•
CGM readings/download
•
12-lead ECG (only if there is suspicion of cardiac problems)
7.3.4.3Day 270 follow-up visit 
Following observations and procedures will be completed: 
•
Physical Exam
•
Vital Signs
•
Urine pregnancy test (in women of childbearing potential)


Precigen ActoBio T1D, LLC 
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•
Blood sampling for local lab (hematology, chemistry)
•
Blood sampling for mechanistic assessments (only for repeat dose patients in AG019 Cohorts
2 and 4 and for patients in the combination cohorts)
•
Blood sampling for central lab (HbA1c)
•
Record concomitant medications
•
Record adverse events
•
ePRO review including insulin use and hypoglycemic events
•
CGM readings/download
7.3.4.4Day 360 follow-up visit (End of Study) 
Following observations and procedures will be completed: 
•
Physical Exam
•
Vital Signs
•
Urine pregnancy test (in women of childbearing potential)
•
Blood sampling for local lab (hematology, chemistry)
•
Infectious disease monitoring (PCR)
•
Blood sampling for mechanistic assessments (only for repeat dose patients in AG019 Cohorts
2 and 4 and for patients in the combination cohorts)
•
Blood sampling for central lab (HbA1c)
•
Mixed Meal Tolerance Test (MMTT)
•
Record concomitant medications
•
Record adverse events
•
ePRO review including insulin use and hypoglycemic events
•
CGM readings/download
•
12-lead ECG
7.4.Unscheduled visits 
If a patient returns for an unscheduled visit, following observations and procedures will be completed 
at a minimum: 
•
Register visit in IRT
•
Physical Exam
•
Vital Signs
•
12-lead ECG (only if there is suspicion of cardiac problems)
•
Urine pregnancy test (in women of childbearing potential)
•
Blood sampling for local lab (hematology, chemistry)
•
Infectious disease monitoring (PCR)
•
Record concomitant medications
•
Record adverse events


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If a patient returns for an unscheduled visit and this visit results in study discontinuation for any reason, 
the procedures outlined in the End of Study visit (Section 7.3.4.4) should be conducted. 
8. ADVERSE EVENT REPORTING
Throughout the study, AEs will be recorded in the source documents and transcribed onto 
the appropriate pages of the eCRF regardless of whether the AEs are considered treatment related. All 
AEs with onset dates from signature of the ICF through study exit will be recorded as an AE on the 
eCRF. All SAEs with onset dates from signature of the ICF through study exit must be recorded following 
the guidelines in Sections 8.4, 8.6, 8.7, 8.8 and 8.9. Any AE that occurs at any time after completion of 
the study, which the investigator considers to be related to study drug, must be reported.  
Conditions existing prior to screening will be recorded as part of the patient’s medical history. To avoid 
confusion, the AE should be recorded in standard medical terminology. The Investigator is responsible 
for assessing the relationship of AEs to the AG019 as well as to teplizumab (Section 8.3). 
8.1.Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a patient administered an investigational 
product or in whom an investigational product is to be administered, and which does not necessarily 
have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (e.g. 
an abnormal laboratory finding), symptom or disease temporally associated with the use of 
an investigational product, whether or not considered related to this investigational product. This 
includes an event that emerges during treatment having been absent pre-treatment or an event that 
worsens relative to the pre-treatment state (“treatment-emergent adverse event” [TEAE]). Recurrent 
symptoms of a chronic pre-existing condition are not considered AEs unless they occur in a worse or 
unexpected pattern during study drug administration.  
8.2.Assessing Severity of Adverse Events 
The severity of adverse events will be designated as mild, moderate, severe, life threatening, or fatal 
per National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) version 
4.0. If not specifically addressed in NCI CTCAE version 4.0, use the table below: 
Mild – Grade 1 
Transient or mild discomfort; requiring no 
limitation of activity; no therapy 
Moderate – Grade 2 
Mild-moderate impact on activity; requiring 
some assistance and medical intervention 


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Severe – Grade 3 
Marked impact on activity; requiring some 
assistance and medical intervention 
Life Threatening – Grade 4 
Complete 
disability; 
requiring 
significant 
assistance and medical intervention and/or 
hospitalization 
Death – Grade 5 
Adverse event with fatal outcome 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relative minor medical 
significance (such as severe headache). This is not the same as “serious”, which is based on 
patient/event outcome or action criteria usually associated with events that pose a threat to a patient’s 
life or functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
8.2.1Grading of Hypoglycemic and Hyperglycemic Events 
For this study of participants with type 1 diabetes, the NCI-CTCAE will not be used to grade 
hypoglycemia and hyperglycemia. Please refer to the grading criteria for hypoglycemic and 
hyperglycemic events below.  
In line with the Joint Position Statement of the American Diabetes Association and the European 
Association for the Study of Diabetes (International Hypoglycaemia Study, 2017), events of 
hypoglycemia will be classified as outlined below. 
•
hypoglycemia Level 1: A glucose alert value of 3.9 mmol/l (70 mg/dl) or less for at least 20
minutes
•
hypoglycemia Level 2: A glucose level of <3.0 mmol/l (<54 mg/dl), sufficiently low to indicate
serious, clinically important hypoglycemia.
•
hypoglycemia Level 3: Severe hypoglycemia, as defined by the American Diabetes Association,
denoting severe cognitive impairment requiring external assistance for recovery.
Major hyperglycemic events will be defined and graded as follows: 
•
Grade 4 = coma or life-threatening event or event resulting in hospitalization.
•
Grade 5 = death.
For this study diabetic ketoacidosis (DKA) should be reported as grade 4 hyperglycemia (a single 
adverse event) resulting in hospitalization and/or life threatening consequences. 


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8.3.Assessing Relationship to Study Treatment 
All AEs will be categorized by the Investigator with respect to their possible relationship to the IMP. 
The relationship of the AE to AG019, as well as the relationship of the AE to teplizumab, will be assessed 
separately by the investigator to be not related, unlikely, possible, probable or definite, as follows: 
•
Not related: No relationship between the AE and the administration of IMP, judged clearly and
incontrovertibly due to extraneous causes (disease, environment etc.).
•
Unlikely: The AE is more likely due to an alternative explanation such as concomitant
medication(s), concomitant disease(s) and/or the time relationship suggests that a causal
relationship is unlikely.
•
Possible: The AE might be due to the administration of IMP. An alternative explanation such
as concomitant medication(s), concomitant disease(s) is inconclusive. The time relationship is
reasonable therefore the causal relationship cannot be excluded.
•
Probable: The AE might be due to the administration of IMP. An alternative explanation such
as concomitant medication(s), concomitant disease(s) is less likely. The time relationship is
suggestive, i.e., it is confirmed by de-challenge.
•
Definite: There is no uncertainty in relationship to the administration of IMP. The AE cannot
be reasonably explained by an alternative explanation such as concomitant medication(s),
concomitant disease(s). The time relationship is very suggestive, i.e. it is confirmed by de-
challenge and re-challenge.
“Not 
related 
and 
Unlikely 
related” 
correspond 
to 
“no 
reasonable 
possibility”. 
“Possible, probable and definite” correspond to “reasonable possibility”. 
8.4.Recording of Adverse Events 
All AEs encountered during the clinical study will be recorded in detail in the source documents and 
documented in the eCRF, from signature of the ICF through study exit. All AEs that meet the 
seriousness criteria (Section 8.6) should also be recorded on the SAE Report Form. All SAEs must be 
reported to the sponsor or delegated organization within the timeline stated in Section 8.7. 
The recording of AEs will be based on data obtained from the following sources: 
•
Medical and surgical history
•
Physical examinations including vital signs
•
Clinical laboratory test results
•
Information provided by the patient, either during the follow-up visits or in the patient’s diary
All clinical events, including both observed (such as any reaction at sites of application) and 
volunteered problems, complaints, or symptoms, are to be recorded. The need to capture this 
information is not dependent upon whether the clinical event is associated with the use of any IMP. 
If at any time during the study a patient develops symptoms suggesting clinically significant bacteremia 
that can be attributed to L. lactis sAGX0407 (as determined by three consecutive positive blood 
cultures), study treatment will be discontinued. 
A disposition plan for the management of clinical sepsis is provided in Appendix B. 


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For the purposes of this study, hypoglycemia events classified as level 1 as defined in Section 8.2.1 will 
not be recorded separately on the hypoglycemia event eCRF, unless the investigator feels that the 
event is medically important. Hypoglycemia events level 2 and 3 as defined in Section 8.2.1 will be 
recorded separately on the hypoglycemia event eCRF. The evaluation that produced the value or result 
should be repeated until that value or result returns to normal or can be explained and the participant’s 
safety is not at risk. In addition, all hypoglycemia events meeting the definition of SAE as mentioned in 
Section 8.6, should be recorded as serious adverse events in the eCRF.  
Major hyperglycemic events as defined in Section 8.2.1 will be recorded as serious adverse events. In 
addition, all hyperglycemia events meeting the definition of SAE as mentioned in Section 8.6, should 
be recorded as serious adverse events. Any other hyperglycemic event (defined as blood glucose 
>140mg/dL for at least 20 minutes) will not be recorded as adverse event, unless the investigator
considers the event to be medically important.
8.5.Adverse Event Follow-up Period 
All patients with AEs will be followed until the event resolves, stabilizes, becomes chronic, the patient 
completes the study or the patient is lost to follow-up. 
8.6.Serious Adverse Event Definition 
In addition to classifying the AE as mild, moderate, severe, life-threatening or fatal, the Investigator 
should determine whether or not an AE is an SAE. The Investigator shall make an accurate and 
adequate report on any SAE to the Sponsor or its designee and to any IRB/IEC that has reviewed and 
is continuing to review the study regarding any SAEs (see Sections 8.7 and 8.9).  
An SAE is defined as any AE occurring at any dose regardless of relationship to IMP that results in any 
of the following outcomes: 
•
results in death,
•
is life-threatening, NOTE: The term "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 which hypothetically might have caused death if it were more severe.
•
requires inpatient hospitalization or prolongation of existing hospitalization,
•
results in persistent or significant disability/incapacity, or
•
is a congenital anomaly/birth defect.
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually be considered serious. Examples of such events are 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 drug dependency or drug abuse. 
The following situations will be considered important medical events and must be reported as SAEs: 


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1.
Grade 4 or higher lymphopenia for 7 or more days occurring in the first 30 days after the
start of the teplizumab infusion.
2.
Grade 3 or higher lymphopenia occurring anytime later than the first 30 days after the
start of the teplizumab infusion.
Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization, the 
event causing the prolongation is an SAE. Planned hospitalizations are not considered SAEs. 
“Inpatient hospitalization” means the patient has been formally admitted to a hospital for medical 
reasons. This may or may not be overnight. It does not include presentation at an emergency 
department. 
Pregnancy in a study participant, or in the female partner of a male participant, occurring after 
signature of the ICF are considered immediately reportable events using specific reporting forms and 
must be reported within 1 calendar day after the Investigator has gained knowledge of them. The 
patient (if female) will discontinue IMP. Details of the outcome of the pregnancy (e.g. full term delivery, 
stillbirth, congenital anomaly, miscarriage) will be collected and reported no longer than one month 
after the expected due date. Any abnormal outcome in the neonate will be followed-up. 
8.7.Reporting of Serious Adverse Events 
For any SAEs, regardless of causal relationship, the Investigator must inform the Sponsor’s 
pharmacovigilance vendor (XXX), the contract research organization (CRO) Project manager or 
Lead clinical research associate (CRA) as well as the Sponsor’s representatives mentioned on the 
Contact Details page of this protocol within 1 calendar day of becoming aware of the event by 
mailing the completed SAE Report Form and any other pertinent SAE information to XXX as 
indicated on the SAE Report Form. Follow-up information collected for an initial report of an SAE 
must be reported to XXX within 1 calendar day of receipt by the Investigator.  
XXX
Reports of any pregnancy in a patient, or partner of a patient, must also be emailed to the above 
mentioned email address within 1 calendar day (see Section 8.6). 
The information to be recorded for SAEs should include the following: 
•
The onset of any new AE or the worsening of an observation documented from signature of
the ICF
•
The specific type of event in standard medical terminology
•
The duration of the clinical event (start and stop dates)
•
The severity of the clinical event
•
Seriousness (SAE) criteria
•
Relevant laboratory and examination results
•
Dosing schedule of IMP(s)


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•
Indications and dosing schedules of concomitant medications
•
Relationship of the AE to the IMP(s) as defined in Section 8.3
•
Management of IMP(s) administration and other action taken to alleviate the clinical events
•
Past medical and surgical history and concurrent diseases
•
De-challenge/re-challenge results, if applicable
•
The outcome of the clinical event
•
Serious Adverse Event Recording Period
SAEs will be collected and recorded by the Investigator beginning from the signature of the ICF until 
the patient is withdrawn or has completed the study.  
8.8.Serious Adverse Event Follow-up Period 
All patients who experience SAEs will be followed until the events resolve, stabilize, become chronic 
or the patients complete the study or are lost to follow-up. 
8.9.Regulatory Reporting of Adverse Events 
If there are serious, unexpected adverse drug reactions (for Europe, SUSAR: Suspected Unexpected 
Serious Adverse Reaction) associated with the use of the IMP, the appropriate regulatory agency(ies) 
and all participating investigators will be notified by the Sponsor or its designee in accordance with the 
following Guidance for Industry: Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting (ICH-E2A), Detailed Guidance on the Collection, Verification and Presentation of 
Adverse Event/Reaction Reports Arising from Clinical Trials on Medicinal Products for Human Use (CT-
3).  
It is the responsibility of the investigator to promptly notify the IRB/IEC of all unexpected serious 
adverse drug reactions involving risk to human patients. An unexpected event is one that is not 
reported in the current Investigator’s Brochure of AG019 or teplizumab. 
8.10.Expected adverse events 
8.10.1AG019 
As AG019 has not been studied in humans, there are no expected adverse events associated with 
AG019. However, due to the general profile of the IMP, sepsis as a result of systemic exposure of 
AG019 could be expected. Instructions on the management of clinical sepsis attributable to AG019 are 
described in Appendix B. 
All SAEs which are reported, for which a relationship to AG019 cannot be excluded, will be reported as 
SUSARs (see Section 8.9). 


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8.10.2Teplizumab 
A full description of the adverse events experienced by patients in trials using teplizumab is in the 
Investigator’s Brochure.  The descriptions below highlight the most common drug related events and 
potential adverse events. 
XXX


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10.STATISTICAL METHODS
Statistical considerations are briefly described below. 
Descriptive statistical methods will be used to summarize the data from this study. Unless stated 
otherwise, the term descriptive statistics refers to number of patients (n), mean, median, standard 
deviation (SD), standard error of the mean (SEM), minimum and maximum for continuous data and 
frequencies and percentages for categorical data. The term “treatment group” refers to assigned dose 
group/dosing frequency. 
After all patients in all AG019 and Combination cohorts have completed their 6-month follow-up visit 
unblinding will be done and all data will be analyzed and reported. After completion of the full 12 
months follow-up all additional data will be analyzed and reported separately. 
More details on the analysis and presentation of study results will be provided in the statistical analysis 
plan (SAP). The SAP will be finalized prior to the unblinding of treatment allocation codes. 
10.1.Study Endpoints 
Primary Endpoint 
The primary end point will be assessed by analysis of the incidence of treatment-emergent adverse 
events (TEAEs) collected up to the 6-month follow-up visit. A TEAE is defined as any event not present 
prior to the initiation of the treatment(s) or any event already present that worsens in either intensity 
or frequency following exposure to the treatment(s). 
Secondary Endpoints 
The pharmacodynamic activity of the study drug(s) will be assessed by measurement of biomarkers in 
blood and serum samples. Relevant parameters will be assessed, including immune markers for effect, 
relevant T1D parameters and relevant cytokines. Details about the analysis of the collected PD samples 
will be described in the SAP. 
Following parameters will be assessed for analysis of systemic and local exposure to L. lactis: 
•
Presence of live L. lactis clinical strain bacteria in whole blood
•
Measurable serum levels of hIL-10 and hPINS
•
Presence of L. lactis clinical strain bacteria in fecal excretion
Safety information collected at all other time points will be assessed as secondary end points. 
10.2.Sample Size Consideration 
This is a preliminary study designed to provide information to be used in the design of subsequent 
studies. This study is descriptive in nature and is not designed to provide analytical results regarding 


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efficacy. As such, the sample size is not based on statistical considerations, rather it is believed that at 
least 4 patients per dose level in the AG019 cohorts and 12 patients per dose level in the combination 
cohorts will provide sufficient data to evaluate preliminary safety and activity of the IMP as 
administered in this protocol. 
10.3.Definitions of Study Populations for Analysis 
10.3.1The Safety (SAF) Analysis Set 
The safety population will include all patients who receive at least one dose of study medication. Only 
patients with clear documentation that no study medication was received may be excluded from 
analysis. Patients will be analyzed according to the dose received. This population will be used for all 
data summaries. 
10.3.2The Pharmacokinetic (PK) Analysis Set 
For each cohort, all patients who received the IMP as scheduled and provided sufficient samples to 
reliably estimate the PK parameters will be included in the PK analysis set. 
More details on the PK parameters, analysis and presentation of study results will be provided in the 
SAP. 
10.3.3The Pharmacodynamic (PD) Analysis Set 
For each cohort, all patients who received the IMP as scheduled and provided sufficient samples to 
reliably estimate the PD parameters will be included in the PD analysis set. 
More details on the PD parameters, analysis and presentation of study results will be provided in the 
SAP. 
10.4.Baseline Characteristics and Demographic Variables 
Demographics and limited medical history will be summarized by treatment group. 
10.5.Pharmacokinetic Analysis 
Blood samples will be collected at specific time points throughout the study. These will be used to 
evaluate the pharmacokinetics of AG019 by treatment group and study visit. 
Feces samples will be collected from repeat dose patients for pharmacokinetic analysis. 


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Details on collection, storage and handling of blood and feces samples will be included in the central 
lab manual. 
10.6.Pharmacodynamic analysis 
Blood samples will be collected at specific time points throughout the study. These will be used to 
evaluate immune markers for effect, relevant T1D parameters and relevant cytokines.  
Details on collection, storage and handling of blood and feces samples will be included in the central 
lab manual. 
10.7.Safety Analysis 
Safety will be assessed based on TEAEs, physical examination findings, vital sign measurements and 
clinical laboratory tests. 
Adverse events will be coded to a Medical Dictionary for Regulatory Activities (MedDRA) preferred 
term and system organ classification. The occurrence of treatment emergent AEs will be summarized 
by treatment frequency received using preferred terms, system organ classifications and severity. If a 
patient experiences multiple events that map to a single preferred term, the greatest severity and/or 
strongest investigator assessment of relation to study drug will be assigned to the preferred term for 
the appropriate summaries. Separate summaries of treatment emergent SAEs and treatment 
emergent AEs that are related to either IMP will be generated. Summaries may be repeated according 
to study phase. All AEs will be listed for individual patients showing both verbatim and preferred terms. 
Descriptive summaries of vital signs and quantitative clinical laboratory changes will be presented by 
treatment received and study visit. The number and percentage of patients experiencing laboratory 
abnormalities and clinically relevant laboratory abnormalities will be summarized by treatment 
received. Cross tabulations of baseline abnormality vs. worst post treatment abnormality for selected 
laboratory assessments will presented by treatment received. 
Abnormal physical examination findings will be presented by treatment received. The number and 
percentage of patients experiencing each abnormal physical examination finding will be included. 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
dictionary. These data will be listed.  
The number and percentage of patients with presence of sAGX0407 bacteria will be summarized by 
treatment group. 
10.8.Interim Analysis 
Interim analyses will be performed according to the below schedule: 
•
After the last Day 180 follow-up visit of the last patient enrolled into the Phase 1b portion of
the study, a preliminary analysis of the data collected up to 6 months will be performed for
these patients.


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•
Once all patients enrolled in Combination Cohort 1, as well as the 2 patients enrolled into the
open label portion of Combination Cohort 2, have completed the Day 180 follow-up visit,
unblinding will be done and an interim analysis will be performed.
•
After the last Day 180 follow-up visit of the last patient enrolled into Combination Cohort 2, all
patients in this cohort will be unblinded and an interim analysis will be performed on all, which
will include an analysis of the primary endpoint of the study.
10.9.Reporting of Deviations to Original SAP 
 All deviations from the original SAP will be reported in the clinical study report. 
11.ETHICS
11.1.Good Clinical Practice
The Investigator will ensure that this study is conducted in full compliance with the principles of the 
“Declaration of Helsinki”, ICH guidelines, in particular ICH GCP E6, and the laws and regulations of the 
country in which the research is conducted, whichever affords the greatest protection to the study 
patient. 
11.2.Institutional Review Board (IRB) / Independent Ethics Committee (IEC) 
This protocol and any accompanying material for this study provided to the patient (such as patient 
information sheets and informed consent form) as well as any advertising or compensation given to 
the patient must be reviewed and approved by an appropriate IRB/IEC before patients are included 
into the study. It is the responsibility of the Investigator to assure that all aspects of the institutional 
review are conducted in accordance with the requirements of all regulatory authorities. A signed and 
dated letter documenting IRB/IEC approval must be obtained prior to entering patients at the site. The 
IRB/IEC must be notified of all subsequent protocol amendments. 
11.3.Patient Information and Informed Consent 
In accordance with regulatory and local IRB/IEC requirements, before study procedures are performed, 
patients will be informed about the study and required to sign and date the IRB/IEC approved ICF. This 
form will be signed and dated after adequate explanation of the aims, methods, objective and potential 
hazards of the study and prior to undertaking any study-related procedures. The method of obtaining 
and documenting the informed consent and the contents of the consent must comply with ICH GCP 
and all applicable regulatory requirement(s). No patient is to be screened or treated until an ICF, 
written in a language in which the patient is fluent, has been obtained. The signed ICF will be retained 
with the study records. Each patient will also be given a copy of his/her signed ICF.  


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An assent form has also been developed for participants less than 18 years of age. Assent of children 
along with consent of the parents will be obtained prior to any study procedures. 
All participants (or their legally acceptable representative) must read, sign and date a consent form 
prior to participation in the study, and/or undergoing any study specific procedures.  
The informed consent form must be updated or revised whenever important new safety information 
is available, when indicated for a protocol amendment, and/or whenever any new information 
becomes available that may affect a participant’s participation in the study. 
11.4.Data Safety Monitoring Board and Medical Monitor 
11.4.1Medical Monitor 
A Medical Monitor (MM) will be appointed. The role of the MM will entail following duties: 
•
Act as central point of contact for Investigators for addressing medical study related questions
•
Collaborate with the clinical sites and investigators to review the collected data of the trial
patients at pre-defined intervals, to determine whether enrollment can continue
•
Review of safety data, identify possible trends in reported adverse events
The MM will keep close relationships with all participating clinical sites throughout the course of the 
trial. The MM will collaborate with the investigators and will regularly review the collected data, to 
determine whether enrollment in the trial can continue. 
More detailed information on the roles and responsibilities of the MM can be found in the medical 
monitoring plan. 
11.4.2DSMB 
An independent DSMB will be constituted before the start of the study. 
The DSMB is an independent body of experts that serves in an advisory capacity to the Sponsor to 
ensure that clinical trial participants are not exposed to unreasonable or unnecessary risks of AG019 
and/or teplizumab. On fixed time points during the Study, as outlined in the DSMB charter and in Figure 
1 (overall enrollment plan), the DSMB will review the available safety data, which include, but are not 
limited to serious adverse events (SAEs) and adverse events (AEs) related to the study medication. 
The DSMB will supervise the ethical performance of the study and review safety data arising during 
the study according to the procedures described in the DSMB Charter. The Charter will describe the 
following activities: 
The DSMB will consist of at least 3 members. Members are completely independent of the 
investigators and have no financial, scientific, or other conflicts of interest with the trial.   
In order for the DSMB to fulfill its responsibilities, the members will observe the following guidelines: 


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•
Members are free of apparent conflicts of interest involving financial, scientific, or regulatory
matters
•
Members should assess trial objectives and designs in an unbiased way
•
The DSMB members will review data and pertinent procedures in order to be confident that
the data on which the decisions are based are accurate and complete
•
All decisions of the DSMB shall be independent
The DSMB is responsible for recommending to the Sponsor any actions necessary to maintain the 
safety of the patients and the integrity of the trial. The DSMB will also be responsible for 
recommending to the Sponsor if patients should be enrolled into the next cohort. To fulfill these 
responsibilities, the DSMB will do the following: 
•
Review and approve the Data Safety Monitoring Board charter
•
Monitor recruitment figures including data for patients that are lost to follow-up
•
Hold six scheduled teleconferences and any ad hoc meetings as needed to review safety data
•
Request additional information if required to fulfill responsibilities
•
Issue recommendations to the Sponsor using secure communication
•
Consider factors external to the study when relevant information becomes available, such as
scientific or therapeutic developments that may have an impact on the safety of the patients
or the ethics of the trial
•
Ensure the confidentiality of the trial data
•
Securely maintain accurate records of deliberations and decisions
The DSMB chairperson will advise the Sponsor of the DSMB’s recommendations after each meeting. 
Examples of DSMB recommendations include the following: 
•
Administrative changes to the trial if withdrawals are high
•
Modification of inclusion/exclusion criteria for safety reasons
•
Modification of the safety monitoring process
•
Suspension of recruitment pending further safety review, if data received suggest significant
net adverse effect of AG019 and/or teplizumab treatment
•
Continuation of recruitment into the next cohort(s), if data received suggest no significant
adverse effect of AG019
In order to make proper recommendations to the Sponsor on lowering the dose of AG019, and/or on 
opening cohorts for recruitment, the DSMB will review all available safety data from all patients 
enrolled up to that point. 


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11.4.3Study/Treatment Stopping Criteria 
11.4.3.1Criteria for premature study termination 
If clinical sepsis occurs in a patient, and it is exclusively attributable to AG019 bacteria alone (confirmed 
by positive plating and PCR), the study will be terminated. Details about the evaluation and 
management of clinical sepsis of any kind (attributable to AG019 or not) are outlined in Appendix B. 
11.4.3.2Criteria for suspension of enrollment 
Enrollment (defined as initiation of treatment in a new patient) in all ongoing and planned study 
cohorts may be temporarily suspended if one of the following occurs: 
•
XXX
In the event that these criteria are met, the DSMB will be notified in writing within 24 hours. The 
notification will include detailed information of the event(s) and finding(s) that have led to meeting 
the criteria for enrollment suspension. The DSMB will determine whether enrollment needs to be 
suspended until a safety review has been performed, and will notify the Sponsor of their decision in 
writing.  


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•
If the DSMB concludes upon initial notification that enrollment should be suspended until a
more detailed safety review has been performed, the Sponsor will inform the Institutional
Review Boards/Ethics Committees/Research Ethics Board (IRB/EC/REB), FDA and other
applicable regulatory authorities and all participating sites within 24 hours of the DSMB’s
decision and will schedule an ad-hoc DSMB meeting to review the relevant safety information.
The safety review will include a comprehensive evaluation of the safety experience from this
trial. A report of the safety review will be provided to the FDA, other applicable regulatory
authorities, Institutional Review Boards/Ethics Committees/Research Ethics Boards
(IRB/EC/REB) and all participating sites. Enrollment will not resume until a satisfactory report
of the safety review has been provided by the DSMB.
•
If the DSMB concludes that enrollment should not be suspended, the Sponsor may schedule
an ad-hoc DSMB meeting to review the relevant safety information upon request of the DSMB.
*XXX
11.4.3.3Criteria for adjusting AG019 treatment 
If clinically significant safety concerns relating to AG019 are identified in ≥ 20% of all patients treated 
with the high dose of AG019, the DSMB will recommend lowering the AG019 dose in all AG019 and 
Combination cohorts. 
11.4.3.4Criteria for discontinuation of AG019 treatment in a single 
patient 
If at any time during the study a patient develops symptoms suggesting clinically significant sepsis for 
any reason (as determined by 1 positive blood culture), study treatment (both AG019 and teplizumab 
as applicable) will be discontinued. In addition, the guidelines for management of clinical sepsis as 
outlined in Appendix B should be followed. 
In addition, withdrawal of informed consent will result in discontinuation of AG019 treatment. 
Pregnancy in a study participant, or in the female partner of a male participant, occurring after 
signature of the ICF must be reported within 1 calendar day after the Investigator has gained 
knowledge of them. The patient (if female) will discontinue IMP. Details of the outcome of the 
pregnancy (e.g. full term delivery, stillbirth, congenital anomaly, miscarriage) will be collected and 
reported no longer than one month after the expected due date. Any abnormal outcome in the 
neonate will be followed up.  


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11.4.3.5 Teplizumab Withholding in an Individual Patient During the 
12-Day Treatment Period
Total bilirubin, AST, ALT, LDH, Complete Blood Count (CBC), and INR will be evaluated to verify the 
need to withhold teplizumab (or placebo) infusion before each (potential) teplizumab administration, 
as described in the Visit Schedule (Appendix A). 
11.4.3.5.1 Temporary interruption of teplizumab infusions 
If any of the following lab abnormalities is observed (normal range per local lab reference ranges), the 
test may be repeated on the same day. If the repeated test result normalizes, that day’s dose may be 
given. If the value is still in the indicated range or worsens, or if the test cannot be repeated on the 
same day, that day’s dose should be withheld.  
• XXX
If the above event(s) resolve(s) within 2 days, study drug dosing may be resumed according to the 
original schedule. The treatment course will not be extended beyond 12 days.  
If the above events do not resolve after 2 consecutive days of interruption, the Medical Monitor must 
be consulted regarding continuation of study drug dosing. 
11.4.3.5.2Permanent discontinuation of teplizumab infusions 
The following situations, laboratory abnormalities, or adverse events will lead to permanent 
discontinuation of infusions during the treatment course: (Note: Day 1 is the first day of infusion) 
XXX 


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11.4.3.6Further Evaluation after Withholding Teplizumab Infusions 
The following are minimal assessments to be performed for those participants in whom an infusion is 
withheld (as described above): 
•
XXX
11.5.Financial Disclosure by Principal Investigators 
Since this is a “covered” clinical trial, the Investigator will ensure that 21 CFR §54 is adhered to. A 
“covered” clinical trial is any study of a drug or device in humans submitted in a marketing application 


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or reclassification petition patient to this part that the applicant or the FDA relies on to establish that 
the product is effective (including studies that show equivalence to an effective product) or that make 
a significant contribution to the demonstration of safety. This requires that investigators and all sub 
investigators (inclusive of family members) provide documentation of their financial interest or 
arrangement with the Sponsor or proprietary interests in the drug being studied. This documentation 
must be provided prior to the participation of the Investigator and any Sub Investigator. The 
Investigator and Sub-Investigator agree to notify the Sponsor of any change in reportable interests 
during the study and for one year following completion of the study. Study completion is defined as 
the date that the last patient has completed the protocol defined activities. 
12.STUDY MANAGEMENT AND ADMINISTRATION
12.1.Curriculum vitae
An updated copy of the curriculum vitae limited to the experience, qualification and training for each 
investigator and sub-investigator will be provided to the sponsor prior to the beginning of the clinical 
trial. 
12.2.Protocol Modifications 
The Sponsor may modify the protocol at any time during the life of the protocol. Protocol amendments 
will require IRB/IEC approval and CA approval as applicable prior to implementation except when 
changes to the protocol are required to eliminate immediate hazards to the study patients. 
12.3.Data Quality Control and Quality Assurance 
The study will be monitored and managed in accordance with ICH GCP E6. 
Study data will be entered in the eCRF by trained study personnel. Data validation edit checks will be 
defined and implemented. Inconsistent and questionable data detected during data entry or data 
validation process will be queried. Queries will be generated and any discrepancies will be resolved. 
12.4.Monitoring 
The Sponsor or its designee will perform on-site monitoring visits periodically during the study. At 
these visits the monitor will review study documents to ensure adherence to the study protocol and 
regulatory requirements, and to review eCRF entries against source documents. Findings from the visit 
will be discussed with the investigator.  


Precigen ActoBio T1D, LLC 
Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
This document contains confidential information.  It is intended solely for the use of the principal investigator, co-
investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
bodies. 
AG019-T1D-101 CSP Final 9.0 11-Jun-2020 
Page 82/93 
12.5.Audit and Inspection 
The Investigator will agree to receive periodic quality assurance audits conducted by the Sponsor’s 
clinical quality assurance personnel or its designee. In addition, the Investigator will agree to 
inspections by regulatory agencies to the extent permitted by law. Auditors and inspectors will have 
direct access to all relevant study documentation. 
12.6.Source Documents 
The Investigator must allow regulatory agencies, individuals delegated by the IRB/IEC or the Sponsor 
or its designee to have access to all the original documentation of the study, including the ICFs signed 
by the patients enrolled into the study and the relevant patient medical files. The individuals who are 
given access to the documentation must take every reasonable precaution to keep the identity of the 
patients and the proprietary information of the Sponsor as confidential information in accordance with 
relevant applicable legislation. 
12.7.Electronic Data Capture 
Electronic Case Report Forms (eCRFs) will be supplied by the Sponsor or its designee and should be 
handled in accordance with the provided instructions. All eCRFs should be filled out completely by 
authorized study personnel. 
The Investigator should ensure the accuracy, completeness and timeliness of the data recorded on the 
eCRF. Data recorded on the eCRF will be consistent with source documents. Any discrepancies must 
be explained or resolved. 
Completed eCRFs will be reviewed by the Sponsor’s monitoring staff or its designee. An eCRF will be 
completed for each patient enrolled in the study. 
12.8.Premature Termination of the Study 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform 
the investigators and the regulatory authority(ies) of the reason(s) for termination or suspension. The 
IRB/IEC also will be promptly informed by the Sponsor or Investigator and provided with the reason(s) 
for the termination or suspension, as specified by the applicable regulatory requirement(s). 
12.9.Study Report 
The results of the study will be presented in an integrated clinical study report according to GCP and 
ICH-E3 guidance. The Sponsor will ensure that the clinical study reports are prepared and provided to 
the regulatory agency(ies) as required by the applicable regulatory requirement(s). The Principal 
Investigator will submit to the Sponsor a copy of the report issued to the IRB/IEC.  


Precigen ActoBio T1D, LLC 
Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
This document contains confidential information.  It is intended solely for the use of the principal investigator, co-
investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
bodies. 
AG019-T1D-101 CSP Final 9.0 11-Jun-2020 
Page 83/93 
12.10.Finance, Insurance and Publication 
Insurance coverage will be handled to local requirements. 
Finance, insurance and publication rights are addressed in the Investigator/Institution and/or CRO 
agreements as applicable. 
12.11.Archiving and Data Retention 
The Investigator shall retain adequate records for the study including copies of each patient’s eCRFs, 
medical records, laboratory reports, ICF(s), IMP accountability records, safety reports, information 
regarding patients who were withdrawn and any other pertinent data. The Investigator must retain all 
records for at least 20 years after completion or discontinuation of the trial or at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period however if required by the applicable regulatory requirements. The 
sponsor will notify the investigator when the records no longer need to be kept.  
If the responsible Investigator retires, relocates or for other reasons withdraws from the responsibility 
of keeping records, custody must be transferred to a person who will accept the responsibility. The 
Sponsor will be notified in writing of the name and address of the new custodian as soon as possible. 
12.12.Confidentiality 
The Investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. The patient’s identification code and the patient’s 
initials should be recorded on any form submitted to the Sponsor, Sponsor’s designee, or IRB/IEC, 
unless it is forbidden to identify the patient by initials. Where it is forbidden to indicate the patient’s 
initials, only the patient’s identification code and the patient’s year of birth should be recorded. 
The Investigator must keep a screening log showing codes, names and addresses for all patients 
screened and for all patients enrolled into the trial. 
The Investigator agrees that all information received from the Sponsor, including but not limited to the 
Investigator’s Brochure, this protocol, eCRFs and any other study information remain the sole and 
exclusive property of the Sponsor during the conduct of the study and thereafter. This information is 
not to be disclosed to any third party (except with prior written consent from the Sponsor). The 
Investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
IRB/IEC is expressly permitted, the IRB/IEC members having the same obligation of confidentiality. 


Precigen ActoBio T1D, LLC 
Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
This document contains confidential information.  It is intended solely for the use of the principal investigator, co-
investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
bodies. 
AG019-T1D-101 CSP Final 9.0 11-Jun-2020 
Page 91/93 
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Braat H, Rottiers P, Hommes DW et al. A phase I trial with transgenic bacteria expressing 
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Cabrera SM, Rigby MR, Mirmira RG. Targeting regulatory T cells in the treatment of type 1 
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CD4+CD25+ Cell Populations In Vivo and Ameliorates Type 1 Diabetes in Nonobese Diabetic 
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Hagopian W, Ferry RJ, Jr., Sherry N et al. Teplizumab preserves C-peptide in recent-onset type 
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Herold KC, Gitelman S, Greenbaum C et al. Treatment of patients with new onset Type 1 
diabetes with a single course of anti-CD3 mAb Teplizumab preserves insulin production for up 
to 5 years. Clin Immunol 2009; 132(2): 166-173. 


Precigen ActoBio T1D, LLC 
 
Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
This document contains confidential information.  It is intended solely for the use of the principal investigator, co-
investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
bodies. 
AG019-T1D-101 CSP Final 9.0 11-Jun-2020 
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Herold KC, Gitelman SE, Ehlers MR et al. Teplizumab (anti-CD3 mAb) treatment preserves C-
peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: 
metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes 
2013; 62(11): 3766-3774. 
 
Herold KC, Gitelman SE, Masharani U et al. A single course of anti-CD3 monoclonal antibody 
hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical 
parameters for at least 2 years after onset of type 1 diabetes. Diabetes 2005; 54(6): 1763-
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Herold KC, Gitelman SE, Willi SM et al. Teplizumab treatment may improve C-peptide 
responses in participants with type 1 diabetes after the new-onset period: a randomised 
controlled trial. Diabetologia 2013; 56(2): 391-400. 
 
International Hypoglycaemia Study G. Glucose Concentrations of Less Than 3.0 mmol/L (54 
mg/dL) Should Be Reported in Clinical Trials: A Joint Position Statement of the American 
Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 
2017; 40(1): 155-157. 
 
Knip M. Natural course of preclinical type 1 diabetes. Horm Res 2002; 57 Suppl 1: 6-11. 
 
Limaye SA, Haddad RI, Cilli F et al. Phase 1b, multicenter, single blinded, placebo-controlled, 
sequential dose escalation study to assess the safety and tolerability of topically applied 
AG013 in subjects with locally advanced head and neck cancer receiving induction 
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strategies. Clin Immunol 2013; 149(3): 279-285. 
 
Robert S, Steidler L. Recombinant Lactococcus lactis can make the difference in antigen-
specific immune tolerance induction, the Type 1 Diabetes case. Microb Cell Fact 2014; 13 
Suppl 1: S11. 
 
Rottiers P, De Smedt T, Steidler L. Modulation of gut-associated lymphoid tissue functions with 
genetically modified Lactococcus lactis. Int Rev Immunol 2009; 28(6): 465-486. 
 
Sherry N, Hagopian W, Ludvigsson J et al. Teplizumab for treatment of type 1 diabetes 
(Protege study): 1-year results from a randomised, placebo-controlled trial. Lancet 2011; 
378(9790): 487-497. 
 
Steidler L, Hans W, Schotte L et al. Treatment of murine colitis by Lactococcus lactis secreting 
interleukin-10. Science 2000; 289(5483): 1352-1355. 
 


Precigen ActoBio T1D, LLC 
 
Clinical Study Protocol AG019-T1D-101 
Confidentiality Statement 
This document contains confidential information.  It is intended solely for the use of the principal investigator, co-
investigators, staff, appropriate institutional review boards or ethical committees, and other required regulatory 
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Lactococcus lactis for intestinal delivery of human interleukin 10. Nat Biotechnol 2003; 21(7): 
785-789. 
 
Takiishi T, Cook DP, Korf H et al. Reversal of Diabetes in NOD Mice by Clinical-Grade Proinsulin 
and IL-10-Secreting Lactococcus lactis in Combination With Low-Dose Anti-CD3 Depends on 
the Induction of Foxp3-Positive T Cells. Diabetes 2017; 66(2): 448-459. 
 
Takiishi T, Korf H, Van Belle TL et al. Reversal of autoimmune diabetes by restoration of 
antigen-specific tolerance using genetically modified Lactococcus lactis in mice. J Clin Invest 
2012; 122(5): 1717-1725. 
 
Tooley JE, Vudattu N, Choi J et al. Changes in T-cell subsets identify responders to FcR-
nonbinding anti-CD3 mAb (teplizumab) in patients with type 1 diabetes. Eur J Immunol 2016; 
46(1): 230-241. 
 
van Belle TL, Coppieters KT, von Herrath MG. Type 1 diabetes: etiology, immunology, and 
therapeutic strategies. Physiol Rev 2011; 91(1): 79-118. 
 
Waldron-Lynch F, Henegariu O, Deng S et al. Teplizumab induces human gut-tropic regulatory 
cells in humanized mice and patients. Sci Transl Med 2012; 4(118): 118ra112. 
 
 

SAP_001.pdf: 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
A prospective, multi-center, Phase 1b/2a study to assess the safety and tolerability of 
different doses of AG019 administered alone or in association with teplizumab in patients 
with clinical recent-onset Type 1 Diabetes Mellitus (T1D). 
Sponsor Study Code: AG019-T1D-101 
Sponsor 
Precigen ActoBio T1D, LLC 
20374 Seneca Meadows Parkway 
Germantown, MD 20876  
USA 
Product/Compound/Device AG019 
Phase of the study 
EudraCT number 
Author 
Company 
Address 
Phase 1b/2a 
2017-002871-24 
XXX
Senior Biostatistician 
XXX
Telephone number 
Version 
XXX
Final 
Date 28-05-2021


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
2 (22) 
SIGNATURES 
Sponsor Study Code:  
AG019-T1D-101 
Author 
Name, highest 
academic level, job 
title: 
Company 
XXX, Senior Biostatistician 
XXX
Signature: 
Date/time: 
Add time to all dates if on the same 
day as unblinding. 
Reviewing Statistician 
Name, highest 
academic level, job 
title: 
XXX 
Company 
XXX 
Signature: 
Date/time: 
Sponsor Approval 
Name, job title: 
XXX 
Company 
Precigen ActoBio T1D, LLC 
Signature: 
Date/time: 


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
3 (22) 
TABLE OF CONTENTS 
1 
INTRODUCTION ................................................................................................. 6 
2 
STUDY OBJECTIVES ......................................................................................... 6 
2.1 
Primary Objective ................................................................................................ 6 
2.2 
Secondary Objectives .......................................................................................... 6 
3 
EFFICACY AND SAFETY ENDPOINTS .............................................................. 6 
3.1 
Primary Endpoint ................................................................................................. 6 
3.2 
Secondary Endpoints ........................................................................................... 6 
4 
OVERALL STUDY DESIGN................................................................................. 7 
4.1 
Overview of Study Design .................................................................................... 7 
4.1.1 
Phase 1b ............................................................................................................. 7 
4.1.2 
Phase 2a ............................................................................................................. 8 
4.2 
Determination of Sample Size .............................................................................. 8 
5 
DATA SETS TO BE ANALYZED ......................................................................... 9 
6 
STATISTICAL AND ANALYTICAL PLANS .......................................................... 9 
6.1 
Changes in the Planned Analyses ....................................................................... 9 
6.2 
Blind Review ...................................................................................................... 10 
6.3 
Hypotheses and Statistical Methods .................................................................. 10 
6.3.1 
Definitions .......................................................................................................... 10 
6.3.2 
Summary Statistics ............................................................................................ 10 
6.3.3 
Patient/Subject Data Listings ............................................................................. 11 
6.3.4 
Demographic and Other Baseline Characteristics .............................................. 12 
6.3.5 
Pharmacodynamic Assessments ....................................................................... 12 
6.3.6 
Compliance to Treatment ................................................................................... 13 
6.3.7 
Concomitant Medications ................................................................................... 13 
6.3.8 
Adverse Events.................................................................................................. 14 
6.3.9 
Other Safety Assessments................................................................................. 15 
6.4 
Level of Significance, Multiple Comparisons and Multiplicity .............................. 18 
6.5 
Adjustment for Covariates .................................................................................. 19 
6.6 
Handling of Dropouts and Missing Data ............................................................. 19 
6.7 
Multicentre Studies ............................................................................................ 19 
6.8 
Examination of Subgroups ................................................................................. 19 
6.9 
Interim Analysis ................................................................................................. 19 
6.10 
Data Monitoring ................................................................................................. 19 
7 
LIST OF OUTPUT ............................................................................................. 19 
7.1 
Tables to be Produced for the Clinical Study Report (Section 14 according to 
ICH E3) .............................................................................................................. 19 
7.2 
Listings of Individual Patient Data and Other Information to be Produced for the 
Clinical Study Report (Sections 16.1 and 16.2 in ICH E3) .................................. 21 


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
4 (22) 
ABBREVIATIONS 
AE 
Adverse Event 
AG019  
Genetically modified Lactococcus lactis strain sAGX0407 
ALT 
Alaninne Aminotransferase 
ALP 
Alkaline Phosphatase 
AST 
AUC 
BMI 
BUN 
CFU 
CGM 
CMV 
CRO 
Aspartate Aminotransferase 
Area Under the Curve 
Body Mass Index 
Blood Urea Nitrogen 
Colony Forming Units 
Continous Glucose Monitor 
Cytomegalovirus 
Contract Research Organization 
CRF 
CRP 
Case Report Form 
C-Reactive Protein
CSP 
CTCAE 
DSMB 
DSMB-SAP 
EBV 
ECG 
eCRF 
eGRF 
GAD65 
HbA1c 
HBV 
HCV 
HDL 
hIL-10 
HIV 
hPINS 
Clinical Study Protocol
Common Terminology Criteria for Adverse Events
Data Safety Monitoring Board
Data Safety Monitoring Board Statistical Analysis Plan
Eppstein-Barr Virus
Electrocardiogram
Electronic Case Report Form
Estimated Glomerular Filtration Rate
Glutamic Acid Decarboxylase 65
Hemoglobin A1c
Hepatitis B Virus
Hepatitis C Virus
High Density Lipoproteins
Human Interleukin 10
Human Immunodeficiency Viruses
Human Proinsulin
IA-2 
IAP 
Insulinoma-Associated Protein 2
Interim Analysis Plan


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
5 (22) 
ICH 
The International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IDAA1c 
IMP 
INR 
IV 
ITT 
LDH 
LDL 
Insulin dose adjusted HbA1C 
Investigational Medicinal Product 
International Normalized Ratio 
Intravenous 
Intention to Treat 
Lactate dehydrogenase 
Low Density Lipoproteins 
MedDRA 
MCH 
MCHC 
MCV 
MMTT 
PCR 
Medical Dictionary for Regulatory Activities 
Mean Corpuscular Hemoglobin  
Mean Corpuscular Hemoglobin Concentration 
Mean Corpuscular Volume  
Mixed Meal Tolerance Test 
Polymerase Chain Reaction 
PD 
PD-ITT 
PD-PP 
Pharmacodynamic 
Pharmacodynamic Intention To Treat 
Pharmacodynamic Per Protocol 
PK 
PP 
Pharmacokinetic 
Per Protocol 
PT 
RBC 
RDW 
Preferred Term 
Red Blood Cell 
RBC Distribution Width 
SAE 
SAP 
SD 
SEM 
Serious Adverse Event 
Statistical Analysis Plan 
Standard Deviation 
Standard Error of the Mean 
SOC 
TD1 
System Organ Class 
Type 1 Diabetes Mellitus 
TEAE 
TSH 
VLDL 
WBC 
Treatment-Emergent Adverse Event 
Thyroid Stimulating Hormone 
Very Low Density Lipoproteins 
White Blood Cell 
WHO 
ZnT8 
World Health Organization 
Zinc Transporter 8 


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
6 (22) 
1 
INTRODUCTION 
This Statistical Analysis Plan (SAP)  is based on Clinical Study Protocol (CSP) Version 9, 
dated June 10, 2020. This includes all analysis to be performed by XXX. The 
Pharmacokinetic (PK) analysis, the analysis regarding the Mixed Meal Tolerance Test 
(MMTT), the analysis of immune markers and the mechanistic assessments that will be 
performed by other Contract Research Organizations (CROs) are not included. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to assess the safety and tolerability of different doses of 
encapsulated AG019, containing genetically modified Lactococcus lactis (L. lactis) producing 
human proinsulin (hPINS) and human interleukin-10 (hIL-10) (sAGX0407), alone as well as in 
association with teplizumab. 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
•
to obtain pharmacodynamics (PD) data of AG019 alone as well as AG019 in
association with teplizumab,
•
to determine the potential presence of sAGX0407 or its secreted proteins in systemic
circulation (safety – systemic exposure) and the presence of L. lactis bacteria in fecal
excretion (local exposure): pharmacokinetic profile
3 
EFFICACY AND SAFETY ENDPOINTS 
3.1 
Primary Endpoint 
The primary endpoint will be assessed by analysis of the incidence of treatment-emergent 
adverse events (TEAEs) collected up to the 6-month follow-up visit. A TEAE is defined as any 
adverse event (AE) not present prior to the initiation of the treatment(s) or any AE already 
present that worsens in either intensity or frequency following exposure to the treatment(s). 
3.2 
Secondary Endpoints 
The PD activity of the study drug(s) is assessed by measurement of biomarkers in blood and 
serum samples. Relevant parameters are assessed, including immune markers for effect, 
relevant T1D parameters and relevant cytokines. These will be presented by another CRO and 
thus will not be a part of the statistical analysis described in this SAP. This SAP will only discuss 
hemoglobin A1c (HbA1c), insulin use and insulin dose adjusted HbA1c as PD variables 
as these will be analysed by XXX. 
Samples intended for mechanistic assessments are collected from all repeat dose patients in 
AG019 Cohorts 2 and 4, and from all patients in the combination cohorts.  All collected samples 
intended for mechanistic assessments are planned to be analyzed by a central lab and will not 
be a part of the statistical analysis in this SAP.  


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
7 (22) 
Following parameters are assessed for analysis of systemic and local exposure to L. lactis (PK 
profile): 
•
Presence of live L. lactis clinical strain bacteria in whole blood
•
Measurable serum levels of human interleukin 10 (hIL-10) and human proinsulin
(hPINS)
•
Presence of L. lactis clinical strain bacteria  in fecal excretion
The PK profile will be presented by Precigen Actobio so PK will not be a part of this SAP. 
Safety information collected at all other time points (all Adverse Events (AEs), laboratory 
variables, vital signs, physical examination, electrocardiogram (ECG), viral status, 
hypoglycemic 
events, 
hyperglycemic 
events, 
study 
drug 
accountability 
and 
concomitant medication) will be assessed as secondary endpoints and analysed by XXX. 
4 
OVERALL STUDY DESIGN 
4.1 
Overview of Study Design 
This Phase 1b/2a, multi-center study is conducted in patients with clinical recent-onset Type 1 
Diabetes Mellitus (T1D).  
AG019 is the genetically modified L. lactis, strain sAGX0407, containing the gene sequences 
coding for hPINS and hIL-10, and comprising an environmental containment system, 
formulated for oral administration as gastro-resistant hard capsules. 
In addition to the scheduled 19 clinic visits, all patients were asked to keep a diary for collection 
of information relating to the study drug intake, concomitant medication intake, occurrence of 
AEs including hypoglycemic and hyperglycemic events, and insulin use. A detailed schedule 
on the measurements for each visit can be found in the Appendix A to the CSP. Information 
on when the measurements were planned to be collected can also be found under each 
subsection in this SAP.  
Eight (8) single dose patients and a maximum of 48 repeat dose patients were allowed to be 
enrolled in clinical sites in the US and Belgium. AG019 was administered twice daily for 8 
weeks at either a low dose (2 capsules/d) or at a high dose (6 capsules/d). This study consists 
of 2 phases and 6 cohorts. All repeat dose patients in all cohorts described below will be 
followed up for a total of 12 months (8 weeks of treatment plus 10 months of post-treatment 
follow-up). 
4.1.1 
Phase 1b 
This open-label part of the study will investigate the safety and tolerability of different doses of 
AG019, in 2 age groups (18-42 years of age and 12-17 years of age, respectively), 
administered as single or repeat doses. Patients were enrolled in 4 sequential cohorts (AG019 
cohorts): 
•
AG019 Cohort 1: 2 capsules per day, patients  18-42 years
•
AG019 Cohort 2: 6 capsules per day, patients 18-42 years
•
AG019 Cohort 3: 2 capsules per day, patients 12-17 years
•
AG019 Cohort 4: 6 capsules per day, patients 12-17 years


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
8 (22) 
Single dose patients 
In every AG019 cohort, 2 single dose patients were enrolled in a first stage. Each of 
these patients were treated for 1 day with AG019 (2 or 6 capsules of XXX Colony Forming 
Units [CFU], depending on the cohort), and were followed up for a total of 4 days 
(treatment day [Day 1] plus 3 additional days), after which they had completed their study 
participation (Day 4).  
Repeat dose patients 
A minimum of 4 repeat dose patients were enrolled per AG019 cohort. In addition, both single 
dose patients in each AG019 cohort were offered the option of being re-enrolled as repeat 
dose patients in the same AG19 cohort. Therefore, if both single dose patients agree to be re-
enrolled as repeat dose patients, the maximum number of repeat dose patients per cohort 
were 6. All repeat dose patients were planned to be treated for 8 weeks with AG019 and 
followed up for a total of 12 months (8 weeks of treatment plus 10 months of post-treatment 
follow-up).  
4.1.2 
Phase 2a 
The Phase 2a double-blind portion of the study will investigate the safety and tolerability of 
AG019, in association with intravenous (IV) teplizumab in 2 cohorts (“combination cohorts”) of 
12 patients. Each patient is planned to be administered 6 capsules daily of AG019 (or placebo) 
for 8 weeks, in association with daily IV infusions of teplizumab (or placebo) for the first 12 
days of the 8-week treatment period.  
•
Combination Cohort 1: 12 patients (18-40 years) received AG019 (6 capsules per
day, 8 weeks) plus teplizumab (daily infusions, 12 days), or matching placebo capsules
and placebo infusions
•
Combination Cohort 2: 12 patients (12-17 years) received AG019 (6 capsules per
day, 8 weeks) plus teplizumab (daily infusions, 12 days), or matching placebo capsules
and placebo infusions
Within each of these combination cohorts, the first 2 enrolled patients were treated with active 
treatment (AG019 plus teplizumab) in an open label fashion. Patients 3-12 were randomized 
(4:1) to receive double active treatment or double placebo in a double-blind fashion.  
4.2 
Determination of Sample Size 
In total, 8 single dose patients and up to 48 repeat dose patients were planned to be enrolled. 
This is a preliminary study designed to provide information to be used in the design of 
subsequent studies. This study is descriptive in nature and is not designed to provide analytical 
results regarding efficacy. As such, the sample size is not based on statistical considerations, 
rather it is believed that at least 4 patients per dose level in the AG019 cohorts and 12 patients 


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
9 (22) 
in the combination cohorts will provide sufficient data to evaluate preliminary safety and activity 
of the Investigational Medicinal Products (IMP) as administered in the protocol. 
Patients who discontinued after entry into the treatment phase were allowed to be replaced if 
approved by the Sponsor.  
5 
DATA SETS TO BE ANALYZED 
The following analysis sets will be used for the statistical analysis and presentation of data: 
•
The Safety (SAF) Analysis Set. The safety population will include all patients who
received at least one dose of AG019. Only patients with clear documentation that no
study medication was received may be excluded from analysis. Patients will be
analyzed according to dose received. This population will be used for all data
summaries.
•
The Pharmacodynamic Intention To Treat (PD-ITT) Analysis Set. All patients in the
repeat dose and combination cohorts who received at least one dose of AG019  will be
included in the PD-ITT analysis set.
•
The Pharmacodynamic Per Protocol (PD-PP) Analysis Set. All data from patients
in the repeat dose and combination cohorts who received at least 75% of the scheduled
doses of AG019* and at least one dose of teplizumab in the combination cohorts and
had no major protocol deviations affecting the main PD endpoints at the time point of
data collection** will be included in the PD-PP analysis set.
* XXXXXXXXXXXXXXXXXX
** XXXXXXXXXXXXXXXXXX 
All patients to be included in the PD-ITT and PD-PP Analysis sets will be determined before 
data base lock. The Safety Set is considered the primary analysis dataset, and will be used for 
safety presentations and all other data summaries (except for PD summaries). All 
summaries will be performed according to dose received. Baseline presentations will be 
based on the safety set.  
6 
STATISTICAL AND ANALYTICAL PLANS 
The planned tables and listings are presented in Section 7. 
6.1 
Changes in the Planned Analyses 
 There has been no changes to the planned analyses. 


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
10 (22) 
6.2 
Blind Review 
Details regarding a blind review of data will be specified in the Pre-Analysis Review Form. 
6.3 
Hypotheses and Statistical Methods 
6.3.1 
Definitions 
Baseline 
Visit 1 is defined as the baseline visit, however if a measurement is retaken at 
Visit 2 before dosing this will be used as the baseline value instead of the Visit 
1 value. This concerns laboratory measurements, vital signs, physical 
examination and concomitant medication (including insuline use). For fasting 
glucose baseline is defined as the average of the -10 minute and 0 minute 
values at screening (Visit 1).  
Difference from baseline 
The difference from baseline is defined as the difference from the baseline 
according to the definition above.   
Relative day The relative day of an event is derived as: 
Relative day = (Start date) - (Date of first administration of IMP) + 1 
For events occurring or starting before the date of first administration of IMP, 
the relative day is derived as: 
Relative day = (Start date) - (Date of first administration of IMP) 
In this way, there will be no Day 0. Day 1 is the same day as the day of first 
administration of IMP, and Day -1 is the day before. 
TEAE  
A TEAE is defined as any adverse event (AE) not present prior to the initiation 
of the treatment(s) or any AE already present that worsens in either intensity or 
frequency following exposure to the treatment(s). 
6.3.2 
Summary Statistics 
Descriptive statistical methods will be used to summarize the data from this study. 
Unless stated otherwise, the term descriptive statistics refers to number of patients (n), mean, 
median, standard deviation (SD), standard error of the mean (SEM), minimum and maximum 
for continuous data and counts and percentages for categorical data.  
Summary statistics will be presented per cohort (based on age group and number of capsules), 
treatment group and assessment time and/or visit, as applicable. The groups will be divided 
into single dose for 2 and 6 capsules, repeat dose for 2 and 6 capsules, Active and Placebo. 
See Table 1 for details. 


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
11 (22) 
Table 1 
Cohort 
Treatment 
Number of AG019 
capsules per day 
Total 
Number of 
teplizumab 
infusions 
Age Group 
AG019 Cohort 1 
AG019, single dose 2 
NA 
Adults 
AG019 Cohort 1 
AG019, 
repeat 
dose 
2 
NA 
Adults 
AG019 Cohort 2 
AG019, single dose 6 
NA 
Adults 
AG019 Cohort 2 
AG019, 
repeat 
dose 
6 
NA 
Adults 
AG019 Cohort 3 
AG019, single dose 2 
NA 
Adolescents 
AG019 Cohort 3 
AG019, 
repeat 
dose 
2 
NA 
Adolescents 
AG019 Cohort 4 
AG019, single dose 6 
NA 
Adolescents 
AG019 Cohort 4 
AG019, 
repeat 
dose 
6 
NA 
Adolescents 
Combination 
Cohort 1 
AG019, 
repeat 
dose + teplizumab 
infusion 
6 
12 
Adults 
Combination 
Cohort 1 
Placebo capsules, 
repeat dose +  
Placebo infusion 
6 
12 
Adults 
Combination 
Cohort 2 
AG019, 
repeat 
dose + teplizumab 
infusion 
6 
12 
Adolescents 
Combination 
Cohort 2 
Placebo capsules, 
repeat dose +  
Placebo infusion 
6 
12 
Adolescents 
NA: not applicable 
6.3.3 
Patient/Subject Data Listings 
Data collected in the Case Report Forms (CRFs) will generally be listed in Appendix 16.2 (see 
section 7.2). CRF check questions [e.g. Lab samples taken (Yes/No)] and reminders will not 
always be listed. 
Listings will be sorted by cohort, treatment group and patient number and parameter and 
visit/time point as applicable. 
In CRF modules where a date is recorded, the date and the relative day will be included in the 
corresponding listing. In modules where both a start date and stop date are recorded, the 
duration will be given. 


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021
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Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
12 (22) 
6.3.4 
Demographic and Other Baseline Characteristics 
Demographic data and baseline characteristics will include: 
-
age
-
sex
-
ethnicity
-
weight and body mass index (BMI)
-
insulin use (%) and numbers of units per kilo body weight,
-
baseline HbA1c, and insulin dose adjusted according to baseline HbA1c
-
presence of Glutamic Acid Decarboxylase 65 (GAD65) antibodies, Insulinoma-
Associated Protein 2 (IA-2) antibodies, zinc transporter 8 (ZnT8) antibodies and
insulin antibodies
-
Infectious diseases: Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), human
immunodeficiency viruses (HIV), Hepatitis B (HBV) and Hepatitis C (HCV)
-
time from diagnosis to study treatment start
-
time from insulin start to treatment start
-
tobacco, alcohol and illicit drug consumption
Subject disposition, demographic data and other baseline data will be presented using 
summary statistics.  
Some data as laboratory measurements, vital signs and physical examination are measured 
at baseline, but also at other visits. Baseline data for these parameters will be presented 
together with the rest of the data in by-visit displays. Physical examination included visual 
inspection of skin, examination of eyes, ears and throat, auscultation of heart, lungs and 
abdomen, and percussion/palpation of abdomen. 
The medical history comprises a general medical history (including history of alcohol abuse, 
illicit drug abuse and smoking history), relevant T1D related medical history (including date of 
diabetes diagnosis, relevant glycaemia levels, autoantibody positivity, current insulin use and 
start date of insulin therapy as applicable) and medication history.  
6.3.5 
Pharmacodynamic Assessments 
Throughout the study, following metabolic outcome assessments were performed: 
•
Hemoglobin A1c (HbA1C) at Visit 1 and Visit 15-19
•
Insulin dose adjusted HbA1C (IDAA1c): insulin dose adjusted measurement of glycemic
control calculated as:
HbA1c (%) + [4 x insulin dose (IU/Kg/24h)]. The last collected value of insulin dose 
will be used for Visit 1-13 and the average for the 3 days before each visit will be 
used for Visit 14-19 
Summary statistics, graphs and listings will be given for the PD variables. 
In addition summary statistics for insulin dose per body weight (IU/kg) will be shown per visit. 
For Visit 14-19 the average use the 3 days before the visit will be used. 


Statistical Analysis Plan 
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Date: 28-05-2021
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EudraCT No.: 2017-002871-24 
13 (22) 
6.3.6 
Compliance to Treatment 
Compliance to AG019 and teplizumab will be calculated, separately. 
All patients in the repeat dose cohorts, and all patients in the combination cohorts who are 
randomized to study treatment, were planned to be treated for 8 weeks (56 days) with either 2 
or 6 capsules (low or high dose) of AG019. 
All patients in the combination cohorts were planned to be treated for 12 days with teplizumab 
or teplizumab placebo (daily IV infusions for at least 30 minutes) in addition to their 
AG019/placebo treatment. 
Each patient was instructed to return all used and unused study drug at each visit during the 
active treatment period and at the end of the treatment phase. A count of the used and unused 
capsules was performed to assess compliance. Teplizumab (or corresponding placebo) 
accountability and compliance were verified at every follow-up visit by the site staff. 
AG019 compliance will be calculated as the percentage of total doses received / total planned 
doses that were actually taken x 100. For single dose patients the planned total doses were 2 
or 6 capsules. For patients in the repeat cohorts dosed with 2 capsules/day the total planned 
amount was 112 capsules. For patients in the repeat cohorts dosed with 6 capsules/day and 
patients in the combination cohorts (which were also dosed with 6 capsules/day) the total 
planned amount was 336 capsules. 
Teplizumab compliance will be calculated as the percentage of days teplizumab infusion was 
given of the planned 12 days. Incomplete infusions will be calculated as given for that day.  
Compliance to AG019 and teplizumab will be tabulated with summary statistics for the safety 
set. All individual data will be listed. 
6.3.7 
Concomitant Medications 
All concomitant medications/therapies (including insulin medication) will be classified 
according to ATC level 3 group text and World Health Organization (WHO) Drug Dictionary 
preferred name. The medications will be divided into two timing categories based on start date 
and end date: Prior and Concomitant Medications: 
-
Prior Medications: start date and end date before first day of IMP
-
Concomitant Medications:
o
Start date before first day of IMP and end date after or on same day as first day
of IMP or no end date, i.e. ongoing after first day of IMP; or
o
Start date after or on same day as first day of IMP
If the date for a concomitant medication is completely missing, it will be assumed that the 
medication was started before treatment and classified as Prior Medication. If the year and/or 
month are available, medication start in relation to the first day of IMP will be evaluated as far 
as possible (e.g., if only the year when the medication was started is available and ongoing is 
checked, the medication will be classified as a Concomitant Medication). If the medication was 
started in the same month as the first day of IMP, the medication will be classified as a 


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
14 (22) 
Concomitant Medication. Relative day will not be calculated for medications with incomplete 
dates. 
The concomitant medications will be presented in a summary table according to timing in 
relation to IMP (i.e., Prior and Concomitant). Each subject will only be counted once for each 
medication and timing category, on a preferred name level.  
One list for each timing category (Prior and Concomitant) will be presented. 
6.3.8 
Adverse Events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
system. 
The severity of adverse events will be given in grades 1 to 5 per National Cancer Institute 
common terminology criteria for adverse events (CTCAE) version 4.0. 
All AEs were categorized by the Investigator with respect to their possible relationship to the 
IMP. The relationship of the AE to AG019, as well as the relationship of the AE to 
teplizumab, will be assessed separately by the investigator to be not related, unlikely, 
possible, probable or definite.  The categorization:  
•
reasonably related defined as possible, probable or definite versus
•
not reasonably related defined as not related or unlikely will be given in summaries of
all adverse events.
If a subject has more than one event with the same preferred term (PT), then the worst severity 
and the worst relationship will be used.  
A TEAE is defined as any adverse event (AE) not present prior to the initiation of the 
treatment(s) or any AE already present that worsens in either intensity or frequency following 
exposure to the treatment(s). Hence, events with an onset time at or after the time of treatment 
start are treatment emergent. Events present at baseline that worsen during the study in either 
intensity of frequency are also treatment emergent, whereas events present at baseline that 
become less severe during the study are not. Events that recur during the study are treatment 
emergent if they recur after complete or partial recovery of the initial event, i.e. should the 
event first become less severe and then return to its initial severity, it will be considered as a 
TEAE. AEs reported on the same day as treatment start or after treatment start will be 
considered TEAEs, as investigators are instructed only to report TEAEs after treatment start.  
A Serious Adverse Event (SAE) is defined as any AE occurring at any dose regardless of 
relationship to IMP that results in any of the following outcomes: 
•
results in death,
•
is life-threatening,
•
requires inpatient hospitalisation or prolongation of existing hospitalisation,
•
results in persistent or significant disability/incapacity, or
•
is a congenital anomaly/birth defect.
If the start date of an AE is missing, it will be assumed that the AE started after the first 
administration of IMP. If the start date of an AE is partially missing, and it has started the same 
year and/or month as the IMP it will be assumed that the AE started after the first administration 
of IMP. If an AE occurred on the same day as dosing but the onset time is missing the AE will 
be assumed to be a TEAE. 


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
15 (22) 
The infusion of teplizumab was considered withheld if the answer to the CRF question ‘Was 
the Teplizumab infusion given?” was ‘No, infusion not started’ and/or if the answer on the AE 
page on ‘Action Taken With Study Treatment Teplizumab’ was ‘Drug interrupted’ or ‘Drug 
withdrawn’. 
Study treatment of AG019 was considered discontinued if the answer to the CRF question 
“Action Taken with Study Treatment AG019” was “Drug interrupted” or “Drug withdrawn”. 
A summary table per cohort will present number of TEAEs, number of unique TEAEs (counted 
once within each subject at the preferred term level) and number of subjects with at least one 
event for TEAEs, SAEs, related TEAEs, TEAEs leading to discontinuation of IMP/withdrawal 
and more.  
Tables with 
•
All AEs by System Organ Class (SOC) and PT,
•
All TEAEs by SOC and PT, in total and for the AG019 treatment period only,
•
All TEAEs by SOC and PT according to severity, in total and for the AG019 treatment
period only,
•
All TEAEs by SOC and PT according to relatedness, in total and for the AG019
treatment period only,
•
All serious TEAEs by SOC and PT,
will be given. If there are no events an empty table will be produced. 
All AEs will be listed. In addition all TEAEs leading to AG019 treatment discontinuation and 
study infusion withholding will be listed.  
6.3.9 
Other Safety Assessments 
Vital Signs 
For repeat dose patients, weight, sitting blood pressure, heart rate, respiratory rate and body 
temperature will be measured at Visit 1, 2, 5, 8, 13-19. Height is measured at Visit 1. For single 
dose patients vital signs will be measured at screening, treatment and post treatment. 
For all vital signs parameters summary statistics will be produced for observed values. In 
addition, the difference from baseline to each visit at which they were assessed will be derived 
and presented.  
Shift tables showing the number of subjects who changed from normal, abnormal not clinical 
significant or abnormal clinical significant at baseline to normal, abnormal not clinical significant 
or abnormal clinical significant at each post-baseline time of assessment will be presented. 
All vital signs will be listed. 
Clinical Laboratory Measurements 
From screening to the last visit lab parameters will be collected, see CSP Appendix A for 
details.  
Parameters to be analysed will include: 


Statistical Analysis Plan 
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16 (22) 
•
Hematology: complete blood count: Red Blood Cell (RBC) count, haemoglobin,
haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH),
mean corpuscular haemoglobin concentration (MCHC), RBC distribution width (RDW),
white blood cell (WBC) count, differential count, platelet count
•
Serum 
Chemistry: 
blood 
glucose, 
sodium, 
potassium, 
chloride, 
calcium,
CO2/bicarbonate
•
Liver function tests: alkaline phosphatase (ALP), Aspartate Aminotransferase (AST),
Alanine Aminotransferase (ALT), lactate dehydrogenase (LDH), total protein, albumin,
total bilirubin
•
Pregnancy tests for women of childbearing potential: serum (at screening), urine (at
other visits)
•
Coagulation tests: international normalized ratio (INR)
•
Inflammatory: C-reactive protein (CRP)
Following additional blood parameters will be analysed at screening, and if no concerns are 
identified, these parameters will not require analysis at follow-up visits: 
•
Kidney function tests: uric acid, urea/blood urea nitrogen (BUN), creatinine, estimated
glomerular filtration rate (eGFR)
•
Cardiovascular tests: total cholesterol, triglycerides, high density lipoproteins (HDL),
low density lipoproteins (LDL), very low density lipoproteins (VLDL - optional)
•
Thyroid stimulating hormone (TSH)
In addition to the above lab assessments to be analysed by the site’s local lab, 
EBV/CMV/HCV/HBV/HIV monitoring assessments will be done. These measurements were 
performed at screening for all patients and at Visit 13-16, Visit 19 for repeat dose patients. 
Potential reactivation will be assessed at regular intervals by polymerase chain reaction (PCR) 
for viral load.  
For hematology, clinical chemistry, liver function, coagulation parameters and CRP summary 
statistics will be produced for observed values. In addition, the difference from baseline to each 
visit at which they were assessed will be derived and presented.  
Shift tables showing the number of subjects who changed from normal, abnormal not clinical 
significant or abnormal clinical significant at baseline to normal, abnormal not clinical significant 
or abnormal clinical significant at each post-baseline time of assessment will be presented. 
Figures showing mean and median values over time per chohort will be shown for CRP, AST 
and lymphocytes. 
Number of patients with positive/negative serology at baseline and positive/negative for PCR 
per visit will be tabulated. 
All laboratory parameters will be listed. Abnormal values will be flagged in listings. 
In addition, all study patients (except for the single dose patients) will receive a XXX 
continuous glucose monitor (CGM) device for the entire duration of their study participation. 
The data generated by the device will be downloaded at every site visit. The devices will store 
data for up to 30 days. The device measures glucose every 5 minutes, thus every 
measurement will be said to have a duration of 5 minutes when the calculation of total duration 
is performed. The first measurement is said to measure the glucose value 5 minutes before 
the actual measurement. For the CGM data collected at each visit: 


Statistical Analysis Plan 
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17 (22) 
-
The total CGM recording time,
-
Time in range (the time greater than or equal to 71 mg/dl and less than or equal to
179 mg/dl),
-
Time above range (the time above 179 mg/dl),
-
Time in the low range (the time below 71 mg/dl),
-
Time in the very low range (the time below 50 mg/dl) and
-
Time with missing values
will be summarized in hours/minutes and percentages of the total CGM recording time, per 
cohort. 
Physical Examination 
The physical examination included visual inspection of skin, examination of eyes, ears and 
throat, auscultation of heart, lungs and abdomen, and percussion/palpation of abdomen. The 
results will be recorded as  
•
Normal,
•
Abnormal Not Clinically Significant or
•
Abnormal Clinically Significant.
For repeat dose patients the physical examination will be performed at Visit 1, 2, 5, 8, 13-19. 
For single dose patients the physical examination will be performed at screening, treatment 
and post treatment. 
The frequencies (and percentage) of normal, abnormal but not clinically significant or abnormal 
and clinically significant will be tabulated.  
Physical Examination data will be listed. 
ECG 
The investigator will perform a 12-lead ECG. The results will be recorded as 
•
Normal,
•
Abnormal Not Clinically Significant or
•
Abnormal Clinically Significant.
For single dose patients ECG status will be collected at screening (Visit 1) and at post 
treatment only if there is a suspicion of cardiac problems. For repeat dose patients ECG status 
will be collected at Visit 1, Visit 15, Visit 19 and in addition at Visit 17 if there is a suspicion of 
cardiac problems. 
The frequencies (and percentage) of normal, abnormal but not clinically significant or abnormal 
and clinically significant will be tabulated.  
ECG data will be listed. 


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
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Study Code: AG019-T1D-101 
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18 (22) 
Hypoglycemic events 
Hypoglycemic events will be documented in the patient diary. Events of hypoglycemia will be 
classified as outlined below. 
•
hypoglycemia Level 1: A glucose alert value of 3.9 mmol/l (70 mg/dl) or less for at least
20 minutes
•
hypoglycemia Level 2: A glucose level of <3.0 mmol/l (<54 mg/dl), sufficiently low to
indicate serious, clinically important hypoglycemia.
•
hypoglycemia Level 3: Severe hypoglycemia, as defined by the American Diabetes
Association, denoting severe cognitive impairment requiring external assistance for
recovery.
For the purposes of this study, hypoglycemia events classified as level 1 will not be recorded 
separately on the hypoglycemia event electronic case report form (eCRF), unless the 
investigator feels that the event is medically important. Hypoglycemia events level 2 and 3 will 
be recorded separately on the hypoglycemia event eCRF. The evaluation that produced the 
value or result should be repeated until that value or result returns to normal or can be 
explained and the participant’s safety is not at risk. In addition, all hypoglycemia events 
meeting the definition of SAE should be recorded as serious adverse events in the eCRF.  
Time of the events will be divided in the following time periods: 
•
Pre-treatment: all events until the day before treatment start
•
During treatment: all events reported on the day of treatment start (Day 1) and up to
the last treatment day
•
Post-treatment: all events reporter after the last treatment day
The number of hypoglycemic events and patients with hypoglycemic events will be 
summarized per cohort, treatment, level and time period.  
All hypoglycemic events recorded in the eCRF will be listed. Relative day to treatment start will 
be included in the listing. 
Hyperglycemic events 
Major hyperglycemic events will be defined and graded as follows: 
•
Grade 4 = coma or life-threatening event or event resulting in hospitalization.
•
Grade 5 = death.
For this study diabetic ketoacidosis should be reported as grade 4 hyperglycemia (a single 
adverse event) resulting in hospitalization and/or life threatening consequences. 
Hyperglycemic events will be collected and presented as SAEs with no separate tabulation. 
See section 6.3.9 for futher details on presentation. 
6.4 
Level of Significance, Multiple Comparisons and Multiplicity 
The primary objective of this study is to assess safety and tolerability of AG019. The study is 
descriptive in nature and is not designed to provide analytical results regarding efficacy.  


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
19 (22) 
6.5 
Adjustment for Covariates 
Not applicable as the output will contain no statistical analyses. Summary tables will show 
changes from baseline. 
6.6 
Handling of Dropouts and Missing Data 
The data will be analysed as is except for missing dates for concomittant medication and 
adverse event, see those sections. 
6.7 
Multicentre Studies 
Since this is only a small study primarily focused on safety no site or country effect will be 
studied.  
6.8 
Examination of Subgroups 
No examination of subgroups is planned. 
6.9 
Interim Analysis 
Preliminary results (interim analysis 1) for the open-label part of the study and a second interim 
analysis (described in the Interim Analysis Plan [IAP]) has been performed previously. 
The primary analysis will be performed when all patients have passed the Day 180 visit. This 
interim analysis will contain the same TFLs that will be produced for the final output, if possible. 
All decisions on data for blinded subjects will be taken before breaking the blind for the third 
interim analysis. Since this is a study of descriptive nature, with no statistical tests, the 
influence of the interim analyses should be considered negligible. 
6.10 
Data Monitoring 
A Data Safety Monitoring Board (DSMB) has reviewed the eCRF-reported safety related 
data for all enrolled patients at predefined time points.  
7 
LIST OF OUTPUT 
7.1 
Tables to be Produced for the Clinical Study Report (Section 14 according to 
ICH E3) 
(Table numbers refer to section numbers in ICH E3) 
14.1 DEMOGRAPHIC DATA 
(Baseline presentations will be based on the safety set if not otherwise stated below) 
•
Subject Disposition in Analysis Sets and Reason for Exclusion (all included subjects)
•
Subject Discontinuation (all included subjects)
•
Screening Failures including Reasons for Failure
•
Demographics (age, sex and ethnicity)


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
20 (22) 
•
Background Characteristics (% of patients on insulin, HBA1c, insuline adjusted HBA1c,
time from diagnosis to treatment start, EBC, CMV, HIV, HBV, HCV, GAD65 antibodies,
IA-2 antibodies, ZnT8 antibodies and insulin antibodies)
•
Weight, BMI and use of tobacco, alcohol and illicit drugs
•
Baseline insulin use (dose in IU/kg and time from insulin start to treatment start)
14.2 EFFICACY DATA 
Pharmacodynamic Assessments: 
Summary statistics for absolute values and change from baseline for (PD Analysis Set): 
•
HbA1c
•
Insuline dose adjusted HbA1c
Summary statistics for insulin use per kg body weight per visit (PD Analysis Set) 
Pharmacodynamic Assessments - Figures: 
•
Average HbA1c
•
Individual HbA1c values (spaghetti plots)
•
Average insulin dose adjusted HbA1c
•
Individual insulin dose adjusted HbA1c (spaghetti plots)
14.3 SAFETY DATA  
(Safety presentations will be based on the safety set unless otherwise stated below) 
14.3.1.x 
Summary of All Adverse Events for single dose AG019 patients 
14.3.1.x 
Summary of All Adverse Events for repeat dose AG019 patients 
14.3.1.x 
Summary of All Adverse Events for combination cohort patients 
14.3.1.x 
All Adverse Events by System Organ Class and Preferred Term 
14.3.1.x 
Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term  
14.3.1.x 
Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term during AG019 treament period  
14.3.1.x 
Treatment-Emergent Adverse Events by Severity, System Organ Class and 
Preferred Term    
14.3.1.x 
Treatment-Emergent Adverse Events by Severity, System Organ Class and 
Preferred Term during AG019 treatment period    
14.3.1.x 
Treatment-Emergent Adverse Events by Relationship to AG019, System Organ 
Class and Preferred Term    
14.3.1.x 
Treatment-Emergent Adverse Events by Relationship to AG019, System Organ 
Class and Preferred Term during AG019 treatment period    


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
21 (22) 
14.3.1.x 
Treatment-Emergent Serious Adverse Events by System Organ Class and  
Preferred Term  
14.3.1.x 
Treatment-Emergent Adverse Events Leading to Premature AG019 Treatment 
Discontinuation by System Organ Class and Preferred Term 
14.3.4.x 
Laboratory Measurements: 
Summary Statistics by Visit with Difference from Baseline (Hematology & INR, 
Clinical Chemistry, Liver Function & CRP and HbA1c)  
Shift Tables  (Hematology & INR, Clinical Chemistry, Liver Function & CRP) 
Figures of mean and median CRP, AST and Lymphocytes over time 
Number of patients with positive/negative serology at baseline and 
positive/negative for PCR per visit 
Summary of CGM Recording Time 
14.3.5 
Compliance to treatment with AG019 
Compliance to treatment with teplizumab 
14.3.6.x 
Vital Signs: 
Summary Statistics with Difference from Baseline 
Shift Tables 
14.3.7.x 
Physical Examination per visit and treatment  
14.3.8.x 
ECG per visit and treatment 
14.3.9.x 
Summary of Hypoglycemic Events 
14.3.10.x 
Concomitant Medication and Therapy (including insulin medication) 
•
Prior Medications and Therapies
•
Concomitant Medications and Therapies
7.2 
Listings of Individual Patient Data and Other Information to be Produced for the 
Clinical Study Report (Sections 16.1 and 16.2 in ICH E3) 
(Listing numbers refer to the relevant appendix number in ICH E3. CRF check 
questions/reminders will not be listed.) 
16.2.1.x 
Discontinued Patients, Reason for Discontinuation 
Visit Dates and AG019 Treatment End Date 
16.2.2 
Protocol Deviations  
16.2.3.x 
Patients Excluded from the Pharmacodynamic Analysis 
(Evaluability, Reason for Evaluability Classification) 
Treatment Allocation and Evaluability for All Subjects 


Statistical Analysis Plan 
Version: Final 
Date: 28-05-2021 
Sponsor: Precigen ActoBio T1D, LLC 
Study Code: AG019-T1D-101 
EudraCT No.: 2017-002871-24 
22 (22) 
16.2.4.x 
Demographics and Other Background Characteristics 
Medical History 
History of T1D (diagnosis and insulin use) 
Smoking, Alcohol and Illicit Drug Use 
Inclusion Criteria Not Met and Exclusion Criteria Met 
16.2.5.x 
Compliance to treatment with AG019 
Compliance to treatment with teplizumab 
16.2.6.x 
Pharmacodynamic Measurements:  
•
HbA1c
•
Insulin dose adjusted HbA1c
16.2.7.x 
Adverse Events  
Adverse Events for patients with infusion withholding 
16.2.8.x 
Listing of Individual Laboratory Measurements  
16.2.9.x 
Vital Signs  
16.2.10.x 
Physical Examination 
16.2.11.x 
ECG 
16.2.12.x 
Concomitant Medication and Therapy (including insulin medication) 
•
Prior Medications and Therapies
•
Concomitant Medications and Therapies
16.2.13.x 
Hypoglycemic Events