A Randomized, Double-blind, Placebo-controlled Study of the Safety, Pharmacodynamics, Efficacy, and Pharmacokinetics of TIMP-GLIA in Subjects With Well-controlled Celiac Disease Undergoing Oral Gluten Challenge
Phase: PHASE2
Conditions: Celiac Disease
Sponsor: Takeda

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Title: A randomized, double-blind, placebo-controlled study of the safety, pharmacodynamics, 
efficacy, and pharmacokinetics of TIMP-GLIA in subjects with well-controlled celiac disease 
undergoing oral gluten challenge. 
NCT Number: NCT03738475
Protocol Approve Date: 10 December 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

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COUR Pharmaceuticals Development Company 
TGLIA-5.002 
IND #: 17579 
Version 2.0 
10 December 2018 
Page 2 of 62 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ..................................................................................................5 
INVESTIGATOR SIGNATURE PAGE......................................................................................6 
SYNOPSIS ......................................................................................................................................7 
LIST OF ABBREVIATIONS .....................................................................................................12 
1 
INTRODUCTION............................................................................................................14 
1.1 
Background on Indication ..................................................................................................14 
1.2 
Limitations of Current Treatments .....................................................................................14 
1.3 
TIMP-GLIA .......................................................................................................................15 
1.4 
Nonclinical Pharmacology and Toxicology Studies ..........................................................15 
1.4.1 Nonclinical Models of Antigen-Specific Immune Tolerance ................................15 
1.4.2 Pharmacokinetics ...................................................................................................16 
1.4.3 Toxicology .............................................................................................................16 
1.5 
Clinical Trials of TIMP-GLIA ...........................................................................................17 
2 
OBJECTIVES AND ENDPOINTS ................................................................................19 
2.1 
Objectives ..........................................................................................................................19 
2.1.1 Primary Objective ..................................................................................................19 
2.1.2 Secondary Objectives.............................................................................................19 
2.2 
Endpoints ...........................................................................................................................19 
2.2.1 Pharmacodynamic Endpoints .................................................................................19 
2.2.2 Histology Endpoints...............................................................................................19 
2.2.3 CD Signs and Symptoms: ......................................................................................19 
2.2.4 Pharmacokinetic Endpoints ...................................................................................20 
2.2.5 Safety Endpoints ....................................................................................................20 
3 
STUDY DESIGN ..............................................................................................................21 
3.1 
Overall Study Design .........................................................................................................21 
3.2 
Rationale for Study Design ................................................................................................21 
3.2.1 General Design Issues ............................................................................................21 
3.2.2 Selection of Population ..........................................................................................22 
3.2.3 Selection of Dose ...................................................................................................22 
3.3 
Date Monitoring Committee ..............................................................................................22 
3.4 
Subject Participation and Study Duration ..........................................................................22 
4 
SUBJECT POPULATION ..............................................................................................23 
4.1 
Inclusion Criteria ...............................................................................................................23 
4.2 
Exclusion Criteria ..............................................................................................................23 
4.3 
Subject and Study Discontinuation ....................................................................................25 
4.3.1 Screening Failures ..................................................................................................25 
4.3.2 Premature Discontinuation from Investigational Product ......................................25 
4.3.3 Premature Discontinuation from Study .................................................................25 
4.3.4 Replacement of Subjects ........................................................................................26 
4.3.5 Study or Site Termination ......................................................................................26 
5 
INVESTIGATIONAL PRODUCT.................................................................................27 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

COUR Pharmaceuticals Development Company 
TGLIA-5.002 
IND #: 17579 
Version 2.0 
10 December 2018 
Page 3 of 62 
5.1 
TIMP-GLIA .......................................................................................................................27 
5.1.1 Packaging and Labeling .........................................................................................27 
5.1.2 Storage ...................................................................................................................27 
5.2 
Placebo ...............................................................................................................................27 
5.3 
Preparation of Investigational Product ...............................................................................27 
5.4 
Blinding and Unblinding....................................................................................................27 
5.5 
Administration of Investigational Product .........................................................................28 
5.6 
Management of Infusion Reactions ...................................................................................28 
5.7 
Gluten Challenge ...............................................................................................................29 
5.8 
Investigational Product and Wheat Gluten Accountability, Dispensing, and Destruction 29 
5.9 
Prior and Concomitant Medications ..................................................................................29 
5.10 
Other Study Restrictions ....................................................................................................29 
5.10.1 Food and Fluid Intake ............................................................................................29 
5.10.2 Subject Activity Restrictions .................................................................................30 
5.10.3 Birth Control ..........................................................................................................30 
5.11 
Treatment Compliance .......................................................................................................30 
6 
STUDY PROCEDURES .................................................................................................31 
6.1 
Definitions and Descriptions of Assessments and Procedures ..........................................31 
6.2 
Screening............................................................................................................................32 
6.3 
Randomization ...................................................................................................................32 
6.4 
On-Study Procedures .........................................................................................................32 
6.4.1 Study Days 1 (Dose 1) and 2 .................................................................................32 
6.4.2 Study Days 8 (Dose 2) and 9 .................................................................................33 
6.4.3 Study Day 15 – Beginning of Gluten Challenge ...................................................34 
6.4.4 Study Day 20..........................................................................................................35 
6.4.5 Study Day 29..........................................................................................................35 
6.4.6 Study Day 35 (± 1 day) or Early Termination .......................................................35 
6.5 
Research Storage Samples .................................................................................................36 
7 
ADVERSE EVENTS .......................................................................................................37 
7.1 
Reporting Responsibilities .................................................................................................37 
7.2 
Definitions..........................................................................................................................37 
7.2.1 Adverse Event ........................................................................................................37 
7.2.2 Serious Adverse Event ...........................................................................................37 
7.2.3 Relatedness (Causality) ..........................................................................................38 
7.2.4 Severity ..................................................................................................................38 
7.3 
Clinical Laboratory Abnormalities ....................................................................................38 
7.4 
Physical Exam Abnormalities ............................................................................................39 
7.5 
Pregnancy ...........................................................................................................................39 
7.6 
Reporting of Serious Adverse Events ................................................................................39 
7.7 
Toxicity Management ........................................................................................................40 
7.7.1 Suspected Drug-Induced Liver Injury ...................................................................40 
7.7.2 Other Grades 1 and 2 Laboratory Abnormality or Clinical Event .........................40 
7.7.3 Other Grade 3 Laboratory Abnormality or Clinical Event ....................................40 
7.7.4 Other Grade 4 Laboratory Abnormality or Clinical Event .....................................41 
8 
STATISTICAL CONSIDERATIONS ...........................................................................42 
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COUR Pharmaceuticals Development Company 
TGLIA-5.002 
IND #: 17579 
Version 2.0 
10 December 2018 
Page 4 of 62 
8.1 
Sample Size ........................................................................................................................42 
8.2 
Analysis Conventions ........................................................................................................42 
8.3 
Analysis Populations ..........................................................................................................42 
8.4 
Demographic Data and Baseline Characteristics ...............................................................42 
8.5 
Pharmacodynamic Analyses ..............................................................................................43 
8.6 
Histology Analyses ............................................................................................................43 
8.7 
Celiac Signs and Symptoms...............................................................................................43 
8.8 
Pharmacokinetic Analyses .................................................................................................43 
8.9 
Safety Analyses ..................................................................................................................43 
8.9.1 Adverse Events ......................................................................................................43 
8.9.2 Laboratory Evaluations and Vital Signs ................................................................44 
8.9.3 Concomitant Medications ......................................................................................44 
8.10 
Interim Analysis .................................................................................................................44 
9 
ETHICAL AND ADMINISTRATIVE RESPONSIBILITIES ....................................45 
9.1 
Ethical Conduct of the Study .............................................................................................45 
9.2 
Institutional Review Board Approval ................................................................................45 
9.3 
Informed Consent...............................................................................................................45 
9.4 
Confidentiality ...................................................................................................................45 
9.5 
Protocol Amendments ........................................................................................................45 
9.6 
Case Report Forms .............................................................................................................46 
9.7 
Source Document Maintenance .........................................................................................46 
9.8 
Retention of Records..........................................................................................................46 
9.9 
Study Monitoring ...............................................................................................................46 
9.10 
Protocol Deviations ............................................................................................................47 
9.11 
Financial Disclosure...........................................................................................................47 
9.12 
Publication and Disclosure Policy .....................................................................................47 
10 
REFERENCES .................................................................................................................49 
APPENDIX 1 
SCHEDULE OF EVENTS ..........................................................................50 
APPENDIX 2 
TOXICITY GRADING SCALE .................................................................52 
APPENDIX 3 
CELIAC SYMPTOM INDEX-MODIFIED (CSI-M) ...............................56 
APPENDIX 4 
AMENDMENT TO THE PROTOCOL .....................................................57 
 
 
 
 
 
 
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COUR Pharmaceuticals Development Company 
TGLIA-5.002 
IND #: 17579 
Version 2.0 
10 December 2018 
Page 6 of 62 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TGLIA-5.002 
A randomized, double-blind, placebo-controlled study of the safety, pharmacodynamics, 
efficacy, and pharmacokinetics of TIMP-GLIA in subjects with well-controlled celiac 
disease undergoing oral gluten challenge.  
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  
 
Signed: 
 
Date: 
 
 
 
Print Name: 
 
 
Site Name: 
 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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IND #: 17579 
Version 2.0 
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Page 9 of 62 
3. Positive for human leukocyte antigen (HLA)-DQ2 or HLA-DQ2/DQ8 – results will be obtained at 
Screening if unknown or results are not available. 
4. Self-reported to be on a GFD for at least 6 months prior to Screening and agree to continue GFD 
throughout study, with the exception of the oral gluten challenge. 
5. Normal or negative celiac serology, at screening, defined as:  
a. Measurable total serum immunoglobulin A (IgA) 
AND 
b. Negative or weak positive tissue transglutaminase (tTG) IgA titer  
OR 
c. If IgA deficient, defined by a serum IgA level of < 3 mg/dL, negative or weak positive DGP- 
IgG titer. 
6. Vh:Cd ≥ 1.5 on screening biopsy. 
7. Intact spleen (no history of splenectomy or splenic disorders). 
8. Willing and able to provide written informed consent. 
9. Willing to perform and comply with all study procedures including attending clinic visits as 
scheduled, completion of the gluten challenge, and completion of biopsies. 
10. Men and women of child bearing potential (WOCBP) must be willing to practice a highly effective 
method of contraception that may include, but is not limited to, abstinence, sex only with persons 
of the same sex, monogamous relationship with vasectomized partner, vasectomy, hysterectomy, 
bilateral tubal ligation, licensed hormonal methods, intrauterine device (IUD), or use of spermicide 
combined with a barrier method (e.g., condom, diaphragm) for 28 days before and after receiving 
the investigational product (IP). 
Exclusion Criteria 
1. Positive for only HLA-DQ8. 
2. History of clinically confirmed immunoglobulin E (IgE)-mediated reaction and/or anaphylaxis to 
wheat (i.e., “wheat allergy”), barley or rye.  
3. Uncontrolled CD and/or active signs/symptoms of CD, in the opinion of the investigator. 
4. Untreated or active gastrointestinal disease such as peptic ulcer disease, esophagitis (Los Angeles 
Classification ≥ Grade C), irritable bowel syndrome, inflammatory bowel disease, or microscopic 
colitis. 
5. Immunocompromised individuals, including those receiving immunosuppressive doses of 
corticosteroids (more than 20 mg of prednisone given daily or on alternative days for 2 weeks or 
more within 6 months prior Dose 1, any dose of corticosteroids within 30 days of Day 1, or high 
dose inhaled corticosteroids [> 960 µg/day of beclomethasone dipropionate or equivalent]) or other 
immunosuppressive agents. 
6. Type 1 diabetes. 
7. Active malignancy, or history of malignancy or chemotherapy within the past 5 years other than 
history of localized or surgical removal of focal skin cancer, or cervical cancer in situ treated 
successfully in the past by local treatment (including but not limited to cryotherapy or laser 
therapy) or by hysterectomy. 
8. Pregnant or nursing women. 
9. Current infection with human immunodeficiency virus (HIV) or hepatitis B or C virus.  
10. Any acute illness including, fever (>100.4°F or >38°C) within 14 days of Day 1. 
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COUR Pharmaceuticals Development Company 
TGLIA-5.002 
IND #: 17579 
Version 2.0 
10 December 2018 
Page 11 of 62 
Safety:   
- 
AEs and serious AEs (SAEs) (clinically significant abnormal physical exam findings and 
laboratory results will be reported as AEs) 
- 
Vital signs 
- 
Serum chemistries and hematology 
- 
DGP-IgG antibodies  
- 
Serum complement levels: C1q binding, C3a, C5a, SC5B-9 
- 
Serum cytokines: IFN-gamma, IL1-beta, IL-2, IL-4, IL-6, IL-8 , IL-10, IL-12p70, TNF-alpha 
Statistical Methods:  
Sample Size: For the primary efficacy endpoint, using a 2-sided 0.05 significance level, a statistical 
power of ~70%, and assuming an increase in mean IFN- ɣ SFUs in the placebo group of 75 (standard 
deviation [SD] 100) and in the TIMP-GLIA group of 5 (SD 10), 15 subjects per group will allow 
detection of a difference of 70 in mean reductions in SFUs between the TIMP-GLIA and placebo 
groups. 
An interim analysis will be performed when Day 29 data are available for the 30 subjects.  The final 
sample size will be determined based on the operating characteristics for a decision criterion using a 
Bayesian approach.  An additional 20 subjects (10 per arm) may be randomized based on the interim 
results. 
Analyses: 
Efficacy/Pharmacodynamics: 
The mean changes from baseline in IFN-γ SFUs within and between treatment groups will be 
compared using a Wilcoxon Signed Rank Test and a Wilcoxon Rank Sum Test, respectively. 
The proportion of subjects with a 2-fold increase (and an increase of at least 10) in IFN-γ SFUs in the 
placebo and TIMP-GLIA groups will be compared using a Fisher’s Exact Test.   
The mean changes from baseline in villus height, crypt depth, and their ratio (Vh:Cd) within and 
between treatment groups will be compared using a Wilcoxon Signed Rank Test and a Wilcoxon Rank 
Sum Test, respectively. 
The proportion of subjects with a decrease of ≥ 0.4 in Vh:Cd in the placebo and TIMP-GLIA groups 
will be compared using a Fisher’s Exact Test.   
The mean changes from baseline in IELs within and between treatment groups will be compared using 
a Wilcoxon Signed Rank Test and a Wilcoxon Rank Sum Test, respectively. 
Descriptive statistics will be used to summarize all other pharmacodynamic endpoints. 
Subject responses to the CSI-M will be summarized using descriptive statistics.  
PK: 
Individual subject TIMP-GLIA concentrations and derived PK parameters will be summarized using 
descriptive statistics. 
Safety: 
Frequencies and percentages of subjects with AEs and SAEs will be summarized by treatment group.  
Safety labs and vital signs data will be summarized with descriptive statistics by treatment group. 
 
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COUR Pharmaceuticals Development Company 
TGLIA-5.002 
IND #: 17579 
Version 2.0 
10 December 2018 
Page 12 of 62 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AP 
Aalkaline phosphatase 
APCs 
Antigen-Presenting Cells 
AST 
Aspartate Aminotransferase 
CD 
Celiac Disease 
CSI-M 
Celiac Symptom Index-Modified 
CO2 
Carbon Dioxide/Bicarbonate 
CFR 
Code of Federal Regulations 
DGP-IgG 
Deamidated gliadin peptide immunoglobulin G 
DMC 
Data Monitoring Committee 
DTH 
Delayed-type hypersensitivity 
eCRF 
Electronic case report form 
ELISA 
Enzyme-linked immunosorbent assay 
ELISpot 
Enzyme-linked immunospot assay 
ER 
Emergency room 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFD 
Gluten-free diet 
CFR 
Code of Federal Regulations 
GLP 
Good Laboratory Practice 
HBsAG 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
IgA 
Immunoglobulin A 
IgE 
Immunoglobulin E 
ICF 
Informed consent form 
IR 
Infusion reaction 
IRB 
Institutional Review Board 
ICH 
International Conference on Harmonisation 
ICH-GCP 
International Conference of Harmonisation-Good Clinical Practice 
INR 
International normalized ratio 
IFN-γ 
Interferon-gamma 
IL-15 
Interleukin-15 
IV 
Intravenous 
IUD 
Intrauterine device 
IP 
Investigational Product 
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TGLIA-5.002 
IND #: 17579 
Version 2.0 
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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Affairs 
MHC 
Major histocompatibility complex 
NOAEL 
No observed adverse effect level 
PBMC 
Peripheral blood mononuclear cells 
PLGA 
Poly(DL-lactide-coglycolide) 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SFUs 
Spot forming units 
TIMP 
Tolerogenic Immune Modifying Particles 
TIMP-GLIA 
Tolerogenic Immune Modifying Particles - Gliadin 
TBL 
Total bilirubin 
tTG-IgA 
Tissue transglutaminase immunoglobulin A 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
WOCBP 
Women of child bearing potential 
 
 
 
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COUR Pharmaceuticals Development Company 
TGLIA-5.002 
IND #: 17579 
Version 2.0 
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Page 14 of 62 
1 INTRODUCTION 
1.1 
Background on Indication 
Celiac disease (CD) is an autoimmune disorder involving both an innate and adaptive immune 
response that occurs among genetically predisposed subjects who are exposed to gluten-
containing foods and other environmental factors (Green 2016).  The prevalence of CD in the 
United States is ~0.7%, similar to that found in several European countries (Rubio-Tapia 2012).   
CD develops in genetically predisposed subjects as a consequence of an abnormal inflammatory 
T cell response to dietary prolamin protein, predominately gliadin, which becomes deamidated 
by tissue transglutaminase in the intestine. When deamidated gliadin-specific CD4+ T cells 
recognize their cognate gliadin epitope presented by human leukocyte antigen (HLA)-DQ2 or 
HLA-DQ8 on antigen-presenting cells (APCs) in the lamina propria, they become activated and 
produce proinflammatory cytokines such as interferon-gamma (IFN-γ). This triggers an 
inflammatory cascade resulting in crypt hyperplasia and villous flattening characteristic of CD 
biopsy findings.  Within the intestinal epithelium gliadin also triggers local production of 
interleukin-15 (IL-15) by enterocytes.  This IL-15 increases expression of major 
histocompatibility complex (MHC) class I surface antigens (such as MHC class I polypeptide-
related sequence A) on epithelial cells and also increases expression of corresponding MHC 
receptors (such as NKG2D) on intraepithelial T cells (i.e., CD8+αβ T cells and γδ T cells, natural 
killer [NK] cells), leading to epithelial cell destruction. (Fasano 2012; Green 2007; Mazzarela 
2008; Schuppan 2009). 
Classic intestinal symptoms of CD include diarrhea, malnutrition, or a malabsorption syndrome 
(indicated by weight loss, steatorrhea, and edema secondary to hypoalbuminemia) (Ludvigsson 
2013).  Extraintestinal symptoms include osteoporosis, anemia, and dermatitis herpetiformis.  
Less than 50% of adults present with classical intestinal symptoms (Fasano 2003; Green 2001). 
1.2 
Limitations of Current Treatments 
Gluten avoidance by dietary modification, the “gluten-free” diet (GFD), is the only effective 
treatment for CD as there are currently no medications that can reliably and safely prevent the 
mucosal damage caused by exposure to gluten. While the GFD has been shown to alleviate many 
of the symptoms of disease, strict adherence is difficult, and creates an additional burden on the 
day-to-day functioning of the celiac patient.  In reality, the complete elimination of gluten from 
the diet is not realistic and repeated gluten exposure, albeit unintentional or in small amounts, 
prevents complete recovery of symptoms and repair of intestinal damage (Laurin 2002; Leffler 
2017; Rubio-Tapia 2013).  
Therapeutic approaches rendering T cells tolerant to gluten could potentially cure CD, thus 
eliminating the burdens associated with lifetime GFD and co-morbidities associated with the 
disease such as cancer. There are no Food and Drug Administration (FDA) approved treatments 
for CD in the US. 
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1.3 
TIMP-GLIA 
COUR is developing Tolerogenic Immune Modifying Particles (TIMP) - Gliadin (TIMP-GLIA) 
as a first-in-class, non-immunosuppressive agent to specifically inactivate, or tolerize, gliadin-
specific T cells, thereby abrogating and/or reversing the underlying pathology of CD.  
TIMP-GLIA is comprised of gliadin extract drug substance within a negatively charged polymer 
matrix of poly(DL-lactide-coglycolide (PLGA) particles. TIMP-GLIA delivers the gliadin 
antigen via natural phagocytosis of the PLGA particles to APCs in a noninflammatory process.   
Negatively charged particles delivered intravenously leads to antigen presentation of the gliadin 
in the spleen and liver by APCs.  Gliadin-specific T cells are likely tolerized by at least one of 
the following mechanisms: they become anergic, are deleted, or switch to T regulatory cells.  As 
a result of tolerance, the deleterious immune cascade is minimized or eliminated in response to 
gliadin.  TIMP-GLIA is designed and directed to specifically address and limit the T cell 
response that drives CD (Getts 2015). 
1.4 
Nonclinical Pharmacology and Toxicology Studies 
Summaries of the nonclinical pharmacology and toxicology studies are provided below.  
Additional details of the studies can be found in the current Investigator Brochure. 
1.4.1 
Nonclinical Models of Antigen-Specific Immune Tolerance 
In Vivo Pharmacology - Mice 
In vivo pharmacology studies to demonstrate the ability of TIMP-GLIA (compared to controls) 
to induce antigen-specific tolerance were performed in 3 mouse models: 
Table 1 
Mouse Models of Immune Tolerance 
Model 
Objectives 
Measures 
Prophylaxis (active priming)  
Demonstrate antigen-specific 
tolerance 
Ear swelling (delayed-type 
hypersensitivity [DTH]) 
Anti-gliadin antibody 
Ex-vivo splenic T cell 
proliferation, inflammatory 
cytokine secretion 
Gliadin-induced intestinal 
autoimmunity (adoptive transfer 
of splenocytes) 
 
Demonstrate reversal or 
prevention of intestinal pathology 
Weight loss 
Severity of histological duodenitis 
Ex-vivo splenic inflammatory 
cytokine secretion 
Transgenic mouse expressing 
celiac associated HLA DQ8 / 
huCD4 
Demonstrate antigen-specific 
tolerance in the context of HLA-
DQ8 
Anti-gliadin antibody 
Ex-vivo splenic inflammatory 
cytokine secretion 
 
In each model, mice received intravenous (IV) doses of TIMP-GLIA, up to 125 mg/kg (human 
equivalent dose [HED] ~10 mg/kg), administered 7 days apart. 
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In the prophylaxis and transgenic mouse models, treatment with TIMP-GLIA reduced the 
immune response as measured by: reduction in anti-gliadin antibodies, and reduction in 
activation of ex vivo gliadin-specific splenic T cells measured by proliferation and inflammatory 
cytokines, including IFN-γ, compared to the control group. In the prophylaxis model, treatment 
with TIMP-GLIA reduced DTH (ear swelling) compared to the control group. 
In the gliadin-induced intestinal autoimmunity model, treatment with TIMP-GLIA prevented 
weight loss, reduced the severity of duodenitis, and reduced secretion of ex vivo splenic gliadin-
specific inflammatory cytokines compared to control group.  The outcomes for mice treated with 
TIMP-GLIA were similar to those of mice receiving a GFD. 
TIMP-GLIA induced gliadin-specific immune tolerance in each model.  Additionally, TIMP-
GLIA was not associated with adverse events (AEs) or immune activation. 
Ex Vivo Pharmacology - Human-Donor Peripheral Blood Mononuclear Cells  
Peripheral blood (from which peripheral blood mononuclear cells [PBMCs] were harvested) was 
collected from healthy donors, donors with CD adhering to a GFD, and newly diagnosed celiac 
donors not on a GFD. TIMP-GLIA incubation with PBMCs from these patients at concentrations 
as high as 1.25 mg/mL (HED 100 mg/kg) did not cause T cell proliferation or inflammatory 
cytokine production. 
1.4.2 
Pharmacokinetics 
Pharmacokinetic study results in repeat dose toxicology studies in rats suggest that the 
pharmacokinetics of plasma gliadin (measured via enzyme-linked immunosorbent assay 
[ELISA]) is similar on Days 1 and 8 and that the kinetics are similar in male and female rats. 
Maximum plasma gliadin concentrations (Cmax) occurred rapidly and declined in an apparent 
biphasic manner with plasma concentration declining relatively rapidly over the first 1 to 4 
hours. The time to reach the lower limit of quantitation varied but in general, plasma 
concentrations were below the lower limit of quantification (0.25 μg/mL for plasma gliadin) 
within 24 hours. Cmax increased with increasing dose. The area under the concentration versus 
time curve from the start of dose administration to the last observed quantifiable concentration 
(AUC(0-t)) also increased with increasing dose.  Half-life estimates across doses and genders were 
similar and ranged from 5.4 to 6.8 hours. 
1.4.3 
Toxicology 
Three repeat-dose toxicology studies of TIMP-GLIA were conducted in rats.  Two studies were 
non-Good Laboratory Practice (GLP) dose range finding studies; the third study was a GLP 
study.  In the non-GLP studies, TIMP-GLIA was administered by IV bolus on 2 days (Days 1 
and 8, and Days 1 and 5).  In the GLP study, TIMP-GLIA was administered by IV bolus on Days 
1, 8, and 15. 
In the GLP study, all animals survived until the scheduled necropsy and remained in good health 
throughout the course of the study. There were no significant abnormal clinical findings during 
the study and no drug-related effects were noted on body weight, body weight gain, food 
consumption, ophthalmology exams, physical exams, clinical observations, functional 
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observational battery, body temperature and serum cytokine levels.  The results of the 
microscopic evaluation of the tissues obtained at necropsy of the animals terminated on Day 16 
or Day 43 from each sex and dose group did not exhibit any pathologically significant findings. 
One animal treated with 75 mg/kg and euthanized on Day 16 (rat number 5011) had a +2 liver 
necrosis but this was considered by the board-certified pathologist to be within the background 
for Sprague Dawley rats. There was some evidence of local hemorrhage and inflammation at the 
tail vein injection site, but these were restricted to the immediate region of the injection (with no 
evidence of similar changes in any other tissues examined), occurred in control animals, and 
were considered to be typical results from an IV injection.  The no observed adverse effect level 
(NOAEL) from this pivotal GLP toxicology study in rats was determined to be 75 mg/kg. 
Because the NOAEL (75 mg/kg) occurred at the maximum dose in the GLP toxicology study, a 
small follow up study was performed to evaluate 2 doses of TIMP-GLIA at 100 and 150 mg/kg, 
administered by IV bolus.  All animals survived until euthanasia for necropsy and no abnormal 
clinical behaviors were observed.  TIMP-GLIA-related effects were noted on clinical chemistry 
and hematology tests and generally were mild or moderate.  IV bolus administration of TIMP-
GLIA to rats at 100 or 150 mg/kg on Day 1 and 5 was associated with liver and spleen effects. 
The primary effect in the liver and spleen was infiltration of monocytes/macrophages which was 
considered to be potentially consistent with infusion of highly concentrated nanoparticles.  A no-
effect level was not determined in this study. 
1.5 
Clinical Trials of TIMP-GLIA 
Study TGLIA-5.001 is a Phase 1 study designed to evaluate the safety and tolerability of single 
and multiple ascending doses of TIMP-GLIA in subjects aged 18 to 75 with biopsy proven CD.  
Single doses range from 0.1 to 8 mg/kg of TIMP-GLIA (Part A); repeat doses of TIMP-GLIA 
include 2, 4, and 8 mg/kg (Part B).   
Dosing in Part A is complete and all subjects have a minimum of 16 weeks follow-up (as of 
December 10, 2018).  A total of 17 subjects were enrolled sequentially into Part A of the study.  
Two subjects each received doses of 0.1 and 0.5 mg/kg; 3 subjects each received doses of 1, 2, 
and 4 mg/kg; and 4 subjects received 8 mg/kg.  At total of 6 subjects were enrolled sequentially 
into Part B of the study.  Two subjects each received 2 doses of 2 mg/kg, 4 mg/kg, and 8 mg/kg. 
Twelve subjects in Part A have completed the study.  The remaining subjects will be followed 
for safety through Day 180.  
During Part A of the study, 2 of the 4 subjects who received a single 8 mg/kg dose experienced a 
mild to moderate infusion reaction (IR).  The first subject developed a rash (grade 2), systolic 
hypotension (grade 2), and concentration disturbance (grade 1) at ~5 minutes into the infusion.  
The investigator discontinued the infusion and the symptoms resolved within minutes.  The 
second subject experienced flushing (grade 2), nausea (grade 1), vomiting (grade 1), back pain 
(grade 1), and visual changes (grade 1).  The onset of symptoms occurred within the first few 
minutes of the infusion.  The investigator stopped the infusion and the symptoms resolved.  The 
investigator subsequently treated the subject with IV diphenhydramine, 12.5 mg, and restarted 
the infusion per protocol at 25% of the original rate, increasing to 50% of the original rate, and 
then to the full rate at 15 minute intervals.  The subject completed the infusion without further 
incident. 
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Upon review of all safety data, an independent Data Monitoring Committee (DMC) 
recommended that 1) the IP be diluted in 200 mL of normal saline (originally 100 mL), and 2) 
the IP be infused over ~2.5 hours - 20mL/hour for the first 15 minutes, 40 mL/hour for the next 
15 minutes, and then 80 mL/hour for the duration of the infusion (originally the drug was infused 
at a constant rate over 30 minutes). 
During Part B of the study, 1 subject (of 2) receiving 4 mg/kg experienced mild back pain during 
both infusions at ~10 minutes into the infusion.  The investigator briefly interrupted the first 
infusion and did not interrupt the second infusion.  There were no other AEs reported in any of 
the other 5 subjects receiving a repeat dose of TIMP-GLIA 
There were no serious AEs (SAEs) reported in any subject in Part A or Part B to date.  All but 1 
AE were ≤ grade 2 (moderate); 1 subject reported grade 3 (non-celiac) colitis that the 
investigator deemed not related to TIMP-GLIA.  The most frequent events observed in ≥ 2 
subjects include: flushing (n=5, 22%), headache (n=4, 17%), back pain (n=3, 13%), fatigue (n=2, 
9%), abdominal pain (n=2, 9%), and diarrhea (n=2, 9%).  Flushing was only observed in the 
single dose subjects.  Two subjects in Part A experienced back pain (1 at 4 mg/kg, 1 at 8 mg/kg) 
compared to 1 subject (4 mg/kg) in the repeat dose group.    There was no trend for any other 
AE. 
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2.2.4 
Pharmacokinetic Endpoints 
- 
Maximal observed concentration (Cmax) 
- 
Time of maximal observed concentration (Tmax) 
- 
Area under the concentration-time curve (AUC) from time zero and extrapolated to 
infinity (AUCinf) 
- 
AUC from time zero to time of the last measurable concentration (AUClast) 
2.2.5 
Safety Endpoints 
- 
AEs and SAEs (clinically significant abnormal physical exam findings and laboratory 
results will be reported as AEs) 
- 
Vital signs 
- 
Serum chemistries and hematology 
- 
DGP-IgG antibodies  
- 
Serum complement levels: C1q binding, C3a, C5a, SC5B-9 
- 
Serum cytokines: IFN-gamma, IL1-beta, IL-2, IL-4, IL-6, IL-8 , IL-10, IL-12p70, 
TNF-alpha 
 
 
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COUR Pharmaceuticals Development Company 
TGLIA-5.002 
IND #: 17579 
Version 2.0 
10 December 2018 
Page 22 of 62 
3.2.2 
Selection of Population 
The study population consists of patients with biopsy-confirmed, asymptomatic CD and 
following a GFD.  This study population reflects a population most likely to respond to a gluten 
challenge. 
3.2.3 
Selection of Dose 
In the Phase 1 study (Section 1.5) the TIMP-GLIA dose of 8 mg/kg up to a maximum of 650 mg 
was the highest dose tolerated, thus will be evaluated for pharmacodynamics and efficacy in this 
study. 
3.3 
Date Monitoring Committee 
An independent DMC will be commissioned for this study.  The DMC will be comprised of 3 
physicians with expertise in CD, immunology, and interventional clinical trials.  The DMC 
safety monitoring plan will be detailed in the DMC Charter. 
The primary responsibility of the DMC is to safeguard study subjects by reviewing and assessing 
the clinical safety data being collected during the performance of the study.  The DMC will 
review SAEs (Section 7.2.2) and ≥ Grade 3 AEs that are “Likely” (Section 7.2.3) to be related to 
IP as these events may occur.  They will also meet periodically throughout the study to review 
cumulative safety data.   
Based on these evaluations of the data, the DMC will make recommendations to the Sponsor to 
continue the study as planned, or to modify, temporarily suspend, or terminate the study.  The 
DMC will also be responsible for identifying issues and making recommendations regarding the 
monitoring of subjects for safety, including collection of additional safety data. 
The Sponsor will be responsible for notifying Investigators and Regulatory Authorities of any 
DMC recommendations, as appropriate. 
3.4 
Subject Participation and Study Duration 
The total duration of enrollment is estimated to be 3-4 months.  The duration of each subject’s 
participation (including Screening) is approximately 78 days (11 weeks).  Thus, the study is 
expected to last approximately 7 months. 
 
 
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4 SUBJECT POPULATION 
Approximately 30 subjects who meet the eligibility criteria will be enrolled. 
4.1 
Inclusion Criteria 
1. Male or nonpregnant female, ages 18 to 70 years inclusive, at Screening Visit.  
2. Biopsy-confirmed CD (intestinal histology showing villous atrophy). 
3. Positive for HLA-DQ2 or HLA-DQ2/DQ8 – results will be obtained at Screening if unknown 
or results are not available. 
4. Self-reported to be on a GFD for at least 6 months prior to Screening and agree to continue 
GFD throughout study, with the exception of the oral gluten challenge. 
5. Normal or negative celiac serology, at screening, defined as:  
a. Measurable total serum immunoglobulin A (IgA) 
AND 
b. Negative or weak positive tissue transglutaminase (tTG) IgA titer  
OR 
c. If IgA deficient, defined by a serum IgA level of < 3 mg/dL, negative or weak 
positive DGP IgG titer. 
6. Vh:Cd ≥ 1.5 on screening biopsy. 
7. Intact spleen (no history of splenectomy or splenic disorders). 
8. Willing and able to provide written informed consent 
9. Willing to perform and comply with all study procedures including attending clinic visits as 
scheduled, completion of the gluten challenge, and completion of the biopsies. 
10. Men and women of child bearing potential (WOCBP) must be willing to practice a highly 
effective method of contraception that may include, but is not limited to, abstinence, sex only 
with persons of the same sex, monogamous relationship with vasectomized partner, 
vasectomy, hysterectomy, bilateral tubal ligation, licensed hormonal methods, intrauterine 
device (IUD), or use of spermicide combined with a barrier method (e.g., condom, 
diaphragm) for 28 days before and after receiving the investigational product (IP). 
4.2 
Exclusion Criteria 
1. Positive for only HLA-DQ8. 
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2. History of clinically confirmed immunoglobulin E (IgE)-mediated reaction and/or 
anaphylaxis to wheat (i.e., “wheat allergy”), barley or rye.  
3. Uncontrolled CD and/or active signs/symptoms of CD, in the opinion of the investigator. 
4. Untreated or active gastrointestinal disease such as peptic ulcer disease, esophagitis (Los 
Angeles Classification ≥ Grade C), irritable bowel syndrome, inflammatory bowel disease, or 
microscopic colitis. 
5. Immunocompromised individuals, including those receiving immunosuppressive doses of 
corticosteroids (more than 20 mg of prednisone given daily or on alternative days for 2 
weeks or more within 6 months prior Dose 1, any dose of corticosteroids within 30 days of 
Day 1, or high dose inhaled corticosteroids [> 960 µg/day of beclomethasone dipropionate or 
equivalent]) or other immunosuppressive agents. 
6. Type 1 diabetes. 
7. Active malignancy, or history of malignancy or chemotherapy within the past 5 years other 
than history of localized or surgical removal of focal skin cancer, or cervical cancer in situ 
treated successfully in the past by local treatment (including but not limited to cryotherapy or 
laser therapy) or by hysterectomy. 
8. Pregnant or nursing women. 
9. Current infection with human immunodeficiency virus (HIV) or hepatitis B or C virus.  
10. Any acute illness including, fever (>100.4°F or >38°C) within 14 days of Day 1. 
11. Clinically significant abnormality on electrocardiogram (ECG). 
12. Clinically significant serum chemistry or hematology abnormalities ≥ Grade 2 (Appendix 2, 
Toxicity Grading Scale). 
13. Other active comorbidities that, in the opinion of the Investigator, would make the subject 
unsuitable for the study or unable to comply with the study requirements. 
14. Changes to medication used to manage an underlying comorbidity within 60 days prior Day 
1. 
15. Known allergy to PLGA, sucrose, or mannitol. 
16. Receipt of TIMP-GLIA in prior clinical trial. 
17. Receipt of any investigational drug within 28 days or 5 half-lives prior to Day 1. 
18. Receipt of a live vaccine within 28 days prior or a subunit vaccine within 14 days prior to 
Day 1 or planned vaccination prior to Day 35. 
19. Donation of blood or plasma within 56 days prior to Day 1. 
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20. Receipt of blood products, monoclonal antibody, or other systemic protein therapy within 6 
months prior to Day 1.  NOTE: oral protein supplements are permitted. 
21. Participation in an oral gluten challenge within 6 months prior to Day 1. 
22. History of drug or alcohol abuse that, in the opinion of the Investigator, would interfere with 
the subject’s ability to comply with the study requirements. 
23. Any other condition that, in the opinion of the Investigator would make the subject 
unsuitable for the study or unable to comply with the study requirements. 
4.3 
Subject and Study Discontinuation 
A clear distinction will be made between subjects who are withdrawn from dosing and those who 
prematurely discontinue from the study.  Only those subjects who withdraw consent or refuse 
any further contact with respect to the study will be discontinued from the study.  Subjects 
withdrawn from dosing will be encouraged to remain on the study for safety follow-up and have 
clinic visits/telephone calls in accordance with the Schedule of Events (Appendix 1).   
4.3.1 
Screening Failures 
Subjects who sign and date the informed consent form (ICF) but who fail to meet the inclusion 
and exclusion criteria are defined as screen failures.  A screening log, which documents the 
subject’s initials and reason(s) for screen failure, is to be maintained for all screen failures.  A 
copy of the log should be retained in the Investigator’s study files.   
4.3.2 
Premature Discontinuation from Investigational Product 
A subject may be prematurely discontinued from IP dosing for any of the following reasons: 
 Safety, including AEs or development of clinically significant laboratory abnormalities.  The 
subject must be followed clinically until the event is resolved or deemed stable. 
 Pregnancy. 
 Subject wishes to withdraw consent for reasons other than an AE. 
 Subject non-compliance or unwillingness to comply with the procedures required by the 
protocol. 
 Investigator discretion. 
 Sponsor request. 
Efforts will be made to follow all subjects who discontinue IP for any reason.  Such follow up 
will include all relevant evaluations for safety including clinical assessments and collection of 
laboratory study results as set out in this protocol. 
4.3.3 
Premature Discontinuation from Study  
A subject may be prematurely discontinued from the study for any of the following reasons: 
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 Subject wishes to withdraw consent for reasons other than an AE. 
 Subject is lost to follow-up. 
 Subject non-compliance or unwillingness to comply with the procedures required by the 
protocol. 
 Investigator discretion. 
 Sponsor request. 
4.3.4 
Replacement of Subjects 
Subjects who do not complete all study procedures, per protocol, through Day 29 (complete 14-
day gluten challenge and second biopsy) may be replaced. 
4.3.5 
Study or Site Termination 
Conditions may arise during the study that could prompt the study to be halted or the study site 
to be terminated.  Conditions that may prompt such considerations include, but are not limited to, 
the following: 
 The discovery of unexpected, serious, or unacceptable risk to the subjects enrolled in the 
study. 
 A decision on the part of Sponsor to suspend, discontinue, or shorten the study. 
 Study conduct at the study site may warrant termination under conditions that include the 
following: 
- 
Failure of Investigator(s) to enroll eligible subjects into the study. 
- 
Failure of Investigator(s) to comply with International Conference of Harmonisation-
Good Clinical Practice (ICH-GCP) guidelines, or FDA guidelines and regulations. 
- 
Submission of false information from the research facility to the Sponsor, the Clinical 
Monitor, the FDA, or Institutional Review Board (IRB). 
- 
Insufficient adherence to protocol requirements. 
- 
A conflict of interest of the Investigator, his/her institution, or site personnel that 
would negatively impact the integrity of the clinical trial. 
- 
Institution or IRB under investigation for cause by a regulatory agency. 
 
 
 
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IND #: 17579 
Version 2.0 
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Page 27 of 62 
5 INVESTIGATIONAL PRODUCT 
5.1 
TIMP-GLIA 
TIMP-GLIA is comprised of gliadin extract within a negatively charged (-35mV to -50mV) 
polymer matrix of PLGA particles with an average size between 400 nm – 800 nm.  There is 
approximately 10 μg of refined gliadin per mg of PLGA particles. 
Prior to IV administration, TIMP-GLIA is reconstituted in sterile water for infusion and diluted 
in 0.9% Sodium Chloride Injection USP (normal saline). 
5.1.1 
Packaging and Labeling 
TIMP-GLIA is manufactured, packaged, and labeled by the Sponsor’s designee(s) in accordance 
with legal and regulatory requirements. 
TIMP-GLIA is supplied as a lyophilized powder in a single-use, 20-mL glass vial containing 
approximately 1 mg refined gliadin and 100 mg of PLGA particles.  Vials have rubber, 
siliconized, 20 mm single-vent gray stoppers and an aluminum, 20 mm, flip-off seal.   
Each vial and carton will bear a label conforming to regulatory guidelines which identifies the 
contents and including required statutory phrases (e.g., “New Drug – Limited by Federal (US) 
law to investigational use.”), and other required elements including but not limited to the sponsor 
name, lot number, expiry date or reevaluation date as applicable, and storage conditions. 
5.1.2 
Storage  
TIMP-GLIA vials should be stored at 2°C to 8℃ (36°F to 46°F) and protected from light in a 
secure, temperature-monitored, limited access location.  A daily temperature log must be 
maintained and temperature excursions documented. 
5.2 
Placebo 
The placebo for this study is 0.9% Sodium Chloride Injection USP (normal saline).  Placebo 
should be stored at ambient room temperature in accordance with the product label.  
5.3 
Preparation of Investigational Product 
Preparation of the TIMP-GLIA and placebo must be performed by a designated unblinded site 
pharmacist (or otherwise qualified personnel) in accordance with the Pharmacy Manual 
provided by the Sponsor.   
Dose will be determined by subject weight on Day 1. 
5.4 
Blinding and Unblinding 
Investigators, subjects, and all study staff with direct subject contact will be blinded to treatment 
assignment.  A designated unblinded pharmacist (or otherwise qualified personnel) at each site 
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will prepare each dose.  That individual should have no contact with the subjects and minimize 
contact with other site study personnel. 
Because TIMP-GLIA is an opaque milky white suspension once reconstituted and diluted, and 
the placebo is a clear solution (normal saline), both the IV bag containing IP and the IV tubing 
will be covered at the time the IP leaves the pharmacy. 
Unblinding of treatment assignment is discouraged.  In the event of a medical emergency for 
which the identity of the treatment assignment is critical to the care of a subject, the Investigator 
should call the Medical Monitor to discuss.  In the event that unblinding is deemed necessary, an 
unblinded statistician will provide the treatment assignment to the Medical Monitor who will 
provide the information to the Investigator.  A decision to discontinue a subject from further IP 
administration is not a rationale to unblind the treatment assignment. 
5.5 
Administration of Investigational Product 
TIMP-GLIA or placebo will be administered by unblinded, trained study personnel.  
TIMP-GLIA or placebo will be administered at the following escalating rates: 
 20 mL per hour for 15 minutes, then 
 40 mL per hour for the next 15 minutes, then 
 80 mL per hour for the duration of the infusion 
The total infusion time will be approximately 2.5 hours.  Additional instructions will be provided 
in the Pharmacy Manual provided by the Sponsor.   
5.6 
Management of Infusion Reactions 
Subjects must be monitored closely for signs and symptoms of an IR.  In the event of an IR, the 
infusion should be slowed, or stopped and restarted at a slower rate at the discretion of the 
Investigator.  If a severe IR occurs (Grade 3 or 4 signs or symptoms), discontinue infusion and 
institute treatment as needed.  
In addition, if a subject experiences an IR, the following procedures will be undertaken: 
 A symptom driven physical examination to capture medically relevant details, including but 
not limited to, a thorough dermatologic examination; a chest examination for breath sounds, 
stridor or wheezing; and a cardiac examination with attention to irregular heartbeat. 
 Vital signs (sitting or supine blood pressure, heart rate, and body temperature) will be 
captured at the time of the IR and at least every 15 minutes until the resolution or 
stabilization of the IR. 
 Blood samples for serum cytokines, and C3a, C5a, SC5b-9 complement levels will be drawn 
at the time of the IR  
The Investigator may administer any medically indicated pharmacologic agent or procedure 
intended to relieve symptoms (CAUTION: no other drugs may be mixed in the IP infusion bag).  
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Signs and symptoms of the IR and drugs given for treatment are to be recorded in the medical 
record and in the electronic case report form (eCRF). 
Subjects experiencing a Grade 3 or 4 IR should be discontinued from further doses of IP.  After 
the first experience of an IR that is ≤ Grade 2, the Investigator may elect to initiate the next 
infusion at a slower rate (start at 25% of rate in Section 5.5).  All changes to infusion rate are to 
be recorded in the medical record and in the eCRF. 
5.7 
Gluten Challenge 
Bob's Red Mill Vital Wheat Gluten (75-80% Protein) powder will be used for the gluten 
challenge.  It will be supplied by the sponsor in individual foil packets, each containing 
approximately 6 g gluten (approximately 8.5 g of powder) per packet. 
Subjects will consume 12 g of gluten for the first 3 days of the gluten challenge (Days 15-17); 2 
packets per day.  For the remainder of the gluten challenge (Days 18-28), subjects will consume 
6 g of gluten per day; 1 packet.  Packets of wheat gluten will be mixed into half to one cup of 
applesauce (subject choice) and consumed in one sitting. 
Gluten packets should be stored in a refrigerated (2-8°C), dry location. 
5.8 
Investigational Product and Wheat Gluten Accountability, Dispensing, and 
Destruction 
The Investigator (or designee) will maintain an accurate record of the receipt of the IP and wheat 
gluten as shipped by the Sponsor (or designee), including the date received.  In addition, an 
accurate IP/wheat gluten disposition record will be kept, specifying the amount dispensed (vials 
and packets) to each subject and the date of dispensation.   
At the completion of the study, all unused IP/wheat gluten supplies will be returned to the 
Sponsor (or designee) or disposed of by the site in accordance with the Sponsor’s (or designee’s) 
written instructions. 
5.9 
Prior and Concomitant Medications 
Subjects may not receive a live vaccine within 28 days prior or a subunit vaccine within 14 days 
prior to Day 1 or planned vaccination prior to Day 35. 
All prior and concomitant medications, including prescription and nonprescription medicines, 
will be reported in the eCRF beginning at Screening through the last study visit.   
5.10 Other Study Restrictions 
5.10.1 
Food and Fluid Intake  
With the exception of the gluten challenge (Days 15-28) subjects must adhere to a gluten free 
diet throughout the study.  There are no other restrictions on food or fluid intake during the 
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study.  Because of the large volume of whole blood drawn for isolation of PBMCs, subjects 
should be well-hydrated on the days of collection. 
5.10.2 
Subject Activity Restrictions 
To reduce the occurrence of exercise induced elevated creatine kinase, subjects should be 
instructed to refrain from excessive physical activity (as defined by the Investigator) for 48 hours 
before each study visit. 
5.10.3 
Birth Control 
Men and WOCBP must be willing to practice a highly effective method of contraception that 
may include, but is not limited to, abstinence, sex only with persons of the same sex, 
monogamous relationship with vasectomized partner, vasectomy, hysterectomy, bilateral tubal 
ligation, licensed hormonal methods, IUD, or use of spermicide combined with a barrier method 
(e.g., condom, diaphragm) for 28 days before and after receiving the IP. 
5.11 Treatment Compliance 
To ensure compliance with the dosing regimen, all doses will be administered at the 
investigational site by trained study personnel who have been delegated that responsibility by the 
Investigator.   
Subjects will be observed consuming the wheat gluten on the first day of the challenge and report 
adherence on all subsequent days (Day 16 through Day 28).  Additionally, subjects will have a 
urine gluten test on Days 15, 20, and 29. 
 
 
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6 STUDY PROCEDURES 
Refer to Appendix 1 for the Schedule of Events. 
6.1 
Definitions and Descriptions of Assessments and Procedures 
CD history – CD history should include date of diagnosis, date of biopsy proven diagnosis,, and 
date subject started GFD.  A copy of the biopsy must be maintained in the subject’s medical 
record. 
CSI-M – modified celiac symptoms index (Appendix 3); to be used to assess symptoms before, 
during, and after the oral gluten challenge. 
Complete physical exam – examination of the following systems:  cardiovascular; 
dermatological; ear, nose, and throat; extremities; gastrointestinal; musculoskeletal; 
ophthalmological; neurological; respiratory.   
Symptom-driven physical exam – brief, focused examination of the subject following medical 
history, including assessment for AEs.   
Vital Signs - temperature, heart rate, blood pressure.  Heart rate and blood pressure should be 
obtained after subject is resting for 5 minutes. 
Small bowel biopsy – a small bowel biopsy will be performed by a qualified gastroenterologist 
at each site.  All study gastroenterologists will be trained on the study-specific procedures for 
obtaining the biopsy, including the location and number of biopsies to be obtained, and 
procedures for storing and shipping of samples. 
Serum chemistries* – glucose, calcium, albumin, total protein, carbon dioxide/bicarbonate 
(CO2), chloride, potassium, sodium, total bilirubin (TBL), alkaline phosphatase (AP), alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen, creatinine, 
creatine kinase. 
* Fasting is required at screening only. 
Hematology - hemoglobin, red blood cell count, white blood cell count and differential, platelet 
count. 
Serum cytokines - IFN-gamma, IL1-beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-
alpha 
Whole blood – whole blood samples will be obtained for pharmacodynamic assays.  Blood will 
be shipped to a central lab for processing into PBMCs. 
Women of child bearing potential (WOCBP) - not surgically sterile or post-menopausal 
defined as age > 40 years without menses for ≥ 2 years. 
AEs and SAEs – refer to Section 7.2. 
 
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6.2 
Screening 
Subjects will be screened to assess eligibility criteria within 45 days prior to Study Day 1 (first 
dose of IP).  Prior to performing the assessments below, it is important to obtain the Subject ID 
from iMedNet eCRF. 
The following assessments and procedures will be performed: 
 Written informed consent 
 Medical history, including celiac, dietary, and concomitant medications 
 Demographics 
 Complete physical exam, including vital signs, height and weight 
 Electrocardiogram 
 Laboratory Assessments, including: 
- 
Fasting serum chemistries 
- 
Hematology 
- 
Serum pregnancy test for WOCBP 
- 
HIV and hepatitis C virus serology; hepatitis B surface antigen  
- 
High definition allelic HLA testing  
- 
Celiac serology: IgA, tTG-IgA, DGP-IgG 
 Small bowel biopsy - the biopsy may be performed any time within the 45 days prior to 
Day 1/ randomization 
 Confirm eligibility 
6.3 
Randomization 
Upon determination that a subject meets all eligibility criteria, the subject will be randomized to 
treatment assignment.  Randomization should occur via eCRF on Study Day 1 just prior to IP 
administration. 
6.4 
On-Study Procedures 
6.4.1 
Study Days 1 (Dose 1) and 2 
This visit will take approximately 5 hours, including observation for 2 hours after dosing.  The 
following procedures will be performed prior to IP administration: 
 Weight - to be used to calculate dose 
 Symptom-driven physical exam 
 Vital signs 
 Laboratory Assessments, including: 
- 
Serum chemistries 
- 
Hematology 
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- 
Urine pregnancy test for WOCBP 
- 
DGP-IgG  
- 
Serum cytokines 
- 
C1q binding level 
- 
C3a, C5a, SC5b-9 complement levels  
- 
Whole blood 
- 
Plasma for future research 
 Assessment of concomitant medications 
 Confirm eligibility 
 IP administration 
The following procedures will be performed at the times specified below, during and after IP 
administration: 
 Vital signs at 15, 30, and 60 minutes after the start of infusion, end of infusion, and 2 hours 
after the end of the infusion 
 C3a, C5a, SC5b-9 complement levels at 30 minutes after start of infusion and end of infusion  
 Monitoring for AEs, including IRs 
In the event of an IR, blood samples for serum cytokines, and C3a, C5a, SC5b-9 complement 
levels will be drawn at the time of the IR. 
The subject will return to the clinic 24 hours after the dose (Day 2) to have blood drawn for: 
- 
Serum cytokines 
- 
C3a, C5a, SC5b-9 complement levels  
- 
Plasma for future research 
6.4.2 
Study Days 8 (Dose 2) and 9 
This visit will take approximately 5 hours, including observation for 2 hours after dosing.  The 
following procedures will be performed prior to IP administration: 
 Symptom-driven physical exam 
 Vital signs 
 Laboratory Assessments, including: 
- 
Serum chemistries 
- 
Hematology 
- 
Urine pregnancy test for WOCBP 
- 
DGP-IgG  
- 
Serum cytokines 
- 
C3a, C5a, SC5b-9 complement levels  
- 
PK sample 
- 
Plasma for future research 
 Assessment of concomitant medications 
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 IP administration 
The following procedures will be performed at the times specified below, during and after IP 
administration: 
 Vital signs at 15, 30, and 60 minutes after the start of infusion, end of infusion, and 2 hours 
after the end of the infusion 
 C3a, C5a, SC5b-9 complement levels at 30 minutes after start of infusion and end of infusion  
 PK sample at end of infusion and 2 hours after the end of the infusion 
 Monitoring for AEs, including IRs 
In the event of an IR, blood samples for serum cytokines, and C3a, C5a, SC5b-9 complement 
levels will be drawn at the time of the IR.  
The subject will return to the clinic 24 hours after the dose (Day 2) to have blood drawn for: 
- 
Serum cytokines 
- 
C3a, C5a, SC5b-9 complement levels  
- 
Plasma for future research 
6.4.3 
Study Day 15 – Beginning of Gluten Challenge 
This visit will take approximately 2 hours, including observation for 1 hour after consuming the 
wheat gluten.  The following procedures will be performed prior to consuming wheat gluten. 
 Symptom-driven physical exam 
 Vital signs 
 Laboratory Assessments, including: 
- 
Serum chemistries 
- 
Hematology 
- 
DGP-IgG  
- 
Serum cytokines 
- 
C1q binding level 
- 
C3a, C5a, SC5b-9 complement levels  
- 
Whole blood 
- 
Urine gluten test 
 Assessment of concomitant medications 
 Subject to complete CSI-M questionnaire 
 Assessment of AEs 
 Consume first day of wheat gluten 
Prior to discharge from the clinic, the site will dispense additional wheat gluten packets and the 
subject will be instructed on consuming wheat gluten on Study Days 16 through 28. Subjects 
should be instructed to call the site if they have any trouble with the gluten challenge. 
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6.4.4 
Study Day 20 
This visit will take approximately 1 hour and after the subject has consumed their daily wheat 
gluten.  The following procedures will be performed:  
 Assessment of adherence to gluten challenge 
 Symptom-driven physical exam 
 Vital signs 
 Laboratory Assessments, including: 
- 
Serum chemistries 
- 
Hematology 
- 
C1q binding 
- 
DGP-IgG  
- 
Whole blood 
- 
Urine gluten test 
 Assessment of concomitant medications 
 Subject to complete CSI-M questionnaire 
 Assessment of AEs 
6.4.5 
Study Day 29  
This visit will take approximately 3 hours, including the biopsy.  The following procedures will 
be performed:  
 Small bowel biopsy - the biopsy may be performed on Day 28 or Day 29 
 Assessment of adherence to gluten challenge 
 Symptom-driven physical exam 
 Vital signs 
 Laboratory Assessments, including: 
- 
Serum chemistries 
- 
Hematology 
- 
C1q binding 
- 
DGP-IgG  
- 
Urine gluten test 
 Assessment of concomitant medications 
 Subject to complete CSI-M questionnaire 
 Assessment of AEs 
6.4.6 
Study Day 35 (± 1 day) or Early Termination 
This visit will take approximately 1 hour.  The following procedures will be performed:  
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 Symptom-driven physical exam 
 Vital signs 
 Laboratory Assessments, including: 
- 
Serum chemistries 
- 
Hematology 
- 
Serum pregnancy test for WOCBP  
- 
C1q binding 
- 
DGP-IgG  
 Assessment of concomitant medications 
 Subject to complete CSI-M questionnaire 
 Assessment of AEs 
Subjects who discontinue the study after Day 17 (after 3-days of gluten challenge) will have the 
following additional procedures performed on Day 20: 
 Whole blood 
 Small bowel biopsy 
6.5 
Research Storage Samples 
Approximately 3 mL of blood will be collected on Days 1, 2, 8, and 9, frozen and stored. In 
addition, 4 biopsy samples will be collected at the time of each biopsy.  These stored samples 
may be used by the Sponsor or its research partners for celiac or celiac-related disease, for 
retesting of planned tests, for testing to learn more about how TIMP-GLIA works, or clinical 
laboratory testing to provide additional safety data. No human genetic testing will be performed 
on these samples without expressed consent of study subjects. At the conclusion of this study, 
these samples may be retained in storage by the Sponsor or its research partners for a period up 
to 15 years. 
 
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7 ADVERSE EVENTS 
AEs will be reported in a manner consistent with the FDA Guidance for Industry and 
Investigators, “Safety Reporting Requirements for IND and BA/BE Studies,” December 2012 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM227351.pdf). 
7.1 
Reporting Responsibilities 
All AEs will be recorded in the eCRF, from Study Day 1 through Study Day 35.  It is the 
responsibility of the Investigator or Subinvestigator(s) to perform periodic assessment of all AEs.  
Data describing AEs, including SAEs, will be entered in the subject’s medical record and eCRF.  
SAEs will be reported to the Sponsor as described in Section 7.6. 
Subjects who experience AEs, whether serious or not serious, should receive appropriate 
treatment and medical supervision as clinically indicated.  All AEs must be followed until 
resolution/stabilization or until a time that is mutually agreed upon between the Medical Monitor 
and the Investigator. 
7.2 
Definitions 
7.2.1 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an IP, 
whether or not related to the IP. 
7.2.2 
Serious Adverse Event 
An AE or suspected adverse reaction is considered “serious” (SAE) if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
 Death 
 Life-threatening  
 An AE is considered “life-threatening” if, in the view of either the Investigator or Sponsor, 
its occurrence places the patient or subject at immediate risk of death. It does not include an 
AE that, had it occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 A congenital anomaly/birth defect 
 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
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they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room (ER) or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
If it is not certain that an event meets the above definitions of an SAE, contact the Medical 
Monitor to discuss. 
7.2.3 
Relatedness (Causality) 
Causality assessment is required for AEs (and SAEs) that occur during clinical investigations.  
There is currently no standard international nomenclature to describe the degree of causality or 
relatedness of an AE with the IP.  The following terms will be used during this study:  
 Likely - Reasons to consider an AE likely related to treatment may include, but are not 
limited to the following: 
- 
Timing of the event relative to the administration of the IP 
- 
Location of the AE relative to the site of IP administration 
- 
Likelihood based on experience with similar products 
- 
There is a biologically plausible explanation based on the mechanism of action or 
mode of delivery of the treatment 
- 
The AE is repeated on subsequent treatments 
- 
No other explanation is likely 
 Unlikely - An AE with no temporal association with the IP but rather related to other 
etiologies such as concomitant medications or conditions, or subject's known clinical state. 
7.2.4 
Severity 
Severity will be reported in accordance with the Guidance for Industry Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials 
(Appendix 2, Toxicity Grading Scale).   
If an appropriate listing is not present in this table for an AE, the AE will be graded as follows: 
 Grade 1 (Mild) - No interference with daily activity 
 Grade 2 (Moderate) - Some interference with daily activity but medical intervention not 
required (e.g., doctor visit and/or prescription medicine); over the counter medicine permitted 
 Grade 3 (Severe) - Prevents daily activity and requires medical intervention (e.g., doctor 
visit and/or prescription medicine) 
 Grade 4 (Potentially Life-threatening) - ER visit or hospitalization 
7.3 
Clinical Laboratory Abnormalities 
Any laboratory abnormality deemed clinically significant by the Investigator should be reported 
as an AE.  A clinically significant abnormality is a confirmed abnormality (by repeat test) that is 
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changed sufficiently from Screening/Baseline so that in the judgment of the Investigator a 
change in management is warranted.  This alteration may include:  monitoring the laboratory test 
further, initiating other diagnostic tests or procedures, changing ongoing treatment, or 
administering new treatment.   
Whenever possible, the underlying medical diagnosis (e.g., anemia) should be reported as the AE 
term.  Repeated additional tests and/or other evaluations required to establish the significance 
and etiology of an abnormal result should be obtained when clinically indicated.  
7.4 
Physical Exam Abnormalities 
Any physical exam abnormality deemed clinically significant by the Investigator at Day 1 should 
be reported as medical history. Any new physical exam abnormality deemed clinically 
significant by the Investigator during the study should be reported as an AE.  
7.5 
Pregnancy 
No additional doses should be administered to a subject who becomes pregnant during the 
conduct of the trial.  All remaining safety assessments should be performed.  All pregnancies 
that occur –including female partners of male subjects – during the study must be reported 
to the Sponsor and followed to conclusion. The outcome of each pregnancy must be 
reported.   
Pregnancy alone is not an AE, nor is an induced elective abortion to terminate a pregnancy 
without medical reason.  However, an induced therapeutic abortion to terminate a pregnancy due 
to complications or medical reasons must be reported as an SAE.  The underlying medical 
diagnosis for this procedure should be reported as the SAE term.  A spontaneous abortion is 
always considered an SAE. 
7.6 
Reporting of Serious Adverse Events  
SAEs must be reported to the Sponsor or designee within 1 business day of becoming aware of 
the event by entering the data on the AE eCRF. If at the time the Investigator submits an initial 
SAE report the event has not resolved, the Investigator must provide a follow-up as soon as it 
resolves (or upon receipt of significant information if the event is still ongoing). All SAEs must 
be followed until resolution/stabilization or until a time that is mutually agreed upon between the 
Medical Monitor and the Investigator. Upon checking “serious” on the AE eCRF, a notification 
will be sent to the Medical Monitor and/or designee. Relevant eCRFs (including Medical 
History, Concomitant Medications, and Adverse Events) must also be completed to provide 
supporting documentation for the SAE. If there are additional documents that support the SAE 
(e.g., clinic or hospital records or procedure reports), they should be uploaded to the AE eCRF.   
The Sponsor is responsible for notifying the relevant Regulatory Authorities of certain events. It 
is the Investigator’s responsibility to notify the IRB/EC of all SAEs that occur at his or her site. 
Investigators will also be notified of all unexpected, serious, IP-related events that occur during 
the clinical trial. Each site is responsible for notifying its IRB/EC of these additional SAEs.  
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7.7 
Toxicity Management 
All clinical and clinically significant laboratory AEs (i.e., toxicities) will be managed as outlined 
below. 
 Clinical and clinically significant laboratory abnormalities will be graded according to the 
Toxicity Grading Scale in Appendix 2. 
 Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before IP discontinuation, unless such 
a delay is not consistent with good medical practice. 
 Any questions regarding toxicity management should be directed to the Medical Monitor. 
7.7.1 
Suspected Drug-Induced Liver Injury 
 For any ALT or AST > 3x the upper limit of normal (ULN), the results will be confirmed by 
repeat testing within 3 calendar days of receipt of results and prior to further administration 
of IP.  Testing for AP, TBL, direct bilirubin, and international normalized ratio (INR) will be 
obtained at the same time.  The subject will also be assessed for signs and symptoms. 
 If repeat testing shows that ALT or AST > 3x ULN, IP will be permanently discontinued and 
the subject will be monitored closely until a time that is mutually agreed upon between the 
Medical Monitor and the Investigator.  Subjects should be referred to a gastroenterologist for 
further hepatic investigations. 
 Subjects will be permanently discontinued from further IP administration for any of the 
following laboratory abnormalities: 
- 
ALT or AST > 8x ULN 
- 
ALT or AST > 3x ULN and TBL 2x ULN or INR >1.5 
- 
ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
7.7.2 
Other Grades 1 and 2 Laboratory Abnormality or Clinical Event 
Administer IP at the discretion of the Investigator.  If the event is an IR, follow instructions 
outlined in Section 5.6. 
7.7.3 
Other Grade 3 Laboratory Abnormality or Clinical Event 
 For Grade 3 clinically significant laboratory abnormality or clinical event, IP may be 
administered if the event is considered to be Unlikely related to IP. 
 For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be Likely related to IP, IP will be discontinued/interrupted 
until the event is resolved.  IP may be administered/restarted if the event is resolved within 
24 hours and at the discretion of the Investigator. If the event is an IR, follow instructions 
outlined in Section 5.6. 
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7.7.4 
Other Grade 4 Laboratory Abnormality or Clinical Event 
 For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered to be Likely related to IP, IP will be 
permanently discontinued and the subject managed according to local practice. The 
subject should be followed as clinically indicated until the condition returns to baseline or 
is otherwise explained, whichever occurs first.  
 IP may be continued without dose interruption for a clinically non-significant Grade 4 
laboratory abnormality (e.g., Grade 4 creatine kinase after strenuous exercise) or a clinical 
event considered unrelated to IP after discussion with the Medical Monitor.  
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8 STATISTICAL CONSIDERATIONS 
8.1 
Sample Size 
For the primary efficacy endpoint, using a 2-sided 0.05 significance level, a statistical power of 
~70%, and assuming an increase in mean IFN- ɣ SFUs in the placebo group of 75 (standard 
deviation [SD] 100) and in the TIMP-GLIA group of 5 (SD 10), 15 subjects per group will allow 
detection of a difference of 70 in mean reductions in SFUs between the TIMP-GLIA and placebo 
groups. 
8.2 
Analysis Conventions 
Planned statistical analyses will be detailed in the Statistical Analysis Plan (SAP).  This plan will 
be finalized prior to locking of the final data set and unblinding of results.  The general principles 
are outlined below.  Ad hoc exploratory analyses may be performed in addition to those 
specified, but no claims or conclusions will be drawn other than hypotheses to be tested in future 
clinical trials.  
In general, descriptive statistics for continuous variables will consist of subject count, mean (or 
geometric mean), median, SD, and range; and descriptive statistics for categorical variables will 
consist of subject counts and percentages.   
No imputation of values for missing data will be performed.   
All pharmacodynamic, histology, PK, and safety data will be included in data listings and 
summaries. 
8.3 
Analysis Populations 
The following populations will be used for analysis of the study data. 
Safety population: All randomized subjects who receive at least 1 dose of IP.  Subjects will be 
analyzed according to the treatment actually received. 
PK population: All randomized subjects who receive 2 doses of IP.  Subjects will be analyzed 
according to the treatment actually received. 
Pharmacodynamic population: All randomized subjects who receive 2 doses of IP, complete at 
least the first 3 days of the gluten challenge (12 g per day for 3 days) and have pharmacodynamic 
results on Study Day 1, 15 and 20. 
Histology population: All randomized subjects who receive 2 doses of IP, complete the gluten 
challenge per protocol and have both a baseline and Day 29 biopsy. 
8.4 
Demographic Data and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group and consist of 
(but not limited to) the following: age, height, weight, sex, ethnicity/race, and CD history.  
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Additionally, the number and percent of subjects with past and current medical disorders (i.e., 
Medical History) at Study Day 1 will be presented overall and by treatment group.    
8.5 
Pharmacodynamic Analyses 
The mean changes from baseline in IFN-γ SFUs within and between treatment groups will be 
compared using a Wilcoxon Signed Rank Test and a Wilcoxon Rank Sum Test, respectively. 
The proportion of subjects with a 2-fold increase from baseline (and an increase of at least 10) in 
IFN-γ SFUs in the placebo and TIMP-GLIA groups will be compared using a Fisher’s Exact 
Test. 
Descriptive statistics will be used to summarize the additional pharmacodynamic endpoints. 
8.6 
Histology Analyses 
The mean changes from baseline in villus height, crypt depth, and their ratio (Vh:Cd) within and 
between treatment groups will be compared using a Wilcoxon Signed Rank Test and a Wilcoxon 
Rank Sum Test, respectively. 
The proportion of subjects with a decrease of ≥ 0.4 in Vh:Cd in the placebo and TIMP-GLIA 
groups will be compared using a Fisher’s Exact Test. 
The mean changes from baseline in IELs within and between treatment groups will be compared 
using a Wilcoxon Signed Rank Test and a Wilcoxon Rank Sum Test, respectively. 
8.7 
Celiac Signs and Symptoms 
Subject responses to the CSI-M will be summarized using descriptive statistics. 
8.8 
Pharmacokinetic Analyses 
Individual subject TIMP-GLIA concentrations and derived PK parameters will be summarized 
using descriptive statistics, including coefficient of variation.. 
8.9 
Safety Analyses 
8.9.1 
Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Affairs (MedDRA).  
Frequency tables will be presented by treatment group for all AEs and SAEs by System Organ 
Class (SOC) and Preferred Term (PT).  Frequency tables will also be produced by treatment 
group for AEs leading to discontinuation from IP and study, by severity, and by causality.  No 
formal statistical testing will be done. 
Clinically significant physical exam and lab abnormalities will be reported as AEs, and 
summarized as described above. 
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8.9.2 
Laboratory Evaluations and Vital Signs 
Quantitative data (e.g. clinical lab results) will be summarized by mean, median, SD, and range.  
Laboratory abnormalities will be analyzed as safety outcomes by summarizing frequency, 
severity, and changes from baseline.  Other analyses may include but are not limited to the 
following: examination of shift tables and pre-established severity grades. 
8.9.3 
Concomitant Medications 
Concomitant medications will be coded using the most current World Health Organization 
(WHO) drug dictionary and summarized by drug class and medication term, with results 
presented by treatment group. 
8.10 Interim Analysis 
An interim analysis will be performed when Day 29 data are available for the 30 subjects.  The 
analysis will involve looking at results for change from baseline in IFN-γ SFUs and change from 
baseline in Vh:Cd.  The final sample size will be determined based on the operating 
characteristics for a decision criterion using a Bayesian approach applied to both of these 
endpoints.  An additional 20 subjects (10 per arm) may be randomized based on the interim 
results.  Details of this interim analysis will be provided in the SAP. 
 
 
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9 ETHICAL AND ADMINISTRATIVE RESPONSIBILITIES 
9.1 
Ethical Conduct of the Study 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor, its authorized US 
representative and Investigator abide by good clinical practice (GCP) as described in the ICH 
guideline E6, and in US regulations described in 21 Code of Federal Regulations (CFR) parts 50, 
54, 56, and 312.  Compliance with these regulations also constitutes compliance with the ethical 
principles that have their origins in the Declaration of Helsinki. 
9.2 
Institutional Review Board Approval 
This protocol and the ICF and any subsequent modifications will be reviewed and approved by 
the relevant IRB responsible for oversight of the study.  A letter from the IRB indicating 
approval of the study to be conducted by the Investigator will be provided to the Sponsor prior to 
initiation of any enrollment at that site.  All reviews and approvals by the IRB will be in 
accordance with 21 CFR part 56. 
9.3 
Informed Consent 
The ICF document must be signed and dated prior to the initiation of study-related tests, and 
prior to administration of IP.  The original signed ICF for each participating subject shall be filed 
with records kept by the Investigators.  A copy of the ICF must be provided to the subject.  If 
applicable, the ICF will be provided in a certified translation of the local language. 
9.4 
Confidentiality 
Personal study subject data collected and processed for the purposes of this study should be 
managed by the Investigator and his/her staff with adequate precautions to ensure the 
confidentiality of those data, and in accordance with applicable national and/or local laws and 
regulations on personal data protection. 
Monitors, auditors and other authorized agents of the Sponsor, the IRB approving this research, 
and any applicable regulatory authorities will be granted direct access to the study subjects’ 
original medical records for verification of clinical trial procedures and/or data, without violating 
the confidentiality of the subjects, to the extent permitted by the law and regulations.  In any 
presentation of the results of this study at meetings or in publications, the subjects’ identity will 
remain confidential.    
9.5 
Protocol Amendments 
Any changes to the protocol will be made in writing by the Sponsor in the form of a protocol 
amendment.  All protocol amendments will be sent to the Investigator, who is responsible for 
submitting the amendment to the IRB for approval. 
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9.6 
Case Report Forms  
An eCRF will be used to record subject data specified by this protocol.  The eCRF must be 
completed by designated and trained study personnel.  The eCRF will be signed by the 
Investigator or a Sub-Investigator listed on the Form FDA 1572.  It is the responsibility of the 
Investigator to ensure the eCRFs are completed and submitted to the Sponsor (or designee) in an 
accurate and timely manner.  The processing of eCRFs will include an audit trail (to include 
changes made, reason for change, date of change and person making change).   
9.7 
Source Document Maintenance 
Source documents are defined as the results of original observations and activities of a clinical 
investigation.  Source documents may include, but are not limited to, study progress notes, e-
mail correspondences, computer printouts, laboratory data, and drug accountability records.  All 
source documents produced in this study will be maintained by the Investigator(s) and made 
available for inspection by the Sponsor’s representatives, the IRB, the FDA, or other regulatory 
authorities. 
9.8 
Retention of Records 
US regulations (21 CFR part 312.62) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drugs including medical records, 
eCRFs, ICFs, test results, and IP records be kept on file by the Investigator for 2 years after a 
marketing application is approved for the drug for the indication for which it is being studied.  If 
no application is filed or approved, these records must be kept for 2 years after the investigation 
has been discontinued and the FDA has been notified.  ICH guidelines indicate that documents 
should be retained until 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 at least 2 years have elapsed since the formal discontinuation of clinical development 
of the IP.  No study records should be destroyed without prior authorization from the Sponsor. 
9.9 
Study Monitoring 
Site visits will be conducted by an authorized Sponsor representative (the monitor) to inspect 
study data, subjects’ medical records, and eCRFs in accordance with ICH guidelines, GCPs, and 
the respective US or national regulations and guidelines, as applicable.  It will be the monitor’s 
responsibility to inspect the eCRFs at regular intervals throughout the study, to verify the 
adherence to the protocol and the completeness, consistency and accuracy of the data being 
entered.  The monitor should have access to laboratory test reports and other subject records 
needed to verify the entries on the eCRFs. 
The Investigator will permit representatives of the Sponsor, the IRB, the FDA, and/or respective 
health authorities to inspect facilities and records relevant to this study. 
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9.10 Protocol Deviations 
Sites are responsible for abiding by their IRB rules and regulations for reporting protocol 
deviations.  Additionally, the following important protocol deviations will be reported in the 
eCRF: 
 Subject did not meet study eligibility criteria 
 Subject did not receive the correct treatment assignment 
 Subject received the wrong amount of a dose IP (i.e., ± 20% of assigned dose) 
 Subject received a prohibited concomitant medication 
A subject who has 1 of the above deviations will not receive further doses but will be followed 
for safety per protocol. 
9.11 Financial Disclosure 
Investigators participating in this study will provide accurate financial disclosure information to 
the Sponsor as required by 21 CFR Part 54. Investigators will update the financial information if 
any relevant changes occur during the study and for 1 year following completion of the study. 
9.12 Publication and Disclosure Policy 
Investigators and their staff shall hold confidential, and not disclose directly or indirectly to any 
third party other than those persons involved in the study who have a need to know, the protocol, 
the data arising out of the study, and any other information related to the study or to Sponsor’s 
products or research programs that is provided to the Investigator. All such persons must be 
instructed not to further disseminate this information to others. Investigators shall not use the 
Confidential Information for any purpose other than the study. The foregoing obligations of 
confidence and non-use assumed by the Investigator shall not apply to: (a) information which at 
the time of disclosure is in the public domain; (b) information which thereafter lawfully becomes 
part of the public domain other than disclosure by or through the Investigator; (c) information 
which, as evidenced by the Investigator’s written records, was known by the Investigator prior to 
the Sponsor’s disclosure; (d) information which is lawfully disclosed to the Investigator by a 
third party not under any obligation of confidence to the Sponsor; or (e) information which is 
required to be disclosed by law or government regulatory agency, provided reasonable advance 
notice of such disclosure is given to the Sponsor.  
All data and discoveries arising out of the study, patentable or non-patentable, shall be the sole 
property of the Sponsor.  The Sponsor reserves the right of prior review of any publication or 
presentation of information related to the study. The Sponsor reserves the right of prior review of 
any publication or presentation of information related to this study. The Sponsor may use these 
data now or in the future for presentation or publication at the Sponsor’s discretion or for 
submission to government regulatory agencies. 
The Sponsor adheres to the general principles of publication of scientific data as articulated by 
the International Committee of Medical Journal Editors and acknowledges its responsibility to 
publish results of clinical trials.  Persons that fulfill the criteria for authorship 
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(http://www.icmje.org/recommendations/) may be authors on publications based on their 
contributions to the design, conduct, results, and/or analysis of this clinical trial.  Investigators 
will have access to the data from this clinical trial for the preparation of scientific presentations 
and publications subject to the requirements of confidentiality.  The Sponsor reserves the right to 
review, within a reasonable time frame, results or analyses from data generated in this study that 
are intended for public presentation, including scientific meetings. 
In signing this protocol, Investigator agrees to the release of the data from this study and 
acknowledges the above confidentiality and publication policy. The provisions of this Statement 
shall survive the completion of the study.  
 
 
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10 REFERENCES 
Fasano A, Berti I, Gerarduzzi T, Not T, Colletti RB, Drago S, Elitsur Y, Green PH, Guandalini 
S, Hill ID, Pietzak M, Ventura A, Thorpe M, Kryszak D, Fornaroli F, Wasserman SS, Murray 
JA, Horvath K.  Prevalence of celiac disease in at-risk and not-at-risk groups in the United 
States: a large multicenter study.  Arch Intern Med. 2003 
Fasano A, Catassi C. Clinical practice. Celiac Disease. N Engl J Med. 2012. 
Getts DR, Shea LD, Miller SD, King NJC. Harnessing nanoparticles for immune modulation. 
Trends Immunol. 2015. 
Green PHR, Stavropoulos SN, Panagi SG, Goldstein SL, Mcmahon DJ, Absan H, Neugut AI.  
Characteristics of adult celiac disease in the USA: results of a national survey.  Am J 
Gastroenterol. 2001. 
Green PH, Cellier C.  Celiac disease. N Engl J Med. 2007. 
Green PH, Lebwohl B, Greywoode R.  Celiac disease. J Allergy Clin Immunol. 2015. 
Laurin P, Wolving M, Fälth-Magnusson K. Even small amounts of gluten cause relapse in 
children with celiac disease.  J Ped Gastroenterol Nutr. 2002. 
Leffler DA, Dennis M, Edwards George J, Jamma S, Cook E, Schuppan D, Kelly CP. A 
Validated Disease Specific Symptom Index for Adults with Celiac Disease. Clinical 
Gastroenterology and Hepatology. 2009 Dec;7(12):1328-34, 1334.e1-3. Epub 2009 Aug 7. 
Leffler DA, Acaster S, Gallop K, Dennis M, Kelly CP, Adelman DC. A Novel Patient-Derived 
Conceptual Model of the Impact of Celiac Disease in Adults: Implications for Patient-Reported 
Outcome and Health-Related Quality-of-Life Instrument Development. Value Health. 2017. 
Ludvigsson, J.F., Leffler, D.A., Bai, J.C. et al.  The Oslo definitions for coeliac disease and 
related terms. Gut.  2013. 
Mazzarella G, Stefanile R, Camarca A, Giliberti P, Cosentini E, Marano C et al. Gliadin 
activates HLA class I-restricted CD8+ T cells in celiac disease intestinal mucosa and induces the 
enterocyte apoptosis. Gastroenerol. 2008. 
Rubio-Tapia A, Ludvigsson JF, Brantner TL, Murray JA, Everhart JE. The prevalence of celiac 
disease in the United States. Am J Gastroenterol. 2012. 
Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA.  ACG clinical guidelines: 
diagnosis and management of celiac disease.  Am J Gastroenterol. 2013. 
Schuppan D, Junker Y, Barisani D. Celiac disease: from pathogenesis to novel therapies.  
Gastroenterology. 2009 
 
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Screen 
Dose 
1 
 
Dose 
2 
 
Gluten Challenge 
EOS/ET 
Study Day 
D -45 
to -1 
D1 
D2 
D8 
D9 
D15 
D20 
D29 
D35 ± 1 
Informed consent 
X 
  
 
  
 
  
  
  
  
Medical History, including celiac, 
dietary, and medication history 
X 
  
 
  
 
  
  
  
  
Demographics 
X 
  
 
  
 
  
  
  
  
Confirm eligibility criteria 
X 
X 
 
  
 
  
  
  
  
Complete physical examination 
X 
  
 
  
 
  
  
  
  
Symptom-driven physical 
examination 
  
X 
 
X 
 
X 
X 
X 
X 
Vital Signs a 
X 
X b 
 
X b 
 
X 
X 
X 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
Small bowel biopsy 
X 
  
 
  
 
  
  
X c 
  
Laboratory Tests 
  
  
 
  
 
  
  
  
  
Serum chemistries  
X d 
X 
 
X 
 
X 
X 
X 
X 
Hematology 
X 
X 
 
X 
 
X 
X 
X 
X 
High definition allelic HLA 
testing 
X 
  
 
  
 
  
  
  
  
HCV and HIV serology; HBsAg 
X 
  
 
  
 
  
  
  
  
IgA, tTG-IgA 
X 
  
 
  
 
  
  
  
  
DGP-IgG 
X 
X 
 
X 
 
X 
X 
X 
X 
Pregnancy test (WOCBP only) 
Serum 
Urine 
 
Urine 
 
  
  
  
Serum 
Urine gluten test 
 
 
 
 
 
X 
X 
X 
 
Serum cytokines 
  
X 
X 
X 
X 
X 
  
  
  
C1q binding level 
 
X 
 
 
 
X 
X 
X 
X 
C3a, C5a, SC5b-9 complement 
levels  
  
X e 
X 
X e 
X 
X 
 
 
 
Whole blood for IFN- ɣ ELISpot f 
  
X 
 
  
 
X 
X 
 
 
Whole blood for gliadin-specific 
T cell proliferation, cytokine 
secretion f 
  
X 
 
  
 
X 
X 
  
  
Plasma for future research 
 
X 
X 
X 
X 
 
 
 
 
Blood for PK 
 
 
 
X g 
 
 
 
 
 
Randomization 
  
X 
 
  
 
  
  
  
  
Dosing 
  
X 
 
X 
 
  
  
  
  
Oral gluten challenge 
  
  
 
  
 
D15-17: 12g; D18-28: 6g 
  
Concomitant medication 
assessment 
X 
X 
 
X 
 
X 
X 
X 
X 
CSI-M Questionnaire 
 
 
 
 
 
X 
X 
X 
X 
AE assessment  
  
X 
 
X 
 
X 
X 
X 
X 
a 
Vital signs include temperature, blood pressure, and heart rate; height and weight will be collected at the 
Screen Visit. Weight will be collected again on Day 1.  Vital signs should be obtained after subject is resting for 
5 minutes. 
b 
On Days 1 and 8, vital signs will be obtained prior to dose and at 15, 30, and 60 minutes after the start of 
infusion, end of infusion, and 2 hours after the end of the infusion. 
Property of Takeda: Fo
on
For 
ommercial use only and subject to the applicable Terms of Use
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T
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X
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s
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X
an
y
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y a
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o y
X
X
o
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X
se
X e
u
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c 
Biopsy may be obtained on Day 28 or Day 29 
d 
Fasting is required at screening only 
e 
C3a, C5a, and SC5b-9 complement levels will be obtained pre-dose, 30 minutes after start of infusion, and end 
of infusion 
f 
Pre-dose on Day 1, pre-gluten consumption on Day 15 and post-gluten consumption on Day 20 
g 
Pre-dose, end of infusion, and 2 hours after the end of infusion 
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Appendix 2 Toxicity Grading Scale 
Tables for Clinical Abnormalities 
Local Reaction to Injectable 
Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life Threatening 
(Grade 4) 
Pain 
Does not interfere with activity 
Repeated use of non-narcotic 
pain reliever > 24 hours or 
interferes with activity 
Any use of narcotic pain 
reliever or prevents daily 
activity 
ER visit or hospitalization 
Tenderness 
Mild discomfort to touch 
Discomfort with movement 
Significant discomfort at rest 
ER visit or hospitalization 
Erythema/Redness 
2.5 - 5 cm 
5.1 - 10 cm 
> 10 cm 
Necrosis or exfoliative 
dermatitis 
Induration/Swelling 
2.5 - 5 cm and does not 
interfere with activity 
5.1 - 10 cm or interferes with 
activity 
> 10 cm or prevents daily 
activity 
Necrosis 
 
Vital Signs  
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life Threatening 
(Grade 4) 
Fever (°C) ** 
           (°F) ** 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Tachycardia - beats per minute 
101 – 115 
116 – 130 
> 130 
ER visit or hospitalization for 
arrhythmia 
Bradycardia - beats per minute*** 
50 – 54 
45 – 49 
< 45 
ER visit or hospitalization for 
arrhythmia 
Hypertension (systolic) - mm Hg 
141 – 150 
151 – 155 
> 155 
ER visit or hospitalization for 
malignant hypertension 
Hypertension (diastolic) - mm Hg 
91 – 95 
96 – 100 
> 100 
ER visit or hospitalization for 
malignant hypertension 
Hypotension (systolic) – mm Hg 
85 – 89 
80 – 84 
< 80 
ER visit or hospitalization for 
hypotensive shock 
Respiratory Rate – breaths per minute 
17 – 20 
21 – 25 
> 25 
Intubation 
  
 
 
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Systemic 
(General) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Nausea/vomiting 
No interference with activity or 1 
- 2 episodes/24 hours 
Some interference with activity 
or > 2 episodes/24 hours 
Prevents daily activity, requires 
outpatient IV hydration 
ER visit or hospitalization 
for hypotensive shock 
Diarrhea 
2 - 3 loose stools or < 400 
gms/24 hours 
4 - 5 stools or 400 - 800 gms/24 
hours 
6 or more watery stools or > 
800gms/24 hours or requires 
outpatient IV hydration 
ER visit or hospitalization 
Headache 
No interference with activity 
Repeated use of non-narcotic 
pain reliever > 24 hours or some 
interference with activity 
Significant; any use of narcotic 
pain reliever or prevents daily 
activity 
ER visit or hospitalization 
Fatigue 
No interference with activity 
Some interference with activity Significant; prevents daily activity ER visit or hospitalization 
Myalgia 
No interference with activity 
Some interference with activity Significant; prevents daily activity ER visit or hospitalization 
 
Systemic Illness 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Illness or clinical adverse event (as 
defined according to applicable 
regulations) 
No interference with activity 
Some interference with activity 
not requiring medical 
intervention 
Prevents daily activity and 
requires medical intervention 
ER visit or hospitalization 
 
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Tables for Laboratory Abnormalities 
Serum * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life Threatening 
(Grade 4)** 
Sodium – Hyponatremia mEq/L 
132 – 134 
130 – 131 
125 – 129 
< 125 
Sodium – Hypernatremia mEq/L 
144 – 145 
146 – 147 
148 – 150 
> 150 
Potassium – Hyperkalemia mEq/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
> 5.6 
Potassium – Hypokalemia mEq/L 
3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1 
Glucose – Hypoglycemia mg/dL 
65 – 69 
55 – 64 
45 – 54 
< 45 
Glucose – Hyperglycemia 
Fasting – mg/dL 
Random – mg/dL 
 
100 – 110 
110 – 125 
 
111 – 125 
126 – 200 
 
>125 
>200 
Insulin requirements or 
hyperosmolar coma 
Blood Urea Nitrogen 
BUN mg/dL 
23-26 
27 – 31 
> 31 
Requires dialysis 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires dialysis 
Calcium – hypocalcemia mg/dL 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
< 7.0 
Calcium – hypercalcemia mg/dL 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 12.0 
> 12.0 
Magnesium – hypomagnesemia mg/dL 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9 
Phosphorous – hypophosphatemia 
mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK – mg/dL 
1.25 – 1.5 x ULN*** 
1.6 – 3.0 x ULN 
3.1 –10 x ULN 
> 10 x ULN 
Albumin – Hypoalbuminemia g/dL 
2.8 – 3.1 
2.5 – 2.7 
< 2.5 
-- 
Total Protein – Hypoproteinemia g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
-- 
Alkaline phosphate – increase by factor 
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
3.1 – 10 x ULN 
> 10 x ULN 
Liver Function Tests –ALT, AST increase 
by factor 
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10 x ULN 
> 10 x ULN 
Bilirubin – when accompanied by any 
increase in Liver Function Test increase 
by factor 
1.1 – 1.25 x ULN 
1.26 – 1.5 x ULN 
1.51 – 1.75 x ULN 
> 1.75 x ULN 
Bilirubin – when Liver Function Test is 
normal; increase by factor 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
Cholesterol 
201 – 210 
211 – 225 
> 226 
--- 
Pancreatic enzymes – amylase, lipase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
 
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Hematology * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life Threatening 
(Grade 4) 
Hemoglobin (Female) - gm/dL 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (Female) change from 
baseline value - gm/dL 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - gm/dL 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
Hemoglobin (Male) change from baseline 
value – gm/dL 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC Increase - cell/mm3 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25, 000 
> 25,000 
WBC Decrease - cell/mm3 
2,500 – 3,500 
1,500 – 2,499 
1,000 – 1,499 
< 1,000 
Lymphocytes Decrease - cell/mm3 
750 – 1,000 
500 – 749 
250 – 499 
< 250 
Neutrophils Decrease - cell/mm3 
1,500 – 2,000 
1,000 – 1,499 
500 – 999 
< 500 
Eosinophils - cell/mm3 
650 – 1500 
1501 - 5000 
> 5000 
Hypereosinophilic 
Platelets Decreased - cell/mm3 
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000 
< 25,000 
PT – increase by factor (prothrombin time) 1.0 – 1.10 x ULN** 
1.11 – 1.20 x ULN 
1.21 – 1.25 x ULN 
> 1.25 ULN 
PTT – increase by factor (partial 
thromboplastin time) 
1.0 – 1.2 x ULN 
1.21 – 1.4 x ULN 
1.41 – 1.5 x ULN 
> 1.5 x ULN 
Fibrinogen increase - mg/dL 
400 – 500 
501 – 600 
> 600 
-- 
Fibrinogen decrease - mg/dL 
150 – 200 
125 – 149 
100 – 124 
< 100 or associated with 
gross bleeding or 
disseminated intravascular 
coagulation (DIC) 
 
Source: Guidance for Industry Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials. Food and Drug 
Administration Center for Biologics Evaluation and Research. September 2007 
 
 
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Appendix 3 Celiac Symptom Index-Modified (CSI-M) 
 
Question 
1 
2 
3 
4 
5 
1. Have you been bothered by pain or 
discomfort in the upper abdomen or 
the pit of the stomach during the past 
7 days? 
None of the time 
A little of the time 
Some of the time 
Most of the time 
All of the time 
2. Have you been bothered by nausea 
during the past 7 days? 
None of the time 
A little of the time 
Some of the time 
Most of the time 
All of the time 
3. Have you been bothered by rumbling 
in your stomach during the past 7 
days? 
None of the time 
A little of the time 
Some of the time 
Most of the time 
All of the time 
4. Has your stomach felt bloated during 
the past 7 days? 
None of the time 
A little of the time 
Some of the time 
Most of the time 
All of the time 
5. Have you been bothered by diarrhea 
during the past 7 days? 
None of the time 
A little of the time 
Some of the time 
Most of the time 
All of the time 
6. Have you been bothered by low 
energy level during the past 7 days? 
None of the time 
A little of the time 
Some of the time 
Most of the time 
All of the time 
 
Leffler DA, Dennis M, Edwards George J, Jamma S, Cook E, Schuppan D, Kelly CP. A Validated Disease Specific Symptom Index for Adults with Celiac 
Disease. Clinical Gastroenterology and Hepatology. 2009 Dec;7(12):1328-34, 1334.e1-3. Epub 2009 Aug 7. 
 
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Appendix 4 Amendment to the Protocol 
Amendment 1, Protocol Version 2.0, XX December 2018 
The overall purpose of the amendment is to: 
 Update results from Phase 1 study, TGLIA-5.001 
 Add an interim analysis after 30 subjects have completed Day 29 to determine whether 
additional subjects should be added 
 Add collection of complement levels and serum cytokines at 24 hours following each 
infusion of Study Drug (Days 2 and 9) 
 Add collection plasma for future research on Days 1, 2, 8, 9, 15; remove whole blood for 
future research on Days 1, 15, and 20 
 Add collection of celiac signs and symptoms before, during, and after the oral gluten 
challenge 
 Allow for inclusion of subjects with thyroid disease (Exclusion 6 – modified) 
 Other minor changes 
Effect on Informed Consent Form 
 Add collection of complement levels and serum cytokines at 24 hours following each 
infusion of Study Drug (Days 2 and 9) 
 Add collection plasma for future research on Days 1, 2, 8, 9, 15; remove whole blood for 
future research on Days 1, 15, and 20 
 Add collection of celiac signs and symptoms before, during, and after the oral gluten 
challenge 
Summary of Changes 
Section 
Change 
Rationale 
Synopsis and Section 2.1.2  
Secondary Objectives 
Modified: 
• To compare the proportion of 
subjects who have a 32-fold 
increase (and an increase of at 
least 10) from baseline in   
IFN-γ SFUs following an oral 
gluten challenge in subjects 
treated with TIMP-GLIA or 
placebo. 
Assay validated in prior Phase 0 
study demonstrates a “responder” 
a the 2-fold increase level 
Synopsis and Section 2.1.2 
Secondary Objectives  
Added: 
• To compare celiac disease 
(CD) signs and symptoms 
before and during an oral 
gluten challenge in subjects 
Additional measure of efficacy 
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Section 
Change 
Rationale 
treated with TIMP-GLIA or 
placebo. 
Synopsis and Section 3.1  
(Overall) Study Design, ¶2 
Added: 
Subjects will be asked to 
complete the Celiac Symptom 
Index-Modified (CSI-M) 
questionnaire on Days 15, 20, 
29, and 35. 
Instrument to measure symptoms 
and timepoints for measurement 
Synopsis and Section 3.1  
(Overall) Study Design, ¶4 
Added: 
Safety laboratory tests for 
complement levels (C3a, C5a, 
and SC5b-9), and serum 
cytokines will be performed on 
Days 1, 2, 8, 9, and 15.  
Additional s Samples for C1q 
binding will be performed on 
Days 1, 15, 20, 29, and 35. 
To obtain safety samples at 24 
hours following each infusion of 
Study Drug 
Days 1 and 15 inadvertently left 
out of original protocol 
Synopsis and Section 4.1 
Inclusion Criteria 
7. Intact spleen (no history of 
splenectomy or splenic 
disorders). 
Clarification that assessment can 
be made by history 
Synopsis and Section 4.2  
Exclusion Criteria 
Modified 
6. Presence or history of celiac-
associated thyroid disease or 
Type 1 diabetes, regardless of 
current treatment. 
 
16. Receipt of TIMP-GLIA in prior 
clinical trial. 
 
 
 
21. Participation in an oral gluten 
challenge within 12 6 months 
prior to Day 1. 
Subjects with thyroid disease are 
allowed into the trial 
 
 
 
Subjects who have ever been 
exposed to TIMP-GLIA will be 
excluded 
 
A 6 month “washout” post-gluten 
challenge is a sufficiently long 
time period to allow for a return to 
baseline on a gluten free diet 
Synopsis and Section 2.2.3  
Criteria for Evaluation 
Added: 
CD Signs and Symptoms: 
• Responses to CSI-M 
(Appendix 3) 
Additional measure of efficacy 
Synopsis – Statistical Methods, 
Sample Size 
Added: 
An interim analysis will be 
performed when Day 29 data 
are available for the 30 
subjects.  The final sample size 
will be determined based on 
the operating characteristics 
for a decision criterion using a 
Bayesian approach.  An 
additional 20 subjects (10 per 
Interim analysis to determine the 
need for additional subjects 
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Section 
Change 
Rationale 
arm) may be randomized based 
on the interim results. 
Synopsis Statistical Methods, 
Analyses – Efficacy/ 
Pharmacodynamics, ¶2 and 
Section 8.5 Pharmacodynamic 
Analyses, ¶2 
Modified: 
The proportion of subjects with a 
32-fold increase…. 
Consistency with endpoint 
definition 
Synopsis Statistical Methods, 
Analyses – Efficacy/ 
Pharmacodynamics, ¶7 
Added: 
Subject responses to the CSI-
M will be summarized using 
descriptive statistics. 
Provide analysis for endpoint 
Synopsis Statistical Methods, 
Analyses – PK and Section 8.8 
Pharmacokinetic Analyses 
Deleted: 
PK parameters will be calculated 
using noncompartmental 
methods. 
Not enough timepoints for 
noncompartmental analysis. 
Section 1.5 – Clinical Trials of 
TIMP-GLIA 
Entire section updated to reflect 
current study status, and 
completion of Part B dosing.  
Updated study status and 
findings 
Section 5.3 Preparation of 
Investigational Product, ¶2 
Added: 
Dose will be determined by 
subject weight on Day 1. 
Clarification of dosing weight 
Section 5.5 Administration of 
Investigational Product, ¶1 
Modified: 
TIMP-GLIA or placebo will be 
administered by unblinded, 
trained study personnel.   
Clarify that person administering 
Study Drug will be unblinded 
Section 5.6 Management of 
Infusion Reactions, ¶2, bullet 3 
Added: 
• Blood samples for serum 
cytokines, and C3a, C5a, 
SC5b-9 complement levels 
will be drawn at the time of 
the IR 
Obtain information about 
cytokines and complement at the 
time of IR, in addition to protocol 
timepoints 
Section 6.1 Definitions and 
Descriptions of Assessments and 
Procedures – CD History 
Changed: 
CD history should include date of 
diagnosis, date of biopsy proven 
diagnosis, signs and symptoms 
at the time of diagnosis and prior 
to starting a GFD, and date 
subject started GFD, current 
signs and symptoms.  A copy of 
the biopsy must be maintained in 
the subject’s medical record. 
Signs and symptoms will be 
collected using the CSI-M 
Section 6.1 Definitions and 
Descriptions of Assessments and 
Procedures – CSI-M 
Added: 
CSI-M – modified celiac 
symptoms index (Appendix 3); 
to be used to assess 
symptoms before, during, and 
after the oral gluten challenge.  
Validated instrument to collect 
celiac symptoms 
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Section 
Change 
Rationale 
Section 6.1 Definitions and 
Descriptions of Assessments and 
Procedures – Serum cytokine 
Added: 
IL-13 
Inadvertently left out of original 
protocol 
Section 6.1 Definitions and 
Descriptions of Assessments and 
Procedures – Whole blood 
Deleted: 
…whole blood samples will be 
obtained for pharmacodynamic 
assays and future research. 
Whole blood will not be collected 
for future research; replaced by 
plasma 
Section 6.4.1 Study Days 1 
(Dose 1) and 2 
Added the following procedure: 
Day 1  
- Weight - to be used to 
calculate dose 
- Plasma for future research 
- C3a, C5a, SC5b-9 complement 
levels at 15 30 minutes after start 
of infusion and end of infusion 
- Monitoring for AEs, including 
IRs 
In the event of an IR, blood 
samples for serum cytokines, 
and C3a, C5a, SC5b-9 
complement levels will be 
drawn at the time of the IR 
Day 2  
The subject will return to the 
clinic 24 hours after the dose 
(Day 2) to have blood drawn 
for: 
- Serum cytokines 
- C3a, C5a, SC5b-9 
complement levels  
- Plasma for future research 
Specify that subject weight at Day 
1 will be used to calculate dose 
Modifications and additions to 
timepoints for collection of 
complement and serum cytokines 
was made at the request of the 
DMC 
Plasma for future research will be 
used for additional/repeat safety 
assessments as needed 
Section 6.4.2 Study Days 8 
(Dose 2) and 9 
Added: 
Day 1 
- Plasma for future research- 
C3a, C5a, SC5b-9 complement 
levels at 15 30 minutes after start 
of infusion and end of infusion 
- Monitoring for AEs, including 
IRs 
In the event of an IR, blood 
samples for serum cytokines, 
and C3a, C5a, SC5b-9 
complement levels will be 
drawn at the time of the IR 
Day 2  
The subject will return to the 
clinic 24 hours after the dose 
Modifications and additions to 
timepoints for collection of 
complement and serum cytokines 
was made at the request of the 
DMC 
Plasma for future research will be 
used for additional/repeat safety 
assessments as needed 
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Section 
Change 
Rationale 
(Day 2) to have blood drawn 
for: 
- Serum cytokines 
- C3a, C5a, SC5b-9 
complement levels  
- Plasma for future research 
Sections 
6.4.3 Study Day 15 
6.4.4 Study Day 20 
6.4.5 Study Day 29, and  
6.4.6 Study Day 35 (± 1 day) or 
Early Termination 
Added: 
• Subject to complete CSI-M 
questionnaire 
To assess celiac-specific 
symptoms before, during, and 
after the oral gluten challenge 
Section 6.4.6 Study Day 35 (± 1 
day) or Early Termination 
Added: 
A window for Day 35 
To provide flexibility for 
scheduling Day 35 
Section 6.5 Research Storage 
Samples 
Modified: 
Approximately 20 3 mL of blood 
will be collected on Days 1,15 2, 
8, and 20 9, frozen and stored. In 
addition, 2 4 biopsy samples will 
be collected at the time of each 
biopsy. 
Plasma (and not whole blood) for 
future research will be used for 
additional/repeat safety 
assessments as needed 
4 not 2 biopsy samples will be 
collected at each biopsy 
Section 8.7 Celiac Signs and 
Symptoms 
Added: 
Subject responses to the CSI-
M will be summarized using 
descriptive statistics. 
Describe analysis method for 
endpoint 
Section 8.10 Interim Analysis 
Added: 
An interim analysis will be 
performed when Day 29 data 
are available for the 30 
subjects.  The analysis will 
involve looking at results for 
change from baseline in IFN-γ 
SFUs, and change from 
baseline in Vh:Cd.  The final 
sample size will be determined 
based on the operating 
characteristics for a decision 
criterion using a Bayesian 
approach applied to both of 
these endpoints.  An additional 
20 subjects (10 per arm) may 
be randomized based on the 
interim results.  Details of this 
interim analysis will be 
provided in the SAP. 
Interim analysis to determine the 
need for additional subjects 
Section 10 References 
Added: 
Leffler DA, Dennis M, Edwards 
George J, Jamma S, Cook E, 
Schuppan D, Kelly CP. A 
Reference for CSI-M 
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Section 
Change 
Rationale 
Validated Disease Specific 
Symptom Index for Adults with 
Celiac Disease. Clinical 
Gastroenterology and 
Hepatology. 2009 
Dec;7(12):1328-34, 1334.e1-3. 
Epub 2009 Aug 7. 
Appendix 1 Schedule of Events 
Updated  
To reflect changes to Section 6 
Appendix 3 Celiac Symptom 
Index-Modified (CSI-M) 
Added 
Provide the instrument to be used 
 
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