Clinical trial NCT03486990
Conditions: Celiac Disease
Keywords: safety tolerability pharmacokinetics celiac gliadin gluten
Sponsor: Takeda
Start date: 2018-01-23; Completion date: 2019-07-22
Enrollment: 23 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is to characterize the safety and tolerability of an investigational drug called TIMP-GLIA when either one or two intravenous doses are given to subjects with celiac disease. The way the body reacts to TIMP-GLIA is being checked by laboratory tests of the blood and urine, and study subject health will also be monitored by vital signs such as blood pressure, electrocardiogram (ECG), and physical examination.

Detailed description:
This study is a 2-part, multicenter study. In Part A, eligible subjects will be enrolled into escalating dose cohorts (n = 2/cohort for 2 dose levels followed by n = 3/cohort for 4 dose levels). TIMP-GLIA will be administered as a single intravenous (IV) infusion on Day 1. A staggered dosing strategy will be used in Part A. Subjects will undergo medical observation in the clinic for at least 48 hours after dosing and participate in outpatient follow-up visits. Adverse events (AEs), vital signs, and electrocardiograms (ECGs) and laboratory data (serum chemistry, coagulation, hematology and urinalysis, cytokines) will be assessed by a Safety Committee before the next cohort will be dosed at a higher dose level.

After completion of Part A and confirmation by the Safety Committee to proceed, eligible subjects (n=3) will receive two IV infusions of TIMP-GLIA, 7 days apart, on Day 1 and on Day 8. Each subject in Part B will be observed in clinic for 48 hours after each dose and undergo similar testing and follow-up visits as in Part A.

The safety and pharmacokinetic profile of TIMP-GLIA will be characterized.

Arms: arm 1: TIMP-GLIA 0.1 mg/kg, infusion, intravenously, once on Day 1. arm 2: TIMP-GLIA 0.5 mg/kg, infusion, intravenously, once on Day 1. arm 3: TIMP-GLIA 1.0 mg/kg, infusion, intravenously, once on Day 1. arm 4: TIMP-GLIA 2.0 mg/kg, infusion, intravenously, once on Day 1. arm 5: TIMP-GLIA 4.0 mg/kg, infusion, intravenously, once on Day 1. arm 6: TIMP-GLIA 8.0 mg/kg, infusion, intravenously, once on Day 1. arm 7: TIMP-GLIA 2.0 mg/kg, infusion, intravenously, once on Days 1 and 8. arm 8: TIMP-GLIA 4.0 mg/kg, infusion, intravenously, once on Days 1 and 8. arm 9: TIMP-GLIA 8.0 mg/kg, infusion, intravenously, once on Days 1 and 8.
Interventions: intervention 1: TIMP-GLIA
Intervention descriptions: intervention 1: intravenous infusion.

Protocol documents:
Prot_000.pdf: 



Title: A PHASE 1, FIRST-IN-HUMAN, 2-PART, MULTICENTER DOSE ESCALATION AND 
REPEAT DOSE STUDY OF THE SAFETY, TOLERABILITY AND PHARMACOKINETICS OF 
TIMP-GLIA IN SUBJECTS WITH CELIAC DISEASE
NCT Number: NCT03486990
Protocol Approve Date: 11 September 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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A PHASE 1, FIRST-IN-HUMAN, 2-PART, MULTICENTER DOSE ESCALATION AND REPEAT 
DOSE STUDY OF THE SAFETY, TOLERABILITY AND PHARMACOKINETICS OF 
TIMP-GLIA IN SUBJECTS WITH CELIAC DISEASE
Sponsor:
COUR Pharmaceutical Development Company, Inc.
2215 Sanders Road, Northbrook, IL 60062
Study Number:
TGLIA-5.001
IND Number:
17579
Compound:
TIMP-GLIA 
Version: 
10.0
Protocol Incorporating Amendment 9.0
Date:
11 September 2018
Previous Version(s):
Version 1.0 / 18 Jul 2017
Version 2.0 / 28 Aug 2017
Version 3.0 / 30 Aug 2017
Version 4.0 / 16 Oct 2017
Version 5.0 / 1 Dec 2017
Version 6.0 / 9 Feb 2018
Version 7.0 / 9 May 2018
Version 8.0 / 25 Jul 2018
Version 9.0 / 8 Aug 2018
Sponsor Contacts
Medical Monitor
Cour VP, Clinical Development 
and Regulatory Affairs
24-Hour SAE Reporting
PPD
PPD
PPD
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TABLE OF CONTENTS
TABLE OF CONTENTS..........................................................................................................2
I.
PROTOCOL APPROVAL............................................................................................7
II.
INVESTIGATOR AGREEMENT................................................................................8
III.
PROTOCOL SYNOPSIS ..............................................................................................9
IV.
SCHEDULES OF ASSESSMENTS............................................................................17
V.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS......................21
1
INTRODUCTION .......................................................................................................26
1.1
Celiac Disease Overview ...............................................................................................26
1.2
Investigational Product: TIMP-GLIA ............................................................................27
1.3
Nonclinical Studies........................................................................................................27
1.3.1
Pharmacology/Mechanism of Action .......................................................................27
1.3.2
Pharmacology..........................................................................................................28
1.3.2.1
In vitro Pharmacology........................................................................................28
1.3.2.2
In vivo Pharmacology (Mouse) ..........................................................................28
1.3.2.3
Ex vivo Pharmacology (Human-Donor PBMCs)................................................29
1.3.3
Toxicology ..............................................................................................................31
1.3.3.1
Non-GLP Dose-Ranging Toxicology Study .......................................................31
1.3.3.2
GLP Toxicology Study ......................................................................................31
1.3.3.3
Non-GLP Follow-Up Study to GLP Toxicology Study.......................................32
1.4
Clinical Studies .............................................................................................................33
1.5
Benefit-Risk Assessment ...............................................................................................33
2
STUDY DESIGN AND RATIONALE........................................................................38
2.1
Overview of Study Design.............................................................................................38
2.2
Rationale for the Trial....................................................................................................39
2.3
Rationale for the Trial Design........................................................................................39
2.4
Rationale for the Subject Population..............................................................................40
2.5
Rationale for Dose Selection..........................................................................................41
2.5.1
TIMP-GLIA Toxicology and the NOAEL................................................................41
2.5.2
TIMP-GLIA Pharmacologically Active Dose...........................................................42
2.5.3
TIMP-GLIA Maximum Recommended Starting Dose .............................................43
3
STUDY OBJECTIVES AND ENDPOINTS...............................................................45
3.1
Objectives .....................................................................................................................45
3.1.1
Primary Objective....................................................................................................45
3.1.2
Secondary Objectives...............................................................................................45
3.1.3
Exploratory Objective..............................................................................................45
3.2
Endpoints ......................................................................................................................45
3.2.1
Safety and Tolerability Endpoints ............................................................................45
3.2.2
Pharmacokinetics Endpoints ....................................................................................46
4
STUDY POPULATION ..............................................................................................47
4.1
Inclusion Criteria...........................................................................................................47
4.2
Exclusion Criteria..........................................................................................................48
5
DISCONTINUATION.................................................................................................51
5.1
Discontinuation of Subjects ...........................................................................................51
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5.1.1
Handling of Withdrawals .........................................................................................51
5.1.2
Replacements of Withdrawn Subjects ......................................................................52
5.2
Discontinuation of the Study..........................................................................................52
5.3
Discontinuation of the Site.............................................................................................52
6
STUDY TREATMENTS.............................................................................................53
6.1
Identity of Investigational Product.................................................................................53
6.2
Management of Clinical Supplies ..................................................................................53
6.2.1
Study Drug Packaging and Labeling ........................................................................53
6.2.2
Storage and Handling...............................................................................................54
6.2.3
Inventory and Accountability...................................................................................54
6.2.4
Ancillary Materials ..................................................................................................55
6.3
Method of Assigning Subjects to Treatment Groups ......................................................55
6.4
Blinding ........................................................................................................................55
7
TREATMENT ADMINISTRATION .........................................................................56
7.1
Dose and Regimen.........................................................................................................56
7.2
Safety Committee (Dose Levels < 2 mg/kg)...................................................................56
7.3
Data Monitoring Committee (Dose Levels ≥2 mg/kg)...................................................56
7.4
Progression or Termination of Dosing ...........................................................................57
7.4.1
Premature Termination of An Individual Subject’s Infusion.....................................57
7.4.2
Dosing Subjects Within A Dose Level (Within A Cohort) .......................................58
7.4.3
Dose Escalation – Dosing Subjects At the Next Dose Level.....................................59
7.4.4
Dose Reduction .......................................................................................................59
7.4.5
Dose Limiting Toxicity Definition...........................................................................59
7.4.6
Study Stopping Rules...............................................................................................60
7.5
Treatment Compliance...................................................................................................60
7.6
Emergency Procedures and Management of Overdose...................................................60
7.7
Restrictions During the Study/Treatment Conditions .....................................................61
7.7.1
Clinic Residency and Clinic Visits...........................................................................61
7.7.2
Dietary and Fluid Restrictions..................................................................................61
7.7.3
Exercise...................................................................................................................62
7.7.4
Use of Tobacco- or Nicotine-Containing Products ...................................................62
8
EVALUATIONS AND ASSESSMENTS....................................................................63
8.1
Demographics and Baseline Characteristics...................................................................63
8.2
Medical History, and Medication History ......................................................................63
8.3
Diet History (Subjects With Celiac Disease)..................................................................63
8.4
Concomitant Medications..............................................................................................63
8.5
Safety Assessment.........................................................................................................64
8.5.1
Physical Examination...............................................................................................64
8.5.2
Vital Sign Measurements.........................................................................................64
8.5.3
Pulse Oximetry........................................................................................................65
8.5.4
Routine Electrocardiogram for Safety......................................................................65
8.5.5
Real-time Cardiac Monitoring (Electrocardiogram Telemetry).................................65
8.5.6
Laboratory Assessments ..........................................................................................66
8.5.6.1
Standard Clinical Laboratory Tests for Screening/Safety....................................66
8.5.6.2
Celiac Genetics ..................................................................................................68
8.5.6.3
Celiac-Related Serology.....................................................................................68
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8.5.6.4
Immunogenicity (Anti-Gliadin Antibodies) and Immune Complex Formation
..........................................................................................................................68
8.5.6.5
C3a and SC5B-9 Complement Levels ................................................................69
8.5.6.6
Cytokines and Laboratory Tests to Follow-Up Suspected 
Anaphylaxis/Anaphylactoid Reaction.................................................................69
8.6
Adverse Events..............................................................................................................70
8.6.1
Treatment Emergent Adverse Events .......................................................................70
8.6.2
Serious Adverse Events ...........................................................................................71
8.6.3
AE Severity Assessment ..........................................................................................72
8.6.4
Causality of AEs......................................................................................................72
8.6.5
Documenting AEs....................................................................................................73
8.6.6
Collection and Reporting of Serious Adverse Events ...............................................74
8.6.7
Collection and Reporting of Special Situations ........................................................74
8.6.8
Follow-up of SAEs ..................................................................................................75
8.6.9
Pregnancy................................................................................................................75
8.7
TIMP-GLIA Concentration and Pharmacokinetics.........................................................75
8.7.1
Blood Collection for PK ..........................................................................................75
8.7.2
Estimation of PK Parameters ...................................................................................76
8.8
Total Amount of Blood..................................................................................................76
8.9
Priority of Actions .........................................................................................................76
9
STATISTICAL METHODS .......................................................................................78
9.1
Sample Size...................................................................................................................78
9.2
Analysis Sets.................................................................................................................78
9.2.1
Safety Set ................................................................................................................78
9.2.2
Pharmacokinetic Analysis Set..................................................................................78
9.3
Demographics and Other Baseline Characteristics .........................................................78
9.4
Subject Disposition........................................................................................................78
9.5
Safety Analysis..............................................................................................................79
9.5.1
Adverse Events........................................................................................................79
9.5.2
Vital Sign Measurements and Pulse Oximetry..........................................................80
9.5.3
Clinical Laboratory Test Results..............................................................................80
9.5.4
Physical Examination and Safety ECG Findings ......................................................80
9.5.5
Previous and Concomitant Medication.....................................................................80
9.5.6
Statistical Analysis of Pharmacokinetics ..................................................................80
9.6
Missing or Outlier Data .................................................................................................81
9.7
Interim Analysis ............................................................................................................81
10
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ........................82
10.1
Procedure for Clinical Study Quality Control and Study Management ...........................82
10.1.1
Data Collection/Documentation ...............................................................................82
10.1.2
Specification of Source Documents..........................................................................82
10.1.3
Clinical Study Monitoring........................................................................................83
10.1.4
Direct Access to Source Data/Documents/Inspection of Records..............................83
10.1.5
Data Management....................................................................................................84
10.1.6
Protocol Deviations..................................................................................................84
10.1.7
Modification of the Protocol ....................................................................................85
10.1.8
End of Trial in All Participating Countries...............................................................85
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10.2
Ethics and Protection of Subject Confidentiality............................................................85
10.2.1
Institutional Review Board/Ethics Committee/Regulatory Authorities .....................85
10.2.2
Ethical Conduct of the Study....................................................................................85
10.2.3
Informed Consent of Subjects ..................................................................................86
10.2.4
Subject Confidentiality ............................................................................................86
10.3
Insurance and Compensation for Injury .........................................................................86
10.4
Publication, Disclosure, and Clinical Trial Registration Policy ......................................86
10.4.1
Use of Study Information and Publication of Clinical Study.....................................86
10.4.2
Clinical Trial Registration........................................................................................87
10.4.3
Clinical Trial Results Disclosure..............................................................................87
11
INVESTIGATOR’S OBLIGATIONS ........................................................................88
11.1
Case Report Forms and Source Documents....................................................................88
11.2
Adherence to Protocol ...................................................................................................88
11.3
Reporting Adverse Events .............................................................................................88
11.4
Investigator’s Final Report ............................................................................................88
11.5
Clinical Study Report ....................................................................................................88
11.6
Records Retention .........................................................................................................89
12
REFERENCES ............................................................................................................90
13
APPENDICES .............................................................................................................92
13.1
Liver Safety Monitoring and Assessment (Drug Induced Liver Injuiry, DILI)................92
13.2
Elements of the Subject Informed Consent ....................................................................95
13.3
Windows For PK Blood Sample Collection ...................................................................97
13.4
Responsibilities of the Investigator ................................................................................98
13.5
Amendment 1: Summary of Changes To Protocol Version 1.0.....................................100
13.6
Amendment 2: Summary of Changes To Protocol Version 2.0.....................................105
13.7
Amendment 3: Summary of Changes To Protocol Version 3.0.....................................107
13.8
Amendment 4: Summary of Changes To Protocol Version 4.0.....................................110
13.9
Amendment 5: Summary of Changes To Protocol Version 6.0.....................................115
13.10 Amendment 6: Summary of Changes to Protocol Version 7.0......................................120
13.11 Amendment 7: Summary of Changes to Protocol Version 8.0......................................122
13.12 Amendment 8: Summary of Changes to Protocol Version 9.0......................................124
13.13 Amendment 9: Summary of Changes to Protocol Version 10.0....................................129
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LIST OF FIGURES
Figure 1.
Schematic of Planned Dosing in Subjects With Celiac Disease, Part A and Part B...16
LIST OF IN-TEXT TABLES
Table 1. 
Schedule of Procedures, Part A................................................................................17
Table 2. 
Schedule of Procedures, Part B ................................................................................19
Table 3. 
Summary of TIMP-GLIA Primary Pharmacology In Mouse Models........................30
Table 4. 
Summary of Nonclinical Observations and Clinical Risk Minimization Actions ......36
Table 5. 
Calculations of Maximum Recommended Starting Dose Based upon 
Toxicology (NOAEL) Data......................................................................................42
Table 6. 
Calculations of Maximum Recommended Starting Dose Based upon 
Pharmacologically Active Dose for Full and Partial DTH Inhibition ........................43
Table 7. 
Planned Dose Levels and Rationale .........................................................................44
Table 8. 
Categories of Subject Discontinuation......................................................................51
Table 9. 
Clinical Laboratory Tests.........................................................................................67
Table 10. Severity Criteria Descriptions for AE not covered by CTCAE .................................72
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I.
PROTOCOL APPROVAL
Study Title: 
A Phase 1, First-in-Human, 2-Part, Multicenter Dose Escalation and Repeat 
Dose Study of the Safety, Tolerability and Pharmacokinetics of 
TIMP-GLIA in Subjects with Celiac Disease
Protocol Number:
TGLIA-5.001
Version/Protocol Date:
v 10.0, 11 Septmeber 2018
Protocol Incorporating Amendment 9.0
Protocol Accepted and Approved by:
Date
(dd mmm yyyy)
Date
(dd mmm yyyy)
PPD
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mmm
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II.
INVESTIGATOR AGREEMENT
Study Title: 
A Phase 1, First-in-Human, 2-Part, Multicenter Dose Escalation and Repeat 
Dose Study of the Safety, Tolerability and Pharmacokinetics of 
TIMP-GLIA in Subjects with Celiac Disease
Protocol Number
TGLIA-5.001
Version/Protocol Date:
v 10.0, 11 September 2018
Protocol Incorporating Amendment 9.0
I confirm that I have read all pages of this study. I understand the study protocol and agree to conduct the 
study according to the procedures therein and according to the International Conference on Harmonisation 
(ICH) and FDA Good Clinical Practices (GCP) guidelines and applicable local regulations. I will also 
ensure that subinvestigator(s) and other relevant members of my staff have access to copies of this protocol 
and the GCP guidelines to enable them to work in accordance with the provisions of these documents.
Signature of Principal Investigator
Date
(dd mmm yyyy)
Investigator Name (print or type)
Investigator’s Title (print or type)
Location of Facility (City, State) (print or type)
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III.
PROTOCOL SYNOPSIS
Sponsor:  COUR Pharmaceutical Development Company, Inc.
Study Title:  A Phase 1, First-in-Human, 2-Part, Multicenter Dose Escalation and Repeat Dose Study of the
Safety, Tolerability and Pharmacokinetics of TIMP-GLIA in Subjects with Celiac Disease
Test Product:  TIMP-GLIA 
Name of Active Ingredients: poly(lactic-co-glycolic acid), gliadin
Study Number:  TIMP-GLIA -5.001
Study Phase:  1
Study Centers:  Up to 6 centers
Study Duration: planned 3Q2017-3Q2018
Primary Objective:  
The primary objective is to assess the safety and tolerability of TIMP-GLIA when administered 
intravenously (IV) as a single dose at ascending dose levels and as a repeat dose in subjects with celiac 
disease (CD).
Secondary Objectives: 
The secondary objectives are:
!
To characterize the pharmacokinetics (PK) of TIMP-GLIA based upon concentrations of 
TIMP-GLIA in plasma over time in subjects with CD .  
!
To establish a safe and tolerable dose that may be tested during a future Phase 2 Proof of Concept 
study in subjects with CD. 
Exploratory Objective:
Study Design:
This study is a Phase 1, first-in-human (FIH), 2-part, multicenter study to assess the safety, tolerability and 
PK of TIMP-GLIA in subjects with CD .  Part A includes an accelerated titration 2+2 and traditional 3 + 3 
design with rapid dose escalationduring which successive cohorts of subjects will receive a single dose of 
TIMP-GLIA. Part B will follow as a repeat dose design using the dose level selected from Part A.
Consenting subjects will be screened within 28 days (Day -28 to -1) prior to admission to the clinical 
research unit on Day -1 for baseline assessments. 
Part A
In Part A, eligible subjects (at least 19 CD subjects) will be enrolled into escalating dose cohorts (n = 
2/cohort for 2 dose levels followed by n = 3/cohort for 5 dose levels).  TIMP-GLIA will be administered as 
a single intravenous (IV) infusion on Day 1. A staggered dosing strategy will be used in Part A.  One subject 
in a cohort will be dosed at a time and undergo medical observation in the clinic for at least 48 hours 
post-infusion. 
At least 168 hours (7 days) will elapse prior to dosing the next subject. Adverse events (AEs), vital signs, 
pulse oximetry, and electrocardiograms (ECGs) and laboratory data (serum chemistry, coagulation, 
hematology and urinalysis, cytokines) from samples obtained through at least 24 hours post dose will be 
assessed before dosing the subsequent subject(s). 
AEs will be graded according to National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0 (Published: May 28, 2009 [v4.03: June 14, 2010]) or most current version.  If 
safety and tolerability are confirmed by the investigator, TIMP-GLIA will be administered to the next 
subject. 
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Dose Escalation, Part A
After all the subjects in a dose cohort complete study procedures through at least 168 hours (7 days) post 
dose the safety data will be reviewed by the Data Monitoring Committee (DMC).  Dose escalation will 
proceed only if Study Stopping Criteria (“Study Stopping Rules”) are not met. If dose-limiting toxicity 
(DLT) occurs in 1 of the subjects in a cohort in Part A, the DMC may decide to increase enrollment at the 
same dose level by 2 subjects (accelerated titration cohort) or by 3 subjects (standard 3+3). After a rate of 
DLTs has been identified for a specific dose in 3- or 6-subject cohorts, the DMC may recommend that up to 
a total of 12 subjects may be accrued at any dose level to better define the relationship between dose and 
emerging safety signals. It is also possible that the DMC could recommend an intermediate dose (lesser 
escalation) or reduced dose level (dose reduction) if warranted by the emerging safety data.  Before 
continuing to Part B, available safety data for all subjects Part A through at least 168 hours (7 days) after 
dosing will be evaluated by the DMC.
Part B
Part B will evaluate 2 doses of TIMP-GLIA administered on Days 1 and 8.  Two subjects will be enrolled 
into each of 3 cohorts at dose levels of 2, 4, and 8 mg/kg up to a maximum of 650 mg. Dose escalation will 
proceed only if Study Stopping Criteria (“Study Stopping Rules”) are not met. If dose-limiting toxicity 
(DLT) occurs in 1 of the 2 subjects in a cohort, the DMC may decide to increase enrollment at the same 
dose level by 2 subjects. (2+2 design).
Clinic Residency and Visits
Subjects in both parts of the study will remain in the clinic from admission (Part A: Day -1; Part B: Day -1 
and Day 7) through the final post-dose procedure at 48 hours (Part A: Day 3; Part B: Day 3 and Day 10) and 
will be thereafter discharged if safety parameters are acceptable to the investigator.  Subjects will return to 
the clinical research unit for follow-up assessments and will be contacted by telephone as shown in the 
Schedules of Procedures for Part A (SCHEDULES OF ASSESSMENTS
Table 1) and Part B (Table 2).
Duration of Study Period
Part A:  
Total duration of the study investigational period is up to 91 days (screening up to 28 days + 1 treatment day 
+ follow-up at Day 60 +/- 3 days). In addition, telephone follow-up by a health care practitioner is required 
after the Day 60 outpatient visit (i.e. Day 90, Day 120 and Day 180, all +/- 3 days). 
Part B: 
Total duration of the study investigational period is up to 91 days (screening up to 28 days + 2 treatment 
days, 7 days apart + follow-up at 60 +/- 3 days after last dose. In addition, telephone follow-up by a health 
care practitioner is required after the Day 60 outpatient visit (i.e. Day 90, Day 120 and Day 180, all +/- 3 
days).
Dose Limiting Toxicity Definition: 

A CTCAE Version 4.0 Grade 3 or higher that is at least possibly related to TIMP-GLIA 

Suspected drug-induced liver injury (DILI) at least possibly related to TIMP-GLIA in any dosed 
subject indicated by

ALT or AST > 3x upper limit of normal (ULN) and increase of total bilirubin > 2x ULN without 
evidence of intra- or extra-hepatic bilirubin obstruction (elevated ALP) or Gilbert’s syndrome 
(“Hy’s Law”) or 

ALT or AST > 3x ULN and INR > 1.5x ULN or

ALT or AST >8xULN or
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
ALT or AST >5xULN for more than 2 weeks or 

ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash, and/or eosinophilia (>5%) 

Any other toxicity which in the opinion of the DMC would not allow continued dosing if this were 
a repeat dose study
Study Stopping Rules:

First occurrence of a CTCAE Grade 4 or Grade 5 toxicity at least possibly related to TIMP-GLIA 

2 or more of the same CTCAE Grade 3 toxicity considered to be at least possibly related to 
TIMP-GLIA (among total number of subjects dosed)

1 subject experiences a CTCAE Grade 3 toxicity considered to be at least possibly related to 
TIMP-GLIA in the same organ system as experienced by another subject at CTCAE Grade 2 or 
higher considered to be at least possibly related to TIMP-GLIA (at the same dose level).

Any other toxicity which in the opinion of the DMC would have precluded administration of a 
second dose if this were a multi-dose study.
Safety Committee:
A Safety Committee was convened to monitor the safety of subjects up to the 2  mg/kg dose cohort.   The 
Safety Committee included the: principal Investigators (PIs) or PI’s delegate and a medical consultant with 
expertise in CD.
The role of the Safety Committee is described in prior versions of this protocol under which the 0.1 mg/kg, 
0.5 mg/kg, and 1 mg/kg doses were administered.
Data Monitoring Committee:
An independent DMC will be commissioned for this study for dose levels ≥ 2 mg/kg.  The DMC will be 
comprised of 3 physicians with expertise in immunology and/or vaccines clinical trials.  A 4th physcician 
with expertise in CD will serve as an advisor to the DMC, but in a non-voting capacity.
The sponsor medical monitor will not be a member of the DMC. The sponsor medical monitor and other 
study team members will be available to answer questions of the DMC as necessary and during Open 
Sessions of the DMC.  The medical monitor and other study team members will not participate in Close 
Sessions of the DMC. The DMC will perform ongoing safety surveillance.  The medical monitor will be 
notified of any serious adverse event (SAE) and any CTCAE Grade 2 or greater adverse event within 
24 hours of investigator’s (or designee’s) awareness of such an event.  An ad hoc DMC meeting may 
convene to evaluate safety and tolerability data to determine if it remains acceptable to continue dosing 
(within cohorts at same dose level) or to dose escalate (between cohorts) or explore lower doses.  
The DMC will evaluate the available safety data post-infusion, including but not limited to, AEs, vital 
signs, pulse oximetry, 12-lead ECGs and available laboratory results (hematology, chemistry, coagulation,
and urinalysis, cytokines). 
The following decisions may be made if stopping criteria (“Study Stopping Rules”) are not met: 

Escalate the dose as planned

Expand the dose cohort to 4 subjects (accelerated titration 2+2, Part A and Part B) or to 6 subjects
(standard 3+3, Part A)
After a rate of DLTs has been identified for a specific dose in 3- or 6-subject cohorts, the DMC may 
recommend that up to a total of 12 subjects may be accrued at any dose level to better define the 
relationship between dose and emerging the safety signals.

Decrease the dose either to a previous lower dose or to an intermediate dose
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
Escalate the dose to an intermediate level if warranted based on events in the previous cohort
The decision(s) of the DMC to continue dosing will be documented and provided to the investigators prior
to dosing any new subjects. 
Additionally, the DMC may meet ad hoc to determine if it remains acceptable to continue dosing.
Selection of Study Population:  
At least 23 male and female subjects 18 to 75 years of age with historical evidence of biopsy-confirmed CD
and who have negative celiac serology and quiescent CD symptomology and are otherwise healthy or with 
stable comorbidity at screening are planned to be enrolled.   
Collectively, subjects will be enrolled at up to 6 clinical research sites in the United States.  
Subjects who withdraw before receiving the first dose of study drug will be replaced. Subjects who 
withdraw after receiving study drug will be replaced at the sponsor’s discretion.  
After fully informing prospective subjects of the present study and obtaining their written informed 
consent, the investigator will perform screening tests.  Based on the results of these screening tests, the 
investigator will identify “provisional subjects” (including reserve [alternate] subjects, if available). The 
provisional subjects will be individuals who meet the inclusion criteria without meeting any of the 
exclusion criteria. Ethical and scientific aspects, the study objectives, and individual health status up to the 
selection date will also be carefully considered during the selection process.  The provisional subjects will 
be admitted to the study site on the day on Day -1, whereupon they will undergo the tests scheduled for that 
day and confirmatory assessment of study eligibility criteria. Those who are deemed eligible for enrollment 
will then be selected as enrolled subjects.
Eligibility Criteria:
Inclusion Criteria
1.
In the opinion of the investigator, the subject is capable of understanding and complying with protocol 
requirements.
2.
The subject provides written informed consent to participate as indicated by a signature on the informed 
consent form and any required privacy authorization prior to the initiation of any study procedures. 
3.
The subject is an adult man or women, 18 to 75 years of age, inclusive, at Screening Visit. 
4.
The subject has a body mass index (BMI) that is >16 kg/m2 with a minimum body weight of 33 kg up to 
a maximum body weight of 129 kg, inclusive, at Screening Visit and if BMI <18 (“underweight”) or 
>25 (“overweight” or “obese”), is otherwise healthy in the opinion of the investigator. 
5.
The subject has celiac disease characterized as follows: 
a.
The subject has a history of biopsy-confirmed celiac disease (intestinal histology showing villous 
atrophy) according to expert guidelines current at the time of diagnosis; and
b.
The subject has no known gluten exposure for at least 10 days prior to the Screening Visit and is 
willing to maintain a gluten-free diet for the duration of the study; and 
c.
The subject has a total immunoglobulin A (IgA) titer within normal limits or has partial IgA 
deficiency (~5% of celiac patients) defined by a reduced serum IgA level of 3 – 70 mg/dL at 
Screening
AND
The subject has negative or weak positive recombinant human transglutaminase (tTG)-specific IgA 
titer at Screening 
OR
For a subject with selective IgA deficiency (~2% of celiac patients), deamidated gliadin peptide 
(DGP)-specific IgG titer is negative or weak positive at Screening. 
6.
If male subject, agrees to practice medically approved contraception that may include, but is not limited 
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to, abstinence, monogamous relationship with a female who is not of child-bearing potential, surgical 
sterilization procedure (vasectomy), and or condoms throughout the study.
If female subject, is not of child bearing potential (postmenopausal or premenopausal with surgical 
sterilization) or agrees to practice medically approved contraception that may include, but is not limited 
to, abstinence, monogamous relationship with a male who is post-surgical sterilization procedure 
(vasectomy), or agrees to use medically acceptable and highly effective birth control methods (e.g., an 
intrauterine device, a double-barrier method such as condom and spermicide or condom and diaphragm 
with spermicide, a contraceptive implant, injectable contraceptive, or oral contraceptive) throughout 
the study.  
7.
The subject is able and agrees to comply with study requirements.
8.
The subject agrees not to participate in another interventional study while participating in the present 
study, defined as signing the informed consent form until completion of the last study visit.
Exclusion Criteria
1.
The subject has a history of clinically confirmed immunoglobulin E (IgE)-mediated reaction and/or 
anaphylaxis to wheat (i.e., “wheat allergy”), barley or rye. 
2.
The subject has uncontrolled celiac disease and/or complications of celiac disease, or otherwise has 
experienced celiac symptomology within 10 days of screening, in the opinion of the investigator.
3.
The subject has a history of, or has an active, significant, clinically relevant, comorbidity (including 
Type 1 and Type 2 diabetes mellitus and other autoimmune disorders, splenectomy) that, in the opinion 
of the investigator, would make the subject unsuitable for participation in the study and/or could 
adversely affect interpretation of the study results. 
4.
The subject has had significant changes to or anticipates changes to prescription or non-prescription 
medication used to manage an underlying comorbidity within 30 days prior to Day 1. 
5.
The subject is currently taking or received systemic biologics 6 months prior to Day 1. 
6.
The subject has a compromised immune system, e.g.: 
a.
Known human immunodeficiency virus (HIV) infection or positive for HIV antibodies at 
Screening;
b.
Subject is or has been taking an immune suppressing medical treatment (e.g., azathioprine, 
methotrexate) during the 2 months prior to Day 1;
c.
Subject is receiving immunosuppressive doses of corticosteroids (more than 20 mg of prednisone 
given daily for 2 weeks or more within 2 months prior to Day 1 , any dose of corticosteroids within 
30 days of Day 1, or high dose inhaled corticosteroids [>960 µg/day of beclomethasone 
dipropionate or equivalent]) within 30 days of Day 1.
7.
The subject has a known history of hypersensitivity or allergies to TIMP-GLIA components or any 
other known severe hypersensitivity  or allergic reaction (any reaction that resulted in hospitalization 
[initial or prolonged], congenital anomaly, or disability, or that required medical intervention to prevent 
permanent impairment or damage) to any other allergens (medications, food or environmental). 
8.
The subject has currently 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.
9.
The subject has a history of any acute illness including, fever (>100.4°F or >38°C) within 14 days of 
Check-In Day-1.
10. The subject has an active malignancy, or history of malignancy or chemotherapy, within the past 5 
years other than history of localized or surgical removal of focal basal cell skin cancer, cervical cancer 
in situ treated successfully in the past by local treatment (including but not limited to cryotherapy or 
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laser therapy) or by hysterectomy.
11. The subject has known liver disease or serology positive for hepatitis C infection; positive hepatitis B 
surface antigen (HBsAg) at Screening Visit. 
12. The subject has a positive test result for drugs of abuse (amphetamines, barbiturates, benzodiazepines, 
cocaine metabolites, opiates, cannabinoids, methylenedioxymethamphetamine) or alcohol in urine –
except when the positive result arises from treatment under supervision of a medical doctor - at 
Screening Visit or at Check-in.
13. The subject has a history of any drug or alcohol abuse in the past 5 years, or alcohol consumption 
greater than 21 units per week that, in the opinion of the investigator, would interfere with the subject’s 
ability to comply with the study requirements. A unit of alcohol is equivalent to: 12 ounces of beer, 4 
ounces of wine, or 1 ounce of spirits/hard liquor.  Alcohol consumption will be prohibited 24 hours 
prior to entry into the clinical research unit until discharge.
14. The subject has the inability to undergo venipuncture or tolerate venous access as determined by the 
investigator or designee.
15. The subject has a history or presence of anorexia nervosa or other eating disorder.
16. If female, the subject is pregnant or lactating or intending to become pregnant before or during the 
study.  The lack of pregnancy will be confirmed by serum assay for qualitative human chorionic 
gonadotropin (hCG) at Screening and a urine assay performed at Check-in. Women with 
postmenopausal status confirmed by screening follicle-stimulating hormone (FSH) result need not 
undergo subsequent urine pregnancy testing.
17. The subject has clinically significant laboratory results at Screening, as determined by the investigator, 
including, but not limited to the following: 
a.
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase 
(ALP) ≥ 1.5 times Upper Limit of Normal (ULN)
b.
Direct bilirubin outside the normal range
c.
Serum Creatinine > 1.2 mg/dL
d.
Hemoglobin < 10 g/dL
e.
Hematocrit < 30%
f.
Platelet count < 150,000 or > 400,000 
g.
Serum Potassium, Prothrombin Time (PT), Partial Thromboplastin Time (PTT), international 
normalized ratio (INR), or white blood cell count (WBC) outside the normal range (and judged 
clinically significant by the investigator)
18. The subject has clinically significant, abnormal electrocardiogram (EGC) at Screening, as determined 
by the investigator, including but not limited to:
a.
Mean QTcF interval >430 msec for males or >450 msec for females;
b.
ECG evidence of complete left bundle branch block (LBBB) or right bundle branch block (RBBB), 
or incomplete LBBB; 
c.
Mean intraventricular conduction delay with QRS duration >120 msec;
d.
Pathological Q-waves, defined as Q-wave >40 msec or depth >0.4 to 0.5 mV;
e.
Evidence of ventricular preexcitation according to the investigator.
19. The subject has received any investigational drug within 30 days or 5 half-lives prior to first 
dosing/Day 1.
20. The subject was previously enrolled and dosed in a clinical trial with TIMP-GLIA.
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21. The subject received a live or inactive vaccine within 28 days prior or a subunit vaccine within 14 days 
prior to first dosing/Day 1 or the subject has a planned vaccination during the study. 
22. The subject has donated blood or plasma ≤ 56 days prior to Screening and plans to donate blood or 
plasma within 5 weeks of completing the study. 
23. The subject has received blood products, monoclonal antibody, or other systemic protein therapy 
within 6 months prior to first dosing/Day 1.  NOTE: oral protein supplements are permitted.
24. The subject is an immediate family member, study site employee, or is in a dependent relationship with 
a study site employee who is involved in conduct of this study (e.g., spouse, parent, child, sibling) or 
may consent under duress.
25. The subject is unsuitable for enrollment in the opinion of the investigator for any other reason not 
specified above.
Duration of Treatment: 
Part A: Single IV infusion administered on Day 1
Part B: Two IV infusions, one administered on Day 1 and the other on Day 8
Test Product; Dose; and Mode of Administration: 
Part A: TIMP-GLIA: 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg; 2 mg/kg; 4 mg/kg; and 8 mg/kg, administered by IV 
infusion.
Part B: TIMP-GLIA: 2, 4, and 8 mg/kg up to a maximum of 650 mg, administered by IV infusion.
Reference Therapy; Dose; and Mode of Administration: NA
Endpoints:[Note: Timed Procedures Are Relative To Infusion Start Time.]
Safety and Tolerability:  
Safety will be characterized by incidence, severity, and reversibility of AEs, physical examination findings, 
12-lead ECG results, arterial oxygen saturation levels by pulse oximetry, vital signs measurements, 
anti-gliadin antibody (i.e., anti-drug antibody as deamidated gliadin peptide (DGP)-specific IgG), immune 
complex detection by C1q binding and by C3a and SC5B-9 (Part B only); routine clinical laboratory test 
results (hematology, serum chemistry, coagulation, urinalysis) and other specialized laboratory test results 
(e.g., acute phase cytokines; additional vascular / thrombotic markers; mast cell activation via tryptase; 
additional complement markers, peripheral blood gliadin-specific T-cell proliferation and cytokine 
secretion). Post-dose assessment of peripheral blood T cell proliferation and cytokine secretion in response 
to ex vivo gliadin stimulation relative to baseline will be performed for the single dose groups ≥4 mg/kg in 
Part A and the for the repeat dose groups in Part B. 
The analysis of samples drawn for cytokine testing (EGF, fractalkine, GM-CSF, GRO α, IFNα, IFN-γ, 
IL-1α, IL-1 β, IL-2, IL-2 soluble receptor, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IP-10, MIP1α, 
and MIP1β,  TNF-α) should be performed as follows:
The IFN-γ, IL-1 β, IL-2, IL-2 soluble receptor, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IP-10, 
and TNF-α results through 24 hours post dose will be used for dose escalation decision (i.e., analyzed at 
the end of each dose cohort). This acute phase cytokine testing should be performed promptly and 
results are to be reported to the investigator as soon as possible in the event clinical symptoms occur. 
The scheduled predose and post dose samples for the other cytokines can be batched and analyzed at the 
end of the trial unless otherwise specified by the medical monitor, sponsor, or DMC or as necessary for 
compliance with the established sample stability.
Results of peripheral blood T-cell proliferation and cytokine secretion in response to ex vivo 
stimulation with gliadin will be reported at the end of the study or as otherwise specified by the sponsor, 
medical monitor, or DMC. 
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Tolerability will be characterized by extent of dose escalation attained without dose limiting toxicity.
Pharmacokinetics: 
Individual subject TIMP-GLIA concentrations in plasma over time will be used to derive PK parameters by 
noncompartmental analysis. The primary PK parameters are maximal observed concentration (Cmax), last 
measurable concentration (Clast), time of maximal observed concentration (Tmax), time of last measurable 
concentration (Tlast), and area under the curve from time zero and extrapolated to infinity (AUCinf) and area 
under the concentration-time curve from time zero to time of the last measurable concentration (AUClast).  
Other PK variables will be derived if feasible. The results of the PK analysis will be reported at the end of 
the study. 
Statistical Methods: 
Safety 
No formal statistical analyses will be conducted; all analyses will be descriptive. Quantitative data will be 
summarized by summary statistics and change from baseline. 
Pharmacokinetics (PK):
Individual subject TIMP-GLIA concentrations and derived PK parameters which will be summarized using 
descriptive statistics (N, mean, standard deviation (SD), coefficient of variation (CV), median, minimum, 
and maximum and geometric mean where applicable).  The PK parameters will be calculated using 
noncompartmental methods.
Figure 1.
Schematic of Planned Dosing in Subjects With Celiac Disease, Part A 
and Part B
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IV.
SCHEDULES OF ASSESSMENTS
Table 1. 
Schedule of Procedures, Part A
Screening†
Investigational period*,***
Follow up period
Study Day
-28 to 
-2
-1
1†
2
3
4
5
6
7±1
F/U
14±2
F/U
21±2
F/U
30 ±2
F/U
60±3
F/U
90±3
F/U
120±3
F/U
180±3
LFU
Clinic residency, outpatient visit or telephone 
contact visit
V
Adm
Dis
T
T
T
V
V
T
V
V
T
T
T
Informed Consent
X
Inclusion and exclusion criteria
X
X¶¶
Demographics, height, weight, BMI
X
X^
Medical/medication/dietary history, baseline 
conditions
X
X
X‼
X‼
X‼
X‼
X‼
X‼
X‼
X‼
X‼
X‼
X‼
Physical examination
X«
X»
X»
X»
X»
X»
X»
Vital signs¶
X
X
Predose, every 15 min during infusion, 2h, 4h, 
8h, 12h, 24h
48h
X
X
X
X
Pulse oximetry‡
Predose, 1h, 2h, 4h, 8h, 12h, 24h
12-lead ECG††
3X
3X
Predose; 1h, 4h, 12h, 24h
48h
X†††
X†††
X†††
X†††
Continuous real time ECG/telemetry♥
Predose-8h
Contact designee re: enrollment, dose scheduling, 
screen failure
X
X
Predose
X
X
Clinical chemistry tests§
X
X
24h
48h
X
X
X
X
Pregnancy test (hCG) § **
X
X
X
X
X
X
Coagulation tests§
X
X
24h
48h
X
X
X
X
Hematology§
X
X
24h
48h
X
X
X
X
Hepatitis & HIV serology§
X
Drugs of abuse & alcohol§
X
X
Urinalysis + microscopic examination and UPCR§
X
X
24h
48h
X
X
X
X
HLA-DQ2.5, HLA-DQ8.1§§
X
Anti-drug antibody IgG‡‡
X
Predose
48h
XY
X
X
X
Immune Complex Detection by C1q Binding
Predose
48h
XY
X
X
X
IgA level, IgA-tTG, IgG-DGP serology §, ‡‡‡
X
Cytokine (& chemokine) panel§ ##
Predose, 8h and prn##
24h
X
X
Whole blood for PBMC isolation§ #
Predose and prn#
X
Anaphylactic/anaphylactoid response testing§ #
Predose and prn#
Pharmacokinetics TIMP-GLIA plasma 
Predose (0hr), 30min, 35 min (or end of 
infusion), 1h, 4h, 12h, 24h 
48h
144h
Dose (intravenous infusion)*
X
Adverse event recording^^
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication^^
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adm: Clinic admission; Dis: Clinic discharge (Shading denotes clinic residency period); V: Outpatient visit; T: Telephone contact visit by a health care practitioner; BMI: body mass index; ECG: 
electrocardiogram; ESV: end-of-study visit; F/U: Follow-up; LFU: Late (last) follow-up; UPCR: urine protein to creatinine ratio; prn: pro re nata, as necessary; PBMC: Peripheral blood mononuclear cell
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†Screening is the time from signing of informed consent up to but not including first administration of study drug, during which a subject is being evaluated for study eligibility. 
*All post-dose times shown relative to infusion start time. Samples for PK are to be drawn from the opposite arm from which study drug is being infused. Subjects should remain supine during dosing.
¶¶Confirm eligibility.  If the subject is found to be ineligible, record the reasons for screen failure in the source and the primary reason for screen failure in the applicable CRF.
^Weight only.
‼Inquiry regarding diet since prior visit (in-clinic or telephone)
«Full physical exam (PE) includes an assessment of general appearance, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest (lungs)/respiratory system, cardiovascular system, abdomen 
(liver, spleen), skin, extremities, musculoskeletal, neurological system (including mental status) and any other assessment not categorized but deemed necessary by the investigator.
»Abbreviated PE includes an assessment of general appearance, skin, chest (lungs)/respiratory system, cardiovascular system, abdomen (liver, spleen). Additional assessments/full PE may be conducted 
as clinically indicated at any time.
¶Vital signs except body temperature should be performed after the subject has been supine for at least 5 minutes. Vital signs include body temperature (oral and/or tympanic measurement), blood 
pressure (SBP and DBP), pulse (beats per minute) and respiratory rate (breaths per minute).
‡Pulse oximetry will be monitored from approximately 1 hour prior to the start of study drug infusion (0 hour) through 4 hours post dose and values also recorded at times indicated.
§See in-text Table 9, Clinical Laboratory Tests, for list of specific tests.
**Women with postmenopausal status confirmed by screening follicle-stimulating hormone (FSH) result need not undergo subsequent urine pregnancy testing.
#Symptoms of anaphylactoid/anaphylactic response or infusion-related reaction (IRR) (e.g., fever, nausea, chills, rigors, hypotension, tachycardia, asthenia, headache, rash, scratchy throat, and dyspnea) 
will be followed up with additional laboratory testing for vascular / thrombotic markers (e.g., von Willebrand Factor [vWF], intercellular adhesion molecule [ICAM-1]), mast cell activation (tryptase), 
complement markers (C3a, C5a, CH50, C5-9) and for T cell proliferation and cytokine secretion in response to ex vivo gliadin stimulation for ≥ 4 mg/kg dose cohorts.  Samples are to be drawn predose 
Day 1, as needed to follow up signs/symptoms of anaphylactoid/anaphylactic response or IRR, and on Days 7 and 14.
##Samples are to be drawn predose and post dose as shown but additional samples for cytokine (& chemokine) panel are to be drawn post dose if clinically indicated (by appearance of systemic 
symptoms of anaphylaxis/anaphylactoid reaction or IRR such as fever, nausea, chills, rigors, hypotension, tachycardia, asthenia, headache, rash, scratchy throat, and dyspnea).
††ECGs in triplicate (“3X”), 1 minute apart, within 5 minutes (predrug baseline).  Scheduled ECGs at other timepoints will be performed as a single measurement (“X”). All ECGs should be performed 
after the subject has been supine for at least 5 minutes. 
†††Follow–up visit ECG only necessary if prior ECG was abnormal, clinically significant.
♥Continuous, real-time cardiac monitoring (telemetry) will be monitored starting approximately 1 hour prior to the start of study drug infusion (0 hour) through 8 hours post dose.
§§Perform phenotyping for HLA-DQ2.5 (HLA-DQA1*0501 / B1*0201) and HLA-DQ8.1 (DQA1*0301/B1*0302) if unknown OR if historical documentation not available. Sample may be taken any 
time on Day 1 from an enrolled subject. 
‡‡Anti-gliadin antibody test which serves as an anti-TIMP-GLIA antibody test (anti-drug antibody test) will be deamidated gliadin peptide (DGP)-specific IgG antibody (IgG-DGP). 
YSample should correspond to the 144 hour PK sample.
‡‡‡Additional tissue transglutaminase (tTG)-specific IgA antibody or deamidated gliadin peptide (DGP)-specific IgG antibody (IgA-tTG or IgG-DGP) serology is to be performed post dose upon 
appearance of celiac disease-related symptoms as determined by the investigator.
^^Adverse events (AEs) and concomitant medication will be collected from the time of signing of the informed consent through the final follow up.  Treatment-emergent AEs will be differentiated at time 
of first dosing. Data collected during scheduled in-clinic or telephone visits and any spontaneously reported information through the AE reporting period are to be documented in the subject’s record.
***The procedures as listed under the Study Day 14 visit should be performed as the final study procedures in the event a subject discontinues the study prematurely during the investigational period.  If 
the subject discontinues on or before Day 7, a PK sample should also be collected, if possible, provided no other PK samples were already collected on the day of discontinuation.
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Table 2. 
Schedule of Procedures, Part B
Screening†
Investigational period*,***
Follow up period
Study Day
-28 to 
-2
-1
1†
2
3
4-6
7
8
9
10
11-13 14±1
F/U
21±2
F/U
28±2
F/U
38±2
F/U
60±3
FU
90±3
FU
120±3
FU
180±3
L/FU
Clinic residency, outpatient visit or 
telephone contact visit
V
Adm
Dis
T
Adm
Dis
T
V
V
T
V
V
T
T
T
Informed Consent
X
Inclusion and exclusion criteria
X
X¶¶
Demographics, height, weight, BMI
X
X^
X^
Medical/medication/dietary history, baseline 
conditions
X
X
X‼
X‼
X‼
X‼
X‼
X‼
X‼
X‼
X‼
X‼
X‼
Physical examination
X«
X»
X»
X»
X»
X»
X»
X»
Vital signs¶
X
X
Predose, every 15 min during 
infusion, 2h, 4h, 8h, 12h, 24h 48h
X
Predose, every 15 min during 
infusion, 2h, 4h, 8h, 12h, 24h
48h
X
X
X
Pulse oximetry‡
Predose, 1h, 2h, 4h, 8h, 12h, 24h
Predose, 1h, 2h, 4h, 8h, 12h, 24h
12-lead ECG††
3X
3X
Predose; 1h, 4h, 12h, 24h
48h
X
Predose; 1h, 4h, 12h, 24h
48h
X†††
X††† X†††
Continuous real time ECG/telemetry♥
Predose-8h
Predose-8h
Contact designee re: enrollment, dose 
scheduling, screen failure
X
X
Predose
X
X
Clinical chemistry tests§
X
X
24h
48h
X
24h
48h
X
X
X
Pregnancy test (hCG) § **
X
X
X
X
X
X
Coagulation tests§
X
X
24h
48h
X
24h
48h
X
X
X
Hematology§
X
X
24h
48h
X
24h
48h
X
X
X
Hepatitis & HIV serology§
X
Drugs of abuse & alcohol§
X
X
X
Urinalysis + microscopic examination and 
UPCR§
X
X
24h
48h
X
24h
48h
X
X
X
HLA-DQ2.5, HLA-DQ8.1§§
X
Anti-drug antibody IgG‡‡
X
Predose
48h
XY
Predose
48h
XY
X
X
Immune Complex Detection by C1q 
Binding
Predose
48h
XY
Predose
48h
XY
X
X
IgA level, IgA-tTG, IgG- DGP serology ‡‡‡
X
Cytokine (& chemokine) panel§ ##
Predose, 8h and prn##
24h
Predose, 8h and prn##
24h
X
X
Whole blood for PBMC isolation§ #
Predose and prn#
Predose and prn#
XY
Anaphylactic/anaphylactoid response 
testing§ #
Predose and prn#
Predose and prn#
C3a, C5a, and SC5B-9 complement levels
15 min, 30 min
24h
15 min, 30 min
24h
Pharmacokinetics TIMP-GLIA in plasma
Predose (0hr), 30min, , 1h, end 
of infusion, 4h, 12h, 24h
48h
144h Predose (0hr), 30min,  , 1h, end 
of infusion, 4h, 12h, 24h
48h
144h
Dose (intravenous infusion)*
X
X
Adverse event recording^^
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication^^
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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CONFIDENTIAL
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Adm: Clinic admission; Dis: Clinic discharge (Shading denotes clinic residency period); V: Outpatient visit; T: Telephone contact visit by a health care practitioner; BMI: body mass index; ECG: 
electrocardiogram; ESV: end-of-study visit; F/U: Follow-up; LFU: Late (last) follow-up; UPCR: urine protein to creatinine ratio; prn: pro re nata, as necessary; PBMC: peripheral blood mononuclear cell
†Screening is the time from signing of informed consent up to but not including first administration of study drug, during which a subject is being evaluated for study eligibility. 
*All post-dose times shown relative to infusion start time. Samples for PK are to be drawn from the opposite arm from which study drug is being infused. Subjects should remain supine during dosing.
¶¶Confirm eligibility.  If the subject is found to be ineligible, record the reasons for screen failure in the source and the primary reason for screen failure in the applicable CRF.
^Weight only.
‼Inquiry regarding diet since prior visit (in-clinic or telephone)
«Full physical exam (PE) includes an assessment of general appearance, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest (lungs)/respiratory system, cardiovascular system, abdomen 
(liver, spleen), skin, extremities, musculoskeletal, neurological system (including mental status) and any other assessment not categorized but deemed necessary by the investigator.
»Abbreviated PE includes an assessment of general appearance, skin, chest (lungs)/respiratory system, cardiovascular system, abdomen (liver, spleen). Additional assessments/full PE may be conducted 
as clinically indicated at any time.
¶Vital signs except body temperature should be performed after the subject has been supine for at least 5 minutes. Vital signs include body temperature (oral and/or tympanic measurement), blood 
pressure (SBP and DBP), pulse (beats per minute) and respiratory rate (breaths per minute).
‡Pulse oximetry will be monitored from approximately 1 hour prior to the start of study drug infusion (0 hour) through 4 hours post dose and values also recorded at times indicated.
§See in text Table 9, Clinical Laboratory Test, for list of specific tests. 
**Women with postmenopausal status confirmed by screening follicle-stimulating hormone (FSH) result need not undergo subsequent urine pregnancy testing.
#Symptoms of anaphylactoid/anaphylactic response or IRR (e.g., fever, nausea, chills, rigors, hypotension, tachycardia, asthenia, headache, rash, scratchy throat, and dyspnea) will be followed up with 
additional laboratory testing for vascular / thrombotic markers (e.g., von Willebrand Factor [vWF], intercellular adhesion molecule [ICAM-1]), mast cell activation (tryptase), complement markers (C3a, 
C5a, CH50, C5-9) and for T cell proliferation and cytokine secretion in response to ex vivo gliadin stimulation.  Samples are to be drawn predose as shown, post dose as needed to follow up
signs/symptoms of anaphylactoid/anaphylactic response or IRR, and on Day 14. 
##Samples are to be drawn predose and post dose as shown but additional samples for cytokine (& chemokine) panel are to be drawn post dose if clinically indicated (prn) (by appearance of systemic 
symptoms of anaphylaxis or anaphylactoid reaction or infusion-related reaction such as fever, nausea, chills, rigors, hypotension, tachycardia, asthenia, headache, rash, scratchy throat, and dyspnea).
††ECGs in triplicate (“3X”), 1 minute apart, within 5 minutes  (predrug baseline).  Scheduled ECGs at other timepoints will be performed as a single measurement (“X”). All ECGs should be performed 
after the subject has been supine for at least 5 minutes. 
†††Follow–up visit ECG only necessary if prior ECG was abnormal, clinically significant.
♥Continuous, real-time cardiac monitoring (telemetry) will be monitored starting approximately 1 hour prior to the start of study drug infusion (0 hour) through 8 hours post dose.
§§Perform phenotyping for HLA-DQ2.5 (HLA-DQA1*0501 / B1*0201) and HLA-DQ8.1 (DQA1*0301/B1*0302) if unknown OR if historical documentation not available. Sample may be taken 
anytime on Day 1 from an enrolled subject. 
‡‡Anti-gliadin antibody test which serves as an anti-TIMP-GLIA antibody test (anti-drug antibody test) will be deamidated gliadin peptide (DGP)-specific IgG antibody (IgG-DGP).
Y Sample should correspond to 144 hour PK.
‡‡‡Additional tissue transglutaminase (tTG)-specific IgA antibody or deamidated gliadin peptide (DGP)-specific IgG antibody (IgA-tTG or IgG-DGP) serology is to be performed post dose upon 
appearance of celiac disease-related symptoms as determined by the investigator.
^^Adverse events (AEs) and concomitant medication will be collected from the time of signing of the informed consent through the final follow up.  Treatment-emergent AEs will be differentiated at time 
of first dosing. Data collected during scheduled in-clinic or telephone visits and any spontaneously reported information through the AE collection period are to be documented in the subject’s record.
***The procedures as listed under the Study Day 14 visit should be performed as the final study procedures in the event a subject discontinues the study prematurely during the investigational period.  If 
the subject discontinues on or before Day 14, a PK sample should also be collected, if possible, provided no other PK samples were already collected on the day of discontinuation.
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V.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
ADA
Anti-drug antibody
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
APCs
Antigen presenting cells
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AT
Aminotransferase
AUC
Area under the concentration-time curve
AUCt
Area under the curve from time zero (time of dosing) to time t, where a relevant t will be 
determined based upon the observed data
AUCτ
Area under the curve over the dosing interval, τ
AUCinf
Area under the concentration-time curve from time zero extrapolated to time infinity
AUClast
Area under the concentration-time curve from time zero to the last measurable 
concentration (Clast)
BSA
Body surface area
BMI
Body mass index
C3a, C5a 
Complement proteins
CD
Celiac disease
CD3
Cluster of Differentiation 3
CFR
Code of Federal Regulations
CH50
Total complement activity test
Clast
Concentration of study drug corresponding to the time of the last measurable concentration
CL
Total body clearance
Cmax
Maximum observed concentration
CNS
Central nervous system 
(e)CRF
(Electronic) Case report form
CRO
Contract research organization
CS
Clinically significant
CTCAE
Common Terminology Criteria for Adverse Events
CTLA
Cytotoxic T-lymphocyte antigen
D-dimer
Fragment D-dimer, Fibrin degradation fragment
DGP
Deamidated gliadin peptide
DILI
Drug-induced liver toxicity
DLT
Dose limiting toxicity
DMC
Data Monitoring Committee
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DTH
Delayed type hypersensitivity 
ECG
Electrocardiogram
EGF
Epidermal growth factor
ESV
End-of-study visit
FDA
Food and Drug Administration
FIH
First-in-human
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GFD
Gluten-free diet
GGT
-Glutamyl transferase
GLP
Good Laboratory Practice
GM-CSF
Granulocyte macrophage colony stimulating factor (also known as colony stimulating 
factor 2, CSF2)
GMP
Good Manufacturing Practice
GRO α
Growth regulated alpha protein (also known as chemokine (C-X-C motif) ligand 1 
[CXCL1])
HAV
Hepatitis A virus
HBc
Hepatitis B core
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HED
Human equivalent dose
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
ICAM-1
Intercellular adhesion molecule 1 (also known as cluster of differentiation 54 [CD54])
ICF
Informed consent form
ICH
International Conference on Harmonisation
IFN-α
Interferon alpha
IFN-γ
Interferon gamma
IgA, IgE, IgG Immune globulin A/E/G antibodies
IL-10
Interleukin 10
IL-1α
Interleukin 1 alpha (also known as hematopoietin 1)
IL-1β
Interleukin 1 beta, also known as leukocytic pyrogen, leukocytic endogenous mediator, 
mononuclear cell factor, lymphocyte activating factor
IL-2
Interleukin 2
IL-4
Interleukin 4
IL-5
Interleukin 5
IL-6
Interleukin 6
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IL-8
Interleukin 8
IL-12
Interleukin 12
IL-13
Interleukin 13
IL-15
Interleukin 15
IL-17
Interleukin 17
IND
Investigational New Drug
INR
International normalized ratio
IP-10
IFN-γ-induced protein (also known as C-X-C motif chemokine [CXCL-10] or 
small-inducible cytokine B10) 
IRB/IEC
Institutional review board/Independent ethics committee
IRR
Infusion-related reaction
IV
Intravenous(ly)
LA-CRF
Liver abnormality case report form 
LDH
Lactate dehydrogenase
LFT
Liver function test(s) (e.g. bilirubin, INR)
LLN
Lower limit of normal
LLOQ
Lower limit of quantification
LT
Liver test(s) (e.g., enzymes)
MARCO
MAcrophage Receptor with COllagenous
MedDRA
Medical Dictionary for Regulatory Activities
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MHC
Major histocompatibility complex
MIP-1α
Macrophage inflammatory protein (also known as chemokine (C-C motif) ligand 3, 
[CCL3])
MIP-1β
Macrophage inflammatory protein (also known as chemokine (C-C motif) ligand 4, 
[CCL4])
MRSD
Maximum recommended starting dose
MTD
Maximum tolerable dose
NCI
National Cancer Institute
NCL
Nanotechnology Characterization Laboratory
NCS
Not clinically significant
NOAEL
No observed adverse effect level
PAD
Pharmacological active dose
PBMC
Peripheral blood mononuclear cell
PDAS
Pharmacodynamic analysis set
PK
Pharmacokinetic
PKAS
Pharmacokinetic analysis set
PLGA
Poly(lactic-co-glycolic acid)
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POC
Proof-of-concept
PT
Prothrombin time
PTT
Partial thromboplastin time
Racc
Accumulation index
RBC
Red blood cell
SAD
Single ascending dose
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SC5B-9
Complex of complement proteins, C5b-6-7-9 (also known as C5-9 complex)
SD
Standard deviation
SOP
Standard operating procedure
SWI 
Sterile water for injection
t½
Terminal elimination half-life
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TIMP-GLIA 
Tolerogenic Immune Modifying Particles-Gliadin
TLFs
Tables, listings and figures
Tmax
Time of the maximum observed concentration
TNF-α
Tumor necrosis factor alpha
TT
Thrombin time
tTG
Tissue transglutaminase antibodies
ULN
Upper limit of normal
UPCR
Urine protein to creatinine ratio
WBC
White blood cell
WHO
World Health Organization
WHO-Drug
World Health Organization’s Drug Dictionary
Vd
Volume of distribution
λz
Terminal rate constant 
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Definition of Key Terms
Terms
Definition 
Baseline
Observed values/findings which are the starting point for comparison.
Clinical study entry
To register or enter into a clinical study, i.e., upon signing of informed consent form.  Once 
a subject has provided written informed consent the protocol applies to the subject.
Clinical study period
Period of time from the first subject signing informed consent to the last subject’s last visit.
Enrollment
A subject is enrolled in a clinical study when he/she has signed the informed consent form 
and all screening procedures have been successfully completed, the subject is confirmed 
eligible (inclusion/exclusion criteria) and starts the interventional phase of the clinical 
study. Subjects who fail to pass screening are not enrolled.
Dose limiting toxicity
Dose-limiting toxicity is defined to be a toxicity that prevents further administration of the 
agent at that dose level.
Intervention
The study drug, therapy or process under investigation in a clinical study that is believed to 
have an effect on outcomes of interest in a clinical study (e.g., health-related quality of life, 
efficacy, safety, pharmacoeconomics).
Investigational period
Period of time during which the major protocol objectives are observed, and the test drug or 
comparative drug (sometimes without randomization) is usually given to a subject, and 
continues until the last assessment after completing administration of the test drug or 
comparative drug.
Post investigational 
period
Period of time after the last assessment of the protocol.  Follow-up observations for 
sustained adverse events and/or survival are done in this period.
Randomization
The process of assigning clinical study subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
Screening
1) Process for retrieving candidates for the clinical study.  2) Process of active consideration 
of potential subjects for enrollment in a clinical study during the screening period.
Screening failure
Potential subject who did not meet 1 or more eligibility criteria required for participation in 
a clinical study or any subject who did pass screening but was not randomized/allocated to
or who did not receive treatment.
Screening period
Period of time before a subject’s entering the investigational period; i.e., from the time of a 
subject signing informed consent until just before the test drug or comparative drug 
(sometimes without randomization) is first given to a subject.
Source data
All information in original records and certified copies of the original records of clinical 
findings, observations or other activities in a clinical study necessary for the reconstruction 
and evaluation of the clinical study.  Source data exist in source documents (original 
records or certified copies) or in an electronic data capture system.
Source documents
Original documents, data and records including source data.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have different 
qualitative or quantitative values.
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1
INTRODUCTION
1.1
Celiac Disease Overview
Celiac disease (CD) is a common immunological disorder with an estimated prevalence of 0.3 to 
2.4% among people of European ancestry (Fasano 2012). It develops in genetically predisposed 
subjects as a consequence of an abnormal 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)-DQ/8 or HLA-DQ2 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; Leffler 2017; Mazzarela 2008; Tack 2010)
The enteropathy resulting from the T cell activation produces the chronic diarrhea, abdominal 
distension/pain, constipation, and other gastrointestinal symptoms, increased intestinal 
permeability, malabsorption, and occult gastrointestinal bleeding commonly observed in CD. 
Other manifestations might include weight loss, chronic fatigue, osteoporosis, refractory iron 
deficiency, anemia, infertility, growth failure in children, arthritis, peripheral neuropathy, 
dermatitis herpetiformis, gluten ataxia, and malignancy (Farrell 2002; Fasano 2012; Fasano 2001; 
Green 2007; Leffler 2017). In rare cases CD patients, primarily children, experience a 
life-threatening metabolic emergency termed celiac crisis, characterized by hypokalemia and 
acidosis secondary to profuse diarrhea (Baranwal 2003, Farrell 2002; Fasano 2012).  
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 disease 
such as cancer. Numerous therapies have been designed to induce immune tolerance in 
autoimmune diseases. However, these treatments have yielded only marginal efficacy in clinical 
trials (Kaukinen 2014).
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1.2
Investigational Product: 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 may also be thought of as a noninfectious disease therapeutic vaccine or “inverse 
vaccine” (Steinman 2010).
TIMP-GLIA is comprised of gliadin extract drug substance within a negatively charged polymer 
matrix of PLGA (Poly(DL-lactide-coglycolide)) particles. TIMP deliver the gliadin antigen via
natural phagocytosis of the PLGA particles, a noninflammatory process.   This phagocytosis of the 
particles leads to antigen presentation of the gliadin by antigen presenting cells (APCs) primarily 
in the spleen and liver.  The gliadin specific T cells become anergic, or are deleted, or switch to 
T regulatory cells, thereby tolerizing the immune system to the gliadin antigen, and eliminating the 
deletirious immune cascade typically initated by the gliadin specific T cells in response to gliadin.  
TIMP-GLIA is designed and directed to specifically address and abrogate the T cell response that 
drives CD. (Getts 2015)
1.3
Nonclinical Studies
The safety and potential efficacy of TIMP-GLIA has been evaluated and supported in a robust set 
of nonclinical studies, including: a panel of in vitro nanoparticle characterization studies as 
described by the National Cancer Institute (NCI) Nanotechnology Characterization Laboratory 
(NCL) for assessing the potential toxicity and immune effects of nanoparticle therapeutics; in vivo
pharmacology studies in mice; in vivo toxicology studies in rats; and an ex vivo study of T cell 
proliferation/mitogenicity and cytokine secretion in human peripheral blood mononuclear cells
(PBMCs) (Phase 0) from both celiac and non-celiac subjects. The distribution, metabolism, and 
excretion of nanoparticles is also well-published. For detailed information refer to the 
Investigator’s Brochure for TIMP-GLIA (Edition 1, 2017 or subsequent editions as they become 
available). 
1.3.1
Pharmacology/Mechanism of Action
Splenic and liver APC populations express numerous scavenger receptors which during 
homeostasis play an important role in the recognition and recycling of dying leukocytes, red blood 
cells, and other debris on a daily basis. Targeting of and tolerogenic stimulation of APCs is crucial 
for immune tolerance induction. Importantly, these activities occur without triggering 
inflammation or breaking peripheral immune tolerance. TIMP have been designed to take 
advantage of this targeting pathway. All previously attempted immune tolerance strategies either 
using monoclonal antibodies (i.e., anti-CD3, cytotoxic T-lymphocyte antigen 4 [CTLA-4]) or 
small molecules (rapamycin) have not exploited this pathway. Specifically, the TIMP mechanism 
of action depends upon uptake of particles by APCs, particularly splenic marginal zone 
macrophages expressing scavenger receptors, such as the MAcrophage Receptor with 
COllagenous structure (MARCO), in a fashion similar to the clearance of apoptotic debris. Studies 
using particles or apoptotic cells have shown that treatment induced production of the regulatory 
cytokines interleukin-10 (IL-10) and transforming growth factor beta (TGF-β) in the spleen, as 
well as upregulation of inhibitory ligands on macrophages, such as programmed death-1 (PD-1). 
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Downstream events include the induction of T cell anergy and the activation of regulatory T cells. 
The overall result is abrogation of pro-inflammatory T cell activity, reduction of leukocyte 
accumulation in tissues, and importantly, disappearance of signs of disease. (Getts 2015).
1.3.2
Pharmacology
1.3.2.1
In vitro Pharmacology
The in vitro nanoparticle studies focused on hematology [blood contact] (hemolytic potential, 
platelet aggregation potential, complement activation potential, effects on coagulation), 
immunology (effect on granulocyte and macrophage colony formation, macrophage nitric oxide 
production, chemotaxis, phagocytosis, maturation of dendritic cells) and cytotoxicity (caspase 3 
and caspase 3/7 activation, MTT and LDH release) and oxidative stress (levels of glutathione, lipid 
peroxidation, reactive oxygen species) of liver cell preparations. Test concentrations of 
TIMP-GLIA in mg/mL were translated to “human equivalent doses” (HEDs) for these studies 
assuming an estimated human blood volume of 5.6 L for an average 70 kg human.
Collectively, key findings in the in vitro studies demonstrated that:

No effects of TIMP-GLIA indicative of toxicity on hemolytic potential, platelet aggregation, 
complement activation and prothrombin time (PT, extrinsic pathway) were observed at HEDs 
as high as 162 mg/kg (applied concentration 2 mg/mL). Prolonged activated partial 
thromboplastin time (aPTT, intrinsic pathway) and thrombin time (TT, common pathway) 
were observed at HED 162 mg/kg, and for TT at HED 16 mg/kg (applied concentration 0.2 
mg/kg); however, the data generated were considered to be inconclusive due to potential assay 
interference from the nanoparticles at higher concentrations.

TIMP-GLIA was not associated with overt macrophage activation, increased dendritic cell 
(DC) maturation, and was not a chemoattractant at HEDs up to 162 mg/kg. A decrease in 
expression of DC surface antigens was observed with the highest HED (162 mg/kg; applied 
concentration 2 mg/mL) ascribed to nanoparticle interference with the assay.

TIMP-GLIA was not associated with any hepatocyte toxicity at HEDs as high as 200 mg/kg. A 
finding of increased caspase 3/7 activity at HED 400 mg/kg (5 mg/mL applied concentration) 
that was attributed to assay interference by the nanoparticle. Similarly, TIMP-GLIA was not 
associated with oxidative stress (increased fluorescence response from oxidation of 
dichlorofluorescein diacetate [DCFH-DA]) at any concentration tested up to HED 400 mg/kg 
(applied concentration of 5 mg/mL). Decreased DCFH-DA fluorescence response was 
observed for HEDs of 24.8, 100, 200, and 400 mg/kg (applied concentrations of 0.31, 1.25, 2.5, 
5 mg/mL, respectively) for which particle interference with the assay was suspected.
1.3.2.2
In vivo Pharmacology (Mouse)
Primary pharmacology of TIMP GLIA was studied in mouse models that incorporated one or more 
disease characteristics associated with human CD:

Presence of activated and expanding gliadin-specific T cells and/or, 

Intestinal disease (villous atrophy, crypt hyperplasia) and/or, 

Anti-gliadin antibody development.
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In these studies mice received two intravenous (IV) administrations of TIMP GLIA, 7 days apart. 
TIMP-GLIA showed the potential to induce antigen specific T cell tolerance to gliadin, whether 
treatment preceded (prevention model) or followed (treatment model) animal sensitization to 
gliadin. The optimal active dose of TIMP-GLIA observed during these studies, 125 mg/kg, is the 
HED of 10.16 mg/kg.
The key elements and outcomes of these studies are summarized in Table 3. TIMP-GLIA was not 
found to bind anti-gliadin antibody.
In addition, the mouse tissues underwent histological examination for signs of potential Type III 
hypersensitivity. Type III hypersensitivity occurs when there is accumulation of immune 
complexes (antigen-antibody complexes) that are not adequately cleared by the mononuclear 
phagocyte system and instead accumulate in the kidneys where they trigger inflammatory changes. 
Histological evidence of recent or ongoing inflammation and complement deposition was not 
evident in the TIMP-GLIA treated mice.
Taken collectively the in vivo data supports the activity of TIMP-GLIA in physiologic systems 
involved in CD without untoward biologic effects at the proposed human doses. 
1.3.2.3
Ex vivo Pharmacology (Human-Donor PBMCs)
Peripheral blood (from which PBMCs were harvested) was collected from healthy donors, donors 
with CD adhering to a GFD, and newly diagnosed celiac donors who were not adhering to a GFD. 
TIMP-GLIA incubation with PBMCs from these patients at concentrations as high as 1.25mg/mL 
(HED 100 mg/kg) did not cause T cell proliferation or pro-inflammatory cytokine production, 
indicating that the product is non-mitogenic.
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Table 3.
Summary of TIMP-GLIA Primary Pharmacology In Mouse Models
TIMP-GLIA induces immune tolerance without causing adverse immune response in a gliadin-induced DTH 
Model
Model
Purpose
Measures of treatment 
success
Outcomes
Tolerance 
induction in 
gliadin-specific 
DTH mouse 
model
Show that two infusions of 
up to 125mg/kg (HED 
10.16mg/kg) TIMP-GLIA 
induce T cell tolerance in 
mice when applied as 
prevention or treatment in 
gliadin immunized mice
1.Prevent gliadin induced 
ear swelling
2.Inhibit gliadin-specific T 
cell proliferation
3.Inhibit gliadin-specific T 
cell Interferon-γ
TIMP-GLIA induced antigen specific 
immune tolerance.
1.TIMP-GLIA resulted in antigen specific 
inhibition of gliadin induced ear 
swelling.
2.TIMP-GLIA resulted in inhibition of 
gliadin-specific T cell proliferation.
3.TIMP-GLIA resulted in inhibition of 
gliadin-specific T cell Interferon-
No immune 
activation / 
adverse immune 
response in 
DTH mouse 
model
Show that two infusions of 
up to 125mg/kg (HED 
10.16mg/kg) TIMP-GLIA 
do not activate or sensitize 
the immune system of 
mice when applied as 
prevention or treatment in 
gliadin immunized mice
1.Examine symptoms after 
two TIMP-GLIA 
infusions
2.Show no sensitization by 
looking at 
gliadin-specific 
antibody levels
1.TIMP-GLIA was not associated with 
adverse immune responses 
(anaphylaxis like) upon infusion. 
2.TIMP-GLIA was not sensitizing, as it 
was not associated with anti-gliadin
antibody production.
TIMP-GLIA induces immune tolerance and prevents gluten-induced intestinal pathology in adoptive transfer 
mouse model
Model
Purpose
Measures of treatment 
success
Outcomes
Tolerance 
induction in 
gliadin induced 
intestinal 
autoimmune 
model (Adoptive 
transfer model) 
Show that two infusions of 
up to 125mg/kg (HED 
10.16mg/kg) TIMP-GLIA 
induce T cell tolerance in a 
mouse model of gluten 
induced intestinal 
autoimmunity (Rag 
adoptive transfer model).
Prevent gluten diet 
induced weight loss
1.Prevent gluten diet 
intestinal pathology
2.Inhibit gliadin-specific T 
cell proliferation
3.Inhibit gliadin-specific T 
cell Interferon-γ
TIMP-GLIA induced antigen specific 
immune tolerance. 
1.TIMP-GLIA resulted in antigen specific 
prevention of weight loss.
2.TIMP-GLIA resulted in prevention from 
gluten induced intestinal pathology.
3.TIMP-GLIA resulted in inhibition of 
gliadin-specific T cell proliferation.
4.TIMP-GLIA resulted in inhibition of 
gliadin-specific T cell Interferon--γ
TIMP-GLIA induces immune tolerance in a mouse expressing human HLADQ8 and human CD4
Model
Purpose
Measures of treatment 
success
Outcomes
TIMP-GLIA 
tolerance 
induction in 
transgenic 
mouse 
expressing 
celiac associated 
HLA DQ8 / 
huCD4
Show that two infusions of 
up to 125mg/kg (HED 
10.16mg/kg) TIMP-GLIA
induce T cell tolerance in a 
mouse expressing the 
common celiac HLA DQ8 
and human CD4 can 
induce immune tolerance 
and modulate B cell 
responses. 
1.Inhibit gliadin-specific T 
cell proliferation
2.Inhibit gliadin-specific T 
cell Interferon-γ
3. Prevent gliadin-specific 
antibody production
TIMP-GLIA induced antigen specific 
immune tolerance. 
1.TIMP-GLIA resulted in inhibition of 
gliadin-specific T cell proliferation.
2.TIMP-GLIA resulted in inhibition of 
gliadin-specific T cell Interferon-
3.TIMP-GLIA resulted in inhibition of 
anti-gliadin IgG2c levels.
DTH: delayed type hypersensitivity; Source: Investigator Brochure, Edition 1
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1.3.3
Toxicology
Rats were chosen as the relevant toxicology species for TIMP-GLIA toxicology studies in 
collaboration with FDA. A non-GLP repeat dosage range finding study and the required GLP 
repeat-dose study were conducted with IV drug since this is the route intended for the Phase 1 
administration. 
1.3.3.1
Non-GLP Dose-Ranging Toxicology Study
TIMP-GLIA (Lot 36054) dosages used during the non-GLP study were 0, 10, 50, 75, 100, and 200 
mg/kg (HED: 0, 1.6, 8, 12, 16, and 32 mg/kg) and administered IV on Days 1 and 8, with the 
necropsy being on Day 15 or Day 17 depending upon tissue/blood sampling requirements. In 
summary, TIMP-GLIA produced no significant toxicological or pathological effects at 10 mg/kg 
when administered IV on Days 1 and 8.  A number of clinical pathology and microscopic 
histopathological effects were seen at dosages of > 50 mg/kg, predominately in the liver and the 
spleen.  At 200 mg/kg two animals were euthanized due to drug-related effects. (See Table 4, 
Summary of Nonclinical Observations and Clinical Risk Minimization Actions, findings shown in 
italics font.)  
Following the observation of liver pathology occurring in the high dose groups (> 50 mg/kg), a 
product purification change was implemented prior to formulating the TIMP-GLIA lot used in the 
pivotal GLP repeat dose toxicology study and all subsequent lots.  This change provided for 
greater removal of small particulates by use of a higher cut-off filter (200 nm) than employed in 
the non-GLP material (50 nm). It is noteworthy that the adverse effects observed during the 
non-GLP toxicology study at doses ≥ 50 mg/kg were not observed during the GLP toxicology 
study (summarized below).
1.3.3.2
GLP Toxicology Study
TIMP-GLIA (Lot 36092) that had undergone the product purification mentioned above was 
administered IV to rats (10/sex/group) at dosages of 0, 4, 10, 50, and 75 mg/kg (HED: 0, 0.64, 1.6, 
8, and 12 mg/kg). Infusions occurred on Days 1, 8, and 15 with the necropsy being on Day 16.  An 
additional 5 rats/sex/group underwent the same dosing regimen followed by a 28-day recovery 
period after the last dose and necropsy on Day 43. Another 5 rats/sex/group were dosed on Day 1 
and Day 8 and euthanized on Day 11 for pathology investigations and groups of 
12 rats/sex/TIMP-GLIA group plus 6 /sex/control group were dosed on Days 1 and 8 for 
measurement of TGLIA-concentrations over time for TK analysis and for cytokine measurement.  
The animals in the TK/cytokine group were euthanized after the last blood draw.
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 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 
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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 a IV injection.
Several minor statistically significant changes were noted in the clinical pathology but were not 
judged by the study director to be drug-related as they were of insufficient magnitude or failed to 
show a relationship to dose. For example, a modest decrease was seen in total numbers of white 
blood cells (WBC) for the 75 mg/kg females at the recovery (Day 43) necropsy.  This effect was 
judged to be of minimal toxicological significance because no corresponding effect was noted at 
the end of drug treatment necropsy (Day 16) or for the 75 mg/kg males at the end of the Recovery 
necropsy. Other observations from the GLP toxicology study are noted in Table 4, Summary of
Nonclinical Observations and Clinical Risk Minimization Actions, findings shown in underline 
font.
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. 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 a IV injection.  
The no observed adverse effect level (NOAEL) from this pivotal GLP toxicology study in rats was 
determined to be 75 mg/kg.
1.3.3.3
Non-GLP Follow-Up Study to GLP Toxicology Study
Because the NOAEL (75 mg/kg; HED 12 mg/kg) occurred at the maximum dose in the GLP 
toxicology study, a small scale follow up study testing 100 mg/kg (HED 16 mg/kg) and 150 mg/kg 
(HED 24 mg/kg) using the same TIMP-GLIA (Lot 36092) was performed in rats to characterize 
the toxicity profile at higher doses.  TIMP-GLIA was administered as a slow bolus IV to rats 
(3/sex/group) at dosages of 0 (0.9% saline), 100, or 150 mg/kg (HED: 0, 16, 24 mg/kg) on Days 1 
and 5 with daily clinical observations and laboratory testing (clinical chemistry, coagulation, 
hematology) and histopathology performed on Days 4 and 8. Necropsy occurred on Day 9. 
All animals survived until euthanasia for necropsy and no abnormal clinical behaviors were 
observed.  Findings are presented in Table 4. Summary of Nonclinical Observations and Clinical 
Risk Minimization Actions. As previously observed, liver and spleen were the target organs of 
toxicity. 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.
TIMP-GLIA-related effects were noted on clinical chemistry and hematology tests and generally 
were mild or moderate.  Histopathological findings in the liver included dose-dependent minimal 
to moderate mononuclear sinusoidal infiltrates and non-dose dependent minimal to mild increased 
hematopoiesis (females only) and at 150 mg/kg included minimal increased mitosis in hepatocytes 
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and minimal biliary hyperplasia. Findings correlated with laboratory changes. Histopathological 
findings in the spleen included dose-dependent minimal to moderate increased cellularity 
(mononuclear) in the red pulp and marginal zone and minimal to moderate increased 
hematopoiesis. Effects at 150 mg/kg included minimal to mild decreased marginal zone 
lymphocyte cellularity. Spleen effects correlated with macroscopic observation of increased 
spleen weight/enlargement and laboratory changes.
These data are consistent with prior observations and do not change safety conclusions.
1.4
Clinical Studies
To date no clinical studies of TIMP-GLIA have been conducted.
1.5
Benefit-Risk Assessment
The subjects participating in this first-in-human (FIH) study will not benefit directly from 
administration of TIMP-GLIA. Subjects may derive satisfaction from their contribution towards 
the development of a potential new treatment for CD.  
In contrast, subjects may experience adverse events (AEs) related to study drug, including 
exposure to residual trace amounts of non-particle-associated gliadin protein present within the 
reconstituted TIMP-GLIA drug product. Subjects may experience procedural complications 
related to blood draws or infusion including infusion-related reaction (IRR), and/or slight skin 
irritation from the adhesive of the electrocardiogram (ECG) electrodes. Risk of 
anaphylaxis/anaphylactoid response, characterized by rapid induction of proinflammatory 
cytokines and accompanied by headache, dyspnea, myalgias, nausea, diarrhea, erythema, 
vasodilatation, and hypotension, with subsequent life-threatening lung injury, renal failure, and 
disseminated blood clots (Suntharalingam 2006) is not probable based upon the nonclinical data 
and observations whereby gliadin exposure does not induce anaphylaxis. Notwithstanding, this 
risk cannot be entirely ruled out.
At the time of this amended protocol (Version 9), TIMP-GLIA has been given as a single infusion 
to 17 subjects with celiac disease (Part A of this study).  At the highest dose tested, approximately 
650 mg, 2 of 4 subjects experienced a moderate IRR.  For one of the subjects the infusion was 
stopped and the signs and symptoms went away immediately.  For the second subject, the infusion 
was stopped and the signs and symptoms went away immediately, and the infusion was restarted at 
a slower rate.  The subject completed the infusion without any other problems.
Signs and symptoms of IRR to TIMP-GLIA have included flushing (warm feeling or reddening of 
face, back and/or chest), rash, nausea, vomiting, back pain, low or high blood pressure, or increase 
in heart rate.  These symptoms were either mild or moderate.  All symptoms started within 2 
minutes of the infusion starting and went away very quickly when the infusion was stopped or 
interrupted.
A conservative approach is being implemented to minimize risks to subjects in the first-in-human 
(FIH) study. Safety precautions are included in the design to address all findings observed during 
nonclinical studies, even those observed in the non-GLP toxicology study that were not observed 
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during the GLP toxicology study. A summary of nonclinical observations and the strategy to 
mitigate the risk are summarized in Table 4.
The sponsor believes that the potential for immunoreactivity and anaphylaxis/anaphylactoid 
response by subjects in this FIH trial is low based on the following characteristics and findings for 
TIMP-GLIA:

The key components of TIMP-GLIA are PGLA polymer and gliadin.  
o
PLGA is a biodegradable (hydrolyzed to its original monomers, lactic acid and glycolic 
acid) and biocompatible component of 15 FDA-approved products. These products 
have demonstrated minimal systemic toxicity associated with PLGA for drug delivery 
or biomaterial device applications (Makadia 2011, Wang 2016).  
o
Gliadin is prolamin protein that is the same as occurs in wheat-containing foods 
ingested by healthy individuals or intentionally or unintentionally ingested by patients 
with CD, or administered during gluten challenge studies (Anderson 2005, Han 2013, 
Leffler 2013).

TIMP-GLIA decreased antigenic response during nonclinical studies.  TIMP deliver the 
gliadin antigen via natural phagocytosis of the PLGA particles, a noninflammatory process.  
Following this, nonclinical data showed treatment- induced production of the regulatory 
cytokines IL-10 and TGF-β in the spleen as well as upregulation of inhibitory ligands on 
macrophages, such as programmed death-1 (PD-1). Downstream events included the induction 
of T cell anergy and the activation of regulatory T cells (Getts 2015).

There is low expectation of an IgE-mediated (classic anaphylaxis) or IgG-mediated 
anaphylaxis in subjects treated with TIMP-GLIA. IgE-mediated anaphylaxis results from cross 
linking of protein-specific antibody bound to mast cells/basophils. This is highly unlikely 
because CD is characterized by gliadin-specific IgG, not IgE, and subjects with wheat allergy 
(which is IgE-mediated) are excluded from participation. Furthermore, there is little surface 
protein on the TIMP-GLIA particle that can bind to any gliadin-specific receptor (of IgE or 
IgG isotype), whether circulating or bound to mast cells.

In vitro studies with peripheral blood mononuclear cells from healthy donors and donors with 
celiac disease show that TIMP-GLIA does not cause T-cell proliferation or proinflammatory 
cytokine production, indicating the product is not mitogenic in either population. TIMP-GLIA 
does not interact directly with the T cell receptor (TCR) nor does it cause activation of T cells 
through binding of co-stimulation molecules expressed on T cells, platelets and other 
leukocytes. TIMP-GLIA regulates gliadin specific T cells indirectly, through antigen 
presenting cells. Therefore, TIMP-GLIA is unlikely to trigger positive co-stimulatory 
molecule activation (as observed with TGN1412) and potential for cytokine storm is very low.
Although the characteristics of TIMP-GLIA suggest a downregulation of immune response, the 
study design features and safety precautions to be implemented during the study will minimize 
medical risk to the subjects. These include:

TIMP-GLIA will be administered IV, the route generally considered to be the least likely to 
elicit an immune response compared to intradermal, subcutaneous, and inhalational routes of 
administration. 
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
A safe starting dose was calculated taking into consideration the no observed adverse effect 
level (NOAEL) from the GLP toxicology study and the pharmacologic activity observed 
during the in vivo mouse study of DTH (see Section 2.5 Rationale for Dose Selection).

Subjects will be carefully screened for participation in the trial. Subject enrollment will be 
limited to those who are otherwise healthy or who have stable comorbidity in compliance with 
the study-specific inclusion and exclusion criteria.
o
Subjects who have a history of allergic reaction to wheat or who have a known 
hypersensitivity or allergies to the TIMP-GLIA excipients (as specified in the 
investigator brochure), or who have any other history of severe hypersensitivity or 
allergic reaction to any allergen are excluded from participation in the study. 
o
Subjects with cardiac conduction abnormalities or clinically significant laboratory test 
results (e.g., cell counts, LTs, INR) will be excluded.

This study will be conducted in clinical research units with adequate equipment and staff 
training to manage clinical emergencies (crash carts) and proximity to hospital emergency 
departments for rapid delivery of urgent care.  

Subjects will be resident in the clinic for continuous medical monitoring for 48 hours after
dosing. Prior to clinic discharge subjects will be evaluated medically including review of 
safety laboratory results from samples collected 24 hours post dose including electrolytes, 
white blood cell counts with differential, coagulation (see Table 9. Clinical Laboratory Tests) 
and occurrence of AEs including clinically significant cardiovascular (safety ECG)-, renal-, 
gastrointestinal- and CNS-related symptoms. Discharge may be delayed if the investigator 
determines additional medical follow up is necessary. Follow up assessments will be 
conducted on an outpatient basis or by telephone (see the Schedules of Procedures for Part A 
(SCHEDULES OF ASSESSMENTS

Table 1) and Part B (Table 2) and unscheduled in-clinic visits and laboratory tests may be 
performed as needed to follow-up suspected AE(s). 

Part A of the protocol TGLIA-5.001 uses a staggered dosing strategy across sites.  One subject 
in a cohort will be dosed at a time, and undergo medical observation in the clinic for at least 48
hours. Seven days (168 hours) will elapse before the next subject will be dosed at the same 
level.

For Part B, subjects within a cohort may be enrolled/dosed concurrently.

If none of the subjects in the cohort experiences a dose-limiting toxicity and stopping criteria 
(“Study Stopping Rules”) are not met based upon Data Monitoring Committee (DMC)
assessment of accumulating safety data, then escalation to the next higher dose may proceed.  
However, if 1 of the subjects at a dose level exhibits a dose-limiting toxicity, additional 
subject(s) will be dosed at the same level to clarify ambiguous safety findings. 

In Part A, when all subjects in a dose cohort complete procedures through 168 hours post dose, 
the overall safety and tolerability data (AEs, vital signs, 12-lead ECGs, clinical laboratory 
tests, cytokines) for the current cohort and available cumulative AE data from previous cohorts 
will be reviewed by the DMC who will determine the progression or termination of dosing. In 
Part B, the DMC will review all safety date from a cohort when the last subject in a cohort has 
completed procedures through 48 hours.
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
A summary of nonclinical risk factors and the strategy to mitigate the risk are summarized in Table 
4. Taken collectively, the nonclinical data and drug characteristics suggest that there are no undue 
risks to subjects who participate in this FIH study.
Table 4. 
Summary of Nonclinical Observations and Clinical Risk Minimization 
Actions
Target
Species
All Observations†
From non-GLP (italics) and GLP
(underlined) toxicology, or in vitro NCL 
panel
Risk Minimization Action
Liver
Rat
↑ALT; ↑AST; ↑ALP; ↑GGT; ↑bilirubin;
↑triglycerides; hepatocellular necrosis & 
congestion; red discoloration of the liver;
hepatic infiltrates; ↓cholesterol, ↑cholesterol;
↓albumin; ↓fibrinogen; also ↑fibrinogen; 
prolonged aPTT and PT; Kupffer cell 
erythrophagocytosis
hepatocellular necrosis (n=1); ↑ALT;
↑triglycerides; ↓total bilirubin; ↓PTT; 
↑fibrinogen
<↑fibrinogen; ↑ALT; ↑AST; ↑ALP; ↑GGT;
↑bilirubin; mononuclear sinusoidal infiltrates 
and ↑hematopoiesis; ↑mitosis in hepatocytes; 
biliary hyperplasia>
Standard liver function tests; coagulation 
tests, monitor CTCAE Investigations and 
Hepatobiliary AE;
Subjects with clinically significant 
abnormal LFTs, coagulation tests are 
excluded from participation. 
In vitro
Prolonged aPTT, TT; ↓reactive oxygen species; 
↑apoptosis
Kidney
Rat
↑BUN; renal medulla tubular necrosis;
granular casts; tubular dilatation
Standard chemistry and urinalysis; 
monitor CTCAE Investigations & Renal 
and Urinary Disorders AEs; Subjects 
with clinically significant laboratory 
results or baseline conditions are 
excluded from participation.
Electrolytes 
/metabolic
Rat
↓glucose
Standard chemistry and urinalysis; 
monitor CTCAE Investigations &  
Metabolism & Nutrition Disorders AEs; 
Subjects with clinically significant 
laboratory results or baseline conditions 
are excluded from participation.
Table 4 continued next page.
CTCAE: Common terminology criteria for adverse events
† All clinical pathology and gross/histopathology findings are noted even if deemed biologically non-significant /minimal /mild; 
thought to be an NCL assay artifact; observed only at ↑dose relative to planned clinical doses; OR observed only with the non-GLP 
manufacturing batch of drug and the effect was not observed during GLP toxicity study.
Following the non-GLP toxicology study, a product purification change was implemented prior to formulating the TIMP-GLIA lot 
used in the pivotal GLP repeat dose toxicology study and all subsequent lots.  This change provided for greater removal of small 
particulates via a higher cut-off filter (200 nm) than employed in the non-GLP material (50 nm).
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< > Denotes new data from a non GLP toxicology study TGLIA-1.039 which were available after the Investigator’s Brochure and 
original TGLIA-5.001 protocol were finalized. These data are consistent with prior observations and do not change safety 
conclusions.
Table 4. Continued, Summary of Nonclinical Observations and Clinical Risk Minimization Actions
Target
Species
All Observations†
From non-GLP (italics) and GLP 
(underlined) toxicology, or in vitro NCL 
panel
Risk Minimization Action
Hematopoietic 
system
Rat
↑Reticulocytes; ↓red cell mass (RBC, HGB, 
Hct); ↑RBC distribution width; ↓platelets;
↑neutrophils, ↑monocytes, ↑basophils, and 
↑eosinophils; also ↓eosinophils and ↓basophils;
↑lymphocytes; ↑immature hematopoietic 
precursors; ↑hematopoiesis in liver and spleen 
and bone marrow; enlargement of spleen;
↓lymphoid cellularity of marginal zone;
↓cellularity and/or apoptosis of lymphoid cells 
in non-spleen lymphoid tissue; dark color of 
mesenteric lymph nodes; capsular fibrosis; 1+ 
to 3+ numbers of band neutrophils and Dohle 
bodies on blood smear
↓WBC; ↓neutrophils; ↓eosinophils; 
↑monocytes; ↓lymphocytes; ↓platelets; 
↑reticulocytes; ↑MCV; ↑RBC distribution 
width; ↓MCHC; ↓spleen weight
<↑Reticulocytes; ↓red cell mass (↓RBC ↓HGB 
↓Hct); ↑RBC distribution width; ↑WBC; 
↑monocytes; ↑neutrophils; ↑spleen 
weight/spleen enlargement; microscopic 
findings of ↑hematopoiesis and infiltrates of 
mononuclear cells; ↑cellularity (mononuclear) 
in the red pulp and marginal zone; ↓marginal 
zone lymphocyte celluarity>
Standard hematology laboratory 
parameters including MCV, RBC, and 
reticulocytes; monitor CTCAE 
Investigations AEs; Subjects with 
clinically significant abnormal 
laboratory results or baseline conditions 
are excluded from participation.
Cardiovascular 
system
Rat
Cardiac myofiber necrosis and hemorrhage
Telemetry 8 hours post dose; serial 
ECGs post dose compared to predrug 
baseline triplicates; monitor CTCAE 
Cardiac Disorders AEs; Subjects with 
abnormal, clinically significant 
screening ECG or baseline conditions are 
excluded from participation.
Other
Rat
Dark foci of the lungs/congestion; Type 2 
pneumocyte hypertrophy within lungs; 
epithelial necrosis of glandular stomach;
epithelial apoptosis and/or atrophy of various 
tissues, including epididymis
Physical exam, monitor CTCAE AEs; 
birth control requirement during study
CTCAE: Common terminology criteria for adverse events
† All clinical pathology and gross/histopathology findings are noted even if deemed biologically non-significant /minimal /mild; 
thought to be an NCL assay artifact; observed only at ↑dose relative to planned clinical doses; OR observed only with the non-GLP 
manufacturing batch of drug and the effect was not observed during GLP toxicity study.
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Following the non-GLP toxicology study, a product purification change was implemented prior to formulating the TIMP-GLIA lot 
used in the pivotal GLP repeat dose toxicology study and all subsequent lots.  This change provided for greater removal of small 
particulates via a higher cut-off filter (200 nm) than employed in the non-GLP material (50 nm).
< > Denotes new data from a non GLP toxicology study TGLIA-1.039 which were available after the Investigator’s Brochure and 
original TGLIA-5.001 protocol were finalized. These data are consistent with prior observations and do not change safety 
conclusions.
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2
STUDY DESIGN AND RATIONALE
2.1
Overview of Study Design
This study is a Phase 1, FIH, 2-part, multicenter study to assess the safety, tolerability and 
pharmacokinetics (PK) of TIMP-GLIA in subjects with CD.  Part A includes an accelerated 
titration 2+2 and traditional 3 + 3 design with rapid dose escalationduring which successive 
cohorts of subjects will receive a single dose of TIMP-GLIA. Part B will follow as a repeat dose 
design using the dose level selected from Part A. (See Error! Reference source not found., 
Error! Reference source not found..)
Consenting subjects will be screened within 28 days (Day -28 to -1) prior to admission to the 
clinical research unit on Day -1 for baseline assessments. 
Part A
In Part A, eligible subjects (at least 19 subjects) will be enrolled into escalating dose cohorts (n = 
2/cohort for 2 dose levels followed by n = 3/cohort for 5 dose levels).  TIMP-GLIA will be 
administered as a single IV infusion on Day 1. A staggered dosing strategy will be used in Part A.  
One subject in a cohort will be dosed at a time and undergo medical observation in the clinic for at 
least 48 hours post-infusion. 
At least 168 hours (7 days) will elapse prior to dosing the next subject. AEs, vital signs, pulse 
oximetry, and ECGs and laboratory data (serum chemistry, coagulation, hematology and 
urinalysis, cytokines) from samples obtained through at least 24 hours post dose will be assessed 
before dosing the subsequent subject(s). 
AEs will be graded according to National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0 (Published: May 28, 2009 [v4.03: June 14, 2010]) or most 
current version. If safety and tolerability are confirmed by the investigator, TIMP-GLIA will be 
administered to the next subject. 
Dose Escalation, Part A
After all the subjects in a dose cohort complete study procedures through at least 168 hours (7 
days) post dose the safety data  by the DMC.  Dose escalation will proceed only if Study Stopping 
Criteria (“Study Stopping Rules”) are not met. If dose-limiting toxicity occurs in 1 of the subjects
in the cohort, the DMC may decide to increase enrollment at the same dose level by 2 subjects
(accelerated titration cohort) or by 3 subjects (standard 3+3). After a rate of DLTs has been 
identified for a specific dose in 3- or 6-subject cohorts, the DMC may recommend that up to a total 
of 12 subjects may be accrued at any dose level to better define the relationship between dose and 
emerging the safety signals. It is also possible that the DMC could recommend an intermediate 
dose (lesser escalation) or reduced dose level (dose reduction) if warranted by the emerging safety 
data.  Before continuing to Part B, available safety data for all subjects in Part A through at least 
168 hours (7 days) after dosing will be evaluated by the DMC. 
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Part B
Part B will evaluate 2 doses of TIMP-GLIA administered on Days 1 and 8.  Two subjects will be 
enrolled into each of 3 cohorts at dose levels of 2, 4, and 8 mg/kg up to a maximum of 650 mg. 
Dose escalation will proceed only if Study Stopping Criteria (“Study Stopping Rules”) are not met. 
If dose-limiting toxicity (DLT) occurs in 1 of the 2 subjects in a cohort, the DMC may decide to 
increase enrollment at the same dose level by 2 subjects. (2+2 design).
Clinic Residency and Visits
Subjects in both parts of the study will remain in the clinic from admission (Part A: Day -1; Part B: 
Day -1 and Day 7)) through the final post-dose procedure at 48 hours (Part A: Day 3; Part B: Day 
3 and Day 10) and will be thereafter discharged if safety parameters are acceptable to the 
investigator.  Subjects will return to the clinical research unit for follow-up assessments or may be 
contacted by telephone as shown in the Schedules of Procedures for each part of study. 
Duration of Study
Part A:  Total duration of the study investigational period is up to 91 days (screening up to 28 days 
+ 1 treatment day + follow-up at Day 60 +/- 3 days).  In addition, telephone follow-up by a health 
care practitioner is required after the Day 60 outpatient visit (i.e., Day 90, Day 120, Day 180, all 
+/- 3 days).
Part B: Total duration of the study investigational period is up to 91 days (screening up to 28 days 
+ 2 treatment days, 7 days apart + follow-up at 60 +/- 3 days after last dose). In addition, telephone 
follow-up by a health care practitioner is required after the Day 60 outpatient visit (i.e., Day 90, 
Day 120, Day 180, all +/- 3 days).
2.2
Rationale for the Trial
This study is being conducted to obtain initial safety, tolerability, and pharmacokinetic 
information of single and repeat IV doses of TIMP-GLIA in adult subjects with CD.  Nonclinical 
pharmacology data with TIMP-GLIA have suggested a mechanism of action relevant to the 
pathophysiology of CD. In the mouse model of CD, TIMP-GLIA has been shown to induce T cell
tolerance by systemically targeting and controlling, gluten-reactive T cells. (See Investigator’s 
Brochure.)  Since T cell activation is considered to be the major cause of the mucosal 
inflammation, consequent antibody production, and tissue destruction observed in CD, further 
evaluation of a therapeutic agent capable of specifically inactivating, or tolerizing, these gliadin 
specific T cells is warranted. Results from the GLP repeat dose toxicology study in rats has raised
no safety concerns associated with TIMP-GLIA administration but appropriate precautions will be 
engaged to protect and evaluate subject safety after single and repeat (2) doses of TIMP-GLIA.
2.3
Rationale for the Trial Design
This FIH clinical study in patients with stable CD will consist of 2 parts.  Part A is a traditional, 
open-label, single ascending dose (SAD) study with staggered dosing.  The dose escalation and 
cohort size in Part A are based upon accepted methodology for phase I studies (Le Tourneau 2009, 
Rubinstein 2003). In Part A, an accelerated titration (2+2) model will be followed at the lowest 
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doses followed by the standard 3+3 model at higher doses. In Part B, an accelerated titration (2+2) 
model will be followed.  See also Figure 1. Schematic of Planned Dosing in Subjects With Celiac 
Disease, Part A and Part B  and further description in Section 2.1, Overview of Study Design.)
In Part A, this design will allow the study proceed more quickly through the lowest doses at which 
little or no effect is anticipated to be observed.  Cohort size increases to 3 at the doses for which 
pharmacologic or clinical effect would be more likely, based upon the nonclinical studies.  The 
cohort size in the accelerated titration phase of 2 subjects and an additional 2 subjects if warranted, 
and the cohort size in the standard 3+3 phase of at least 3 and up to 6 subjects if warranted, have 
been employed to facilitate a reasonable rate of accrual of subjects and to confirm ambiguous 
safety or tolerability findings.  In Part B, the accelerated model allows the study to proceed at the 
lower doses at which little or no affect is expected.
Subject safety is prioritized at all doses.
Should a dose limiting toxicity (DLT) occur in one subject, an additional cohort will be dosed at 
the same dose level to follow up ambiguous safety observations, provided no stopping criteria 
(“Study Stopping Rules”) have been met according to the DMC (see Section 7.2, Safety 
Committee). Stopping criteria have been set in accordance with traditional phase I study 
methodology. Decisions to advance or modify dose level(s) within Part A will be guided by 
evaluation of accumulating safety and tolerability data by the DMC.  
Part B will be a repeat-dose study with 2 subjects who will receive the first infusion on Day 1 and 
the second infusion on Day 8. If a dose-limiting toxicity occurs in 1 of the 2 subjects in Part B, the 
DMC may decide to enroll an additional 2 subjects at the same dose to confirm ambiguous safety 
or tolerability findings. Repeat dosing will provide support for safe and tolerable dosing using the 
2-dose regimen to be investigated in the future proof-of-concept (POC) clinical trial.  
The 48-hour minimum observation period prior to discharge was selected because the major 
potential toxicities are anticipated to emerge within this duration. 
The Day 60 (+/- 3 days) outpatient follow-up visit of the investigational period and Day 180
(+/- 3 days) telephone contact follow up after last dose will allow sufficient time to capture 
potential delayed-onset AEs and evaluate the potential for antibody response to TIMP-GLIA.
2.4
Rationale for the Subject Population 
The rationale for going directly into the subject population of interest (CD subjects) in this 
first-in-human (FIH) study is to allow early assessment of any disease-specific safety issues and is 
supported as follows:

CD is characterized by an immune reaction to the gliadin component of gluten. Only celiac 
patients have gliadin-specific T cells. (Anderson 2000, Han 2013, Christophersen 2016) As the 
mechanism of action of TIMP-GLIA involves gliadin-specific T cells, the potential drug 
effects on T cells cannot be measured in healthy individuals, only those reactive to gluten. In 
other words, healthy individuals are tolerant to gluten and as such data obtained from studies 
using healthy subjects may provide incomplete information/conclusions regarding 
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TIMP-GLIA safety.  Thus, subjects with CD provide the most likely opportunity to determine 
any potential adverse safety signal in the presence of gliadin-specific T cells.

CD patients on a GFD provide the best opportunity to measure PK of TIMP-GLIA without the 
potential for confounding background levels of gliadin.

Restricting enrollment to subjects with negative celiac serology and quiescent CD
symptomology (clinically inactive) who are otherwise healthy or with stable comorbidity will 
minimize the potential to confound the interpretation of safety data. 

Excluding subjects with history of immunoglobulin E (IgE)-mediated reaction and/or 
anaphylaxis to wheat (i.e., “wheat allergy”), barley or rye or a known history of 
hypersensitivity or allergies or severe allergic reaction to any other allergens (medications, 
food or environmental) is a safety precaution.
2.5
Rationale for Dose Selection
The determination of the planned starting dose of this study and the dose range to be tested is 
consistent with the principles set out in FDA 2005 Guidance for Industry Estimating the Maximum 
Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (FDA 
July 2005) and FDA 2011 Guidance for Industry Clinical Considerations for Therapeutic Cancer 
Vaccines (FDA October 2011).  The rationale for determining a safe starting dose for the FIH 
study takes a multi-faceted approach considering all of the data and experience obtained during 
nonclinical studies, summarized previously. The maximum recommended starting dose (MRSD) 
was determined conservatively, taking into account both the NOAEL in rat GLP toxicology study
and the pharmacologically active doses (PAD) causing partial inhibition and full inhibition of ear 
swelling in a mouse DTH model pharmacology study; to these a ten-fold safety margin was 
applied. 
The findings from the in vivo nonclinical pharmacology and toxicology studies of TIMP-GLIA 
have provided reasonable assurance that there are no undue risks for the first administration of 
TIMP-GLIA to humans at the dose levels proposed in this study.
2.5.1
TIMP-GLIA Toxicology and the NOAEL
The GLP repeat-dose toxicology study of TIMP-GLIA is required by FDA to assess toxicity in the 
appropriate animal model (rat). This GLP study also utilized TIMP-GLIA formulation that 
underwent the additional purification step that is applicable to the clinical lots.  For these reasons,
the NOAEL has been identified from the GLP toxicology data for calculation of the maximum 
recommended starting dose (MRSDtox) for the FIH trial. 
Upon evaluation of the GLP toxicology data (Section 1.3.3.2, GLP Toxicology Study and 
Investigator Brochure, Edition 1), the study director identified a NOAEL of 75 mg/kg.
Using both standard conversions (by body surface area and body weight) described in the FDA 
2005 Guidance for Industry, the MRSDtox based upon NOAEL in rat is calculated as shown in 
Table 5.
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Table 5. 
Calculations of Maximum Recommended Starting Dose Based upon 
Toxicology (NOAEL) Data
Step 1: Determination of NOAEL in most sensitive animal species
NOAEL in Rat: 75 mg/kg/day
Step 2:Conversion of Animal Dose to HED
Body surface area conversion
Conversion of Rat Dose in mg/kg to 
mg/m²
[75 mg/kg]NOAEL x [6 kg/m2]Rat Conv Factor
=  450 mg/m2
Conversion of Rat Dose in mg/m² to 
HED
in mg/kg, assuming 60 kg 
human with mean BSA of 1.79 m2
450 mg/m2 × 1.79 m2 = 805.5 mg 
÷ 60 kg = 13.4 mg/kg*
Body weight conversion
Conversion of Rat Dose in mg/kg 
to HED in mg/kg assuming a 60 kg 
human
[75 mg/kg]NOAEL x [.162]Rat Conv Factor
=  12.1 mg/kg*
Or 
[75 mg/kg]NOAEL ÷ [6.2]Rat Conv Factor =  
12.1 mg/kg*
*NOAEL rounded down to 10.0 mg/kg
Step 3: Apply 10-fold safety factor
10.0 mg/kg ÷ 10  = 1.0 mg/kg
HED: Human Equivalent Dose; BSA: body surface area
2.5.2
TIMP-GLIA Pharmacologically Active Dose 
TIMP-GLIA pharmacologic effect was evaluated in vivo using a mouse model of DTH.  Mice
were treated with two infusions of TIMP-GLIA after sensitization with gliadin (Table 3). 
Pharmacologic activity was initially observable at 12.5 mg/kg as partial inhibition of 
gliadin-specific inflammation (ear swelling) comparted to non-treated controls (“subtherapeutic 
response”). Full inhibition (“therapeutic response”) was observed at 125 mg/kg compared to 
non-treated controls.   This is the relevant dose range of TIMP-GLIA pharmacologic activity 
(pharmacological active dose, PAD).
Applying the standard conversions (by body surface area or body weight) described in the FDA 
2005 Guidance for Industry to the TIMP-GLIA doses, MRSDPAD based upon full or partial 
inhibition of DTH response is calculated as shown in Table 6.
NOAEL
HEDtox
Apply 
animal-to-human 
conversion factor
Apply 
10-fold safety 
f
MRSDtox
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Table 6. 
Calculations of Maximum Recommended Starting Dose Based upon 
Pharmacologically Active Dose for Full and Partial DTH Inhibition
Step 1: Determination of PAD in relevant animal model
PAD in Mouse, partial inhibition of DTH: 12.5 mg/kg/day
PAD in Mouse, complete inhibition of DTH: 125 mg/kg/day
Step 2:Conversion of Animal Dose to HED
Body surface area conversion
Conversion of Rat Dose in mg/kg to 
mg/m²
[12.5 mg/kg]Partial inhibition x [3 kg/m2]Mouse 
Conv Factor = 37.5  mg/m2
Conversion of Rat Dose in mg/m² to 
HED in mg/kg, assuming 60 kg 
human with mean BSA of 1.79 m2
37.5 mg/m2 × 1.79 m2 = 67.12 mg 
÷ 60 kg = 1.12 mg/kg
Corresponding HED for 
[125 mg/kg]Complete inhibition is 11.2 mg/kg.
Body weight conversion
Conversion of Rat Dose in mg/kg to 
HED in mg/kg assuming a 60 kg 
human
[12.5 mg/kg]Partial inhibition x [.081]Mouse Conv 
Factor =  1.02 mg/kg
Or 
[12.5 mg/kg]Partial inhibition ÷ [12.3]Mouse Conv 
Factor =  1.02 mg/kg
Corresponding HED for 
[125 mg/kg]Complete inhibition is 10.2 mg/kg.
Step 3: Apply 10-fold safety factor
1.12 mg/kg ÷ 10  = 0.11 mg/kg
11.2 mg/kg ÷ 10  = 1.12 mg/kg
1.02 mg/kg ÷ 10  = 0.10 mg/kg 
10.2 mg/kg ÷ 10  = 01.0 mg/kg
HED: Human Equivalent Dose; BSA: body surface area
In addition to the in vivo toxicology and DTH data, TIMP-GLIA was studied for its potential to 
induce T cell proliferation / mitogenicity in a Phase 0 ex vivo study using peripheral blood 
mononuclear cells (PBMCs) from human donors: healthy subjects, celiac subjects adhering to a 
GFD, and subjects newly diagnosed with CD who were not yet adhering to a GFD.  Subjects with 
CD adhering to a GFD are most representative of the subjects to be enrolled in the Phase 1 clinical 
study. 
T cell mitogenicity was not observed from samples collected from any of the subject cohorts up to 
the maximum concentration studied of 1.25 mg/mL (HED  ~100 mg/kg assuming a 70 kg human 
with 5.6 L of blood volume using the conversion method described in NCL in vitro study 
protocols).  In addition, no immune cytokine activation was observed in the samples from the 
human donors.  Based upon this result, immune activation may only be anticipated to occur at 
some level greater than ~100 mg/kg.  
2.5.3
TIMP-GLIA Maximum Recommended Starting Dose 
Applying the most conservative approach for the FIH clinical study, a starting dose of 0.1 mg/kg 
followed by 0.5 mg/kg will be explored in 2 subjects each via an accelerated titration 2 + 2
schedule.  This is followed by dosing cohorts of 3 subjects according to a standard 3+3 escalation 
schedule beginning with a dose of 1 mg/kg.   The larger cohorts are employed at 1 mg/kg when 
pharmacologic effects are more likely to be observable.
PAD
HEDPAD
MRSDPAD
Apply 
animal-to-human 
conversion factor
Apply 10-fold 
safety factor
Select lowest 
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The planned doses and escalation schedule are illustrated in Figure 1. Schematic of Planned 
Dosing in Subjects With Celiac Disease, Part A and Part B and listed below Table 7.
Table 7.
Planned Dose Levels and Rationale
Part A
Single dose
mg/kg
Rationale
Accelerated Titration 
2 + 2
Level 1
= 0.1
100x below NOAEL
10x below PAD for initial pharmacologic 
activity
Level 2
= 0.5
20x below NOAEL
Standard 3+3
Level 3
= 1.0
10x below NOAEL
At PAD for initial pharmacologic activity
Level 4
= 2.0
2x escalation
Level 5
= 4.0
2x escalation
Level 6
= 8.0
2x escalation
Level 7
= 10.0 or a maximum of 750 mg
Not administered;
 
At PAD for complete inhibition of DTH
Part B
Repeat dose mg/kg
Accelerated Titration 
2 + 2
Level 1
2 mg/kg
Level 2
4 mg/kg
Level 3
8 mg/kg to a maximum of 650 mg
Maximum dose found to be safe and 
tolerable in Part A
CCI
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3
STUDY OBJECTIVES AND ENDPOINTS
3.1
Objectives
3.1.1
Primary Objective
The primary objective is to assess the safety and tolerability of TIMP-GLIA when administered IV 
as a single dose at ascending dose levels and as a repeat dose in subjects with CD.
3.1.2
Secondary Objectives
The secondary objectives are:
!
To characterize the PK of TIMP-GLIA based upon concentrations of TIMP-GLIA in plasma
over time in subjects with CD.  
!
To establish a safe and tolerable dose that may be tested during a future Phase 2 Proof of 
Concept study in subjects with CD.
3.1.3
Exploratory Objective
3.2
Endpoints
3.2.1
Safety and Tolerability Endpoints
Safety will be characterized by incidence, severity, and reversibility of AEs, physical examination 
findings, 12-lead ECG results, arterial oxygen saturation levels by pulse oximetry, vital signs 
measurements, anti-gliadin antibody (i.e., anti-drug antibody as deamidated gliadin peptide 
(DGP)-specific IgG), immune complex detection by C1q binding and by C3a and SC5B-9 (Part B 
only), routine clinical laboratory test results (hematology, serum chemistry, coagulation, 
urinalysis) and other specialized laboratory test results (e.g., acute phase cytokines; additional 
vascular / thrombotic markers; mast cell activation via tryptase; additional complement markers, 
peripheral blood gliadin-specific T-cell proliferation and cytokine secretion).  Post-dose
assessment of peripheral blood T cell proliferation and cytokine secretion in response to ex vivo 
gliadin stimulation relative to baseline, will be performed for the single dose groups ≥4 mg/kg in 
Part A and for the repeat dose groups in Part B.  
The analysis of samples drawn for cytokine testing (EGF, fractalkine, GM-CSF, GRO α, IFNα, 
IFN-γ, IL-1α, IL-1 β, IL-2, IL-2 soluble receptor, IL-4, IL-5, IL-6, , IL-8, IL-10, IL-12, IL-13,
IL-17, IP-10, MIP1α, and MIP1β, TNF-α)should be performed as described in Section 8.5.6.5,
C3a and SC5B-9 Complement Levels
For Part B, C3a and SC5B-9 complement levels will be obtained during the infusion and 24 
hours following the infusion (refer to Table 2. Schedule of Procedures, Part B).
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Cytokines and Laboratory Tests to Follow-Up Suspected Anaphylaxis/Anaphylactoid 
Reaction.
Results of peripheral blood T-cell proliferation and cytokine secretion in response to ex vivo
stimulation with gliadin following exposure to TIMP-GLIA assay is performed, results will be 
reported at the end of the study or as otherwise specified by the sponsor, medical monitor, or 
DMC. 
Tolerability will be characterized by extent of dose escalation attained without dose limiting 
toxicity.
3.2.2
Pharmacokinetics Endpoints 
The PK of TIMP-GLIA will be derived from the plasma TIMP-GLIA concentration – time curve
by noncompartmental analysis.  The primary PK parameters are maximal observed concentration 
(Cmax), last measurable concentration (Clast), time of maximal observed concentration (Tmax), and 
area under the curve from time zero and extrapolated to infinity (AUCinf) and area under the 
concentration-time curve from time zero to time of the last measurable concentration (AUClast).  
Other PK variables will be derived if feasible. The results of the PK evaluation will be reported at 
the end of the study.
Establishment of a maximal feasible dose (MFD) to administer during the future proof-of-concept 
study in CD patients is another secondary endpoint.
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4
STUDY POPULATION
At least 23 male and female subjects 18 to 75 years of age with historical evidence of 
biopsy-confirmed CD and who have negative celiac serology and quiescent CD symptomology 
and are otherwise healthy or with stable comorbidity at screening are planned to be enrolled. 
Subjects will be enrolled at up to 6 clinical research sites in the United States.  
Subjects who withdraw before receiving the first dose of study drug will be replaced. Subjects who 
withdraw after receiving study drug will be replaced at the sponsor’s discretion.  
After fully informing prospective subjects of the present study and obtaining their written 
informed consent, the investigator will perform screening tests.  Based on the results of these 
screening tests, the investigator will identify “provisional subjects” (including reserve 
[“alternate”] subjects, if available). The provisional subjects will be individuals who meet the 
inclusion criteria without meeting any of the exclusion criteria. Ethical and scientific aspects, the 
study objectives, and individual health status up to the selection date will also be carefully 
considered during the selection process.  The provisional subjects, if available, will be admitted to 
the study site on the day on Day -1, whereupon they will undergo the tests scheduled for that day 
and confirmatory assessment of study eligibility criteria. Those who are deemed eligible for 
enrollment will then be selected as enrolled subjects (including reserve subjects).
There will be no waivers or exemptions (a prospective approved deviation) from the inclusion or 
exclusion criteria.
4.1
Inclusion Criteria
A subject must meet all the following criteria to qualify for entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject provided written informed consent to participate as indicated by a signature on the 
informed consent form and any required privacy authorization prior to the initiation of any 
study procedures. 
3. The subject is an adult man or women, 18 to 75 years of age, inclusive, at Screening Visit. 
4. The subject has a body mass index (BMI) that is >16 kg/m2 and with a minimum body weight 
of 33 kg up to a maximum body weight of 129 kg, inclusive, at Screening Visit and if BMI <18 
(“underweight”) or >25 (“overweight” or “obese”), is otherwise healthy in the opinion of the 
investigator. 
5. The subject has celiac disease characterized as follows: 
a.
The subject has a history of biopsy-confirmed celiac disease (intestinal histology showing 
villous atrophy) according to expert guidelines current at the time of diagnosis; and
b. The subject has no known gluten exposure for at least 10 days prior to the Screening Visit 
and is willing to maintain a gluten-free diet for the duration of the study; and 
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c.
The subject has a total immunoglobulin A (IgA) titer within normal limits or has partial 
IgA deficiency (~5% of celiac patients) defined by a reduced serum IgA level of 3 – 70 
mg/dL at Screening 
AND
The subject has negative or weak positive recombinant human transglutaminase 
(tTG)-specific IgA titer at Screening 
OR
For a subject with selective IgA deficiency (~2% of celiac patients), deamidated gliadin 
peptide (DGP)-specific IgG titer is negative or weak positive at Screening. 
6. If male subject, agrees to practice medically approved contraception that may include, but is 
not limited to, abstinence, monogamous relationship with a female who is not of child-bearing 
potential, surgical sterilization procedure (vasectomy), and or condoms throughout the study.
If female subject, is not of child bearing potential (postmenopausal or premenopausal with 
surgical sterilization) or agrees to practice medically approved contraception that may include, 
but is not limited to, abstinence, monogamous relationship with a male who is post-surgical 
sterilization procedure (vasectomy), or agrees to use medically acceptable and highly effective 
birth control methods (e.g., an intrauterine device, a double-barrier method such as condom 
and spermicide or condom  and diaphragm with spermicide, a contraceptive implant, injectable 
contraceptive, or oral contraceptive) throughout the study.  
7. The subject is able and agrees to comply with study requirements.
8. The subject agrees not to participate in another interventional study while participating in the 
present study, defined as signing the informed consent form until completion of the last study 
visit.
4.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has a history of clinically confirmed immunoglobulin E (IgE)-mediated reaction 
and/or anaphylaxis to wheat (i.e., “wheat allergy”), barley or rye. 
2. The subject has uncontrolled celiac disease and/or complications of celiac disease, or 
otherwise has experienced celiac symptomology within10 days of screening, in the opinion of 
the investigator.
3. The subject has a history of, or has an active, significant, clinically relevant, comorbidity 
(including Type 1 and Type 2 diabetes mellitus and other autoimmune disorders, splenectomy) 
that, in the opinion of the investigator, would make the subject unsuitable for participation in 
the study and/or could adversely affect interpretation of the study results. 
4. The subject has had significant changes to or anticipates changes to prescription or 
non-prescription medication used to manage an underlying comorbidity within 30 days prior to 
Day 1. 
5. The subject is currently taking or received systemic biologics 6 months prior to Day 1. 
6. The subject has a compromised immune system, e.g.: 
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a.
Known human immunodeficiency virus (HIV) infection or positive for HIV antibodies at 
Screening;
b. Subject is or has been taking  immune suppressing medical treatment (e.g., azathioprine, 
methotrexate) during the 2 months prior to Day 1;
c.
Subject is receiving immunosuppressive doses of corticosteroids (more than 20 mg of 
prednisone given daily for 2 weeks or more within 2 months prior to Day 1, any dose of 
corticosteroids within 30 days of Day 1, or high dose inhaled corticosteroids [>960 µg/day 
of beclomethasone dipropionate or equivalent]) within 30 days of Day 1.
7. The subject has a known history of hypersensitivity or allergies to TIMP-GLIA components or 
any other known severe hypersensitivity or allergic reaction (any reaction that resulted in 
hospitalization [initial or prolonged], congenital anomaly, or disability, or that required 
medical intervention to prevent permanent impairment or damage) to any other allergens 
(medications, food or environmental). 
8. The subject has currently 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.
9. The subject has a history of any acute illness including, fever (>100.4°F or >38°C) within 14
days of Check In Day-1.
10. The subject has an active malignancy, or history of malignancy or chemotherapy within the 
past 5 years other than history of localized or surgical removal of focal basal cell skin cancer, 
cervical cancer in situ treated successfully in the past by local treatment (including but not 
limited to cryotherapy or laser therapy) or by hysterectomy.
11. The subject has known liver disease or serology positive for hepatitis C infection; positive 
hepatitis B surface antigen (HBsAg) at Screening Visit. 
12. The subject has a positive test result for drugs of abuse (amphetamines, barbiturates, 
benzodiazepines, cocaine metabolites, opiates, cannabinoids, 
methylenedioxymethamphetamine), or alcohol in urine- except when positive result arises 
from treatment under a medical doctor’s supervision - at Screening Visit or at Check-in.
13. The subject has a history of any drug or alcohol abuse in the past 5 years, or alcohol 
consumption greater than 21 units per week that, in the opinion of the investigator, would 
interfere with the subject’s ability to comply with the study requirements. A unit of alcohol is 
equivalent to: 12 ounces of beer, 4 ounces of wine, or 1 ounce of spirits/hard liquor. Alcohol 
consumption will be prohibited 24 hours prior to entry into the clinical research unit until 
discharge.
14. The subject has the inability to undergo venipuncture or tolerate venous access as determined 
by the investigator or designee.
15. The subject has a history or presence of anorexia nervosa or other eating disorder.
16. If female, the subject is pregnant or lactating or intending to become pregnant before or during 
the study.  The lack of pregnancy will be confirmed by serum assay for qualitative human 
chorionic gonadotropin at Screening and a urine assay performed at Check-in. Women with 
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postmenopausal status confirmed by screening follicle-stimulating hormone (FSH) result need 
not undergo subsequent urine pregnancy testing.
17. The subject has clinically significant laboratory results at Screening, as determined by the 
investigator, including, but not limited to the following: 
a.
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline 
phosphatase (ALP) ≥ 1.5 times Upper Limit of Normal (ULN)
b. Direct bilirubin outside the normal range
c.
Serum Creatinine > 1.2 mg/dL
d. Hemoglobin < 10 g/dL
e.
Hematocrit < 30%
f.
Platelet count < 150,000 or > 400,000 
g. Serum Potassium, Prothrombin Time (PT), Partial Thromboplastin Time (PTT), 
international normalized ratio (INR), or white blood cell count (WBC) outside the normal 
range (and judged clinically significant by the investigator)
18. The subject has clinically significant, abnormal electrocardiogram (EGC) at Screening, as 
determined by the investigator, including but not limited to:
a.
Mean QTcF interval >430 msec for males or >450 msec for females;
b. ECG evidence of complete left bundle branch block (LBBB), right bundle branch block 
(RBBB) or incomplete LBBB; 
c.
Mean intraventricular conduction delay with QRS duration >120 msec;
d. Pathological Q-waves, defined as Q-wave >40 msec or depth >0.4 to 0.5 mV;
e.
Evidence of ventricular preexcitation.
19. The subject has received any investigational drug within 30 days or 5 half-lives prior to first 
dosing/Day 1.
20. The subject was previously enrolled and dosed in a clinical trial with TIMP-GLIA.
21. The subject received a live or inactive vaccine within 28 days prior or a subunit vaccine within 
14 days prior to first dosing/Day 1 or the subject has a planned vaccination during the study. 
22. The subject has donated blood or plasma ≤ 56 days prior to Screening and plans to donate 
blood or plasma within 5 weeks of completing the study. 
23. The subject has received blood products, monoclonal antibody, or other systemic protein 
therapy within 6 months prior to first dosing/Day 1.  NOTE: oral protein supplements are 
permitted.
24. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (e.g., spouse, 
parent, child, sibling) or may consent under duress.
25. The subject is unsuitable for enrollment in the opinion of the investigator for any other reason 
not specified above.
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5
DISCONTINUATION
5.1
Discontinuation of Subjects
Subjects are free to withdraw consent for participating in the study at any time. Subjects will be 
informed that they are free to withdraw from the study drug treatment or study participation at any 
time and for any reason.
Subject participation in the study may be stopped at any time at the discretion of the investigator or 
at the request of the sponsor.
Possible reasons for subject discontinuation include the following categories:
Table 8. 
Categories of Subject Discontinuation

Withdrawal of consent

Occurrence of a pretreatment AE event that presented an unacceptable risk to the subject’s 
health or the subject was unwilling to continue due to the AE, or occurrence of any other 
exclusion criteria prior to first dosing. 

Occurrence of a DLT or other serious or clinically significant AE that warranted 
discontinuation, in the opinion of the investigator.

Major protocol deviation, including noncompliance with an inclusion or exclusion criterion, 
that is clinically relevant and affects subject safety or data integrity.

Participation in a concurrent clinical study.

Lost to follow-up.

Study termination by Cour, the institutional review board (IRB) or FDA. 

Pregnancy.
5.1.1
Handling of Withdrawals
When a subject withdraws from the study, the reason(s) for withdrawal shall be recorded by the 
investigator in the source documentation and the primary reason for discontinuation by category 
(above) will be recorded in the electronic case report form ((e)CRF). Whenever possible, all 
subjects who withdraw from the study prematurely during the investigational period (through Day 
60 visit) will undergo all final visit safety assessments (see SCHEDULES OF ASSESSMENTS
Table 1. Schedule of Procedures, Part A and Table 2. Schedule of Procedures, Part B).
Subjects who fail to return for study procedures during the investigational period will be contacted 
by the principal investigator or designee to seek compliance. A minimum of 2 documented phone 
calls should be made over the course of at least 2 weeks. If the study site personnel receive no 
response, and if the local government or regulatory agency permits, they should send a certified 
letter requesting that the subject contact the study site regarding his or her status in the study. The 
letter delivery certification should be retained in the source. Similar due diligence to obtain subject 
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status by telephone during the follow-up period and documentation thereof shall also be 
implemented.
5.1.2
Replacements of Withdrawn Subjects
Subjects who withdraw before receiving the first dose of study drug will be replaced. Subjects who 
withdraw after receiving study drug will be replaced at the sponsor’s discretion.  Replacement 
must occur to the same dose cohort.
5.2
Discontinuation of the Study
Although Cour has every intention of completing the study, it reserves the right to discontinue the 
study at any time for clinical or administrative reasons or if required by the FDA. The DMC will 
review the safety of TIMP-GLIA throughout the study. The occurrence of any medically important 
AE that could impact the safety of other subjects may lead to the discontinuation of the study after 
discussions between the medical monitor and Cour.  The study will be terminated if the DMC
determines that the Study Stopping Rules have been met.
5.3
Discontinuation of the Site
If the investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor.
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6
STUDY TREATMENTS
6.1
Identity of Investigational Product 
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 and 
approximate size distribution between ~200 nm and ~700 nm.  There is ~10 μg of refined gliadin 
per mg of PLGA particles.
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.  
TIMP-GLIA is to be reconstituted with 2.5 mL of Sterile Water for Injection (SWI), and further 
diluted for infusion with 0.9 % Sodium Chloride Injection, USP.   The drug solution is to be 
administered by IV infusion using a controlled infusion device on the day of preparation.  Specific 
reconstitution and dilution and storage instructions will be provided in the Pharmacy Manual.
6.2
Management of Clinical Supplies
6.2.1
Study Drug Packaging and Labeling
TIMP-GLIA will be manufactured, packaged, and labeled under the responsibility of qualified 
staff at Cour and/or Cour’s designee(s) in accordance with the designee(s)’s standard operating 
procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, International Conference on 
Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human 
Use Good Clinical Practice (GCP) guidelines and applicable local laws and regulations.
Bulk vials will be provided to the study sites. 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, protocol number, lot number, expiry date or 
reevaluation date as applicable, and storage conditions.
TIMP-GLIA infusion solution will be prepared and labeled for individual subject dosing in the 
pharmacy of each clinical site. The IV bags containing study drug will bear a label conforming to 
regulatory guidelines including:

Protocol number

Subject identifier

Drug and dose 

Date and time of preparation

Date and time of expiration

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6.2.2
Storage and Handling
TIMP-GLIA vials should be stored at 2oC to 8oC (36o to 46o F) and protected from light in a secure, 
temperature-monitored, limited access location. All sponsor-supplied drugs must be stored under 
the conditions specified on the label, and remain in the original container until dispensed. A daily 
temperature log of each drug storage area must be maintained and temperature excursions 
documented. Detailed information on the storage conditions following reconstitution and dilution 
of study drug are provided in the Pharmacy Manual.
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries from the 
sponsor are received by a responsible person (e.g. pharmacist), and

that such deliveries are recorded;

that study drug is handled and stored safely and properly in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those authorized 
by the investigator to dispense these test drugs;

that study drug is only dispensed to study subjects in accordance with the protocol;

that any unused study drug is returned to the sponsor or standard procedures for the alternative 
disposition of unused study drug are followed.
6.2.3
Inventory and Accountability 
Study drug will be provided to the clinical site by Cour or its designee. 
Drug inventory and accountability records for the study drugs will be kept by the investigator or 
designee (e.g., pharmacist).
The investigator or designee will acknowledge date of receipt and verify condition/quantities by 
signing the packing list/shipping form in the shipment. In addition, the date and time and quantity 
of study material prepared for/dispensed to each subject and by whom must be recorded on the 
drug accountability log.  The required accountability for this study is vial count. Date/time vial is 
reconstituted and subject number should be written on the vial label to facilitate accountability. All 
used and unused containers are to be stored until accountability procedures are completed.
At the conclusion or termination of this study, the investigator or designee is to reconcile records 
of study drug delivery, preparation, dispensation, usage, and final disposition (destroyed or 
returned) to ensure completeness of the Drug Accountability Log and agreement with other 
clinical study records. Any discrepancies must be accounted for, including reasons for departure 
from the expected administration regimen and corresponding vial quantities. Appropriate forms 
and records must be signed by the person responsible.
Used or unused study drug may be destroyed at the study site according to standard institutional
procedures after drug accountability has been conducted by the sponsor or representative, only if 
agreed upon by the sponsor. A copy of the standard institutional procedure for destroying 
investigational drugs will be provided to the sponsor or designee upon request. Unused study drug 
not destroyed at the site must be returned to the sponsor or designee at the end of the study or upon 
expiration.
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An institutional standard operating procedure for inventory and accountability may be 
implemented if reviewed and approved by the sponsor.
6.2.4
Ancillary Materials
Detailed information regarding necessary ancillary supplies (e.g., syringes, filters, infusion sets, 
IV bags) are provided in the Pharmacy Manual.  Ancillary supplies may be provided by the 
sponsor or obtained by the clinical site from commercial sources. 
6.3
Method of Assigning Subjects to Treatment Groups
Enrollment will occur competitively across initiated clinical sites. Prior to enrollment of an 
eligible subject, the investigator or designee is to request enrollment in writing to the sponsor’s 
designee who will provide dose assignment and confirm subject identification (ID) number as 
appropriate and who will track subject enrollment/dose date/completion/discontinuation and 
screen failures.  The designee will also coordinate dose scheduling such that dosing of individual 
subjects within a cohort (Part A and Part B) is compliant with protocol requirments.
Subjects meeting eligibility criteria who are enrolled in this study will receive open-label 
TIMP-GLIA.  
The 9-digit subject ID number will be as follows:
3-digit country code-3-digit site number-3-digit sequential number
Once a subject ID number has been assigned to a subject it will not be reused for another subject.   
If a subject withdraws prematurely from the study and is replaced, a new subject ID number will be 
assigned to the replacement subject.  The replacement subject will receive the same treatment as 
the person being replaced.
6.4
Blinding 
Not applicable for this study.
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7
TREATMENT ADMINISTRATION
7.1
Dose and Regimen
Aseptic technique must be used for the preparation and administration of TIMP-GLIA.  Detailed 
instruction will be provided in the Pharmacy Manual.
TIMP-GLIA will be administered once as an IV infusion by a controlled infusion device. The 
planned doses will range as shown in Error! Reference source not found.. The dose to be 
investigated in Part B will be the maximum tolerable dose reached in Part A.
The lyophilized drug product will be reconstituted in the vial with SWI and then further diluted for 
infusion according to the Pharmacy Manual.  The preparation of the dose will be confirmed by a 
second member of the study site staff.
Dosing will occur on Day 1 in Part A and on Day 1 and Day 8 in Part B (7 days apart). Subjects 
should remain supine during dosing.
As a safety precaution, venous access should be maintained for emergency use for 24 hours after 
dosing.
On dosing days, subjects will receive the assigned study drug after the subject has fasted from food 
and beverage approximately 2 hours prior to infusion start and 1 hour after infusion end. Water 
may be provided ad libidum.
For Part B, TIMP-GLIA should 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 
7.2
Safety Committee (Dose Levels < 2 mg/kg)
A Safety Committee was convened to monitor the safety of subjects up to the 2  mg/kg dose 
cohort..  The Safety Committee included the: principal Investigator(s) (PIs) or PI(s)’s delegate(s)
and a medical consultant with expertise in CD. 
The role of the Safety Committee is described in prior versions of this protocol under which the 0.1 
mg/kg, 0.5 mg/kg, and 1 mg/kg doses were administered.
7.3
Data Monitoring Committee (Dose Levels ≥2 mg/kg)
An independent DMC will be commissioned for this study for dose levels ≥2 mg/kg.  The DMC 
will be comprised of 3 physicians with expertise in immunology and/or vaccines clinical trials.  A 
4th physcician with expertise in CD will serve as an advisor to the DMC, but in a non-voting 
capacity.
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The sponsor medical monitor will not be a member of the DMC. The sponsor medical monitor and 
other study team members will be available to answer questions of the DMC as necessary and 
during Open Sessions of the DMC.  The medical monitor and other study team members will not 
participate in Closed Sessions of the DMC. The DMC will convene when each dose cohort is 
completed to determine if it remains acceptable to continue dosing subjects. The DMC may also 
convene ad hoc to address emerging safety concerns. The DMC will evaluate the available safety 
data post-infusion, including but not limited to, AEs, vital signs, pulse oximetry, 12-lead ECGs 
and available laboratory results (e.g., hematology, chemistry, coagulation, and urinalysis, 
cytokines) in the context of the established Study Stopping Rules. 
The following decisions may be made if stopping criteria are not met: 

Escalate the dose as planned

Expand the dose cohort to 2 subjects (accelerated titration 2 + 2, Part A and Part B) or 6 
subjects (standard 3+3, Part A)
After a rate of DLTs has been identified for a specific dose in 3- or 6-subject cohorts, the DMC
may recommend that up to a total of 12 subjects may be accrued at any dose level to better 
define the relationship between dose and emerging the safety signals.

Decrease the dose either to a previous lower dose or to an intermediate dose

Escalate the dose to an intermediate level if warranted based on events in the previous cohort
The decision(s) of the DMC to continue dosing will be documented and provided to the 
investigators prior to dosing any new subjects. 
Additionally, the DMC may meet ad hoc to determine if it remains acceptable to continue dosing.
The medical monitor is to be notified of any serious adverse event (SAE) and any CTCAE Grade 2 
or greater toxicity within 24 hours of investigator’s (or designee’s) awareness of such an event. 
7.4
Progression or Termination of Dosing
Dosed subjects will remain under medical supervision in the clinic for 48 hours after dosing.
Emerging safety data will be evaluated by the DMC against the Study Stopping Rules (Section 
7.4.6) and defined dose limiting toxicity (Section 7.4.5).
7.4.1
Premature Termination of An Individual Subject’s Infusion
If a subject develops signs and symptoms of IRR (dyspnea, generalized cutaneous reactions, 
tachypnea, hypoxia, tachycardia, or if the subject experiences a decrease in blood pressure the 
investigator should stop the infusion for a minimum of 5 minutes or until signs and symptoms 
subside.  Depending upon the severity of the signs and symptoms, and at the investigator and 
subject discretion, the infusion may be restarted as follows:
o
Restart the infusion at 25% of original rate for 15 minutes
o
If subject tolerates the reduced rate, increase to 50% of original rate for another 15 
minutes, then increase to the original rate until infusion is complete
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Infusion will be permanently discontinued if the subject develops clinical signs and symptoms of 
Grade 3 or 4 IRR or anaphylaxis/ anaphylactoid reaction (any combination of nausea, vomiting, 
myalgia, rigors, fever [oral temperature ≥2oC above baseline]) and/or clinically significant 
dyspnea, generalized cutaneous reactions, tachypnea (doubling of baseline respiratory rate, 
resting), hypoxia (oxygen saturation < 90% on room air), tachycardia (resting heart rate 
> 120 bpm), or if the subject experiences a decrease in blood pressure that requires therapeutic 
intervention or other SAE, or if the subject experiences any other clinically significant AE which, 
in the opinion of the investigator, warrants termination of infusion.
7.4.2
Dosing Subjects Within A Dose Level (Within A Cohort)
Part A
During Part A (dose escalation), 1 subject will be dosed at a time followed by in-clinic observation 
for at least 48 hours. At least 168 hours (7 days) will elapse prior to dosing the next subject at the 
same level. This staggering is to provide sufficient time for acute adverse effects to emerge before 
additional subjects are exposed.
Dosing additional subjects in a cohort will be stopped if 1 of the subjects at a dose level exhibits a 
dose-limiting toxicity (DLT) or should any subjects in the current dose cohort or any previously 
dosed subject (in any dose group) develop clinical signs and symptoms of Grade 3 or 4 IRR or 
anaphylaxis/anaphylactoid reaction (any combination of nausea, vomiting, myalgia, rigors, fever 
[oral temperature ≥2oC above baseline]) and/or clinically significant dyspnea, generalized 
cutaneous reactions, tachypnea (doubling of baseline respiratory rate, resting), hypoxia (oxygen 
saturation < 90% on room air), tachycardia (resting heart rate > 120 bpm), or a decrease in blood 
pressure that requires therapeutic intervention or other SAE.
Dosing of additional subjects in a cohort will also be stopped upon the occurrence of 2 or more of 
the same CTCAE Grade 3 toxicity (among total subjects dosed ) or the first occurrence of a
CTCAE Grade 4 or Grade 5 toxicity, irrespective of relationship to study drug.
In this situation, the DMC will evaluate the cause of the abnormalities and whether they represent 
a drug-related safety concern, warrant implementation of additional safety precautions, dose 
groups, or other protocol changes, or justify study termination (i.e., Study Stopping Rules
fulfilled). 
If 1 of the subjects at a dose level exhibits dose-limiting toxicity and the DMC confirms the study 
will continue, an additional 2 subjects (accelerated titration 2+2, Part A) or 3 subjects (standard 
3+3, Part A) will be dosed at the same level, staggered appropriately, so that a total of 4 subjects 
(accelerated titration 2+2) or 6 subjects (standard 3+3) will receive the same dose. (See Error! 
Reference source not found. .) After a rate of DLTs has been identified for a specific dose in 3- or 
6-subject cohorts, the DMC may recommend that up to a total of 12 subjects may be accrued to 
better define the relationship between dose and emerging safety signals.
When all subjects in a dose level cohort complete procedures through 168 hours (7 days) post 
dose, the overall safety and tolerability data (AEs, vital signs, 12-lead ECGs, clinical laboratory 
tests, cytokines) and available cumulative AE data from previous cohorts will be reviewed by the 
DMC who will determine the progression or termination of dosing to the next dose level.
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Part B
During Part B (repeat dose), subjects will receive 2 doses followed by in-clinic observation for at 
least 48 hours after each dose. At least 48 hours (2 days) will elapse after the second dose and 
safety confirmed before subjects in next higher dose cohort can be dosed. If dose-limiting toxicity 
occurs in 1 of the 2 subjects in Part B, the DMC may decide to increase enrollment at the same 
dose level by 2 subjects (n=4). 
7.4.3
Dose Escalation – Dosing Subjects At the Next Dose Level
After all subjects at a dose level have completed study procedures through Day 8 (168 hours
[7 days] post dose), the overall safety and tolerability of the dose will be determined by DMC
evaluation of the safety data (AEs, vital signs, 12-lead ECGs, clinical laboratory tests) for the 
current cohort and available cumulative AE data from previous cohorts against the Study Stopping 
Rules. 
The DMC will decide whether dose escalation and enrollment of the next dose group should occur. 
If none of the subjects in the cohort experiences a DLT and stopping criteria are not met based 
upon DMC assessment of accumulating safety data, then escalation to the next higher dose may 
proceed.
If 2 or more subjects experience DLT(s) at a dose level, the prior dose level will be defined as the 
maximum tolerable dose (MTD) . The highest dose level that did not cause unacceptable side 
effects will be considered the MTD.
7.4.4
Dose Reduction
Depending upon emerging safety data, the DMC may recommend dosing a cohort of 2 subjects
(accelerated titration 2 + 2, Part A and Part B) or 3 subjects (standard 3+3, Part A) at a dose lower 
than the planned level to better identify the maximum tolerable dose of TIMP-GLIA.
7.4.5
Dose Limiting Toxicity Definition
DLT is defined to be an AE or set of AEs that prevents further administration of the agent at that 
dose level.  For this study DLT is defined as occurrence of:

A CTCAE Version 4.0 Grade 3 or higher that is at least possibly related to TIMP-GLIA; or

Suspected drug-induced liver injury (DILI) at least possibly related to TIMP-GLIA in any 
dosed subject indicated by
o
ALT or AST > 3x upper limit of normal (ULN) and increase of total bilirubin > 2x ULN 
without evidence of intra- or extra-hepatic bilirubin obstruction (elevated ALP) or 
Gilbert’s syndrome (“Hy’s Law”) or 
o
ALT or AST > 3x ULN and INR > 1.5x ULN or
o
ALT or AST >8xULN or
o
ALT or AST >5xULN for more than 2 weeks or 
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o
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 

Any other toxicity which in the opinion of the DMC would not allow continued dosing if this 
were a repeat dose study
7.4.6
Study Stopping Rules

First occurrence of a Grade 4 or Grade 5 toxicity at least possibly related to TIMP-GLIA 

2 or more of the same Grade 3 toxicity considered to be at least possibly related to TIMP-GLIA
(among total number of subjects dosed) 

1 subject experiences a Grade 3 toxicity considered to be at least possibly related to 
TIMP-GLIA and in the same organ system another subject experience a Grade 2 or higher 
toxicity considered to be at least possibly related to TIMP-GLIA (at same dose level)

Any other toxicity which in the opinion of the DMC would have precluded administration of a 
second dose if this were a multi-dose study
7.5
Treatment Compliance
The subject will be administered study drug in the clinical research unit by qualified staff.  The 
date and infusion start and stop time and total volume infused are to be recorded. In the event of an 
interruption of an infusion, the stop/restart times of the interruption should also be documented as 
well as reason/circumstances. Compliance will be evaluated through review of study drug 
dispensing and administration records. 
7.6
Emergency Procedures and Management of Overdose
In the event of adverse clinical responses to TIMP-GLIA infusion, interventions should be guided 
by the subject’s symptoms and condition.  Acute interventions for anaphylaxis/anaphylactoid 
reaction may include, but are not limited to, supplemental oxygen, endotracheal intubation and 
mechanical ventilatory support, supportive IV fluid administration, and/or Advance Cardiac Life 
Support (ACLS) therapies. If appropriate, transfer to an acute care hospital facility should be 
performed.
An overdose is defined as a known deliberate or accidental administration of TIMP-GLIA to a 
study subject at a dose above that which was assigned to the subject according to the study 
protocol. 
There are no defined emergency procedures for an overdose of study drug. Treatment should be 
guided by symptoms. 
All cases of overdose and any AE resulting from the overdose are to be documented in the source.
Any case of overdose should be reported to the sponsor as a “special situation” (see protocol 
section 8.6.7 Collection and Reporting of Special Situations). Serious AEs arising from overdose 
are to be reported accordingly (see 8.6.2 Serious Adverse Events and 8.6.6 Collection and 
Reporting of Serious Adverse Events).
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7.7
Restrictions During the Study/Treatment Conditions
Subject habits will be assessed at screening for study eligibility. Compliance with study 
restrictions with respect to eligibility criteria is to be confirmed at Day 1/prior to first dosing and 
thereafter compliance with study restrictions are to be assessed at each visit, including telephone 
“visits”.
7.7.1
Clinic Residency and Clinic Visits
Subjects participating in Parts A and B will report to the clinical research unit one day (Day-1) 
before the first dose and will remain residential in the clinic until completion of study procedures 
on Day 3. If, in the opinion of the investigator, a subject’s condition warrants longer medical 
observation, clinic discharge may be delayed. Subjects participating in Part B will return for clinic 
admission one day (Day 7) prior to the second dose and will remain residential until completion of 
study procedures on Day 10.  Clinic discharge may be delayed if extended medical observation is 
indicated.
All subjects will report to the clinic for scheduled outpatient visits, which are indicated in the 
Schedules of Procedures for Part A (SCHEDULES OF ASSESSMENTS
Table 1) and Part B (Table 2). Unscheduled clinic visits to follow up suspected AEs or to permit 
sample collection may also be arranged at the discretion of the investigator. If necessary 
arrangements can be made, visits to remote sample collection laboratories to permit sample 
collection may be allowed, if necessary to avoid missed procedures or to facilitate AE follow-up, 
with prior discussion between the sponsor and investigator.
Follow up via telephone contact is to be arranged according to the Schedules of Procedures for 
Part A (SCHEDULES OF ASSESSMENTS
Table 1) and Part B (Table 2) and as needed by the subject or clinic staff to ensure safety, data 
completeness, and logistics for future study activities.
7.7.2
Dietary and Fluid Restrictions
Consumption of alcohol will be prohibited from 24 hours prior to clinic admission until discharge 
from the clinic. To avoid false-positive results from the drug screen, food and drinks containing 
poppy seeds will not be allowed during the study. To facilitate compliance subjects should be 
reminded that testing for the presence of drugs of abuse and alcohol will be performed at Screening 
and each clinic admission (check-in).
Standardized gluten-free meals (breakfast, lunch, dinner) and non-alcoholic beverages will be 
served at consistent times relative to dosing and performance of study procedures while subjects 
are confined in the clinic. Meals must not interfere with any study procedures. The menu and 
nutritional information is to be archived in the study file.
When not confined, subjects are to maintain a GFD from the time of screening through the final 
study procedure.
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7.7.3
Exercise
Subjects are to refrain from strenuous exercise from screening through the last study 
procedure/Late Follow-up Visit. Subjects should be encouraged to walk and stretch while in clinic 
to avoid AEs associated with the sedentary environment. 
7.7.4
Use of Tobacco- or Nicotine-Containing Products
Subjects are not allowed to smoke or use tobacco- or nicotine-containing products during clinic 
residency. 
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8
EVALUATIONS AND ASSESSMENTS
8.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be collected at Screening. This will include sex, 
race, ethnicity, and date of birth, height, weight, and calculated BMI. Weight may be recorded at 
additional timepoints.
Height (m) and weight (kg) are to be recorded while the subject is wearing indoor clothing with 
shoes off. Body mass index (BMI) will be calculated as weight (kg)/ height (m)2. 
8.2
Medical History, and Medication History
A complete medical history, medication history and history of smoking/tobacco and alcohol habits 
will be recorded at Screening and reviewed for any changes at clinic check in (Day 1) to ensure 
compliance with the study eligibility criteria.
The medication history includes use of any prescribed or nonprescription medications, 
medications given as part of any surgical procedure, and dietary supplements (including vitamins, 
minerals, natural and herbal remedies) taken at least once in the 6 months before Screening.  
The medical history should include clinically significant medical or surgical history ongoing at 
baseline or with onset in the previous 2 years.  Subjects will be asked about previous diseases and 
conditions to allow thorough evaluation of the study eligibility criteria.  Medical history 
assessment will include but is not limited to questions about gastrointestinal disease, malignancies, 
diseases associated with immunosuppression, allergies and hypersensitivity reactions, hepatitis, 
HIV, and infectious diseases requiring systemic treatment within the last 2 weeks and about any 
participation in other clinical trials.
8.3
Diet History (Subjects With Celiac Disease)
A dietary history will be obtained from each subject via interview/questionnaire and adherence to 
a GFD is to be confirmed at Screening. Because the CD serology titers (tTG, DGP) are likely to be 
positive if subjects have not been following a GFD for at least 6 months or if they have recently 
(within at least 10 days) experienced gluten exposure, the outcome of the diet history discussion 
may prevent unnecessary blood tests.  Performance of the CD serology may proceed at the 
discretion of the investigator if diet history is not completely known and there is a reasonable 
possibility for negative or weak positive titers. 
8.4
Concomitant Medications
All concomitant medications from the time of the first study drug dose through the last study visit
will be recorded.  Medication used prior to first dosing will be recorded as medication history as in 
Section 8.2 Medical History, and Medication History).
Concomitant medication includes all medicinal products other than TIMP-GLIA including 
prescribed or nonprescription medications, medications given as part of any surgical procedure, 
and dietary supplements (including vitamins, minerals, natural and herbal remedies). If a subject 
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discloses participation in another interventional clinical trial during the course of the current study, 
the investigational product administered to the subject will be recorded as a concomitant 
medication.
Subjects must be instructed not to take any medications, including over-the-counter medications, 
without first consulting with the investigator. Only stable medication to manage underlying 
comorbidity, stable hormone replacement therapy, or contraceptives identified at Screening and 
approved by the investigator and sponsor may continue during the study. Occasional use of 
acetaminophen (no more than 2 g/day) may be allowed but non-medication treatment such as a 
cold compress should be tried before over-the-counter analgesic use. 
Any concomitant medications deemed necessary for the management of an AE during the study 
may be given at the discretion of the investigator. It is the responsibility of the investigator to 
ensure that the details regarding the medication are recorded in full (e.g., product name [with 
description if necessary], dose/quantity, method of administration, frequency, usage start/stop 
date, usage start/stop time if applicable, reason). Usage of any concomitant medication other than 
acetaminophen may result in withdrawal of the subject unless, after discussion between the 
investigator and sponsor’s medical monitor, it is concluded that the medication is not expected to 
influence the outcome of the study.
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (WHO Drug).
8.5
Safety Assessment
8.5.1
Physical Examination 
Physical examination will be performed according to the Schedules of Procedures for Part A 
(SCHEDULES OF ASSESSMENTS
Table 1) and Part B (Table 2).
A full physical examination (PE) will consist of an assessment of general appearance; eyes; ears, 
nose, throat; cardiovascular system; chest (lungs)/respiratory system; abdomen (liver, spleen);
skin; extremities; musculoskeletal system; neurological system, including mental status; 
neck/thyroid/lymph nodes; and other. The abbreviated PE will include assessment of general 
appearance; skin; chest (lungs)/respiratory system; cardiovascular system; abdomen (liver, 
spleen). 
Any abnormal finding observed during the screening visit must be assessed and documented as not 
clinically significant (NCS) if a subject is to be enrolled in the clinical study. After study drug 
administration, new abnormal findings or a worsening of an ongoing abnormal condition will be 
recorded as an AE.
8.5.2
Vital Sign Measurements 
Vital signs will be measured every 15 minutes during the infusion and as otherwise specified in the 
Schedules of Procedures for Part A (Table 1) and Part B (Table 2).  
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Body temperature will be an oral or tympanic measurement and methodology documented. 
Systolic blood pressure and diastolic blood pressure (SBP and DBP) and pulse (beats per minute) 
will be measured using a semiautomatic blood pressure recording device with an appropriate cuff 
size.  Blood pressure and pulse will be measured after the subject has rested for at least 5 minutes 
in the supine position. Respirations will be counted and documented in breaths per minute.  
Additional vital sign measurements may be performed as needed at the investigator’s discretion.  
8.5.3
Pulse Oximetry
Oxygen saturation will be continuously monitored via pulse oximetry with a fingertip monitor,
predose through 4 hours postdose.  Values should be recorded at the timepoints specified in the 
Schedules of Procedures for Part A (SCHEDULES OF ASSESSMENTS
Table 1) and Part B (Table 2).
Additional timepoints should also be recorded if necessary, at the discretion of the investigator, to 
follow up suspected adverse events.
8.5.4
Routine Electrocardiogram for Safety
Routine ECG measurements will be performed according to the Schedules of Procedures for Part 
A (SCHEDULES OF ASSESSMENTS
Table 1) and Part B (Table 2) after the subject has been in a supine position for at least 5 minutes. 
Routine ECG measurements will be performed in triplicate at Screening visit and on Day -1 
(predrug baseline).  Triplicate ECGs will be performed with a 1 minute interval and all 3 ECGs 
completed within 5 minutes.  At all other time points, routine ECG measurements will be 
performed as a single measurement.
The investigator will review, sign and date the ECG after recording to ensure the subject’s safety.  
The time of the ECG, as well as an overall conclusion, will be documented within the source.  The 
investigator will interpret the ECG using 1 of the following categories: normal, abnormal but not 
clinically significant (NCS), or abnormal and clinically significant (CS). If the overall conclusion 
is abnormal CS, the applicable AE must be recorded within the source. 
The ECG tracings should be collected and retained with the source documents for study 
monitoring.  
If possible the electronic data file with all generated ECG variables and electronic files with the 
digitized tracings will be transferred to the sponsor at the end of the clinical study.
8.5.5
Real-time Cardiac Monitoring (Electrocardiogram Telemetry)
Real-time cardiac monitoring will be performed as depicted in the Schedules of Procedures for 
Part A (SCHEDULES OF ASSESSMENTS
Table 1) and Part B (Table 2) as a tool to facilitate medical management of the subjects after 
dosing. The telemetry results will be reviewed by the investigator on a regular basis to identify 
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potential abnormalities. Start and end date and time of the telemetry will be documented within the 
source and any findings will be appropriately characterized (normal, abnormal NCS or abnormal 
CS). If telemetry findings are evaluated as abnormal CS, the appropriate AE should be 
documented within the source.
8.5.6
Laboratory Assessments
Samples for standard clinical laboratory tests will be obtained according to the Schedules of 
Procedures for Part A (SCHEDULES OF ASSESSMENTS
Table 1) and Part B (Table 2). Laboratory tests to be performed in this study are shown in Table 9.
Clinical Laboratory Tests.  
Blood samples will be collected via a peripherally placed IV cannula or by direct venipuncture in a 
suitable forearm vein.  Samples for clinical chemistry will be collected under fasting conditions 
and in accordance with acceptable laboratory procedures/protocols. 
A “clean catch” method will be used for urine collections.
Non-standard laboratory tests will be performed by appropriate bioanalytical laboratories 
specified by the sponsor.  Details for collection, processing, storage (if applicable), and shipment 
are provided in the Laboratory Manual.
8.5.6.1
Standard Clinical Laboratory Tests for Screening/Safety
Standard laboratory tests for screening/safety will be performed by each site’s local laboratory. 
Abnormal clinical laboratory values will be flagged as either high or low (or normal or abnormal) 
based on the reference ranges for each laboratory parameter. The investigator will determine 
whether any of the abnormally high or low results are clinically significant or not clinically 
significant. Clinical significance is defined as any variation in results that has medical relevance 
and may result in an alteration in medical care (e.g., active observation, diagnostic measures, or 
therapeutic measures). If a clinically significant change from the screening value is noted, the 
clinically significant value and reason for clinical significance will be documented as an AE (as 
described in Section 8.6.1). The investigator will continue to monitor the subject with additional 
assessments until the values have reached reference range or the values at Screening, or until the 
investigator determines that follow-up is no longer medically necessary.
Results should be reported immediately to the investigator and transferred electronically at the end 
of the study for incorporation into the trial database. Test data transfers should be performed to 
check accuracy and completeness.

Standard hematology, serum chemistry, coagulation, and urinalysis.

A 24-hour urine collection for protein and creatinine measurement may be ordered at the 
investigator’s discretion to follow up an abnormal urine-protein-to-creatinine ratio (UPCR)
indicating protein in the urine.
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
Urine testing for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine and opiates) and alcohol. (Breathalyzer testing for presence of alcohol may also be 
used at clinic check in place of the urine test.)

A serum pregnancy test (qualitative human chorionic gonadotropin [hCG]) is required at 
screening. A urine pregnancy test may be performed at each clinic check in. 

A follicle-stimulating hormone (FSH) test may be performed at screening to confirm 
menopausal status. Women with postmenopausal status confirmed by screening FSH result 
need not undergo subsequent urine pregnancy testing.

Serology for hepatitis and HIV
Table 9. 
Clinical Laboratory Tests
Hematology
Serum Chemistry
Coagulation
Urinalysis 
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Red blood cells (RBC)
Reticulocytes (Retic)
Hemoglobin (HGB)
Hematocrit (Hct)
Mean corpuscular volume (MCV)
Platelets (PLT)
White blood cells (WBC) 
WBC differential (absolute, relative 
%)
Neutrophils (Neutro)
Monocytes (Mono)
Eosinophils (Eos)
Basophils (Baso)
Lymphocytes (Lymph)
Alanine aminotransferase (ALT)
Albumin
Alkaline phosphatase (ALP)
Aspartate aminotransferase (AST)
Bilirubin, indirect
Bilirubin, total (TBL)
Blood urea nitrogen (BUN)
BUN/creatinine ratio
Calcium (Ca)
Carbon dioxide (CO2) or Bicarbonate
Chloride (Cl)
Cholesterol (total)
Creatinine (Cr)
Creatine kinase (CK)
Glucose
γ-Glutamyl transferase (GGT)
Globulin
Calculated Albumin/globulin ratio
Lactate dehydrogenase (LDH)
Magnesium
Phosphorus/Inorganic phosphate
Potassium
Sodium
Triglycerides
Total protein
Uric acid
Calculated creatinine clearance
Human chorionic gonadotropin (hCG)
Follicle-stimulating hormone (FSH) if 
menopause is suspected
Prothrombin time (PT)
Partial Thromboplastin Time
(PTT)
International Normalized Ratio
(INR)
Additional thrombotic/vascular 
markers (a)
D-dimer
vWF
ICAM-1 
Fibrinogen 
Prothrombin Fragment 1,2
P-selectin
Dipstick
Bilirubin
Blood
Glucose
Ketones
Leukocytes 
Nitrate (Nitrite)
Protein
Urobilinogen
pH
Color
Specific gravity
Turbidity
Urinary protein to 
creatinine ratio (UPCR)
(by random [spot] direct 
measurement)
Microscopy (if 
abnormalities observed on 
parameters above)
Casts
Crystals
Epithelial cells
Leucocytes
Erythrocytes
Bacteria
Hepatitis & HIV Serology
Anti-Drug and CD-Related Serology
Additional Tests
Drugs of Abuse and Urine 
Pregnancy
Hepatitis B surface antigen 
(HBsAg)
Hepatitis C virus antibodies 
(Anti-HCV)
Human immunodeficiency virus 
(types 1 and 2) HIV-1 and 2 
antibodies
Anti-gliadin antibody (i.e., Anti-drug 
antibody as deamidated gliadin peptide 
[DGP]-specific IgG antibody)
Total serum Immunoglobulin A (IgA)
(total IgG and IgM may be obtained 
when necessary to clarify results of IgA 
test)
“Celiac Serology” Tests
Tissue transglutaminase (tTG)-specific 
IgA antibody  
Deamidated gliadin peptide 
(DGP)-specific IgG antibody
Serum-Anaphylaxis/anaphylacto
id reaction
Acute phase cytokines multiplex 
cytokine panel(s): EGF, 
fractalkine, GM-CSF, GRO α, 
IFNα, IFN-γ, IL-1α, IL-1 β, IL-2, 
IL-2 soluble receptor, IL-4, IL-5, 
IL-6, IL-8, IL-10, IL-12, IL-13, 
IL-17, IP-10, MIP1α, and 
MIP1β,  TNF-α  (b)
Mast cell activation
Tryptase (a)
Additional Complement markers
C3a, C5a, CH50, SC5B-9 (a, d)
Urine
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Opiates
Breath/Blood/Urine
Alcohol
Urine Pregnancy
Human chorionic 
gonadotropin (hCG) 
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Table 9. Clinical Laboratory Tests, continued
Hepatitis & HIV Serology
Anti-Drug and CD-Related 
Serology
Additional Tests
Drugs of Abuse
Whole blood /isolated PBMCs
Phenotyping for HLA-DQ2.5 
(HLA-DQA1*0501 / B1*0201) 
and HLA-DQ8.1 
(DQA1*0301/B1*0302)
T-cell proliferation and cytokine 
secretion in response to ex vivo 
gliadin stimulation (a) (c)
Immune Complex Detection
C1q binding
Abbreviations defined in Section V, List of Abbreviations.
See protocol text regarding timing of sample analysis.
a)
Collect sample Predose but post dose if /when clinically indicated (prn) upon appearance of symptoms of 
anaphylaxis/anaphylactoid reaction or IRR (such as fever, nausea, chills, rigors, hypotension, tachycardia, asthenia, headache, 
rash, scratchy throat, and dyspnea).  
See protocol text regarding timing of sample analysis.
b)
Collect sample Predose and at scheduled post-dose timepoints (see Table 1. Schedule of Procedures, Part A or Table 2.
Schedule of Procedures, Part B) but additional times post dose if/when clinically indicated (prn) upon appearance of systemic 
symptoms of anaphylaxis/anaphylactoid reaction/cytokine release syndrome or IRR such as fever, nausea, chills, rigors, 
hypotension, tachycardia, asthenia, headache, rash, scratchy throat, and dyspnea. 
See protocol text regarding timing of sample analysis.
c)
Post-dose blood samples will be collected at approximately 144 hoursfor the single dose groups ≥4 mg/kg in Part A and on 
Days 8 (pre-dose) and 14 for the repeat dose group in Part B, for measurement of peripheral blood T cell proliferation and 
cytokine secretion in response to ex vivo gliadin stimulation. 
d)
For Part B, collect sample for C3a, C5a, and SC5B-9 complement levels at 15 and 30 minutes during infusion and at 24 hours 
following infusion.
8.5.6.2
Celiac Genetics
Phenotyping for HLA-DQ2.5 (HLA-DQA1*0501 / B1*0201) and HLA-DQ8.1 
(DQA1*0301/B1*0302) will be performed by a bioanalytical laboratory specified by the sponsor. 
Blood sampling, processing, and shipment instructions are provided in the laboratory manual.
8.5.6.3
Celiac-Related Serology
Total serum Immunoglobulin A (IgA), tissue transglutaminase (tTG)-specific IgA antibody or 
deamidated gliadin peptide (DGP)-specific IgG antibody will be measured at a bioanalytical 
laboratory specified by the sponsor.  Instructions for blood sampling, processing, and shipment are 
provided in the laboratory manual.
8.5.6.4
Immunogenicity (Anti-Gliadin Antibodies) and Immune Complex Formation
Measurement of anti-gliadin antibodies (i.e., anti-drug antibodies) and immune complex detection 
by C1q binding in serum will be performed using validated methodology at a bioanalytical 
laboratory(ies) specified by the sponsor. Specifically, deamidated gliadin peptide (DGP)-specific 
IgG antibody will be used as the anti-drug antibody test.
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Blood sampling, processing, storage, and shipment instructions are provided in the Laboratory 
Manual. 
8.5.6.5
C3a and SC5B-9 Complement Levels
For Part B, C3a and SC5B-9 complement levels will be obtained during the infusion and 24 hours 
following the infusion (refer to Table 2. Schedule of Procedures, Part B).
8.5.6.6
Cytokines and Laboratory Tests to Follow-Up Suspected 
Anaphylaxis/Anaphylactoid Reaction
These tests will be performed by a bioanalytical laboratory specified by the sponsor, with 
instructions for blood sampling, processing, storage (if applicable), and shipment provided in the 
Laboratory Manual.  Performance of testing (relative to collection or processing time) should be 
compliant with sample stability limits and validated procedure requirements, as applicable.
8.5.6.6.1
Cytokines
Samples for determination of acute phase cytokines (EGF, fractalkine, GM-CSF, GRO α, IFNα, 
IFN-γ, IL-1α, IL-1 β, IL-2, IL-2 soluble receptor, IL-4, IL-5, IL-6, , IL-8, IL-10, IL-12, IL-13,
IL-17, IP-10, MIP1α, and MIP1β, TNF-α,) are to be collected predose and at scheduled post dose
timepoints (for all subjects). (See Table 1. Schedule of Procedures, Part A and Table 2. Schedule 
of Procedures, Part B.)  Additional samples are to be obtained as needed from subjects exhibiting 
systemic symptoms of anaphylaxis/anaphylactoid reaction/cytokine release syndrome or IRR such 
as fever, nausea, chills, rigors, hypotension, tachycardia, asthenia, headache, rash, scratchy throat, 
and dyspnea.
The IFN-γ, IL-1 β, IL-2, IL-2 soluble receptor, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, 
IP-10, and TNF-α results through 24 hours post dose will be used for dose escalation decision. In 
the event of the appearance of clinical symptoms, this acute phase cytokine testing should be 
performed promptly and results are to be reported to the investigator as soon as possible.
The scheduled predose and post dose samples can be batched and tested for the other cytokines at 
the end of the trial unless otherwise specified by the medical monitor, sponsor, or DMC or as 
necessary for compliance with the established sample stability.
8.5.6.6.2
Mast Cell Activation and Complement Activation and Supplementary 
Vascular/Thrombotic Assessment
Symptoms of anaphylaxis/anaphylactoid response or IRR (e.g., fever, nausea, chills, rigors, 
hypotension, tachycardia, asthenia, headache, rash, scratchy throat, and dyspnea) will be followed 
up with additional laboratory testing for mast cell activation (Tryptase), complement activation 
(C3a, C5a, CH50, SC5B-9), and for vascular/thrombotic markers (D-dimer, vWF, ICAM-1, 
Fibrinogen, Prothrombin Fragment 1,2 and P-selectin).
Predose samples will be obtained from all subjects, with additional post dose samples to be taken
from symptomatic subjects prn if clinically indicated by the appearance of symptoms.  
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Samples should be analyzed promptly and results are to be reported to the investigator as soon as 
possible in the event of clinical presentation of anaphylaxis/anaphylactoid response or IRR. 
If clinical symptoms did not arise the (predose) samples will not be analyzed unless otherwise 
specified by the sponsor, medical monitor, or DMC or as necessary for compliance with the 
established sample stability (e.g., if predose sample must be analyzed to prevent sample expiration 
prior to end of trial).
8.5.6.6.3
Whole Blood for PBMC Isolation
Samples will be obtained from all subjects predose. Additional post dose sample(s) will be 
collected prn if clinically indicated by the appearance of symptoms of anaphylaxis/anaphylactoid 
response/cytokine release syndrome or IRR.  Peripheral blood mononuclear cells (PBMCs) will be 
isolated from whole blood samples. PBMCs will be used to determine T cell proliferation and 
cytokine secretion in response to ex vivo gliadin stimulation (by an established proliferation 
assay). Surplus PBMCs, if any, might be used to perform the alternative assay.
Scheduled post-dose blood samples will be collected at approximately 144 hoursfor dose groups ≥ 
4 mg/kg in Part A and on Days 8 (predose) and 14 for the repeat dose group in Part B.
8.6
Adverse Events 
AEs will be collected from time of consent until final follow up. The investigator is responsible for 
reporting all AEs that are observed or reported during the study, regardless of their relationship to 
study drug or their clinical significance. If there is any doubt as to whether a clinical observation is 
an AE, the event should be reported.
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with study participation or study treatment. AEs that occur after a subject provides 
informed consent but before the time of the first dose of study drug will be considered pretreatment 
AEs.  
8.6.1
Treatment Emergent Adverse Events
A treatment emergent adverse event (TEAE) is defined as any untoward medical occurrence in a 
clinical investigation subject administered study drug; it does not necessarily have a causal 
relationship with study drug. For simplicity, the protocol will refer to AEs.  The distinction of 
TEAE will be made in the data by a subject’s exposure to at least one dose of study drug.
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the study drug. 
The following should not be recorded as AE: 

Preplanned procedures unless the condition for which the procedure was planned has 
worsened after the subject signed informed consent; (however, complications resulting from 
an elective surgery should be reported as AEs).
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
Preexisting conditions found as a result of screening procedures.  These should be recorded as 
medical history; (however, worsening of an ongoing abnormal preexisting condition is to be 
recorded as an AE). 
Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or 
symptoms, are considered clinically significant, require therapy or further diagnosis beyond repeat 
testing for confirmation alone. See also CTCAE Version 4.0 (Published: May 28, 2009 [v4.03: 
June 14, 2010]) or most current version.
Refer to Appendix 13.1, Liver Safety Monitoring and Assessment (Drug Induced Liver 
Injuiry, DILI) for detailed information on identifying, monitoring and assessing liver 
abnormalities if increases in liver function test values occur or a TEAE is suspected to be 
due to hepatic dysfunction.
8.6.2
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose:

Results in death

Is immediately life-threatening

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death if it 
were more severe

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions

Leads to a congenital anomaly/birth defect

Is an important medical event: 
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, 
they may jeopardize the 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 or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.

Any potential “Hy’s Law” or severe hepatic function abnormality as defined below, in the 
absence of another etiology, is to be considered an important medical event and must be 
promptly reported as an unexpected SAE associated with the use of the drug (i.e., reported 
even before all other possible causes of liver injury have been excluded). (See also Appendix 
13.1.)
o
ALT or AST > 3x upper limit of normal (ULN) and increase of total bilirubin > 2x ULN 
without evidence of intra- or extra-hepatic bilirubin obstruction (elevated ALP) or 
Gilbert’s syndrome (“Hy’s Law”) or 
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o
ALT or AST > 3x ULN and INR > 1.5x ULN or
o
ALT or AST >8xULN or
o
ALT or AST >5xULN for more than 2 weeks or 
o
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
The initial report must occur before fully working up the patient to rule out other etiologies. 
Reporting should include all available information, especially that needed for evaluating the 
severity and likelihood that the drug caused the reaction, and should initiate a close follow-up until 
complete resolution of the problem and completion of all attempts to obtain supplementary data. 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death.
8.6.3
AE Severity Assessment
The CTCAE Version 4.0 (Published: May 28, 2009 [v4.03: June 14, 2010]) or most current 
version will be used to assess and grade severity for AEs and laboratory abnormalities judged to be 
clinically significant.  Within each category, AEs are listed accompanied by their descriptions of 
severity (Grade 1-5).  Each AE term will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) term and code.  For this study, the CTCAE will only be used for grading the 
severity for the AE and not for causality assessment. 
If an event is not covered by CTCAE Version 4.0, the guidelines shown in Table 10 should be used 
to assess severity.
Table 10. 
Severity Criteria Descriptions for AE not covered by CTCAE
Toxicity Grade / Severity
Description
Grade 1
Mild
The event is transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign or 
symptom, but tolerates it reasonably well. 
Grade 2
Moderate
The event causes mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Grade 3
Severe
The event causes marked limitation in activity, medical intervention/therapy 
required. Hospitalization possible.  
Grade 4
Life-threatening
The subject is at risk of death due to the AE as it occurred.  This does not refer to 
an event that hypothetically might have caused death if it was more severe. 
Grade 5
Fatal
The subject dies due to the event. 
8.6.4
Causality of AEs
The relationship of each AE to study medication(s) will be assessed by the investigator or
delegated doctor of medicine (MD) subinvestigator using the following categories.  If a licensed 
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physician assistant who is delegated responsibility by the investigator provides initial assessment 
of causality, it must be confirmed in writing by the investigator or MD subinvestigator.
Causal relationship to the 
study drug
Criteria for causal relationship
Not related
A clinical event, including laboratory test abnormality, with a temporal relationship to 
study drug administration which makes a causal relationship improbable, and/or in 
which other drugs, chemicals or underlying disease provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a reasonable temporal 
sequence to administration of the study drug, but which could also be explained by 
concurrent disease or other drugs or chemicals. Information on drug withdrawal may be 
lacking or unclear.
Probable
A clinical event, including laboratory test abnormality, with a reasonable temporal 
sequence to administration of the study drug, unlikely to be attributed to concurrent 
disease or other drugs or chemicals, and which follows a clinically reasonable response 
on re-administration (re-challenge) or withdrawal (de-challenge).
8.6.5
Documenting AEs
AEs should be recorded as descriptively as possible (investigator terms) in the source.  Time of AE 
onset and resolution (if applicable) should be recorded for AEs occurring while the subjects are in 
the clinic.  Source should be sufficiently detailed to allow appropriate medical evaluation of AEs 
and the circumstance under which they occurred and to facilitate accurate and efficient coding and 
eCRF reporting and determine the necessity of medical follow up. 
At every study visit or telephone follow up, subjects will be asked a nondirected question to elicit 
any medically related changes in their well-being. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant medication 
regimens (both prescription and non-prescribed/over-the-counter medications).
AEs must be followed to satisfactory resolution or until the investigator deems the event to be 
chronic or the condition to be stable. The description of the AE will include the onset date, 
duration, date of resolution, severity, seriousness, etiology, and the likelihood of relationship of 
the AE to study drug.
Collection of pretreatment AEs will commence from the time the subjects signs the informed 
consent to participate in the study and continue until the subject is first administered study drug. 
For subjects who discontinue study participation prior to study drug administration, pretreatment 
events are collected until the subject discontinues. Collection of TEAEs will begin from the time 
that the subject is first administered study drug through the last study procedure. 
Assessment of relationship to study drug will only be captured for TEAEs (AEs arising after the 
subject is first administered study drug). For AEs prior to dosing relationship to AEs will be 
deemed “not related”.
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8.6.6
Collection and Reporting of Serious Adverse Events
The investigator may consult with the Cour medical monitor at any time regarding an AE; 
however, the Cour medical monitor is to be notified of any serious adverse event (SAE) and any 
Grade 2 or greater toxicity or DILI case within 24 hours of investigator’s (or designee’s) 
awareness of such an event.  
When a SAE occurs through the AE collection period it should be reported according to the 
following procedure.
A Cour SAE form must be completed and signed by the investigator immediately or within 
24 hours of first onset or notification of the event. The information should be completed as fully as 
possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug

Causality assessment.
The SAE form should be transmitted byfax within 24 hours of awareness to the attention of the 
contact listed below: 
Attn: Drug Safety Coordinator
US Fax: +1 888-301-7843
The AE eCRF and other relevant eCRFs (such as General Medical and Surgical History, 
Prior/Concomitant Medications, Vital Signs, and Concomitant Procedures) for the subject must be 
completed promptly and updated promptly with new information. If there are additional 
documents that support the SAE (e.g., clinic or hospital records, laboratory reports, or procedure 
reports), they should be obtained. Any SAE spontaneously reported to the investigator following 
the AE collection period should be reported to the sponsor if considered related to study drug.  
SAEs spontaneously reported >30 days after the last subject’s last procedure will not be captured 
in the trial database.
8.6.7
Collection and Reporting of Special Situations
Some events will be considered “special situations” and reported using the SAE form (special 
situation section) even though an associated SAE may not have been experienced by the study 
subject.  Examples are pregnancy (of a study subject or female partner of a male study subject; see 
also Section 8.6.9), overdose (see also Section 7.6), and medication error (i.e., an unintended 
failure in the drug treatment process that leads to, or has the potential to lead to harm to the 
patient).  Other “special situations” may be identified case-by-case.
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8.6.8
Follow-up of SAEs
All SAEs should be followed up until resolution or until the investigator deems the event to be 
chronic or stable. The timelines and procedure for follow-up reports are the same as those for the 
initial report.
8.6.9
Pregnancy
Women with known or suspected pregnancy are excluded from the study. 
If a female subject or partner of a male subject becomes pregnant during the study dosing period or 
within 30 days from the last procedure or last dose, whatever is greater, the subject should inform 
the investigator immediately and subsequently the investigator should report the information to the 
sponsor on the SAE form (special situation section) as if it is an SAE.  The expected date of 
delivery or expected date of the end of the pregnancy, last menstruation, estimated conception 
date, pregnancy result and neonatal data etc., should be included in this information.  Should the 
partner of the male subject become pregnant, a separate informed consent form will be submitted 
for IRB review and approval that, upon signing by the pregnant female (subject’s partner), will 
allow medical supervision during the pregnancy and allow follow-up after the birth of the infant.
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs (spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly [including congenital anomaly 
or developmental delay in the fetus or the child]), the investigator should respond in accordance 
with the report procedure for SAEs.  Additional information regarding the outcome of a pregnancy 
(which is categorized as an SAE) is mentioned below.

“Spontaneous abortion” includes miscarriage, abortion and missed abortion.

Death of an infant within 1 month after birth should be reported as an SAE regardless of its 
relationship with the study drug.

If an infant dies more than 1 month after the birth, the death should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as “possible” by the 
investigator.

In the case of a delivery of a living newborn, the “normality” of the infant is evaluated at the 
birth (e.g., the Apgar score).

Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination.
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8.7
TIMP-GLIA Concentration and Pharmacokinetics
8.7.1
Blood Collection for PK
Serial blood samples will be collected in a K2 EDTA tube for measurement of TIMP-GLIA in 
plasma at the times relative to infusion start time as shown in the Schedules of Procedures for 
Part A (SCHEDULES OF ASSESSMENTS
Table 1) and Part B (Table 2). The scheduled times relative to infusion start should be 
implemented as indicated; however, some time windows of PK blood collection will be allowed, if 
necessary, as shown in Appendix 13.3. 
Samples for PK are to be drawn from the opposite arm from which study drug is being infused.  
Sample processing, storage, and shipment instructions are described in the Laboratory Manual. 
TIMP-GLIA concentration measurement will be performed by a validated ELISA assay (LLOQ = 
0.05 μg/mL) by a bioanalytical laboratory specified by the sponsor. The method detects gliadin 
that has been released from the TIMP-GLIA matrix and is present in plasma.
8.7.2
Estimation of PK Parameters
Individual subject plasma TIMP-GLIA concentrations over time (actual time elapsed from dosing) 
will be used to derive PK parameters using non-compartmental analysis (NCA). The primary PK 
parameters are maximal observed concentration (Cmax), last measurable concentration (Clast), time 
of maximal observed concentration (Tmax), time of last measurable concentration (Tlast), and area 
under the curve from time zero and extrapolated to infinity (AUCinf) and area under the 
concentration-time curve from time zero to time of the last measurable concentration (AUClast).  
Other PK variables will be derived if feasible: terminal elimination half-life (t½), area under the 
curve over the dosing interval (AUCτ), area under the curve from time zero (time of dosing) to time 
t, where a relevant t will be determined based upon the observed data (AUCt), total body clearance 
(CL), volume of distribution (Vd), and accumulation index (Racc).  The terminal half-life will be 
calculated as t½ = ln(2)/λz, where λz is the terminal rate constant. λz will be estimated as the slope 
from a linear regression with the natural logarithm to the concentration as the response variable, 
and time as the explanatory variable. Valid observations from the final part of the curve, which is 
approximately linear, will be used for the analysis. Pharmacokinetic analysis results may be 
provided in a separate PK report.
8.8
Total Amount of Blood
The approximate total blood volume taken per CD subject in Part A is 307mL and in Part B is
462 mL over 3 months (screening through Day 60).  Volumes may increase should the subject 
require unscheduled testing to follow up suspected adverse events.  
8.9
Priority of Actions
The following order of procedures will be in effect when more than 1 assessment is required at a 
time point with blood sampling for pharmacokinetics/metabolic profiling being collected nearest 
to the scheduled time point:
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1. Routine 12-lead ECG
2. Supine vital signs
3. Dosing
4. Blood sample for PK collected at the nominal time point relative to dose (infusion START) 
time
5. Blood sampling for screening/safety and specialty laboratory tests
6. Urine sampling for safety laboratory tests
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9
STATISTICAL METHODS
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock, at the latest. 
This document will provide further details regarding the definition of analysis variables and 
analysis methodology to address all study objectives along with specifications for tables, listings 
and figures (TLFs) to be produced. Any changes from the analyses planned in the SAP will be 
justified in the clinical study report.
Prior to database lock a review of the clinical study data will be performed and final data queries 
identified, if necessary.
9.1
Sample Size
No sample size calculation was performed. The sample size is based upon precedent set by other 
clinical studies of similar nature and is considered sufficient to achieve the study objectives. 
9.2
Analysis Sets
9.2.1
Safety Set
The safety analysis set (SAF) will include all enrolled subjects who received at least 1 dose of 
study drug. 
The SAF will be used for summaries of demographics and baseline characteristics and all safety 
and tolerability variables.
9.2.2
Pharmacokinetic Analysis Set
The PK analysis set (PKAS) is a subset of the SAF for which concentration data are available to 
facilitate derivation of at least 1 primary PK parameter and for whom the time of dosing on the day 
of sampling is known. Inclusion of subjects in the PKAS with missing data or protocol deviations
will be considered by the pharmacokineticist on a case-by-case basis.
The PKAS will be used for all tables and graphical summaries of PK data. 
9.3
Demographics and Other Baseline Characteristics
Demographics and other baseline characteristics including sex, age, race, ethnicity, height, weight, 
and the HLA type (HLA-DQ2.5 or HLA-DQ8.1) will be summarized for the SAF and PKAS.   
Medical history data will be summarized for the SAF using the number of observations and 
percentage of subjects reporting each category.  
9.4
Subject Disposition
The number of subjects who enter and complete each phase of the study will be tabulated.  
Numbers of subjects who fail to complete the study will be tabulated and categorized by reason for 
termination.  
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All screen failures and corresponding primary reason for screen failure will be listed.
9.5
Safety Analysis
No formal statistical analyses will be conducted. All safety and tolerability data for the SAF will 
be listed. In general, all data will be summarized with descriptive statistics (number of subjects, 
mean, standard deviation [SD], coefficient of variation [CV], minimum, median, and maximum 
and geometric mean where applicable) for continuous endpoints, and frequency and percentage for 
categorical endpoints.  Percentages by categories will be based on the number of subjects with no 
missing data, i.e., will add up to 100%.  Changes from predose baseline may also be presented for 
laboratory values, pulse oximetry, and vital signs as appropriate. Physical examination findings 
and ECG abnormalities will be listed.  
Data will be presented overall and by dose level for each phase of study (Part A, Part B).
Presentation by dose (mg) administered may also be included, as appropriate.
9.5.1
Adverse Events
AEs will be coded using MedDRA. All AEs will be listed.
AE summary tabulations will specify number and percentage of subjects who experienced an AE
presented by MedDRA System Organ Class and MedDRA Preferred Term, and CTCAE grading 
(severity) overall and by dose level for each study phase (Part A, Part B). Separate summaries will 
be presented for TEAEs, serious TEAEs, TEAEs leading to discontinuation, and TEAEs related to 
study drug. The number of events will also be presented by MedDRA System Organ Class and 
MedDRA Preferred Term, and CTCAE grading (severity) overall and by dose level for each study 
phase (Part A, Part B). AE tabulation and listing descriptions will be provided in the SAP. 
At each level of incidence reporting, a subject will be counted once if the subject reports 1 or more 
events at that level.
In the case of duplicate preferred terms for a subject:

the most severe case will be reported 

drug relatedness status, most conservative assessment, will be reported 
Additional AE data capture and reporting conventions include but are not limited to:

If the onset time of an AE starting on Day 1 is not known relative to dosing start time on Day 1, 
the AE will be considered treatment-emergent.

If only a partial AE onset date is available (month/year) and it is the same as the month/year of
Day 1 and the full AE end date (day/month/year) is on or after Day 1, the AE will be 
considered treatment-emergent. 

If only a partial AE onset date is available (month/year) and the full AE end date is before 
Day 1, the AE will not be considered treatment-emergent.

If only a partial AE onset date (month/year) and only a partial AE end date (month/year) are 
available and both are the same month/year of Day 1, the AE will be considered 
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treatment-emergent unless documentation specifies the onset date and time was prior to Day 1
dosing.
9.5.2
Vital Sign Measurements and Pulse Oximetry
Vital sign measurements (systolic and diastolic blood pressure [mmHg], heart rate [beats/minute], 
respiration rate [breaths/minute], and body temperature [°C]) and oxygen saturation (SO2, %) 
measurements will be displayed in the listings and will be summarized in tabulations. In addition 
to summary statistics, inner quartile percentiles will be reported. Change from baseline by 
visit/timepoint will also be reported using the number of subjects with the reported value, mean, 
median, SD, minimum value, maximum value, and inner quartile percentiles. Subjects with 
missing data for a given visit will not contribute to the tabulations for that visit.
9.5.3
Clinical Laboratory Test Results
Laboratory test results will be listed with each out of range value classified as low (L) or high (H) 
according to the laboratory-supplied reference ranges or defined reference range for the study. 
Results will be summarized in tabulations by treatment group and visit/timepoint using descriptive 
statistics where applicable for quantitative laboratory measurements. 
Tables showing shift from baseline will also be presented.
The presence of antibodies, where detected, will be summarized descriptively and/or graphically 
presented.  Further details will be provided in the SAP. 
9.5.4
Physical Examination and Safety ECG Findings
All physical examination results will be listed.
Changes from Screening in PE and ECG results will be listed by subject for all subjects in the SAF. 
Height and weight will be summarized by summary statistics. The number of baseline abnormal 
findings and the percentage of subjects with abnormalities will be reported. A table will be 
provided, to report findings that represent changes from the baseline condition at each visit (for PE 
this table will be subdivided by each of the body systems).
9.5.5
Previous and Concomitant Medication 
Previous and concomitant medications will be coded with the World Health Organization’s Drug 
Dictionary (WHO-Drug).  Previous medication (medication history) is defined as drugs and 
therapies taken before first dosing.  Concomitant medication is defined as drugs and therapies used 
after first dosing, including those that started before dosing and continued after dosing.
All previous and concomitant medications will be listed by subject.
9.5.6
Statistical Analysis of Pharmacokinetics
Individual subject concentrations of TIMP-GLIA will be listed by subject and summarized by 
study phase (Part A, Part B), dose level, and scheduled sample time (nominal time) and study day.  
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Descriptive statistics (number of subjects, mean, SD, CV, median, minimum, maximum and 
geometric mean) will be used to summarize TIMP-GLIA concentrations at each scheduled time, as 
well as derived pharmacokinetic parameters.
Graphics for TIMP-GLIA concentrations, including mean concentration-time profiles, individual 
subject concentration-time profiles (both linear and logarithmic-linear) and overlay (“spaghetti”) 
plots of concentrations-time profiles will be produced as appropriate overall and by study phase 
(Part A, Part B) and dose level. Presentation taking into account dose (mg) administered may also 
be included, as appropriate.
9.6
Missing or Outlier Data
Missing values for safety data (except for dates) will not be imputed. Missing or partial dates will 
be imputed as described in the SAP.
As a general principle, no imputation of missing data will be done.  Incomplete data for AEs (e.g., 
partial dates) and inaccurate data for laboratory parameters (e.g., values below the lower limit of 
quantification, LLOQ) will be considered for imputation.
TIMP-GLIA concentration values below the LLOQ will be set to zero for calculation of summary 
statistics.  If one or more values are less than the LLOQ, the geometric mean will not be calculated. 
The handling of missing concentration data points, below the LLOQ data points, outlier data 
points, and individual outlier PK parameter values will be described in the SAP.
Further details will be provided in the SAP.
9.7
Interim Analysis 
Interim data locks for data collected through the end of the investigational period (Day 60) may be 
performed and after each part of study so that the key data can be reviewed and reported. Datasets 
affected by data availability during the follow-up period will be augmented. Details will be 
provided in the SAP. 
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10 OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
10.1
Procedure for Clinical Study Quality Control and Study Management
10.1.1
Data Collection/Documentation
All procedures conducted under the protocol must be documented.  For screening failures, the 
minimum demographic data (sex, birth date, race and informed consent date), outcome of 
eligibility assessment (inclusion and exclusion criteria), reason for screening failure and AEs 
details must be document within the source.
The investigator or designee will be responsible for case report form completion and that all data 
and queries are accurate, complete and are verifiable with the source.  The source should be 
appropriately maintained by the clinical unit.
Electronic case report forms (eCRFs) and any supporting documents should be available for 
review/retrieval by the sponsor/designee at any given time.
10.1.2
Specification of Source Documents
Source data may be paper and/or electronic and must be available at the clinical unit to document 
the existence of the study subjects and to substantiate protocol adherence and integrity of study 
data.  Source data must include the original documents relating to the study, as well as the medical 
treatment and medical history of the subject. 
The following information should be included within the source records:
1. Demographic data (date of birth [DD MMM YYYY], sex, race, ethnicity, height and body 
weight, BMI),
2. Inclusion and exclusion criteria details,
3. Participation in clinical study and signed and dated informed consent forms, 
4. Visit dates,
5. Medical and medication history and physical examination details,
6. Key pharmacokinetic and safety data (including dates and times of scheduled and unscheduled 
procedures, events, tests),
7. AEs and concomitant medication (if applicable),
8. Results and medical interpretation of relevant examinations,
9. Laboratory printouts (if applicable),
10. Detailed record of receipt, dispensing, and final disposition of study drug, and study drug 
storage conditions,
11. Administration of study drug details including administration conditions,
12. Reason for premature discontinuation (if applicable),
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13. Subject ID number and randomization number (if applicable),
14. A record of the pharmacokinetic sample processing and storage history, including date/time 
each sample is transferred to the freezer, freezer identification and the temperature log for the 
freezer,
15. Records of clinical study-related telephone conversations with clinical study subjects
(e.g., AEs, concomitant medications, well-being), ad hoc medical consultation pertaining to 
study subjects.
10.1.3
Clinical Study Monitoring
The sponsor or delegated contract research organization (CRO) is responsible for monitoring the 
clinical study to ensure that subject's human rights, safety and well-being are protected, that the 
study is properly conducted in adherence to the current protocol and GCP, and study data reported 
by the investigator/subinvestigator are accurate and complete and that they are verifiable with 
study-related records such as source documents.  The sponsor is responsible for assigning study 
monitor(s) to this study for proper monitoring.  They will monitor the study in accordance with 
planned monitoring procedures. This includes verifying that the FDA Form 1572 and site 
signature log and PI’s delegation of responsibility log and other regulatory documents are current, 
and that any protocol deviations are documented with appropriate notifications made (e.g., 
sponsor, IRB, regulatory authorities) in a timely manner. Monitoring will include a combination of 
procedural verification (e.g., study drug preparation, timing of procedures) as well as source data 
verification (e.g., reconciliation of source data to (e)CRFs, verification of study records for GCP 
compliance) as appropriate.
It is important that the investigator and other study personnel are available during the monitoring 
visits to support clinical study monitoring.
10.1.4
Direct Access to Source Data/Documents/Inspection of Records
The investigator must permit monitoring and auditing by the sponsor or delegated CRO as well as 
inspections from the IRB/independent ethics committee (IEC) and relevant regulatory authorities.  
In these instances, they must provide all study-related records, such as source documents, when 
they are requested by the sponsor monitors and auditors, the IRB/IEC, or regulatory authorities.  
The confidentiality of the subject's identities shall be well protected consistent with local and 
national regulations when the source documents are subject to direct access.  The sponsor or 
designee monitor will not collect individually identifying information (e.g., name, address, social 
security number) on trial participants.
The auditor or inspector may ask to visit the facilities where procedures are performed, records are
collected, where the study drug is stored and prepared, and any other facility used during the study. 
In the event of an audit, investigator agrees to allow the sponsor, representatives of the sponsor, the 
FDA, or other regulatory agency access to inspect relevant facilities. 
If the study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately.
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10.1.5
Data Management
Data Management will be coordinated by the designee of the sponsor and the designee’s 
procedures and documentation policies will be followed. All study-specific processes and 
definitions will be documented by Data Management.  Coding of medical terms and medications 
will be performed using MedDRA and WHO-Drug respectively.
10.1.6
Protocol Deviations
A protocol deviation is an unplanned excursion from the protocol that is not implemented or 
intended as a systematic change.  A significant deviation occurs when there is nonadherence to the 
protocol that results in a significant, additional risk to the subject when the subject or investigator 
has failed to adhere to significant protocol requirements. Significant deviations can include 
nonadherence to inclusion or exclusion criteria, enrollment of the subject without prior sponsor 
approval, or when there is nonadherence to FDA or other applicable regulations and/or ICH 
E6(R2) guidelines. 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol and must protect the rights, safety and 
welfare of subjects.  The investigator should not implement any deviation from, or changes of, the 
protocol, unless it is necessary to eliminate an immediate hazard to study subjects.
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol.  Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to sponsor are defined as any 
unplanned incidents involving noncompliance with the final approved protocol, including but not 
limited to, any subject who:

Protocol deviation 1 – Entered the study even though they did not satisfy entry criteria 

Protocol deviation 2 – Developed withdrawal criteria during the study and was not withdrawn

Protocol deviation 3 – Received wrong treatment or incorrect dose 

Protocol deviation 4 – Received excluded concomitant treatment
When a deviation from the protocol is identified for an individual subject, the investigator or 
designee must ensure the sponsor is notified.  The sponsor or designee will follow-up with the 
investigator, as applicable, to assess the deviation and the possible impact on the safety and/or 
pharmacokinetic parameters of the subject to determine subject continuation in the study. 
If a deviation impacts the safety of a subject, the investigator must contact the sponsor or 
designated Clinical Contact immediately.
The investigator will also assure that deviations meeting IRB’s and applicable regulatory 
authorities’ criteria are documented and communicated appropriately to the IRB and applicable 
regulatory authorities.  All documentation and communications to the IRB and applicable 
regulatory authorities will be provided to the sponsor or designee and maintained within the trial 
master file.
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NOTE:  Other deviations outside of the categories defined above that are required to be reported to 
the IRB in accordance with local requirements will be reported, as applicable.
10.1.7
Modification of the Protocol
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the subject, must be reviewed and approved by the sponsor or its designee. Amendments 
to the protocol must be submitted in writing to the investigator’s IRB and, if applicable, to the 
appropriate regulatory authorities for approval before subjects can be enrolled into an amended 
protocol.
10.1.8
End of Trial in All Participating Countries
The end of the clinical study is defined as the last subject’s last study visit (late follow-up visit).
10.2
Ethics and Protection of Subject Confidentiality
10.2.1
Institutional Review Board/Ethics Committee/Regulatory Authorities
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, the 
investigator’s brochure, the informed consent form(s) and all other forms of subject information 
related to the study (e.g., advertisements used to recruit subjects) and any other necessary 
documents be reviewed by an IRB/IEC. The IRB/IEC will review the ethical, scientific and 
medical appropriateness of the study before it is conducted. IRB/IEC approval of the protocol, 
informed consent form(s) and subject information and/or advertising, as relevant, will be obtained 
prior to the authorization of drug shipment to a study site.
Any substantial amendments to the protocol will require IRB/IEC approval prior to 
implementation of the changes.  The investigator will be required to submit, maintain and archive 
study essential documents according to ICH GCP.
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to both 
responsible ethics committees and regulatory agencies, as required. During the conduct of the 
study, the investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IRB/IEC of any changes that affect the 
conduct of the study and/or increase the risk to subjects. Written documentation of the submission 
to the IRB/IEC should also be provided to the sponsor.
If required by local regulations, the investigator shall make accurate and adequate written progress 
reports to the IRB/IEC at appropriate intervals, not exceeding 1 year. The investigator shall make 
an accurate and adequate final report to the IRB/IEC within the applicable requirements.
10.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that have 
their origin in the Declaration of Helsinki (1996).
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10.2.3
Informed Consent of Subjects
The requirements of the informed consent are described in Appendix 13.2. 
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study.  Prior to any 
study-related screening procedures being performed on the subject, the informed consent 
statement will be reviewed and signed and dated by the subject or his/her guardian or legal 
representative, the person who administered the informed consent and any other signatories 
according to local requirements. A copy of the signed informed consent form will be given to the 
subject and the original will be placed in the subject’s medical record. An entry must also be made 
in the subject’s dated source documents to confirm that informed consent was obtained prior to any 
study-related procedures and that the subject received a signed copy.
The signed informed consent forms will be retained by the investigator and made available (for 
review only) to the study monitor and auditor, regulatory authorities and other applicable 
individuals upon request.
10.2.4
Subject Confidentiality
Individual subject medical information obtained because of this study is considered confidential.
The sponsor affirms the subject's right to protection against invasion of privacy. Only a subject 
identification number and/or initials, sex, and date of birth (or year of birth as per local 
requirement) will identify subject data retrieved by the sponsor. However, the sponsor requires the 
investigator to permit the sponsor, sponsor's representative(s), the IRB/IEC and when necessary, 
representatives of the regulatory authorities to review and/or to copy any medical records relevant 
to the study.
The sponsor will ensure that the use and disclosure of protected health information obtained during 
a US research study is consistent with federal and/or regional legislation related to the privacy and 
protection of personal information (i.e., Health Insurance Portability and Accountability Act).
10.3
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
10.4
Publication, Disclosure, and Clinical Trial Registration Policy
10.4.1
Use of Study Information and Publication of Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific data, 
the investigator's brochure and other pertinent information is confidential and remains the property 
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of the sponsor. Details should be disclosed only to the persons involved in the approval or conduct 
of the study. The investigator may use this information only for the purpose of the study. It is 
understood by the investigator that the sponsor will use the information obtained during the 
clinical study in connection with the development of the drug and therefore may disclose it as 
required to other clinical investigators or to regulatory agencies. In order to allow for the use of the 
information derived from this clinical study, the investigator understands that he/she has an
obligation to provide the sponsor with all data obtained during the study.
After completion of the study, the data may be considered for reporting at a scientific meeting or 
for publication in a scientific journal. In these cases, the sponsor will be responsible for these 
activities and will work with the investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and other 
related issues. The sponsor has final approval authority over all such issues.
Data are the property of the sponsor and cannot be published without prior authorization from the 
sponsor, but data and publication thereof will not be unduly withheld.
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During the study, only the sponsor may make study information 
available to other study investigators or to regulatory agencies, except as required by law or 
regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
All publications and presentations must be prepared in accordance with this section and the 
Clinical Study Site Agreement. In the event of any discrepancy between the protocol and the 
Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
10.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, Cour will, at a minimum register all 
applicable clinical trials conducted in subjects that it sponsors anywhere in the world on 
ClinicalTrials.gov or other publicly accessible websites before trial initiation. 
10.4.3
Clinical Trial Results Disclosure
Cour will post the results of this clinical trial, regardless of outcome, on ClinicalTrials.gov or other 
publicly accessible websites, as required by applicable laws and/or regulations.
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11 INVESTIGATOR’S OBLIGATIONS
This study will be conducted according to the protocol, the ethical principles that have their origin 
in the Declaration of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each 
investigator will conduct the study according to applicable local or regional regulatory 
requirements and align his or her conduct in accordance with the “Responsibilities of the 
Investigator” that are listed in Appendix 13.4.
11.1
Case Report Forms and Source Documents
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this protocol. 
The investigator agrees to maintain accurate (e)CRFs and source documentation as part of the case 
histories. These source documents include laboratory reports and original ECGs, and electronic 
capture that will be used to record study data. The sponsor’s representative will supply the (e)CRF.
11.2
Adherence to Protocol
The investigator agrees to conduct the study as outlined in this protocol in accordance with ICH 
E6(R2) and all applicable guidelines and regulations.
11.3
Reporting Adverse Events
By participating in this study, the investigator agrees to submit reports of SAEs according to the 
time line and method outlined in the protocol. In addition, the investigator agrees to submit annual 
reports to his/her IRB/IEC as appropriate. The investigator also agrees to provide the sponsor with 
an adequate report shortly after completion of the investigator’s participation in the study.
11.4
Investigator’s Final Report
Upon completion of the study, the investigator, where applicable, should inform the institution; the 
investigator/institution should provide the IRB with a summary of the study’s outcome, and the 
sponsor and regulatory authority(ies) with any reports required.
11.5
Clinical Study Report
The ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final clinical 
study report which forms part of a marketing authorization application be signed by the 
coordinating investigator or the principal investigator(s). The coordinating investigator 
(representative investigator) or principle investigator will have the responsibility to review the 
final study results to confirm to the best of his/her knowledge it accurately describes the conduct 
and results of the study. For multicenter studies, the coordinating investigator (representative 
investigator) may be selected from the participating investigators by the sponsor prior to database 
lock.
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11.6
Records Retention
The investigator will archive all study data (e.g., subject identification code list, source data, 
(e)CRFs [if applicable] and investigator's file) generated by the methods described in the protocol 
and relevant correspondence.  Data will be recorded in the subjects’ medical records and/or study 
progress notes and source documentation.  
Essential 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 investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an agreement 
with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to 
when these documents no longer need to be retained.
The sponsor or designee will archive and retain all documents pertaining to the study (trial master 
file) according to local regulations.
The documents and the judgments of any committee outside the study sites (e.g., minutes and 
SOPs and others), if applicable, shall be retained by the sponsor or designee.
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12 REFERENCES
Anderson RP, van Heel DA, Tye-Din JA, et al. T cells in peripheral blood after gluten challenge in 
coeliac disease. Gut. 2005;54:1217-23.
Anderson RP, Degano P, Godkin AJ, et al. In vivo antigen challenge in celiac disease identifies a 
single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat Med. 
2000; 6:337–342.
Baranwal AK, Singhi SC, Thapa BR, Kakkar N. Celiac Crisis. Indian J Pediatr. 2003;70:433-35.
Christophersen A, Risnes LF, Bergseng E, et al. Healthy HLA-DQ2.5+ subjects lack regulatory 
and memory t cells specific for immunodominant gluten epitopes of celiac disease. J Immunol. 
2016;196(6):2819-26.
Farrell RJ, Kelly C. Celiac Sprue. N Engl J Med. 2002;346:180-8.
Fasano A, Catassi C. Celiac Disease. N Engl J Med. 2012;367:2419-26.
Fasano A, Catassi C. Current Approaches to Diagnosis and Treatment of Celiac Disease: An 
Evolving Spectrum. Gastroenterol. 2001;120:636–51.
Getts DR, Shea LD, Miller SD, King NJC. Harnessing nanoparticles for immune modulation. 
Trends Immunol. 2015;36(7):419-27.
Green PHR, Cellier C. Celiac Disease. N Engl J Med. 2007;357:1731-43.
Han A, Newell EW, Glanville J, et al. Dietary gluten triggers concomitant activation of CD4+ and 
CD8+ αβ T cells and γδ T cells in celiac disease. PNAS. 2013; 110(32):13073-8. 
www.pnas.org/cgi/doi/10.1073/pnas.1311861110
Kaukinen K, Lindfors K, Mäki M. Advances in the treatment of coeliac disease: an 
immunopathogenic perspective. Nat Rev Gastroenterol Hepatol. 2014;11:36-44.
Laurin P, Wolving M, Fälth-Magnusson K. J Ped Gastroenterol Nutr. 2002; 34:26–30
Leffler DA, Schuppan D, Pallav K, et al. Kinetics of the histological, serological and symptomatic 
responses to gluten challenge in adults with coeliac disease. Gut. 2013;62(7):996-1004.
Leffler DA, Acaster S, Gallop K, et al. 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 in Health. 2017;20:637-43.
Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase 1 cancer trials. J Natl Cancer 
Inst. 2009;101:708-20.
Makadia HK, Siegel SJ. Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug 
delivery carrier. Polymers (Basel). 2011;3(3): 1377–97.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Cour Pharmaceutical Development Company
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v 10.0, 11 September 2018
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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;134:1017-27.
Rubio-Tapia A, Hill ID, Kelly CP et al. ACG Clinical Guidelines: Diagnosis and Management of 
Celiac Disease. Am J Gastroenterol. 2013;108:656-76.
Rubinstein LV, Simon RM. Phase 1 Clinical Trial Design. In Handbook of Anticancer Drug 
Development. Budman DR, Calvert AH, Rowinsky EK (eds). Lippincott Williams & Wilkens, 
Baltimore, MD, 2003. pp. 297-308.
Steinman L. Inverse vaccination, the opposite of Jenner’s concept, for therapy of autoimmunity. J 
Intern Med. 2010; 267: 441–51.
Suntharalingam G, Perry MR, Ward S, et al.  Cytokine storm in a phase 1 trial of the anti-CD28 
monoclonal antibody TGN1412. N Engl J Med 2006;355(10):1018-28.
Tack GJ, Verbeek WHM, Schreurs MWJ, Mulder CJJ. The spectrum of celiac disease: 
epidemiology, clinical aspects and treatment. Nat Rev Gastroenterol Hepatol. 2010;7:204–13.
TIMP-GLIA Investigator’s Brochure version 1 2017.
Wang Y, Qu W, Choi S. FDA’s Regulatory Science Program for Generic PLA/ PLGA-Based Drug 
Products.  Center for Drug Evaluation and Research FDA. Posted: June 15, 2016. 
http://www.americanpharmaceuticalreview.com/Featured-Articles/188841-FDA-s-Regulatory-Sc
ience-Program-for-Generic-PLA-PLGA-Based-Drug-Products/
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13 APPENDICES
13.1
Liver Safety Monitoring and Assessment (Drug Induced Liver Injuiry, DILI)
Any subject enrolled in a clinical study with active drug therapy that reveals an increase of serum 
aminotransferases > 3 x ULN or bilirubin > 2 x ULN should undergo detailed testing for liver 
enzymes (including at least ALT, AST, ALP and TBL).  Testing should be repeated within 48 to 
72 hours of notification of the test results.  For studies for which a central laboratory is used, alerts 
will be generated by the central laboratory regarding moderate and severe liver abnormalities to 
inform the investigator, study monitor and study team.  Subjects should be asked if they have any 
symptoms suggestive of hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
TBL
Moderate
> 3 x ULN 
or
> 2 x ULN
Severe†
> 3 x ULN
and
> 2 x ULN
† Hy’s Law Definition: Drug-induced jaundice caused by hepatocellular injury, without a significant obstructive component, has a 
high rate of bad outcomes, from 10% to 50% mortality (or transplant).  The 2 “requirements” for Hy’s Law are: 1) Evidence that a 
drug can cause hepatocellular-type injury, generally shown by an increase in transaminase elevations higher than 3 x ULN (“2 x 
ULN elevations are too common in treated and untreated patients to be discriminating”).  2) Cases of increased bilirubin (at least 2 
x ULN) with concurrent transaminase elevations at least 3 x ULN and no evidence of intra- or extra-hepatic bilirubin obstruction 
(elevated ALP) or Gilbert’s syndrome [Temple, 2006].
In addition, the subject should be considered to have severe hepatic abnormalities for any of the 
following:

ALT or AST > 8 x ULN.

ALT or AST > 5 x ULN for more than 2 weeks.

ALT or AST > 3 x ULN and International Normalized Ratio (INR) > 1.5 (if INR testing is 
applicable/evaluated).

ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash and/or eosinophilia (> 5%).
The investigator may determine that abnormal liver test (LT) results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring and 
follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests.  The investigator or designee should complete a liver 
abnormality case report form (LA-CRF) or collective of appropriate CRFs capturing required 
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information, and/or another appropriate document (e.g., liver abnormality source document(s)).  
Subjects with confirmed abnormal LT results should be followed up as described below.
Confirmed moderately abnormal LTs should be repeated 2 to 3 times weekly then weekly or less if 
abnormalities stabilize or the study drug has been discontinued and the subject is asymptomatic.
Severe hepatic function abnormalities as defined above, in the absence of another etiology, may be 
considered an important medical event and may be reported as an SAE.  The sponsor should be 
contacted and informed of all subjects for whom severe hepatic liver function abnormalities 
possibly attributable to study drug are observed.
To further assess abnormal hepatic laboratory findings, the investigator is expected to:

Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms and 
new-onset diseases should be recorded as “AEs” on the AE page within the source.  Illnesses 
and conditions such as hypotensive events and decompensated cardiac disease that may lead to 
secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis is seen in obese 
hyperlipoproteinemic and/or diabetic patients, and may be associated with fluctuating 
aminotransferase (AT) levels.  The investigator should ensure that the medical history 
documentation captures any illness that predates clinical study enrollment that may be relevant 
in assessing hepatic function. 

Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and special 
diets.  Medications, including dose, should be entered on the concomitant medication page 
within the source.  Information on alcohol, other substance use and diet should be entered on 
the LA-CRF or collective of appropriate CRFs and/or other appropriate documents (e.g., liver 
abnormality page(s) from the source).

Obtain a history of exposure to environmental chemical agents.

Based on the subject’s history, other testing may be appropriate including: 
o
Acute viral hepatitis (A, B, C, D, E or other infectious agents), 
o
Ultrasound or other imaging to assess biliary tract disease,
o
Other clinical laboratory tests including INR, direct bilirubin.

Consider gastroenterology or hepatology consultations.

Submit results for any additional testing and possible etiology on the LA-CRF or collective of 
appropriate CRFs and/or other appropriate documents (e.g., liver abnormality page(s) from the 
source).
Study Subject Discontinuation
In the absence of an explanation for increased LTs, such as viral hepatitis, preexisting or acute 
liver disease or exposure to other agents associated with liver injury, the subject may be 
discontinued from the study.  The investigator may determine that it is not in the subject’s best 
interest to continue study enrollment.  Alternatively, the investigator may determine that it is in the 
subject’s best interest to continue study enrollment to undergo planned and additional medical 
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supervision and testing to adequately follow up the subject’s condition. Discontinuation of 
treatment should be considered if:

ALT or AST > 8 x ULN.

ALT or AST > 5 x ULN for more than 2 weeks.

ALT or AST > 3 x ULN and TBL > 2 x ULN or INR > 1.5 (if INR testing is 
applicable/evaluated).

ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash and/or eosinophilia (> 5%).
In addition, if close monitoring of a subject with moderate or severe hepatic laboratory tests is not 
possible, study drug should be discontinued.
References
Temple R. Hy’s law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
April;15(Suppl 4):241-3
Guidance for Industry titled “Drug-induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009.
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13.2
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
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20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
23. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a.
that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Cour and business partners 
assisting Cour, its affiliates, and licensing partners; (2) regulatory agencies and other 
health authorities; and (3) IRBs/IECs;
b. that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
c.
that the subject’s identity will remain confidential in the event that study results are 
published.
24. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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13.3
Windows For PK Blood Sample Collection 
Nominal Time Relative to Infusion 
Start
Window
Predose (0 hour)
Within 15 minutes prior to dose start
Post dose Part A
≤35 minutes
± 1 minute
1 hour
± 3 minutes
2 hours
± 6 minutes
Post Dose Part B – end of infusion 
± 6 minutes
4 hours
± 12 minutes
6 hours
± 18 minutes
8 hours
± 24 minutes
10 hours
± 30 minutes
12 hours
± 36 minutes
14 hours
± 42 minutes
24 hours
± 72 minutes
36 hours
± 108 minutes
48 hours
± 144 minutes
≥144 hours
± 24 hours
Blood samples for PK should be collected as soon as possible to the scheduled time relative to 
infusion start time.  In the event of an interference, PK collections within the windows above will 
not be considered protocol deviations.
Reasons that a collection fell out of the windows above must be identified in the source 
documentation.
Actual time elapsed from dose start will be used for PK calculations.
Nominal times in bold, black font apply to the study.  Nominal times in gray font are not scheduled 
for this study and are only shown to provide context. 
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13.4
Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
The investigator agrees to assume the following responsibilities by signing a “Statement of 
Investigator” Form FDA1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study-specific screening assessments are NOT 
performed on potential subjects, prior to the receipt of written approval from relevant 
governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR 56 ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
(e)CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 2 
years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
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12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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13.5
Amendment 1: Summary of Changes To Protocol Version 1.0
The final protocol TGLIA-5.001 version 1.0 dated 18 Jul 2017 has been revised to version 2.0 
dated 28 Aug 2017 to include substantantial and nonsubstantial (administrative) changes as 
detailed in the table below. 
SUBSTANTIAL CHANGES
Description of Change
Affected Section(s) in Amended Protocol Version 
2.0
Design – Enrollment for Dose Escalation Cohorts
Accelerated titration design for the first 2 dose levels 
of Part A was changed from 1+1 to 2+2. Cohorts of 2 
subjects will be enrolled at dose level 1 and dose level 
2. If dose-limiting toxicity (DLT) occurs in 1 of the 
subjects, the Safety Committee may expand
enrollment at the same dose level by 2 subjects.
Synopsis, Study Design, Dose Escalation Part A
Synopsis, Safety Committee
Synopsis, Selection of Study Population
Figure 1. Schematic of Planned Dosing
Section 2.1 Overview of Study Design
Section 2.3 Rationale for the Trial Design
Section 4.0 Study Population
Section 7.3.2 Dosing Subjects Within A Dose Level 
(Within A Cohort)
Design – Cohort Expansion
Beyond the 2+2 and 3+3 cohort expansions in the 
event of a DLT, a provision was added to allow the 
Safety Committee to expand a dose cohort up to a 
total of 12 subjects to better define the relationship 
between dose and emerging safety signals.
Synopsis, Study Design, Dose Escalation Part A
Synopsis, Study Design, Part B
Synopsis, Safety Committee
Section 2.1 Overview of Study Design, Dose 
Escalation Part A
Section 2.1 Overview of Study Design, Part B
Section 7.2 Safety Committee
Section 7.3.2 Dosing Subjects Within A Dose Level 
(Within A Cohort)
Description of maximum tolerable dose (MTD)
Was: If no more than 1 subject experiences a DLT in 
each of the planned dose cohorts, the highest tested 
dose will be the MTD.  
In the context of the cohort expansions, the 
description has been revised such that the highest 
dose level that did not cause unacceptable side effects 
will be considered the MTD.
Section 7.3.3 Dose Escalation – Dosing Subjects At 
the Next Dose Level
Planned Number of Subjects
Because each of the first 2 dose levels will enroll at 
least 2 subjects, the planned enrollment for Part A 
increased from 17 to 19 subjects and the overall 
planned enrollment for the study increased from 20 to 
22 subjects. 
Synopsis, Study Design, Part A
Synopsis, Selection of Study Population
Section 2.1 Overview of Study Design, Part A
Section 4.0 Study Population
Design – Staggering of Individual Subject Dosing, 
Part A
Synopsis, Study Design, Part A
Section 1.5 Benefit-Risk Assessment (solid bullet 
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Description of Change
Affected Section(s) in Amended Protocol Version 
2.0
The time between dosing successive subjects was 
increased from 24 hours to 168 hours (7 days).
items 8 and 9)
Section 2.1 Overview of Study Design, Part A
Section 2.3 Rationale for the Trial Design
Section 6.3 Method of Assigning Subjects to 
Treatment Groups
Section 7.3.2 Dosing Subjects Within A Dose Level 
(Within A Cohort)
Design – Staggering of Individual Subject Dosing, 
Part B
The time between dosing successive subjects was 
increased from 24 hours to 168 hours (7 days) after 
the second dose.  
The staggering interval will be applied between all 
subjects enrolled in Part B. Subjects in Part B may not 
be dosed on the same day.
Synopsis, Study Design, Part B
Section 2.1 Overview of Study Design, Part B
Section 2.3 Rationale for the Trial Design
Section 6.3 Method of Assigning Subjects to 
Treatment Groups
Section 7.3.2 Dosing Subjects Within A Dose Level 
(Within A Cohort)
Design –Dose Escalation Interval
The dose escalation interval was increased from 48 
hours to 168 hours (7 days). Therefore, the last 
subject enrolled in a dose cohort will be observed and 
data collected for at least 168 hours (7 days) before 
the Safety Committee will consider the progression or 
termination of dosing.
Synopsis, Study Design, Dose Escalation Part A
Section 1.5 Benefit-Risk Assessment (solid bullet 
items 10 and 11)
Section 2.1 Overview of Study Design, Dose 
Escalation Part A
Section 2.3 Rationale for the Trial Design
Section 7.3.2 Dosing Subjects Within A Dose Level 
(Within A Cohort)
Section 7.3.3 Dose Escalation – Dosing Subjects At 
the Next Dose Level
Design- Progression from Part A to Part B
The minimum available safety data from the last 
cohort in Part A increased from 48 hours to 168 hours 
(7 days) for evaluation by the Safety Committee. 
Synopsis, Study Design, Dose Escalation Part A
Section 2.1 Overview of Study Design, Dose 
Escalation Part A
Safety Committee
To ensure independence of the Safety Committee, the 
Cour medical monitor will not be a member. The 
sponsor medical monitor will be available by 
telephone to answer data questions that arise but 
otherwise will not be present for the Safety 
Committee meeting and decision-making process.
Synopsis, Safety Committee
Section 7.2 Safety Committee
Dose Stopping Rules
An additional dose stopping rule was added. Dosing 
of additional subjects in a cohort will also be stopped
upon the occurrence of 2 or more of the same CTCAE 
Grade 3 toxicity (among total subjects dosed) or the 
first occurrence of a CTCAE Grade 4 or Grade 5 
Section 7.3.2 Dosing Subjects Within A Dose Level 
(Within A Cohort)
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Description of Change
Affected Section(s) in Amended Protocol Version 
2.0
toxicity, irrespective of relationship to study drug. At 
such time the toxicity will be investigated by the 
Safety Committee to determine whether the study can 
resume or if the Study Stopping Criteria were met.
Visits
In Part A, the Day 14 (+/- 2 days) visit was changed 
from a telephone contact visit to an outpatient visit so 
that safety tests and assessments could be performed. 
Another outpatient visit at Day 60 (+/-3 days) was 
added. Telephone contact visits (regarding the 
subject’s diet, well-being, occurrence of adverse 
events, and concomitant medication use) by a health
care practitioner were added at Day 90, Day 120 and 
Day 180 (all +/- 3 days).
In Part B an outpatient visit at Day 60 (+/-3 days) was 
added so that safety tests and assessments could be 
performed. Telephone contact visits (regarding the 
subject’s diet, well-being, occurrence of adverse 
events, and concomitant medication use) by a 
healthcare practitioner were added at Day 90, Day 
120 and Day 180 (all +/- 3 days).
Synopsis, Exploratory Objective
Synopsis, Duration of Study Period
Table 1. Schedule of Procedures Part A
Table 2. Schedule of Procedures Part B
Section 2.1 Overview of Study Design, Duration of 
Study
Section 2.3 Rationale for the Trial Design
Section 3.1.3 Exploratory Objective
Tests
Sampling for an additional test, C1q binding for 
immune complex detection, was added at:
predose Day 1 (for Parts A and B), 
predose Day 8 (for Part B), 
Day 14 +/-1 day (Parts A and B), 
Day 30 +/- 2 days (for Part A) or Day 38 +/- 2 days 
(for Part B) and 
Day 60 +/- 3 days (Parts A and B).
Synopsis, Endpoints, Safety and Tolerability
Table 1. Schedule of Procedures Part A
Table 2. Schedule of Procedures Part B
Section 3.2. Endpoints
Section 8.5.6.4 Immunogenicity (Anti-Gliadin 
Antibodies) and Immune Complex Formation
Tests
Sampling timepoints for anti-drug antibody testing 
(as deaminated gliadin peptide [DGP]-specific 
antibody IgG) were added at:
Day 14 +/-1 day (Parts A and B) and 
Day 60 +/- 3 days (Parts A and B).
Table 1. Schedule of Procedures Part A
Table 2. Schedule of Procedures Part B
Tests
Sampling timepoints for cytokine testing were added 
at:
24 hours post dose (i.e., Day 2) (Parts A and B) and
24 hours post dose (i.e., Day 8) (Part B).
Synopsis, Endpoints, Safety and Tolerability
Table 1. Schedule of Procedures Part A
Table 2. Schedule of Procedures Part B
Table 9. Clinical Laboratory Tests (footnote b)
Section 8.5.6.5 Cytokines and Laboratory Tests to 
Follow-Up Suspected Anaphylaxis/Anaphylactoid 
Reaction - Cytokines
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Description of Change
Affected Section(s) in Amended Protocol Version 
2.0
Tests – Prioritization for Dose Escalation Decision
Cytokine results will be evaluated for dose escalation 
decision. The planned cytokine tests were reviewed 
and those needed for dose escalation decision were 
identified (i.e., TNF-α, IFN-γ, IL-2, IL-8, IL-10).  The 
analyses for the other cytokines can be performed at 
the end of the study.
Synopsis, Study Design, Part A
Synopsis, Safety Committee
Synopsis, Endpoints, Safety and Tolerability
Section 1.5 Benefit-Risk Assessment (solid bullet 
item 10)
Section 2.1 Overview of Study Design, Part A
Section 2.3 Rationale for the Trial Design
Section 3.2. Endpoints
Section 7.2 Safety Committee
Section 7.3.2 Dosing Subjects Within A Dose Level 
(Within A Cohort)
Section 8.5.6.5 Cytokines and Laboratory Tests to 
Follow-Up Suspected Anaphylaxis/Anaphylactoid 
Reaction - Cytokines
Approximate Total Amount of Blood for Scheduled 
Tests
The approximate total amounts of blood drawn for 
scheduled tests were revised to take into account the 
additional visits and blood draws and also the 
volumes needed with prioritized multiplex assay of 
analytes for dose escalation decision vs. samples that 
could be batch tested at the end of the study.  The net 
changes in approximate total volume were an increase 
in Part A from 301 mL to 320 mL and decrease in 
Part B from 463 to 445 mL.
Section 8.8 Total Amount of Blood
NONSUBSTANTIAL (ADMINISTRATIVE) CHANGES
Description of Change
Affected Section(s) in Amended Protocol Version 
2.0
Study Stopping Rules
The word “Study” was added to “Study Stopping 
Rules” in the section heading and cross references to 
ensure distinction in purpose from dose stopping 
conditions. 
The study will be terminated if the Safety Committtee 
determines that the Study Stopping Rules have been 
met.
Synopsis, Study Design, Dose Escalation Part A
Synopsis, Study Stopping Rules
Synopsis, Safety Committee
Section 1.5 Benefit-Risk Assessment (solid bullet 
item 9)
Section 2.1 Overview of Study Design, Dose 
Escalation Part A
Section 2.3 Rationale for the Trial Design
Section 5.2 Discontinuation of the Study
Section 7.2 Safety Committee
Section 7.3.2 Dosing Subjects Within A Dose Level 
(Within A Cohort)
Section 7.3.3 Dose Escalation – Dosing Subjects At 
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Description of Change
Affected Section(s) in Amended Protocol Version 
2.0
the Next Dose Level
Section 7.3.6 Study Stopping Rules
Correction of Cytokine Test Names
IFN-δ (IFN-delta) was corrected to IFN-γ 
(IFN-gamma).  Because IFN-γ is a cytokine test 
specified for safety monitoring it was important to 
correct this typographical error to ensure the correct 
test would be performed.
Fractaline was corrected to fractalkine. Because 
fractalkine is a cytokine test specified for safety 
monitoring it was important to correct this 
typographical error to ensure the correct test would be 
performed.
Synopsis, Endpoints, Safety and Tolerability
Section 3.2 Endpoints
Table 9 Clinical Laboratory Tests
Section 8.5.6.5 Cytokines and Laboratory Tests to 
Follow-Up Suspected Anaphylaxis/Anaphylactoid 
Reaction - Cytokines
Clarification of Anti-Gliadin-Antibody (Anti-Drug 
Antibody) Test
Clarification that deamidated gliadin peptide 
(DGP)-specific IgG antibody will be the anti-drug 
antibody test for TIMP-GLIA was added. 
The abbreviation AGA for “anti-gliadin antibody”
test was deleted where it was listed separately from 
the deamidated gliadin peptide (DGP) test.
Synopsis, Endpoints, Safety and Tolerability
Table 1. Schedule of Procedures Part A
Table 2. Schedule of Procedures Part B
Section 3.2 Endpoints
Section 8.3 Diet History
Table 9 Clinical Laboratory Tests
Section 8.5.6.4 Immunogenicity (Anti-Gliadin 
Antibodies) and Immune Complex Formation
Clarification of Endpoint Categories for Consistency 
with Synopsis
For consistency with the Synopsis and to avoid 
mischaracterization of the revisions implemented in 
Section 3.2 Endpoints via Amendment 1:
Subsection 3.2.1 “Primary Endpoint” was renamed 
“Safety and Tolerability Endpoints”
Subsection 3.2.2 “Secondary Endpoints” was 
renamed “Pharmacokinetic Endpoints”
Subsection 3.2.3 “Exploratory Endpoints” was 
omitted because anti-gliadin antibody to TIMP-GLIA 
(i.e. anti-drug antibody) is included within “Safety 
and Tolerability Endpoints”.
Section 3.2 Endpoints
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13.6
Amendment 2: Summary of Changes To Protocol Version 2.0
The final protocol TGLIA-5.001 version 2.0 dated 28 Aug 2017 incorporating Amendment 1 has 
been revised to version 3.0 dated 30 Aug 2017 to include substantantial and nonsubstantial 
(administrative) changes as detailed in the table below. 
SUBSTANTIAL CHANGES
Description of Change
Affected Section(s) in Amended Protocol Version 
3.0
Laboratory Assessments
Urine protein-to-creatinine ratio (UPCR) [using spot 
urine samples] was added to routine urine testing to 
enhance monitoring of kidney function. 
Table 9 Clinical Laboratory Tests
List of Abbreviations and Definition of Key Terms
Table 1 Schedule of Procedures Part A (and 
footnotes)
Table 2 Schedule of Procedures Part B (and 
footnotes)
Laboratory Assessments
A 24-hour urine collection may be ordered at the 
investigator’s discretion to follow up an abnormal 
UPCR indicating protein in the urine.
Section 8.5.6.1 Standard Clinical Laboratory Tests 
for Screening/Safety
Laboratory Assessments/Screening
A clarification was added that women with 
postmenopausal status confirmed by screening 
follicle stimulating hormone (FSH) test result need 
not undergo subsequent urine pregnancy testing.
Synopsis Exclusion Criterion #16
Table 1 Schedule of Procedures Part A (and 
footnotes)
Table 2 Schedule of Procedures Part B (and 
footnotes)
Section 4.2 Exclusion Criteria, Criterion #16
Section 8.5.6.1 Standard Clinical Laboratory Tests 
for Screening/Safety
Laboratory Assessments
To enhance evaluation of the immune response to 
TIMP-GLIA, measurement of IL-1β, IL-4, IL-5, and 
IL-13 are added to the cytokine panel.  These results 
are not required for dose escalation decision but may 
be analyzed and reported at the end of each dose 
cohort if they are included in the multiplex assay with 
TNF-α, IFN-γ, IL-2, IL-8, and IL-10.
Synopsis, Endpoints, Safety and Tolerability
List of Abbreviations and Definition of Key Terms
Section 3.2.1 Safety and Tolerability Endpoints
Table 9 Clinical Laboratory Tests
Section 8.5.6.5 Cytokines and Laboratory Tests to 
Follow-Up Suspected Anaphylaxis/Anaphylactoid 
Reaction - Cytokines
Eligibility
The upper limit for body mass index (BMI) was 
increased from 30 kg/m2 to 32 kg/m2
Synopsis Inclusion Criterion #4
Section 4.1 Inclusion Criteria, Criterion #4
Eligibility
The time restriction for high dose inhaled 
corticosteroids [>960 μg/day of beclomethasone 
dipropionate or equivalent] “within 30 days of 
Day 1” was added.
Synopsis Exclusion Criterion #6c
Section 4.2 Exclusion Criteria, Criterion #6c
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Description of Change
Affected Section(s) in Amended Protocol Version 
3.0
Final visit safety assessments
Whenever possible, all subjects who withdraw from 
the study prematurely are to undergo all final visit 
safety assessments.  For clarity these assessments 
were specified to include those listed in the Schedules 
of Procedures for Study Day 14 of Part A or Part B, 
as applicable. 
Table 1 Schedule of Procedures Part A (and 
footnotes)
Table 2 Schedule of Procedures Part B (and 
footnotes)
NONSUBSTANTIAL (ADMINISTRATIVE) CHANGES
Description of Change
Affected Section(s) in Amended Protocol Version 
3.0
Dosing Procedure
Clarification that subjects should remain supine 
during dosing was added.
Table 1 Schedule of Procedures Part A footnote
Table 2 Schedule of Procedures Part B footnote
Section 7.1 Dose and Regimen
Correction in Table 9 Clinical Laboratory Tests
Hepatitis B core antibodies (Anti HBc) listed under 
“Hepatitis & HIV Serology” was deleted.  It is not a 
required test for this study.
Table 9 Clinical Laboratory Tests
Clarification in Table 9 Clinical Laboratory Tests
The subheading to distinguish coagulation tests for 
follow-up of potential anaphylaxis/anaphylactoid 
reaction was updated to “Predose &” PRN only (a).
Table 9 Clinical Laboratory Tests
The statement was updated to specify that 
“applicable” clinical trials will be registered in 
accordance with applicable law, regulation, and 
guidance.
Section 10.4.2 Clinical Trial Registration
Misspelling of health care “practioner” was corrected 
to “practitioner”
Table 1 Schedule of Procedures Part A footnote
Table 2 Schedule of Procedures Part B footnote
Exploratory Objective
Synopsis Exploratory Objective
Section 3.1.3 Exploratory Objective
CCI
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13.7
Amendment 3: Summary of Changes To Protocol Version 3.0
The final protocol TGLIA-5.001 version 3.0 dated 30 Aug 2017 incorporating Amendment 2 has 
been revised to version 4.0 dated 16 Oct 2017 to include substantantial and nonsubstantial 
(administrative) changes as detailed in the table below. 
SUBSTANTIAL CHANGES
Description of Change
Affected Section(s) in Amended Protocol Version 
4.0
A minimum body weight of 33 kg was added to the 
requirement of BMI of >16 kg/m2.  The maximum 
BMI of 32 kg/m2 was replaced with a maximum body 
weight of 129 kg.  The requirement that subjects who 
are underweight or overweight or obese must be 
otherwise healthy in the opinion of the investigator 
remains unchanged. This adjustment prevents 
unnecessary exclusion of otherwise healthy patients 
of smaller or larger stature in the celiac disease 
community. In addition, the minimum and maximum 
weights provide consistency with the pharmacy 
manual dose calculations for subjects whose stature 
may be at the extremes. 
Synopsis Inclusion Criterion #4
Section 4.1 Inclusion Criterion #4
The duration of no known gluten exposure was 
reduced from “approximately 2 months prior to 
enrollment” to “at least 10 days prior to the Screening 
Visit.” The antigen-specific IgG response to gluten 
would generally peak at ~2 weeks and would last for 
~4-5weeks. Therefore, a bonafide immune response 
to the gluten intake would be identified by the 
screening celiac serology testing. In addition, a 
predose DGP-specific IgG will be recorded to capture 
the change from the screening value and to set the
predose baseline. 
Synopsis Inclusion Criterion #5c
Section 4.1 Inclusion Criterion #5c
Section 8.3 Diet History
The criterion was revised such that either a weak 
positive or negative celiac serology value is 
acceptable (either tTG-specific IgA or, for 
IgA-deficient subjects, DGP-specific IgG).  The 
study does not include a gluten challenge that would 
necessitate an optimization of the pre-challenge 
conditions.  Relaxing the criterion is not expected to 
alter safety or tolerability and should facilitate 
recruitment.
Synopsis Inclusion Criterion #5d
Section 4.1 Inclusion Criterion #5d
Consumption of alcohol will be prohibited from 24 
hours prior to clinic admission (when testing for 
presence of alcohol will be performed) until discharge 
from the clinic. Updates were made to ensure that 
exclusion criterion 13 is consistent with the body of 
Synopsis Exclusion Criterion #13
Section 4.2 Exclusion Criterion #13
Section 7.6.2 Dietary and Fluid Restricions
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Description of Change
Affected Section(s) in Amended Protocol Version 
4.0
the protocol pertaining to dietary and fluid 
restrictions.
A 28-day exclusion for an inactive vaccine was added 
consistent with the exclusion for a live vaccine. This 
was for simplicity and consistency in approach since 
both an inactive and live vaccine contain viral 
particles as opposed to the subunit vaccine which 
contains viral protein.
Synopsis Exclusion Criterion #21
Section 4.2 Exclusion Criterion #21
NONSUBSTANTIAL (ADMINISTRATIVE) CHANGES
Description of Change
Affected Section(s) in Amended Protocol Version 
4.0
The name of the Clinical Research Contact, Trial 
Manager and the name and role of the Recruitment 
and Enrollment Coordinator were updated to reflect 
current assignments by the study CRO.
Title page
The reference to ICH E6 was updated from “R1” to 
“R2” for consistency with Sections 10.1.6 and 11.2.
Title page
The planned study duration was increased from 1Q to 
3Q 2018 to reflect the increased duration between 
dosing subjects and follow up visits.
Protocol Synopsis, Study Duration
A typographical error regarding duration of study for 
an individual subject in Part B was corrected from “up 
to 99 days” to “up to 91 days” reflecting the 
maximum 28-day screening period and 60 (+3 
days)-day investigational period.  
Protocol Synopsis, Study Design, Duration of Study 
Period
Section 2.1 Overview of Study Design, Duration of 
Study
The typographical error of 0.25 mg/kg was corrected 
to 0.1 mg/kg in the figure legend.
Figure 1 Schematic of Planned Dosing, Part A and 
Part B
Format change to header rows of the respective
Schedules of Procedures for Parts A and B such that 
“Investigational Period” continues through the 
Day 60 visit, consistent with its definition as per the 
Definition of Key Terms. 
Table 1 Schedule of Procedures Part A 
Table 2 Schedule of Procedures Part B 
Residual references to the enrollment of 1 subject in 
the accelerated titration portion of Part A were 
changed to 2 subjects. Residual descriptions of a 1+1 
accelerated titration were updated to 2 + 2 as per 
Amendment 1. 
Section 2.5.3 TIMP-GLIA Maximum 
Recommended Starting Dose
Table 7 Planned Dose Levels and Rationale
Section 4.0 Study Population
Section 7.2 Safety Committee
Section 7.3.4 Dose Reduction
“Prior to study initiation” was removed. Drug will be 
supplied on demand by Cour or its designee prior to 
subject dosing.
Section 6.2.3 Inventory and Accountability
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Description of Change
Affected Section(s) in Amended Protocol Version 
4.0
A clarification was added that the sponsor’s designee 
will “confirm” (rather than assign) the 9-digit unique 
subject ID number when a site has requested 
enrollment of an eligible subject.   The site will follow 
the subject ID numbering convention described in this 
section of the protocol.
Section 6.3 Method of Assigning Subjects to 
Treatment Groups
A cross reference to Section 8.6.1 which contains a
description for when an abnormal laboratory value 
constitutes an AE, was added for clarification.
Section 8.5.6.1 Standard Clinical Laboratory Tests 
for Screening/Safety
Urine testing for drugs of abuse and alcohol was 
separated using a bullet for clarification.
Section 8.5.6.1 Standard Clinical Laboratory Tests 
for Screening/Safety
Addition to Table 9 Clinical Laboratory Tests
C1q binding was listed under “Additional Tests” for 
consistency with the Schedules of Procedures for 
Parts A and B and with Section 8.5.6.4.
Table 9 Clinical Laboratory Tests
A statement was added that a presentation of data by 
dose (mg) administered may be added, if appropriate.
Section 9.5 Safety Analysis
Section 9.5.6 Statistical Analysis of 
Pharmacokinetics
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13.8
Amendment 4: Summary of Changes To Protocol Version 4.0
The final protocol TGLIA-5.001 version 4.0 dated 16 Oct 2017 incorporating Amendment 3 has 
been revised to version 5.0 dated 1 Dec 2017 to include substantantial and nonsubstantial 
(administrative) changes as detailed in the table below. 
NOTE: Amendment 4 was not reviewed by any IRB/IEC and was not implemented at any 
clinical sites.
SUBSTANTIAL CHANGES
Description of Change
Affected Section(s) in Amended Protocol Version 
5.0
Healthy subjects were included as a population in 
which the primary and secondary study objectives 
are being explored.
Synopsis, Primary Objective and Secondary 
Objectives
Section 3.1.1 Primary Objective
Section 3.1.2 Secondary Objectives
The text of the study design description was revised 
to specify inclusion of healthy subjects to the study. 
It was also specified that cohorts from each 
population will proceed through the study at their 
own rate, contingent upon enrollment rate and safety 
reviews by the Safety Committee.  
Cross references to the schematics of planned dosing 
of healthy subjects were added.
Enrollment of 19 healthy subjects in Part A and of 3 
subjects in Part B was specified.  Possibilities for 
healthy subject cohort expansion in the event of DLT 
or to better investigate the relationship between dose 
and emerging safety signals (in the same manner as 
for CD cohorts) were described.
Synopsis, Study Design
Section 2.1 Overview of Study Design, Part A and 
Part B
The procedure for staggering individual healthy 
subject doses by a minimum 48-hour wait period was 
described.
Synopsis, Study Design
Section 2.1 Overview of Study Design, Part A and 
Part B
Section 1.5 Benefit-Risk Assessment
Section 7.3.2 Dosing Subjects Within A Dose Level 
(Within A Cohort)
Clarification was added that decisions regarding 
progression or termination of dosing will be made 
separately for each population (CD or healthy 
subjects) based upon the respective safety data.
Synopsis, Study Design
Section 2.1 Overview of Study Design, Part A
Section 7.3.2 Dosing Subjects Within A Dose Level 
(Within A Cohort)
Clarification that the up to 91-day duration of study 
in Parts A and B pertains to the investigational period 
was added for CD subjects.
Total duration of the study investigational period for 
Synopsis, Duration of Study Period
Section 2.1 Overview of Study Design, Duration of 
Study Period
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Description of Change
Affected Section(s) in Amended Protocol Version 
5.0
Parts A and B for healthy subjects was added.
The rationale for adding healthy subject cohorts was 
added. The rationale for including CD subjects with 
respect to presence of gliadin-specific T-cells was 
refined.
Section 2.4 Rationale for the Subject Population
Enrollment of 22 male and female healthy subjects 
across the clinical sites was added. Clarification that
healthy subjects who withdrew from study prior to 
dosing was added. Redundant text was deleted.
Synopsis, Selection of Study Population
Section 4.0 Study Population
“CD” was added to each criterion in the existing lists 
of inclusion and exclusion criteria to distinguish 
them from the newly added eligibility criteria for 
healthy volunteers. 
Synopsis, Eligibility Criteria, Inclusion Criteria, CD 
Subjects and Exclusion Criteria, CD Subjects
Section 4.1.1 Inclusion Criteria for Subjects With CD
Section 4.2.1 Exclusion Criteria for Subjects With 
CD
Splenectomy was added to CD subject exclusion 
criterion #3
Synopsis, Eligibility Criteria, Exclusion Criteria, CD 
Subjects
Section 4.2.1 Exclusion Criteria for Subjects With 
CD
Separate lists of inclusion and exclusion criteria for 
healthy subjects was added. These were the same as 
the eligibility criteria specified for CD subjects with 
the exception of celiac disease-related requirements.
Synopsis Eligibility Criteria, Inclusion Criteria, 
Healthy Subjects and Exclusion Criteria, Healthy 
Subjects
Section 4.1.2 Inclusion Criteria for Healthy Subjects
Section 4.2.2 Exclusion Criteria for Healthy Subjects
The approximate volume of blood to be collected for 
scheduled testing from screening until the last 
in-clinic procedure was presented for each 
population in context of the study duration. The 
estimated blood draw volumes were slightly adjusted
to 300 mL (formerly ~320 mL) for CD subjects in 
part A and ~500 mL (formerly ~ 445 mL) CD 
subjects in part B.  
Because screening celiac serology and HLA typing is 
not needed, the volume is approximately 11 mL less 
for healthy subjects in either part of the study.
Section 8.8 Total Amount of Blood
A general statement was added at the beginning of 
the section that TLFs and methods will be performed 
for each study population.
Section 9.0 Statistical Methods
The word “patient” was substituted with “subject” to 
make the section more inclusive to both populations 
in the study.
Section 9.4 Subject Disposition
Text describing the potential interim analyses was 
Section 9.7 Interim Analysis
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Description of Change
Affected Section(s) in Amended Protocol Version 
5.0
added (with details to be provided in the SAP). 
NONSUBSTANTIAL (ADMINISTRATIVE) CHANGES
Description of Change
Affected Section(s) in Amended Protocol Version 5.0
“and Healthy Subjects” was added to the protocol 
title.
Title page, protocol approval page, investigator 
agreement page, and synopsis
The telephone number for the Clinical Research 
Contact, Trial Manager was revised.
Title page
A facsimile (“fax”) number was added for SAE 
reporting.
Title page
Section 8.6.6 Collection & Reporting of SAEs
Clarification was added throughout the protocol as 
needed to specify which study procedures refer to 
both/each population(s) (CD and healthy) or which 
study procedures are specifically designated for 
subjects with CD or healthy subjects.
Throughout, including but not limited to:
Synopsis, Study Design
Section 2.1 Overview of Study Design, Part A and 
Part B
Section 1.5 Benefit-Risk Assessment
Section 2.2 Rationale for Tria
Section 2.3 Rationale for Trial Design
Cross references to the Schedules of Procedures, Part 
A or Part B and to the schematics of planned dose 
cohorts were updated to include references to both 
the CD-specific and healthy subject-specific 
versions.
Throughout the document.
Clarification was added that clinic residency and visit 
requirements pertained to healthy subjects as 
specified in the corresponding Schedules of 
Procedures.
Synopsis, Clinic Residency and Visits
Section 2.1 Overview of Study Design, Clinic 
Residency and Visits
7.6.1 Clinic Residency and Clinic Visits
Clarification was added where risks or lack thereof 
pertained to both healthy and CD subjects. A cross 
reference to the Schedules of Procedures for healthy 
subjects was added with that for the CD subjects.
Additional details were provided regarding the 
in-vitro data relevant to the conclusion that 
TIMP-GLIA did not exhibit mitogenicity in PBMCs 
from healthy and CD donors.
Rationale for the expected low risk of immune 
response to the gliadin in TIMP-GLIA and non-acute 
immune complex formation by healthy subjects was 
added.
Section 1.5 Benefit-Risk Assessment
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Affected Section(s) in Amended Protocol Version 5.0
Clarification was added that the Safety Committee 
will monitor emerging safety data from healthy 
subjects and that the decision-making process 
pertains to both healthy volunteer and CD cohorts.
Synopsis, Safety Committee
Section 7.2 Safety Committee
Clarification was added that procedures and 
assessments pertaining to cohort expansion or dose 
stopping refer to both CD and healthy subjects in Part 
A and Part B. Cross references to the schematics for 
planned dosing for healthy subjects was added.
Section 7.3.2 Dosing Subjects Within A Dose Level 
(Within A Cohort)
Clarification was added that the criteria for 
identifying maximum tolerable dose (MTD) applies 
to both CD and healthy subjects. 
Section 7.3.3 Dose Escalation – Dosing Subjects and 
the Next Dose Level
Clarification was added that Safety Committee may 
recommend dosing a CD or healthy cohort at a dose 
level that is lower than planned.
Section 7.3.4 Dose Reduction
Clarification was added that NCI CTCAE Version 
4.0 (Published May 28, 2009 [v4.03: June 14, 2010]) 
or most current version would be used for AE 
grading. 
Synopsis, Study Design
Section 2.1 Overview of Study Design
Section 8.6.3 AE Severity Assessment
Cross reference to Edition 1 of the Investigator’s 
Brochure was expanded to include “subsequent 
editions as they become available.”
1.3 Nonclinical Studies
The potential, in general, for reporting other 
cytokines (not otherwise specified) that might be 
included in the multiplex assay was acknowledged.
Synopsis, Endpoints, Safety and Tolerability
Section 8.5.6.5 Cytokines and Laboratory Tests to 
Follow up Suspected Anaphylaxis/Anaphylactoid 
Reaction
The title of the schematic of planned dosing for celiac 
disease cohorts was updated to include population.
A new schematic was added for healthy subject 
cohorts.
Cross references to these 2 figures were updated.
Figure 1 Schematic of Planned Dosing in Subjects 
With Celiac Disease, Part A and Part B.
Figure 2 Schematic of Planned Dosing in Healthy 
Subjects, Part A and Part B.
The titles of the Schedules of Procedures for celiac 
disease subjects, Parts A and B were updated to 
specify population.
A clarification was added to the last item in the table 
legend that subjects who discontinues prematurely 
during the investigational period (not the follow up 
period) is to undergo final visit procedures. 
A new set of Schedules of Procedures was added for 
healthy subjects in Part A and Part B.
Table 1 Schedule of Procedures For Subjects With 
Celiac Disease, Part A/Part B
Table 2 Schedule of Procedures For Healthy 
Subjects, Part A/B
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Affected Section(s) in Amended Protocol Version 5.0
Clarification was added that the accelerated titration 
design would allow the study to proceed more 
quickly. 
Redundant text describing the Safety Committee 
review of safety data in the context of DLT and study 
stopping rules was deleted.
Clarification was added that Day 60 is part of the 
investigational period applicable to both populations, 
whereas the long-term follow-up by telephone out to 
Day 180 pertains to CD subjects.
Section 2.3 Rationale for the Trial Design
Clarification was added that subjects who 
discontinue participation during the investigational 
period are to be contacted by telephone at least twice 
over 2 weeks.   Similar due diligence is to be applied 
to follow up missed telephone follow up calls.
Section 5.1.1 Handling of Withdrawals
Clarification was added that standardized meals will 
be served to healthy subjects and gluten-free meals 
will be served to CD subjects while they are resident 
in the clinic.
Section 7.6.2 Dietary and Fluid Restrictions
Clarification was added that subjects will be 
distinguished within the data as healthy or CD.
Section 8.1 Demographics and Baseline 
Characteristics
Clarification was added that dietary history will be 
taken only for subjects with celiac disease.
8.3 Diet History (Subjects With Celiac Disease)
Clarification was added that if a subject discloses 
participation in another interventional trial during 
his/her participation in TGLIA-5.001, the 
investigational product should be recorded as a 
concomitant medication.
Prohibition of concomitant medication was specified 
for healthy subjects, exception for contraceptives and 
stable hormone replacement therapy.
8.4 Concomitant Medications
Because CD-related testing is not applicable to 
healthy subjects, a more inclusive/descriptive 
subheading within the Table of Laboratory Tests was 
added, “Anti-Drug and CD-Related Serology”
Table 11 Clinical Laboratory Tests
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13.9
Amendment 5: Summary of Changes To Protocol Version 6.0
The final protocol TGLIA-5.001 version 5.0 dated 1 Dec 2017 incorporating Amendment 4 has 
been revised to version 6.0 dated 9 Feb 2018 to include substantantial and nonsubstantial 
(administrative) changes as detailed in the table below. 
SUBSTANTIAL CHANGES
Description of Change
Affected Section(s) in Amended Protocol Version 
6.0
The healthy subject arm that was intended to run in 
parallel with the celiac disease subject arm (added 
via Amendment 4) has been removed.   The dosing 
schematic, schedules of procedures, number of 
subjects, duration of study for healthy subjects, and 
text pertaining to the eligibility, objectives, and study 
procedures involving healthy subjects have been
deleted.
Minor editorial adjustments were made where 
necessary to accommodate the removal of the 
references to healthy subjects and the procedures 
involving healthy subjects.
Also deleted for readability are references to celiac 
disease subjects or “CD” subjects in the context of 
distinguishing them from healthy subjects.
Tables were renumbered owing to the removal of the 
healthy subject schedules of procedures Tables 3 and 
4.
Throughout document, including 
Synopsis, 
Figure 2 Schematic of Planned Dosing in Healthy 
Subjects, Part A and Part B (deleted), 
Table 3 Schedule of Procedures for Healthy Subjects, 
Part A (deleted), Table 4 Schedule of Procedures for 
Healthy Subjects, Part B (deleted), 
Protocol sections 1.5 Benefit-Risk Assessment, 2.0 
Study Design and Rationale, 3.1.1 Primary 
Objective, 3.1.2 Secondary Objectives, 4.0 Study 
Population, 6.3 Method of Assigning Subjects to 
Treatment Groups, 7.0 Treatment Administration,
7.6.1 Clinic Residency and Clinic Visits, 7.6.2 
Dietary and Fluid Restrictions, 8.1 Demographics, 
8.4 Concomitant Medications, Table 9 footnote (c), 
8.8 Total Amount of Blood, 9.0 Statistical Methods. 
Suspected drug-induced liver injury at least possibly 
related to TIMP-GLIA was added to the 
dose-limiting toxicity (DLT) definition. This brought 
forward the DILI monitoring and reporting 
requirments already present in Appendix 13.1 Liver 
Safety Monitoring and Assessment (Drug Induced 
Liver Injury, DILI).
Synopsis, Dose Limiting Toxicity Definition 
Protocol section 7.3.5 Dose Limiting Toxicity 
Definition
The maximum age for study eligibility was increased 
from 65 to 75 years.
Synopsis Selection of Study Population and 
Inclusion Criterion # 3
Protocol section 4.0 Study Population and Inclusion 
Criterion #3.
Positive HLA DQ2.5 or HLA DQ8.1 was removed as 
an eligibility requirement. Instead this testing will be 
performed for enrolled subject for information only.
Synopsis, Inclusion criterion #5b
Table 1 Schedule of Procedures, Part A and Table 2 
Schedule of Procedures, Part B
Protocol section 4.0 Study Population, Inclusion 
Criterion #5b
For clarification the phrase “and for 30 days after 
Synopsis, Inclusion Criterion #6
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Description of Change
Affected Section(s) in Amended Protocol Version 
6.0
receiving study drug” was removed from inclusion 
criterion #6 pertaining to practice of contraception.  
The criterion correctly specifies that medically 
approved contraception should be used throughout 
the study, and this phrase is unnecessary and 
inconsistent with the study duration.
The investigational period of the study extends to 
Day 60 and the follow-up period to Day 180.
Protocol section 4.0 Study Population, Inclusion 
Criterion #6
The time that celiac symptomology will be 
exclusionary was reduced from within 8 weeks to 
within 10 days of screening.  This is for consistency 
with the timing of no known gluten exposure in 
inclusion criterion #5.
Synopsis, Exclusion Criterion #2
Protocol section 4.0 Study Population, Exclusion 
Criterion #2
The number of days for which changes to 
prescription or nonprescription medication is 
exclusionary was reduced from 60 days to 30 days 
prior to Day 1.
Synopsis, Exclusion Criterion #4
Protocol section 4.0 Study Population, Exclusion 
Criterion #4
For clarification of exclusion criterion #6b, the 
descriptor “immunomodulatory” was deleted from 
“immunomodulatory or immune suppressing 
medical treatment (e.g., azathioprine, 
methotrexate).”  In addition, the relative milestone 
for which this medication is exclusionary was 
changed from the Screening Visit to Day 1 for 
consistency with other medication-related criteria.
For clarification of exclusion criterion #6c, the 
phrase “or on alternative days” with respect to 
prednisone regimen was removed. For consistency 
with the exclusionary period of other immune 
suppressing treatment, the time for which >20 mg 
daily prednisone is exclusionary was reduced from 6 
months to 2 months prior to Day 1. 
Synopsis, Exclusion Criterion #6b and #6c
Protocol section 4.0 Study Population, Exclusion 
Criterion #6b and #6c
For clarification the description of exclusionary 
hypersensitivity was changed to “severe 
hypersensitivity or allergic reaction…”, with 
individual symptoms of hypersensitivity that might 
or might not be severe, deleted from the criterion.
Synopsis, Exclusion Criterion #7
Protocol section 4.0 Study Population, Exclusion 
Criterion #7
The number of days for which acute illness is 
exclusionary was reduced from 28 days to 14 days, 
which allows reasonable time for recovery.
Synopsis, Exclusion Criterion #9
Protocol section 4.0 Study Population, Exclusion 
Criterion #9
Additional blood collections for anti-drug antibody 
IgG (as DGP-IgG) and immune complex detection 
by C1q binding were added: In Part A on Day 3/48 
Table 1 Schedule of Procedures, Part A and Table 2 
Schedule of Procedures, Part B
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Description of Change
Affected Section(s) in Amended Protocol Version 
6.0
hours and Day 7/144 hours post dose; In Part B on 
Day 3 and Day 10/48 hours and Day 7/144 hours post 
dose. In Part B a Day 14 collection is already 
scheduled so a clarification was added that it should 
correspond to 144 hour post (second) dose. This will 
provide values for gliadin antigen level (TIMP-GLIA 
PK), anti-drug antibody, and C1q binding at the 
common timepoints of predose, 48 hours, and 144 
hours after each dose.  
Peripheral blood mononuclear cells will be collected 
at the same timepoints, i.e., predose and post dose 
upon appearance of symptoms of 
anaphylaxis/anaphylactoid reaction/cytokine release 
syndrome or IRR.  However, the PBMCs will be used 
for either the ELISpot (for number of IFN-gamma 
and IL-10-producing T-cells) OR assay for T-cell 
proliferation in response to ex vivo gliadin 
stimulation as most appropriate and informative. If 
sufficient cells remain, the alternative test may be 
performed.  This will halve the blood volume to be 
collected.
Protocol section 8.5.6.5 Cytokines and Laboratory 
Tests to Follow-Up Suspected 
Anaphylaxis/Anaphylactoid Reaction, Whole Blood 
for PBMC Isolation
New data obtained from a non-GLP follow up study 
TGLIA-1.039 conducted after the pivotal GLP study 
was summarized in a new subsection and specific 
findings were added to the table.  The findings are 
supplementary information and did not change the 
conclusions drawn from the prior GLP and non-GLP 
toxicology studies.
In addition, the finding “↓spleen weight” was moved 
within the table from Liver observations to 
Hematopoietic system observations.
Protocol section 1.3.3.3
Table 4 Summary of Nonclinical Observations and 
Clinical Risk Minimization Actions
NONSUBSTANTIAL (ADMINISTRATIVE) CHANGES
Description of Change
Affected Section(s) in Amended Protocol Version 
6.0
Study title was updated to remove reference to 
healthy subjects.
Protocol version and amendment number was 
updated.
Title page, protocol approval page, investigator 
agreement page, and synopsis
The telephone number for the CRO Clinical 
Research Contact, Trial Manager was removed to 
avoid future changes due to personnel changes.
Information will be communicated by a different 
route.  
Medical monitor and sponsor contact remains.
Title page
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Description of Change
Affected Section(s) in Amended Protocol Version 
6.0
24-hour SAE reporting information was replaced with a 
new vendor fax number. On the title page reference is 
made to the SAE “form” rather than “worksheet” for 
consistency with section 8.6.6 Collection and Reporting of 
Serious Adverse Events.
Title page 
Protocol Section 8.6.6 Collection and Reporting of Serious 
Adverse Events
Clarification was added that the Safety Committee may 
include ad hoc members with relevant expertise, such as 
consultant with expertise in immune complex formation 
and serum sickness or with expertise in hepatology.  
Synopsis, Safety Committee
Protocol section 7.2 Safety Committee
For clarification “Predose – 4h” was removed. It was 
intended to denote the duration of constant monitoring but 
was less informative than the table footnote. The 
procedure was not changed.
Table 1 Schedule of Procedures, Part A and Table 2
Schedule of Procedures, Part B
Pulse oximetry row
Minor editorial corrections were made to the table legends 
for clarification or to eliminate redundancy with the table 
information:
Added to footnote #: “upon appearance of symptoms”
Deleted from footnote ††: “at screening and Day 1”
Deleted from footnote ♥: “on Day 1”
Replaced in footnote ^^: “Day 30”by “the AE reporting 
period”
Added to footnote ^^: “through the final follow up”
Legend to Table 1 Schedule of Procedures, Part A and
Legend to Table 2 Schedule of Procedures, Part B
The abbreviation AT for aminotransferase was added.
IV List of Abbreviations
A clarification was added that all subjects who withdraw 
from the study prematurely during the investigational 
period (through Day 60 visit) will undergo all final
in-clinic visit safety assessments as shown in Table 1. 
Schedule of Procedures, Part A and Table 2. Schedule of 
Procedures, Part B and footnote ***.  
Protocol section 5.1.1 Handling of Withdrawals
Acknowledgement that an institutional SOP may be used 
if reviewed and approved by the sponsor was added.  Some 
research institutions have their own policies for inventory 
and accountability
Protocol Section 6.2.3 Inventory and Accountability
“IRR” was added where it was missing from the phrase 
“symptoms of IRR or anaphylaxis/ anaphylactoid 
reaction”
Protocol section 7.3.2 Dosing Subjects Within A Dose 
Level (Within A Cohort)
To remove ambiguity and for consistency with the other 
study stopping rules where it was spelled out, the phrase
“considered to be at least possibly related to TIMP-GLIA” 
was added to a study stopping rule. This does not represent 
a change to the rule, as this was already implied by 
context.  
Synopsis, Study Stopping Rules
Protocol section 7.3.6 Study Stopping Rules
Clarification was added that total volume infused should 
be recorded along with infusion start and stop time.
Protocol section 7.4 Treatment Compliance
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Description of Change
Affected Section(s) in Amended Protocol Version 
6.0
Clarification was added that cases of overdose should be 
reported to the sponsor as a “special situation” and any 
SAEs arising from overdose should be reported according 
to the specified procedures.
Protocol section 7.5 Emergency Procedures and 
Management of Overdose
Within the table of Clinical Laboratory Tests, the 
descriptive subtitle “Additional thrombotic/vascular 
markers” was added for the tests D-dimer, vWG, ICAM-1, 
fibrinogen, prothrombin fragment 1, 2, P-selectin.
Table 9 (was Table 11) Clinical Laboratory Tests
Cross reference to NCI CTCAE Version 4.0 (Published 
May 28, 2009 [v4.03: June 14, 2010]) or most current 
version was added in context of assessment of laboratory 
abnormalities as adverse events.
Section 8.6.1 Treatment Emergent Adverse Events
For emphasis, the description of Hy’s Law or severe 
hepatic function abnormality in the absence of 
another etiology was duplicated from Appendix 13.1 
Liver Safety Monitoring and Assessment (Drug 
Induced Liver Injury, DILI) in the protocol section 
defining SAEs and important medical events.
Protocol section 8.6.2 Serious Adverse Events
DILI case was called out to be reported to the medical 
monitor within 24 hours.
Protocol section 8.6.6 Collection and Reporting of Serious 
Adverse Events
Overdose, medication error, and pregnancy were defined 
as special situations to report to the sponsor.  Note: 
Subsequent level 3 subsections were renumbered owing to 
this addition.
Protocol section 8.6.7 Collection and Reporting of Special 
Situations
Pregnancy outcome “congenital anomaly” description was 
revised for clarification. Reference is made to the SAE 
“form” rather than “worksheet” for consistency with 
section 8.6.6 Collection and Reporting of Serious Adverse 
Events.
Protocol section 8.6.9 (formerly 8.6.8) Pregnancy
For clarification, rationale for 30 minute and 35 minute 
post dose collection is provides and instruction to 
postpone the 35 minute collection to actual end of infusion 
if an infusion interruption >5 minutes occurs.
Protocol section 8.7.1 Blood Collection for PK
Clarification was made within Follow-up Procedures that 
liver abnormality information may  be collected via a 
collective of appropriate CRFs not just one liver 
abnormality CRF (LA-CRF).
Clarification was added that the last section refers to 
subject, not study, discontinuation.
A statement was added that it could be in the subject’s best 
interest to continue enrollment in the study to facilitate the 
additional testing and close medical observation to follow 
up a potential DILI. This is particularly relevant in a study 
with a single dose arm.  Discontinuation of treatment 
would be considered separately from discontinuation from 
study.
Appendix 13.1 Liver Safety Monitoring and Assessment 
(Drug Induced Liver Injury, DILI)
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13.10 Amendment 6: Summary of Changes to Protocol Version 7.0
The overall purpose of the amendment includes the following:

Change to the composition of the Safety Committee to an independent Data Monitoring 
Committee

Addition of the following safety laboratory tests
o
Cytokines via multiplex assay on Days 7 and 14 (Part A) and Days 14 and 21 (Part B)
o
Gliadin-specific T cell proliferation and cytokine secretion on Day 7 (Part A) Days 8 
and 14 (Part B)

Clarification to the cytokines reported as part of the multiplex assay

Corrections to minor typographical errors
Effect on Consent Form: 
For Part B of the study, the telephone visit at Day 21 has been changed to a clinic visit.
In most cases the site informed consent(s) for Parts A and B will NOT require a change because the 
language used to describe the tests above is not specific, nor does the volume of blood drawn over 
the course of the study change significantly.  All sites are instructed to review their consent to 
ensure a change is not required.
Section
Change
Rationale
Throughout the synopsis and main 
body of the protocol.
Safety Committee changed to Data 
Monitoring Committee (DMC).
To create an independent review 
committee to review all safety 
data.
III. Synopsis, Study Design, Data 
Monitoring Committee
7.2 Data Monitoring Committee
Changed composition of DMC to:
An independent DMC will be 
commissioned for this study.  The 
DMC will be comprised of 3 
physicians with expertise in 
immunology and/or vaccines 
clinical trials.  A 4th physcician 
with expertise will serve as an 
advisor to the DMC, but in a 
non-voting capacity.
Clarified role of medical monitor 
and other study team members 
with regard to interaction with 
DMC:  The sponsor medical 
monitor will not be a member of 
the DMC. The sponsor medical 
monitor and other study team 
members will be available to
answer questions of the DMC as 
To ensure independence of DMC
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Section
Change
Rationale
necessary and during Open 
Sessions of the DMC.  The medical 
monitor and other study team 
members will not participate in 
Close Sessions of the DMC.
III. Synopsis, Endpoints, Safety 
and Tolerability
IV. Schedule of Assessments, 
Table 1 and Table 2
3.2.1  3.2.1Safety and Tolerability 
Endpoints
8.5.6.1 Standard Clinical 
Laboratory Tests for 
Screening/Safety - Table 9
8.5.6.5 Cytokines and Laboratory 
Tests to Follow-Up Suspected 
Anaphylaxis/Anaphylactoid 
Reaction
Added pre and post-dose 
peripheral blood gliadin-specific T 
cell proliferation and cytokine 
secretion for subjects enrolled in 
the single dose groups ≥4 mg/kg 
in Part A (Day 7) and the for the 
repeat dose group in Part B (Day 
14).
To determine whether 
TIMP-GLIA activates peripheral 
blood gliadin-specific T cells 
following dosing
III. Synopsis, Endpoints, Safety 
and Tolerability
8.5.6.5 Cytokines and Laboratory 
Tests to Follow-Up Suspected 
Anaphylaxis/Anaphylactoid 
Reaction
Added post-dose serum cytokine 
multiplex assay at Day for Part A 
(Day 7) and Part B (Days 14 and 
21).
To determine whether 
TIMP-GLIA activates serum 
cytokines following dosing
III. Synopsis, Endpoints, Safety 
and Tolerability
8.5.6.1 Standard Clinical 
Laboratory Tests for 
Screening/Safety - Table 9
Clarified complete set of serum 
cytokines assayed in multiplex and 
additional cytokine assays: EGF, 
fractalkine, GM-CSF, GRO α, 
IFNα, IFN-γ, IL-1α, IL-1 β, IL-2, 
IL-2 soluble receptor, IL-4, IL-5, 
IL-6, , IL-8, IL-10, IL-12, IL-13, 
IL-17, IP-10, MIP1α, and MIP1β,  
TNF-α
Clarified minimum serum 
cytokines to be used by DMC for 
dose escalation recommendation: 
IFN-γ, IL-1 β, IL-2, IL-2 soluble 
receptor, IL-4, IL-5, IL-6, IL-8, 
IL-10,  IL-12, IL-13, IL-17, IP-10, 
and TNF-α 
Multiplex assay contained more 
cytokines than originally listed in 
protocol
8.8 Total Amount of Blood
Changed total blood volume in 
Part A is 307 mL and in Part B is 
444 mL over 3 months (screening 
through Day 60).  
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13.11 Amendment 7: Summary of Changes to Protocol Version 8.0
The overall purpose of the amendment includes the following:

Instructions to manage mild to moderate infusion related reactions (IRR)

Change to highest dose from 10 mg/kg to 10 mg/kg or a maximum of 750 mg
Effect on Consent Form: 
The informed consent must be updated to include a change in the rate of infusion from 30 minutes 
to 2 -2.5 hours.  The suggested wording is as follows:
“You will receive your dose by intravenous infusion over 2 or 2 ½ hours.   Your health is being 
monitored continuously during the infusion.  If you begin to develop signs of a reaction the 
infusion will be stopped for at least 5 minutes and the study doctor will determine if it is safe to 
proceed.  If the infusion continues, the flow will be slowed and your dosing will take longer.”
Section
Change
Rationale
III. Synopsis – Test Product; Dose; 
and Mode of Administration
Added: TIMP-GLIA: 0.1 mg/kg, 
0.5 mg/kg, 1 mg/kg; 2 mg/kg; 4 
mg/kg; 8 mg/kg; and 10 mg/kg (up 
to 750 mg), administered by IV 
infusion.
To limit the amount of test product 
used subjects weighing more than 
75 kg.  This is not a safety issue.  
This is a clinical trial material 
inventory issue.
IV. Schedule of Assessments –
Part A
Added:  Predose, every 15 min 
during infusion, 1h, 2h, 4h, 8h, 
12h, 24
To provide additional safety 
monitoring during the infusion
IV. Schedule of Assessments –
Part A
Added: Predose (0hr), 30min, 35 
min (or end of infusion), 1h, 4h, 
12h, 24h
To ensure a sample is obtained at 
the end of the infusion when rate is 
slowed.
IV. Schedule of Assessments –
Part B
Added for both Days 1 and 8:
Predose, every 15 min during 
infusion, 1h, 2h, 4h, 8h, 12h, 24
To provide additional safety 
monitoring during the infusion
IV. Schedule of Assessments –
Part B
Added for both Days 1 and 8: 
Predose (0hr), 30min, 35 min (or 
end of infusion), 1h, 4h, 12h, 24h
To ensure a sample is obtained at 
the end of the infusion when rate is 
slowed.
2.5.3  TIMP-GLIA Maximum 
Recommended Starting Dose –
Table 7. Planned Dose Levels
Added: Level 7 = 10.0 or a 
maximum of 750 mg
To limit the amount of test product 
used subjects weighing more than 
75 kg.  This is not a safety issue.  
This is a clinical trial material 
inventory issue.
7.4.1  Premature Termination of 
An Individual Subject’s Infusion
Added new ¶ 1:
If a subject develops signs and 
symptoms of IRR (dyspnea, 
generalized cutaneous reactions, 
tachypnea, hypoxia, tachycardia, 
To provide for investigator 
instructions and discretion to 
restart the infusion should a subject 
so intial signs or symptoms of an 
IRR.
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Section
Change
Rationale
or if the subject experiences a 
decrease in blood pressure the 
investigator should stop the 
infusion for a minimum of 5 
minutes or until signs and 
symptoms subside.  Depending 
upon the severity of the signs and 
symptoms, and at the investigator 
and subject discretion, the infusion 
may be restarted as follows:
-
Restart the infusion at 25% of 
original rate for 15 minutes
-
If subject tolerates the reduced 
rate, increase to 50% of original 
rate for another 15 minutes, 
then increase to the original rate 
until infusion is complete
7.4.1  Premature Termination of 
An Individual Subject’s Infusion
Modified ¶ 2:
Infusion will be permanently 
discontinued terminated if the 
subject develops clinical signs and 
symptoms of Grade 3 or 4 IRR or 
anaphylaxis/ anaphylactoid
reaction….
To provide more specificity to 
when an infusion must be 
discontinued.
7.4.2  Dosing Subjects Within A 
Dose Level (Within A Cohort) –
Part A
Modified ¶ 2:
Dosing additional subjects in a 
cohort will be stopped if 1 of the 
subjects at a dose level  exhibits a 
dose-limiting toxicity (DLT) or 
should any subjects in the current 
dose cohort or any previously 
dosed subject (in any dose group) 
develop clinical signs and 
symptoms of Grade 3 or 4 IRR or 
anaphylaxis/anaphylactoid 
reaction…
To provide more specificity of 
when an IRR or anaphylaxis/
anaphylactoid reaction results in 
the halting of dosing additional 
subjects within a cohort.
8.5.2  Vital Sign Measurements
Modified ¶ 1:
Vital signs will be measured every 
15 minutes during the infusion 
and as otherwise specified in the 
Schedules of Procedures for Part A 
(Table 1) and Part B (Table 2).  
To provide additional safety 
monitoring during the infusion
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13.12 Amendment 8: Summary of Changes to Protocol Version 9.0
The overall purpose of the amendment includes the following:

Specifying dose to be administered to subjects enrolled into Part B: 8 mg/kg up to a maximum 
of 650 mg

Instructions for escalating rate of dose administration for subjects enrolled into Part B to 
minimize risk of infusion reaction

Add collection of C3a and SC5B-9 complement levels at 15 and 30 minutes during infusion 
and at 24 hours following infusion for subjects enrolled in Part B to monitor for (sub-)clinical 
complement activation

Clarify timing of pharmacokinetic sampling times
Effect on RISKS Section of the Consent Form for Part B: 
The “Risk” Section of the Informed Consent for Part B should be updated as follows:
“TIMP-GLIA has been given as a single infusion to 17 subjects with celiac disease (Part A of this 
study).  At the highest dose tested, approximately 650 mg, 2 of 4 subjects experienced a moderate 
infusion reaction.  For one of the subjects the infusion was stopped and the signs and symptoms 
went away immediately.  For the second subject, the infusion was stopped and the signs and 
symptoms went away immediately, and the infusion was restarted at a slower rate.  The subject 
completed the infusion without any other problems.
Signs and symptoms of an infusion reaction to TIMP-GLIA include flushing (warm feeling or
reddening of face, back and/or chest), rash, nausea, vomiting, back pain, low or high blood 
pressure, or increase in heart rate.  These symptoms were mostly mild to moderate.  All symptoms 
started within 2 minutes of the infusion starting and went away very quickly when the infusion was 
stopped or interrupted.
During studies in animals, some animals developed abnormalities in laboratory tests or in their 
tissues when TIMP-GLIA was given at doses higher than what is planned for this research study. 
Based on these animal studies it is is possible that TIMP-GLIA could cause an increase in the time 
it takes for your blood to coagulate, which may cause bleeding, or abnormal liver function tests. 
This could indicate that your liver may be harmed by TIMP-GLIA. Your blood tests may show 
that you have decreases in the numbers of white blood cells, platelets, and red blood cells and 
increases in the number of cells that turn into red blood cells ("reticulocytes"). This could indicate 
that your spleen and bone marrow may be harmed by TIMP-GLIA.
Since the TIMP-GLIA contains a gliadin extract, there is a possibility that you may experience 
worsening of your celiac disease symptoms (nausea, vomiting, bloating, diarrhea, abdominal pain, 
fatigue) after receiving the study medicine. TIMP-GLIA is designed to present gliadin in a 
noninflammatory way, but individual responses may vary.
All medications have a risk of an allergic reaction. Seek immediate medical help if you have any of 
the following signs of a serious allergic reaction: swelling of the face, mouth, lips, gums, tongue, 
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or neck. Other allergic reactions may include rash, hives, or blisters. Tell your study doctor as soon 
as possible if any of these reactions happen.
There may be other side effects of TIMP-GLIA that we don’t know about.  Tell your study doctor 
or study staff as soon as possible about all side effects that you have. If you are not honest about 
your side effects, it may not be safe for you to stay in the study.”
Section
Change
Rationale
III. Synopsis – Exclusion Criteria 
#12
Changed:
12.The subject has a positive test 
result for drugs of abuse 
(amphetamines, barbiturates, 
benzodiazepines, cocaine 
metabolites, opiates, cannabinoids, 
methylenedioxymethamphetamine
) or alcohol in urine – except when 
the positive result arises from 
treatment under supervision of a 
medical doctor -  at Screening 
Visit or at Check-in.
Because medical cannabinoids are 
legal in many states and in this setting 
it would not be considered a drug of 
abuse – the intent of the exclusion 
criteria
III. Synopsis – Test Product; Dose; 
and Mode of Administration
Changed: 
Part A: TIMP-GLIA: 0.1 mg/kg, 
0.5 mg/kg, 1 mg/kg; 2 mg/kg; 4 
mg/kg; and 8 mg/kg; and 10 
mg/kg (up to 750 mg), 
administered by IV infusion.
Part B: TIMP-GLIA: 8 mg/kg 
up to a maximum of 650 mg, 
administered by IV infusion.
To specify the dose to be 
administered in Part B
III. Synopsis – Endpoints: Safety 
and Tolerability, ¶1
Added:
Safety will be characterized by 
…immune complex detection by 
C1q binding and by C3a and 
SC5B-9 (Part B only);…
To obtain complement levels 
during and after infusion to 
monitor for (sub-)clinical 
complement activation
IV. SCHEDULES OF 
ASSESSMENTS – Table 2. 
Schedule of Procedures, Part B
Added:
Collection of C3a and SC5B-9 at 
15 and 30 minutes during each 
infusion and 24 hours after each 
infusion 
To monitor for (sub-)clinical 
complement activation
IV. SCHEDULES OF 
ASSESSMENTS – Table 2. 
Schedule of Procedures, Part B
Changed:
Predose (0hr), 30min, 35min (or 
end of infusion), 1h, end of 
infusion, 4h, 12h, 24h after each 
infusion
To reflect new dose rate
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1.5  Benefit-Risk Assessment, ¶3 
and 4
Added:
At the time of this amended 
protocol (Version 9), 
TIMP-GLIA has been given as a 
single infusion to 17 subjects 
with celiac disease (Part A of this 
study).  At the highest dose 
tested, approximately 650 mg, 2 
of 4 subjects experienced a 
moderate IRR.  For one of the 
subjects the infusion was 
stopped and the signs and 
symptoms went away 
immediately.  For the second 
subject, the infusion was stopped 
and the signs and symptoms 
went away immediately, and the 
infusion was restarted at a 
slower rate.  The subject 
completed the infusion without 
any other problems.
Signs and symptoms of IRR to 
TIMP-GLIA have included 
flushing (warm feeling or 
reddening of face, back and/or
chest), rash, nausea, vomiting, 
back pain, low or high blood 
pressure, or increase in heart 
rate.  These symptoms were 
either mild or moderate.  All 
symptoms started within 2 
minutes of the infusion starting 
and went away very quickly 
when the infusion was stopped 
or interrupted.
To update risks based on results 
from Part A
2.5.3 TIMP-GLIA Maximum 
Recommended Starting Dose, 
Table 7 - Planned Dose Levels and 
Rationale
Added:
Part A, Level 7; = 10.0 or a 
maximum of 750 mg - Not 
administered; 
 
Changed:
Part B To be determined 8 mg/kg 
up to a maximum of 650 mg
CCI
Property of Takeda: For no
A Maxim
Maxi
d Starting
Startin
non-commercial use only and subject to the applicable Terms of Use
out 
ut 
ubj
of IRR to
f IRR
nd
ncluded
clude
a
feeling o
eeling 
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face, bac
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on
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, low 
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3.2.1 Safety and Tolerability 
Endpoints, ¶1 
Added:
Safety will be characterized by… 
immune complex detection by C1q 
binding and by C3a and SC5B-9
(Part B only), routine clinical 
laboratory….
To monitor for (sub-)clinical 
complement activation
4.2 – Exclusion Criteria #12
Changed:
12.The subject has a positive test 
result for drugs of abuse 
(amphetamines, barbiturates, 
benzodiazepines, cocaine 
metabolites, opiates, cannabinoids,
methylenedioxymethamphetamine 
) or alcohol in urine – except when
the positive result arises from
treatment under supervision of a
medical doctor - at Screening 
Visit or at Check-in.
Because medical cannabinoids are 
legal in many states and in this 
setting it would not be considered a 
drug of abuse – the intent of the 
exclusion criteria
7.1  Dose and Regimen, ¶7
Added:
For Part B, TIMP-GLIA should 
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
To minimize risk of infusion 
reaction
8.5.6.1  Standard Clinical 
Laboratory Tests for 
Screening/Safety – Table 9
Added footnote d for when 
additional complement markers 
will be obtained
Clarification 
8.5.6.5  C3a and SC5B-9 
Complement Levels
Added new section
For Part B, C3a and SC5B-9 
complement levels will be 
obtained during the infusion and 
24 hours following the infusion 
(refer to Table 2. Schedule of 
Procedures, Part B).
To monitor for (sub-)clinical 
complement activation
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8.7.1 Blood Collection for PK, ¶2, 
3, 4 
Deleted:
Scheduled blood collections for 
TIMP-GLIA measurement for 
pharmacokinetics are to occur at 
30 minutes and at 35 minutes 
relative to start of infusion. The 
former represents the planned 
end-of-infusion collection. 
Because the clearance from the 
blood compartment is expected to 
be rapid, the latter blood collection 
facilitates the characterization of 
Tmax, even in the event of a brief 
unforseen procedural delays.
In the event that the study drug 
infusion is interrupted (particularly 
> 5 minutes), the scheduled 
collection at 35 minutes post 
infusion start time should be 
postponed until the actual 
end-of-infusion. This should be 
documented in a similar manner as 
any other blood collection falling 
outside the defined window.
The 30-minute collection should 
proceed relative to the infusion 
start time, with corresponding 
documentation that it does not 
represent the end-of-infusion. In 
addition, the volume of study drug 
administered at 30 minutes (as 
indicated by the infusion pump or 
estimated, as feasible) is to be 
recorded in the source.
To avoid confusion and refer back 
to Schedule of Assessments 
8.8 Total Amount of Blood
Changed:
The approximate total blood 
volume taken per CD subject in 
Part A is 307mL and in Part B is 
444 462 mL over 3 months 
(screening through Day 60).
Updated to reflect additional 
samples for complement levels 
Appendix 13.3 Windows For PK 
Blood Sample Collection
Changed: 
Post dose Part A 
≤ 35 minutes 
Added: 
Post dose Part B – end of 
infusion - ± 6 minutes 
Clarify when 35 minute or end of 
infusion timepoint should be 
obtained
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13.13 Amendment 9: Summary of Changes to Protocol Version 10.0
The overall purpose of the amendment includes the following:

Expand Part B to include evaluation of 2 and 4 mg/kg dose levels in 2 subjects for each cohort, 
in addition to 2 subjects at the 8 mg/kg (up to a maximum of 650 mg) dose level

Incorporate a 2+2 accelerated dose escalation model, in the event of a DLT in 1 subject in a 
cohort.
Effect on the Consent Form for Part B: 

Six to 12 subjects will be enrolled into Part B

Part B will evaluate 3 dose levels of TIMP-GLIA: 2, 4, and 8 mg/kg up to a maximum of 650 
mg.  Two subjects will be enrolled into each dose group, beginning with 2 mg/kg.

A safety committee will review the safety data when both subjects in a dose group have 
completed Study Day 3.  If the committee thinks it is safe, the next group of 2 subjects will 
receive the next higher dose (e.g., 4 mg/kg).
Section
Change
Rationale
III. Synopsis – Study Design, Part 
B and 2.1 Overview of Study 
Design, Part B
Changed: 
Part B
At this point, the study will enter 
Part B.  Eligible subjects (at least 3 
CD subjects) will receive the 
maximum safe and tolerable dose 
of TIMP-GLIA identified from 
Part A.  TIMP-GLIA will be 
administered as a single IV 
infusion, 7 days apart, on Day 1 
and on Day 8. Each subject in Part 
B will be observed in clinic for 48 
hours after each dose. 
At least 168 hours (7 days) will 
elapse after the second dose and 
safety confirmed before the next 
subject will be dosed.  If 
dose-limiting toxicity occurs in 1 
of the 3 subjects in Part B, the 
DMC may decide to increase 
enrollment by 3 subjects or to 
enroll another cohort of 3 subjects 
at a lower dose level. The DMC 
may recommend that up to a total 
of 12 subjects may be accrued to 
better define the relationship 
between dose and emerging safety 
signals.
Per FDA request to start at lower 
dose (2 mg/kg)
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Section
Change
Rationale
Part B
Part B will evaluate 2 doses of 
TIMP-GLIA administered on 
Days 1 and 8.  Two subjects will 
be enrolled into each of 3 cohorts 
at dose levels of 2, 4, and 8 mg/kg 
up to a maximum of 650 mg. Dose 
escalation will proceed only if 
Study Stopping Criteria (“Study 
Stopping Rules”) are not met. If 
dose-limiting toxicity (DLT) 
occurs in 1 of the 2 subjects in a 
cohort, the DMC may decide to 
increase enrollment at the same 
dose level by 2 subjects. (2+2 
design).
III. Synopsis – Study Design, Data 
Monitoring Committee, ¶4, bullet 
2 and 7.3 Data Monitoring 
Committee (Dose Levels ≥ 2 
mg/kg), ¶3, bullet 2
Changed:
-
Expand the dose cohort to 4 
subjects (accelerated titration 
2+2, Part A and Part B) or to 6 
subjects (standard 3+3, Part A 
and Part B)
Per FDA request
III. Synopsis – Study Design, Data 
Monitoring Committee, ¶5 and 7.3
Data Monitoring Committee (Dose 
Levels ≥ 2 mg/kg), ¶5
Changed:
Additionally, the DMC will 
continue to monitor emerging 
safety data in Part B and may meet 
ad hoc to determine if it remains 
acceptable to continue dosing.
For consistency with change to Part 
B
III. Synopsis – Selection of Study 
Population , ¶1 and 4 Study 
Population, ¶1
Changed:
At least 22 23 male and female 
subjects 18 to 75 years of age 
with….
Per FDA request
III. Synopsis – Test Product; Dose; 
and Mode of Administration, Part 
B
Added:
2, 4, and 8 mg/kg up to a 
maximum of 650 mg, 
administered by IV infusion.
Per FDA request
IV. Schedules of Assessments, 
Table 2 - Schedule of Procedures, 
Part B
Added:
C3a, C5a, and SC5B-9 
complement level
C5a will be collected as part of the 
panel for complement – no 
additional blood required
1.5 Benefit-Risk Assessment, ¶1, 
Bullet 6
Changed:
-
Part A of the FIH safety study
protocol TGLIA-5.001 uses a 
staggered dosing strategy 
across sites….  
To differentiate from Part B
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Section
Change
Rationale
1.5 Benefit-Risk Assessment, ¶1, 
Bullet 7
Added:
-
For Part B, subjects within a 
cohort may be enrolled/dosed 
concurrently.
To differentiate from Part A
1.5 Benefit-Risk Assessment, ¶1, 
Bullet 8
Changed:
-
…..  However, if 1 of the 
subjects at a dose level exhibits 
a dose-limiting toxicity, an
additional cohort subject(s) 
will be dosed in a staggered 
manner at the same level to 
clarify ambiguous safety 
findings.
Corrected to reflect the actual 
addition of subject for toxicity.
1.5 Benefit-Risk Assessment, ¶1, 
Bullet 9
Changed/Added:
-
In Part A, when all subjects in 
a dose cohort complete 
procedures through 168 hours 
post dose, the overall safety 
and tolerability data (AEs, vital 
signs, 12-lead ECGs, clinical 
laboratory tests, cytokines) for 
the current cohort and available 
cumulative AE data from 
previous cohorts will be 
reviewed by the DMC who will 
determine the progression or 
termination of dosing. In Part 
B, the DMC will review all 
safety date from a cohort 
when the last subject in a 
cohort has completed 
procedures through 48 
hours.
Part A remains the same.
The 2 infusion reactions observed 
in Part A at 8 mg/kg occurred 
within minutes of the start of the 
infusion.  Symptoms for both 
subjects resolved within an hour 
(maximum) of stopping the 
infusion.  Forty-eight hours is a 
sufficient waiting period to observe 
an infusion reaction and its 
resolution.
1.5 Benefit-Risk Assessment, ¶1, 
Bullet 10
Deleted
Redundant to bullet 9
2.3 Rationale for the Trial Design, 
¶1
Changed and Added:
…. In Part A, an accelerated 
titration (2+2) model will be 
followed at the lowest doses 
followed by the standard 3+3 
model at higher doses. (See also 
Figure 1. Schematic of Planned 
Dosing in Subjects With Celiac 
Disease, Part A and Part B  and 
further description in Section 2.1, 
Overview of Study Design.) In 
For clarity and FDA request
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Section
Change
Rationale
Part B, an accelerated titration 
(2+2) model will be followed.
2.3Rationale for the Trial Design, 
¶2
Changed and Added:
This In Part A, this design model
will allow the study proceed more
quickly through the lowest doses 
at which little or no effect is 
anticipated to be observed….    In 
Part B, the accelerated model 
allows the study to proceed at 
the lower doses at which little or 
no affect is expected.
For clarity and at FDA request
2.3Rationale for the Trial Design, 
¶5
Changed:
Part B will be a repeat-dose study 
with 3 2 subjects who will receive 
the first infusion on Day 1 and the 
second infusion on Day 8. The 
dose selection for Part B will be 
based on the emerging safety and 
tolerability data from Part A as 
decided by the DMC. If a 
dose-limiting toxicity occurs in 1 
of the 3 2 subjects in Part B, the 
DMC may decide to enroll an 
additional 3 2 subjects at the same 
dose to confirm ambiguous safety 
or tolerability findings. Depending 
upon the emerging safety data, 
they may also recommend 
enrollment of an additional cohort 
of 3 subjects at a lower dose to 
discern the safety profile of repeat 
dosing….
To reflect FDA request for design 
change to Part B
2.5.3 TIMP-GLIA Maximum 
Recommended Starting Dose, 
Table 7
Added/Changed:
Accelerated Titration 2 + 2
Levels 1 – 3; 2, 4, and 8 mg/kg up 
to a maximum of 650 mg
Safe & tolerable dose identified 
from Part A Maximum dose 
found to be safe and tolerable in 
Part A
To reflect FDA request for design 
change to Part B
7.4.2 Dosing Subjects Within A 
Dose Level (Within A Cohort), 
Part B
Changed:
During Part B (repeat dose), 1 
subjects will receive 2 doses 
followed by in-clinic observation 
for at least 48 hours after each 
To reflect FDA request for design 
change to Part B.
The 2 infusion reactions observed 
in Part A at 8 mg/kg occurred 
within minutes of the start of the 
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Section
Change
Rationale
dose. At least 168 48 hours (7 2
days) will elapse after the second 
dose and safety confirmed before 
the subjects in next subject higher 
dose cohort in Part B can be dosed. 
If dose-limiting toxicity occurs in 
1 of the 3 2 subjects in Part B, the 
DMC may decide to increase 
enrollment at the same dose level 
by 3 2 subjects (n=6 4) or to enroll 
another cohort of 3 subjects at a 
lower dose level. The DMC may 
recommend that up to a total of 12 
subjects in a cohort may be 
accrued to better define the 
relationship between dose and 
emerging safety signals.
infusion.  Symptoms for both 
subjects resolved within an hour 
(maximum) of stopping the 
infusion.  Forty-eight hours is a 
sufficient waiting period to observe 
an infusion reaction and its 
resolution.
7.4.4 Dose Reduction
Changed:
Depending upon emerging safety 
data, the DMC may recommend 
dosing a cohort of 2 subjects 
(accelerated titration 2 + 2, Part A 
and Part B) or 3 subjects 
(standard 3+3, Part A and Part B) 
at a dose lower than the planned 
level to better identify the 
maximum tolerable dose of 
TIMP-GLIA.
For clarity
8.5.6 Laboratory Assessments, 
footnote d to Table 9
Added:
d) For Part B, collect sample for 
C3a, C5a, and SC5B-9 
complement levels at 15 and 30 
minutes during infusion and at 24 
hours following infusion.
C5a will be collected as part of the 
panel for complement – no 
additional blood required
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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A PHASE 1, FIRST-IN-HUMAN, 2-PART, MULTICENTER DOSE ESCALATION AND 
REPEAT DOSE STUDY OF THE SAFETY, TOLERABILITY AND PHARMACOKINETICS 
OF TIMP-GLIA IN SUBJECTS WITH CELIAC DISEASE
NCT Number: NCT03486990
SAP Approve Date: October 9, 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
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.
Please note that the statistical output shells have been removed for brevity, since they are not a 
requirement of the statistical analysis plan.


Statistical A nal ysis Pla n 
Versi o n 2. 0 
C O U R P har mace uticals De vel o p me nt C o m pa n y Pr ot oc ol T G LI A- 5. 0 0 1 
Oct o ber 9, 2 0 1 8 
S T A TI S TI C A L A N D P H A R M A C O KI N E TI C A N A L Y SI S P L A N 
( S A P) 
Pr ot oc ol N u m ber:  
T G LI A -5. 0 0 1  
Pr ot oc ol Title:  
A P hase I, First -i n-H u ma n, 2 -Part, M ultice nter D ose 
Escalati o n a n d Re peat D ose St u d y of t he Safet y, 
T olera bilit y a n d P har mac o ki netics of TI M P -G LI A i n 
S u bj ects wit h Celiac Disease  ( versi o n 1 0. 1, Se pte m ber 
1 3, 2 0 1 8)  
Pr o d uct Na me or N u m ber:  
TI M P -G LI A  
S p o ns or:  
C O U R P har mace utical s De vel o p me nt C o m pa n y, I nc.  
2 2 1 5 Sa n ders R oa d  
N ort h br o o k, I L 6 0 0 6 2  
U S A  
S A P Pre pare d b y : 
S A P Versi o n N u m ber ( Date):  
Versi o n 2. 0  (Oct o ber 9, 2 0 1 8 ) 
Pa ge 1 of 1 7 5
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci a 
nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
P P D


Statistical Analysis Plan 
Version 2.0 
COUR Pharmaceuticals Development Company Protocol TGLIA-5.01 
October 9, 2018 
2 
TABLE OF CONTENTS 
1 
LI
ST OF ABREVIATIONS AND DEFINITIONS OF TERMS .4 
2 
S TUDY OVERVIEW .6 
3 
S TUDY OBJECTIVES .8 
4 
GE
NERAL METHODS.8 
4.1 
Ana
lysis Populations .8 
4.2 
S umarization of Data .8 
4.3 
S ample Size Justification and Randomization .8 
4.4 
S tatistical Output Production and Validation .8 
5 
S UBJECT DISPOSITION .9 
6 
DE
MOGRAPHIC AND BASELINE CHARACTERISTICS .9 
7 
P ROTOCOL DEVIATIONS .9 
8 
MED
ICAL AND SURGICAL HISTORY .9 
9 
P HYSICAL EXAM .9 
10 
P RIOR AND CONCOMITANT MEDICATION .10 
1 
DRUG
 EXPOSURE.10 
12 
S AFETY ANALYSES.10 
12.1
 
Adverse Events .10 
12.2
 
Laboratory Tests (Hematology, Serum Chemistry, Coagulation and Urinalysis) .10 
12.3
 
Vital Signs and Pulse Oximetry .1 
12.4
 
Electrocardiograms .1 
12.5
 
Electrocardiogram Telemetry .1 
12.6
 
Serum Cytokines .12 
12.7
 
Celiac Serology, Anti-Drug Antibody and Imune Complexes .
12
 
12.8 
Mast Cel Activation, Complement Activation and Suplementary 
Vascular/Thrombotic Asesment .12 
12.9
 
Gliadin-Specific T Cel Proliferation and Cytokine Release (PBMC) .13
 
13 
P HARMACOKINETIC ANALYSES .13 
13.1
 
General Methods .
13
 
13.2 
PK Parameters and Definitions .15
 
13.3 
Sumary Statistics .
16
 
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COUR Pharmaceuticals Development Company Protocol TGLIA-5.01 
October 9, 2018 
3 
14
 
SUBJECT LISTINGS .16 
15 
DA
TA MONITORING COMITE .16 
16 
I NTERIM ANALYSES .16 
17 
F INAL SIGN-OF FOR COUR PHARMACEUTICALS DEVELOPMENT 
COMPANY, PROTOCOL TGLIA-5.01 STATISTICAL ANALYSIS PLAN.17 
18 
R EVISIONS TO STATISTICAL ANALYSIS PLAN .18 
19 
AP
ENDIX .19 
19.1
 
Conventions for Statistical Tables and Subject Listings .19 
19.2
 
Table of Contents for Mockups of Statistical Tables .21 
18.3
 
Table of Contents for Mockups of Subject Listings .96 
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October 9, 2018 
4 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Definition 
AE
 
adverse event
 
ANOVA
 
Analysis of Variance
 
AUC
 
Area 
under the plasma concentration versus time curve
 
AUC
0 - last
 
Area under the concentration time curve from zero (pre
- dose) to time of 
last measurable concentration
 
AUC
0 - t  
Area under the concentration time curve from zero (pre
- dose) to time t
 
AUC
0 - tau  
Area 
under the concentration
- time curve from time zero to tau (dosing 
interval)
 
AUC
0 - inf  
Area under the concentration time curve from zero (pre
- dose) 
extrapolated to infinite time
 
%AUC
extrap
 
Percent of AUC extrapolated to infinity
 
BMI
 
body mas index
 
C  
Celsius
 
CI
 
Confidence interval
 
C
last
 
Concentration of study drug coresponding to the time of the last 
measurable concentration
 
C
max
 
Peak concentration observed
 
CD 
Celiac disease
 
CL
 
Total body clearance
 
C
last
 
Last 
measurable
 drug concentration
 
CRU
 
DMC
 
Clinical Research Unit
 
Data Monitoring Comite
 
ECG
 
electrocardiogram
 
FIH
 
first
- in - human
 
GFD
 
Gluten
- fre diet
 
Ln 
Natural logarithm
 
MedDRA
 
Medical Dictionary for Regulatory Activities
 
n, N
 
number
 
PK
 
pharmacokinetic(s)
 
PT
 
prefered term
 
MRT
 
Mean residence time
 
R
ac
 
Acumulation index
 
SAE
 
serious adverse event
 
SAP
 
statistical analysis plan
 
SD
 
standard deviation
 
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October 9, 2018 
5 
Abbreviation or Term 
Definition 
SOC
 
system organ clas
 
SOP
 
standard operating procedure
 
TEAE
 
Treatment
- emergent adverse event
 
TIMP
- GLIA
 
Tolerogenic Imune 
Modifying Particles
- Gliadin
 
TLFs
 
Tables, listings and figures
 
T
last
 
Time of last measurable concentration
 
T
max
 
Time to peak concentration, observed
 
λz
Terminal phase elimination rate constant
 
t 1/2
 
Terminal phase half
- life
 
V
s  
Volume of distribution
 
WHODRUG
 
World Health Organization Drug Dictionary
 
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Statistical Analysis Plan 
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COUR Pharmaceuticals Development Company Protocol TGLIA-5.01 
October 9, 2018 
 
6 
2 
STUDY OVERVIEW 
This study 
wa
s a Phase 1, first-
in -human (FIH), 2-part, multicenter study to ases the safety, 
tolerability and pharmacokinetics (PK) of TIMP-GLIA in subjects with celiac disease (
CD
) . 
Part A included an acelerated titration 2 + 2 and traditional 3 + 3 design with rapid dose 
e scalation during which sucesive cohorts of subjects received a single dose of TIMP-GLIA. 
P art B folowed
 as a repeat dose design using 3 cohorts at dose levels of 2, 4 and 8 mg/kg up to a 
maximum of 650 mg. 
C onsenting subjects were screned within 28 days (Day -28 to -1) prior to admision to the 
c linical research unit (CRU) on Day -1 for baseline asesments. 
Table 1: Planned Dose Levels and Rationale 
 
Part A 
Single Dose 
mg/kg 
Rationale 
Acelerated Titration 
2+2
 
Level 1
 
= 0.1
 
10x below NOAEL
 
10x below PAD for initial 
pharmacologic activity
 
Level 2
 
= 0.5
 
20x below NOAEL
 
Standard 3+3
 
Level 3
 
= 1.0
 
10x below NOAEL
 
Level 4
 
= 2.0
 
2x escalation
 
Level 5
 
= 4.0
 
2x 
escalation
 
Level 6
 
= 8.0
 
2x escalation
 
Level 7
*  
= 10.0
 
At PAD for complete inhibition 
of DTH
 
 
Part B 
Repeat dose mg/kg 
Acelerated Titration 
2+2
 
Level 1
 
Level 2
 
2 mg/kg
 
4 mg/kg
 
 
Level 3
 
8 mg/kg to a 
maximum of 650 
mg
 
Maximum dose found to be safe 
and tolerable in Part 
A .  
DTH=delayed type hypersensitivity; PAD = pharmacologic active dose; NOAEL = no observed efect level. 
*Due to adverse reactions in the 8 mg/kg dose group, patients were not dosed at the 10 mg/kg level. 
Part A 
In Part A, eligible subjects (at least 19 subjects) were enroled into escalating dose cohorts 
( n = 2/cohort for 2 dose levels folowed by n = 3/cohort for 5 dose levels). TIMP-GLIA was 
a dministered as a single IV infusion on Day 1. A stagered dosing strategy was 
used in Part A. 
One
 subject in a cohort was 
dosed at a time and underwent 
medical observation in the clinic for 
at least 48 hours post-infusion. 
At lea
st 168 hours (7 days) elapsed
 prior to dosing the next subject. Adverse events (A
Es
) , vital 
signs, pulse oximetry, electrocardiograms (ECGs) and laboratory data (serum chemistry, 
c oagulation, hematology and urinalysis, cytokines) from samples obtained through at least 24 
hours postdose 
were asesed before dosing the subsequent subject(s). 
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October 9, 2018 
7 
AEs were graded acording to National Cancer Institute Comon Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0 (Published: May 28, 209 [v4.03: June 14, 2010]) or most 
c urent version. If safety and tolerability were confirmed by the investigator, TIMP-GLIA was 
a dministered to the next subject. 
Dose Escalation, Part A 
After al the subjects in a dose cohort completed al study procedures through at least 168 hours 
(7
 days) postdose, the safety data was reviewed by the Safety Comite. Dose escalation 
proc
ed
ed
 only if Study 
Stopping Criteria (“Study Stopping Rules”) were not met. If dose-
limiting toxicity (DLT) ocured in 1 of the subjects in the cohort, the Safety Comite could 
have decided to increase enrolment at the same dose level by 2 subjects (acelerated titration 
c ohort) or by 3 subjects (standard 3+3). After a rate of DLTs had ben identified for a specific 
dose
 in 3- or 6-subject-cohorts, the Safety Comite could have recomend
ed
 that up to a total 
of 12
 subjects should be acrued at any dose level to beter define the relationship betwen dose 
a nd emerging safety signals. It was also posible that the Safety Comite could have 
re comend
ed
 an intermediate dose (leser escalation) or reduced dose level (dose reduction) if 
wa
ranted by the emerging safety data. Before continuing to Part B, available safety data for al 
subj
ects in Part A through at least 168 hours (7 days) after dosing was evaluated by the Safety 
Comite. 
Part B 
Part B evaluated 2 doses of TIMP-GLIA administered on Days 1 and 8. Two subjects were 
enroled into each of 3 cohorts at dose levels of 2, 4 and 8 mg/kg up to a maximum of 650 mg. 
Dose escalation could proced only if Study Stoping Criteria were not met. If dose limiting 
toxicity (DLT) ocured in 1 of the 2 subjects in a cohort, the Data Monitoring Comite 
( DMC) had the option to decide to increase enrolment at the same dose level by 2 subjects (2+2 
de
sign). 
Clinic Residency and Visits 
Subjects from 
both parts of the study remain
ed
 in the 
CRU
 from admision (Part A: Day -1; Part 
B:
 Day -1 and Day 7) through the final post-dose procedure at 48 hours (Part A: Day 3; Part B: 
Da
y 3 and Day 10) and were thereafter discharged if safety parameters were aceptable to the 
investi
gator. Subjects return
ed
 to the CRU 
for folow-up asesments or were 
contacted by 
telephone as shown in the 
Schedules of Procedures for each part of study. 
Duration of Study 
Part A: Total duration of the study investigational period was 
up to 91 days (screning up to 28 
days + 1 treatment day + folow-up at Day 60 +/- 3 days). In adition, telephone folow-up by a 
he
alth care practitioner was required after the Day 60 outpatient visit (i.e., Day 90, Day 120, 
Da
y 180, al +/- 3 days). 
P art B: Total duration of the study investigational period was 
up to 91 days (screning up to 28 
days + 2 treatment days, 7 days apart + folow-up at 60 +/- 3 days after last dose). In adition, 
tele
phone folow-up by a health care practitioner was required after the Day 60 outpatient visit 
(i.e
., Day 90, Day 120, Day 180, al +/- 3 days). 
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Statistical A nal ysis Pla n 
Versi o n 2. 0 
C O U R P har mace uticals De vel o p me nt C o m pa n y Pr ot oc ol T G LI A- 5. 0 0 1 
Oct o ber 9, 2 0 1 8 
 
8 
3  
S T U D Y O B J E C TI V E S 
T he pri mar y o bje cti ve w as t o assess t he safet y a n d t olera bilit y of TI M P- G LI A w he n 
a d mi nistere d I V as a si n gle d ose at asce n di n g d ose le vels a n d as a re pe at d ose i n s u bjects wit h 
C D . 
T he  sec o n d ar y o bjecti ves we re: 
 T o c haracteriz e t he P K of TI M P- G LI A base d u p o n c o nce ntr ati o ns of TI M P- G LI A i n 
plas ma o ver ti me i n s u bjects wit h C D. 
 T o e sta blis h a safe a n d t olera ble d ose t h at ma y be teste d d uri n g a f ut ure P hase 2 pr o of- of-
c o nce pt st u d y i n s u bjects wit h C D.  
4  
G E N E R A L M E T H O D S  
4. 1  
A n al ysis P o p ul ati o ns 
S afet y P o p ul ati o n : T he safet y p o p ulati o n was defi ne d as all s u bjects w h o si g n t he st u d y-s pecific 
i nf orme d c o nse nt d oc u m e nts a n d recei ve d at least o ne d ose of st u d y me dicati o n.  
P h ar m a c o ki netic P o p ul ati o n : T he P K c o nce ntrati o n p o p ulati o n was defi n e d as all s u bjects w h o 
recei v e d at least o ne d ose of st u d y dr u g (a n d ti me of d osi n g is k n o w n) a n d ha d at least 1 dr u g 
co nce ntr ati o n meas ure m e nt.  T he P K para meter p o p ulati o n was defi ne d as all s u bjects w h o 
recei v e d at least o ne d ose of st u d y dr u g a n d ha d at least 1 P K para met er re p orte d.   
In cl usi o n of s u bjects i n t he P K a nal ysis datasets ( P K A D) wit h missi n g dat a or pr ot oc ol 
de viati o ns was c o nsi dere d b y t he p h ar mac o ki n eticist o n a case- b y -cas e basis. 
4. 2  
S u m m ariz ati o n of D at a 
St u d y res ults were s u m marize d b y Part A a n d Part B a n d b y tr eat me nt ( d ose) gr o u p u nless 
ot her wise s pec ifie d.   
N o i m p utati o n of missi n g dat a was perf or m e d.  N o wi n d o wi n g of visits was perf or me d u nl ess 
ot her wise s pecifie d. 
4. 3  
S a m ple Size J ustific ati o n a n d R a n d o miz ati o n  
N o sa m ple siz e calc ulati o n was perf or me d.  T h e sa m ple siz e was base d u p o n prece d e nt set b y 
ot her  cli nical st u dies of si milar nat ure a n d is c o nsi dere d s ufficie nt t o ac hi e v e t he st u d y 
o bjecti ves. 
4. 4  
St atistic al O ut p ut Pr o d ucti o n a n d V ali d ati o n 
All statistical a nal yses w ere perf or m e d usi n g S A S V 9. 3 or hi g h er ( S A S I nstit ute, I nc, Car y, 
N or t h Car oli na, U S A).  Vali dati o n a n d q ualit y c o ntr ol of t he ta bles a n d listi n gs, w hic h dis pla y 
t he res ults of t he statistical a nal ysis of t he data fr o m t his st u d y, f oll o w e d t he a p pr o pri ate 
sta n dar d o perati n g pr oce d ures ( S O Ps). 
Pa ge 8 of 1 7 5
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
C CI


Statistical Analysis Plan 
Version 2.0 
COUR Pharmaceuticals Development Company Protocol TGLIA-5.01 
October 9, 2018 
 
9 
5 
SUBJECT DISPOSITION 
The number of subjects who were treated, completed the study, and discontinued study drug 
pre
maturely were sumarized in tabular format for the safety population and displayed in a 
subj
ect listing. The number of subjects who were in the safety population, who completed the 
stud
y, and who discontinued from the study, along with reason of study discontinuation, were 
sum
arized in t
abular format by Part, treatment group, and overal for al enroled subjects. In 
adition, the number of subjects in the PK concentration population and in the PK plasma 
parameter population were sumarized by part, treatment group, and overal. Subject 
dispo
sition information was displayed for the safety population in a subject listing. 
6 
D EMOGRAPHIC AND BASELINE CHARACTERISTICS 
For quantitative variables (e.g., 
age, height, weight, body mas index [BMI]), 
disease duration 
(years), and gluten fre diet duration (months), sumary statistics (number [n], mean, standard 
deviation [SD], minimum, median, and maximum) were presented for the safety population. For 
the q
ualitative variables (e.g., sex, race, ethnicity, and HLA type), results were sumarized as 
c ounts and percentages for the safety population. Individual demographic information for the 
safety population were displayed in subject listings. 
F or the folowing variables: HLA-DQ2 Qual, HLA-DQ8 Qual, HLA-DQA1 High Res. Alel-1, 
H LA-DQA1 High Res. Alel-2, HLA-DQB1 High Res. Alel-1, HLA-DQB1 High Res. Alel-2, 
we
re displayed in a subject listing. 
Celiac disease history, date of biopsy/diagnosis and treatment were displayed in a subject listing. 
7 
P ROTOCOL DEVIATIONS 
Al protocol deviations were presented in a subject listing. 
8 
M
EDICAL AND SURGICAL HISTORY 
Medical and surgical history items were coded using the Medical Dictionary for Regulatory 
Ac
tivities (MedDRA) co
ding
 system (version 20.1).
 The 
number and percent of subjects with 
past and curent medical disorders were presented overal by SOC and prefered term, and 
finding
s we
re 
displayed in a subject listing. 
9 
PHYSICAL EXAM 
A complete physical examination (PE) was 
done at Screning 
for both Part A and Part B.
 
Abreviated PEs were colected on Days -1, 3, 7, 14, 30, and 60 for Part A of the study. 
S imilarly, abreviated PEs were colected on Days -1, 3, 7, 10, 14, 38, and 60 for Part B of the 
stud
y. Any clinicaly significant findings were recorded on the adverse event forms. Al findings 
we
re displayed in subject listings. 
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COUR Pharmaceuticals Development Company Protocol TGLIA-5.01 
October 9, 2018 
 
10 
10  
PRIOR AND CONCOMITANT MEDICATION 
Sumaries of the concomitant medications were done by Anatomical Therapeutic Chemical 
(ATC) Clas and Prefered Name using the World Health Organization (WHO) dictionary 
(version WHO Mar2017 Enhanced). The sumaries present
ed
 the number and percentage of 
subj
ects using each medication. Subjects who reported
 more than one medication within the 
sa
me ATC clas or within the same prefered term were counted only once within each level. 
The
 subject listing included al prior and concomitant medications. 
1
 
D RUG EXPOSURE 
For Part A, subjects received an intravenous infusion on Day 1. For Part B, subjects received an 
intravenous infusion on Days 1 and 8. 
Sumary statistics of the total dose received (mg) were presented. 
Al findings were displayed in subject listings. 
12  
SAFETY ANALYSES 
 
12.1
 
Adverse Events 
Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
c oding system (version 20.1).
 An overal sumary table was 
presented by treatment group that 
sum
arized al treatment-emergent adverse events, al serious treatment-emergent adverse 
e vents, al drug-related adverse events, al study drug discontinuations due to adverse events, 
number
 of deaths, and al severe treatment-emergent adverse events for the safety population. In 
adition, for the safety population, frequency tables were 
presented by treatment group, System 
Organ Clas (SOC) and prefered term for al treatment-emergent adverse events, for al 
tre
atment-emergent adverse events by severity, and for al treatment-emergent adverse events by 
c ausality. The frequency tables were ordered by SOC. Subject listings of al adverse events were 
a lso be provided. 
Subjects who had more than 1 of the same adverse event were counted only once for that event. 
S ubjects who had more than one adverse event within a System Organ Clas were counted only 
once in that System Organ Clas. 
Al 
adverse events 
were 
listed by treatment group
, subject, and 
timing of event. 
 
12.2
 Laboratory Tests (Hematology, Serum Chemistry, Coagulation and 
Urinalysis) 
Safety laboratory tests were colected at Screning, Day -1, Days 2, 3, 7, 14, 30, and 60 for Part 
A. 
For Part B, safety laboratory tests were colected at Screning, Day -1, Days 2, 3, 7, 9, 10, 14, 
38, and 60. 
F or hematology,
 serum chemistry, and coagulation quantitative tests, sumary statistics (n, 
mea
n, SD, minimum, median, and maximum) were presented for the observed values at each 
ti me point for the safety population. Sumary statistics were also presented for the change from 
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October 9, 2018 
1 
baseline values to each postbaseline time point. In these displays, baseline was 
defined as the 
sample colected prior to the first dose of study medication. 
Al l
aboratory results, including urinalysis and screning laboratory results (e.g., drug and 
a lcohol tests, HIV and hepatitis B and C serology), were displayed in subject listings, with those 
va
lues faling outside the laboratory reference range flaged. Laboratory reference ranges were 
provided by the laboratory site(s) and were included in an apendix of the clinical study report. 
1 2.3
 
Vital Signs and Pulse Oximetry 
For Part A, vital signs were colected 
at Screning, Day -1, Day 1 at hours 1, 2, 4, 8, and 12, and 
Days 2, 3, 7, 14, 30, and 60. For Part B, vital signs were colected at Screning, Day -1, Day 1 at 
hours 1, 2, 4, 8, a
nd 12, and Days 2, 3, 7 at hours 1, 2, 4, 8, and 12, and Days 10, 14, 38 and 60. 
P ulse oximetry measurements were colected on Day 1 at predose and hours 1, 2, 4, 8, 12, and 24 
for Part A and then for Part B, pulse oximetry measurements were colected on Days 1 and 8 at 
predose and hours 1, 2, 4, 8, 12, and 24. 
Sumary statistics (n, mean, SD, minimum, median, and maximum) were presented for the 
observed values for systolic and diastolic blod presure, pulse, oral temperature and pulse 
oximetry
 at each time point by treatment group for the safety population. Sumary statistics 
we
re also presented for the change from baseline values to each post baseline time point. In 
these
 displays, baseline was defined as the values that are obtained imediately predose to each 
treatment. 
Al vi
tal signs and pulse oximetry results were displayed in subject listings. 
1 2.4
 
Electrocardiograms 
For Part A, 12-lead ECGs were colected in triplicate at Screning and Day -1. Single ECGs are 
colected on Day 1 at the folowing times: predose, 1, 4, 12, 24, and 48 hours postdose. Folow 
up ECGs 
on Days 7, 14, 30 and 60 are only colected if a prior ECG was abnormal and clinicaly 
sig
nificant. 
For Part B, 12-lead ECGs were colected in triplicate at Screning and Day -1. Single ECGs were 
c olected on Day 1 and Day 8 at the folowing times: predose, 1, 4, 12, 24, and 48 hours 
post
dose. Folow up ECGs on Days 14, 38, and 60 were only colected if a prior ECG was 
a bnormal and clinicaly significant. 
Sumary statistics (n, mean, SD, minimum, median, and maximum) were presented for the 
observed values for heart rate, R, PR, QRS, QT and QTcF at each time point by treatment 
group for the safety population. Sumary statistics were also presented for the change from 
baseline values to each postbaseline time point. In these displays, baseline was defined as the 
va
lues that are obtained imediately pre-dose on Day 1. 
Al data wil be listed in subject listings, including abnormal ECG results. 
12.5
 
Electrocardiogram Telemetry 
For Part A, continuous, real-time cardiac monitoring was 
utilized starting aproximately 1 hour 
prior to the start of study drug infusion through 8 hours post dose. This ocured on both Days 1 
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12 
and 8 for Part B. Start and end date/time of the telemetry was documented within the source and 
any findings were apropriately characterized as normal, abnormal not clinicaly significant or 
a bnormal clinicaly significant. These data were al presented in subject listings. 
1 2.6
 
Serum Cytokines 
For Part A, cytokines were colected on Day 1 at predose, 8 hours, 24 hours, Days 7 and 14, and 
a t aditional time points if clinicaly indicated. Similarly, for Part B, cytokines were colected on 
Da
ys 1 and 8 at predose, 8 hours, 24 hours, Days 14 and 21, and at aditional time points if 
clinicaly indicated. 
Cytokines colected include: EGF, GM-CSF, GRO 
α, fractalkine, INF- α, INF- γ, IL-2, IL-2 
Receptor Soluble, IL-6, IL-
1α, IL- 1β, IL-4, IL-5, IL-8, IL-10, 
IL
- 12, IL-13, IL-17, IP-
10, MIP1α,
MIP1β, TNF- α. 
Sumary statistics (n, mean, SD, minimum, median, and maximum) were presented for the 
observed values b
y treatment group for the safety population. Sumary statistics were also 
pre
sented for the change from baseline values to each post baseline time point. In these displays, 
baseline was defined as the values that are obtained Day 1 predose. 
Al 
cytokine results were displayed in subject listings. 
1 2.7
 
Celiac Serology, Anti-Drug Antibody and Imune Complex
es
 
For Parts A and B, IgA and Tisue Transglutaminase Specific IgA Ab (tTG) were al colected at 
Screnin
g and at post dose upon apearance of celiac disease-related symptoms. 
De
aminated Gliadin Peptide Ab (DGP) IgG was colected at Screning, Day 1 predose, 48 hours, 
Days 7, 14, 30 and 60 for Part A and at Screning, Day 1 predose, 48 hours, Day 7, Day 8 
predose, Days 10, 14, 38 and 60 for Part B. 
Imune complex endpoint C1q Binding Asay w
as
 colected on Day 1 at predose, 48 hours, 
Days 7, 14, 30 and 60 for Part A. For Part B, this imune complex endpoint was colected Day 
1 a
t predose, 48 hours, Day 7, Day 8 at predose, and at Days 10, 14, 38 and 60. 
I mune complex C3a, C5a and SC5B-9 were colected for subjects enroled into Part B at pre-
dose
, 15 and 30 minutes, and 24 hours post-dose. 
S umary statistics (n, mean, SD, minimum, median, and maximum) were presented for C1q 
Binding Asay, DGP IgG, C3a, C5a and SC5B-9 for the observed values by treatment group for 
the sa
fety population. Sumary statistics were also presented for the change from baseline 
va
lues to each post baseline time point. In these displays, baseline was defined as the values that 
a re obtained Day 1 predose. 
Al endpoints were displayed in a subject listing. 
1 2.8
 
Mast Cel Activation
, Complement Activation and Suplementary 
V ascular/Thrombotic Asesment 
Symptoms of anaphylaxis/anaphylactoid response were folowed up with aditional laboratory 
testing for mast cel activation (Tryptase), complement activation (C3a, C5a, CH50, C5-9) and 
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COUR Pharmaceuticals Development Company Protocol TGLIA-5.01 
October 9, 2018 
13 
for vascular/thrombotic markers (D-dimer, vWF, ICAM-1, Fibrinogen, Prothrombin Fragment 
1,2 and P-selectin). Predose samples were obtained from al subjects, with aditional post dose 
sampled taken from symptomatic subjects as neded if clinicaly indicated by the apearance of 
symptoms. 
Al results were presented in a subject listing. 
1 2.9
 
Gliadin-Specific T Cel Proliferation and Cytokine Release (PBMC) 
For Part A, Gliadin-specific T Cel Proliferation and Cytokine Release parameters were colected 
at predose and Day 7 (4 and 8 mg/kg only), aditional testing could be done, as neded. 
S imilarly, for Part B, the parameters were colected at predose for both Days 1 and 8, Day 14, 
and as neded. 
The parameters include T cel Proliferation Index, IFN-
γ, IL- 1β, TNF- α, IL-2, IL-4, IL-5, IL-6, 
IL
-10 and IL-13. 
S umary statistics (n, mean, SD, minimum, median, and maximum) were presented for the 
observed values at each time point for the safety population. Sumary statistics were also 
pre
sented for the change from baseline values to each postbaseline time point. In these displays, 
baseline was defined as the sample colected prior to the first dose of study medication. 
Al par
ameters were displayed in a subject listing. 
13  
P HARMACOKINETIC ANALYSES 
Plasma drug concentrations and actual sampling times were used for the estimation of PK 
parameters of TIMP-GLIA folowing a single dose of TIMP-GLIA during Part A and 2 doses of 
T IMP-GLIA during part B. Parameters were estimated using noncompartmental methods as 
im
plemented in Phoenix WinNonlin, version 7.0. 
Blod samples were colected at the folowing scheduled times relative to the start of each 
infusion:
 
Part A, Day 1: predose, 30 min, 35 min, and 1, 4, 12, 24, 48, and 14 hours. 
Part B, Day 1 and Day 7: predose, 30 min, end of infusion, and 1, 4, 12, 24, 48, and 14 hours. 
13.1
 
General Methods 
The folowing methods were utilized for analysis of PK data: 

T he exact time of sample colection was 
used for 
PK
 calculations and for individual
subject graphs;

The scheduled time of sample colection was used in sumary statistics for concentration
re sults and in mean graphs;

Predose sampling times was 
set to a time value of zero;

Mising predose concentrations and values below the limit of quantitation (BLQ) before
the first quantifiable conc
entration were 
set to a concentration value of zero for the PK
a nalyse
s (and for sumary statistics). Mising postdose values or BLQ values after the
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Statistical Analysis Plan 
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COUR Pharmaceuticals Development Company Protocol TGLIA-5.01 
October 9, 2018 
14 
first quantifiable concentration were treated as mising for the PK analysis (and sumary 
statis
tics); 

C oncentration-dependent PK parameters were reported in the same units as the asay
results;

La
mbda z (
z ) was estimated if a given subject has > 2 concentration values in the
ter
minal portion of the curve and was reported if r
2  (godnes of fit) >0.80;

C
max
 was excluded from al 
z  estimations;

The
 values included in the regresion analyses was determined by WinNonlin and was
re viewed by the pharmacokineticist;

No value for λz,  AUC
0 -inf,
 %AUC
extrap
, AUC
0-tau 
(if extrapolation 
is required
),  V
s  (if based
on extrapolated value for AUC), CL (if based on extrapolated value for AUC), or t
½  wil
be reported for cases where a valid estimate of λz  is not obtained
;

No va
lue for AUC
0-inf
,  CL
, or V
s  wil be reported when %AUC
e xtrap
 exceds 20%, and
%
AUC
ex
trap
 wil be reported in the listings only; the same condition aplies to AUC
0 -tau
,
and AUC
0-t
au -dependent parameters.

A concentration-time profile was considered inadequately characterized, and therefore
e xcluded from the concentration and/or PK parameter datasets, if thre or more
c onsecutive blod samples had mising values, if C
max
 could not be acurately
determined, or if there were les than 3 quantifiable concentrations in the profile.
The
 folowing guidelines aply to the calculation of sumary statistics for plasma concentrations 
and PK parameters: 

For concentrations, individual subject data for the time point must have ben colected
within ±10% of the scheduled pr
otocol time.

For time points after the first quantifiable concentration, at least two-thirds of the
individual subject data
 for the time point must have ben quantifiable measurements. If
fe wer than two-thirds of the subjects had quantifiable measurements at a given time
point, the sumary statistics were reported as not calculated.

F or a given PK parameter, at least two-thirds of subjects must have had estimable values;
otherwise, desc
riptive statistics for the given parameter was reported as not calculated.
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Statistical Analysis Plan 
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COUR Pharmaceuticals Development Company Protocol TGLIA-5.01 
October 9, 2018 
15 
13.2
 
PK Parameters and Definitions 
TIMP-GLIA PK parameters wil be derived from the plasma concentration-time profiles for each 
tre
atment for Part A and Part B, unles noted otherwise, as outlined in the table below. 
PK 
Parameter 
Definition 
Calculation Method 
C
max
maximum drug concentration 
observed
 
T
max
 
time of maximum drug concentration
 
observed
 
C
last
 
last measurable drug concentration
 
observed
 
T
last
 
time of last measurable drug concentration
 
observed
 
AUC
0 - last
 
area under the concentration
- time curve 
from 
time zero to time of the last measurable 
concentration (Part A and Part B)
 
linear
- log trapezoidal rule
 
AUC
0 - t  
area under the concentration
- time curve 
from time zero to time t (Part A only)
 
linear
- log trapezoidal rule
 
AUC
0 - tau
 
area under the 
concentration
- time curve 
from time zero to tau (dosing interval) (Part 
B only)
 
linear
- log trapezoidal rule
 
AUC
0 - inf
 
area under the concentration
- time curve 
from time zero extrapolated to infinite time 
(posibly aplicable to Part A and/or first 
dose for P
art B depending on t ½)
 
AUC
0 - last
 + (C
last
/ z ) where
 C
last
 is the last 
measurable (non
- zero) concentration and 
z  is the terminal elimination rate
constant
%AUC
extrap
 
percent of AUC extrapolated to infinity
 
[AUC
0 - inf  – AUC0
- last
]/AUC
0 - inf  x 10%
 
z
terminal elimination rate constant 
the negative of the slope from linear 
regresion of the natural logarithm 
concentration
- time curve during the 
terminal phase 
 
t½
 
terminal elimination half
- life 
Ln (2) /
z  
CL
 
total body clearance
 
Dose/AUC
0 - inf 
or
 Dos
e/AUC
0 - tau
 
V
s  
steady
- state volume of distribution
 
Dose/AUC
0 - inf 
x MRT or Dose/AUC
0 - tau  
x MRT
 
R
ac
 
acumulation index (Part B)
 
AUC
0 - inf  Dose 2/ AUC
0 - inf  Dose, or
 
AUC
0 - tau  Dose 2/ AUC
0 - tau 
Dose 1
 
C
max
/D
 
maximum drug concentration corected for 
dose (Part
 A)
 
C
max
/dose
 
AUC
0 - last
/D
 
area under the concentration
- time curve 
from zero (pre
- dose) to the last measurable 
concentration, corected for dose
 (Part A)
 
AUC
0 - last
/dose
 
AUC
0 - inf /D
 
area under the concentration
- time curve 
from zero (pre
- dose) extrapolated 
to infinite 
time, corected for dose
 (Part A)
 
AUC
0 - inf /dose
 
MRT = mean residence time; tau = dosing interval. 
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Statistical Analysis Plan 
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COUR Pharmaceuticals Development Company Protocol TGLIA-5.01 
October 9, 2018 
16 
single-dose MRT = (AUMC
0-inf 
/ A
UC
0-inf
) – infusion duration/2; 
steady-state MRT = {[AUMC
0-tau + 
tau
 (AUC
0 -inf 
-AUC
0-tau
) ]/AUC
0 -tau
} – infusion duration/2.
 
13.3
 
Sumary Statistics 
Sumary statistics (n, arithmetic mean, 
SD
, percent coeficient of variation [%CV], minimum, 
median, and maximum) were presented for TIMP-GLIA concentrations through 14 hours after 
dosi
ng of TIMP-GLIA for the PK population. In adition, sumary statistics (n, arithmetic 
mea
n, SD
, CV, minimum, median, maximum, geometric mean [converting back to the original 
units], and %CV for the geometric mean) were presented for the pharmacokinetic parameters for 
e ach trea
tment. Al PK data were displayed in subject listings
. 
14  
SU
BJECT LISTINGS 
Data that were colected and entered into the study database but that are not displayed in the 
sum
ary tables specified in the preceding sections were presented in subject listings. These 
include
 (but are not be limited to) data from the folowing modules: 

Dosing Information

Protocol Deviations

Prior Medications

Ur
inalysis

Telemetry

Drugs of Abuse

Hepatitis and HIV Serology
15  
DATA MON
ITORING COMITE 
A n independent DMC was commissioned for this study for dose levels ≥ 2 mg/kg.  The DMC
was comprised of 3 physicians with expertise in imunology and/or vacines clinical trials. A 
4 th  physician with expertise in celiac disease served as an advisor to the DMC, but in a non-
voti
ng capacity. 
The DMC reviewed tables and listings with the folowing data: adverse events, safety laboratory 
tests, cytokines and imunology. 
16  
INTERIM ANALYSES 
No statistical interim analyse
s were 
planed. 
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St atistical A nal ysis Pla n
V ersi o n 2. 0
C O U R P har mace uticals De vel o p me nt C o m pa n y Pr ot oc ol T G LI A- 5. 0 0 1 
Oct o ber 9, 2 0 1 8 
 
1 7 
 
 
Dat e 
 
 
Dat e 
 
 
Dat e 
Pa ge 1 7 of 1 7 5
Pr o p ert y of T a k e d a: F or n o n- c
e ct t o t h e a p pli c a bl e T er m s of U s e
P P D


Statistical Analysis Plan 
Version 2.0 
COUR Pharmaceuticals Development Company Protocol TGLIA-5.01 
October 9, 2018 
 
18 
18  
REVISIONS TO STATISTICAL ANALYSIS PLAN 
Date
 
Revision
 
Statistician’s Signature 
October 9, 2018
 
Update SAP to match Protocol version 
10.1, adition of 2 cohorts in Part B
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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