A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of AMG 714 in Adult Patients With Celiac Disease
Phase: PHASE2
Conditions: Celiac Disease
Sponsor: Amgen

CLINICAL STUDY PROTOCOL 
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Efficacy and Safety of AMG 714 in Adult Patients with Ccliac Disease 
Protocol Number: 
CELTM-N RC0-001 
Version No: 
3 
Protocol Date: 
29 August 2016 
EudraCT Number: 
2015-003647-l 9 
lnvestigational Product: 
AMG 714 
Phase: 
Phase 2a 
Sponsor: 
Celimmune. LLC 
850 I River Rock Terrace. 
Bethesda, MO 208 17. US/\ 
This document contains confidential information. This information cannot be used for any 
pw11ose other than evaluation or conduct of the cli11ica/ investigation. The recipienT agrees 
!hat no i1?for111atio11 contained in this protocol will be published or disclosed withow the 
prior wrillen approval of Ce/immune. LLC. Study stafj7associates and lnstitwional Revie11· 
Boards/ Ethics Commillees may have access to this informatinn on a co1?ftdential basis as 
may be necessary 10 conduct this clinical s/u((\'. 
Protocol Version J 
(J<>-AUG-20 16) 
CELIM-NRCD-00 I 
Page I of 110 
Confidential 
NCT Number: 02637141
This NCT number has been applied to the document 
for purposes of posting on clinicaltrials.gov

SPONSOR APPROVAL 
PROTOCOL NUMBER: 
CELIM-NRCD-001 
PROTOCOL VERSION: 
3 
PROTOCOL DATE: 
29Aug2016 
PROTOCOL TITLE: 
A Phase 2a. Randomized, Double-Blind. Placcbo-Conlrolled. 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
AMG 714 in Adult Patiems with Celiac Disease 
I. on behalf of Celimmune. LLC. approve this protocol and agree to comply with all 
requirements regarding the obligations of the Sponsor and all other pertinent requirements of 
the International Conference on Harmonization (ICH), Guidance on Good Clinical Practice 
(GCP). the Declaration or Helsinki. and applicable laws ::md regulations. 
 MD. PhD 
CEO & Chief Medical Officer 
Celimmune. LLC 
Protocol Version 3 
(29-A G-2016) 
CELIM·NRCD-001 
August 291h. 20 16 
Date 
Page 2 of 110 
Confidential 
PPD
PPD

COORDINATING TNVESTlGA TOR APPROVAL 
PROTOCOL NUMBER: 
CELIM-NRCD-00 I 
PROTOCOL VERSION: 
3 
PROTOCOL DATE: 
29 August 2016 
PROTOCOL TITLE: 
A Phase 2a. Randomized, Double-Blind. Placebo-Controlled. 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
AMG 714 in Adult Patients with Celiac Disease 
I certify that I have reviewed and approve this protocol and agree to comply with all 
requirements regarding the obligations of the Sponsor and all other pertinent requirements of 
the International Conference on Harmonization (!CH). Guidance on Good Clinical Practice 
(GCP). the Declaration of Helsinki. and applicable laws and regulations. 
. MD, PhD 
University of Tampere 
School of Medicine 
Protocol Version 3 
(29-A UG-2016) 
CELIM-NRCD-00 I 
Date 
Page3 of110 
Confidt:ntial 
PPD

INVESTIGATOR AGREEMENT 
PROTOCOL NUMBER: 
CELIM-NRCD-001 
PROTOCOL VERSION: 
3 
PROTOCOL DATE: 
29 August 20 16 
PROTOCOL TITLE: 
A Phase 2a. Randomized. Double-Blind. Placebo-Controlled. 
Parallel-Group Study to Evalunte the Efficacy and Safety of 
AMG 714 in Adult Patients with Celiac Disease 
By signing below. I certif)r that I have read and understand the protocol. I agree to personally 
conduct or supervise the described investigation. in accordance with Good Clinical Practice (GCP) 
requirements. the International Conference on Harmonization (ICll) guidelines, the Declaration of 
Helsinki, and any applicable laws and regulations. 
I agree not to implement any changes to the protocol without prior agreement from Celimmune. 
LLC or its appropriate agents and prior review/written approval from the lRB/Ethics Committee 
or equivalent. except as would be necessary to eliminate an immediate hazard to study s u~j ee t(s ). 
I will ensure that all person assisting me with the study are qualified to do so and are adequately 
informed about the investigational product(s) and of their study-related duties as described in the 
protocol. 
I agree to complctel) infonn all subjects in thi study concerning the pertinent details and purpose 
of the study prior to their agreement to participate in the study in accordance with GCP and 
regulatory authority requirements. 
I agree I am responsible for maintaining each subject's consent form in the study file and providing 
each subject with a signed copy of the consent form. 
I certify that J will allow access to files for audit or in pection purposes by Celimmune. LLC. its 
agents. or competent regulatory authorities. 
I agree to the content of this protocol and tht: confidential nature of the documentation associated 
with this study. 
Signature of Investigator 
Printed Name 
Protocol Version 3 
(29-AUG·:Wl6) 
CELIM-NRCD-001 
Date 
Page 4of1 10 
Confidential 

ST UD Y PERSONNEL CONTACT INFORMATION 
Sponsor: 
Medical Monitor: 
SAE Reporting: 
Contract Research 
Organizations: 
Protocol Version J 
(29-A G-2016) 
CELI M-NRCD-00 I 
Celimmunc, LLC 
Address: 850 I River Rock Terrace. Bethesda. MO 208 17, USA 
Phone: + I 30 I 798 4988 
Fax: + I 301 798 4988 
, MD, PhD 
Chief Med ical Officer 
Celimmune LLC 
Address: 850 I River Rock Terrace. Belhesda. MD 208 17. USA 
Chiltern International 
Email : CilohalSJ\Elnbn:-. a chiltcrn.t.:um 
See SAE reporting section of the study protocol for 
instructions regarding SAE reporting. 
Clinical Monitoring 
Crown CRO 
Rcpresenlalive: 
Address: Vaisalantie 4 Fl-02130. Espoo. Finland 
Data Management 
Statf inn. Oy 
Representative: 
Address: MUUrivahe 22. I 0140 Tallinn. Estonia 
Email: 
Biostatistics 
StatFinn, Oy 
Representative: -
Address: Kitsas 8; 51003 Tartu Estonia 
Email: 
Page 5 of 110 
Conlidential 
PPD
PPD
PPD
PPD
PPD

ADA 
ADME 
AE 
ANCOVA 
Anti-tTG 
APC 
AUCU-t 
13hCG 
BP 
BSFS 
CD 
CFR 
CcD-GSRS 
CeD-PRO 
cGCP 
CL/F 
Cma.' 
CRf 
CRP 
C1roul!h 
DH 
DGP 
DSMB 
ECG 
EDC 
eCRr 
ePRO 
FDA 
FOCBP 
FSH 
GERO 
GFD 
eGFR 
GI 
GIP 
g 
GSRS 
lib 
HbAIC 
Hep B 
Heo C 
HE ENT 
HIV 
Pro1ocol Version 3 
(29-A UG-20 16) 
CELIM-NRCD-001 
LIST OF ABBREVIATIONS 
Anti-drug antibodies 
Absorption, distribution. metabolism. and excretion 
Adverse event 
Analysis of covariance 
Anti-tissue transglutam inase 
Antigen presenting cells 
Area under concentration time curve 
Beta human chorionic gonadotropin 
Blood pressure 
Bristol Stool Form Scale 
Cluster of Differentiation 
United States Code of Federal Regulation 
Celiac Disease - Gastrointestinal Symptom Rating Scale 
Ccliac Disease - Patient-Reported Outcome 
Current Good Clinical Practice 
Apparent clearance 
Maximum observed concentration 
Case report form 
C Reactive Protein 
Trough concentration 
Dermatitis herpetifonnis 
Deamidated gliadin peptide 
Data Safety Monitoring Board 
Electrocardiogram 
Electronic Data Capture system 
Electronic case report form 
Electronic patient reported outcome 
Food and Drug Administration 
Females of child bearing potential 
Follicle stimulating hormone 
Gastroesophageal reflux disease 
Gluten-free diet 
Estimated glomerular filtration rate 
Gastrointestinal 
Gluten immunogenic peptide 
Gram 
Gastrointestinal Symptom Rating Scale 
Hemoglobin 
Glvcosvlated hemoglobin 
Hepatitis B 
Hepatitis C 
I lead. eyes, ears, nose, throat 
Human Immunodeficiency Virus 
Page 6 of 110 
Conliden1ial 

HLA 
ICF 
ICH 
IEC 
lELs 
lNR 
IRB 
IIT 
IUD 
IV 
kDa 
kg 
MedDRA 
mg 
ml 
MMRM 
NK 
NYHA 
PD 
PGA 
PK 
pp 
POC 
PT 
RBC 
RCD 
RCD-l 
RCD-11 
SAE 
SAP 
soc 
SUSAR 
TEAE 
TE SAE 
t 12 z 
TB 
TK 
lmax 
tTG 
VH:CD 
Vz/F 
WBC 
WHO 
Protocol Version 3 
(29-AUG-2016) 
CELIM- RCD-00 I 
Human leukocyte antigen 
In formed consent form 
International Conference on Harmonization 
Independent ethics committee 
lntraepithelial lvmohocvtes 
International normalized ratio 
Institutional Review Board 
Intent to treat 
Intrauterine device 
Intravenous 
Kilodalton 
Kilogram 
Medical dictionary for regu latory activities 
Milligram 
Milliliter 
Mixed effects repeated measures model 
Natural killer 
New York Heart Association 
Phannacodynamics 
Physician Global Assessment of Disease 
Phannacokinetics 
Per protocol 
Proof of concept 
Preferred Term 
Red Blood Cell 
Refractory ccliac disease 
Type I refractory celiac disease 
Tvoe 2 refractory celiac disease 
Serious adverse event 
Statistical analysis plan 
Svstem Organ Class 
Suspected unexpected serious adverse reaction 
Treatment emergent adverse event 
Treatment emergent serious adverse events 
Terminal half-life 
Tuberculosis 
Toxicokinetics 
Time to maximum concentration 
Tissue transglutaminase 
Vil lous height to crypt depth ratio 
Volumes of distribution at elimination phase 
White Blood Cell 
World Health Organization 
Page 7of110 
Conlidcntial 

T ITLE 
INTENDED 
INDICATION 
ST UDY 
OBJECTIVES 
STUDY 
ENDPOINTS 
Protocol Version 3 
(29-AUG-2016) 
CELIM-1 RCD-001 
PROTOCOL SYNOPSIS 
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallcl-
G r·oup Study to Evaluate the Efficacy and Safety of AMC 714 in Ad ult 
Patients with Celiac Disease 
AMG 714 is a human anti-!L-1 5 monoclonaJ antibody indicated for the 
trealment of gluten-free diet (GFD) non-responsive celiac disease (NRCD) 
in adult patients. 
Primarv Objective: To assess the efficacy of AMG 71 4 in attenuating the 
effects of gluten exposure in adults with celiac disease 
Secondary Objective: To assess the safety and tolerability of AMG 714 
when administered to adult patients with celiac disease exposed lo a gluten 
challenge 
Exploratorv 
Objective: 
To 
assess 
the 
pharmacokinctics 
(PK). 
pharmacodynamics (PD). and PK/ PD correlations of AMG 7 14 
Primary efficacy endpoint: 
• 
Anenuation 
of 
gluten-induced 
small 
intestinal 
mucosaJ 
morphological injury, measured morphometrically as villous height 
to crypt depth (VH:CD) ratio 
Secondarv efficacy endpoints: 
• 
Attenuation 
of 
gluten-induced 
small 
intestinal 
mucosa! 
innammation measured as intraepithelial lymphocyte (lELs) 
density 
• 
Attenuation 
of 
gluten-induced 
small 
intestinal 
mucosa! 
morphological injury using a grouped classification of Marsh score 
• 
Attenuation of gluten-induced serum antibodies: 
• 
Anti-tissue transglutaminase antibodies (anti-tTG lgA) 
• 
Anti-deamidated gliadin peptide (anti-DGP) lgA and lgG 
• 
Attenuation of gluten-induced clinical symptoms as assessed by: 
• 
Bristol Stool Form Scale (BSFS) 
• 
Gaslrointestinal Symptom Rating Scale (GSRS) and celiac 
disease GSRS (CeD-GSRS) 
Exploratory endpoints: 
• 
Pharmacokinetics 
(PK), 
Phannacodynamics 
(PD) 
and 
Exposure/Response (PK/PD) 
• 
Physician Global Assessment of Disease (PGA) 
• 
Biomarkers of disease activity 
• 
Celiac Disease Patient-Reported Outcome (CeD PRO) 
Page 8 of 110 
Confidential 

STUDY 
DESIGN 
Protocol Version 3 
(29-AUG-20 16) 
CELIM-
RCD-001 
Safetv endpoints: 
• 
Adverse events (AEs) 
• 
Clinical laboratory tests 
• 
Physical examination 
• 
Vital signs 
• 
lmmunogenicity 
Protocol CELI M-NRCD-00 I is designed to be a Phase 2a, randomized. 
double-blind. placebo-controlled, parallel-group study lo evaluate the 
efficacy and safety of AMG 714 for the attenuation of the effects of gluten 
exposure in adult patients with celiac disease during a gluten challenge. 
After signing consent, subjects will be screened for the study. All subjects 
who meet the study entry criteria wi It be randomized at a I: I: I ratio to 
receive 150 mg or 300 mg AMG 714 or placebo once every two weeks for 
10 \.veeks. Randomization will be stratified by sex. The study drug (AMG 
714 or placebo) will be administered at the clinical site in a double-blind 
fashion via subcutaneous (SC) injection. 
Jn addition to receiving study medication or placebo, all subjects will be 
required to consume either placebo gluten or active gluten administered in 
a single-blind fashion. Beginning on the day following Visit I (i.e. Weck 
O/Day I, since Visit l is defined as Week O/Day 0) through Visit 2 (Week 
2/Day 14), all randomized subjects wi ll consume placebo gluten. in the 
form of gluten-free foodstuffs (e.g .. rusks) provided b) the Sponsor. twice 
a day (BID) at the time of two regularly consumed gluten-free meals 
(chosen by the subject). 
Starting at Visit 2. subjects will switch to 
consuming a daily total of approximately 4g of active gluten. provided in 
the fonn of foodstuff identical in appearance to that provided during the 
two-week single-blind placebo-gluten period. 
These gluten-containing 
foodstuffs. supplied by the sponsor. will be consumed in approximately 2g 
doses BID at the time of two regularly consumed gluten-free meals (as 
chosen by the subject) from Visit 2 (Weck 2/Day 14) through the end of the 
treatment period at Visit 7 (Week 12/Day 84). Consumption of additional 
products containing gluten will be prohibited and subjects will be expected 
to continue total adherence to their former GFD from the time of screening 
until the follow-up study visit (Visit 8. Week 16/Day l 12). 
Subjects· adherence LO GFD and consumption of provided gluten will be 
assessed via stool and urine sample testing using the iVYLISA gluten 
immunogenic peptide (GIP) stool and urine gluten tests. Subjects with 
known or suspected GFD transgressions or those suspected of non-
compliance to protocol-specified gluten dosing will be counseled and 
allowed to continue in the study. 
Page 9of11 0 
Confidential 

STUDY 
SAMPLE SIZE 
ANTICIPATED 
NUMBER OF 
CLINICAL 
SITES 
INCLUSION 
CRITERIA 
Protocol Version 3 
(29-AUG-2016) 
C'ELIM-
RC0-001 
A study staff member wi II contact each subject by telephone one day and 
one \ eek arter the first swdy drug dose in order to assess for any AEs. 
Subjects will return to the clinic every two weeks for study drug 
administration and/or efficacy and safety assessments as indicated in the 
study schedule of events (Table I). The final study drug dose will be 
administered at Visit 6 (Week l O/Day 70). 
An end-of-study efficacy 
assessment will be collected at Visit 7 (Week 12/Day 84). /\ final study 
visit will be conducted 6 weeks after the last dose of study drug at Week 16 
(Visit 8/Day 112). 
All study subjects will undergo upper gastrointestinal endoscopy and 
biopsy prior to baseline (Visit I. Week O/Day 0) and at the end of the 12-
weck study period while still on the gluten challenge and within 5 days 
before Visit 7 (Week 12/Day 84) in order lo assess changes from baseline 
in VH:CD ratio. IELs. and Marsh score. 
All subjects enrolled in the study will complete the BSFS at the time of each 
bowel movement from baseline (Visit I: Weck O/Day 0) up to the final 
study visit, Visit 8 (Week 16/Day 11 2). Subjects will complete the CeD 
PRO daily from baseline lo the final study visit. Subjects wi ll also complete 
the GSRS at screening and. thereafter, weekly from base I ine through the 
study final study visit. The BSFS. GSRS, and the daily CeD PRO will be 
completed using a handheld electronic diary at the times specified in the 
Schedule of Events (Table I). 
Safety will be monitored on an ongoing basis and subjects may undergo 
unscheduled visits if needed for safety reasons. 
afety will be assessed 
throughout the study by clinical laboratory tests. physical examination. vital 
signs, and AE monitoring. In addition to the investigators and the Sponsor. 
an independent Data Safety Monitoring Board (DSMB) will monitor safety. 
A total of approximately 63 subjects will be randomized into the study in 
order to achieve approximately 51 evaluable subjects ( 17 subjects per 
treatment arm). 
The study will be conducted at approximately 3 clinical sites in Finland. 
Subjects must fulfill all of the following inclusion criteria to be eligible for 
participation at screening and at Visit 1 (Week O/Oay 0): 
I. 
Adult males or females 18 to 80 years of age, inclusive. 
2. 
Demonstrate willingness to participate in the study as documented by 
signed informed consent. 
Page 10of110 
Confidential 

EXCLUSION 
CRITERIA 
Protocol Versio11 3 
(29-A UG-2016) 
CELI 1- RCD-001 
3. 
Subjects must have a diagnosis of celiac disease by intestinal biopsy 
al least 12 months prior to screening as confirmed by medical records. 
written physician statement or by the Kela statement, the national 
social 
security 
institution 
determining 
the 
governmental 
reimbursement for biopsy-proven celiac disease patients. 
4. 
Subjects must have been on a GFD for at least 12 consecutive months 
prior to screening and must be willing to remain on a GFD for the 
duration of study participation (apart from the Sponsor-supplied 
approximately 2g of gluten taken Bl D during the I 0-week gluten 
challenge period of the study). 
5. 
Negative anti-tTG (lgA) at screening. 
6. 
Negative H-pylori test prior to study drug administration. 
7. 
Human leukocyte antigen DQ (HLA-DQ) typing compatible with 
celiac disease provided or obtained before baseline biopsy. 
8. 
Body mass index (BMI) between 16.0 and 45.0 kg/m2, inclusive. 
9. 
Screening laboratory values within the fo llowing parameters (unless 
investigator considers an abnormality to be not clinically significant): 
a) Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase (AST) < 2.5 x the upper limit of normal 
(ULN). 
b) Hemoglobin > 10 g/dL (> 100 g/L in SI units) 
c) Platelet count > 125,000 mm3 (> 125 !Lin ST units). 
d) White blood cell count > 3,500 cells/mm3 (>3.5x109/L). 
e) Estimated glomerular filtration rate (eGFR) ~ 60 ml/min. 
t) Glycosylated hemoglobin (HbA IC) <7% (<53 mmol/mol) in 
subjects with a diagnosis of Type I or Type 2 Diabetes 
Mellitus 
I 0. 
Females of non-childbearing potential defined as postmenopausal 
(>45 years of age with amenorrhea for at least 12 months or any age 
with amenorrhea for at least 6 months and a serum fol I icle stimulating 
hormone (FSH] level >40 IU/L at Screening); or pennanently 
sterilized (eg, bilateral tubal occlusion. hysterectomy. bilateral 
salpingectomy. oophorectomy): or otherwise incapable of pregnancy 
OR 
Females of child bearing potential (FOCBP) or males who agree to 
practice two highly effective methods of birth control (as determined 
by the fnvestigator; one of the met.hods must be a barrier technique) 
from Screening through the end of study participation (Visit 8, Week 
16/Day 112) and for 6 months after the end of the study. 
11 . 
Willingness and ability to comply with study procedures and protocol 
stipulated concomitant medication guidelines. 
12. 
Willingness to return for all scheduled fo llow-up visits. 
Subjects will be excluded from the study if there is evidence of any of the 
fo llowing: 
Pagell of llO 
Confidential 

Protocol Version J 
I. 
Current diagnosis of any severe complication of celiac disease. such 
as Refractory Celiac Disease Type l or Type JI (RCD-1 or RCD-11). 
enteropathy-associated 
T-cell 
lymphoma 
(EATL). 
ulcerative 
jejunitis or perforation. 
2. 
Diagnosis of any autoimmune disease. other than celiac disease or 
dermatitis herpctiformis (DH), that might interfere with the conduct 
of the study or require systemic immunomodulation therapy. 
3. 
Occurrence of celiac disease-related symptoms (CcD-GSRS >2.3) 
as assessed by screening GSR . 
4. 
Diagnosis of any chronic. actil'e gastrointestinal (G I) disease other 
than celiac disease (e.g .. active. untreated peptic ulcer. esophagitis, 
gastroesophageal reflux disease [GERO]: active ulcerative colitis; 
Crohn·s disease. or irritable bowel syndrome] that might, in the 
Investigator"s opinion. interfere with assessment of symptoms of 
abdominal pain. diarrhea. or other components of celiac disease. 
5. 
Any known. symptomatic food allergy, including an allergy to the 
ingredients of the gluten challenge vehicle that. in the opinion of the 
Investigator. might interfere with the conduct of the study or result in 
anaphylaxis. 
6. 
Presence of any of the fol lowing related to infection: 
a) 
Active acute infection requiring systemic treatment 
(antibiotics. anti fungal, or antiviral) 
b) 
Active GI infection 
c) 
Persistent or severe infection within the three months 
prior to randomization 
d) 
History of tuberculosis (TB) 
e) 
Positive Interferon Gamma Release Assay (IGRA) test 
at screening or known recent exposure(-.: ithin 6 months 
prior to screening) to a patient with active TB; subject 
can be enrolled if he or she has been successfully treated 
with appropriate chemoprophylaxis. 
I) 
History within 3 years prior to screening of an 
opportunistic infection typical of those seen in 
immunocompromised patients (e.g.. herpes zoster, 
systemic 
candida 
infection. or systemic 
fungal 
infection). 
7. 
Use of systemic immune suppressants (including steroids) within 3 
months or 5 half-lives. whichever is longer, prior to randomization. 
8. 
Required use of a prohibited medication at the time of randomization 
(prohibited medications required for treatment of nn AE occurring 
after randomization are permitted). 
9. 
Current diagnosis or history of cancer within the past 5 years, except 
successfully treated basal cell or squamous cell carcinoma, cervical 
carcinoma-in-situ. or early stage prostate cancer. 
I 0. 
Administration of a live vaccine within I 4 days prior to the fi rst 
administration of study dru!!. 
('.'!9-AUG-2016) 
Page 12of 110 
CELIM-1 RCD-00 I 
Conlidential 

STATISTICAL 
METHODS 
Protocol Version 3 
(19-A UG-10 16) 
CELIM-NRCD-00 1 
11. 
History or presence of clinically significant disea e that in the opinion 
of the Investigator would confound the subject's participation and 
fo llow-up in the clinical trial or put the subject at unnecessary risk. 
including but not limited to: 
a) 
Cardiovascular disease (e.g., uncontrolled hypertension 
defined as office systolic blood pressure fBPl equal to or 
greater than 180 mmHg or office diastolic BP equal or 
greater than I I 0 mm/Hg. unstable angina. congestive 
heart failure worse than New York Heart Association 
fNYHA l Class II. coronary angioplasty or myocardial 
infarction within the last 6 months. unconcrolled atrial or 
ventricular cardiac arrhythmias clinically significant 
pleural or pericardia! effusion or ascites) 
b) 
pulmonary disease (e.g., severe chronic pulmonary 
disease) 
c) 
renal. hematological. gastrointe.stinal, endocrine {e.g .. 
poorly controlled diabetes), immunologic. dermatologic, 
neurological, or psychiatric disease 
12. 
History or significant drug or alcohol abuse during the year prior to 
study screening as obtained by medical record and/or subject report. 
13. 
History of clinically significant hypersensitivity to the study drug. 
any related drugs. or to any of the cxcipients. 
14. 
History of anaphylactic reactions (e.g. lgE-mediated reactions) to 
wheat or gluten. 
15. 
Positive Hepatitis B (Hep B). Hepatitis C (Hep C), or I luman 
Immunodeficiency Virus (HIV) infection test results at the time of 
screening. 
16. 
Females who are pregnant or planning to become pregnant during the 
study participation period. or are cu1Tently breastfeeding. 
17. 
Participation in another investigarional drug or device study or 
treatment with an invcstigational drug within 3 months or 5 half-
lives. whichever is longer. prior to randomization. 
18. 
Any additional reason .... vhich in the opinion of the Investigator, 
would prevent the subject from safely participating in the study or 
complying with protocol requirements including the endoscopies and 
biopsy collections. 
The primary endpoint is the difTerence in the Baseline-to-Week-1 2 % 
reduction of VH:CD ratio between the two AMG 714 dose anns and the 
placebo arm. 
The primary endpoint will be tested for each of the two dose levels. 150 mg 
or 300 mg. separately as follows: 
H 10: µ AMO 714 (300mg) = ~tPJac.:bo 
Page 13of110 
Con fidcntial 

Protocol Version 3 
I 29-A UG-2016) 
CELI M -NRCD-00 I 
against the alternative 
H 11: µ AMG 7 14 (300mg) -:/= µ riuccbo 
l-1 20: ~lAMG714 (1 50mg) = µ Placebo 
against the alternative 
H 2 1: µ AMG 714 (l 50mg) -:f µPlacebo 
where µ AMG 714 (JOOmg). µAMG 11.i (150mg) and µr1ncebo denote the mean Baseline-
to-Week-1 2 % reduction of VH:CD ratio in the high dose, low dose and 
placebo arm. respectively. Each of the two hypotheses will be tested using 
a two-sided type I error level of 5% without any adjustments for multiple 
comparisons. 
The primary efficacy endpoint will be analyzed using analyses of 
covariance (ANCOVA), where baseline VH:CD ratio. site, and sex will be 
covariates and treatment group will be included to test the primary 
hypotheses. The primary analyses wi ll be based on the intent-to-treat (fTI) 
population. Secondary analyses will be based on the per-protocol (PP) 
population. 
The secondary efficacy endpoints will also be analyzed for both the lTI 
and the PP population. Change in lELs density will be analyzed using the 
same method as for the primary endpoint YH:CD ratio. Anti-tTG fgA and 
anti-OGP (lgA and lgG) will be analyzed using a linear mixed effects 
repeated measures model (MMRM). with baseline value, site. sex, time, 
treatment group, and a time-by-treatment group interaction tenn as fixed 
effects, subject as random effect, and an underlying correlation structure 
between the time points that provides the best fit for the model. 
The Marsh scores will be analyzed using a multinomial logistic regression 
model, where treatment group, time point, and a time point by treatment 
group interaction term wi II be included in the model. 
The secondary variable BSFS will be analyzed by calculating daily and 
weekly number and type of bowel movements. The bowel movement 
counts will be analyzed using generalized linear mixed models with subject 
as random effect. The statistical model will also include treatment group, 
time (week), and their interaction. The change in the weekJy BSFS scores 
will mainly be assessed with descriptive statistics, where change from the 
'normal (midscale)" will be explored. The GSRS and CeO PRO (daily and 
Pagt• 14 of I 10 
Confidential 

Protocol Version 3 
(29-AUG-2016) 
CELIM-
RCD-001 
weekly averages) will be analyzed using the same method as that for the 
secondary endpoint anti-tTG JgA. 
The exploratory variables such as PK parameters, PGA, and biomarkers of 
disease activity will be tabulated by treatment groups, and will be done 
using both the ITT and the PP populations. 
In addition. dose 
proportionality. achievement on steady-state, and accumulation ratio based 
on Ctrough concentrations, comparison of Ctrough levels with corresponding 
values in study 20060349, and correlation of Ctraugh concentrations with 
biomarkers of disease activity will be evaluated. Dose proportionality will 
be analyzed using a power model and PKJPD correlation will mainly be 
assessed graphically. 
The safety variables. including AEs (coded using the Medical Dictionary 
for Regulatory Activities (MedDRA]), clinical laboratory tests, physical 
examination, vital signs, and immunogenicity, will be summarized by 
treatment group. Some of the variables will be tabulated by treatment and 
by visit. 
Page 15 of 1 I 0 
Conlidcnti:il 

Table 1. Schedule of Study Procedures 
Screening 
Period 
Study 
(Up to 28 
Procedures 
Dnys) 
lnfom1ed consent 
x 
Demographics 
x 
Medical history 
x 
Physical 
x 
examination 
Bodv weight 
x 
Height. BMI 
x 
calculation 
Vital signs 
x 
12-lead ECG 
x 
Collection of 
blood and urine 
xiJ 
for clinical 
laboratory tests 
Serum pregnancy 
x 
test (all FOCilP) 
Urine pregnancy 
test Call FOCBP) 
Urine for gluten 
detection~ 
iVYLISA GIP 
x 
Stool Test5 
Randomization 
Sernm 
biomarkers6 
Serum PK7•8 
Serum ADA 
Protocol Version 3 
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CELIM-NRCD-00 I 
Phone 
Visit I 
Call I 
WeekO 
Week O 
(D11y 0) 
(Day I) 
+I Dav 
x 
x• 
x 
x 
x 
x 
x 
x 
x x 
Final 
Double-Blind Randomization Period 
Visit 
Phone 
Call 2 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit8 
Week 12 (Day 
Week 16 
Week I 
Weck2 
Week4 
Week6 
Weck8 
Week 10 
(Day 7) 
(Day 14) 
(Day 28) 
(Day 42) 
(Day SG) 
(Day 70) 
84 or Early 
(Day 
Termination) 
112) 
±1 D:w 
±3 Davs 
±3 Dnvs 
±3 Davs 
±3 Dnvs 
±3 Davs 
±3 Davs 
±7 Davs 
x 
x 
x 
x 
x 
x 
x 
x 
x• 
x• 
x• 
x• 
x• 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
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Screening 
Final 
Double-Blind Randomization Period 
Visit 
Period 
Phone 
Phone 
Visit 1 
Call 1 
Call 2 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Study 
(Up to 28 
Weck 12 (Day 
Week 16 
Procedures 
Days) 
WeekO 
WeckO 
Weck 1 
Weck 2 
Weck 4 
Wcek6 
Week8 
Week 10 
84 or Early 
(Day 
(Day 0) 
(Day 1) 
(Day 7) 
(Day 14) 
(Day 28) 
(Day 42) 
(Day 56) 
(Day 70) 
Termination) 
112) 
+ I Dav 
± 1 Day 
±3 Days 
±3 Davs 
±3 Oavs 
±3 Davs 
±3 Oavs 
±3 Days 
±7 Davs 
Anti-LTG9 
x 
x 
x 
x 
x 
x 
ocr•0 
x 
x 
x 
x 
x 
Blood cell pellet11 
x 
Eligibility 
x 
x 
confirmation 
Study drug 
x 
x 
x 
x 
x 
x 
administration 
Single-bl ind 
gluten challenge 
x 
x 
12. IJ. 14 
Prior and 
concomitant 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
medications 
Assessment of 
x 
adverse events 
x 
;\ 
x 
x 
x 
x 
x 
x 
x 
x 
Endoscopy and 
x 
x 11.1s 
biopsy•~. 16 
BSFS.CeD 
x 
:x 
PRQ•9 
GSRS20 
x 
x 
. 
x 
PGA 
x 
x 
x 
x 
x 
x 
Abbreviations: ADA=anti-drug antibody, BSFS==Bristol Stool Form Scale. CeD-GSRS=Celiac Disease Gastrointestinal Symptom Rating Scale. CeD PRO=Celiac 
Disease 
Patient 
Reported Outcome. 
DGP--dcamidatcd gliadin 
peptide antibody. 
ECG: clcctrocardiogram. 
GIP=gluien immunogenic peptide, 
GSRS"'GastrointestinaJ Symptom Rating Scale. PGA=Physician Global Assessment. PK=phannacokinctics, tTG=tissue transglutamin:ise. 
I) 
Vital signs will be rnken prior to a11d 30 minutes after srudy drug administration. 
2) 
Including blood sample for HLA typing if report not previously supplied. 
3) 
HbA IC' should be tested in those subjects with known or suspected diagnosis ofT) pc l or T) pc 1 DM only. 
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..J) 
An aliquot of urine will be collected from the urine supplied for urinalysis 1es1 for future iVYDAL urine sampling. 
5) 
The manda1ory screening iVYLISA GIP sarnple will be collected after the signing of informed consent either at the time of the screening visit or within 
the first 7 days folio" ing the initial ~creening visii. The iVYLISA GIP stool samples collected during the randomization period arc optional. except Week 
12 which is mandatory. The samples will ideally be collec1ed by the patient the day before each scheduled s1udy visit or during the visit (with a window 
of three dnys before or after the visit). 
6) 
Biomarker samples should be taken prior to study drug administration. The time and date of these samples must the accurately recorded. 
7) 
The PK sample should be collected before study drug admiuistration. 
8) 
Exact time and date of sample collection must be recorded. 
9) 
Anti-ITG lgJ\ antibodies will be dctennined in blood at screening (by Biocard test) and in serum thereafter (by ELISA). 
10) 
Anti-DGP tmtibodics lgA and lgG will be measured in serum. 
11 ) 
Collected and stored for future testing. This sample can be collected at any time during the study. 
12) 
Placebo gluten will be dispensed in a single-blind fashion. Subjcc1s will be instructed to consume the provided placebo gluten BID beginning on the day 
following Visit I (Week O/Day 0) until Visit 2 (Week 2/Day I ..J). Subjects will return any unused placebo gluten to the study site. 
13) 
Active gluten will be dispensed in a single-blind fashion from Visit 2 to Visit 6. Subjects will return any unused gluten lo the study site at each follow-up 
study visit. 
14) 
Subjects will start the gluten challenge with the next main meal·(e.g .. breakfast) on the day after Visit 2 (Week 2/Day 14), i.e .. Day 15. Subjects will be 
instructed to consume the provided gluten BID with two main gluten-free meals of their choosing (e.g .. at breakfast and dinner) for I 0 weeks through 
Visit 7 (Week 12/0uy 84). 
15) 
The screening biopsy can be collec1ed any time prior lo the day of randomil.<ltion. The biopsy should only be collected from those subjects who mcc1 all 
other entry criteria. 
16) 
If the screening biopsy shows villous atrophy with a VH:CD ofless than 1.5 (I .4or lower). and after notificaiion to the sponsor, the subject may be allowed 
to stay in the study bur the gluten challenge will not be started. or will be interrupted if i1 had already started. and the subject will not be included in the 
main efficacy assessmen1s. Subjects with a VH:CD of 1.5 or higher will receive the gluten challenge. 
17) 
The end-of-study biopsy cnn he collected within 5 days before Visit 7. while 1he subject is still consuming the single-blind gluten challenge. 
18) 
A Visit 7 or Early Termination endoscopy and biopsy are required for all subjects. Early frrmination endoscopies and biopsies should be conducted unless 
a medical condition suggests otherwise. at the investigator's discretion. 
19) 
The BSFS is co llected episodically at the time of c01eh bowel movement from baseline to the end or participa1ion the subject's involvement in the study. 
The CeD PRO is captured daily. 
20) 
The GSRS is collected at screening to establish inclusion/exclusion criteria based on CeD-GSRS. The GSRS will be collected weekly from randomized 
subjects lrom baseline to the end of participation. 
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TABLE OF CONTENTS 
LlST OF ABBREVIATIONS .............................................................................................................. 6 
PROTOCOL YNOPSIS ..................................................................................................................... 8 
TABLE OF CONTENTS ................................................................................................................... 19 
l 
INTRODUCTION ................................................................................................................. 24 
1.1 
BACKGROUND .........................................................................................................•.......... 24 
I. I . I 
IL- 15 ............................................................................................................................. 24 
l.2 
CELlAC DISEASE ............................................................................................................... 25 
1.1.1 
Current Management of Celiac Disease: The Gluten-Free Diet ................................... 27 
1.3 
ROLE OF IL-15 IN CELlAC OISEASE ............................................................................. 27 
1.4 
AMG 714 ................................................................................................................................ 28 
1.5 
SUMMA RY OF PRE-CLINICAL ST UDIES ..................................................................... 28 
1.5. I 
Pharn1acology ............................................................................................................... 29 
1.5.2 
Toxicology .................................................................................................................... 29 
1.6 
EFFECTS OF AMG 714 JN HUMANS ............................................................................... 30 
1.6. I 
Pharmacokinetics of AMG 714 in Humans .................................................................. 32 
1.6. I .1 
Phannacokinetics of AMG 714-HYB ...................................................................... 32 
1.6.1.2 
Pharmacokinetics of AMG 7 14-CHO ...................................................................... 32 
1.6.2 
Pharmacodynamics of AMG 714 in Humans ............................................................... 33 
1.7 
EFFICACY OF AMG 714 tN R UMANS ............................................................................ 33 
1.7. I 
Efficacy of AMG 714-HYB in Rheumatoid Arthritis ................................................... 33 
1.7.1.l 
tudy Hx-ILI S-001 .................................................................................................. 33 
I. 7. 1.2 
Study 200302 10 ....................................................................................................... 33 
J.8 
SAFETY OF AMG 714 IN HUMANS ................................................................................. 34 
1.8.1 
Safety in AMG 7 14-HYB Clinical Studies ................................................................... 34 
1.8.1.I 
Study Hx-ILIS-00 1 .................................................................................................. 34 
1.8.1.2 
Study 200302 10 ....................................................................................................... 35 
1.8.2 
Safety in AMG 7 14-Cl-IO Clinical Swdies ................................................................... 36 
1.8.2. 1 
Study 20050 193 ....................................................................................................... 36 
1.8.2.2 
Study 20060349 ....................................................................................................... 37 
2 
KNOWN AND ANTICIPATED RISKS ............................................................................. 37 
2.1 
NATURAL KILLER (NK) CELL DEPLETJON AND RISK OF INFECTION ............ 37 
2.2 
IMMUNOGENICITY ........................................................ - ................................................. 38 
2.3 
INJECTION SJTE REACTION AND ANAPHYLAXIS .................................................. 38 
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3 
RA T l ON ALE ......................................................................................................................... 38 
4 
OBJECTIVES ........................................................................................................................ 40 
4.1 
PRIMARY OBJECTrvE ...................................................................................................... 40 
4.2 
SECONDARY OBJECTIVE ................................................................................................ 40 
4.3 
EXPLORATORY OBJECTlVE .......................................................................................... 40 
5 
ENDPOINTS .......................................................................................................................... 40 
5.1 
PRIMARY EFFICACY ENDPOINT .................................................................................. 40 
5.2 
SECONDARY EFFICACY ENDPOJNTS .......................................................................... 40 
5.3 
EXPLORATORY ENDPOINTS .......................................................................................... 40 
5.4 
SAFETY ENOPOINTS ......................................................................................................... 41 
6 
STUDY DESIGN ................................................................................................................... 41 
7 
RANDOMIZATION AND TREATMENT ASSIGNMENT ............................................. 45 
8 
DURATION OF STUDY ...................................................................................................... 45 
9 
SUBJECT POPULATION ................................................................................................... 45 
9.1 
INCLUSION CRITERIA ..................................................................................................... 45 
9.2 
EXCLUSION CRITERIA .................................................................................................... 46 
JO 
CONCOMITANT MEDICATIONS .................................................................................... 48 
10.l 
PROHIBITED MEDICATIONS ......................................................................................... 48 
10.2 
GUIDELINES FOR THE MANAGEMENT OF ANTI-COAGULANT AND ANTL-
PLATELET CONCOMITANT MEDICATIONS ............................................................. 48 
l l 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ .i9 
l1.1 
ASSESSMENTS AT EACH VISIT ..................................................................................... 49 
J J.2 
SCR EENING PERIOD ......................................................................................................... 50 
Jl.3 
12-WEEKRANDOM-IZATlON PERJ00 .......................................................................... 51 
11.3.1 
Dosing Preparation ........................................................................................................ 51 
11.3.2 
Visit 1 (Week O/Day 0) ................................................................................................ 51 
11.3.3 
Safety Pbonc Calls (Week O/Day 1 & Week l/Day 7) .............................................. 52 
11.3.4 
Visit 2 (\'Veek 2/Day 14) .............................................................................................. 52 
l l.3.5 
Visit 3 (Week 4/Day 28) .............................................................................................. 53 
l 1.3.6 
Visit 4 (Weck 6/Day 42) ............................................................................................... 54 
11.3. 7 
Visit 5 (Weck 8/Day 56) .............................................................................................. 54 
11.3.8 
Visit 6 (Week JO/Day 70) ............................................................................................ 55 
11.3.9 
Visit 7 (Week 1_2/Day 84) ............................................................................................ 56 
11.4 
FINAL ST UDY VTSIT .......................................................................................................... 56 
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11.4. I 
Visit 8 (Week 16/Day 11 2) or 6 Weeks After Last Study Drug Administration .......... 56 
ll.5 
EARLY TERMINATION .................................................................................................... 57 
12 
DEFINIT ION OF END OF STUDY .................................................................................... 57 
13 
EFFlCACY ASSESSMENTS ............................................................................................... 58 
13.l 
HISTOLOG ICAL ASSESSMENT OF DUODENO-JEJ UNAL BIOPSY: VH:CD 
RA T IO, l EL DENSITY AND MARSH SCORE ................................................................ 58 
13.2 
SEROLOGY: ANTI-TISSUE TRANSGLUTAMINASE AND ANTI-DEAMIDATED 
GLlADIN PEPTIDES ANTIBODJES ................................................................................. 59 
13.3 
BRISTOL STOOL FORM SCALE ..................................................................................... 59 
13.4 
GASTROINTEST INAL SYMPTOM RATlNG SCALE (GSRS) .................................... 59 
13.5 
CELIAC DISEASE PATIENT-REPORTED OUTCOME (CED PR0) .......................... 60 
14 
EXPLORATORY ASSESSMENTS .................................................................................... 60 
14.l 
PHARMACOKINECTICS AND PHARMACODYNAMICS .......................................... 60 
14.2 
IVYLISA GIP TE TS ........................................................................................................... 60 
14.3 
PHYSIC IAN GLOBAL ASSESSMENT OF DISEASE ..................................................... 61 
14.4 
BIOMARKERS OF DISEASE ACT IVITY ........................................................................ 61 
14.5 
IMMUNOGENICJTY ........................................................................................................... 62 
15 
SAFETY ASSESSMENTS .................................................................................................... 62 
15.l 
VITAL SIGNS ....................................................................................................................... 62 
15.2 
PHYSICAL EXAM ............................................................................................................... 63 
15.3 
CLINICAL LABO RA TORY RES UL TS ............................................................................ 63 
15.3.1 
Pregnancy Testing ......................................................................................................... 63 
16 
LOCAL AND CENTRAL LABO RA TORIES ................................................................... 63 
17 
LIFESTYLE AND DIETARY RESTRICTIONS .............................................................. 63 
18 
INVESTIGATIONAL PRODUCTS .................................................................................... 6-t 
18.l 
DESCRIPTION OF INVESTIGATIONAL PRODUCT ................................................... 64 
18.2 
PLACEBO .............................................................................................................................. 64 
18.3 
DOSE RATIONALE ............................................................................................................. 64 
18.4 
BLINDING ............................................................................................................................. 65 
18.5 
UN BLINDING ....................................................................................................................... 65 
18.6 
RANDOMIZATION ANO TREATMENT ASSIGNMENT ............................................. 65 
18.7 
DRUG SUPPLIES, DISPENSING, STORAGE AND ACCOUNTING ........................... 66 
18.7.1 
Packaging and Fonnulation .......................................................................................... 66 
18. 7 .2 
Storage .......................................................................................................................... 66 
18. 7.3 
Preparation .................................................................................................................... 66 
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18.7.4 
Administration of Study Drug ....................................................................................... 67 
18. 7 .5 
Supply and Return of Drug ........................................................................................... 67 
I 8. 7.6 
Investigational Product Accountability ......................................................................... 68 
18.8 
TREATMENT OF INVESTIGATIONAL PRODUCT OVERDOSE ............................. 68 
l9 
GLUT EN C HALLENGE ...................................................................................................... 68 
19.1 
PLACEBO GLUT EN AND ACTIVE GLUTEN CHALLENGE PRODUCT ................. 68 
19.2 
GLUTEN C HALLENGE COMPLIANCE ASSESSMENT .............................................. 69 
20 
STOPPING CRITERLA ........................................................................................................ 69 
20.1 
INTERRUPTION OF DOSING IN AN JNDIVIDUAL SUBJECT .................................. 69 
20.2 
INTERRUPTION OF DOSING FOR ALL SUBJECTS IN THE ENT IRE TRIAL ...... 69 
21 
SUBJECT COMPLETION AND WITHDRAWAL .......................................................... 69 
21.1 
UBJECT COMPLETION .................................................................................................. 69 
21.2 
SUBJECT W ITHDRAWAL ................................................................................................ 70 
21.2. t 
Withdrawal Procedures ................................................................................................. 70 
22 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............................................ 70 
22.1 
llEPORTING RESPONSIBILITY ...................................................................................... 70 
22.2 
DE FINITION OF AN ADVERSE EVENTS ...................................................................... 71 
22.3 
SEVETllTY ............................................................................................................................ 71 
22.4 
RELATIONSHIP .................................................................................................................. 71 
22.5 
SERIOUS ADVERSE EVENTS ........................................................................................... 72 
22.6 
SPECIAL REPORTING SlTUA T IONS ............................................................................. 73 
22.6.1 
Death ............................................................................................................................. 73 
22.6.2 
Hospitalizations for Surgical or Diagnostic Procedures ............................................... 73 
22.6.3 
Pregnancy ...................................................................................................................... 73 
22.6.4 
Inadvertent Exposure or Overdose ................................................................................ 73 
22.6.5 
Suspected Unexpected Serious Adverse Reactions (SUSA Rs) .................................... 73 
22.7 
PROCEDURES FOR REPORTING ADVERSE EVENTS .............................................. 7-4 
22.8 
PROC EDURES FOR REPORTING SERIOUS ADVERSE EVENTS ........................... 7-4 
22.9 
FOLLOW-U P FOR ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ......... 75 
22.10 SAFETY REVIEW COMM ITTEE ..................................................................................... 75 
23 
DAT A ANALYSIS AND ST A TIST ICS .............................................................................. 76 
23.1 
SAMPLE SIZE DETERMINATION .................................................................................. 76 
23.2 
POPULATIONS FOR ANALYSIS .... ~ ................................................................................ 77 
23.3 
MISSING DAT A ................................................................................................................... 77 
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23.4 
ST ATISTICAL ANALYSES ................................................................................................ 77 
23.4.1 
Subject Disposition ...................................................................................................... 77 
23.4.2 
Protocol Deviations ..................................................................................................... 78 
23..4.3 
Demographic and Baseline Characteristics .............................................................. 78 
23.5 
EFFICACY ANAL YSES ...................................................................................................... 78 
23.5. I 
Primary Endpoint .......................................................................................................... 78 
23.5.2 
Secondary Efficacy Endpoints ...................................................................................... 79 
23.5.3 
Exploratory Endpoints .................................................................................................. 79 
23.6 
SAFETY ANALYSES ........................................................................................................... 80 
23.6. l 
Adverse Events ............................................................................................................ 80 
23.6.2 
Other Safety Assessn1enrs ........................................................................................... 80 
23.6.3 
Prior and Concomitant Medications ......................................................................... 80 
24 
INTERIM ANALYSIS .......................................................................................................... 80 
25 
DATAJ\llANAGEM ENT ...................................................................................................... 80 
25.I 
CASE REPORT F ORMS ..................................................................................................... 80 
25.2 
DATA MANAGEMENT PLAN AND DATABASE DESIGN .......................................... 81 
25.3 
DATA VALfDAT ION ........................................................................................................... 81 
25.4 
MEDICAL CODING ............................................................................................................ 81 
25.5 
DATABASE LOCK .............................................................................................................. 81 
26 
REFERENCES ...................................................................................................................... 81 
APPENDIX A. ADMINISTRATfVE, ETHICAL AND REGU LATORY POLJCl ES ................ 86 
APPENDLX B. LABORATORY PARAMET ERS .......................................................................... 90 
APPENDIX C. BRISTOL STOOL FORM SCALE (BSFS) .......................................................... 94 
APPENDIX D. SAMPLE GASTROINTESTINAL SYMPTOM RATING SCALE (GSRS) ..... 95 
APPENDIX E. SAMPLE PHYSICIAN GLOBAL ASSESSMENT OF DISEASE .................... 103 
APPENDIX F. INTERPRETATION OF HEPATITIS RESU LTS ............................................. 104 
APPENDIX G. SAMPLE INVEST IGATION PRODUCT LABEL ............................................ 105 
APPENDIX I. SAMPLE CELTAC DISEASE PRO (CED PRO) ................................................. I06 
APPENDIX J. P ROTOCOL AMENDMENTS ............................................................................. 109 
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J 
I NTRODUCTION 
I. l 
BACKGROUND 
The disease intended to be treated is gluten-free diet (GFD) non-responsive celiac disease 
(NRCO). Celimmune is also investigating AMG 714 for the treatment or a rare yet potentially 
fatal complication of NRCO, Type II refractory celiac disease (RCD-11). which appears to be 
independent of gluten 
consumption. 
I L-15 
plays 
an 
overlapping. 
yet distinct, 
pathophysiological role in these two diseases. responsible for mucosa! damage in NRCD and 
aberrant IEL proliferation in RCD-11. 
1.1.1 
JL-15 
Interleukin 15 (IL-15). a glycoprotein or approximately 14-15 kDa. is a proinfiammatory 
cytokinc with structural similarities to IL-2. IL-1 5 exerts biological effects on many 
immunologically relevant cells (Fehniger and Caligiuri, 2001). While important differences. 
discussed below, are present across species. JL-15 generally acts as a development, 
homeostasis and activation factor for NK cells and memory phenotype C08+ T cells, and it 
induces the production of chemokines and cytokines by these cell types. I L-15 potently 
stimulates the production orprointlammatory cytokines such as IL-I . IL-6. and tumor necrosis 
factor alpha (TNF-a) by monocytes/macrophagcs. IL-1 5 produced by follicular dendritic cells 
is reported to support germinal center B cell proliferation and immunoglobulin class switching 
(Park et al. 2004: Lilinskiy et al. 2002). Targeted disruption of either the I L-15 or the I L-15 
receptor alpha (IL-15Ra) genes in mice has been shown to result in the loss of NK, NK-T, 
TCRyo+ intraepithelial lymphocytes. and memory CD8+ cells (Lodolce et al. 1998). Jn I L-1 5 
knockout mice. these defects are reversible by the administration of exogenous IL-1 5 
(Kennedy el al. 2000). l n contrast. human N K cells are not entirely dependent on I L-15 ( Lebrcc 
et al. 2013 ). 
I L-15 messenger RNA (mRNA) is expressed in a wide variety of tissues and cell types. 
However. expression of I L-15 protein is much more restricted and is subject to multiple post-
transcriptional control mechanisms. Immunologically relevant sources of IL-15 protein include 
monocytes. macrophages. epithelial and fibroblastic cells. and bone marrow stromal cells 
(Fehniger and Caligiuri. 2001). IL-15 and its receptor are also expressed in some organs 
outside the immune system: the role of I L-15 in these systems is less well understood. The 
absence of any overt defects outside the immune system in I L-15 and IL- I 5Ra knockout mice 
suggests that I L-15 may not be essential in any other system. 
I L-15 binds to a heterotrimeric receptor that consists of a p chain that is shared with the I L-2 
receptor (CD 122 or I L-2/IL-l 5Rp), the common y chain (yC). shared with the IL-2. -4. -7. -9. 
and -2 1 receptors. and a unique u chain. IL-1 5 binds with high affinity to the IL-I 5Ra chain. 
which then interacts with the LL-2/1 L-15RP and the yC. The association of the I L-15/1L-l5Ro. 
complex with the other two components of the complete receptor complex can occur in a cis 
configuration where all three receptor components arc present on the same cell. or in a trans 
configuration where the IL 15/IL I 5Ra pair is on one cell and the receptor P and yC chains are 
on another (Schluns et al. 2005). I L-15 can also associate with IL~ I 5Ra on the cell surface 
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and then be cleaved into soluble cytokine/receptor complexes that have the potential to 
stimulate CD8+ T cells and NK cells (Anthony el al. 20 15). 
Increased expression of IL- 15 has been demonstrated in a variety of inflammatory conditions. 
including rheumatoid arthritis (RA). psoriasis. inflammatory bowel disease, graft-versus-host 
disease, solid organ transplant rejection (Blaser el al, 2005; Conti el al, 2003: Gianfrani et al, 
2005; Mcinnes and Gracie, 2004) and celiac disease (reviewed in Gianfrani et al, 2005; 
Mcresse el al. 2012). 
1.2 
CELIAC DISEASE 
Celiac disease is a systemic autoimmune disease triggered by gluten consumption in 
genetically susceptible individuals (Green and Cellier. 2007). Cunently approximately I% of 
the western population is affected by celiac disease. The prevalence is twice that in countries 
with very high hygiene standards and/or very high gluten consumption. It is estimated that 15-
20 million patients are affected by celiac disease, although only 1-1.5 million have been 
diagnosed. This number has been reported to be doubling every 20 years (Riddle er al. 20 12). 
Gluten. the antigen responsible for celiac disease. is the main protein present in some or the 
most common cereals (wheat, barley, rye). Modern diets are increasingly enriched with gluten 
and it is also used as an additive in processed foods. cosmetics and oral medications. Gluten is 
the second most common food ingredient after sugar and, in some countries, is present in up 
to 80% of foodstuff. Gluten is also present in trace amounts in foods labeled as "gluten-free'". 
as a tableting excipient. and in products such as toothpaste and lipstick. As little as 50mg/day 
of gluten triggers the disease (Catassi el al. 2007). A normal diet contains > I 0 g/day. 200 
times the amount that causes damage and intestinal histological abnormalities. As such, celiac 
patients face enormous challenge to follow a strict gluten-free diet (GFD). 
The pathophysiology of celiac disease is characterized by an abnomial immune response to 
gluten. Gluten, which is normally a well-tolerated dietary component, elicits innate and 
adaptive immune responses in celiac patients (Green and Cellier. 2007). Humans lack ervymes 
to fully digest gluten, which against the right genetic background triggers inOammation and 
autoimmunity in the intestine and in other organs. An adaptive irnrmmc response is triggered 
when gluten peptides are deamidated in the extracellular space. by tissue transglutaminase 
(tTG). normally an intracellular enzyme that is released by damaged cells. This deamidation 
renders gluten peptides high-avidity binders to I ILA-DQ2 and HLA-DQ8. which present these 
peptides to intestinal C04+ T cells, thereby activating these T cells and initiating the 
inflammatory cascade. The innate immune system's intraepithelial lymphocytes (IELs), 
primarily CDS+. are able to directly lyse and destroy intestinal epithelial cells. damaging the 
mucosal lining of the small intestine. in response to the IL-1 5 release. stimulated by gluten 
peptides (Abadie and Jabri, 2014 ). In healthy individuals. the activated Teel Is are controlled 
by regulatory T cells (Tregs), but this does not happen in celiac disease as IL-15 confers the 
effector CD4+ T cells resistance to suppression by Trcgs (Abadie and Jabri, 2014 ). Anti-tTG 
auto-antibodies appear as a hallmark of the celiac autoimmune process and are used in 
accurately diagnosing the disease (Green and Cellier, 2007). 
Celiac disease causes debilitating symptoms and serious medical complications. rn many 
patients. gastrointestinal symptoms derived from intestinal mucosa I damage dominate the 
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patient reported symptoms at diagnosis. The normal villi (absorptive finger-like prolongations) 
present in the gut of healthy individuals are lost in active celiac disease as a result of mucosa( 
atrophy and crypt enlargement. The ratio of the villous height (VH) to the intestinal crypt 
depth (CO), the VI l:CD ratio. is one of the main descriptors of the severity of celiac disease 
(Taavela el al. 2013). Small bowel damage often leads to nutrient malabsorption that can resull 
in a range of further clinical manifestations (anemia, osteopenia, failure to thrive in children). 
In addition. extra-intestinal symptoms and systemic manifestations are often present, such as 
dermatitis. infertility. or neurological and skeletal disorders (Green and Cellier. 2007). 
Mortality is increased in subjects with persistent intestinal mucosa( damage (Ludvigsson et al. 
2009). 
The most serious complication of celiac disease is the development of an in situ smal I bowel 
T cell lymphoma after many years of exposure, voluntary or inadvertent, to gluten (l...ebwohl 
el al. 2013). This malignant complication ofNRCD. which appears to be independent of gluten 
or responsive to a strict GFD, is termed Type 11 refractory celiac disease (RCD-11) when the % 
of aberrant IEL is >20% and Type I refractory celiac disease (RCD-1 ) when the % is <20%. 
Jn RCD-11, aberrant IELs proliferate in what represents a slow-growing non-llodgkin 
lymphoma localized (in siLU) in the small bowel. primarily in the epithelial compartment. RCD-
11 affect approximately 0.5% of celiacs and can lead lo overt and systemic enteropathy-
associatcd T cell lymphoma (EA TL) (Nijeboer el of, 20 I Sa). with very poor prognosis and 
>80% mortality in 5 years (N ijeboer el al. 20 15b). The incidence of EATL is increasing. and 
this increase could be related to increasing rates of gluten contamination in the diet over 
prolonged periods of time (Sharaiha el al, 2012). Finally, it should be noted that as many as 
50% of undiagnosed patients with celiac disease are asymptomatic despite the underlying 
intestinal damage and malabsorption (Walker el al. 20 I 0). which makes disease diagnosis and 
monitoring even more challenging. 
Table 2. Cha racteristics of Celiac Disease, Refractory Celiac Disease and EATL 
Nature of the 
Disease 
Celiac 
Autoimmune 
Disease 
RC D-1 
Unknown 
RCD-Il 
Malignant, slow 
growing 
EATL 
Malignant, rapid 
progression 
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Gluten 
Dependence 
Yes 
Probably 
Probably not 
No 
Aberrant 
Clonality 
Progression to 
IE Ls 
Overt Systemic 
Lymphoma 
No 
Polyclonal 
No 
Yes, <20% 
Oligo-clonal 
No 
Yes, >20% 
Monoclonal 
>50% 
(in situ 
lymphoma) 
Yes. >20% 
Monoclonal 
NIA 
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l.2.1 
Current Management of Ccliac Disease: The G luten-Free Diet 
Celiac disease is the only common autoimmune disorder with no approved medication. The 
only current available strategy for the management of celiac disease is a lifelong total 
avoidance of gluten. While simple in theory. the ubiquity of gluten in foodstuffs. medications. 
household substances. cosmetics. and gluten-free items makes total avoidance of gluten 
difficult - if not impossible. 
The main challenge to the successful maintenance of a gluten-free diet is that cereal flours are 
widely used in the food industry and are present in numerous food products either naturally or 
as additives. Although gluten-free products can be purchased. commercially manufactured 
gluten-free products may be difficult to find. tend to be less flavorful and are more expensive 
than regular gluten containing foods. In addition, labeling of food products is deficient in many 
countries. Even in countries with superior labeling guidelines foods labeled "gluten-free'· may 
nevertheless contain gluten. For example. in northern European countries amounts of up to 100 
parts per million (ppm) are petmitted in gluten-free products designated apt for celiac sufferers 
(Gibert et al, 2006). 
For these reasons, celiac sufferers are regularly exposed to gluten contamination in the food 
and beverages they consume. Th is exposure to gluten contamination and the associated 
physiological and psychological consequences results in a self-limitation or social activities 
and/or a reduction in the variety of foods consumed. Thus. the only currently available 
management option of a gluten-free diet (GFD) presents both a considerable challenge and 
substantial burden for patients. A study by Shah er al (2014) found the burden of celiac disease 
and a GFD on patient quality of life was ranked second only to end-stage renal disease - a 
condition that requires multiple, weekly dialysis treatments. 
As a result of the difficulty in maintaining total avoidance of gluten while on a GFD gluten 
contamination t:auses 50% or more of all diagnosed celiac patients on a GFD to continue to 
experience disease activity (Lee. 2003; Cranney. 2007: Hopper. 2007; Midhagen 2003 ). 
Patients who continue to have symptoms despite attempting to maintain a GFD are deemed to 
have diet ·'non-responsive celiac disease·' or NRCD. Non-responsive celiac disease has been 
defined as ··persistent symptoms. signs or laboratory abnormalities typical of celiac disease 
despite 6- 12 months of dietary gluten avoidance" (Rubio-Tapia el al, 201 3). As reqm:sted by 
patient support groups and experts, alternative treatment options that can be administered 
independently or in combination with a GFD. as well as treatments for refractory eel iac 
disease. are required in order to improve the quality of li fe for celiac patients. 
1.3 
ROLE OF IL-15 TN CELlAC DISEASE 
Substantial evidence suggests a pathophysiological role for I L-15 in eel iac disease (reviewed 
in Abadie and Jabri el al. 20 14): 
Innate immunity: 
• 
I L-15 is an essential. non-redundant growth and activation factor for the I El s 
which destroy the intl.!stinal mucosa; 
• 
The expression of 1 L-15 in the intestinal epithelium is necessary for vi l lous 
atrophy; 
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• 
In some patients. I L-15 drives progression towards lymphomagenesis and 
potentially fatal RCD-11 (Malamut et al. 20 I 0) 
Adaptive immunity: 
• 
IL-15 enhances the presentation of deamidated gluten peptides (DGP) by 
antigen-presenting cells (A PCs): 
• 
lL-15 renders the activated CD4+ T cells resistant to inhibition by regulatory T 
cells; 
• 
IL-15 has been proven to be a key factor in the loss of tolerance to food antigens 
(De Paolo et al, 20 I I; Korneychuk, et al. 20 14) 
By activating the intraepithelial lymphocytes (!Els). I L-15 is believed to be the main 
mediator in the mucosa! damage that ensues in response to gluten exposure in celiac disease 
(Korneychuk el al, 2014). The expression of IL-15 in the intestinal epithelium is necessary 
for villous atrophy in animal models of celiac disease and circumstantial evidence suggests 
this to be the case in humans. as well. In addition, IL-1 5 renders effector T cells resistant to 
inhibition by regulatory T cells (Tregs) (Abadie and Jabri, 2014). promoting loss of tolerance 
to food antigens (DePaolo et al. 20 11, Komeychuk el al. 20 14). 
One or the studied mouse models of celiac disease is an I L-1 5-transgenic mouse. in which lL-
15 overexpression by gut epithelial cells leads to celiac-like disease. including T and B cell-
rnediated pathology (Yokoyama et al, 2009 and 2011 ). IEL apoptosis has been observed in this 
animal model after treatment with anti-IL-15 (Malamut et ol 2010) or anti-IL-IS-receptor 
mAbs (Yokoyama el al 2009). 
1.4 
AMG 714 
AMG 714. a fully human immunoglobulin (lgG I K) monoclonal antibody (formerly HuMax-
IL 15, Genmab), binds to and inhibits rhe function of IL-15 in all its forms (cis, trans. soluble 
IL-15 bound to IL-15Ra). AMG 714 inhibits IL-IS-induced T cell proliferation and shows a 
dose-dependent inhibition of lL-1 5-induced TNF-a production. AMG 714 was originally 
produced in a hybridoma cell line. The hybridoma-derived material (referred to in this 
document as AMG 714-HYB) underwent preclinical testing and was subsequently evaluated 
in a Phase I and Phase 2 stud in sub· ects with rheumatoid arthritis (13aslund et al, 2005). 
AMG 714 is now 
been tested in two studies in healthy volunteers and in patients with psoriasis. All future 
clinical studies \\ill be performed with AMG 714-CHO. 
1.5 
SUMMARY OF PRE-CLI NICAL STUDIES 
The nonclinical development or AMG 714 consisted of a series or in vitro studies 
demonstrating the binding properties of AMG 7 I 4 against hi L-15: in vitro and in vivo studies 
providing proof-of-concept for the benefit of blocking the I L-15 pathway in celiac disease: and 
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a series of GLP studies evaluating che nonclinical safety profile of Hu714MuXHu. the AMG 
714 surrogate molecule active in macaques. The full description of the pre-clinical studies can 
be found in the Investigator's Brochure. 
1.5.1 
Pharmacology 
In nonclinical experiments conducted with the original hybridoma-derived antibody, AMG 
714-HYB was found to recognize an epitope that is essential for the interaction between human 
IL-15 (hlL-15) and its receptor complex. AMG 7 I 4-1 IYB showed a dose-dependent inhibition 
of lL-1 5-induced proliferation of peripheral blood T cells, and cell lines expressing IL- 15 
receptors. as well as a dose-dependent inhibition of hl L- 15-induced TNF-a production. 
Specificity for IL-15 was demonstrated by lack of inhibitory effects on human IL-2 (hl L-2)-
mediated proliferation of peripheral blood T cells. on hlL-2-mediated TNF-a production, or on 
IL-2 induced cytotoxic T cell line (CTLL2) cell proliferation. 
AMG 714-CHO was found to be efficacious in a mouse model of eel iac disease triggered by 
the transgenic expression of human IL-1 5 in the gut epithelium (Malamut el al. 20 I 0). In this 
model, AMG 714-CHO prevented IEL activation and proliferation, as well as histological 
abnormalities. In addition, AMG 714-CHO was able to induce apoptosis of human IELs in ex 
vivo culture of small intestinal explants from active celiac disease and RCD-11 patients 
(Malamut et al, 20 I 0). In this culture experiment, AMG 714-CHO resulted in a suppression of 
IL- 15-driven anti-apoplotic signaling via JAK3 and STATS. 
In vitro studies demonstrated that AMG 714-CHO had high binding affinity for hlL- 15. but 
lower affinity for macaque I L-15. Additionally. AMG 7 14-CHO neutralized hlL-15 but did not 
efficiently neutral izc macaque I L-15. To enable prccl inical studies in macaques. a surrogate 
antibody. Hu71 4MuXHu. was developed by fusing the F(ab) portion of a mouse anti-hl L-1 5 
monoclonal antibody known to neutralize macaque IL-1 5. M 111 . with human lgG I Fe. 
I lu7 I 4MuXHu was shown to neutralize macaque IL-15 with approximately the same potency 
as AMG 714-CHO neutralizes hf L-1 5. 
In a safety pharmacology study. cardiovascular, respiratory, and neurobehavioral endpoints 
were evaluated in cynomolgus monkeys that received a single intravenous (IV) bolus dose of 
~ 300 mg/kg Hu7 I 4MuXHu. In this study. the no-observed-effect level (NOEL) was 2: 300 
mg/kg. the highest dose tested. 
1.5.2 
Toxkology 
Because of the low binding affinity of AMG 714 for macaque J L-15 and the very low inhibitory 
activity of AMG 714 against macaque IL-1 5. the safety profile of AMG 714-CHO has been 
evaluated in nonclinical studies in non-human primates (cynomolgus monkeys) using the 
surrogate molecule Hu714MuXHu in a single dose safety pharmacology study (described 
above) and in repeated-dose toxicology studies. 
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1.6 
EFFECTS OF AMG 714 IN HUMANS 
The original hybridoma-derived material produced 
evaluated in sub.eels with RA in a Phase I stud 
(20030210). 
a CHO cell line. 
AMG 714-CHO was studied in a first-in-human trial to 
investigate safety. tolerability. pharmacokinetics. and pharmacodynamics in healthy subjects 
(Phase I Study 20050193) and in a proof-of-concept study in patients with psoriasis (Phase 2 
Study 20060349). To date. AMG 714 has been shown to have clinical effect in RA: tolerability 
comparable lo placebo in - 200 subjects exposed (including - 140 exposed for 12 weeks of bi-
weekly dosing): a favorable phannacokinetic profile with three weeks half-life; and no 
significant immunogenicity signal. 
All completed clinical studies of AMG 714-CHO and AMG 714-HYB are summarized in 
Table 3. 
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Table 3. Summary of AMG 714 Clinical Studies 
Study umber 
(Phase) 
AMG 714-CHO 
20050 193 
(Phase I : 
Amgen) 
Key Design Features 
Double-blind, placebo-
controlled, single SC or 
IV 
doses. 
dose-
escalat ion study 
Dose Route, Duration 
Study Population 
SC doses: 0. 30, I 00, 
300 
or 
700 
mg 
(cohorts I to 4) 
IV dose: 0 or IOOmg 
IV infusion (cohort 5)0 
Single dose 
40 healthy 
subjects 
Status 
Completed 
20060349 
Double-blind. placebo-
0 or 
150 mg SC 
22 subjects with 
Completed 11 
(Phase 
1 b/2a: 
Amgen) 
AMG 714-HYB 
Hx-TL 15-00 I 
(Phase I: 
Genmab) 
20030210d 
(Phase 2: 
Gcnmab/Amgen) 
controlled. multiple SC 
doses. dose-escalating 
study 
Double-blind. placebo-
controlled, single SC 
infusion, 
dose 
escalation, study with 
open-label. repeat-dose 
(-l weekly 
doses) follow-up 
Double-blind, placcbo-
controllcd. multiple SC 
infusion. 
parallel-
group, 
mullicenter 
study 
(cohon I) 
0 or 300 
mg SC 
(cohort 2) 
Dose every 2 weeks 
for 12 weeks 
Initial single dose: 0 or 
0.15 to 8 mg/kg SC 
infusion 
Repeated dose: 0.5 to 
4 mg/kg SC infusion 
once \veekly for 4 
weeks 
5 doses total over 8 
weeks 
0 or 40 to 280 mg SC 
infusion 
dose every 2 weeks for 
12 weeks with initial 
200% loading dose 
moderate 
to 
severe psoriasis 
30 subjects with 
RN 
180 subjects with 
RA 
• Dose escalation occurred approximately CVCI)' 4 weeks: dosing cohorts initiated sequentially. 
b l"t:rminatell early due to leek ofetTicacy in psoriasis 
Completed 
Completed 
<All 30 subjects recci\ ed initial single dose (0 or 0. 15 - 8 mg/kg AMG 714-llYll): 24 of the 30 subjects entered into 
the repeated dosing ponion (0.15 - 4 mg/kg AMO 714-1 IYB) 
d Genmab initiated study as l-Lx-1 L 15-002 
IV = intravenous: RA = rheum:itoid arthritis: C = subcutaneous 
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l.6.1 
Pharmacokinctics of AMG 714 in Humans 
1.6.1.1 
Pharmacokinetics of AMG 714-HYB 
1.6.J.2 
Pharmacokinetics of AMG 714-CHO 
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J.6.2 
Pharmacodynamics of AMG 714 in Humans 
The effects of AMG 714-HYB and AMG 714-CHO on NK cell counts were explored in three 
Phase I and 2 clinical studies (Hx-1L15-001. 200302 lO. 20060349) using imrnunophenotyping 
that included markers specific for NK cells. This analysis was based on the observed 
pharmacodynamic efTects in preclinical species. No changes in absolute or relative numbers of 
NK cells were observed in either swdy at any of the dose levels tested. This result contrasts 
with observations in cynomolgus monkeys, where a marked reduction in NK cell counts was 
noted after administration of the surrogate antibody, Hu7 l 4MuXHu. 
This difference between observations in preclinical and clinical studies appears related to a 
differential sensitivity or human versus cynomolgus monkey NK cells to IL- 15 deprivation. 
Human NK cells are not dependent on I L-15 for their survival (Lebrcc et al. 2013 ). possibly 
due lo the redundant role of ll-2 on human NK cells. 
1.7 
EFFICACY OF AMC 714 IN HUMANS 
1.7.J 
Efficacy of AMG 714-HYB in Rbeumatoid Arthritis 
1. 7.1. l 
Study Hx-ILJ 5-001 
Phase I Study I Ix-IL I 5-00 I was executed in 2 stages in subjects with RA . The first stage was 
a randomized, double-blind, placebo-controlled, single escalating dose design (0.1 5. 0.5. I .0. 
2.0. -LO, and 8.0 mg/kg AMG 714-HYB), follo-.ved by a second stage that was a repeat dose 
(0.5. 1.0. 2.0. and 4.0 mg/kg AMG 714-HYB: 5 doses over 8 weeks), open-label extension. 
Twenty-eight of 30 subjects completed Lhe single dose stage ofche study. and 20 of 24 subjects 
compleLed the repeat-dose stage. 
Evaluations of efficacy included ACR response assessment. Following a single dose of 
investigational product. the ACR20 response rate was similar in the AMG 7 14-HYB groups 
compared with placebo. However. repeated doses of AMG 714-HYB led to greater ACR20 
response rates. without a clear dose response (Baslund et al. 2005). 
1. 7. 1.2 
Study 20030210 
Jn Phase 2 Study 20030210. subjects were enrolled in two cohorts.' ith 110 subjects in Cohort 
I randomized equally to placebo or AMG 714-HYB (40. 80. 160. or 280 mg) and an additional 
70 subjects in Cohort 2 randomized equally to placebo or 280 mg AMG 714-l-IYB. The primary 
efficacy endpoint was the 14-week ACR20 response rate in the 280 mg group compared with 
placebo after 12 weeks of study treatment. Secondary endpoints included the 14-week ACR50 
and ACR70 response rates (50%, and 70% improvement in the ACR criteria from baseline): 
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ACR response rates throughout the study; the change from baseline 1n individual ACR 
components; and the disease acti ity score (DAS28). 
The ACR20 response rate in the 280-mg group (Cohorts I and 2 combined) increased over 
placebo at 14 weeks (54% vs 38%), but the difference was not statistically significant (p = 
0.097. Cochran-Mantel-1 laenszel test). However, a statistically significant difference in 
ACR20 response in the 280 mg group compared with placebo was obser ed at weeks 12 (64% 
vs 34%: p = 0.003) and 16 (66% vs 38cYo; p = 0.003). The overall distribution of the 0AS28 
scores (non-responder imputation) decreased significantly in the 280-mg group compared with 
placebo at weeks 8, 12. and 16 (p = 0.02. 0.005. and 0.0 I. respectively. Wilcoxon rank-sum 
test), with medians of 5.1 vs 6.1 , 4.9 vs 5.8. and 4.9 vs 5. 7 (280 mg vs placebo). For observed 
data, a similar trend was observed. The mean score in the 280mg group decreased from 6.8 at 
baseline to a low of 4.9 al week 16. Additionally, all of the intermediate-range dose groups 
showed an improvement over placebo. Additionally. improvements were evident in ACR 
components and especially in acute phase reactants. Beginning at week 4, concentrations of 
acute phase reactants decreased significantly in the 280 mg AMG 714-HYB group compared 
with placebo (C-reactive protein fCRP]. p < 0.000 I; erythrocyte sedimentation rate [ESRJ. p 
== 0.005). and remained significantly decreased throughout the study. Of note, CRP 
concentrations in the 280 mg AMG 714-HYB group decreased by 60% at week 4 and remained 
50% to 67% lower than CRP concentrations in the placebo group for the remainder of the 
study. SignificanL improvements also were seen in other ACR components (weeks 12 and 16) 
and in DA S28 (weeks 8, 12. and 16). 
Although the primary efficacy endpoint (significant difference in ACR20 responses at week 
14 for subjects who received 280 mg AMG 714-HYB compared with placebo) was not met. 
the overall clinical results suggested AMG 714-HYB pharmacological activity, as indicated by 
the reduction of acute phase reactant concentrations and the efficacy of AMG 714-HYB in the 
treatment of RA refractory to disease-modifying anti-rheumatic drugs (DMARDs). 
1.8 
AFETY OF AMG 714 IN HUMANS 
J .8.1 
Safety in AMG 714-HYB Clinical Studies 
1.8./. I 
Study Hx-lll 5-001 
The study results indicated that single doses of ::S 8 mg/kg and multiple doses of 4 mg/kg /\MG 
7 14-1 IYB were well tolerated. and no serious adverse e ents or infections were observed at the 
highest doses (8 mg/kg single dose. 4 mg/kg repeated dose). No deaths or serious infections 
occurred at any dose during the study. 
All 30 subjects receivt:d the initial double-blind dose, and of the 24 subjects who enrered the 
repeat dosing period. two subjects in the 0.5-mg/kg group withdrew from the study due to 
worsening of RA. and two subjects in the 4-mg/kg repeated-dose group (8 mg/kg single dose) 
withdrew consent for participation. 
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During the double-blind. single-dose periou. adverse events were reported by 8 or 30 (27%) 
subjects. and rates were similar among dose cohorts. All repo11cd adverse events were mild to 
moderate in severity. Two subjects reported infections during this period. One subject in the 
0. 15-mg/kg cohort reported herpes simplex. and I subject in the 4 mg/kg cohort reported 
nasopharyngitis. One serious adverse event occurred in a subject in the 0.15 mg/kg cohort. The 
subject was hospitalized because of RA nare and the disease flare was considered by the 
investigator to be unrelated to investigational product. One subject in the 0.5 mg/kg cohort 
reported mild pyrexia and rigors and subsequently withdrew from the study prior to continuing 
into the open-label, repeat-dose stage. Treatment is unknown, however. the subject fully 
recovered from the reported events. 
During the open-label, repeat-dose period, 15 of 24 ( 63%) subjects reported adverse e ents. 
also with simi lar rates among cohorts. All reported adverse events were mild lo moderate in 
severity. Five subjects reported infections during this period. One subject in the 0.5 mg/kg 
cohort had an upper respiratory tract infection. sinusitis, and a urinary tract infection; three 
subjects in the I mg/kg cohort had an upper respiratory tract infection. nasopharyngitis, and 
pneumonia. respectively; and one subject in the 2 mg/kg cohort had bronchitis and herpes 
simplex. One subject in the 0.5 mg/kg cohort withdrew from the study after 3 repeated doses 
due to an upper respiratory tract infection described as being moderate in severity. 
No clinically significant changes in laboratory parameters were observed. no depletion ofNK 
cells occurred. and no subject developed anti-AMG 714-HYB antibodies. 
J.8. 1.2 
Study 20030210 
/\MG 714-HYB was well Lolerated in this study at doses of up to 280 mg every other week, 
with a safety profile similar to that of placebo. There were few serious adverse events or serious 
infections and the rates were similar in the AMG 714-HYB and placebo groups; no dose-
related trends were evident. No deaths occurred during the study. 
Injection site reactions, the most common adverse event, were more frequent in the AMG 714-
HYB groups than placebo (9% vs 2%) and appeared to increase with dose (I of 21 subjects. 
5% (40 mgJ ~ 2 of23 subjects. 9% l80 mg]; 3 of22 subjects. 14% (160 mg]: 5of55 subjects. 
9% (280 mg]); no injection site reaction was considered severe or serious or led to a study 
withdrawal. Serious adverse events were reported in two (3%) subjects in the placebo group 
and in two (9%) and three (5%) subjects in the 80 and 280 mg AMG 7 14-HYB groups. 
respectively. No single event occurred in > I subject in a treatment group. Serious adverse 
events considered by the investigator as possibly re lated to investigational product were sepsis 
and deep vein thrombosis. with one (4%) event each in two subjects in the 80 mg group. 
The overall incidence of infections was similar in the placebo and 280 mg groups (24% vs 
25%. respectively). Repo11ed events for > I subject in any treatment group were bronchitis" 
influenza, nasopharyngitis, pharyngitis. upper respiratory tract infection. and urinary tract 
infection. These events occurred with similar frequency in the placebo and AMG 714-1 IYB 
treatment groups. The most freq uently occurring events in the 280mg group were 
nasopharyngitis (5% vs 2% in placebo group) and pharyngitis (5% vs 2% in placebo group). 
erious infectious events were reported by two subjects: one in the placebo group (viral 
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bronchitis). and one in the 80 mg AMG 714-HYB group (sepsis); the serious adverse event of 
sepsis led to study withdrawal. Adverse events leading to withdrawal occurred in five subjects. 
a ll of whom were in the intermediate AMG 714-HYB dose groups (I [40 mg], 2 [80 mg], and 
2 [160 mg] subjects). 
Clinical laboratory assessments showed only minor differences between placebo and AMG 
7 14-HYB treatment groups and no depletion ofNK cells. One serious event (sepsis). reported 
by a subject in the 80 mg cohort. was associated with Common Toxicity Criteria grade 4 
neutropenia. Following treatment with IV antibiotics and a blood transfusion. the subject fully 
recovered. No subject developed antibodies ro AMG 714-HYB. 
1.8.2 
Safety in AMG 714-CHO Clinical Studies 
1.8.2.l 
Study 20050193 
Of the 43 subjects enrolled in the study. 40 subjects (93%) received one dose of AMG 714 or 
placebo and were analyzed for safety. Three subjects did not receive investigational product 
{two subjects due to assessment of ineligibility and one subject due to a change in eligibility 
status). Thirty-nine or 40 subjects (98% ) completed the study; one subject who received I 00 
mg AMG 71 4 SC discontinued due to non-study related reasons. 
AMG 714 was generally well tolerated at all doses administered during the study. No deaths. 
seriou adverse events. or study discontinuations due to adverse events were reported. 
Treatment-emergent adverse events were reported across all dose levels by subjects who 
received investigational product. No relationship was apparent between the subject incidence 
of treatment-emergent adverse events and the dose of AMG 714. or between the subject 
incidence or treatment-emergent adverse events and the route of administration of AMG 71 4 
( C versus IV). Twenty of thirty subjects (67%) who received AMG 714 and seven of ten 
subjects (70%) who received placebo reported treatment-related adverse events. All but eight 
adverse events were reported as mild in severity: seven adverse events were moderate ::ind one 
event was severe. The severe adverse event was a tooth infection (placebo). and was not 
considered by the investigator ::is related to investigational product. four of the seven moderate 
adverse events were reported as related to investigational product: injection site pain (I 00 mg 
AMG 714 SC). upper respiratory tract infection (700 mg AMG 714 SC). headache ( I 00 mg 
AMG 7 14 l V). and gastroenteritis ( 100 mg AMG 714 I Y). Three of the seven moderate events 
were reported as not related to investigational product: diarrhea (placebo). lower respiratory 
tract infection (placebo). and vessel puncture site bruist: (700 mg AMG 714 SC). Among the 
forty subjects who received investigational product. the most commonly reported adverse 
event was injection itc reaction in fi ve subjects ([ 17%] (700 mg AMG 714 SC). and 2 subjects 
(20%] (placebo). All injection site reactions were considered by the investigator to be treatment 
related. Other commonly reported adverse events included headache (two in AMG 7 14 l 7%]. 
two in placebo [20%]). pharyngolaryngeal pain (four in AMG 714 [ 13%1). and upper 
respiratory tract infection (four in AMG 714 [ 13%)). No clinically important efft:cts of AMG 
7 14 on selected laboratory variables. ECGs. or other vital signs were evident. Additionally. 
treatment with AMG 714-CHO did not result in a specific reduction in NK-cells. One serum 
sample from Day 57 from I subject in cohort 5 ( I 00 mg. IV) was positive for anti-A MG 714 
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binding and neutralizing antibodies. but with no noticeable reduction in serum AMG 714 
concentration at any time during the study. 
1.8.2.2 
Study 20060349 
Subject Disposition: In total. 22 subjects were enrol led into this study; of these, 20 (9 1 %) 
subjects received at least one SC dose of investigational product and were included in the safety 
analysis set. Overall. I 7 (77%) subjects received all six planned doses of investigational 
product: 16 (73%) subjects completed all study visits and completed the study. 
Twenty subjects received ? I dose of investigational product and were im:luded in the principal 
analysis of safety (six placebo. six AMG 714 ISO mg, eight AMG 714 300 mg). There were 
no deaths. serious adverse events, or study withdrawals because of an adverse event reported 
during this study. One subject (AMG 7 I 4 300 mg) discontinued investigational product in 
response to an adverse event of worsening psoriasis, but completed all study assessments. 
Overall, most (90%) s u~jecls had ? I adverse event. Adverse events were no more common in 
the AMG 714 groups than in the placebo group and were not dose-related (fi ve 183%] AMG 
714 150 mg. seven f88%j AMG 714 300 mg. and six [100%) placebo subjects). Across 
treatment groups. the most commonly reported adverse events were headache (six subjects. 
30%), upper respiratory tract infection (four subjects. 20%). and nasopharyngitis (three 
subjects. 15%). The overall subject incidence of Lreatment-related adverse events was 45% . 
with headache being the most common among all subjects (occurring in I. 2. and 2 subjects in 
the placebo, AMG 714 I SO mg. and AMG 714 300 mg groups. respectively); no other 
treatment-related 
adverse 
event 
was 
experienced 
by 
more 
than 
one 
subject. 
lmmunophenotyping findings revealed several notable differences between subjects in the 
placebo and AMG 714 groups; however. these differences were isolated. and appeared to be 
driven by chance due to the large number of comparisons. No depletion ofNK cells occurred. 
None of the treatment differences appeared to be clinically significant. Changes from baseline 
in hematology. chemistry, and urinalysis laboratory results were not clinically meaningful. 
Out-of-range values were generally intennittent and indiscriminate. as were the minor shifts in 
either direction that were evident for most hematology and chemistry parameters. No out-of-
rangc laboratory result was reported as an adverse event. No subject developed binding, non-
neutralizing antibodies, and none of the tested samples in the immunoassay were positive for 
binding antibodies at any time point. No clinically important observations in ECG or vital signs 
were reported. 
2 
KNOWN AND ANTICIPATED RISKS 
2.1 
NATURAL 
KILLER (NK) CELL 
DEPLETION AND 
RISK O F 
INFECTION 
NK cell counts and NK cell activity were significantly decreased by blocking IL- 15 in 
cynomolgus monkeys. This effect is thought to be a consequence of a pharma<.:odynami<.: 
response. given the known role of £L- 15 in NK cell biology in monkeys and other animal 
species. Episodes of diarrhea required treatment with enronoxacin in several animals. These 
observations started approximately two to three weeks after initiation of treatment in some 
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animals and as laLc as I 0 weeks after initiation of treatment in one animal. Shigella in fections 
were diagnosed via stool culture in most or the animals treated for diarrhea episodes. Given 
the described role of N K activity in the defense against Shige!lt1 species, the observed effect 
on NK cells is considered a possible adverse event in Lhe cynomolgus monkey. 
In contrast. no reduclion of N K cells has been observed in humans. and gastroenteritis and 
cnteric infections have not been reported as a frequent adverse event in human studies. 
Experimental work has concluded that human NK cells. unlike murine and non-human primate 
NK cells, are not dependenl on IL-15 for Lheir survival and funcLion (Lebrec et al. 2013 ). The 
absence of NK cell depletion in humans reduces concerns. and the risk of enleric infections 
will be closely monitored in forthcoming clinic;al studies including the proposed CELI M-
NRCD-00 1. 
The sponsor interprets the lack of efficacy in psoriasis as suggestive of AMO 714 's selective 
effect on specific immune pathways, rather than a broad systemic immune suppression (since 
most systemic immune suppressants are efficacious in psoriasis). 
2.2 
IMMUNOGENICITY 
lmmunogenicity. as determined by the generation of anti-drug antibodies (ADA). is a potential 
risk for any biologic therapeutic. I mmunogenicity may lead lo injection reactions and to loss 
of efficacy when the antibodies are neutralizing and high-titer. 
AMG 714-HYB and J\MG 714-CHO are fully human anti-IL-1 5 monoclonal antibodies. Only 
one of the approximately 200 subjects dosed with active drug in al I four studies conducted with 
AMG 714 developed anti-AMG 714 antibodies (single time point, neutralizing), with no 
impact on PK. 
In summary. imrnunogenicity has been exceptionally reported with AMO 714, and the risk of 
immunogenicity will be closely monitored with robust and fully validated assays. 
2.3 
INJECTION SITE REACTION AND ANAPHYLAXIS 
In AMO 714 studies. injection site reactions have been mild and have appeared ' ith low 
frequency (typically below I 0%). There have not been any reports of anaphylaxis to AMO 
714. A II administrations or study drug wi II be monitored for I hour to detect any possible 
injection site reaction and/or anaphylaxis. 
3 
RATIONALE 
There is considerable unmet need in celiac disease. especially in NRCD and Type 11 refractory 
celiac disease RCD-11. Interleukin 15 (IL-1 5) is considered to be a central regulator of celiac 
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disease immunopathology and a non-redundant driver oflymphomagenesis in refractory celiac 
disease. AMG 714 is a fully human monoclonal antibody which binds to bioactive IL-15 and 
has been was well-tolerated and ' ith demonstrated clinical and biochemical effects in RA. 
AMG 714 has been studied in approximately 200 subjects to date, including approximately 
140 subjects dosed for 12 weeks. Its selectivity. favorable safety and pharmacokinetic profile 
in conjunction with the proof-of-mechanism in RA support the testing of AMG 714 in NRCD 
and RCD-11. 
The most efficient trial design for exploring proof-of-concept (POC) in celiac disease and. by 
extension. NRCD, is a gluten challenge study done in wet I-controlled celiac patients who are 
exposed to a known amount of gluten for a few months. A substantial peer-reviewed body of 
work exists demonstrating the value of gluten challenge as a diagnostic method (e.g., to 
diagnose celiac disease in subjects who initiated a GFD before receiving an accurate diagnosis) 
and well as in clinical trials (Uihdeaho et al, 20 11 : Lahdeaho et al. 2014 ). In clinical drug trials. 
the subjects continue their normal gluten-free diet and a controlled amount of gluten is added 
into an otherwise gluten-free foodstuff. A gluten challenge trial design allows POC testing with 
minimum sample size and short time of exposure to an experimental medication. Well-
controlled gluten challenge studies with doses of gluten of up to 6 g/day for 12 weeks have been 
reported to be safe in celiac patients [Lahdeaho el al. 2011 ]. as the gut mucosa recovers after 
the challenge is completed and subjects return to a strict GFD. 
The main hypothesis of this study is that AMG 714 administered once every two weeks via SC 
administration will be significantly more eflicacious than placebo in attenuating gluten-
induced small intestinal mucosa! morphological injury. and that it wi ll be safe and well 
tolerated in subjects with eel iac disease. 
The study wi ll enrol l clinically well controlled patients on a GFD. After a two-week single-
blind administration of placebo gluten. subjects will be exposed to 4 grams of gluten per day 
for I 0 weeks in the presence or absence of 150 mg or 300 mg of AMG 714-CHO administered 
every other week, beginning at the time of the single-blind placebo gluten dosing. for a total of 
I 0 weeks. Toxicology and human studies to date support the dosing regimens selected for this 
celiac study. The highest doses of AMG 714 tested in clinical trials are 700 mg single dose and 
300 mg every two weeks for 12 weeks with no safety signals identified to date. Given th~ 
acceptable safety profile observed in previous trials, Celimmune intends to dose at or below 
the levels previously demonstrated as safe in this proposed trial in celiac disease. 
The iVYLISA GIP assay wi ll be used in the study to assess whether subjects are compliant 
with the GFO before enrollment and during the single-blind placebo gluten period (i.e .. below 
a threshold of positivity) and thereafter. to confirm GFD compliance and correct consumption 
of the active gluten challenge material (i.e., neither above nor below a threshold appropriate 
for the consumption of approximately 4 grams of gluten daily for I 0 weeks: this threshold will 
be specified in the SAP and will be used for subgroup and sensitivity analyses). 
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4 
OBJECTIVES 
4.J 
PRIMARY OBJECTIVE 
The primary objective of this study is to assess Lhe efficacy of AMG 714 in attenuating the 
effects of gluten exposure in adults with celiac disease. 
4.2 
SECONDARY OBJECTIVE 
The secondary objective of this study is to assess the safety and tolerability of AMG 714 when 
administered to adult patients with celiac disease exposed to a gluten challenge. 
4.3 
EXPLORATORY OBJECTIVE 
The exploratory objective of this study is to assess the pharmacokinetics (PK), 
pharmacodynamics (PO). and PK/PD correlations of AMG 714. 
5 
ENDPOINTS 
5.1 
PRIMARY EFFICACY ENDPOINT 
• 
At1enuation of gluten-induced smal l intestinal mucosa( morphological injury. 
measured morphometrically as VH:CD ratio. 
5.2 
SECONDARY EFFICACY ENDPOINTS 
• 
Attenuation of gluten-induced small intestinal mucosa I inflammation as measured by 
the density ol'IELs. 
• 
Attenuation of gluten-induced small intestinal mucosa! morphological inju1)' using a 
grouped classification of Marsh score. 
• 
Attenuation of gluten-induced scrum antibodies: 
• 
Anti-tTG lgA 
• 
Anti-DGP lgA and lgG 
• 
Attenuation of gluten-induced clinical symptoms. as assessed by: 
• 
Bristol Stool Form Scale (BSFS) 
• 
Gastrointestinal ymptom Rating Scale (GSRS) and celiac disease GSRS 
(CeD-GSR ) 
5.3 
EXPLORATORY ENDPOINTS 
• 
Pharmacokinetics (PK). Pharmacodynarnics (PD) and Exposure/Response (PK/PD) 
• 
Dose propo11ionality, time to steady-state. and accumulation ratio based on 
Ctr0\1gh concentrations 
• 
Comparison of C trough levels with corresponding values in study 20060349 
• 
Correla lion of Crough concentrations with biomarkers of disease activity 
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• 
Physician Global Assessment of Disease (PGA) 
• 
Biomarkers of disease activity 
• 
Ccliac Disease Patient-Reported Outcome (CeD PRO) 
In subjects with dermatitis herpetiformis (DH), photography' ill be conducted according the 
study manual. Skin biopsies will be allowed per investigator's discretion but will not be part 
of this protocol. Any skin infomiation on DH will be summarized for descriptive purposes 
without fonnal statistical analysis. 
5.4 
SAFETY ENDPOINTS 
• A Es 
• Clinical laboratory tests 
• 
Physical examination 
• Vital signs 
• lmmunogenicity 
6 
STUDY DESIGN 
Protocol CELIM-NRCD-00 I is designed to be a Phase 2a randomized. double-blind. placcbo-
controlled, parallel-group study to evaluate the efficacy and safety of AMG 714 for the 
artenuation of the effects of gluten exposure in adult patients with celiac disease during a gluten 
challenge. 
After signing consent subjects will be screened for the study. All subjects who meet the study 
entry criteria will be randomized at a 1: 1: I ratio to receive 150 mg or 300 mg /\MG 7 14 or 
placebo once every two weeks for 10 weeks. Randomization' ill be stratified by sex. The 
study drug (AMG 714 or placebo) will be administered at the clinical site in a double-blind 
fashion via subcutaneous (SC) injection. Subjects wi ll remain confined to the study site for a 
minimum of I hour after each administration of study medication. 
During this time the 
Investigator and study site staff will assess the subject for AEs and collect the required PK 
samples and post dose vital signs as outlined in the study schedule of events (Table I ). 
In addition to receiving study medication (AMG 714 or placebo), all subjects will be required 
to consume either placebo gluten or active gluten administered in a single-blind fashion. 
Beginning on the day following Visit 1 (i.e. Week O/Day I, since Visit I is defined as Week 
O/Day 0) through Visit 2 (week 2/Day 14), all randomized subjects will consume placebo 
gluten. in the form of gluten-free foodstuffs (e.g. rusks) provided by the Sponsor. twice a day 
(BID) at the time of two regularly consumed gluten-free meals (chosen by the subject). 
Starting at Visit 2. subjects will switch to consume a daily total of approximately 4g of active 
gluten, provided in the form of foodstuff identical in appearance to that provided during the 
two-week single-blind placebo-gluten period. These gluten-containing foodstuffs. supplied by 
the sponsor. will be consumed in approximately 2g doses BID at the time of two regularly 
consumed gluten-free meals (as chosen by the subje1.:t) from Visit 2 (Week 2/Day 14) through 
the end of the treatment period at Visit 7 (Week 12/Day 84). Consumption of additional 
products containing gluten wi ll be prohibited and subjects will be expected to continue total 
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adherence to their former GFD from the time of screening until the follow-up study visit (Visit 
8. Week 16/Day 112). 
ubjects' adherence to GFD and consumption or provided gluten wi II be periodically a sesseLI 
via stool and urine sample testing using the iVYLISA GIP stool and urine gluten tests. ubjects 
with known or suspected aro transgressions or those suspected of non-compliance to protocol 
specified gluten dosing wi ll be counseled and allowed to continue in the study. 
A study site staff member will contact each subject by telephone both one day and one week 
after the first study drug administration in order to assess for A Es. Subjects will return to the 
cl inic every two weeks for study drug administration and/or efficacy and safety assessments 
as indicated in the study schedule of events (Table I). The final study drug administration will 
occur at Visit 6 (Week I O/Oay 70). An end-of-study efficacy assessment will be collected at 
Visit 7 (Week 12/Day 84 ). A final study visit will be conducted six weeks after the last 
administration of study drug at Week 16 (Visit 8/Day 112). 
ubjects who meet all other study entry criteria will undergo upper gastrointestinal endoscopy 
and biopsy prior to baseline (Visit I. Weck O!Day 0) and at the end of the 12-week randomized 
period while still on the gluten challenge within five days before Visit 7 (Week 12/Day 84) in 
order to assc~ s changes from baseline in VH:CD ratio. IELs. and Marsh score. If the screening 
biopsy shows villous atrophy with a VH:CD less than 1.5 ( 1.4 or lower). and after notification 
to the sponsor. rhe subject may be allowed to stay in the study but the gluten challenge will be 
not be started (or will be interrupted if the patient has been started in the challenge) and the 
subject will not be included in the main efficacy assessments. Subjects with VH:CD 1.5 or 
above will receive the gluten challenge. 
All subjects wi ll complete the BSFS at the time of each bowel movement from baseline (Visit 
I; Week O!Day 0) up to the final study visit, Visit 8 (Week 16/Day 112). Subjects wi ll complete 
the CeD PRO daily from baseline up to the final study visit. Subjects will also complete tht! 
GSRS at screening and, thereafter. weekly from baseline through the study final study visit. 
The BSFS, GSRS and CeD PRO will be completed using a handheld electronic diary at times 
specified in the Schedule of Events (Table I). 
afety will be monitored on an ongoing basis and subjects may undergo unscheduled visits for 
safety reason . if needed. Safety will be assessed throughout the study by clinical laboratory 
tests, physical examination. vital signs, and AE monitoring. 
NOTE: The ponsor may arrange with the study sites the conduct of some of the intermediate 
visits at the subject·s home. provided that appropriate healthcare personnel conducts the visit 
with similar standards to visits conducted at the study site. Visits amendable for home 
administration include Visits 3 through 5 
Figure I represents n schematic drawing of the tud) periods and visits. 
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Con lidl!ntial 

Figure 1. Study Schematic 
150 mg AMG 714 SC q2wk 
Screening Period 
(21!.0ays) 
300 mg AMG 714 SC q2wk 
Sere er 
g 
Placebo SC q2wk 
!ic~ . i:ricr t~ 
rt'ICCl"'l-:t~cr 
(10 Week Cosing Petioo) 
I 
I 
I 
I 
I 
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iWee~r. 
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.;. 
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: s•1 ZJJ 
:,~ ~2 i 
: tv ,,I 
I 
(12 Weeck R;nde>mi:ration Period) 
I 
I 
~~:k - I 
(:O Week Single-Blind Active Gluten 
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Gh . .-ten) 
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I 
vi:1t6 
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::i.t•, ~:> } 
•:o~ ~ l 'lle~I' l~ . :>1y w: 
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CELIM-NRCD-00 I 
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~ ·, u~l 

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v 

7 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Subjects will be randomized at a I: I: I allocation to receive l SO mg AMG 714 or 300 mg AMG 
71 4. or placebo once every two weeks for a total of six administrations over ten weeks. 
Randomization will be stratified by site and sex. 
8 
DURATION OF STUDY 
Screening: Up to 4 weeks (28 days) 
Double-blind randomized period: 12 weeks 
Final Visit: 4 weeks after the last double-blind randomization visit 
Duration of study per subject: Up to 20 weeks 
Duration of entire study: Approximately one year 
9 
SUBJECT POPULATION 
A total of approximately 63 males and females between the age of 18 and 80 years, inclusive. 
will be randomized into the study to in orderto obtain S 1 evaluable subjects. If the number of 
evaluable subjects is expected to be below 51 after exclusion of withdrawn and non-eva luable 
subjects (i.e. subjects dropping out of the study before Week 6. subjects with a diagnosis of 
DH and subjects with villous atrophy at baseline not provided the gluten challenge). enrollment 
in excess of 63 may be required in order to reach SI evaluable subjects. 
Subjects will undergo screening procedures within 28 days of Visit I (Week O/Day 0). Those 
subjects who meet the study entry criteria v ill be invited to participate in the study. 
9.1 
INCLUSION CRITERIA 
Subjects must fulfill all of the fo llowing inclusion criteria to be eligible for participation at 
screening and at Visit 1 (Week O/Day 0): 
I. 
Adult males or females 18 to 80 years of age, inclusive. 
2. 
Demonstrate willingness to participate in the study as documented by signed in formed 
consent. 
3. 
Subjects must have a diagnosis of celiac disease by intestinal biopsy at least 12 months 
prior to screening as confirmed by medical records. written physician statement or by 
the Kela statement, the national social security institution determining the governmental 
reimbursement for biopsy-proven celiac disease patients. 
4. 
Subjects must have been on a GFD for at least 12 consecutive months prior to screening 
and must be willing to remain on a GFD for the duration of study participation (apart 
from the Sponsor-supplied approximately 2g gluten taken BID during the 10-week 
gluten challenge period of the study). 
5. 
Negative anti-tTG (lgA at screening. 
6. 
Negative H-pylori test prior to study drug administration. 
7. 
HLA-DQ typing compatible with celiac disease provided or obtained before baseline 
biopsy. 
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8. 
BMI between 16.0 and 45.0 kg/m2• inclusive. 
9. 
Screening laboratory values within lhe following parameters: (unless investigator 
considers an abnormality to be not clinically significant) 
a) 
ALT and AST < 2.5 x the ULN. 
b) 
I lemoglobin > I 0 g/dL (> I 00 g/L in SI units). 
c) 
Platelet count > 125,000 mm 3 (> 125 x I 09 /L ). 
d) 
White blood cell count > 3.500 cells/mm3 (>3.5 x I 09/L). 
e) 
eGFR ~ 60 ml/min. 
f) 
I lbA IC <7% (<53 mmol/mol) in subjects with a diagnosis of Type I or 
Type 2 Diabelt.:s Mellitus. 
I 0. 
Females of non-childbearing potential defined as postmenopausal (>45 years of age with 
amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months and 
a serum follicle stimulating hormone [FSHJ level >40 IU/L at Screening); or 
permanently sterilized 
(eg. bilateral 
tubal occlusion. hysterectomy. 
bilateral 
salpingect0my. oophorectomy): or otherwise incapable of pregnancy. 
OR 
Females of childbearing potential (FOCBP) or males who agree to practice two highly 
effective methods of bi11h control (as detem1ined by the Investigator; one of the methods 
must be a barrier technique) from Screening through the end of study participation (Visit 
8, Week 16/Day I 12) and for 6 months after the end of the study. 
11. 
Willingness and ability to comply with sllldy procedures and protocol stipulated 
concomitant medication guidelines. 
11. 
Willingness to return for all scheduled follow-up visits. 
9.2 
EXCLUSION CRlTERl A 
Subjects will be excluded from the study if there is evidence of any of the fo llowing: 
I. 
Current diagnosis of any severe complication of celiac disease, such as RCD-1 or RCD-
11. EATL ulcerative jejunitis. or perforalion. 
2. 
., 
.>. 
4. 
Diagnosi of any autoimmune disease (other than celiac disease and DH) that might 
inlerfere with the conduct of the study or require systemic immunomodulation therapy. 
Occurrence of celiac disease-related symptoms (CeD-GSR 
>2.3) as assessed by 
screening GSRS. 
Diagnosis of any chronic. active GI disease other than celiac disease (e.g. active. 
untreated peptic ulcer. esophagilis. GEllD; active ulcerative colitis; Crohn·s disease; or 
irritable bowel syndrome) that might. in the Investigator's opinion. interfere with 
assessment of symptoms of abdominal pain. diarrhea, or other components or celiac 
disease. 
5. 
Any known . . \J'mptomatic food allergy. including an allergy to the ingredients of the 
gluten challenge vehicle that. in the opinion of the Investigator. might intertere with the 
conduct of the study or result in anaphylaxis. 
6. 
Presence of any of the follov,1ing related to in fection: 
a) 
/\ctive acute infection requiring systemic treatment (antibiotics. anti fungal. 
or antiviral) 
b) 
Active GI infection 
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c) 
Persistent or severe infection within the 3 months prior to randomization 
d) 
History of TB 
e) 
Positive IGRA tesr at screening or known recent exposure (within 6 months 
prior to screening) to a patient with active TB; subject can be enrolled if he 
or she has been successfully treated with appropriate chemoprophylax is. 
f) 
History within the 3 years prior to screening of an opportunistic infection 
typical or those seen in immunocompromised patients (e.g. herpes zoster. 
systemic candida infection, or systemic fungal infection). 
7. 
Use of systemic immune suppressants (including steroids) within 3 months or 5 half-
lives, whichever is longer, from randomization. 
8. 
Required use of a prohibited medication at the time of randomization (prohibited 
medications required for treatment of an AE occurring after randomization are 
permitted). 
9. 
Current diagnosis or history of cancer within the past 5 years, except successfully treated 
basal cell or squamous cell carcinoma, cervical carcinoma-in-situ, or early stage prostate 
cancer. 
I 0. 
Administration of a live vaccine within 14 days prior to the first dose of study drug. 
11. 
l listory or presence of clinically significant disease that in the opinion of the Investigator 
would confound the s u~j ect"s participation and follow-up in the clinical trial or put the 
subject at unnecessary risk including but not limited to: 
a) 
Cardiovascular disease (e.g., uncontrolled hypertension defined as office 
systolic blood pressure [BP] equal to or greater than 180 mmHg or office 
diastolic BP equal or greater than 110 mm/Hg). unstable angina. congestive 
heart failure worse than NY! IA. Class 11, coronary angioplasty or 
myocardial infarcrion within the last 6 months, uncontrolled atrial or 
ventricular cardiac arrhythmias cl inically significant pleural or pericardia! 
cff usion or ascites) 
b) 
pulmonary disease {e.g., severe chronic pulmonary disease) 
c) 
renal, hematological. gastrointestinal, endocrine (e.g .. poorly controlled 
diabetes), immunologic, dermatologic, neurological. or psychiatric disease 
12. 
History of significant drug or alcohol abuse during the year prior to study screening as 
obtained by medical record and/or subject report. 
13. 
History of clinically significant hypersensitivity to the study drug, any related drugs. or 
to any of the excipients. 
14. 
History of anaphylactic reactions (e.g. lgE-mediated reactions) to wheat or gluten. 
IS. 
Positive Hep B. Hep C, or HIV infection test results at the time or screening. 
16. 
Females who are pregnant or planning 10 become pregnant during the study participation 
period, or are currently breastfeeding. 
· 
17. 
Participation in another invcstigational drug or device study or treatment with an 
investigational drug within 3 months or 5 hair-lives, whichever is longer. prior to 
randomization. 
18. 
Any additional reason, which in the opinion of the Investigator, would pre cnt the 
subject from safely participating in the study or complying with protocol requirements 
including the endoscopies and biopsy collections 
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10 
CONCOMITANT MEDICATIONS 
10.1 
PROHIBITED MEDICATIONS 
The rollowing medications are not allowed at the time of randomization (Visit I. Week O/Day 
0) or throughout the study: 
• 
Systemic or intestinal immune suppressants, including steroids. Inhaled steroids for 
respiratory diseases such as asthma. and topical steroids {except intestinal) are 
permitted. 
• 
Oral pharmaceutical presentations (e.g .. capsules) of probiotic supplements. 
Probiotics in foods (e.g. yogurt) are accepted. 
• 
Chronic or continuous ora l and IV antibiotics (>2 weeks use). Topical antibiotic use is 
allowed. 
• 
Systemic anti-virals. 
• 
Systemic anti-fungals. 
• 
Live vaccines. 
• 
lnvcstigational drugs or devices. 
Note: After randomization, use of any of these medications is permitted if required for 
treatment of an AE. These medications may be started following discussion with and 
approval of the medical monitor. If discussion is not possible and approval has not been 
obtained prior to starting these medications. the situation should be discussed with the medical 
monitor promptly arter treatment has been instituted to avoid classification as a protocol 
deviation. In the absence of discussion ~ ith the medical monitor. as described, starting these 
medications following randomization will be classified as a protocol deviation. 
If the 
prohibited concomitant medication is detennined to interfere with the results of the study, 
withdrawal of the subject shall occur at the discretion of the Investigator or the sponsor (see 
Section 21 ). 
10.2 
GUIDELINES FOR THE MANAGEMENT OF ANTI-COAGULANT AND 
ANTI-PLATELET CONCOMJTANT MEDICATIONS 
Patients on concomitant anticoagulant or antiplatclet therapy are allowed to pa11icipate in the 
study. 
The investigators wil l follow the Guidelines of the Endoscopy Committee of the British 
Society for I lematology for management of these medications. These guidelines (Veitch et 
al. 2008) have been translated to Finnish and endorsed by the Finnish University Hospitals 
( Peraaho el al. 20 I 0). 
In short, anticoagulation or antiplatclet therapy should be continued. If warfarin is continued, 
then it should be ensured that the international normalized r::itio (IN R) docs not exceed the 
therapeutic range I week before the endoscopy. 1 r the JN R is above the therapeutic range. but 
less than 5, then the daily warfarin dose should be reduced until the INR returns to within the 
therapeutic range. 
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If the LNR is greater than 5, then the endoscopy should be postponed and the 
investigator should discuss the situation with the medical monitor in order to ensure the 
subject's safety. 
11 
STUDY ASSESSMENTS AND PROCEDURES 
All study procedures and their timing are summarized in the Schedule of Events (Table I). 
All visits. except the fol low-up phone calls after Visit I. the Visit 7 endoscopy and biopsy. and 
Visit 8 (Week 16/Day 112). should be conducted within ±3 days from the scheduled visit day 
relative to the randomization (unless otherwise indicated). The folio\: -up phone calls should 
be conducted within + I day from the scheduled dales. The Visit 7 endoscopy and biopsy 
should be conducted while the subject is still on the gluten challenge within 5 days before Visit 
7 {but no later than Visit 7). and Visit 8 (Week 16/0 ay 112) should be within +7 days of chc 
scheduled date. 
All study visits occurring after randomization (Visit I, Week O/Oay 0) should be based on the 
Visit I study visit date. During the 12-week randomization period. detined as the period from 
Visit I to Visit 7. if a visit occurs no more than 4 days outside of the visic window. the study 
drug can be administered and the next visit scheduled in accordance with the original visit 
calendar. Ir a late study visit should occur more than 4 days outside of the study visit window. 
lhe study drug should not be administered and a protocol deviation should be recorded. Under 
no circumstances should any two doses of study drug be administered within fewer than 7 days 
of each other. 
If a subject misses two consecutive doses of study drug, the subject should be terminated from 
the study after consultation with the Sponsor. The subject should complete the Early 
Tennination visit. A final study visit should be conducted at least 6 weeks ( + 7 days) after the 
last administration of study drug. The final study visit is not required if the last administration 
of study drug occurs 6 or more weeks prior to the Early Termination visit. 
NOTE: The Sponsor may arrange with the study sites the conduct of some of the intermediate 
visits at the subject's home. provided that appropriate healthcare personnel conducts the visit 
with similar standards to visits conducted at the study site. Visits amendable for home 
administration include Vi its 3 through 5 
11.1 
ASSESSMENTS AT EACH VISIT 
All subjects who sign an lnfom1ed Consent Form will be assigned a unique subject number. 
This number will be used for identification purposes for all study visits. 
All subjects who sign an Informed Consent but do not enter the study must have a reason 
recorded as to why randomization into the study did not occur. This information will be input 
into the Electronic Case Report Form (eCRF). 
Retesting of screening evaluations is pennitted once for each test without prior approval from 
the Sponsor. 
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Additional retesting of all other parameters may be permitted on a case by case basis after 
consultation with the study Sponsor. 
Rescreening of subjects is permitted at the discretion of the Investigator_ 
11,2 
SCREENING PERIOD 
• 
Obtain informed consent 
• 
Register the visit in the Electronic Data Capture (EDC) system. 
• 
Allow subject to complete GSRS. If subject does not meet the inclusion/exclusion 
criteria for celiac-rclated symptoms (i.e., if subject's CeD-GSRS in past week is>2.3), 
no funher resting should be conducted. The subject may be re-tested for CeD-GSRS 
once after al least a week and resume the rest of the screening procedures if :S2.3. 
• 
Rcvie ... v inclusion/exclusion criteria. For interpretation of hepatitis testing. see 
Appendix f. 
• 
Document demographics and medical history. 
• 
Collect vital signs. 
• 
Measure height and weight. 
NOTE: Height will be measured at the Screening Vi it only. Subjects will nut 
wear shoes during height measurement. Body weight is measured at all visits. 
Body weight should be obtained while the subject is wearing light weight 
clothing. Shoes will not be worn during body weight measurement. 
• 
Calculate BMI. 
• 
Document prior and concomitant medications (including prescription and over-the-
counter medit:ations, nutritional supplements. and herbal preparations taken within 30 
days or screening). 
• 
Perform physical examination Lo include an examination of general appearance: head, 
eyes. cars. nose. throat (HEENT); lymph nodes: respiratory: cardiovascular: 
gastrointestinal: mu sc ~il oskelctal: neurological. psychological and dermatological 
systems. 
• 
Perform 12-lead electrocardiogram (ECG). 
NOTE: A 12-lead resting ECG will be obtained from all subjects at the time of 
screening. 
ECGs wi ll be recorded alter the subject has been supine for 
approximately five minutes. 
Each 12-lcad ECG wi ll be evaluated by an 
appropriately qualified physician at the study site. ECG data will be evaluated 
using the following categories: 
o Normal 
o Abnormal. not clinically significant 
o Abnormal. clinically significant 
Any suspected cardiovascular AE should be followed with an additional ECG 
at the discretion of the Investigator. 
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• 
Collect stool sample for iYYLISA GIP and H-pylori testing. The stool sample should 
be collected after the subject has signed the informed consent form. 
• 
Collect blood and urine specimens for clinical laboratory testing (see Appendix B 
and/or Laboratory manual for the parameters). 
• 
Collect blood for serum pregnancy test for all FOCBP subjects. 
• 
Conduct INR if the subject is on warfarin (see section I 0.2) 
• 
Begin assessment of AEs 
• 
Schedule subject for endoscopy and biopsy procedure. 
When possible. screening clinical laboratory test results should be reviewed by the Investigator 
or appropriate. quali fied designee for clinically significant abnormalities before proceeding 
with the endoscopy and biopsy. .If this is not possible due to site scheduling or subject 
preference (i.e., subject lives too far away and does not what to make multiple visits site) 
review of the laboratory results before the biopsy procedure is not required . . 
I 1.3 
12-WEEK RANDOMlZATION PERIOD 
11.3. t 
Dosing Preparation 
The unblinded pharmacist or unbl inded study staff member assigned to the receipt and 
preparation of study drug materials (see Section 18 for guidance on study drug blinding) should 
register medication dispensing in the EDC system at least 24 hours before the first dosing visit 
to obtain a randomized treatment assignment for the subject. . 
Study drug must be thawed in refrigerated condition overnight and prepared in advance of" the 
study visit as per the guidance in Section 18 of this protocol. 
11.3.2 
Visit J (Week 0/Day 0) 
• 
Review inclusion/exclusion criteria 
• 
Document visit in EDC system. 
• 
Assign e-diary and allow subject to complete the lirst weekly GSRS and first daily CeD 
PRO 
• 
Collect vital signs prior to study drug administration. Perform physical examination to 
include an examination of general appearance; HEENT; lymph nodes; respiratory; 
cardiovascular; gastrointestinal: musculoskeletal; neurological, psychological and 
dermatological systems. 
• 
Complete PGA before study drug administration. 
• 
Collect blood and urine for clinical laboratory testing. 
• 
Collect blood sample for PK. biomarkers and anti-drug antibodies (ADA) before start 
of study drug administration. Record exact date and time of sampling. 
• 
Optional: Collect iYYLISA GIP stool sample. The stool sample may be collected in 
the clinic at the study visit or at the subject's home or preferred location no more than 
3 days before or after the scheduled study visit (a +/-3 day window). 
• 
Perform urine pregnancy test on all FOCBP subjects. 
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• 
Administer study medication. 
ee Section 18 for administration procedures. 
NOTE: Subject should remain in the clinic for a minimum of I hour after study 
drug administration to monitor for new A Es. 
• 
Collect vital signs JO minutes after study drug administration. Record time and date of' 
collection. 
• 
Assess AEs. 
• 
Monitor for changes to concomitant medications. 
• 
Remind subjects to complete the BSFS at each occurrence of a bowel movement ancl 
the CeD PRO daily. 
• 
Remind subject to complete the weekly GSRS. 
• 
Dispense single-blind placebo gluten product and instruct subject to begin consuming 
the product the next day at the first regularly scheduled gluten-free meal. The product 
should be consumed BID at two regularly scheduled gluten-free meals of thc subject's 
choosing. The placebo gluten should be consumed at the same time each day at the 
same meal. 
NOTE: Al no time should subject be made aware that he or she is consuming placebo 
or active gluten. 
• 
Provide subject with iYYLISA GIP test kit(s) and instructions for home collection. 
11.3.3 
Safety Phone Calls (Week O/Day 1 & Week 1/Day 7) 
• 
Assess AEs. 
• 
Monitor for changes to concomitant medicntions. 
• 
Remind subjects to complete the BSF at each occurrence of a bowel movernenc and 
the CeD PRO daily. 
• 
Remind subject to complete the weekly GSRS. 
l l.3A 
Visit 2 (Week 2/Day 14) 
• 
Document visit in EDC system. 
• 
Collect vical signs. 
• 
Perform physical examination to include an examination of general appearance: 
H EENT; lymph nodes; respiratory: cardiovascular: gastrointestinal: musculoskeletal: 
neurological, psychological and dermatological systems. 
• 
Complete the PGA before study drug administration 
• 
Collect blood and urine for clinical laboratory testing. 
• 
Collect blood sample for PK. biomarkers and ADA be.fore study drug administration. 
Record exact date and time of sampling. 
• 
Optional: Collect stool for iVYLISA GIP test. The stool sample will be collected no 
more than three days prior to or after the scheduled study visit. 
• 
Perform urine pregnancy lest on all FOCBP subjects. 
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• 
Administer study medication. See Scclion 18 for administration procedures. 
NOTE: Subject should remain in the clinic for a minimum of I hour after study 
drug administration to monitor for new AEs. 
• 
Collect vital signs JO minutes after study drug administration. Record time and dose 
of collection. 
• 
Collect any unused placebo gluten. Dispense active gluten challenge product provided 
by the Sponsor inn single-blind fashion to the subject and instrucr subject to continue 
consuming the product BIO at two regularly scheduled gluten-free meals (morning. 
midday or evening). The active gluten challenge should be consumed the same time 
each day with each selected meal. 
NOTE: At no time should the subject be made aware that he or she is 
consuming placebo or active gluten. 
• 
Assess AEs 
• 
Monitor for changes to concomitant medications. 
• 
Remind subjects to complete the BSFS at each occurrence of a bowel movement and 
CeD PRO daily. 
• 
Remind subject to complete the week ly GSRS. 
• 
Provide subject with iYYLISA GIP test kit and instructions for home collection. 
t 1.3.5 
Visit 3 (Week 4/Day 28) 
• 
Document visit in the EDC system. 
• 
Collect unused gluten challenge product. 
• 
Collect vital signs. 
• 
Perform physical examination to include an examination of general appearance: 
HEENT: lymph nodes; respiratory: cardiovascular: gastrointestinal; musculoskcletal; 
neurological, psychological and dermatological systems. 
• 
Complete PGA before study drug administration. 
• 
Collect blood and urine for clinical laboratory testing. 
• 
Collect blood sample for PK, biomarkers and ADA before study drug administration. 
Record exact date and time or sampling. 
• 
Optional: Collect stool for iVYLISA GIP test. The stool sample will be collected no 
more than three days prior to or after the scheduled study visit. 
• 
Pcrfom1 urine pregnancy test on al I FOCBP subjects. 
• 
Administer study medication. See section 18 for administration procedures. 
NOTE: Subject should remain in the clinic for a minimum of I hour after study 
drug administration to monitor for new A Es. 
• 
Collect vital signs 30 minutes after study drug administration. 
Record time or 
collection. 
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• 
Dispense active gluten challenge product provided by the Sponsor in a single-blind 
fashion to the subject and instruct subject to continue consuming the product BID at 
two regularly scheduled gluten-free meals (morning, midday or evening). The active 
gluten challenge should be consumed the same time each day with each selected meal. 
• 
Assess AEs. 
• 
Monitor ror changes to concomitant medication. 
• 
Remind subject to complete the BSF at each occurrence of a bowel movement and 
the CeD PRO daily. 
• 
Remind subject to complete the weekly GSRS. 
• 
Provide subject with iVYLISA GIP lest kit and instruction for home collection. 
11.3.6 
Visit 4 (Week 6/Day -t2) 
• 
Document visit in EDC system. 
• 
Collect unused gluten challenge produ<.:t 
• 
Collect vital signs. 
• 
Measure body weight. 
• 
Perform urine pregnancy test on all FOCBP subjects. 
• 
Optional: Collect stool for iVYLISA GIP test. The stool sample will be collected no 
more than three days prior to or after the scheduled study visit. 
• 
Administer study medication. See Section 18 for administration procedures. 
NOTE: Subject should remain in the clinic for a minimum of I hour alter study 
drug administration to monitor for new AEs. 
• 
Collect vitals 30 minutes ofter study drug administration. Record lime or collection. 
• 
Dispense active gluten challenge product provided by the Sponsor in a single-blind 
fashion to the subject and instruct subject Lo continue consuming the product Bl 0 al 
two regularly scheduled gluten-free meals (morning. midday or evening). The active 
gluten challenge should be consumed the same time each day with each selected meal. 
• 
Assess AEs. 
• 
Monitor for changes to concomitant medication. 
• 
Remind subjects to complete the BSFS at each occurrence or a bowel movement and 
the CeD PRO daily. 
• 
Remind subject to complete the weekly GSRS. 
• 
Provide subject with iVYLISA GIP wst kit and instructions for home collection. 
11.3.7 
Visit 5 (Week 8/Day 56) 
• 
Document visit in the EDC system. 
• 
Collect unused gluten challenge product. 
• 
Collect vital signs. 
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• 
Perform physical examination to include an examination of general appearance; 
HEENT; lymph nodes: respiratory; cardiovascular; gastrointestinal; musculoskeletal: 
neurological. psychological and dermatological systems. 
• 
Complete PGA before study drug administration. 
• 
Collect blood and urine for clinical laboratory testing. 
• 
Collect blood sample for PK, biomarkers and ADA before study drug administration. 
Record exact time and date of sampling. 
• 
Perfom1 urine pregnancy test on all FOCBP subjects. 
• 
Optional: Collect stool for iYYLISA GIP test. The stool sample will be collected no 
more than three days prior to or after the scheduled study visit. 
• 
Administer study medication. See Section 18 for administration procedures. 
NOTE: Subject should remain in the clinic for a minimum of I hour after study 
drug administration ro monitor for new adverse events. 
• 
Collect vitals 30 minutes after study drug administration. Record time or collection. 
• 
Dispense active gluten challenge product provided by the Sponsor in a single-blind 
fashion to the subject and instruct subject to continut: consuming. the product BID al 
two regularly scheduled gluten-free meals (morning. midday or evening). The active 
gluten challenge should be consumed the same time each day ' ith each selected meal. 
• 
Assess A Es. 
• 
Monitor for changes to concomitant medication. 
• 
Remind su~jects to complete the BSFS at each occurrence of a bowel movement and 
CeD PRO daily. 
• 
Remind subject to complete the weekly GSRS. 
• 
Provide subject with iVYLJ A GIP test kit and instructions for home collection. 
11 .3.8 
Visit 6 (Week 1 O/Day 70) 
• 
Document visit in the EDC system 
• 
Col lcct unused gluten cha I lenge product. 
• 
Collect vital signs. 
• 
Perform urine pregnancy test on all FOCBP subjects. 
• 
Collect blood sample for PK and biomarker testing before study drug administration. 
Record exact time and date of sample. 
• 
Optional: Collect stool for iVYLIS/\ GIP test. The stool sample will be collected no 
more than three days prior to or after the scheduled visit. 
• 
Administer study medication. See section 18 for administration procedures. 
NOTE: Subject should remain in the clinic for a minimum of I hour afler study 
drug administration to monitor for ne\ AEs. 
• 
Collect vitals 30 minutes arter study drug administration. Record time of collection. 
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• 
Dispense active gluten challenge product provided by the Sponsor in a single-blind 
fashion to the subject and instruct subject to continue consuming the product 131 D at 
two regularly scheduled gluten-free meals (morning. midday or evening). The active 
gluten challenge should be consumed the same time each day with each selected meal. 
• 
Assess A Es. 
• 
Monitor for changes to concomitant medications. 
• 
Remind subjects to complete the BSFS at each occurrence of a bowel movement and 
the CeD PRO daily. 
• 
Remind subject to complete weekly GSRS. 
• 
Provide subject with iVYLISA GIP test kit and instructions for home collection. 
11.3.9 
Visit 7 (Week 12/Day 84) 
NOTE: DO NOT ADMINISTER ST UDY MEDICATION AT THJS VISIT 
• 
Document visit in the EDC system. 
• 
Collect all remaining unused gluten challenge product. 
• 
Collect vital signs. 
• 
Measure body weight. 
• 
Perform physical examination to include an examination of general appearance: 
HEENT: lymph nodes; respiratory: cardiovascular; gastrointestinal: rnusculoskeletal; 
neurological, psychological and dermatological systems. 
• 
Complete PG/\. 
• 
Collect blood and urine for clinical laboratory testing. 
• 
Collect blood for PK. biotnarkers and ADA. Record exact date and time of sampling. 
• 
Perform serum pregnancy test on all FOCBP subjects. 
• 
Mandatory: Collect stool lor iYYLJSA GIP testing. The stool sample will be collected 
no more than three days prior to or after the cheduled visit. 
• 
• 
Assess AEs. 
• 
Monitor for changes to concomitant medications. 
• 
Remind !\ubjects to complete the BSFS at each occurrence of a bowel movement and 
the CeD PRO daily. 
• 
Remind subject to complete the weekly GSRS. 
• 
Provide subject with iVYLJ SA GIP test kit and instructions for home collection. 
• 
Perform endoscopy and collect biopsy specimens within 5 days prior to visit. 
11.4 
FI NAL ST UDY VJSIT 
11.-4.l 
Visit 8 (Week 16/Day 112) or 6 Weeks After Last Study Drug Administration 
• 
Document visit in the EDC system. 
• 
Collect vital signs. 
• 
tleasure body weight. 
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• 
Perform physical examination to include an examination or general appearance; 
HEENT: lymph nodes: respiratory: cardiovascular: gastrointestinal: musculoskeletal; 
neurological, psychological and dermatological systems. 
• 
Complete PGA. 
• 
Collect blood and urine for clinical laboratory testing. 
• 
Collect blood for PK. biomarkers and ADA. Record exact date and time of sampling. 
• 
Perform urine pregnancy test on all FOCBP subjects. 
• 
Optional: Collect stool for iVYLISA GI P testing. The stool sample will be collected 
no more than three days prior to or after the schedule visit. 
• 
Monitor for ongoing A Es. 
• 
Monitor for changes to concomitant medications. 
• 
Collect eDiary and register subject as complete. 
1 l.5 
EARLY TERMlNATJON 
Early Termination visits should be conducted for randomized subjects (subjects who received 
double-blind treatment). Early termination visit procedures are not required for subject who 
do not receive study drug and are therefore considered screen failures. 
• 
Document visit in the EDC system. 
• 
Collect all remaining unused placebo gluten or gluten challenge product. 
• 
Collect vital signs. 
• 
Measure body weight. 
• 
Perform physical examination to include an examination or general appearance; 
I lEENT; lymph nodes: respiratory; cardiovascular; gastrointestinal: musculoskeletal; 
neurological. psychological and dermatological systems. 
• 
Complete PGA. 
• 
Collect blood and urine for laboratory testing. including urine for gluten testing. 
• 
Collect blood sample for PK, biomarkers and ADA. Record exact dale and time of 
sampling. 
• 
Perform scrum pregnancy test on all FOCBP subjects. 
• 
All attempts should be made to collect a final iYYLISA G IP stool sample during the 
Early Termination visit, if a subject does not bring to the study site a sample that was 
col lected no more than three days prior to the visit. 
• 
Collect eDiary and register subject as withdrawn or Early Termination. 
• 
Assess ongoing AEs. 
• 
Monitor for changes to concomitant medications. 
• 
Perform endoscopy and collect biopsy specimens, unless not indicated based on the 
subject' s condition, at the Pt's discretion. 
• 
Schedule Follow-up Visit. A follow-up visit is not required if the Early Termination 
visit occurs six or more weeks after the last ::;tudy drug administration. 
12 
DEFINITION OF END OF STUDY 
The end of study is defined as the final study visit (Visit 8: Week 16/ Day 112) for the last 
subject. 
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13 
E FFICACY ASSESSMENTS 
13.1 
HlSTOLOGICAL ASSESSMENT OF DUODENO-JEJ UNAL BJOPSY: 
VH:CD RATIO, IEL DENSITY AND MARSH SCORE 
At each time point specified in Table 1. small-bowel biopsies will be collected in order to 
perform the histological assessment of mucosa! inflammation. The primary endpoint in the 
study is the attenuation of gluten-induced reduction in small intestinal villous height to crypt 
depth (Vll:CD) ratio. assessed with a validated morphometric analysis (Taavela et al. 2013). 
Small bowel morphological injury as measured by VH:CD ratio is the most robust endpoint 
with which to assess efficacy of a medication targeting the underlying pathophysiology of celiac 
disease (Lahdeaho cl al, 2014 ). A key secondary endpoint is the attenuation of gluten induced 
small intestinal mucosal inflammation as measured by intraepithelial CD3-positive lymphocyte 
(IEL) density. The Marsh-Oberhuber score will also be calculated as a secondary endpoint 
(Marsh, 1992: Oberhuber 2000). 
At each time point specified in Table 1. approximately six to nine (6-9) fragments or specimens 
of small-bowel tissue will be taken from the second part of the duodenum distal to the ampulla 
by trans-oral upper endoscopy and forceps biopsy. Biopsies should be done in the duodenum 
02 segment, avoiding ulcerative lesions. The location and macroscopic appearance of the 
tissue will be noted in the source documents. The potential presence of any observable lesion 
such as ulcerative jejunicis will be also be captured. When necessary. samples will be re-
oriented and sectioned again until they are of good quality. The procedures will be described 
in a Study or Laboratory Manual or similar document. The fragments or specimens will be 
prioritized as fo llows: 
I) The first four ( 4) specimens collected will be fixed in I 0% formal in or other fixative. 
One (I) of them will be used for standard pathology at the site and three (3) of them 
will be embedded in paraffin wax after orientation, for analysis at the histology central 
laboratory. The Central Pathologist. blinded to treatment assignment, will assess villus 
height (YH. in micrometers) and crypt depth (CD, in micrometers) and their ratio. 
VH:CD ratio. which is the primary efficacy measure. Further, the Marsh-Obcrhuber 
core will be given (MO, ML M2. M3a. M3b. or M3c) and the density ofCD3-positi e 
IELs (cells/ I 00 epithelial cells) will be assessed. Histology analysis will be performed 
following standard operating procedures for fixed biopsy specimen orientation. 
paraffin embedding. cutting, staining and scanning for whole slide virtual microscopy. 
Standard operating procedures will also be followed for biopsy morphometry read ings 
using validated methods (Taavela et al, 2013). If it is not feasible to mea ure at least 3 
villus-crypt units for a su~j ect's given biopsies, even after re-cutting, the results will be 
considered not evaluable. 
2) The second two (2) specimens will be placed in mRNA preservative for future mRNA 
analysis of innammatory pathways (e.g. expression analysis ofTL-1 5-related pathways 
to potentially identify predictive biomarkers of response to MG 714) 
3) The last specimens, up to three (3). are optional and for research use. They will only be 
collected at sites with fresh tissue culture capabi Ii ties or able to ship immediately to such 
a site, and wi II be used for functional experiments and analysis of I L-15 related 
biomarkers or the impact of I L-1 5 on epithelial cell biology. In particular, one specimen 
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from approximately 15 subjects (baseline and Week 12) will be used in Finland for 
crypt cell mini-gut cultivation to study biomarkers of epithelial cell di fferentiation in 
the crypt-villus axis. 
Every effort will be made to collect all 6-9 specimens. but if this number cannot be reached. 
the specimens will be allocated in the order indicated. 
13.2 
SEROLOGY: 
ANTI-TISSUE 
TRANSGLUTAMlNASE 
AND 
ANTl-
DEAMIDATED GLJADIN PEPTIDES ANTIBODIES 
Anti-tTG auto-antibodies, while not very responsive to modest dietary transgressions, are very 
specific for celiac disease activity and constitute an important tool to asses disease modification 
(Uihdeaho el al, 2011 ; Kelly et al. 201 3). Blood will be collected for determination of scrum 
anti-tTG (lgA throughout the study and lgG also at screening) by immunoassay al times 
indicated on the Schedule of Events (Table I ). 
Anti-deamidated gliadin peptide (DGP) antibodies (anti-DGP), lgA or lgG, may be positive in 
some patients with celiac disease who are negative for anti-tTG, due to their different kinetics 
and to the possibility of lgA deficiency. in which case, DGP lgG are the most reliable 
antibodies (Brusca. 20 15). Blood wil l be collected for determination of serum DGP antibodies 
(lgA and lgG) at times indicated on the Schedule of Events (Table 1 ). 
13.3 
DRJSTOL STOOL FORM SCALE 
The Bristol Stool Form Scale (BSFS, Appendix C) is a pictorial aid to help subjects identi fy 
the shape and consistency of their bowel movements during the study (Riegler el al 2001 ). 
Subjects will be asked lo complete this form daily using an electronic diary at the time of each 
bowel movement from randomization through the Final Study Visit (Visit 8: Week 16/Day 
11 2). If no bowel movements were experienced by the subject on any given day, the subject 
should document this using the electronic diary. 
13.4 
GASTROINTESTINAL SYMPTOM RATING SCALE (GSRS) 
The GSRS (Appendix 0 ) is a 15-question 7 scale questionnaire used to assess fi c dimensions 
of gastrointestinal syndromes: diarrhea, indigestion, constipation, abdominal pain and renux 
(Svedlund et al 1988). While not specific for celiac disease, the GSRS is widely used in 
gastrocnterology and has been used in several clinical trials of experimental medications in 
celiac disease, thus becoming a very useful tool with abundant existing reference data (Kelly 
el al 201 3: Uihdeaho et al. 20 11; Leffler el al, 20 15). The "Celiac Disease GSRS" (CeD-
GSRS: Leffler et al, 20 15) is a subset of the GSRS that focuses on the ten questions or the 
GSRS which are most relevant Lo celiac disease: l(Pain), 4 (Hunger), 5 (Nausea). 6 
(Rwnbling), 7 (Bloating), 8 (Burping). 9 (Gas). 11 (Diarrhea). 12 (Loose stool). 14 (Urgency). 
Subjects will be asked to complete this questionnaire at the Screening Visit. in order to 
determine the CcD-GSRS. After screening randomized subjects will complete the 
questionnaire weekly using an electronic diary, from the day of randomization through the 
final study visit. 
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13.5 
CELIAC DISEASE PATIENT-REPORTED OUTCOME (CED PRO) 
Subjects will be asked to maintain a daily e-diary for the CeD PRO instrument (Appendix l) at 
times indicated on the Schedule of Events (Table I). This questionnaire was developed to 
assess symptom severity in clinical trials in subjects with ccliac disease. 
Items in the questionnaire were formulated based on one-on-one interviews with patients with 
celiac disease, thus they renect the symptoms that patients consider part of their celiac disease 
experience. The questionnaire is designed as a self-administered daily diary. to be completed 
at the same time each day. and requires less than I 0 minutes to complete. It includes 9-items 
asking participants about the severity of celiac disease symptoms they may experience each 
day. Participants arc asked to rate their symptom severity on an 11-point. 0 to I 0 scale: from 
.. not experiencing the symptom'' to "the worst possible symptom experience". Symptoms 
include abdominal cramping. abdominal pain. bloating, gas, diarrhea. loose stool. nausea. 
headache and tiredness. 
14 
EXPLORATORY ASSESSMENTS 
14.1 
PHARMACOKlNECTICS AND PHARMACODYNAMICS 
Dose proportionality, time of achievement of steady-state. and accumulation ratio between the 
first and sixth dose will be explored based on C1rough serum concentrations. Cuough values for 
each dose group following the sixth dose will also be compared with the corresponding values 
in 20060349. 
The correlation between Cmmsh values after the sixth dose and Pharmacodynamics (PD). based 
on biomarkers. will be explored. 
PK samples must be collected PRIOR to study drug administration at each time point listed in 
the schedule or events (Table I). The time and date or sampling must be carefully recorded 
and reported in the electronic case report forms (eCRFs). 
14.2 
IVYLISA GIP TESTS 
In celiac disease. identification or gluten contamination is essential for the management of the 
disease and for the successful conduct of clinical trials. Contaminating gluten is a confounding 
factor in the evaluation of a potential therapeutic effect of any experimental celiac-related 
medication, since histologic, serologic and clinical endpoints are heavily influenced by the 
presence of gluten in the dieL. 
In addition to measuring symptoms through patient reported diaries, Celimmune plans to use 
the iVYLISA GIP-S stool and urine gluten tests. gluten assays developed to detect inadvertent 
gluten consumption by measuring gluten immunogenic peptides (GIP) in feces (Camino el al. 
20 12) and urine (Moreno el al. 2015). 
The iVYLISA GIP-S test for stools is validated and will be used at screening and study end 
(mandatory) and intermediate visits (optional) per Table I. This test has a CE mark and is 
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commercially available in Europe from Biomedal SL (as a research test) and several central 
laboratories. as a laboratory-developed test. iVY LISA GIP-S m~asure s GIP in stools by 
immunoassay, a sandwich ELISA with antibody G 12, specific for an immunodominant epitopc 
of gluten that is resistant to degradation in the intestine. The lower quantification limit of rhe 
assay is 0.16 µg of GI P/g of feces and the upper quantification limit is 5 µg GIP/g of feces. In 
unpublished results from Biomedal (Deliac clinical trial; manuscript submitted). gluten in feces 
is highly correlated with signs and symptoms in celiac patients on a purported GFD. The 
sensitivity and specificity have been 96.3% and I 00%. respectively. with positive and negative 
predictive values of I 00% and 96.1 %. respectively. in the aforementioned Deliac study. The 
urine test. soon to become commercially avai lable, has shown close correlation with intestinal 
mucosa I atrophy in l:eliac patients on a purported GFD (Moreno el nl, 2015 ). 
These assays will be used in the study to assess whether the patient population is compliant 
with the GFD prior to enrollment (i.e., below a threshold of positivity in the stool test) and. 
thereafter, lo confirm consumption or the gluten challenge and lack or consumption or 
additional non-protocol gluten during the trial. The stool test detects gluten for up to seven 
days after consumption. and the urine test for 1-2 days. Testing will be done every two weeks 
- subjects should provide a urine and optional stool sample collected up to three days before 
or after the visit to the sites. in order to have a good probability of identify ing dietary 
transgressors. 
Testing will be done at a central lab. Pre-specified sensitivity analyses for dietary gluten will 
be conducted based on serial iVYLISA GIP-S stool and urine testing. Stool samples may also 
be used for microbiome analysis. as microbiomes are known to affect gluten composition and 
the biology of I L-15. 
In Finland. celiac patients consume oats as a part of their diet. The trace amounts of gluten 
present in oats will not interfere with the iYYLISA GIP test at screening or during the study 
(Real et al. 2012). 
14.3 
PHYSICIAN GLOBAL ASSESSMENT OF DISEASE 
The PGA (Appendix E) is designed to be used by the Investigator or qualified designec to 
assess the subject's disease activity at the time points specified in the tudy schedule of events 
(Table I). An attempt should be made to use the same assessor at each specified time point. 
Assessments should be made prior to study drug administration using all tools available to the 
assessor. including laboratory test values . 
.1 4.4 
BIOMARKERS OF DISEASE ACTlVITY 
Several biomarkers of disease activity will be analyzed in serum (e.g., CRP. IL-15, sJL- l 5R) 
as exploratory indicators of disease activity and potential predictors of response to AMG 714. 
Biomarkers of IL-15 biology may also be analyzed in fresh biopsies. if available at sites with 
the relevant experimental capabilities. 
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In addition, other exploratory biomarkers may be analyzed at a later time in stored samples. 
including serum (for proLeins. RNA). blood mRNA (for expression profiling. such as IL-1 5 
signature for potential predictive biomarkers). biopsy fragments (for mRNA, protein). stool 
(gluten, microbiome). urine (gluten, metabolites). Future biomarker analysis will solely be 
for the purpose of celiac disease or A MG 714 research and will be reported separately and 
not in the CSR. The sample retention timelines will be described in the informed consent and 
wi I l not be longer than 15 years. 
The DNA sample for HLA testing at screening (HLA DQ2/DQ8) to confirm celiac disease 
will be used sole!_ for that purpose and will be destroyed after Lhe result is obtained. 
Blood samples for biomarkers must be obtained PRIOR lo study drug administration at each 
time point listed in the Schedule of Events (Table I). The time and date of sampling must be 
carefully recorded and reported in the eCRFs. 
14.5 
IMMUNOGf:NlCITY 
A two-tiered immunogenicity testing approach will be used in order to detennine if a sample 
contains ADAs. Samples will be initially tested in an immunoassay (ELISA). Samples that 
test positivt: for binding antibodies will then be tested in a bioassay (CTLL-2 cell line that 
responds to recombinant human IL-15). to detect neutralizing antibodies (NAb). 
The sensitivity of the ELISA assay is approximately 20 ng/mL and the lower limit of reliable 
detection (LLRD), even in the presence of serum levels of drug, is approximately 250 ng/mL. 
The LLRD or the bioassay is approximately 1.5 µg/mL. 
In addition to these existing validated methods. the sponsor will develop and validate a 
bridging immunoassay (for binding ADA) and a target binding method (for neutralizing ADA) 
in the Meso Scale Discovery (MSD) platform to potentially improve performance. The final 
method chosen ' ill be described in the study manual and regulatory submissions. 
15 
SAFETY ASSESSMENTS 
In addition to AE monitoring (Section 22). the procedures listed in this section of the protocol 
must be performed at the required time points to monitor subject safety during the study. 
In addition to the investigators and the Sponsor, an independent Data Safety Monitoring Board 
(DSM f3) wi 11 monitor safety (Section 22.10) 
15. l 
VITAL STCNS 
The Investigator or qualified designee will obtain vital signs including temperature. blood 
pressure (sitting). pulse rate, and respiratory rate at screening and all study visits. 
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I 5.2 
PHYSICAL EXAM 
The Investigator or qualified designee wi ll perfonn a complete physical exam at times 
indicated on the Schedule of Events (Table I). The physical exam should include at a minimum 
the assessment of general appearance, HEENT. lymph nodes. respiratory system, 
cardiovascular 
system, 
gastrointestinal 
system, musculoskeletal 
system 
(including 
extremities), neurological. psychological and dermatological systems. 
15.3 
CLINICAL LABORATORY RESULTS 
Laboratory parameters. as listed in Appendix B and the Central Laboratory Manual or 
equivalent document, wi II be obtained al times indicated on the Study Schedule of Events 
(Table I). Blood and urine samples collected at the Screening visit will require a minimum of 
8 hours of fasting. 
A subject with a clinically significant laboratory finding identified at Screening shou ld not 
participate in the stud). 
All clinically significant findings during the study should be followed until resolution or until 
the finding is clinically stable. Subjects may be withdrawn from the study if the investigator 
or Sponsor deems the clinically significant finding compromises subject safety. 
Detailed information regarding the collection and handling of clinical laboratory specimens. 
including blood dra' totals for each visit and instructions for re-testing of missing or 
compromised specimens. can be found in a separate Specimen Collection and Processing 
Manual or equivalent document supplied by the Sponsor. 
15.3.J 
Pregnancy Testing 
All FOCBP will have urine or serum pregnancy tests throughout the study as outlined in 
Schedule of Events (Table I). Subjects who become pregnant during the study will be 
withdrawn from participation and the outcome of the pregnancy fo llowed. 
16 
LOCAL AND CENTRAL LABORATORIES 
Detailed information about local and central laboratory activities will be provided in a separate 
study specific Specimen Collection and Processing Manual or equivalent document. 
17 
LIFESTYLE AND DIETARY RESTRICTIONS 
Subjects must adhere to the following lifestyle and dietary restrictions: 
• 
Subjects must maintain a diet totally free of gluten. 
• 
Subject must consume the placebo gluten/active gluten product provided by the 
Sponsor 2 times daily as indicated in Section 19 of the study protocol 
• 
Subjects must be willing to return for all scheduled study visits and complete required 
study diaries 
• 
Subjects must refrain from blood donation, illicit drug use and alcohol abuse 
throughout the duration of the study. 
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18 
JNVESTIGATIONAL PRODUCTS 
18.1 
DESCRJPTION OF INVESTIGATION AL PRODUCT 
AMG 714 is a sterile solution for subcutaneous injection and will be administt:red at the study 
site by a qualified staff member in a double-blind fashion via two SC injections once every 
two weeks a total of 6 times for a maximum of I 0 weeks (+/- 3 days). 
Active clinical supply will be provided in glass vials as a frozen. clear, sterile protein solution, 
with a light yellow color. Prolonged exposure to light should be avoided. 
The characteristics and properties of AMG 714. as well as the exact volume and concentration 
of the supplied vials. wi ll be described in the Investigator"s Brochure (lB), lnvestigational 
Product Manual or equivalent document. The vials arc intended for single-dose use only. 
18.2 
PLACEBO 
Placebo will be administered at the study site by a qualified staff member in a double-blind 
fashion via two SC infusions once every two weeks a total of six time for a maximum of l 0 
weeks(+/- 3 days). 
Placebo clinical supply will be provided in glass vials as a frozen. clear, colorless. sterile 
protein-free solution. Sufficient volume will be provided to match the active drug volume to 
preserve the blind. The vials are intended for single-dose use only. 
18.3 
DOSE RATIONALE 
The selection of dosing levels for the study is based on a desire to strike the appropriate 
benefit/risk balance. On the one hand. striving for efficacy by testing an adequate dose of AMG 
714 in an attempt to prevent the presumed effects of I L-15: and, on the other hand, using a 
dose that is similar to doses used in prior studies with tolerability comparable to placebo. The 
selection of dosing levels for the CELIM-NRCD-00 I study ( 150 and 300 mg q2w SC) is thus 
based on the efficacy and safety information from completed studies. The goal of the proposed 
study i:::. to assess POC in celiac disease, hence the choice of 300 mg q2w AMG 714-CHO as 
the top dose based on the efficacy and safety of 280 mg q2w /\MG 714-H YB in RA and the 
safety of300 mg q2w AMG 714-CHO in psoriasis. given SC for 12 weeks in both studies. 
Toxicology and human studies to date support the dosing regimen selected for this study. The 
highest doses of AMG 714 studied in clinical trials arc a single SC dose of 700 mg and SC 
doses or JOO mg every rwo weeks for 12 weeks. with no safety signals identified to date. 
Initial dose selection for RA studies was based on in vitro potency and animal models. In vitro 
potency was assessed by the abili 
to inhibit human IL-l 5 mediated roliferation of the murine 
c totoxil; T cell line, CTLL-2. 
A study conducted in 
cynomolgus monkeys showed that these proteins, when given at the maximum feasible dose 
of 150 mg/kg. had nearly identical PK profiles and generally comparable pharmacodynamic 
effects as assessed by NK cell counts. 
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The dosing regimen is expected to provide trough levels above the concentration of AMG 714 
used in vitro ( L 0 µg/mL) to induce apoptosis of activated I ELs in biopsies of patients with 
active celiac disease (Malamut et al. 20 I 0). 
While there is no prior experience with AMG 714 in celiac disease nor any understanding of 
the potential PK/PD relationship in this disease. the proposed approach of testing the maximum 
doses tested in psoriasis. doses which have been found efficacious in RA, will allow the 
exploration of POC without increasing the risk of side effects. 
Serum exposure will be monitored with frequent PK sampling. Tissue effects will be monitored 
with experimental biomarkers to be measured in the biopsies to be obtained throughout the 
study. 
In summary. toxicology and human studies to date support the dosing regimens chosen for the 
celiac study. given the acceptable safety profile observed and the necessity to test high doses 
for POC in celiac. 
J 8.4 
BLINDING 
This is a double-blind. placebo-controlled study. To maintain blinding. an assigned unblinded 
study staff member wi ll be required to receive and prepare the study drug at each site. Due to 
the difference in appearance between active study drug and placebo. the ponsor will supply 
the assigned unblinded staff member at each site with syringe labels and translucent colored 
tape to wrap around each dosing syringe before allowing the syringes to be provided to blinded 
study staff members. 
18.5 
UNBLINOING 
If there is a need to unblind a subject's treatment assignment for emergency medical 
management, the Investigator will contact the Lead Medical Monitor. The Lead Medical 
Monitor, in consultation with Sponsor. will make a decision to unblind. If the decision has 
been made to unblind. a prompt written or electronic notification will be provided to the 
Investigator. 
If reporting of an AE is to be performed unblinded as per any regulatory authority's guidelines, 
study-unrelated Sponsor personnel will unblind the individual subject" s treatment group and 
will perform the unblinded reporting. No treatment group information would be shared with 
blinded srudy personnel. 
18.6 
RANDOMIZATION AN D TREATMENT ASSIGNMENT 
Subjects will be randomized at a I: I: I allocation ratio to receive AMG 714 150 mg or 300 mg 
AMG 714. or placebo every two weeks for up to I 0 weeks. The randomization will be 
stratified by site and sex. 
The unblinded pharmacist or unblinded study staff designcc wi ll be responsible for dispensing 
the study medication according to the treatment assignment provided by the EDC system. 
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18.7 
DRUG SUP PLIES, DISPENSING, STORAGE AND ACCOUNTING 
In addiLion to the information contained in this section or the study protocol. detailed 
information regarding the study drug will be provided in a separate 18, lnvestigational Product 
l\anual or equivalent document. 
18.7.1 
Packaging and Formulation 
AMG 714 will be manufactured and packaged by Amgen and distributed using the distribution 
procedures of Celimmune's chosen centralized distribution warehouse. 
Active clinical supply \\ ill be pro ided in glass vials as a frozen. clear. sterile protein solution. 
with a light yellow color. The vials supplied arc for single-dose use only. Volume and 
concentration will be provided in the IB. lnvcstigational Product Manual or equivalent 
document. 
18.7.2 
Storage 
AMG 714 must be stored in a secured -30°C (+/-10°C) freezer. protected from light in its 
original packaging. Prolonged exposure to light should be avoided. 
Efforts should be made to ensure that the preparation procedures and conditions are consistent. 
Records of the actual storage conditions for AMG 714 and placebo during the period of the 
study must be maintained and recorded ( eg, daily and continuous freezer temperatures, dace. 
time. and initials of person checking). A temperature alarm should be maintained and be used 
to alert site personnel of significant changes in freezer temperature. Unblinded study site staff 
must notify the Unblinded Sponsor Representative immediately if any clinical supply is 
exposed to excessive or uncontrolled temperatures so that possible replacement clinical 
supplies can be provided if necessary. 
18.7.3 
Preparation 
The unblinded study stuff member responsible for rece1v1ng and preparing the study 
medication must obtain the vial assignment via the EDC system a minimum of 24 hours prior 
to the scheduled subject visit. This will allow for proper thawing and preparation of the study 
drug. 
A separate lnvestigational Product Manual will provide infom1ation with regard to specific 
materials/manufacture of ancillary supplies to be provided by the study site. At a minimum 
these materials will include: 
• 
Latex free syringe and needle for study drug preparation 
• 
Needle for study drug administration 
• 
Gauze. alcohol wipes 
On the day before investigational product administration. AMG 714 must thaw overnight at 2 
to 8° C. Once tha-..ved, vials should be transferred to room temperature and gently swirled to 
ensure mixing. Vigorous shaking or vortexing should be avoided. Mixing may result in che 
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formation of small bubbles. which is normal. Preparation or the clinical supplies should be 
performed using aseptic techniques and under sterile conditions. Vials containing visible 
foreign particles should not be dispensed. Prolonged exposure to light should be avoided. 
AMG 7 14 shou ld be warmed to room temperature, for a minimum of I hour before 
administration. Light exposure should continue to be avoided. After thawing. the product may 
be stored for up to 72 hours at 5 ± 3°C. and no longer than 12 hours at room temperature. 
All prepared syringes must be labeled prior to administration with the fo llowing information: 
• 
Study number 
• 
Subject identification number 
• 
Date and time of preparation 
• 
Initials of pharmacist 
Any remaining medication in the vials should not be used. All used vials or study medication 
should be kept under quarantined conditions until accountabi lity is conducted and destruction 
instructions have been received from the Sponsor. If site SOPs do not permit retaining unused 
vials of medication alternate procedures should be agreed upon with the Sponsor in order to 
assure adequate drug accountability. 
18.7.4 
A dministration of Study Drug 
On any given day, if more than one subject is scheduled to receive study drug at the same 
research fac ility, each dose administration must be given at least 15 minutes apart. 
All doses will be split into t\. o separate syringes. one for each assigned vial, and administered 
into different sites on the subject's anterior abdominal wall. The SC injections should be 
administered in a consecutive fashion approximately 2cm apart, with the injections separated 
no more than 30 seconds. The side of the abdominal wall should be alternated at every visit 
(i.e., left side at one visit, right side at the next visit). 
The syringe should be inspected by the study staff member responsible for administering study 
drug for any visible foreign particles. If the tudy drug is not suitable for injection, it should 
be returned to the unblinded study staff member for processing. 
The study drug should be administered following the guidelines provided in the lnvestigational 
Product Manual. 
18.7.5 
Supply and Return of Drug 
At study initiation. and as needed thereafter, AMG 7 14 wi II be shipped to the assigned 
unblinded pharmacist or unblinded study staff member at the Investigator's institution. To 
maintain blinding only the assigned unblinded pharmacist or unblinded study staff member 
should check the amount and condition of the drug and enter these data into the drug 
accountability form. At the end of the study, or as directed by the Sponsor. all investigational 
product will be desrroyed or returned. Study drug must not be destroyed until destruction is 
approved by the Sponsor and written notification of destruction approval is obtained and filed. 
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18.7.6 
lnvestigational Product Accountability 
An f nvestigational Product Accountability Record for AMG 714 must be kept current and 
should contain: 
• 
The dates and quantities of investigational product received 
Manufacturing batch numbers for product received 
Subject's identification 
Date and quantity of investigational product di pensed 
The initials or the dispenser 
• 
Dose preparation records 
• 
Date and quantity of drug destroyed 
AL the end of the study, the Final lnvestigational Product Disposition Statement must be 
completed and provided to the Sponsor. 
18.8 
TREATMENT OF INVESTIGATION AL PRODUCT OVERDOSE 
There is no information available on the effects of an overdose of AMG 714. Given the known 
safety profile. no specific recommendations can be issued at this time and Investigators shall 
use clinical judgment Lo treat this potential event. 
19 
GLUTEN CHALLENGE 
J 9.1 
PLACEBO GLUTEN AND ACTIVE GLUTEN CHALLENGE PRODUCT 
The placebo gluten and active gluten challenge products must always be dispensed in a singlc-
blind fashion so as not to alert the subject to the material being consumed. 
The first t.:onsurnption of placebo gluten should occur at the time of the first regular gluten-free 
meal on the day after the first study drug administration visit (Week 0/Day l) and should be 
taken BID there afterward, at the time of the two main gluten-free meals (either breakfast. lunch, 
or dinner at the subject" s choosing) up to Visit 2 (Weck 2fDay 14 ). At Visit 2 active gluten 
challenge will be dispensed to the subject in a single-blind fashion. The subjec1 will continue 
to consume the gluten challenge material BID at the time of two regularly scheduled glutcn-
free meals (as chosen by the subject) until Visit 7; Week 12/Day 84. If a subject misses a dose 
of the placebo gluten or active gluten challenge materials at the time of a meal, the missed dose 
of gluten should be consumed as soon as possible or at the next main meal. No more than L\VO 
doses of placebo gluten or active gluten challenge material should be consumed on any one 
day. 
Screening biopsies will be read before Visit 2 if at all possible. lf a subject's screening biopsy 
result shmvs villous atrophy with a VH:CD ratio less than 1.5 (1.4 or lower), the subject may 
be allowed to stay in the study but the gluten challenge will not be started. and the subject will 
not be included in the PP population analyses. 
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Any remaining unused placebo gluten or active gluten challenge product should be returned to 
the study site and accounted for on the appropriate Sponsor provided documentation. 
19.2 
GLUTEN CHALLENGE COMPLI ANCE ASSESSMENT 
Compliance to the gluten challenge will be assessed retrospectively using the iVYLISA GIP 
gluten and urine stool tests. Any subject with known non-compliance to the gluten challenge 
during the study will be counseled by a study staff member. Subjects" ith known or suspected 
GFD transgressions or those suspected of non-compliance to protocol specified gluten dosing 
will be counseled and allowed to continue in the study. 
20 
STOPPING CRITERIA 
20. l 
INTERRUPTION OF DOSING IN AN INDIVIDUAL SUBJECT 
Due to the current safety profile, no specific stopping rules have been identified for individual 
subjects. Investigators will exercise clinical judgment to assess whether an AE merits 
discontinuation of dosing in a given subject. 
If a subject is found to have villous atrophy with crypt hyperplasia (for the purpose of this 
study, defined as VH:CO ratio less than 1.5 ( 1.4 or lower)) in the screening biopsy. the 
subject may be allowed to stay in the study and receive study drug but without active gluten 
challenge. These subjects will be excluded from the PP analysis. 
Dose escalation or reduction is not allowed. 
20.2 
INTERRUPTION OF DOSING FOR ALL SUBJ ECTS JN THE ENTIRE 
TRIAL 
If any of the fol lowing occur: 
• 
Death of any subject 
• 
Anaphylactic reaction in any s u~ject 
• 
A life-threatening AE in any subject 
The Sponsor will assemble an Independent Safety Committee (the Data Safety Monitoring 
Board. DSMB) to review the case. The committee and Sponsor will determine if a study-wide 
interruption in dosing is required. 
21 
SUBJECT COMPLETION AND WITHDRAWAL 
21. l 
SUBJECT COMPLETION 
Subjects will be considered study completers at Visit 7 (Week 12/Day 84). regardless of 
whether or not the Visit 8 (Week 16/Day 11 2) final study visit is attended. 
Randomized subjecrs who withdraw and are not losr to fo llow-up will complete the study at 
the Early Termination Visit. 
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Randomized subjects who withdraw and are considered to be lost to follow-up will complete 
the study at the last attended visit. 
21.2 
SUBJECT WITHDRAWAL 
All subjects are free to withdraw from participating in this study at any time and for whatever 
reason. specified or unspecified. without prejudice. 
Reasons for withdrawal (subjects who refuse to return for any remaining study visits) or 
discontinuation (subjects who prematurely stop the active treatment) at any time during the 
study may include but are not limited to the following: 
• 
Safety reasons, either at the discretion of' the Investigator or at the subject's request. In 
particular. subjects will be discontinued from the study if they develop severe 
complications of celiac disease that require intensive treatment (EA TL jejunitis. 
perforation. etc.). 
• 
Protocol violations at the discretion of the Sponsor. 
• 
Subject noncompliance to study procedures or schedule 
• 
Concomitant therapy that could interfere with the results of the study (the Investigator 
wi ll repo11 all such infonnation on the eCRFs and decide, in accordance with the 
Sponsor. whether the ·ubject is to be withdrawn). 
• 
Subject's decision to withdraw at any time. 
Subjects who withdraw prior to receiving the study drug will be considered screen failures. 
21.2. t 
Withdrawal Procedures 
Ir fo r any reason a subject is withdrawn or discontinues before completing the final study visit. 
the reason for tennination must be recorded in the source documents and reported on the 
appropriate eCRF. All data gathered on the subject prior to termination \Viii be made available 
to the Sponsor. 
Subjects discontinuing study drug should continue to be f'ully evaluated per the protocol event 
schedule. when possible. for safety purposes. However. if the subject discontinues before 
Week 6. the second biopsy wi ll not be collected. If a discontinuation occurs on or after Week 
6. the second biopsy will be obtained. 
22 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
22.1 
REPORTING RESPONSIBILITY 
The investigator and study staff are responsible for detecting and recording A Es and SAEs. 
during scheduled safety evaluations and whenever such information is brought to their 
anention. This section of the protocol provides definitions and detailed procedures to be 
fo llowed. 
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During each visit, the Investigator or qualified designee will assess A Es using an open question 
that does not to influence the subject" s answers. e.g., "have you noticed any change in your 
health?" 
All A Es occurring after signing of the Informed Consent, and at or before the final study visit 
must be reported regardless of suspected relationship to study drug. 
All A Es will be evaluated by the Investigator and intensity (severity) and relationships lo study 
drug wi 11 be assessed and recorded. 
Any A Es already documented at a previous assessment and designated as ongoing, should be 
reviewed at subsequent visits as necessary. If these have resolved. the resolution date should 
be documented. Changes in intensity or frequency of AEs should be recorded as separate 
events (i.e .. a new record started). 
22.2 
DEFINITION OF AN ADVERSE EVENTS 
An AE is any untoward medical occurrence (e.g., sign. symptom. disease. syndrome. 
intercurrent illness) that occurs in a study subject, fo llowing the signing of infonned 
consent, regardless of the suspected cause. Only subjects who have been exposed to study 
drug (active drug or placebo) can experience Treatment Emergent Adverse Events 
(TEAEs). Untoward experiences occurring prior to initiation of first administration of 
study drug are considered non-TEAEs. 
22.3 
SEVERITY 
Severity is used to describe the intensity of' a specific event. The event itsel i: however, may 
be of minor medical significance. Sevl.!rity. thus. is not the same as seriousness. which is 
based on outcome of the event. Seriousness. not intensity. serves as a guide for defining 
regulatory reporting obligations. 
For all AEs. severity will be recorded in the source documents and reported on the 
appropriate AE eCRF page. There are 3 levels of severity, defined as follows: 
Mild: 
Noticeable. but does not disrupt normal daily activity 
Moderate: 
Sufficient to reduce or disturb normal daily activity 
Severe: 
Incapacitating. significantly interferes with or prevents normal daily activity 
22.4 
RELATIONSHIP 
For all AEs, relationship to study drug will be recorded in the source documents and reported 
on the appropriate AE eCRF page. The Investigator must judge whether the study drug caused 
or contributed to the A E. and report it as either: 
Related (definitely, possibly or probably): when there is a reasonable 
possibility that the study drug caused or contributed to the AE; this conclusion 
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may be supported by the following observations: though these are not required 
for a determination or related: 
a. 
There is a plausible time sequence between onset of the AE and study 
drug administration: 
b. 
There is a plausible biological mechanism through which study drug 
may have caused or contributed to the AE: 
or as 
Not related: when it is highly unlikely or impossible that the study drug 
caused or i.;ontribuled to the AE; this conclusion may be supported by the 
following observations. though these are not required for a determination of 
not related: 
a. 
Another cause of the AE is evident and most plausible: 
b. 
The temporal sequence is inconsistent between the onset or the AE and 
study drug administration: 
c. 
A causal relationship is considered biologically implau ible. 
22.5 
SERIOUS ADVERSE EVENTS 
An AE is serious ir: 
• 
it was fatal (i.e., the AE caused or led to death) 
• 
it was lite threatening (i.e .. the AE placed the subject at immediate risk or 
death: an AE that hypothetically might have caused death ir it were more severe is 
not an SAE by this criterion) 
• 
it required or prolonged hospitalization (i.e., the AE resulted in a minimum 
24 hour hospitalization or prolonged a hospitalization beyond the expected length 
or stay: hospital admissions for elective medical/surgical procedures. or 
scheduled treatments are not SAEs by this criterion) 
• 
it resulted in permanent or significant disability/incapacity (i.e., the AE resulted 
in a substantial disruption orthe subject·s ability to carry out normal life functions) 
• 
it resulted in a congenital anomaly/birth defect (i.e .. an ad erse outcome in a 
child or fetus or a subject exposed lo the study drug prior to conception or 
during pregnancy) 
• 
it required significant medical or surgical intervention to prevent permanent 
impairment or damage (e.g .. hypotension requiring pressers to prevent ischemin. 
replacement of broken or malfunctioning device). 
Unexpected adverse drug reaction 
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22.6 
22.6.1 
An adverse reaction whose nature. severity, specificity and outcome are not consistent 
with the applicable product information (e.g., lnvescigaLor·s Brochure for an 
unapproved investigational product). 
SUSARs, Suspected Unexpected Serious Adverse Reactions will be reported to 
FIMEA (Finnish Medicines Agency) within IS days (or within 7 days for death or life 
threatening) as expedited reports. 
SPECIAL REPORTING SITUATIONS 
Death 
Death is an outcome of an event. The AE that resu lted in the death should be recorded and 
reported as the SA E. A ll SAEs that are fatal or life-threatening shall be reported 
expeditiously (within seven days) to Fimea_ If an autopsy is performed. efforts should be 
made to obtain the results. 
22.6.2 
Hospitalizations for Surgical or Diagnostic Procedures 
The AE leading to the surgical or diagnostic procedure should be recorded and reported 
as the SAE. The procedure should be reported as an action in response lo or treatment for 
the medical condition. 
22.6.3 
Pregnancy 
Any pregnancy that occurs during the study or within 6 months of the last dose of study 
drug should be recorded on a Pregnancy Report Form to facilitate o utcome fol low-up. 
Pregnancy should be reported whether occurring in a fema le subject or the partner of a 
male subject. Spontaneous abortion should be reported as an SAE. 
Regardless of subject sex, the Investigator should counsel the subject (and partner. 
if appropriate) regarding possible effects on the fetus and risks of continuing with rhe 
pregnancy. Monitoring should continue until conclusion of the pregnancy. 
22.6.4 
Inadvertent Exposure or Overdose 
Any inadvertent exposure or overdose of study medication should be recorded in the source 
documents and reported immediately to the Sponsor by phone and email. The exposure 
and any A Es should be reponed of the appropriate eCRF forms. 
22.6.5 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
SUSARs shall be reported by the Sponsor to the regulatory authority in Finland (f'imea) and 
to the relevant ethics cornminee to fulfill national (Medical Research Act: Regulation on 
Clinical trials on Medicinal Products in Human Subjects 2/20 12) and EU regulations 
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( .. Detailed guidance on the collection. verificalion and presentation of adverse reaction reports 
arising from clinical trials on medicinal products for human use""). 
Expedited reporting is required electronically to the regulatory authority and EudraVigilance 
database as soon as possible, however no later than within seven (7) days of the Sponsor being 
informed of fatal or life-threatening adverse reaction. 
Serious unexpected adverse reactions which are not life-threatening or fatal must be reported 
to the regulatory authorit) and EudraVigilance database as soon as possible and in any case 
within fincen ( 15) days of the sponsor first being informed. 
Once a year, the Sponsor shall provide a list of all suspected serious adverse reactions 
which ha c occurred during the period in question (Annual Safety Report) to Fimea. The 
Annual Safery Report will be accompanied by a report of the salety of participating study 
subjects prepared and signed by the Coordinating Investigator. 
The Sponsor will also inform the investigators and Fimca of any significant new 
observations relating to the safety of the AMG 714 during the study. 
12.7 
PROCEDURES FOR REPORTING ADVERSE EVENTS 
Adverse events occurring after the subject has signed informed consent will be reported in 
the source documents and recorded on the appropriate AE eCRF pages. 
It is not necessary to complete an AE eCRF page for chronic medical conditions present 
at enrollment that remain stable during the trial. However. if a medical condition 
present at enrollment worsens in intensiry or frequency, it should be reported as an AE. It 
is not necessary to complete an AE eCRF for fluctuations in the disease under study if: 
these fluctuations arc adequately captured by the efficacy assessments. and the degree 
of variation in frequency or severiry is typical of the disease under study. An AE eCRF 
must be completed if the disease course is atypical or there is development of new signs 
or symptoms related to the disease under study. 
Pis should observe the fo llowing guidelines when recording AEs on the AE eCRF pages: 
use recognized medical terms: do noL use jargon. colloquialisms or abbreviations: record a 
diagnosis (i.e.. disease or syndrome) rather than component signs and symptoms 
(e.g .. migraine rather than headache, nausea. transient visual loss): if a diagnosis is not 
feasible, record component signs and symptoms; AEs occurring secondary to other 
events (e.g .. sequelae) should be identified by the primary cause. The MeDRA dictionary 
will be used for coding the event terms. 
22.8 
PROCEDUllES FOR REPORTING SERIOUS ADVERSE EVENTS 
AEs and other specified special reporting situations require expedited reporting to the 
Sponsor regard le s of relationship to study drug. The Investigator must report all 
SAEs to Sponsor by phone AND email as soon as possible but within no 
longer than 24 hours of observing or learning of the event. The initial 
SAE report should include all case details that can be gathered within 24 hours of the 
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event. Additional SAE pages may be submitted later as the case evolves or additional 
information becomes available. 
The AE should be reported immediately to Sponsor at: 
+J 301 789 4988 
The completed SAE Report should be emailed immediately upon completion to the Sponsor 
at: 
Email: G/obaf SA Eln box@chiltem .com 
Additional relevant information or clinical follow-up should be emailed to the same 
contact as soon as it becomes available. 
22.9 
FOLLOW-UP FOR ADVERSE EVENTS AND SERJOUS ADVERSE 
EVENTS 
All A Es will be followed until resolution or until the subject"s participation in the study ends. 
Ho"vevcr. SAEs and non-serious AEs assessed by the Pl and the medical monitor as related 
to AMG 714 will be followed until resolution or until the Pl and the medical monitor assess 
them as "chronic" or '"stable,"' even if this requires extending follow-up beyond the usual 
duration of study participation. The Sponsor should be contacted regarding subject who 
require follow up beyond the usual study duration. 
22.10 
SAFETY REVIEW COMMITTEE 
Safety will be monitored throughout the study by the Sponsor and by a panel of independent 
experts, the DSMB. The DSMB will be formed before the start of study enrollment. The 
members of the DSMB will not be members of the AMG 714 study team. and will include at 
least one physician and a statistician. The DSMB is enabled and is expected to review any or 
all available study data on an ongoing basis in an unblinded fashion, as deemed appropriate for 
protection of subject safely. 
Safety findings insufficient to trigger the stopping rules may. if judged appropriate by the 
DSM B, lead to suspension of enrollment during the review. 
If any of the stopping rules are met. an ad-hoc meeting of the DSMB will occur to assess the 
adverse events or findings. Safety findings will be reported to the investigators. the IRBs/IECs, 
and any other appropriate regulatory authorities. 
After determination of the cause and significance of safety events. the DSMB is ernpowcrcJ 
to recommend continuing cnrorlment. pausing of enrollment. ceasing dosing, changing the 
protocol and study assessments lo enhance subject safety, or terminating the study, as 
appropriate. J f the investigation indicates with a high probability that the observed safety cvt.:nt 
was due to an identifiable cause other than the study drug, the DSM B may recommend 
continuation of study enrollment. 
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A separate DSMB Charter outlines the specific guidelines for all D MB activities. DSMB 
decisions will be communicated to the Investigators by the clinical study team. 
23 
DATA ANALYSIS AND STATISTICS 
In addition to this section of the study protocol. a Statistical Analysis Plan (SAP) wi ll be 
developed and finalized prior to the final database lock and unblinded data analysis. The SAP 
will provide a detailed description for the handling of missing data, subject eligibility criteria 
for the analysis, and statistical methodology for the data summary and between-group 
comparisons. 
In addition to the main analyses. pre-specified subgroup analyses may include: 
• 
Dietary transgressions (insufficient or excessive gluten consumption) based on 
serial iYYLISA GIP testing. 
• 
Sex 
• 
Site 
Non-evaluable subjects are subjects participating in the study whose endpoint data will not 
be part of the primary analysis because they are expected to behave differently with respect to 
the key study endpoints. Non-evaluable subjects are pre-specified before database lock and 
will include subjects dropping out of the study before Week 6 (insufficient duration of the 
gluten challenge), subjects with a diagnosis of DI I (expected to have less histological impact 
and less intestinal symptoms), and subjects with atrophy at baseline (YH :CD ratio 1.4 or lower) 
not provided the gluten challenge. The non-evaluable subjects will be excluded from the PP 
population but will be included in the analyses of the ITT population. Non-evaluable subjects 
are allowed to participate, as they are expected to derive benefit and the information obtained 
could result in future studies focusing on their populations. 
23.1 
SAMPLE SIZE DETERMINATION 
The sample size of approximately 63 subjects (21 subjects/am1) has been calculated to achieve 
at least - 80% power in the primary endpoint, the difference in the Baseline-to-Week-12 %-
reduction of YH:CD ratio between the two AMG 714 arms and placebo. This sample size 
provides close to 90% (88.8%) power to detect a 40-point difference between the placebo arm 
and the 300 mg high-dose arm. and close to 80% (79.3%) power to detect a 35-point difference 
between the placebo am1 and the 150 mg Im -dose arm. 
This sample size calculation is based on the following assumptions: 
• 
a=0.05. 13=80% 
• 
Analysis method: one-way A NOYA by SAS® (proc power) 
• 
SD=36 and 45%-change (decrease) in the placebo group 
• 
%-change (decrease) of I 0% in the 150 mg and 5% in the 300 mg arms 
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• 
Drop-out rate - 19% (assuming non-evaluable drop-outs plus DH <= 15% and 
non-evaluable due to technical issues or villous atrophy at baseline <5%). 
These assumptions are based on the observations made in a similar 12-week gluten challenge 
study done with 3-5 grams of gluten per day (Uihdeaho et al. 2011 ). According to this sample 
size calculation including a 19% drop-out rate, 17 completed evaluable subjects/ann (5 1 
subjects) will be needed for the primary analyses. 
23.2 
POPULATIONS FOR ANALYSIS 
The populations for analysis will be PP and IIT. 
PP Population: l11e Per Protocol population will exclude non-evaluable subjects and subject 
with major protocol deviations thought to impact the abil ity to assess the effect of treatment. 
Exclusion of subjects from the PP set will be reviewed. documented and approved before the 
study is unblinded to the study Sponsor. The criteria for excluding subjects from the PP 
population will be specified in the SAP. 
ITT Population: This population consists of all randomized subjects who have received at 
least one dose of the study drug. Subjects will be analyzed in the treatment group to which 
they are randomized. Subjects with only one measurement available will be excluded from the 
IIT population for all endpoints that are defined as change from baseline. Safety population is 
by definition the same as the ITT population. 
The primary analyses of the primary and secondary endpoints will be based on the ITT 
population. The efficacy. parameters wil l also be analyzed using the PP population. 
Demographics and Safety parameters wi ll be analyzed using the ITT population. Exploratory 
endpoints wi ll use both the ITT and the PP populations. 
23.3 
MISSING DATA 
Subjects withdrawing from study drug administration before Week 6 will be excluded from 
the PP analysis and the second biopsy will not be collected. Subjects withdrawing on or after 
Weck 6 will be included and the second biopsy will be collected. Missing data after Week 6 
will be imputed and the imputation rules will be described in the SAP. 
No other data imputations will be done. 
23.4 
STATISTICAL ANALYSES 
23.4.J 
Subject Disposition 
The number of subjects randomized. completed. or discontinued from the study and the reason 
for study discontinuation will be tabulated by treatment group as appropriate. Subject count 
by analysis population will also be tabulated. 
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23.4.2 
Protocol Deviations 
Major protocol deviations will be summarized by treatment group. Subjects with major 
protocol deviations affecting the efficacy evaluation will be excluded from the PP population. 
23.4.3 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group. 
23.5 
EFFICACY ANALYSES 
23.5.J 
Primary End point 
The primary endpoint is the difference in the Baseline-to-Wcek-12 % reduction of VH:CD 
ratio between the two AMG 714 arms and the placebo arm. The villous height and crypt depth 
are measured and their ratio (VH:CD ratio) is calculated. 
The primary endpoint ' ill be tested for each of the 1wo dose levels. 150 mg or 300 mg. 
separately as fo llows: 
H JO: µ AMU 71-1 (300mg) = µPtuccbo 
against the alternative 
H 11: µ AMG 71·1 IJOOmg)-:/:- ~lf'luccbu 
and 
Hw: ~l AMG 714 (15Umg) = µPtuccbo 
against the alternative 
H ::!1 : ~l 1\Mli71J(J50mg) :/:- µ Placebo 
where µ M .. IG 714 (300mg). µ M1G 11-1 (t5omg) and µ1•1acdJc.1 denote lhe mean Baselinc-to-Week-1 2 % 
reduction ofYH:CD ratio in the high-dose. low-dose and placebo arm. respectively. Each of 
the two hypotheses will be tested using a two-sided type I error level of 5% withouL any 
adjustments for multiple comparisons. 
The primary analyses of the primary endpoint will be analyzed using analyses of" covariance 
(ANCOV /\). where baseline YH:CD ratio. ite. and sex wi ll be covariates. and treatment 
group is added as an addiLional covariate in order to test the primary hypothesis. The primary 
analyses will be based on the ITT population. Secondary analyses will be based on the PP 
populaLion. 
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As an additional exploratory analysis, aclive (both doses combined) will be tested against 
placebo. 
23.5.2 
Secondary E fficacy Endpoints 
The secondary endpoints will be described in lhc SA P and will include: 
• 
IEL: For mucosal inflammation the density of CD3-positive intraepithelial 
lymphocytes/I 00 epithelial cells will be calculated. 
• 
Marsh-Oberhuber classes, Marsh 0. I. 2. 3a-c. Grouping by converting the 
morphometric results into Marsh classes (Maki-Jilab converter). 
• 
GSRS and CeD-GSRS by week 
• 
BSFS and number bowel movements by day and week 
• 
Serology: Anti-tTG lgA and anti-DGP lgA and lgG 
The secondary efficacy endpoints will also be analyzed using both the ITT and the PP 
populations. Change in I ELs denshy will be analyzed using the same method as for the primary 
endpoint VH:CD ratio. Anti-tTG lgA and anti-DGP (lgA and lgG) will be analyzed using an 
MMRM approach. with baseline value, site, sex, and treatment group, time and a time-by-
treatment group interaction as fixed effects, subject as random effect. and an underlying 
correlation structure berween the time points providing the best fit for the model. 
The Marsh scores will be analyzed using a multinomial logistic regression model. where 
treatment group. time point. and a time point by treatment group interaction term will be 
included in the model. 
The GSRS and CeD-GSRS will be analyzed using the same method as that for the secondary 
endpoint anti-tTG lgA. 
The secondary variables of change in IELs density and anti-tTG/DGP will be analyzed using 
the same method as for the primary endpoint. 
23.5.3 
Exploratory Endpoints 
Exploratory endpoints will be described in the SAP and will include: 
• 
PK 
• 
PD and Biomarkers of disease aclivity 
• 
PKJPD relations 
• 
PGA 
• 
CeD PRO 
For PK. PD. and PK/PD correlations the fo llowing will be evaluated: 
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o 
Dose proportionality. achievement on steady-state, and accumulation ratio 
based on C1rough concentrations. 
o Comparison of Cuough levels with corresponding values in study 20060349. 
o 
Correlation or C trough concentrations with biomarkers of disease activity 
Dose proportionality will be analyzed using a power model. which ' ill be described in more 
detail in the SA P. The PK/PD correlation will be mainly assessed graphically. 
The exploratory variable will be summarized by treatment groups for both the ITT and the PP 
populations. 
23.6 
SAFETY ANALYSES 
23.6.t 
Adverse Events 
All AEs will be coded using MedDRA. The AEs will be summarized by system organ class 
(SOC). preferred term and separately by causality and severity. 
23.6.2 
Other Safety Assessments 
The fo llowing safety variables will be assessed: 
o 
Clinical laboratory tests 
o 
Physical examination 
o 
Vital signs 
For the assessment of immunogenicity. the number and percent of subjects who developed 
binding antibodies and who developed neutralizing antibodies will be determined. 
All safety variables will be summarized by treatment group. Some of the variables will be 
tabulated by treatment and by visit. 
23.6.3 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO DD). 
24 
fNTERIM ANALYSIS 
No interim analysis is planned for this protocol. 
25 
DATA MANAGEM ENT 
25. I 
CASE REPORT FORMS 
Data will be collected on electronic case report forms (eCRFs) that are specificall_ designed 
for this study. fhe Jnvestigator or designated study personnel will enter subject data into the 
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eCRFs. Only persons authorized by the Investigator to make original eCRF entries are allowed 
to make corrections. 
All eCRF entries must be verifiable from hospital or subject records. 
25.2 
DATA MANAGEMENT PLAN ANO DAT ABASE DESIGN 
Detailed information on data management will be available in the Data Management Plan 
(DMP) specifically written for this study. The study database and data entry screen design as 
well as edit checks will be defined according to the corresponding eCRf s and the study 
protocol. 
25.3 
DATA VALIDATION 
Data validation or data cleaning procedures are designed to assure validity and accuracy of 
clinical data. A Data Validation Plan wi ll specify the checks that are to be performed on subject 
data to raise data discrepancies. and will define the electronic edit checks. and data validation 
queries to be created for the study. A II study speci fie and standard data validation programming 
wi II be tested in a separate testing environment prior to use on production data. 
25.4 
MEDICAL CODING 
AEs and medical history verbatim terms will be coded using the MedDRA, latest version 
avai lable when approving the DMP. 
Concomitant Medications verbatim terms will be coded using the WI 10 DD. most recent 
version held by data management vendor. 
25.5 
DATABASE LOCK 
All data entry, validation. SAE-reconciliation and medical coding activities will be finalized 
before the database will be locked. All unnecessary user privileges to the study will be 
removed, except for the data manager who wi ll perform the database lock. 
In exceptional circumstances. when critical reasons justify. there may be a need to perform 
updates to the database arter it has been locked. A database that is locked and released for 
analysis wi ll only be unlocked if an error is identified that will significantly affect the statistical 
outcome or the primary analysis or change the safety profile of the stud}. 
26 
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APPENDIX A. ADMINISTRATIVE, ETHICAL AND REGULATORY POLlClES 
Cclimmune is the Sponsor responsible for the entire conduct of the study. 
Study Initiation 
Before staiting the study, the Sponsor will obtain written positive opinion for the start of the 
study from the Independent Ethics Committee (I EC). and written approval from the Regulatory 
Authority. Fimea, to conduct the study in Finland. 
Informed Consent Form 
An Informed Consent Form ( IC F) will be prepared by the Sponsor or its designees and will 
be approved by the Ethics Committee and Regulatory Authorities before study start. 
The ICF must be signed and dated by the subject or the subject's legally authorized 
representative before participation in the study. A copy of the signed ICF must be provided 
to the subject or the subject's legally authorized representative. The source documentation 
and e CRFs will document for each subject that informed consent was obtained prior to 
participation in the study. The signed ICF must remain in each subject's study file and 
must be available for veri fication by study monitors at any time. 
If appropriate. informed consent will be obtained in the subject's primary language using 
a qualified translation of the JCF into that language. 
Humau Research Ethics Committee (HREC) I Independent ethics committee (IEC) 
Approval 
This protocol. the ICF. any anticipated adverti!:;ing materials and relevant supporting 
information must be submitted by the Sponsor to. and approved by. the Fimea/IEC prior to 
study initiation. 
The 
ponsor is responsible for keeping Fimea and the IEC informed of amendments or 
changes to the protocol. and the progress of the study, as appropriate. The Sponsor is also 
responsible for rulfilling any conditions of approval imposed by Fimea/IEC. The Sponsor is 
responsible for keeping Fimea/IEC informed of sarety events. The Sponsor is required to 
promptly notify Fimea/I EC of all A Es which are both serious and unexpected. This generally 
means SAEs that arc not already identified in the 18 or protocol. and that are suspected to be 
related to the study drug by the Investigator (i.e., SUSA Rs. Suspected Unexpected Serious 
Adverse Reactions). Other AEs and SAEs will be reported annually to Fimea/IEC (in the 
DSUR. Development Safety Update Report). 
Case Report Forms 
Electronic CRFs as well as access to an eCRF system (including user names a passwords) will 
be supplied by Celimmune or its designee. 
Instructions for eCRF completion wi ll be provided in a separate cCRF Completion Guideline. 
The completed eCRF should be reviewed and the case book electronical ly signed. and dated 
by the Investigator. Instructions regarding eCRF completion should be followed by site 
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personnel. Data recording, verification and corrections to eCRFs should be made according 
to the instructions. 
Source documentation for subjects should be the physician/Investigator's patient records. 
and as such. wi ll be maintained at the study site. The information on the cCRFs must match 
the source documents. 
Study Monitoring Requirements 
All aspects of the study will be carefully and periodically monitored by Celimmune or its 
designee for conformance to protocol and compliance to good clinical practices (GCPs), 
standard operating procedures (SOPs). and applicable government regulations. 
One or more authorized representatives or Celimmune will periodically inspect study data, 
s u~j ects · medical records. and eCRFs in accordance with current US and European 
community GCPs (ICH E6). 
The Investigator will permit authorized representatives of relevant national and local health 
authorities, as appropriate. to inspect facilities and records pertaining to this study. 
Study Completion 
The fo llowing data and materials are required before a study can be considered complete or 
terminated. This includes but is not limited to clinical data, laboratory test results and any 
special test results from Screening through the end of study for all enrolled su~jects, eCRFs 
(rncluding correction forms) properly completed by appropriate study personnel and signed 
and dated by the Investigator, complete drug accountabi lity records; 
all regulatory 
documents (e.g., curriculum vitae for Investigator and sub investigators): a signed and dated 
protocol amendment acceptance form and HREC/IEC approval/notification (if applicable). 
Study Medication Accountability 
All study drug will be manufactured by Amgen. Inc. and provided by Sponsor and its 
designated representative. The Investigator, with the help of an unblinded pharmacist or 
unblinded study staff member, is responsible for ensuring adequate accountability of all used 
and unused study drug. This includes the acknowledgment of receipt of each shipment of 
study product (quantity and condition) and subject dispensing records. Damaged supplies 
will be replaced as appropriate. 
Accurate records of al I study drug dispensed by the study site should be recorded on the 
appropriate form. 
All drug supplies and associated documentation will be reviewed and verified by the study 
monitor. 
Disclosure of Data 
Subject Confidentiality 
Subject medical in fom1ation obtained during this study is confidential. and disclosure to 
third parties other than those noted below is prohibited. 
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Data generated by this study must be available for inspection. The regulatory authority 
responsible for pharmaceuticals and their safoty (in Finland. the Finnish Medicines Agency 
Fimea). has the right co conduct source data verification and ensure the appropriate conduct of 
the trial. This is done by comparing the trial information to the patient's original medical 
records and information regarding the patient· s state of health. On patient's consent and upon 
request by representatives of the Therapeutic Goods Administration (TGA). European 
Agency for the Evaluation of Medicinal Products (EMEA). FDA. other national or local 
hea lth authorities. and the HREC/IEC. if appropriate. it will be permissible co conduct source 
data verification also for those regulatory authorities responsible for pharmaceuticals and their 
safety in other countries where the medicine will be used. 
With the subject"s permission, medical information may be shared with his or her 
personal physician or with other medical personnel responsible for the subject's welfare. 
If the data from this study are published. the presentation fonnat will not include names. 
recognizable photos. personal information or other data which compromises the anonymity 
or participating subjects. 
The Investigator is responsible for compliance with the Finnish laws, local or institutional 
legislation and regulations related to subject privac. and confidentiality. 
Nondisclosure of Confidential Proprietary Information 
All Investigators have completed Non-Disclosure Agreements with Celimmune. Any 
confidential proprietary inform~tion. including but not limited to. information on the study 
design. 18. efficacy or AE data, study doses, or method of administration should be 
disclosed on a need to know basis for the sole purpose or conducting the study. rr any 
outside parties contact the study site regarding confidential information the study personnel 
are obligated to inform Investigator and Celimmune. 
Retention of Records 
The original trial documents must be stored for at least IS years from the end of the trial 
according to the Fimea Administrative Regulation 2/20 12. 
Records to be retained include. but are not limited to. consent forms, source documentation. 
laboratory test results. medication inventory records. and regulatory documents. 
Quality Assurance 
The e CRFs wi ll be reviewed for completeness by a clinical monitor or other representative 
of Celimmune. Electronic Case Report Forms (eCRFs) will be used for data management and 
analysis. A clinical monitor will contact the Investigator or qualified designee for corrections 
and/or clarifications of discrepant data. All data will be entered into a study database for 
analysis and reporting. A Clinical Monitoring Plan and DPM that describes the quality 
checking to be performed on the data will be produced. Upon completion of data entry. the 
database will be checked to ensure acceptable accuracy and completeness. 
Investigators and other individuals involved in study evaluations will be trained to perfonn 
the safety evaluations and activity measurements described in the protocol. ite staff will be 
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trained on performance of study procedures. The training will be performed during an 
Investigator Meeting or Site Initiation Visit according to a written training plan. 
Financing And Insurance Information 
Financing and insurance issues are addressed in the ICF and in the site contracts. 
Publication Policy 
All data generated from this study are the propeny of Celimmune. and shall be held in strict 
confidence along with all information furnished by Celimmune. Independent analyses and/or 
publication of these data by the Investigator or any member of his/her staff are not permitted 
without the prior written consent of Ce I immune. 
Should the results of this study be published the draft of the publication and the lead authors 
will be determined by a Publication Committee. 
Any formal presentation or publication of data from this trial will be considered as a joint 
publication by the lnvcstigator(s) and appropriate Sponsor personnel. Authorship \ ill be 
determined by mutual agreement. 
For multiccnter studies it is mandatory that the first 
publication is based on data from all centers, analyzed as stipulated in the protocol and not b) 
individual Investigators. Investigators participating in rnulticenter studies agree not to present 
data gathered from one center or a small group of centers before Lhe full publication. unless 
formally agreed to in wriling. Written permission to the Investigator will be contingent on the 
review by the Sponsor of the methodology and statistical analysis and any publication or 
presentation will provide for nondisclosure of Celimmune confidential or proprietary 
information. In all cases. the parties agree to ubmit all manuscripts or abstracts to all other 
parties at least 30 days prior to submission. This wil I enable all parties to protect proprietary 
information and to provide comments based on information that may not yet be available to 
other parties. Authorship of the results of this study will be designated by the Sponsor. All 
participating Investigators will be appropriately acknowledged. 
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APPENDJX B. LABORATORY PARAMETERS 
l) Screening Visit (within 28 Days of Visit 1) 
• 
Comprehensive Metabolic Panel (Albumin. Alkaline Phosphatase. LDH. ALT. A 
BUN, Calcium. Chloride, Creatinine. Glucose. Potassium, Sodium. Total bilirubin, 
Total protein) 
• 
Complete Blood Count (Hemoglobin. Hematocrit. Platelet Count. White Blood Cell 
count ( WBC) with Differential. Red Blood Cell count (RBC)) 
• 
Complement C3 & C4 
• 
HbA I C (Subjects with a diagnosis of Type I or Type 2 Diabetes only) 
• 
BioCard Celiac Test (anti-tTG lgA) 
• 
HLA-DQ (as needed) 
• 
I ICV Antibodies 
• 
HBsAg 
• 
I-ITV Antibodies 
• 
Interferon Gamma Release Assay (lGRA) 
• 
Urinalysis (Protein/Albumin. Glucose. Ketones. Blood Cells) 
• 
IELs 
• 
VJ J:CD 
• 
mRNA/DNA 
• 
iVYLISA GIP Stool Test 
• 
H-pylori Stool Test 
• 
Serum Pregnancy (All FOCBP) 
2) Visit 1 (Randomization - Week O/Day 0) 
• 
Comprehensive Metabolic Panel (Albumin. Alkaline Phosphatase. LDH. ALT, AST. 
BUN. Calcium. Chloride. Crcatinine. Glucose. Potassium. Sodium. Total bilirubin. 
Total protein) 
• 
Complete Blood Count (Hemoglobin. l lematocrit. Platelet Count. WBC with 
Differential. RBC) 
• 
Complement CJ & C4 
• 
Anti-tissue transglutaminase antibodies (lgA) 
• 
Deamidated Gliadin Peptide (lgA and lgG) 
• 
PK/PD/Biomarkcrs (including CRP) 
• 
Anti-drug antibodies 
• 
Urinalysis (Protein/Albumin, Glucose. Ketones. Blood Cells) 
• 
iVYLI A GIP Stool Test (optional) 
• 
iVYDAL Urine Sample 
• 
Urine Pregnancy (All FOCBP) 
3) Visit 2 (Weck 2!Day 14) 
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• 
Comprehensive Metabolic Panel (Albumin, Alkaline Phosphatase, LOH, ALT. AST. 
BUN, Calcium. Chloride, Creatinine, Glucose, Potassium, Sodium. Total bilirubin, 
Total protein) 
• 
Complete Blood Count (Hemoglobin. Hematocrit, Platelet Count. WBC with 
Differential, RBC) 
• 
Complement C3 & C4 
• 
PK./PO/Biomarkers (including CRP) 
• 
Anti-drug antibodies 
• 
Urinalysis (Protein/Album in. Glucose, Ketones, Blood Cells) 
• 
iVYLISA Gf P Stool Test (optional) 
• 
iVYDAL Urine Sample 
• 
Urine Pregnancy (All FOCBP) 
4) Visit 3 (Week 4/Day 28) 
• 
Comprehensive Metabolic Panel (Albumin. Alkaline Phosphatase, LOH, ALT. AST, 
BUN, Calcium, Chloride, Creatinine, Glucose, Potassium, Sodium. Total bilirubin, 
Total protein) 
• 
Complete Blood Count (Hemoglobin, Hernatocrit, Platelet Count, WBC with 
Differential, RBC) 
• 
Complement C3 & C4 
• 
Anti-tissue transglutaminase antibodies (lgA) and anti-DGP (lgA and lgG) 
• 
PK/PO/Biomarkers (including CRP) 
• 
Anti-drug antibodies 
• 
Urinalysis (Protein/Albumin. Glucose. Ketones. Blood Cells) 
• 
iYYLISA GIP Stool Test (optional) 
• 
iYYOAL Urine Sample 
• 
Urine Pregnancy (All FOCBP) 
5) Visit 4 (Week 6/Day 42) 
• 
iVYLISA GIP Stool Test (optional) 
• 
Urine Pregnancy (All FOCBP) 
6) Visit 5 (Weck 8/0ay 56) 
• 
Comprehensive Metabolic Panel (Albumin, Alkaline Phosphatase. LDH. ALT. AST. 
BUN. Calcium. Chloride, Creatinine. Glucose. Potassium, Sodium. Total bilirubin, 
Total protein) 
• 
Complete Blood Count (Hemoglobin. Hematocrit. Platelet Count. WBC with 
Di fferential, RBC) 
• 
Complement C3 & C4 
• 
Anti-tissue transglutaminase antibodies (lgA) and anti-DGP (lgA and LgG) 
• 
PK/PD/Biomarkers (including CRP) 
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• 
Anti-drug antibodies 
• 
Urinalysis (Protein/Albumin. Glucose, Ketones. Blood Cells) 
• 
iVYLISA GIP Stool Test (optional) 
• 
iVYDAL Urine Sample 
• 
Urine Pregnancy (All FOCBP) 
7) Visit 6 (Week 10/Day 70) 
• 
PK/PD/Biomarkers (including CRP) 
• 
iVYLISA GIP tool Test (optional) 
• 
Urine Pregnancy (All FOCBP) 
8) Visit 7 (Week 12/Day 84) OR Early Termination Visit 
• 
Comprehensive Metabolic Panel (Albumin, Alkaline Phosphatase, LOH. ALT. AST. 
BUN. Calcium. Chloride, Crcatinine. Glucose. Potassium. Sodium. Total bilirubin. 
Total protein) 
• 
Complete Blood Count (Hemoglobin, Hematocrit. Platelet Count, WBC with 
Differential, RBC) 
• 
Complement C3 & C4 
• 
Anti-tissue transglutaminase antibodies (lgA) and anti-OGP (lgA and lgG) 
• 
PK/PD/Biomarkers (including CRP) 
• 
Anti-drug antibodies 
• 
Urinalysis (Protein/Albumin. Glucose. Ketones, Blood Cells) 
• 
iVYLISA GIP Stool Test 
• 
iVYDAL Urine Sample 
• 
IELs 
• 
VH:CO 
• 
mRNN ONA 
• 
Serum Pregnancy (All FOCBP) 
NOTE: The Early Termination biopsy will only be required for subjects who terminate on 
or after Week 6 
9) Visit 8 (Final Visit, Week J 6/Day 112) 
• 
Comprehensive Metabolic Panel (A lbumin. Alkaline Phosphatase, LOH. ALT, AST. 
BUN. Calcium, Chloride. Creatinine, Glucose. Potassium, Sodium. Total bilirubin. 
Total protein) 
• 
Complete Blood Count (Hemoglobin. Hematocrit. Platelet Count. WBC with 
Difterential. RBC) 
• 
Complement C3 & C4 
• 
/\nti-tissuc transglutaminasc antibodies (lgA) and anti-DGP (lgA and lgG) 
• 
PK/PD/Biomarkers (including CRP) 
• 
Anti-drug antibodies 
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• 
Urinalysis (Protein/Albumin, Glucose, Ketones, Blood Cells) 
• 
iVYLIS/\ GIP Stool Test (optional) 
• 
iVYDAL Urine Sample 
• 
Urine Pregnancy (All FOCBP) 
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APPENDIX C. BRISTOL STOOL FORM SCALE (BSFS) 
et•:· 
--
~ 
~ 
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Type 1 
Type 2 
Type 3 
Type 4 
Type 5 
Type 6 
Type 7 
Separate hard lumps, like nuts 
Sausage-like but lumpy 
Like a sausage but with cracks in the surface 
Like a sausage or snake, smooth and soft 
Soft blobs with clear-cut edges 
Fluffy pieces with ragged edges, a mushy stool 
Watery, no solid pieces 
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APPENDIX D. SAMPLE GASTROINTESTCNAL SYMPTOM RA T ING SCALE 
(GSRS) 
Please read th is first: 
This survey contains questions about how you have been feeling and what 
it has been like DURING THE PAST WEEK. Mark the choice that best 
applies to you and your situation with an ··x·· in the box 
I. 
Have you been bothered by PAIN OR DISCOMFORT IN YOUR UPPER 
ABDOM EN OR TH E PIT OF YOUR STOMACH during the past week? 
D 
No discomfort at all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
Severe discomfort 
D 
Very severe discomfort 
2. 
Have you been bothered by HEARTBURN during the past week? (By heartburn we 
mean an unpleasant stinging or burning sensation in the chest.) 
D 
No discomfort at all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
Severe discomfort 
D 
Very severe discomfort 
3. 
Have you been bothered by /\CID REFLUX during the past week? (By acid reflux we 
mean the sensation of regurgitating small quantities of acid or now of sour or bitter 
fluid from the stomach up to the throat.) 
D 
No discomfort at all 
D 
Minor discomfort 
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D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
Se ere discomfort 
D 
Very severe discomfort 
-L 
Have you been bothered by HUNGER PAINS in the stomach during the past week'? 
(This hollow feeling in the stomach is associated with the need to eat between 
meals.) 
D 
No discomfort at all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfo11 
D 
Moderately severe discomfort 
D 
evere discomfort 
D 
Very severe discomfort 
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5. 
Have you been bothered by NAUSEA during the past week? (By nausea we mean a 
feeling of wanting lo throw up or vomit.) 
D 
No discomfort at all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfo1t 
D 
Moderate ly severe discomfort 
D 
Severe discomfort 
D 
Very severe discomfort 
6. 
Have you been bothered by RUMBLING in your stomach during the past week? 
(Rumbling refers to vibrations or noise in the stomach.) 
D 
No discomfort at all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately se ere discomfort 
D 
Severe discomfort 
D 
Very severe discomfort 
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7. 
Has your stomach IClt BLOATED during rhe past week? (Feeling bloated refers to 
swelling often associated with a sensation of gas or air in the stomach.) 
D 
No discomfort at all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
Severe discomfort 
D 
Very severe discomfort 
8. 
Have you been bothered by BURPING during the past week? (Burping refers to 
bringing up air or gas from the stomach via the mouth, often associated with easing a 
bloated feeling.) 
D 
No discomfort at all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
evere discomfort 
D 
Very severe discomfort 
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9. 
Have you been bothered by PASS ING GAS OR FLATUS during the past week? 
(Passing gas or flatus refers to the need to release air or gas from the bowel, 
often associated with easing a bloated feeling.) 
D 
No discomfort at al l 
D 
Minor discomfort 
D 
Mild discomfo1t 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
Severe discomfoii 
D 
Very severe discomfort 
I 0. 
Have you been bothered by CONSTIPATION during the past week? (Constipation 
refers to a reduced ability to empty the bowels.) 
D 
No discomfort at all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
Severe discomfort 
D 
Very severe discomfort 
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11. 
Have you been bothered by DIARRHEA during the past week? (Diarrhea refers to a 
too frequent emptying of the bowels.) 
D 
No discomfort at all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfo11 
D 
toderately severe discomfort 
0 
Severe discomfo11 
D 
Very severe discomfo11 
12. 
Have you been bothered by LOOSE STOOLS during rhe past week? (Ir your stools 
(motions) have been alternately hard and loose, this question only refers to the extent 
you have been bothered by the stools being loose.) 
D 
No discomfort al all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfo11 
D 
Severe discomfort 
D 
Very severe discomfort 
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13. 
Have you been bothered by HARD STOOLS during the past week? (lf your stools 
(motions) have been alternately hard and loose. this question only refers to the 
extent you have been bothered by the stools being hard.) 
D 
No discomfort at al l 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
Severe d iscomfort 
D 
Very severe discomfort 
14. 
Have you been bothered by an URGENT NEED TO HAVE A BOW EL MOVEMENT 
during the past week? (This urgent need to go to the ioi let is often associated w ith a 
feeling that you are not in full control.) 
D 
No discomfon ac all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
Severe discomfort 
D 
Very severe discomfort 
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15. 
When going to the toilet during the past week, have you had the SENSATION OF 
NOT COMPLETELY EMPTYfNG THE BOWELS? (This feeling of incomplete 
emptying means that you still feel a need to pass more stool despite having 
exerted yourself to do so.) 
D 
o discomfo11 at all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
evere discomfort 
D 
Very severe discomfort 
PLEASE CHECK THAT ALL QUESTIONS HAVE BEEN ANSWERED! 
THANK YOU FOR YOUR COOPERATION. 
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APPENDIX E. SAMPLE PHYSICIAN GLOBAL ASSESSMENT OF DISEASE 
Based on the information available. chose the box that best represents the subject' s current 
overall disease activity: 
D 
D 
0 
Jnactive 
Mild 
Disease 
Disease 
Symptoms & Signs 
Category 
lnacti\c Disease -
Minimal 
or no 
symptoms 
thought 
to 
be 
related to celiac 
disease 
Mild Oisca-;c 
Mild recurring. or 
persistent 
S) mp1oms 
thought 
IO 
be 
secondary 
lo 
cdiac discnsc 
Moderme Disca..~c 
-
Mndcralc or a 
combination 
of 
mild 
and 
moderate 
recurring 
per~istcnt 
symptoms 
or 
thought to be Jue 
to celiac discusc 
Severe Disease -
or 
a 
Abdominal 
Pain 
Asymptomatic 
Mild 
pain 
secondary 
to 
cdiac 
disease 
occurring . eveml 
times a week 
Moderate 
abdominal 
pain 
thought 
to 
be 
second al) 
to 
ccliac disease 
Se,ert: abdominal 
pain thought to be 
combin:ition 
moderate 
of secondary 
cdiac disease 
and 
10 
severe 
recurring 
or 
persistent 
symptoms 
thought 
to 
be 
n:lated to ccliac 
disease 
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Diarrhea 
One 
or 
1\\0 
episodes 
thni 
resolve 
spontaneously 
Mild 
diarrhea 
lhought 
10 
Ix: 
second al") 
to 
cdiac disea'c 
Moderate 
diarrhea though! 
to be secondary 10 
ccliac disc:i:.e 
Significant 
diarrhea thought 
to be sccondal) to 
ct1liac disca:;c 
D 
D 
Moderate 
Disease 
fatigue 
Asymptomatic or 
symptoms felt to 
bi: due to another 
disorder 
(i.e .. 
depression) 
Asymptomatic or 
mild 
S)mptom~ 
that 
resol\cd 
spomaneously 
Signilic:in1 
l01igue thought to 
be due to celi:ic 
disease 
Significanl 
fatigut: thought tn 
be secondaJ) to 
celiac di.o;case 
Activity 
Asymptomatic or 
symptoms li::lt to 
be due to another 
disorder 
Asymptomatic or 
!>)'mploms felt 10 
Ix: due to another 
disorder 
In 
abilil) 
to 
maintain nonnal 
activities due to 
lhtigur.: or other 
symptoms 
se,erc 
imp:iinnent 
of 
normal activilics 
due to l"atigue or 
other symptoms 
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D 
D 
eve re 
Di ease 
Lab Tesrs 
Normal or minimal 
abnomialities 
Persistent 
and 
~ign ifican1 labomtol) 
nhnormalities fdt to 
be secondary co celiac 
disease with no nr 
mild 
a:.socia1cd 
!>')'mp1orns 
Signi iic.:ant laboratory 
:ibnonnali1ies felt to 
be secondary to ccliac 
disease "ith mild or 
moderate associated 
symptoms 
ignilicant laboratory 
ahnonnalities felt to 
be ,,ccondal)' to "i1h 
moderate tu severe 
associated symptoms 

APPEN DIX F. lNTERPRETATION OF HEPATITIS RESULTS 
Subjects must undergo screening for hepatitis B virus (HBV). AL a minimum, this includes 
testing for HBsAg (HBV surface antigen). anti-HBs (HBY surface antibody). and anti-HBc 
total {HBV core antibody total): 
I 0. Subjects who test negative for all HBY screening tests (ie. HBsAg-. anti-HBc-. and 
anti-1 IBs) are eligible for this study. 
11. Subjects who test positive for surface antigen (HBsAg+) are not eligible for this study. 
regardless of the results of other hepatitis B tests. 
12. Subjects who test negatjve for surface antigen (H BsAg-) and test positive for core 
antibody (anti-HBc+) a11d surface antibody (anti-HBs+) are eligible for this study unless 
local guidelines require additional testing. 
13. Subjects who test positive only for surface antibody (anti-HBs+) are eligible for this 
study unless local guidelines require additional testing. 
14. Subjects who test positive only for core antibody (anti-HBc+) must undergo further 
testing for hepatitis B deoxyribonucleic acid (HBV DNA test). If the HBY DNA Lest is 
positive. the subject is 1101 eligible for this study. If the I IBY DNA test is negative. the 
subject is eligible for this study. In Lhe event the HBV DNA test cannot be performed. the 
subject is not eligible for this study. 
Eligibility batsed on Hepatitis B virus test results 
Hepatitis B test result 
Hepatitis B surface 
Hepatitis B surface 
Hepatitis B 
Action 
antigen 
antibody 
core antibody 
(HBsAg) 
(anti-HBs) 
(anti-HBc 
total) 
Exclude 
+ 
-
or + 
-
or + 
-
-
-
Include 
-
+** 
-
-
+** 
+ 
Require Hepatitis B 
viral 
DNA 
(HBV 
-
-
+ 
DNA) testing* 
• lfHBV DNA is detectable. exclude from clinical trial. lfllBV DNA testing cannot be pcrfom1ed. or there 
is evidence of chronic liver disease, exclude from clinical trial. 
** Local guidelines may require additional testing to rule out the presence of HB V. 
Protocol Version 3 
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APPENDIX G. SAMPLE INVESTIGATION PRODUCT LABEL 
AMG 714: 
AMG 714 100 mglml 1100 mglmL 
21111 ni. 
Vst ru?t>e-
s.c / Soos-0.imee !SC) 
1vl~(M 
., __ 
IJ0'..l0?2 
NL I•= Patt>nlrurmer Sezcekrurmer 
~- C61mrecXo-. .\n-ge'\"' 
Tl'l'.lQ1j~s (;.<91320-t™I USA 
~ 
llOOOlh'~Mlflse. 
Ubn:ln NJ al833 
PLACEBO: 
•·--
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Ill
!•=~~ 
~ --Cdrmn ·-J.""f!'l lrc 
Th:>.6""1();1.l C~91J2C>11')9 l.Go\ 
Cerm.re 110°"!>f!Rf~ lellin:>1 >tJOB!..U 
Protocol Version 3 
(29·AUG-2016) 
CELI M-NRC'D-00 I 
A 
'"~ 
K;Jimn1U11e11 
\lllnsla,lil 
SE 
I• • i>atffll!f 
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M'9'fl he 1ln&nl Cl.1cs CA 91m.1 m us.>. 
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T"~b~~l-'lrc}:n Inc 
1Jv:uml C8ks CA 9131C-I ~. US.\. 
Cermule 110 Ott :.rt·1>1?1 un: 
Cemrir.'. llOOdOrtNail..re 
lebroo NJ amJ 
ES i'Ui-etJ de ·~ 
f~pra~JXY,lfygeii iv:. 
fl'QQld CW. C\ 913Z).17!l9. EE W 
Ce!rrmre. 110 °" Cl1\Nay Lna 
l.tbnrl NJ CM33 
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t' ·~~~~ 
~ 
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Saeat-»r;: \()"C 1·20°C ll~CI 
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SE 
I• = i>aoemt a- nr 
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~~ . CA9132V'~. UY. 
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l~d?'lft 
F~p:.ttCd:rrmrie Pl'"~ II: 
On.&njQib, CA9 1J20. I~ ~ 
Celimve 11QQll['rll<~1lle Um NJOOO:<l 
CAllT1CN Ne•cl\.g limi'<:t'/~~L?• 
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11\);M'd oal.s 0. 9132';-1799 EE llU 
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Page 105of110 
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EH ~"''*""'' 3>1.1z>J 1:>ry.c.,13>:>e .;.:·r..: 1o•c.. 
1·ZJ·c~.t0'*C.1J ~'nJ'nil;'t ' ccrortcXt1fD'tr..l !.H?'CllXC'' 
CA~ 'T):Jli 1.i;..""'9 · 1.rW>!0'(\111ed~..JHJlll~ll'<l l 
-:Jll8dt<~"(""9'0 h: ~°"'> U..91?1(>17;.9 
I.&~ 
11~ 0do-t~1 !.7e -""""" wi:eo.;:; 

APPENDIX I. SAMPLE CELIAC DISEASE PRO (CeD PRO) 
lns1ruc1ions: These questions ask ahoul how you feel each day. Please complete the daily 
diary evel)' evening, at approximately the same time. 
1. Thinking about your worst experience in the past 24 hours, how severe was each of 
the following symptoms? On the following screens, please tap a number to indicate 
how you felt. 
a. How severe was your abdominal cramping? 
0 
2 
:i 
4 
No 
abdominal 
cramping 
b. How severe was your abdominal pain? 
0 
2 
3 
I) 
t'bdominttl 
pain 
c. Hov.• severe was your bloating? 
0 
0 
blmning 
Protocol Version J 
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2 
3 
4 
4 
5 
() 
5 
6 
5 
6 
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7 
8 
9 
7 
8 
9 
7 
8 
9 
10 
Worst possible 
abdominal 
cmmping 
10 
Wor:-1 possible 
abdominal pain 
10 
Worst possible 
bloating 

d. Hov severe was your dianhca? 
0 
No 
di:irrhca 
2 
3 
e. How severe was your gas (flatulence)? 
0 
No 
gas 
2 
3 
f. 
How severe was your loose stool? 
0 
No 
loose stool 
3 
g. How severe was your nausea? 
() 
No 
vomiting 
3 
h. 
How severe was your headache(s)? 
0 
No 
hcndochc(sl 
Protocol Version 3 
(29-AUG-2016) 
CELIM-NRCD-00 I 
3 
4 
4 
s 
6 
7 
5 
6 
7 
5 
6 
7 
5 
6 
7 
5 
6 
7 
Page 107of11 0 
Confidential 
8 
9 
8 
9 
9 
8 
9 
8 
9 
10 
Worst possihlc 
diarrht:a 
10 
Worst 
po~siblc 
gas 
10 
Worst possible 
loose ~too l 
10 
Worst pos'>iblc 
vomiting 
10 
Wor;,t possible 
hcadachc(s) 

i. 
How severe \Vas your tiredness? 
0 
ll 
tiredncs) 
Protocol Version 3 
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3 
4 
5 
6 
7 
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8 
9 
10 
Worst possihlc 
tiredness 

APPENDIX J. PROTOCOL AMENDMENTS 
The protocol was modified to create version 3 on 29 August 2016. The following changes 
and clarifications were made in the sections specified: 
I) Elimination of the stool test as an eligibility criterion, since endoscopy and biopsy 
already identify patients with gluten contamination, as revealed by mucosa I atrophy 
(inclusion Criterion #6; Table I footnote 5; Sections I J. I, 11.2) 
2) Removal of blood donation 3-month pre-study exclusion. initially meant to prevent 
anemia by avoiding administering gluten challenge to patients who may have had a 
recent blood donation; a precaution now considered to be unnecessary and preventing 
otherwise eligible patients from enrolling in the study (Exclus ion Criterion # 17). Blood 
donation remains prohibited during the study (Section 17). 
3) Modest villous atrophy threshold change for patients not receiving the gluten challenge 
to avoid excluding a few candidates, which would otherwise be considered e ligible for 
the study (Table l, footnote 16; Section 6). 
Additional editorial changes and minor clarifications were made throughout the protocol. 
The protocol was modified to create version 2 on 20 May 2016. The following changes 
and clarifications were made in the sections specified: 
I. To reduce burden on patients, gluten stool sample collection was made optional 
e,xcept for the two samples collected at the time of the endoscopy and biopsy 
collection (Screening and Week 12 -or Early Tennination, which remain 
mandatory). The urine gluten samples remain mandatory (Table I , Footnote 5; 
Section 11 ; Section 14.2; Appendix B; and minor changes throughout the protocol 
as needed). 
2. The rules for collection of stool samples have also been revised to allow a more 
flexible window of +/- 3 days and to allow any place of collection, not just the 
patient's home (Table I, Footnote 5; Section 11 ; Section 14.2). 
3. The time of collection of the blood ce ll pellet has been changed to allow 
collection at any time during study (Table I. Footnote I I). 
4. The cut-off of mucosa! damage. under which subjects do not receive the gluten 
challenge, was modestly lowered from 2 to I .8. Subjects with VH:CD 1.8 or 
below will not receive gluten challenge, subjects with YH:CD l .9 or above will 
receive challenge (Table 1. Footnote 16; Section 6; Section 19. 1; Section 20. 1; 
Section 23). 
5. The age limit was increased to 80 years old (Inclusion Criteria I ). 
6. The cut-off of symptoms at baseline was modestly increased from a CcD-GSRS 
of 2 to 2.3 (Exclusion Criterion 3). 
7. The fo llowing discretion was added to Inclusion Criterion 10: " ... unless 
investigator considers the abnormalities to be not clinically significant''. 
Protocol Version 3 
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8. A Note was added to indicate that the Sponsor may arrange with the study sites 
the conduct of some of the intermediate visits at the subject's home. provided that 
appropriate healthcare personnel conducts the visit with similar standards to visits 
conducted at the study site (Sections 6 and 11 ). 
9. A duplicated sentence on mini-gut experiments in biopsy fragments has been 
removed (Section 13.1.3) and minor inconsistencies have been corrected 
throughout Section LJ. I through 13.5. 
I 0. Clarified procedure for retaining unused vials in Section 18.7.3. 
I I. It was clarified that the alternation of side of the abdomen for the SC injections is 
between visits. and not between the two injections in the same visit (Section 
18.7.4). 
12. It has been clarified that the DSMB may. and is expected to, review unblinded 
data. And that safety findings insufficient to trigger the stopping rules may. if 
judged appropriate by the DSMB. lead to suspension of enrollment during the 
review (Section 22. 10). 
Additional editorial changes and minor clarifications were made throughout the protocol. 
The original protocol was modified to create version 1.1 on 12 November 2015. The 
following major changes and clarifications ·were made in the sections specified: 
I. Adel it ion of contact information for study vendors and responsible staff. 
2. Add ition of SAE telephone contact numbers (Section 22.7). 
3. Revision or SAE email contact number (Section 22. 7). 
4. Addition of sample lnvestigational Product labels (Appendix H). 
Additional editorial changes and minor clarifications were made throughout the protocol. 
Protocol version 1.0 was not reviewed by Ethics Committees or used in this trial. As such. a 
formal documentation of changes was not prepared to accompany this protocol amendment. 
Protocol Version 3 
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RCD-00 I 
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