A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of AMG 714 in Adult Patients With Type II Refractory Celiac Disease, an In Situ Small Bowel T Cell Lymphoma
Phase: PHASE2
Conditions: Type II Refractory Celiac Disease (RCD-II), In-situ Small Bowel T-cell Lymphoma
Sponsor: Amgen

CLINICAL STUDY PROTOCOL 
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-G roup Study to 
Evaluate the Efficacy and Safety of AMC 714 in Adult Patients with Type II Refractory 
Celiac Disease, an In Situ Small Bowel T Cell Lymphoma 
Protocol Number: 
CELIM-RCD-002 
Version No: 
3 
Protocol Date: 
11 .July2016 
US IND Number 
126657 
EudraCT Number 
20 15-004063-36 
lnvestigational Product: 
AMG 714 
Phase: 
Phase 2a 
Sponsor: 
Cclimmune. LLC 
850 I River Rock 
Terrace, Bethesda, MD 
20817. USA 
This document contains confidential in.formation. This information cannvt he used.for (1/1)' 
purpose other than evaluation or conduct of the clinical investigation. The recipient agrees 
that no i1?formalion contained in this protoc:ol will be published or disclosed without the 
prior wrillen approval of Ce/immune. LLC. Study stqfflassociares and Institutional Review 
Board~· may have access lo this information on a confidential basis as may be necessm:v to 
conduct this clinical study. 
Protocol CELIM-RC0-002 
Version 3, l 1-J lJL-2016 
Page I of 134 
Confidential 
NCT Number: 02633020
This NCT number has been applied to the document 
for purposes of posting on clinicaltrials.gov

PROTOCOL NUMBER: 
PROTOCOL VERSION: 
PROTOCOL DATE: 
PROTOCOL TITLE: 
SPONSOR APPROVAL 
CELLM-RCD-002 
3 
11July20 16 
!\ Phase 2a. Randomized. Double-Blind. Placebo-Controlled. 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
AMG 714 in Adult Patients with Type II Refractory CeJiac 
Disease. an In Situ Small Bowel T Cell Lymphoma 
I. on behalf of Cclimmune. 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 (JCI I), Guidance on Good Clinical Practice 
(GCP), the Declaration of Helsinki, 21 CFR parts 50, 56, 312 and 320. and applicable United 
States Food and Drug Administration (FDA ) Guidelines for Industry 
. MD, PhD 
CEO & Chief Medical Officer 
Celimmune. LLC 
Protocol CELIM-RC D-002 
Version 3, J 1-J UL-2016 
Page 2 or 134 
Date 
Confidential 
PPD
PPD

INVESTIGATOR AGREEMENT 
PROTOCOL NUMBER: 
CELJM-RCD-002 
PROTOCOL VERSION: 
3 
PROTOCOL DATE: 
11July2016 
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 Type II Refractory Celiac 
Disease. an In Situ Small Bowel T Cell Lymphoma 
By signing below. I certify 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 (ICH) guidelines. the 
Declaration of Helsinki and complying with the requirements and obligation or Clinical 
Investigators listed in 21 CFR parts 50, 54. 56, 312 and 320 in accordance with the study 
procedures provided by Celimmune, LLC and with all applicable local regulations. 
l 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 !RB/Ethics 
Committee or equivalent, except as would be necessary to eliminate an immediate hazard to 
study subject(s). 
I will. ensure that all persons 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 completely inform all subjects in this 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 fonn. 
I certify that I will allow access to fi les for audit or inspection purposes by Celimmunc LLC. 
its agents. or competent regulatory authorities. 
I agree to the content of this protocol and the confidential nature of the documentntion 
associated with this study. 
Signature of Investigator 
Printed Name 
Protocol CELIM-RC D-002 
Version 3, I 1-JUL-201 6 
Page 3 of 13-t 
Date 
Confidential 

STUDY PERSONNEL CONTACT INFORMATION 
Sponsor: 
Medical Monitor, EU: 
Medical Monitor, US: 
SAE Reporting: 
C linical Safety 
Laboratory: 
Contract Research 
Organizations: 
Protocol CELIM-RCD-002 
Version 3, 11-J UL-2016 
Page 4 of 134 
Celimmune. LLC 
Address: 850 I River Rock Terrace, Bethesda. MD 20817, USA 
Phone: + I 30 I 798 4988 
Fax: 
+ I 30 I 798 4988 
Chi I tern International 
Email: GlobalSA.Clnbox <1 l:hiltern.corn 
See SAE reporting section of study protocol for instructions 
regarding SAE reporting 
LabConnect, LLC - US 
Project Manager 
Address: 2304 Silverdale Dr .. Suite I 00. Johnson City. TN 
37601, USA 
Synevo Central Lab - EU 
Address: Smoluchowskiego 18 F Gdansk 80-2 14 
Phone: +48 58 741 09 25 
Fax: +48 58 741 09 35 
www.central lab.synevo.eu 
Clinical Monitoring - EU 
Chiltern International 
Representative: 
Address: Centro Ernpresarial Euronova 3. Ronda de Poniente I 0 -
2a Planta, 28760 Tres Cantos - Madrid. S ain 
Confidential 
PPD

Coordinating 
Investigator (France) 
Protocol CELIM-RC0-002 
Version 3, 11-J L-2016 
Page 5of 134 
Email: 
Clinical Monitoring - US 
2L Pharma. LLC 
Representative: 
Address: 2500 Pickwick Road, Baltimore, MD 21207 USA 
Phone: 
Email: 
Data Management 
StatFinn Oy 
Representative: 
Address: MUUrivahe 22. I 0 I 40 Tallinn, Estonia 
Phone: 
Email: 
Biostatistics 
StatFinn Oy 
Representative: -
Address:Vaike-Turu 5-79; 51003 Tartu Estonia 
Phone: 
Email: 
Professeur 
Chef de Service d·Hepato-gastro-enterologie et Endoscopie 
Digestive 
Hopital Europeen Georges Pompidou 
20, rue Leblanc 
75015 PARIS, France 
Confidential 
PPD
PPD
PPD
PPD
PPD
PPD

ADI\ 
ADME 
AE 
ANCOVA 
Anti-tTG 
APC 
AUC 
Sh CG 
BP 
BMI 
BMT 
BSA 
CCr 
CD 
CeD-GSRS 
CcD-PRO 
CFR 
cGCP 
CL/F 
Cma' 
CRF 
C1rough 
DGP 
DH 
OSMB 
EATL 
ECG 
eCRF 
EDC 
ePRO 
EQ-SD 
FDA 
FOCBP 
FSH 
GERO 
GFD 
GI 
GIP 
g 
GSRS 
Hb 
Protocol CELIM-RC0-002 
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LIST OF ABBREVIATIONS 
Anti-drug antibodies 
Absorption, distribution. metabolism. and excretion 
Adverse event 
Analysis of variance 
Anti-tissue transglutaminase 
Antigen-presenting cells 
Area under concentration time curve 
Beta human chorionic 1wnadotropin 
Blood pressure 
Body mass index 
Bone marrow transplant 
Body surface area 
Creatinine clearance 
Cluster of Differentiation (when used preceding a numeral to 
indicate a marker on lymphocytes: e.g .. CD3. CD45) 
Celiac Disease GSRS 
Celiac Disease - Patient Reported Outcome 
United States Code of rederal Regulation 
Current Good Clinical Practice 
Apparent clearance 
Maximum serum concentration 
Case Report Form 
Trough concentration 
Deamidated gluten peptides 
Dermatitis heroetiformis 
Data Safety Monitoring Board 
Enteropathy-associated T cell lymphoma 
Electrocardiogram 
Electronic Case Report Form 
Electronic Data Caoture system 
Electronic patient reported outcome 
European Quality of Li fe 5 Dimensions questionnaire 
Food and Drug Administration 
Females of child bearing potential 
Follicle stimulating hormone 
Gastrointestinal Renux Disease 
Gluten-free diet 
Gastrointestinal 
Gluten immunogenic peptides 
Gram 
Gastrointestinal Symptom Rating Scale 
Hemoglobin 
Conlidcntial 

HepB 
HepC 
HEENT 
HIV 
HLA 
ICF 
ICH 
IEL 
lgA 
lgG 
IGRA 
IHC 
IRB 
ITT 
IUD 
IV 
kDa 
kg 
MedDRA 
mg 
ml 
MMRM 
NK 
NRCD 
PCR 
PGA 
PK 
PP 
PT 
Pt GA 
Q2W 
RA 
RBC 
RCD 
RCD-l 
RCD-11 
SAE 
SAP 
SC 
SF-1 2 
SU SAR 
TEAE 
soc 
TcR 
Protocol C ELIM-RC D-002 
Version 3, I 1-JUL-2016 
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Hepatitis B 
Hepatitis C 
Head. eyes, ears. nose, throat 
Human immunodeficiency virus 
Human leukocyte antigen 
Informed consent form 
International Conference on Harmonization 
I ntraepithel ial lymphocytes 
lmmunoglobulin A 
lmmunoglobulin G 
Interferon gamma release assay 
lmmunohistochemistry 
Institutional Review Board 
Intent to treat 
Intrauterine device 
Intra venous 
Kilodalton 
Kilogram 
Medical Dictionary for Regulatory /\ctivities 
Milligram 
Milliliter 
Linear mixed effects repeated measures model 
Natural killer 
Non-responsive celiac disease 
Polymerase chain reaction 
Physician Global Assessment of Disease 
Phannacokinetics 
Per protocol 
Preferred Tenn 
Patient Global Assessment of Disease 
Every other week 
Rheumatoid arthritis 
Red Blood Cell count 
Refractory celiac disease 
Type I refractory ccliac disease 
Type II refractory celiac disease 
Serious adverse event 
Statistical analysis plan 
Subcutaneous 
Short Form 12 questionnaire 
Suspected unexpected serious adverse reaction 
Treatment-emergent adverse events 
System Organ Class 
T eel I receptor 
Confidential 

TE SAE 
ty,, 
TB 
TK 
lma' 
Tregs 
tTG 
VH:CD 
WBC 
WHO 
WHO DD 
Protocol CELIM-RC D-002 
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Treatment-emergent serious adverse events 
Terminal half-life 
Tuberculosis 
Toxicokinetics 
Time present at maximum concentration in serum 
Regulatory T cells 
Tissue transglulaminase 
Villous height to crypt depth ratio 
White Blood Cell 
World Health Organization 
World Health Organization Drug Dictionary 
Confidential 

TlTLE 
fNTENDED 
INDICATION 
STUDY 
OBJECTIVES 
STUDY 
ENDPOfNTS 
PROTOCOL SYNOPSJS 
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to EvaJuate the Efficacy and Safety of AMG 
714 in Adult Patients with Type ll Refractory Ccliac Disease, an In 
Situ Small Bowel T Cell Lymphoma 
AMG 714 is a human anti IL-1 5 monoclonal antibody indicated for the 
treatment of Type Il Refractory Celiac Disease (RCD-11). an in situ 
small bowel T cell lymphoma, in adult patients 
Primarv Objective: To assess the efficacy of AMG 714 in treating RCD-
11 in adult patients 
Secondary Objective: To assess the safety and tolerability of AMG 714 
when administered to adult patients \Vith RCD-11 
Exploratorv Objective: To assess the pharmacokinctics (PK). 
pharmacodynamics (PD). and PK/PD correlations of AMG 714 
Primary efficacy endpoint: 
• 
Immunological Response I: Reduction from baseline in the % 
of aberrant intestinal intraepithelial lymphocytes (IELs) vs total 
IELs as assessed by flow-cytometry 
Secondary efficacy endpoints: 
• 
Immunological Response 2: Reduction from baseline in the% 
of aberrant I ELs vs intestinal epithelial cells 
• 
Histological Response: Improvement from baseline in small 
intestinal vi lJous height to crypt depth (VH:CD) ratio, Marsh 
score or total I EL counts 
• 
Clinical response: Change from baseline in clinical symptoms 
o 
Bristol Stool form Scale (BSFS) 
o 
Gastrointestinal 
Symptom 
Rating 
Scale 
(GSRS), 
including the celiac disease GSRS (CeD-GSRS) 
Exploratory endpoints: 
• 
Reduction in aberrant and abnormal IELs by flow cytometry. 
immunohistochemistry and T cell receptor (TcR) clonality 
analyses 
• 
Physician Global Assessment of Disease (PGA) and Patient 
Global Assessment of Disease (Pt GA) 
• 
Quality of Life Assessments: 
o SF-12v.2 
Protocol CELIM-RC0-002 
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Confidential 

o EQ-50 
• 
Biomarkers of disease activity 
• 
Pharmacokinetics 
(PK), 
Phannacodynamics 
(PO) 
and 
Exposure!Response (PK!PD) 
• 
Celiac Disease Patient Reported Outcome (CeD PRO) 
Safetv endpoints: 
• 
Adverse events 
• 
Clinical laboratory tests 
• 
Physical examination 
• 
Vital signs 
• 
lmmunogenicity 
STUDY DESIGN 
Protocol CELIM-RCD-002 is designed to be a Phase 2a randomized, 
double-blind. placebo-controlled. parallel group sLudy Lo evaluate the 
efficacy and safety of AMG 714 for the treatment or adult patients with 
RCD-11. 
After signing consent subjects will be screened for the study. All 
subjects who meet the study entry criteria will be randomized at a 2: I 
ratio to receive either 8 mg/kg A MG 714 or placebo a total of 7 times 
over I 0 weeks, with evaluation of the primary endpoint at Week 12. 
AMG 714 (N=16) or placebo (N=8) will be administered at the clinical 
Sile in a double-blind fashion via intravenous (I Y) infusion over 120 
minutes. 
Concomitam therapy with steroids at a maximum dose of 20 mg of 
prednisone, prednisolone or equivalent per day and/or oral budcsonide 
at a maximum dose of 9 mg per day will be accepted. These doses will 
need to be stable for 4 weeks prior to randomization and remain stable 
for the duration of the study. 
Should AMG 714 show adequate efficacy and safety. as determined by 
the Sponsor. subjects in the study, including those in the placebo arm, 
may be offered participation in an open label extension study of AMG 
7 14 m due course, but under no circumstances prior to study 
completion. In the interim, between the end or the study for an 
individual subject and the slart of the possible open label extension. the 
Sponsor intends to provide a bridging program to allow objective study 
responders to have access to AM G 714 as determined by the site 
investigator or physician. The open label extension study and interim 
bridging program wi ll be described in independent protocols. 
Protocol CELIM-RC0 -002 
Vl'rsion 3, 11 -JlJL-201 6 
Pagt' 10of1 3.t 
C'onlidential 

Subjects will be expected to maintain total adherence to a strict gluten-
free diet (GFD) from 6 months before randomization through the final 
study visit (Visit 9, Week I 6/Day 112). Subject's adherence to GFD 
will be assessed by an expert dietitian and monitored via stool sample 
testing using the iVYLISA gluten immunogenic peptide (GIP) stool 
gluten test. Subjects with known or suspected GFD transgressions wi 11 
be counseled and allowed to continue in the study. 
A study stafT member will contact the subject by phone one day after 
the first dose or study drug to assess for any new or worsening A Es. 
Subjects will return to the clinic for the next administration of study 
drug after I week (Visit 2. Week I/Day 7). After Visit 2. subjects wi ll 
return to the clinic for follow-up and study drug administration at Visit 
3 (Week 2/Day 14) and every two weeks thereafter as indicated in the 
study schedule of events (Table I). The final study dose wi ll be 
administered at Visit 7 (Week IO/Day 70). An end-or-study efficacy 
visit will be conducted at Visit 8 (Week 12/Day 84). The tinal study 
visit will be conducted 6 weeks after the last dose of study drug at Visit 
9(Week 16/Day 112). 
All study subjects will undergo upper gastrointestinal endoscopy with 
mucosa! biopsy prior to baseline (i.e., prior to Visit I. Week O/Day 0) 
and within 7 days of Visit 8 (Week 12/Day 84) in order to assess 
changes from baseline in aberrant and abnormal l ELs, VH :CD ratio. 
TcR clonality. Marsh score and total IEL counts. 
Subjects enrolled in the study will complete the BSFS at the time or 
each bowel movement from baseline (Visit I; Week O/Day 0) up to the 
final study visit, Visit 9 (Week 16/Day 112). Subjects will complete the 
CeD PRO daily from baseline to the final study visit. Subjects will also 
complete the GSRS beginning at Visit I (Week O/Day 0) and, thereafter, 
\ eekly from the time of randomization through the final study visit. 
The BSFS. GSRS and the dai ly CeD PRO will be completed using a 
handheld electronic diary. In addition, subjects will complete paper 
quality of life diaries (SF-1 2 v. 2. EQ-SD and PtGA). Diaries will he 
completed at the times specified in the Schedule of Events (Table I). 
Randomization and initial dosing of the first ten subjects will be 
staggered, with no more than two subjects starting dosing per week. and 
avoiding the initiation of more than one patient on any single day. 
Safety will be monitored on an ongoing basis and subjects may undergo 
unscheduled visits for safety reasons, if needed. Safety will be assessed 
throughout the studv bv clinical laboratory tests, physical examination, 
Protocol CELIM-RCD-002 
Version 3, I l-J UL-201 6 
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STUDY 
SAMPLE SIZE 
ANTICIPATED 
NUMBER OF 
CLINICAL 
SITES 
INCLUSION 
CRlTERIA 
vital sign and AE monitoring. In addition to the investigators and the 
Sponsor. an independent Data Safety Monitoring Board (DSMB) will 
monitor safety. 
An interim analysis for safety and PK will be conducted when the tenth 
patient reaches Week 4. The interim analysis will be performed by an 
independent DSMB, which will also monitor unblinded safety data 
throughout the study. In addition to safety and PK. any other 
information available at the time of the analysis wi II be considered and 
a recommendation to stop. continue or modify the study wi ll be made 
by the DSMB to the Sponsor. The recommendation and decision will 
be shared with the sites and ethics committees. 
Approximately 24 subjects will be randomized into the study. 
The study will be conducted at approximately 5-6 clinical sites in the 
United States and Europe (e.g., France. Holland. Spain. and Finland). 
Subjects must fulfill all of the fo llowing inclusion criteria to be eligible 
for participation at screening and at Visit l (Week 0/Day 0): 
I. 
Adult males or females 18 years of age or older. 
2. 
Demonstrated willingness to participate m the study as 
documented by signed informed consent. 
3. 
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 [FSH] level >40 f UfL at 
Screening); or permanently sterilized (e.g., 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 
detennined by the Investigator; one of the methods must be a 
barrier technique) from Screening through the end of study 
participation (Visit 9, Week I 6fDay 112). 
Protocol CELIM-RCD-002 
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Page 12 of 13.J 
Confidential 

4. 
Prior confirmed diagnosis of RCD-ll defined by the following 
criteria: celiac disease confirmed by histology. endoscopy or 
serology; with persistent and recurrent symptoms (e.g., diarrhea. 
weight loss, abdominal pain); with abnormal small bowel 
histology; with aberrant intraepithelial lymphocytosis of > 20 
aberrant intraepithelial lymphocytes (lEL) per I 00 CD45+ cells 
as determined by flow cytometry (or >50% if determined by 
immunohistochemistry); despite adherence to a strict GFD for at 
least 6 months; and after exclusion of other potential causes of 
symptomatic non-response (e.g., microscopic colitis. bacterial 
overgrowth, 
lactose 
intolerance. 
exocrine 
pancreatic 
insufficiency, hyperthyroidism, etc.) and intestinal histological 
abnormality 
(autoimmune 
enteropathy, 
giardiasis. 
immunodeficiency, collagenous sprue, 
Whipple's disease. 
etc.). 
NOTE: Subjects who have been treated for RCD-11 must continue to 
have increased aberrant lELs (>20% by flow cytometry or 50% 
by IHC) and abnormal small bowel histology (Marsh ::::: I) and 
must have had prior history of symptoms, however symptoms are 
not required of previously treated subjects. or subjects being 
treated with steroids, at the time of study entry. 
5. 
Total attempted adherence to a GFD for at least 6 consecutive 
months prior to screening. Subjects must also agree to make no 
changes to their current GFD for the duration of study 
participation. 
6. 
Anti-tissue transglutaminase (lgA and lgG) at screening <2 x the 
diagnostic level for celiac disease (weak positive or negative). 
7. 
Human leukocyte antigen DQ (HLA-DQ) typing compatible 
with celiac disease provided or obtained prior to baseline biopsy. 
8. 
Life expectancy > 4 months. 
9. 
Laboratory values: 
Protocol CELIM-RCD-002 
Version 3, ll-JUL-2016 
Page 13 of 134 
a) Estimated creatinine clearance (CCr) > 30 mL/min/l. 73m2 
using the Cockcroft-Gault equation 
b) Serum alkaline phosphatase (AP), alanine Lransaminase 
(AL T/SGPT), and aspartate aminotransferase (AST/SGOT) 
less than 3x the upper limits of normal (ULN) 
c) Total bilirubin of less than 2.5 x ULN 
d) Total white blood cell count (WBC) > 300/mm3 
C'onfidcntial 

EXCLUSION 
CRITERIA 
e) Platelet count ~ 85.000/mrn3 
f) INR less than 1.5 
g) Albumin of more than I 0 g/L (i.e., I g/dL or 1.45 µmol/L) 
I 0. 
Subjects receiving systemic steroids must be on a stable dose 
for at least 4 weeks prior to randomization. the dose should not 
exceed 20 mg of prednisone, prednisolone or equivalent per 
day. Oral budesonide will be accepted at a maximum dose of 9 
mg per day. 
11 . 
Willingness and ability to comply with study procedures and 
protocol stipulated concomitant medication guidelines. 
12. 
Willingness to return for all scheduled follow-up visits. 
Subjects will be excluded from participation in the study if there is 
evidence of any of the following. at screening or Visit I: 
I. 
Diagnosis or Type I Refractory Celiac Disease (RCD-1) or 
enteropathy-associated Teel I lymphoma (EA TL. excluded by the 
site's standard imaging techniques for this purpose). 
2. 
Presence of any of the fo llowing related to in fection: 
a) Active acute infection requiring systemic antibiotic. 
parenteral anti fungal. or systemic antiviral treatments 
b) Severe infection within the 3 months prior to screening 
c) History of tuberculosis (TB) 
d) Positive Interferon Gamma Release Assay (IGRA) test al 
screening OR known recent exposure (within 6 months prior 
to screening) to a patient with active TB; the subject can be 
enrolled if he or she has been successfull y treated wjth 
appropriate chemoprophylaxis. 
e) History within the 3 years prior to screening of an 
opportunistic 
infection 
typical of those 
seen 
111 
immunocompromised subjects (e.g.. systemic candida 
infec1ion. or systemic fungal infection). 
3. 
Current diagnosis or history of cancer within the past 5 years. 
except RCD-11. successfully-treated basal cell or squamous cell 
carcinoma. cervical carcinoma-in-situ. or early stage prostate 
cancer. 
4. 
History or presence of clinically signi ficant disease that in the 
opinion of the Investigator would confound the subject's 
Protocol C ELIM-RCD-002 
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Page 14 of134 
Confidenrial 

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 I BPJ equal to or 
greater than 180 mml lg or office diastolic BP equal or 
greater than I I 0 mm/Hg). unstable angina. congestive heart 
failure worse than the New York I leart Association Class 11. 
coronary angioplasty or myocardial infarction within the last 
6 months. uncontrolled atTial or ventricular cardiac 
arrhythmias clinically significant pleural or pericardia! 
effusion 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 
5. 
History of significant immune suppression: 
- Bone marrow transplant (BMT) or cladribine therapy less 
than 6 months prior lo baseline. In other words. cladribine 
and bone marrow transplant na"lve, primary non-responders 
(treatment resistant). secondary non-re. ponders (relapse 
after response/remission) and incomplete responders may 
be enrolled in the study if cladribine therapy and/or BMT 
were not provided within the 6 months prior to 
randomization. 
Potent systemic immune suppressants (e.g., azathioprinc) 
in the 3 months prior to baseline. 
6. 
History of alcohol or drug abuse that would interfere with Lhl'. 
ability to comply with the study protocol. 
7. 
History of clinically significant hypersensitivity lo the study drug 
or any related drugs or to any of the excipients. 
8. 
Positive hepatitis B (Hep B), hepatitis C (Hep C), or Human 
immunodeficiency virus (H IV) infeccion test results at the time of 
screening. 
9. 
Females who are pregnant or are planning to become pregnant 
during the study participation period or 6 months after last dose. 
or are currently breastfeeding. 
Protocol C F.LIM-RCD-002 
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Confidt:ntial 

STATISTICAL 
ANALYSIS 
I 0. 
Participation in another investigational drug or device study or 
treatment with an investigational drug within 30 days or 5 half-
lives, whichever is longer, prior to randomization. 
11. 
An. additional reason, which in the opinion of the Investigator, 
would prevent the subject from safely participating in the study 
or complying with protocol requirements. 
The primary endpoint is the Immunological Response I : reduction at 
Week 12 in the % of aberrant I ELs vs total IELs as assessed by flow-
cytometry bet\\ een the AMG 714 dose and the placebo arm. 
The primary endpoint of Lmmunological Response I wi ll be tested as 
follows: 
against the alternative 
Hi: µAMG 714 *µplacebo 
where µAMG 714 and µplacebo denote the mean baseline to Week 12 
reduction in % aberrant lELs vs total IELs as assessed by flow-
cytometry in the AMG 714 and placebo arm respectively. The 
hypotheses wi II be tested using a two-sided type I error level of I 0%. 
In gemeral, efficacy measures which require pre- and post-treatment 
biopsies will be based on the PP population (at least 2 biopsies, the 
second at least on Week 6 or later). Continuous variables will be 
analyzed based on the ITT population. 
The primary endpoint will be analyzed using analysis of covariance 
(ANCOVA) based on the Per Protocol population (PP), where baseline 
% aberrant lEL will be included as a covariate and treatment group as 
a fixed effect in the statistical model. 
Change from baseline of Immunological Response 2, VH:CD and of 
total IEL counts will be analyzed using the same method as for the 
primary endpoint. 
The Marsh scores will be analyzed using a multinomial logistit: 
regression model, where treatment group, base! ine Marsh score, and a 
treatment group-by-baseline Marsh score 
interaction term will 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 analvzed usinl?. generalized linear mixed models with 
Protocol CELIM-RCD-002 
Version 3, I l-J llL-2016 
Page 16 of 134 
Confidential 

subject as random effect. The statistical model will also include 
treatment group. time (week) and their interaction. The change in the 
weekly BSFS scores will mainly be assessed with descriptive statistics. 
where change from the ·normal (mid-scale)' will be explored. The 
GSRS and the CeO-GSRS will be analyzed using a linear mixed effects 
repeated measures model (MMRM) with the baseline value, treatment 
group, time point, and a time point-by-treatment group interaction term 
as fixed effects with an underlying correlation structure between the 
time points that results in the best fit for the model. Subject will be 
included as a random effect. 
The exploratory variables, which include PK variables. PD variables, 
PK/PO variables, aberrant and abnormal lELs, TcR clonality analyses, 
PGA. quality of life assessments and biomarkers of disease activity wi II 
be tabulated by treatment group and time point (if feasible) using the 
ITI or PP populations as appropriate. 
The exploratory variable CeO PRO will be analyzed using the same 
method as for the GSRS and CeD-GSRS. 
Pharmacokinetics of AMG 714 in RCD-11 patients will also be 
characterized using nonlinear mixed-effects modeling, including 
evaluation of effects of major covariates (e.g., weight or body mass 
index [BMI]), and body surface area [BSA], sex. biochemical 
parameters, and disease characteristics at baseline) on AMO 7 14 
exposure. 
Exploratory exposure-response analysis will be performed for efficacy, 
safety. and biornarker measures. 
Change from baseline (by time point) will also be presented for 
reduction in aberrant and abnormal [£Ls by flow cytometry. 
immunochemistry and TcR clonality analyses, PGA and quality of life 
assessments (SF-12 v. 2 and EQ-5 0 ). 
The safety variables, which include AEs (coded using the Medical 
Dictionary for Regulatory Activities [MedDRA]), clinical laboratory 
tests. physical examination findings, vital signs and immunogenicity 
will be tabulated by treatment group and time point (if feasible) using 
the intent to treat population. 
Protocol C ELJM-RCD-002 
Version 3, I l~J U L-201 6 
Puge 17 of 134 
Confidential 

Table J. Schedule of Study Procedures 
Screening 
Visit 
Up to Day 
Study Procedures 
-28 
Informed Consent 
x 
Demographics 
x 
Medical History 
x 
Physical Examination 
x 
Body Weight 
x 
Height 
x 
Vital Signs 
x 
12-lcad ECG 
x 
K:ol lection of blood 
~nd urine for clinical 
xi 
laboratory tests 
Serum Pregnancy test 
x 
'all FOCBP) 
Urine pregnancy test 
'all FOCBP) 
Blood cell pellet12 
Urine drug and 
x 
~ lco ho l screen 
Serum biomarkers3 
Protocol CELIM-RDC-002 
Vcrsion 3, 1 l -J UL-201 6 
Page 18 of 13.J 
Follow-
Visit 1 up Phone 
CaU 
WeekO WeekO 
(Day 0) (Day 1) 
Window +1 Dav 
x 
x 
x 
x 
x 
x 
x 
12-Week Double-Blind Randomized Period 
Final Visit 
Visit 2 
Visit 3 
Visit 4 
Visit S 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Week 12 
Week 1 Week2 
Week4 
Week6 
Week8 
Week 10 (Day 84) or 
Week 16 
(Day 7) (Day 14) (Day 28) (Day 42) (Day 56) (Day 70) 
Early 
(Day 112) 
Termination 
+0 Davs1 ±3 Davs ±3 Davs 
±3 Oavs 
±3 Davs 
±3 Days 
±3 Days 
±7 Dnvs 
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 
Confidential 

Screening 
Visit 
Up to Day 
Study Procedures 
-28 
Serum PK 
Serum ADA 
Serum tTG 
x 
Whole Blood for 171ow 
Cytometry 
Eligibility 
x 
~on Ii rmation 
Randomization 
Study drug 
administration 
Prior and concomitant 
x 
medications 
~ ssessme nt of adverse 
~vents 
x 
iVYLISA GIP stool 
x 
~est
1 0 
Endoscopy and 
x 
bioosv4 
Bristol stool from 
scale (BSFS), CeD 
PR0 6 
Protocol CELIM-RC0-002 
Vrrsion 3. I 1-JllL-2016 
Confidential 
Follow-
Visit 1 up Phone 
Call 
Week O WeekO 
(Day 0) (Day 1) 
IWindo'~ +1 Day 
x8 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
--
12-Week Double-Blind Randomized Period 
Final Visit 
Visit2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Weck 12 
Week 1 Week2 
Wcek4 
Week6 
Wcek8 Week 10 (Day 84) or 
Weck 16 
(Day 7) (Day 14) (Day 28) (Day 42) (Day 56) (Day 70) 
Early 
(Day 112) 
Termination 
+0 Davs' ±3 Days ±3 Days 
±3 Days 
:1:3 Da~·s 
:1:3 Days 
:1:3 Days 
±7 Davs 
x? 
x9 
xs 
x9 
xs 
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 
xs 
--~-
. 
;:; 
x 
Page 19 of 13..i 

Screening 
12-Week Double-Blind Randomized Period 
Final Visit 
Visit 
Follow-
Visit 1 up Phone Visit 2 
Visit 3 
Visit4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Up to Day 
Call 
Study Procedures 
Week 12 
-28 
WeekO Week 0 Week 1 Week 2 Week 4 
Week6 
Week8 Week 10 (Day 84) or 
Week 16 
(Day 0) (Day 1) (Day 7) (Day 14) (Day 28) (Day42) (Day 56) (Day 70) 
Early 
(Day 112) 
Termination 
Win do\~ +J Day +O Days1 ±3 Days ±3 Days 
±3 Days ±3 Days ±3 Days 
±3 Days 
±7 Days 
Gastrointestinal 
symptom rating scale 
x 
-
----
' -
--- '------ - - ______. 
x 
GSRS)7 
SF-1 2 v. 2 and EQ-SD 
x 
x 
x 
x 
Physician and patient 
global assessments of 
x 
x" 
x" 
x'' 
x" 
x" 
XII 
disease/rating of 
change 
Dietitian assessment 
x 
x 
x 
x 
of the GFD13 
Abbreviations: Abbreviations: ADA=anti-drug.antibody. BSPS=Bristol Stool Form Scale. CeD-GSRS=Cejiac Disease Gastrointestinal Symptom 
Rating Scale. CeD PRO=Celiac Disease Patient Reported Outcome. DGP=dcamidated g,liadin peptide antibody. ECG=electrocardiogram. 
GIP=gluten immunogenic peptide. GSRS=Gastrointestinal Symptom Rating Scale, PGA=Physician Global Assessment. PK=pharmacokinetics. 
PtGJ\ = Patient Global Assessment, tTG=tissuc transglutaminase. 
I. 
All attempts should be made to conduct Visit 2 within 7 days from Visit I (Week 0/Day 0). This visit cannot be conducted early. If 
the visit is conducted late, the proceeding visit schedules must be readjusted based on the date of Visit 2. 
2. 
Including I !LA DQ typing if I-IL/\ DQ typing is not already part of the subject's available existing medical record .. 
3. 
Biomarker samples should be taken prior to study drug dosing. The time and dale of these samples must be accurately recorded. 
4. 
The screening biopsy can be collected any time prior to the day of randomization. The biopsy should preferably be collected after 
reasonable evidence is available that the subjects appear to meet most or all of the other entry criteria. 
Protocol CELIM-RC 0-002 
Version 3, I t-JUL-2016 
Confidential 
Page 20 of 134 

5. 
The Visit 8 endoscopy and biopsy can be collected within 7 days of Visit 8 (7 days before or after Visit 8). If conducting an Early 
Termination visit. an exit endoscopy will be collected unless indicated otherwise based on the subject's condition and at the Prs 
discretion. 
6. 
The BSFS is collected episodically at the time or each bowel movement from Visit I to Visit 9. The CeD PRO is captured daily. 
7. 
The GSRS is collected weekly from Visit I to Visit 9. 
8. 
Two blood samples for PK should be collected: one sample should be collected BEFORE dosing starts. the other sample should be 
collected I hour after END of infusion. 
9. 
One blood sample for PK should be collected BEFORE dosing starts. 
10. The stool sample for iVYLJSA GIP can be collected in the 3 days before or after the visits (i.e .. window is ±3 days). At screening. 
the sample will be collected only after signing the consent form. 
11. The Physician and Patient Rating of Change (''Part B" of the PGA and PtGA) should be administered beginning after Visit I; Week 
O/Day 0 as per the schedule of events. 
12. Collected and stored for future testing. This sample can be collected at any time during the study. 
13.Dietitian can contact the patient by phone within the al lotted visit window. 
Protocol CELIM-RC D-002 
Wrsion 3, 11-JUL-20 16 
C'onfideniial 
Page 21 of 134 

TABLE OF CONTENTS 
STUOY PERSONNEL CONTACT INFORMATION ..................................................................... -4 
LIST OF ABBREVlATIONS .............................................................................................................. 6 
PROTOCOL SYNOPSIS ..................................................................................................................... 9 
TABLE OF CONTENTS ................................................................................................................... 22 
fNTRODUCT lON ................................................................................................................. 27 
l.J 
BACKGROUND .................................................................................................................... 27 
I. I . 1 
IL-15 ............................................................................................................................. 27 
1.2 
CELlAC DlSEASE ............................................................................................................... 28 
1.2. I 
Refractory Ccliac Disease ............................................................................................. 29 
1.2.2 
Current Treatment of Refractory Celiac Disease .......................................................... 31 
1.3 
ROLE OF IL-15 IN CELIAC OJSEASE ...................... ., ..................................................... 31 
1.4 
AMG 714 ................................................................................................................................ 32 
1.5 
SUMMARY OF PRE-CLINICAL STUOIES ..................................................................... 33 
1.5. I 
Pharn1acology ............................................................................................................... 33 
1.5.2 
Toxicology .................................................................................................................... 34 
1.6 
EFFECTS OF AMG 714 IN HUMANS ............................................................................... 35 
1.6.1 
Pharmacokinetics of/\ MG 714 in Humans .................................................................. 37 
1.6.1. I 
Pharmacokinetics of AMG 714-HYB ...................................................................... 37 
1.6.1.2 
Pharmacokinetics of AMG 714-CHO ...................................................................... 37 
1.6.2 
Pharmacodynamics of AMG 714 in Humans ............................................................... 38 
1.7 
EFFICACY OF AMG 714 IN HUMANS ............................................................................ 38 
1.7.1 
Efficacy of AMG 7 14-HYB in Rheumaioid Arthritis ................................................... 38 
1.7.l.1 
Study Hx-ILIS-001 .................................................................................................. 38 
I. 7.1.2 
Study 20030210 ....................................................................................................... 39 
1.8 
SAFETY OF AMG 714 IN HUMANS ................................................................................. 39 
1.8.1 
Safety in AMG 7 14-1 IYB Clinical Studies ................................................................... 39 
1.8.1.1 
Study Hx-ILl5-00 l .................................................................................................. 39 
1.8. 1.2 
Study 20030210 ....................................................................................................... 40 
1.8.2 
Safety in AMG 714-CI 10 Clinical Studies ................................................................... 41 
1.8.2. 1 
Study 20050193 ....................................................................................................... 41 
1.8.2.2 
Study 20060349 ....................................................................................................... 42 
2 
KNOWN AND ANTICIPATED RISKS ............................................................................. 43 
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2.1 
NATURAL KILLER (NK) CELL DEPLETION AND RJSK OF INFECTION ........... A3 
2.2 
IMMUNOGENICITY ........................................................................................................... 43 
2.3 
INJECTION SITE REACTION AND ANAPRYLAXIS ................................................. .44 
3 
RATIONALE ......................................................................................................................... 44 
4 
OBJECTIVES ........................................................................................................................ -t-t 
4.1 
PRIMA-RY OBJECTfVE ...................................................................................................... -t-t 
4.2 
SECONDARY OBJECTIVE ................................................................................................ 44 
-t.3 
EXPLORATORY OBJECTfVES ................................•....................................................... -ts 
5 
ENDPOINTS .......................................................................................................................... 45 
S.1 
PllJMARY EFFICACY ENDPOINT .................................................................................. 45 
5.2 
SECONDARY EFFICACY ENDPOlNTS .......................................................................... 45 
5.3 
EX PLO RA TORY ENDPOINTS .......................................................................................... -ts 
5.4 
SAFETY ENDPOLNTS ......................................................................................................... 45 
6 
STUDY DESIGN ................................................................................................................... 46 
7 
RANDOMIZATION ANDTREATMENT ASSIGNMENT ............................................. 49 
8 
DURATIONOFSTUDY ...................................................................................................... -t9 
9 
SUBJECT POPULATION ................................................................................................... 49 
9.1 
INCLUSION CRITERIA ..................................................................................................... SO 
9.2 
EXCLUSION CRITERIA .................................................................................................... 51 
JO 
CONCOMITANT MEDICATIONS .................................................................................... 52 
10.J 
PROHIBITED MEDICATIONS ......................................................................................... 52 
11 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 53 
11.1 
ASSESSMENTS AT EACH VISIT ..................................................................................... 54 
11.1. I 
Screening Visit. ............................................................................................................. 54 
11.2 
12-WEEK RANDOMLZA TION PERIOD .......................................................................... SS 
11.2. l 
Randomization and Dosing preparation ........................................................................ 55 
11.2.2 
Visit l (Week O/Day 0) ................................................................................................ 56 
1 l.2.3 
Safety Phone Call (Weck O/Day 1) ............................................................................. 57 
11.2.4 
Visit2(Wcck l/Day7) ................................................................................................. 57 
11.2.5 
Visit 3 (Week 2/Day 14) .............................................................................................. 57 
11.2.6 
Visit 4 (Weck 4/Day 28) .............................................................................................. 58 
11.2.7 
Visit 5 (Week 6/Day 42) ............................................................................................... 59 
11.2.8 
Visit 6 (Weck 8/Day 56) .............................................................................................. 59 
11.2.9 
Visit 7 (Week JO/Day 70) ............................................................................................ 60 
Protocol CELIM-RCD-002 
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Page 23 of 134 
Confidential 

11.2.1 O 
Visit 8 (Week 12/Day 84) ............................................................................................ 61 
11.3 
FINAL STUOY VISIT .......................................................................................................... 61 
11.3.1 
Visit 9 (Weck 16f0ay 112) or 6 Weeks After Last Study Drug Administration .... 61 
11.4 
EARLY TERMINATION (ET) ........................................................................................... 62 
12 
DEFINITION OF END OF STUDY .................................................................................... 63 
13 
E FFICACY ASSESSMENTS .................. _ ........................................................................... 63 
13.1 
IMMUNOLOGICAL RESPONSE: ASSESSMENT OF ABERRANT 
INTRAEPITHELIAL LYMPHOCYTES ........................................................................... 63 
13.2 
HlSTOLOGIC RESPONSE: SMALL BOWELL ENDOSCOPY, BIOPSY AND 
HlSTOLOGY ......................................................................................................................... 64 
13.3 
CLINJCAL RESPONSE: BRISTOL TOOL FORM CALE (BSFS) AND 
GASTROINTESTINAL SYMPTOMS RA TING SCALE (GSRS) .................................. 65 
13.3.1 
Bristol Stool Form Test. ................................................................................... , ............ 65 
13.3.2 
Gastrointestinal Symptom Rating Scale (GSRS) .......................................................... 66 
14 
EXPLORATORY ASSESSMENTS .................................................................................... 66 
14.1 
PHARMACOKINETICS/PHARMACODYNAMICS ....................................................... 66 
14.2 
ASSESSMENT OF THE GLUTEN-FREE-DIET: IVYLISA GIP STOOL TEST AND 
DIETITIAN CONSULTATION .......................................................................................... 66 
14.3 
PHYSICIAN GLOBAL ASSESSMENT OF DISEASE (PGA) AND PATIENT 
GLOBAL ASSESSMENT OF DISEASE (PTGA)/RATING OF CHANGE ................... 67 
U.4 
QUALITY OF LIFE QUESTIONNAIRES: SF-12 V. 2 AND EQ-50 .............................. 68 
14.5 
BlOMARKERS OF DISEASE ACTIVITY ........................................................................ 68 
14.6. 
fMMUNOGENICITY ........................................................................................................... 69 
U .7 
CELIAC DISEASE PATIENT REPORTED OUTCOME (GED PR0) .......................... 69 
IS 
AFETY ASSESSMENTS .................................................................................................... 70 
IS.I 
VITAL IGNS ....................................................................................................................... 70 
15.2 
PHYSICAL EXAM ............................................................................................................... 70 
15.3 
CLINICAL LABORATORY RESULTS ............................................................................ 70 
15.3.1 
Pregnancy Testing ......................................................................................................... 71 
16 
CENTRAL LABORATORIES ............................................................................................ 71 
17 
LIFESTYLE AND DIETARY RESTR ICTIONS .............................................................. 71 
18 
INVESTIGATJONAL PRODUCTS .................................................................................... 71 
18.1 
DESCRIPTION OF JNVESTLGATIONAL PRODUCT ................................................... 71 
18.2 
PLACEBO .............................................................................................................................. 72 
18.3 
DOSE RATIONALE ............................................................................................................. 72 
Protocol CELIM-RCD-002 
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18.-' 
BLINDING ............................................................................................................................. 73 
18.5 
UNBLINDING ............................................................................•.......................................... 73 
18.6 
RANDOMIZA TlON AND TREATMENT ASSIGNMENT ............................................. 73 
18.7 
DRUG SUPPLI ES, DISPENSING, STORAGE AND ACCOUNTING ........................... 73 
18.7. I 
Packaging and Fonnulation .......................................................................................... 74 
18.7.2 
Storage .......................................................................................................................... 74 
18.7.3 
Preparation and Administration .................................................................................... 74 
I 8. 7 .4 
Supply and Return of Drug ........................................................................................... 75 
18.7.5 
lnvestigational Product Accountability ......................................................................... 76 
18.8 
TREATMENT OF INVESTlGATIONAL PRODUCT OVERDOSE ............................. 76 
19 
STOPPING CRITERIA ........................................................................................................ 76 
19.1 
INTERRUPTION OF DOSING IN AN INDIVIDUAL SUBJECT .................................. 76 
19.2 
INT ERRUPTION OF DOSING FOR ALL SUBJECTS IN THE ENTIRE TRIAL ...... 76 
20 
SUBJECT COMPLETION AND WITHDRAWAL .......................................................... 77 
20.1 
SUBJECT COMPLETION .................................................................................................. 77 
20.2 
SlJBJECT WITHDRAWAL ................................................................................................ 77 
20.2. I 
Withdrawal Procedures ................................................................................................. 77 
21 
ADVERSE EVENTS AND SEIUOUS ADVERSE EVENTS ............................................ 78 
21.l 
REPORTING RESPONSIBILITY ...................................................................................... 78 
21 .2 
DEFINITION OF AN AE ..................................................................................................... 78 
21.3 
SEVERITY ............................................................................................................................. 78 
21.-' 
RELATIONSHIJ> ................................................................................................................... 79 
21.5 
SERIOUS ADVERSE E\TENTS ........................................................................................... 79 
21.6 
SPEClALREPORTING SITUATIONS ............................................................................. 80 
21.6.I 
Death ............................................................................................................................. 80 
21.6.2 
Hospitalizations for Surgical or Diagnostic Procedures ................................................ 80 
2 1 .6.3 
Pregnancy ...................................................................................................................... 80 
21.6.4 
Inadvertent Exposure or Overdose ................................................................................ 81 
21.6.5 
Suspected Unexpected Serious Adverse Reactions (SUSA Rs) .................................... 81 
21.7 
PROCEDURES FOR REPORTING ADVERSE EVENTS ..... - ....................................... 81 
21.8 
PROCEDURES FOR REPORTfNG SERIOUS ADVERSE EVENTS ............................. 82 
21.9 
FOLLOW-UP FOR ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ......... 82 
21.10 
SAFETY REVIEW COMMITTEE ..................................................................................... 82 
22 
DATA ANALYSIS AND STATISTICS .............................................................................. 83 
Protocol CELIM-RC0-002 
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Confiden1ial 

22.1 
SAMPLE SIZE DETERMINAT ION .................................................................................. 84 
22.2 
POPULATIONS FOR ANALYSIS ...................................................................................... 84 
22.3 
MISSING DATA ................................................................................................................... 85 
22.~ 
ST ATJSTICAL ANALYSE ................................................................................................ 85 
22.4. l 
Subject Disposition ...................................................................................................... 85 
22.4.2 
Protocol Deviations ..................................................................................................... 85 
22A.3 
Demographic and Baseline Characteristics .............................................................. 86 
22.5 
EFFICACY ANALYSES .......... -.......................................................................................... 86 
22.5. I 
PRIMARY ENDPOINT ............................................................................................... 86 
22.6 
SECONDARY ENDPOINTS ............................................................................................... 86 
22.7 
EXPLORATORY ENDPOfNTS .......................................................................................... 87 
22.8 
SAFETY ANALYSES ........................................................................................................... 88 
22.8.1 
Ad\1erse Events ............................................................................................................ 88 
22.8.2 
Other Safety Assessments ........................................................................................... 88 
22.8.3 
Prior and Concomitant Medications ......................................................................... 88 
23 
INTERIM ANALYSIS .......................................................................................................... 89 
24 
REFERENCES ...................................................................................................................... 90 
APPENDIX A. ADMINISTRATIVE, ETHrcAL AND REGULATORY POLICI ES ................ 94 
APPENDIX B. LABORATORY PARAMETERS .......................................................................... 99 
APPENDIX C. BRISTOL STOOL FORM SCALE (BSFS) ....................................................... JOJ 
APPENDIX D. SAMPLE GASTJlOINTESTINAL SYMPTOM RATING SCALE (GSRS) ... 104 
APPENDIX E. SAMPLE PHYSICAN GLOBAL ASSESSMENT OF DISEASE/RATJNG OF 
CHANGE ............................................................................................................................. 112 
APPENDIX F. INTERPRETATION OF HEPATITIS RESULTS ............................................. 115 
APPENOLX G. PREDICTED EXPOSURE ANO SAFETY MARGINS .................................... 117 
APPENDIX H. SAMPLE INVESTIGATIONAL PRODUCT LABEL ...................................... 121 
APPENDIX 1. SAMPLE SF-12 V 2 ................................................................................................ 122 
APPENDIX J. SAMPLE EQ-5D QUESTJONNATRE (SL VER ION) ...................................... 125 
APPENDIX K. SAMPLE CELIAC DISEASE PATIENT REPORTED OUTCOME (CED 
PR0) ..................................................................................................................................... 128 
APPENDIX L. SAMPLE PATIENT GLOBAL ASSESSMENT OF DISEASE/RATING OF 
C HANGE ............................................................................................................................. 131 
APPENDIX M. PROTOCOL AMENDMENTS ............................................................................ 132 
Protocol CELIM-RCD-002 
Version 3, I 1-JUL-2016 
Page 26 of 134 
Confidential 

INTRODUCTION 
1.l 
BACKGROUND 
The disease to be treated is Refractory Celiac Disease Type II (RCD-11). an in situ small bov cl 
T cell lymphoma. RCD-11 appears in ~0 .5% of patients with celiac disease and has - 50% 
probability of progression to a systemic Enteropathy-Associated T cell Lymphoma (EATL). 
The treatment-resistant EA TL has dismal prognosis with <20% survival at 5 years. 
Cclimmune is also investigating AMG 714 for the treatment of diet non-responsive celiac 
disease (N RCD). NRCD and RCD-11 are different diseases, and RCD-11 appears independent 
of gluten consumption. I L-15 plays an overlapping yet distinct pathophysiological role in each 
of these diseases. responsible for mucosal damage in NRCD and for aberrant IEL proliferation 
in RCD-11. 
For the sake of providing a comprehensive background. we describe the presumed responsible 
mediator (IL-15). the precursor condition (celiac disease) and. linally. the specific disease to 
be treated (RCD-IT, the in situ small bowel T cell lymphoma). 
1.1.1 
IL-15 
Interleukin 15 (IL-15), a glycoprotein of approximately 14-1 5 kDa, is a proinflammatory 
cytokine with structural similarities to IL-2. IL- 15 exerts biological effects on many 
immunologically relevam cells (Fehniger and Caligiuri. 200 I). While important differences. 
discussed below, are present across species. I L-1 5 generally acts as a development. 
homeostasis and activation factor for NK cells and memory phenotype CDS+ T cells, and it 
induces the production of chemokines and cytokines by these cell types. I L-1 5 potently 
stimulates the production of proinflammatory cytokines such as I L-1, I L-6, and tumor necrosis 
factor alpha (TNF-a) by monocytes/macrophages. IL-1 5 produced by fo llicular dendritic cells 
is reported lo support genn inal center B cell proliferation and immunoglobulin class switching 
(Park el al, 2004; Litinskiy et al. 2002). Targeted disruption of either the IL- 15 or the IL- 15 
receptor alpha (IL-1 5Ra) genes in mice has been shown to result in the loss of N K. NK-T. 
TCRy8+ intraepithelial lymphocytes, and memory CD8+ cells (Lodolce el al. 1998). In I L-15 
knockout mice. these defects are reversible by the administration of exogenous I L-15 
(Kennedy et al, 2000). In contrasL human NK cells are not entirely dependent on JL-1 5 (Lebrcc 
el al, 20 13 ). 
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 LO multiple post-
transeriptional control mechanisms. Immunologically relevant sources of I L-15 protein inc lude 
monocytes, macrophages, epithelial and tibroblastic cells, and bone marrow stromal cells 
(Fehniger and Caligiuri, 200 I). IL-15 and its receptor are also expressed in some organs 
outside the immune system; the role of I L-1 5 in these systems is less well understood. The 
absence of any overt defects outside the immune system in IL-15 and IL-1 5Ra knockout mice 
suggests that I L- 15 may not be essential in any other system. 
Protocol CELIM-ROC-002 
Version 3, 11-J L-2016 
Page 27 of 13.S 
Confidential 

I L-15 binds to a hcterotrimcric receptor that consists of a p chain that is shared with the I L-2 
receptor (CDl 22 or IL-2/IL-1 5Rf3). the common y chain (yC). shared with the IL-2. -4. -7. -9. 
and -21 receptors. and a unique a chain. IL-15 binds with high affinity to the JL- ISRa chain, 
which then interacts with the I L-2/1 L-1 SRB and the yC. The association of the I L-15/1 L-15 Ru 
complex with the other two components of the complete receptor complex can occur in a cis 
configuration where all three receptor components are present on the same eel I, or in a trans 
configuration where the IL I Sill I 5Ra pair i 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-15Ra on the cell surface and 
then be cleaved into soluble cytokine/receptor complexes that have the potential to stimulate 
CD8+ T cells and NK cells (Anthony et al. 20 15). 
Increased expression of IL-15 has been demonstrated in a variety of innammatory conditions. 
including rheumatoid arthritis (RA}. psoriasis, inflammatory bowel disease, graft-versus-host 
disease. solid organ transplant rejection (Blaser el al. 2005; Conti et al. 2003: Gianfrani et al. 
1005; Mcinnes and Gracie. 2004) and celiac disease (reviewed in Gianfrani et al. 2005: 
Meressc et al, 20 12). 
1.2 
CELIAC DJSEASE 
Celiac disease is a systemic autoimmune disease triggered by gluten consumption in 
genetically susceptible individuals (Green and Cellier, 2007). Currently approximately I% of 
the western population is affected by celiac disease, albeit the vast majority of patients remain 
undiagnosed. The prevalence is rwice that in countries with very high hygiene standards and/or 
very high gluten consumption. Presently it is estimated that 15-20 million patients are affected 
by celiac disease and approximately 1.0-1.5 million patients are diagnosed. This number has 
been reported to be doubling every 20 years (Riddle el al, 20 12). 
Gluten, the antigen responsible for celiac disease. is the main protein present in some of 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 
lo 80% of foodstuff. Gluren 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 linle as 50 mg/day 
of gluten triggers the disease (Catassi el al, 2007). A normal diet contains> I 0 g/day. 200 times 
the amount that causes intestinal histological abnormalities. As such. celiac patients face an 
enormous challenge to fo llow a strict GFD. 
The pathophysiology of celiac disease is characterized by an abnormal immune response to 
gluten. Gluten. which is normally a well-tolerated dietary component. elicits innate and 
adapti c immune responses in celiac patients (Green and Cellier. 2007). Humans lack enzymes 
to fully digest gluten.-. hich against the right genetic background triggers inflammation and 
autoimmunity in the intestine and in other organs. An adaplive immune 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 HLA-DQ2 and HLA-DQ8. which present these 
peptides to intestinal CD4+ T cells. thereby activating these T cells and initiating the 
inflammatory cascade. The innate immune system's intraepithelial lymphocytes (I ELs). 
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primarily CD8+, are able to directly lyse and destroy intestinal epithelial cells, damaging the 
mucosa I lining of the small intestine. in response to the I L- 15 release. stimulated by gluten 
peptides (Abadie and Jabri, 2014). Jn healthy individuals. the activated T cells are controlled 
by regulatory T cells (Tregs), but this does not happen in celiac disease as I L-1 5 confers the 
effector CD4+ T cells resistance to suppression by Tregs (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). 
The only currently available strategy for the management of celiac disease patients is a lifelong 
total avoidance of gluten. While simple in theory. the ubiquity of gluten makes total avoidance 
of gluten very difficult - if not impossible in practice. As little as 50 mg/day (a normal diet 
contains> I 0 gr/day) triggers activation of the T cells of the smal I bowel and cause intestinal 
mucosa! damage (Catassi el al, 2007). A study by Shah el al (2014) found the burden ofceliac 
disease and a Gl7D on patient quality of life was ranked second only to end-stage renal disease 
- a debilitating and li fe-threatening condition that requires polypharmacy and multiple, weekly 
dialysis treatments. For these reasons. celiac patients are unable to comply with a zero gluten 
diet, and more than 50% of diagnosed patients on a GFD continue to present active disease and 
intestinal immune activation and mucosa! atrophy (Lee et al, 2003; Cranney et al. 2007: 
Hopper et al, 2007; Midhagen et al 2003). Celiac patients who continue to have symptoms 
despite attempting to maintain a GFD are deemed to have diet ·'non-responsive celiac disease·· 
or NRCO. NRCD has been defined as "persistent symptoms, signs or laboratory abnomialities 
typical of celiac disease despite 6-1 2 months of dietary gluten avoidance" (Rubio-Tapia et al, 
2013). Mortality is increased in subjects with persistent intestinal mucosal damage 
(Ludvigsson et al. 2009). 
1.2.1 
Refractory Celiac Disease 
A rare but specific complication of persistent diet non-responsive celiac disease is the 
development of Refractory Celiac Disease (RCD). which aITecls approximately I% of celiac 
patients (Lebwohl el al, 20 13) and is characterized by severe gastrointestinal symptoms in the 
absence of gluten consumption and in the presence of small bowel aberrant imraepithelial 
lymphocytes (lELs) (reviewed in Verbeck et al 2008, and in van Wanrooij et al. 20 14). 
Refractory Cel iac Disease patients can be further classified according to the number of aberrant 
lELs. Patients with low numbers of aberrant IELs, defined as less than 20 % of total IELs. as 
determined by now cytometry. are referred to as having Type I RCD (RCD-1). and are not at 
increased risk of developing overt extra-epithelial lymphoma. otherwise referred to as 
enteropathy-associated T cell lymphoma, (EA TL), and have a normal 5-year survival (van 
Wanrooij et al. 20 14 ). 
When the numbers of aberrant IELs exceed the 20% threshold. referred to as Type IT RCD 
(RCD-Jl), the risk of developing EATL is dramatically increased to >50% (Nijeboer et al. 
20 I 5a, 20 15b). EA TL has a very poor 5-year survival of <20% (Nijeboer et al, 20 I 5a) and its 
prevalence is increasing (Sharai ha et ul. 2012). 
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In RCD-1 1. aberrant IELs proliferate in what represents a slow-growing non-Hodgkin 
lymphoma localized (in situ) in the small bowel. primarily in the epithelial compartment. The 
aberrant IELs observed in RCD-11 patients have been demonstrated to be precursors or the 
extra-epithelial lymphoma by observation that the TcR rearrangement repertoire is similar to 
that seen in sequential biopsies taken from RCD-11 patients who developed EA TL. Monoclonal 
I ELs are demonstrated in most patients. which is why RCD-11 is considered to be an in situ lo'vv-
grade lymphoma. A thorough study of the low grade IEL proliferation in RCD-11 has revealed 
a characteristic phenotype (presence of intracellular CD3without surface CD3 or TcR and 
generally no CD8 expression with expression of CD I 03). that is also shared by the high grade 
EA TL proliferations. This phenotype is distinct from the nonnal phenotype of IE Ls in 
uncomplicated celiac disease and. together with the presence of a clonal TcR rearrangement in 
the intestinal biopsy, confirms the diagnosis of RCD-11 and allows follow-up of the expansion. 
Clinical guidelines (Rubio-Tapia et al. 2013) suggest 12 months of persistent disease activity 
while on a GFD as the timeframe that should trigger the suspicion and eventual diagnosis of 
NRCD and then RCD. However, the current study uses 6 months as the required time on GFQ, 
since all patients are evaluated for aberrant IELs >20% by flow cytometry (or >50% by IHC). 
representing definitive evidence of RCD-11 in the context of all other inclusion and exclusion 
criteria of the study (Nijeboer et al, 2015b). This definitive evidence obviates the need to 
c aluate the diet for a full year. a requirement only necessary when advanced diagnostic 
techniques arc unavailable and diagnosis is made by clinical exclusion alone. This approach 
wi II reduce both the risk or complications and disease ~vo luti o n if a patient was required to wait 
for 12 months before receiving a diagnosis. Nevertheless. it is expected that a majority of 
patients enrolled -if not all- will have been on a GFD for longer than a year. Spontaneous 
remission of RCD has not been documented in the literature. neither within the initial 6 months 
post-diagnosis. nor after this time. 
For the purpose of this study, and in agreement with leading experts in RCD-11 (Malamut et 
al. 2010; Nijeboer et al. 2015a, 20 15b). aberrant IELs will be defined by flow cytometry as 
surface CD3-negative. intra-cellular CD3-positive IELs (sCD3-. icCDJ+). The cut-off chosen 
for diagnosis of RCD-11 is 20% in accordance with most recent studies (Nijeboer er al. 20 I 5b ). 
In J HC. these cells are identified as icCDJ+ sCD8- and the cut-off is 50% (Nijebocr cl al. 
20 15b). 
Additionally. standard flow diagrams for the diagnosis of RCD-11 (e.g., Rubio-Tapia el al, 20 13) 
and exclusion of conditions that could simulate RCD-11 clinically and histologically are 
considered in the inclusion/exclusion criteria. 
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Table 2. Characteristics of Celiac Disease, Refractory Ccliac Disease and EA TL 
Nature of 
Gluten 
Aberrant 
Clonality 
Progression 
the disease 
dependence IE Ls 
to overt 
systemic 
lymphoma 
Celiac 
Autoimmune Yes 
No 
Polyclonal 
No 
Disease 
RCD-1 
Unknown 
Probably 
Yes. <20% 
Oligoclonal 
No 
RC0-11 
Malignant. 
Probably not Yes, >20% 
Monoclonal 
>50% 
slow 
(in situ 
growing 
lymphoma) 
EATL 
Malignant. 
No 
Yes, >20% 
Monoclonal 
NIA 
rapid 
progression 
1.2.2 
Current Treatment of Refractory Celiac Disease 
The treatment of RCD is difficult. Abnormal lymphocytes are scattered in the whole small 
intestinal epithelium and usually in the stomach and colon. thereby precluding surgery. 
Currently, there is no standard of care for RCD-1 or RCD-11. In RCD-1. corticosteroid (local or 
systemic), azathioprine. purinethol. anti-TNF agents. or cladribine may be used with limited 
success (Brar et al. 2007; Goerres et al. 2003). In RCD-11, budesonide (Brar ct al. 2007), 
cladribine (Tack et ul, 20 11 a) and autologous bone marrow transplantation (Tack et al. 20 I I h) 
have also been Ltsed with different degrees of success. and better outcomes for autologous 
BMT (Nijeboer et al, 20 l Sb). The prognosis of RCD-11 is still poor with death occurring within 
3- 10 years due mainly to intractable diarrhea and/or development of high grade EA TL 
lymphomas or. more rarely, to dissemination of the low grade proliferation to other tissues 
(e.g .. skin, lungs). The treatment of the high grade lymphoma (EA TL) relies on surgical 
resection and chemotherapy, but the prognosis is very poor. 
An effective treatment for RCD-11 that could reduce the presence of aberrant I ELs and alleviate 
the histological abnormalities and/or the symptoms. remains the highest priority. 
1.3 
ROLE OF IL-15 lN CELIAC DISEASE 
Substantial evidence suggests a pathophysiological role for IL-15 in celiac disease and RCD-
11 (reviewed in Abadie and Jabri et al. 20 14): 
• 
Innate immunity: 
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o 
I L-15 is an essential, non-redundant growth and activation factor for the I Els 
which destroy the intestinal mucosa: 
o The expression of IL-15 in the intestinal epithelium is necessary for villous 
atrophy: 
o 
In some patients, I L-1 5 drives progression towards lymphomagencsis and 
potentially fatal RCD-11 (Malamut et al. 2010) 
• 
Adaptive immunity: 
o 
I L-15 enhances the presentation of deamidated gluten peptides (DGP) by 
antigen-presenting cells (APCs): 
o 
I L-15 renders the activated CD4+ T cells resistant to inhibition by regulatory T 
cells: 
o 
I L-15 has been proven to be a key factor in the loss of tolerance Lo food antigens 
(De Paolo el al. 2011; Korneychuk, et al. 2014) 
By activating the intraepithelial lymphocytes (I ELs). IL-15 is believed to be the main mediator 
in the mucosa! damage that ensues in response to gluten exposure in celiac disease 
(Komeychuk et al, 2014). The expression of IL-15 in the intestinal epithelium is necessary for 
villous atrophy in animal models of c.:eliac disease and circumstantial evidence suggests this to 
be the case in humans, as well. In addition, I L-15 render effector T cells resistant to inhibition 
by regulatory T cells (Tregs) (Abadie and Jabri. 2014 ). promoting loss of tolerance to food 
antigens (DePaolo et of. 2011. Korneychuk et al. 2014). 
One of the studied mouse models ofceliac disease is an IL- IS-transgenic mouse. in which IL-
15 overexpression by gut epithelial cells leads to celiac-like disease. including T and B eell-
mediated pathology (Yokoyama el al. 2009 and 20 I l ). I EL apoptosis has been observed in this 
animal model after treatment with anti-I L-15 (Malamut el nl 20 I 0) or anti-I L-15-reccptor 
mAbs (Yokoyama el al 2009). 
In RCD-11. the role oflL-15 appears even clearer. and IL-15 is believed to be the main dri ver 
of transfonnation and maintenance of the aberrant I ELs (Meresse et al, 2012). lL-15 is up-
rcgu lated in the intestinal mucosa of patients with RCD-11 and, more importantly. incubation 
of RCD-ll patient duodenal biopsies with the anti-JL-1 5 monoclonal antibody. AMG 714. 
blocked anti-apoptotic signaling via JAK3 and ST ATS. leading to apoptosis of rhe clonal 
aberrant I Els (Malamut et al, 20 I 0. reviewed in Meresse et al 2012). 
1.4 
AMG 714 
AMG 7 14, a fully human immunoglobulin (lgG l K) monoclonal antibody (formerly HuMax-
IL 15. Genmab), binds to and inhibits the function of IL-15 in all its forms (cis, trans. soluble 
IL-15 bound to IL-15Ra.). AMG 714 inhibits IL-15-induced Tcell proliferation and shows a 
dose-dependent inhibition of IL-15-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.eels with rheumatoid arthritis (Baslund et al. 2005) . • 
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(CHO) cell line (referred to in this document as AMO 714-CHO). 
been tested in two studies in healthy volunteers and in patients with psoriasis. All future clinical 
studies will be performed with AMG 714-CHO. 
1.5 
SUMMARY OF PRE-CLINICAL STUDIES 
The nonclinical development of AMG 714 consisted of a series of in vitro studies 
demonstrating the binding properties of AMG 71 4 against hl L-1 5: in vitro and vivo studie 
providing proof-of-concept for the benefit of blocking the IL-15 pathway in celiac disease: and 
a series of GLP studies evaluating the nonclinical safety profile of Hu714MuXHu, the AMG 
71 4 surrogate molecule active in macaques. The fu ll description of the pre-clinical studies can 
be found in the Investigator's Brochure. 
1.5.J 
Pharmacology 
In nonclinical experiments conducted with the original hybridoma-derived antibody, AMG 
71 4-HYB was found to recognize an epitope that is essential for the interaction between human 
IL-15 (hlL-15) and its receptor complex. AMG 714-HYB showed a dose-dependent inhibition 
of 1 L-15-induced proliferation of peripheral blood T cells. and cell lines expressing rL- 1 S 
receptors, as well as a dose-dependent inhibition of hlL-1 5-induced TNF-a production. 
Specificity for lL-15 was demonstrated by lack of inhibitory effects on human IL-2 (hlL-2)-
mediated proliferation of peripheral blood Tcells, 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 celiac disease triggered by 
the transgenic expression of human I L-1 S in the gut epithelium (Malamut et 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 RC0-11 patients 
(Malamut er al. 20 I 0). In this culture experiment. AMG 714-CHO resulted in a suppression of 
IL- 15-driven anti-apoptotic signaling via JAK3 and STA T5. 
1 n vitro studies demonstrated that AMG 714-CHO had high binding affinity for hi L-1 5, but 
lower affinity for macaque lL-15. Additionally, AMG 71 4-CHO neutralized hl L-1 5 but did 
not efficiently neutralize macaque IL-1 5. To enable preclinical studies in macaques. a 
surrogate antibody, Hu7 I 4MuXHu, was developed by fusing the F(ab) portion of a mouse anti-
hlL-15 monoclonal antibody known to neutralize macaque IL-1 5, M I 11 , with human lgG I Fe;. 
Hu7 14M uXHu was shown to neutralize macaque IL-1 5 with approximately the same potency 
as AMG 71 4-CHO neutralizes hlL-15. 
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In a safety pharmacology study, cardiovascular, respiratory, and neurobehavioral endpoints 
were evaluated in cynomolgus monkeys that received a single intravenous (rV) bolus dose of 
~ 300 mg/kg Hu7 I 4MuXHu. In this study, the no-observed-effect level (NOEL) was 300 
mg/kg. the highest dose tested. 
1.5.2 
T oxicology 
Because of the low binding affinity of AMG 7 14 for macaque I L-15 and the very low inhibitory 
activity of AMG 714 against macaque IL- 15. the safety profile of AMG 7 14-CHO has been 
evaluated in nonclinical studies in non-human primates (cynomolgus monkeys) using the 
surrogate molecule Hu7 14MuXHu in a single dose safety pharmacology study (described 
above) and in repeated-dose toxicology studies. 
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1.6 
EFFECTS OF AMC 714 IN H UMANS 
The original hybridoma-derived material produced 
evaluated in sub·ects with RA in a Phase I stud 
(2003021 0). 
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 L 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 to placebo in - 200 subjects exposed (including - 140 exposed for 12 weeks of bi-
weekly dosing); a favorable pharmacokinetic profile with 3 weeks half-lite; 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 Number 
(Phase) 
AMG 714-CHO 
20050193 
(Phase I; 
Amgen) 
Key Design Features 
Double-blind. placebo-
controlled, single SC or 
IV 
doses. 
dose-
csca lat ion stt1dy 
Dose Route. Duration 
Study Population 
SC doses: 0. 30, I 00, 
300 
or 
700 
mg 
(cohons I to 4) 
IV dose: 0 or I OOmg 
IV infusion (cohort 5 )·' 
Single dose 
40 healthy 
subjects 
Status 
Completed 
20060349 
Double-blind, placebo-
0 or 150 mg 
SC 
22 subjects with 
Completed" 
(Phase 
lb/2a; 
Amgen) 
AMC 71-'-HYB 
I lx-JL 15-00 I 
(Phase I: 
Genmab) 
200J02 10J 
tPhasc 2: 
Genmab/ Amgen) 
controlled, multiple SC 
doses, 
dose-escalating 
study 
Double-bl ind. placebo-
controlled. single SC 
infusion. 
dose 
escalation. srudy with 
open-label, repeat-dose 
(4 weekly 
doses) follow-up 
Double-blind, placebo-
controllcd. multiple SC 
infusion. 
parallel-
group, 
muhicenter 
study 
(cohort l) 
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 weekly 
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 
100°10 loading dose 
moderate 
to 
severe psoriasis 
30 subjects with 
RA" 
180 subjects with 
RA 
• Dose escalation occurred npproximntcl) C\ cry 4 week.' : dosing cohorts initiated scqucmi:illy. 
~ f crmin;11cu early due 10 lack of cOicac~ in psoriasis 
Completed 
Completed 
" All 30 subjccts received initial ~ inglc Jose (0 or 0. 15 - 8 mg/kg. /\MG 71 ·I-I IYB ): 24 of 1hc 30 subjects entered into 
the repeated dosing portion (Cl.IS - 4 mg/kg AMG 714-llYBl 
d Gcnmnb initiated stud) as I l;>.-1L15-002 
IV = intravenous: RA = rheumatoid anhriti~: SC= subcu1;111cous 
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1.6.1 
Pharmacokinetics of AMG 714 in Humans 
1.6.1.1 
Pharmacoki11etics of AMG 714-HYB 
1.6.1.2 
Pharmacoki11etics of AMG 714-CHO 
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1.6.2 
Pha rmacodynamics of AMG 714 in Humans 
The effects of AMG 714-HYB and AMG 714-CHO on NK cell counts were explored in three 
Phase 1 and 2 clinical studies (Hx-ILI 5-00 I, 20030210, 20060349) using immunophenotyping 
that included markers specific for NK cells. This analysis was based on the observed 
pharmacodynamic effects in preclinical species. No changes in absolute or relative numbers of 
NK cells were observed in either study at any or 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. Hu714MuXHu. 
This difference between observations in preclinical and clinical studies appears related to a 
differential sensitivity of human versus cynomolgus monkey N K cells to IL- 15 deprivation. 
Human NK cells are not dependent on IL-15 for their survival (Lebrec et al. 2013). possibly 
due to the redundant role of IL-2 on human NK cells. 
1.7 
EFFICACY OF AMG 714 IN HUMANS 
1.7.J 
Efficacy of AMG 714-HYB in Rheumatoid Arthritis 
I. 7.1.J 
Study Hx-ILJ 5-001 
Phase 1 Study Hx-IL 15-00 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. 15. 0.5. 1.0. 
2.0. 4.0, and 8.0 mg/kg AMG 714-HYB), fol lowed 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 JO subjects completed the single dose stage of the study. and 20 of24 subjects 
completed 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). 
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1. 7. 1.2 
Study 20030210 
In Phase 2 Study 20030210. subjects were enrolled in two cohorts. wilh 11 0 subjects in Cohort 
I randomized equally to placebo or AMG 7 14-HYB (40, 80, 160, or280 mg) and an additional 
70 subjects in Cohort 2 randomized equally to plncebo or 280 mg AMG 7 14-HYB. 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 ACR 70 response rates (50%. and 70% improvement in the ACR criteria from baseline); 
ACR response rates throughout the study: the change from baseline in individual ACR 
components; and the disease activity score (DAS28). 
The ACR20 response rate in the 280-mg group (Cohorts l and 2 combined) increased over 
placebo at 14 weeks (54% vs 38%), but the difference was not statistically significant (p = 
0.097. Cochran-Mnntel-Haenszel test). However. a statistically significant difference in 
ACR20 response in the 280 mg group compared with placebo was observed at weeks 12 (64% 
vs 34%; p = 0.003) and 16 (66% vs 38%: p = 0.003). The overall distribution of the DAS28 
scores (nonresponder imputation) decreased signi ficantly 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 280 mg group decreased from 6.8 al 
baseline to a low of 4.9 at 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 al week 4, concentrations of 
acute phase reactants decreased significantly in the 280 mg AMG 7 I 4-H YB group compared 
with placebo (C-rcactive protein [CRP], p < 0.000 I; erythrocyte sedimentation rate fESRj. 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% al week 4 and remained 
50% to 67% lower than CRP concentrations in the placebo group for the remainder of the 
study. Significant improvements also were seen in other ACR components (weeks 12 and 16) 
and in DAS28 (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 7 14-HYl3 compared with placebo) was not met. 
the overall clinical results suggested AMG 714-1 IYB pharmacological activity, as indicated by 
the reduction of acute phase reactant concentrations and the efficacy of /\MG 714-1 lYB in the 
treatment of RA refractory to disease-modifying anti-rheumatic drugs (DMARDs). 
1.8 
SAFETY OF AMG 714 JN HUMANS 
1.8. 1 
Safety in AMC 714-HYB Clinical Studies 
1.8.1.l 
Study Hx-/Ll 5-001 
The study results indicated that single doses ofS 8 mg/kg and multiple doses of 4 mg/kg AMG 
714-HYB were well tolerated, and no serious adverse events or infections were observed al the 
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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 received the initial double-blind dose. and of the 24 subjects who entered 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. 
During the double-blind, single-dose period. adverse events were reported by 8 of 30 (27%) 
subjects. and rates were similar among dose cohorts. All reported adverse events were mild to 
moderate in severity. Two subjects reported infections during this period. One subject in the 
0. 15-mg/kg coho1i 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 nare 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 events. 
also with similar rates among cohorts. All reported adverse events were mild to 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 of NK 
cells occurred. and no subject developed anti-A MG 714-H YB antibodies. 
J.8.1.2 
Study 20030210 
AMG 714-H YB was well tolerated 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. 
o 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 2 1 subjects. 
5%1 [40 mg !: 2 of23 subj1::cts, 9% (80 mgl; 3 of22 subjects, 14% f 160 mg]: 5 of 55 subjects. 
9% f280 mgj): 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 
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events considered by the investigator as possibly related 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). Reported events for > 1 subject in any treatment group were bronchitis. 
innuenza. nasopharyngitis. pharyngitis, upper respiratory tract infection. and urinary tract 
infection. These events occurred with similar frequency in the placebo and AMG 714-llYB 
treatment groups. The most frequently occurring events in the 280 mg group were 
nasopharyngiris (5% vs 2% in placebo group) and pharyngitis (5% vs 2% in placebo group). 
Serious infectious events were reported by two subjects: one in the placebo group (viral 
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, 
all of whom were in the intermediate /\MG 714-HYB dose groups ( I [40 mg], 2 [80 mg]. and 
2 [ 160 mgj subjects). 
Clinical laboratory assessments showed only minor differences between placebo and AMG 
714-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 
neurropenia. Following treatment with IV antibiotics and a blood transfusion. the subject fully 
recovered. No subject developed antibodies to AMG 714-HYB. 
1.8.2 
Safety in AMG 7 1 4~CHO Clinical Studies 
1.8.2.J 
Study 20050193 
Of the 43 subjects enrol led 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 ineligibiliry and one subject due to a change in eligibility 
status). Thirty-nine of 40 subjects (98%) completed the study; one subject who received I 00 
mg AMG 7 14 SC discontinued due to non-study related reasons. 
AMG 714 was generally well tolerated at all doses administered during the study. No deaths, 
serious 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 invcstigational 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 of treatment-emergent adverse events and the route or administration of AMG 7 14 
(SC 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 and one 
event was severe. The severe adverse event was a tooth infection (placebo), and was not 
considered by the investigator as 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 mgAMG 714 SC), headache (100 mg 
AMG 714 IV), and gastroenteritis ( I 00 mg AMG 714 IV). Three of the seven moderate events 
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were reported as not related to investigational product: diarrhea (placebo). lower respiratory 
tract infection (placebo), and vessel puncture. site bruise (700 mg AMG 7 J 4 SC). Among the 
fort) subjects who recei ed investigational product, the most commonly reported adverse 
event was injection site reaction in five subjects ([I 7%J (700 mg AMG 7 14 SC), and 2 subjects 
[20%] (placebo). A II inject ion site reactions were considered by the investigator to be treatment 
related. Other commonly reported adverse events included headache (two in AMG 714 [7%]. 
two in placebo f20%]), pharyngolaryngeal pain (four in AMG 714 [ 13% 1), and upper 
respiratory tract infection (four in AMG 714 [ 13%]). No clinically important effects of AMG 
714 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 ( 100 mg. IV) ' as positive for anti-AMG 7 14 
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 enrolled into this study; of these. 20 (9 1 %) 
subjects received al least one SC dose of investigational product and were included in the safely 
analysis set. Overall. 17 (77%) subjects received all six planned doses of investigational 
product; 16 (7 3%) subjects completed all study visits and completed the study. 
Twenty subjects received ~ I dose of investigational product and were included in the principal 
analysis of safety (six placebo, six AMG 714 150 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 {/\MG 714 300 mg) discontinued investigational product in 
response lo an adverse event of worsening psoriasis. but completed all study assessments. 
Overall, most (90%) subjects 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 (ti e [83%] AMG 
714 150 mg. seven [88%] AMG 7 J 4 300 mg. and six [I 00%1 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 treatment-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 714 150 mg. and /\MG 714 300 mg groups, respectively); no other 
treatment-related 
adverse 
event 
was 
experienced 
by 
more 
than 
one 
subject. 
lmmunophenotyping findings revealed everal 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 rhe 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 intermittent and indiscriminate. as were the minor shifts in 
either direction that were evident for most hematology and chemistry parameters. No out-of-
range 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 
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binding antibodies at anytime point. No clinically important observations in ECG or vital signs 
were reported. 
2 
KNOWN AND ANTICIPATED RISKS 
2.1 
NATURAL 
KILLER (NK) 
CELL 
DEPLETION ANO 
RISK OF 
INFECTION 
NK cell counts and NK cell activity were significantly decreased by blocking IL-1 5 in 
cynomolgus monkeys. This effect is thought to be a consequence of a pharmacodynamic 
response, given the known role of IL-15 in NK cell biology in monkeys and other animal 
species. Episodes of diarrhea required treatment with enrofloxacin in several animals. These 
observations started approximately two to three weeks after initiation of treatment in some 
animals and as late as I 0 weeks after initiation of treatment in one animal. Shigefla infections 
were diagnosed via stool culture in most of the animals treated for diarrhea episodes. Given 
the described role of N K activity in the defense against Shigella species, the observed effect 
on NK cells is considered a possible adverse event in the cynomolgus monkey. 
In contrast, no reduction of NK cells has been observed in humans, and gastroenteritis and 
enteric 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 
N K eel Is. are not dependent on lL-J 5 for their survival and function (Lebrec et al, 20 13). The 
absence of NK eel I depletion in humans reduces concerns, and the risk of enteric infections 
will be closely monitored in fotthcoming clinical studies including the proposed CELI M-RCD-
002 and CELIM-NRCD-00 I. 
The sponsor interprets the lack of efficacy in psoriasis as suggestive of AMG 714"s selective 
effect on specific immune pathways, rather than a broad systemic jmmune suppression (since 
most systemic immune suppressants are efficacious in psoriasis). 
2.2 
IMMUNOGENICITY 
lmmunogenicity (generation of anti-drug antibodies [ADA]) is a potential risk for any biologic 
therapeutic. Irnmunogenicity may lead to injection reactions and to loss of efficacy when the 
antibodies are neutralizing and high-titer. 
AMG 714-1 IYB and AMG 7 14-CHO are fully human anti-IL-1 5 monoclonal antibodies. Only 
one of the approximately 200 subjects dosed with active drug in all four studies conducted with 
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AMG 714 developed anti-AMG 714 antibodies (single time point .. neutralizing). with no 
impact on PK. 
In summary, immunogen icity has been exceptionally reported with AMG 714. and the risk of 
immunogenicity will be closely monitored with robust and fully validated assays. Any positive 
ADA will be monitored. even atler completion of the study and study database lock. until the 
ADA level returns to baseline, unless the subject is maintained on AMG 714 outside of the 
scope of the study (i.e., in case of an extension in dosing). 
2.3 
INJECTION SJTE REACTION AND ANAPHYLAXIS 
In AMG 714 studies. injection site reactions have been mild and have appeared with low 
frequency (typically below I 0%). There have not been any reports of anaphylax_is to AMG 
714. All administrations of study drug will 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. and especially in RCD-11, an in situ small 
bowel T cell lymphoma which has 50% frequency of progression to overt systemic lymphoma 
(EA TL). the latter characterized by very poor prognosis (<20% survival at 5 years). There are 
no medications approved for RCD-11. 
Interleukin 15 (IL- 15) is considered to be a central regulator of celiac disease 
immunopathology and a non-redundant driver of lymphomagenesis in RCD-11 . AMG 714 is a 
fully human monoclonal antibody which binds to bioaclive IL-IS and has been well-tolerated 
with demonstrated clinical and biochemical effects in RA. AMG 714 has been studied in 
approximately 200 subjects to dare. including approximately 140 subjects dosed for 12 weeks. 
Its electivity. favorable safety and pharmacokinetic profile in conjunction with the proof-of-
mcchanism in RA support the testing of AMG 714 in RCD-11. an in situ small bowel T cell 
lymphoma. 
4 
OBJECTIVES 
4.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to assess the efficacy of AMG 714 in treating RCD-11. 
an in situ small bowel T cell lymphoma. in adult patients. 
4.2 
SECONDARY OBJECTIVE 
The secondary objecti ve of this study is to assess the safety and tolerability of AMG 714 when 
administered to adult patients with RCD-11. 
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4.3 
EXPLORATORY OBJECTIVES 
The exploratory objective of this study is to assess the PK. PD. and PK/PD coITelations of 
AMG 7 14, 
5 
ENDPOINTS 
5.1 
PRIMARY EFFICACY ENDPOINT 
• 
Immunological response I as measured by reduction from baseline in the % or aberrant 
I ELs vs total I Els 3S assessed by flow cytometry. 
5.2 
SECONDARY EFFICACY ENDPOINTS 
• 
Immunological Response 2: Reduction from baseline in the % of aberrant IELs vs 
intestinal epithelial cells 
• 
Histological response as measured by an improvement from baseline in small intestinal 
VI l:CD ratio. Marsh score or total IEL counts. 
• 
Clinical response as measured by change from baseline in clinical symptoms captured 
using: 
o 
Bristol Stool Form Scale (BSFS) 
o 
Gastrointestinal Symptom Rating Scale (GSRS) and celiac disease GSRS 
(CeD-GSRS) 
5.3 
EXPLORATORY ENDPOINTS 
• 
Reduction in aberrant and abnormal IELs by flow cytometry. immunohistochernistry 
and TcR clonalily analyses 
• 
Physician Global Assessment of Disease (PGA) and Patient Global Assessment of 
Disease (PtGA) 
• 
Qua lity of Life questionnaires: SF-12 v. 2 and EQ-SD 
• 
Biomarkers of disease activity 
• 
Pharmacokinetics (PK). Pharmacodynamics (PD). and Exposure/Response (PK/PK) 
• 
Celiac Disease Patient reported Outcome (CeD PRO) 
5.4 
SAFETY ENDPOINTS 
• 
AEs 
• 
Clinical laboratory tests 
• 
Physical examination 
• 
Vital signs 
• 
lmmunogenicity 
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6 
STUDY DESIGN 
Protocol CELIM-RCD-002 is designed to be a Phase 2a randomized. double-blind, placebo-
controlled. parallel-group study to evaluate the efficacy and safety of AMG 714 for the 
treatment of adult patients with RDC- 11, an in situ small bowel T cell lymphoma. 
After signing consent, subjects will be screened for the study. All subjects who meet the study 
entry criteria will be randomized 2: I ratio to receive either 8 mg/kg AMG 714 or placebo a 
total of 7 times over I 0 weeks, with evaluation of the primary endpoint at Visit 8 (Week 12/Day 
84). 
AMG 7 14 (N= 16) or placebo (N=8) will be administered at the clinical site in a double-blind 
fashion via intravenous (IV) infusion of approximately 120 minutes (2 hours) duration. 
Subjects will remain confined to the study site for a minimum or I hour after the administration 
of study medication. During this time the Investigator and study site stalTwill assess the subject 
for A Es. As per Table I. PK samples are to be collected prior to the infusion and I hour after 
the infusion, at the end of this observation period. The beginning and end of the infusion. as 
well as the PK sample collection times, will be recorded. 
In addition to receiving study medication (AMG 714 or placebo). concomitant therapy with 
steroids at a maximum dose of20 mg of prednisonc. prednisolone or equivalent per day and/or 
oral budesonide at a maximum dose of 9 mg per day will be accepted. Steroid doses must be 
stable for 4 weeks prior to randomization and remain stable for the duration or the sLudy. 
Budesonide has been used in RCD-11 with improvement of symptoms and is considered 
adequate background therapy for RCD-11 (Brar et al, 2007). 
Should AMG 7 14 show adequaLe efficacy and safety. as determined by the Sponsor. subjects 
in the study. including those in the placebo arm. may be offered participation in an open label 
extension study of AMG 714 in due course. but under no circumstances prior to study 
completion. In the interim, between the end of the study for an individual subject and the start 
of the possible open label t:xtension. the Sponsor intends to provide a bridging program to 
allow objective study responders to have access to AMG 714 as determined by their site 
investigator or physician. The open label extension study and interim bridging program will 
be described in independent protocols. 
Subjects will be expected to maintain total adherence to a GFD from 6 months before 
randomization through the final study visit (Visit 9; Week 16/Day I 12). Subject's adherence 
to the GFD will be assessed by an expert dietitian and monitored via stool sample testing using 
the iYYLISA GIP stool gluten Lest. Subjects with known or suspected GFD transgressions will 
be counseled and allowed to continue in the study. 
A study site staff member will contact each subject by telephone one day after the first study 
drug administration to assess for AEs. Subjects will return to the clinic for the ne:-rt 
administration of study drug after I week (Visit 2; Week I/Day 7). After Visit 2. subjects will 
return to the clinic for follow-up and study drug administration at Visit 3 (Week 2/Day 14) and 
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every two weeks thereafter as indicated in the study schedule of events (Table I). The final 
dose of study drug will be administered at Visit 7 (Week 1 O/Day 70). An end-of-study efficacy 
visit will be conducted at Visit 8 (Week 12/Day 84). The final study visit will be conducted 6 
weeks after the last dose or study drug at Visit 9 (Week 16/Day I 12). 
Subjects who meet all other study entry criteria will undergo upper gastrointestinal cndoscOp} 
with biopsy collection prior to baseline (i.e., prior to Visit I. Weck O!Day 0) and within 7 days 
of Visit 8 (Week 12/Day 84) in order to assess changes from baseline to end of treatment in 
aberrant and abnormal IELs. VH:CD ratio. TcR clonality and Marsh score. 
Subjects enrolled in the study will complete the BSFS at the time or each bowel movement 
from baseline (Visit I; Week O/Day 0) up to the final study visit. Visit 9 (Week 16/Day 11 2). 
Subjects will complete the CeD PRO daily from basel ine up to the final study visit. Subjects 
will also complete the GSRS beginning at Visit 1 (Weck O!Day 0) and. thereafter, weekly from 
the time of randomization through the final study visit. The BSFS. GSRS and the daily CeD-
PRO will be completed using a handheld electronic diary. In addition. subjects will complete 
paper quality of life diaries (SF-1 2 v. 2, EQ5D and PtGA). Diaries will be completed at the 
times specified in the Schedule of Events (Table 1 ). Safety will be monitored on an ongoing 
basis and subjects may undergo unscheduled visits if needed for safety reasons. Safety wi ll be 
assessed throughout the sLudy by clinical laboratory tests, physical examination. viral signs and 
AE monitoring. lmmunogenicity will also be monitored. 
Figure I represents a schematic drawing of the study periods and visits. 
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Figure 1. CELIM-RCD-002 Study Schematic 
(Up to 28 Days) 
8 mg/kg AMG 714 (IV) 
Scruning v;sit 
Placebo (IV} 
(10 Week Dosing Period) 
I 
I 
I 
I 
I 
I 
I 
I 
II O!l l"t prior IC 
n~dcmi3ti:>n 
Protocol CELIM-ROC-002 
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Page 48 of 134 
v Ji: 1 
IWte<O, 
Oay 01 
v li: 2 
~·Nee~ 1. 
Oay 71 
IJo;i:) 
IWU '<2. 
Oiy 14) 
\Mil ( 
1Wte'(4, 
Oiy lal 
V•s.i: S 
1Wff< 6, 
Oly '2) 
(12 Week Randomization Period) 
Confidential 
\'c1i16 
1WH<4, 
Oa~ SI!) 
V lil 7 
IWH lC 10 
OiV 70) 
vlrit a (wu k 1.2 
:i.,v Ul Prlmu y 
Endpoint 
aiopw \\1th n 7 
Clyl ol Vil't II 
VISit 51 (Wet~ 1 6, 
01~ 112~ 

An interim analysis for safety and PK will be conducted when the tenth subject reaches Visit 
4 (Week 4/Day 28). The interim analysis. to be pre-specified in the DSMB charter. will be 
performed by an independent DSMB which will also monitor unblinded safety data throughout 
the study. Jn addition to safety and PK, any other information available at the time of the 
analysis will be considered and a recommendation to stop, continue or modify the study will 
be made by the DSMB to the Sponsor. Should the exposure of AMG 714 be below the 
anticipated range. a root analysis will be done, which could result in a protocol amendment. 
The recommendation and decision will be shared with the investigational sites and ethics 
committees. 
7 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Subjects will be randomized at a 2: 1 allocation to receive 8 mg/kg AMG 714 or placebo for a 
total of 7 administrations over 10 weeks. 
Randomization and initial dosing of the first ten (10) subjects will be staggered to alJow 
observation in tbe initial subjects for any possible unanticipated side effe.ct in the RCO-
II population. To this effect. the first dosing of the first ten subjects w ill adhere to the 
following rules: 
No more than one subject per day. 
No more than two subjects per week. 
These rules will be implemented via randomization. The sites will obtain written approval 
from the Sponsor before dosing subjects by means of a Randomizatjon Approval Fo rni. 
8 
DURATION OF STUDY 
Screening Visit: Up to 4 weeks (28 days) 
Double-blind randomized period: 12 weeks 
Final Visit: 4 weeks after last double-blind randomization visit 
Duration of study per subject: Up to 20 weeks 
Duration of entire study: Approximately 1.5 years 
9 
SUBJECT POPULATION 
Approximately 24 males and females I 8 years of age or older will be randomized into the 
study. Non-evaluable subjects will be replaced, if possible, at the discretion of the Sponsor. 
Subjects will undergo screening procedures within 28 days of Visit 1; Week O/Day 0. Those 
subjects who meet the study entry criteria will be invited to participate in the study. 
Protocol C£LIM-RDC-002 
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9.1 
INCLUSION CRITERIA 
Subjects must fulfill all of the fo llowing inclusion criteria to be eligible for participation at 
screening and at Visit I; Week O/Day 0: 
1. 
Adult males or females. 18 years of age or older. 
2. 
Demonstrated willingness to participate in the study as documented by signed 
in formed consent. 
3. 
Females of non-chi Id bearing potential defined as postmenopausal (>45 years of age 
wilh amenorrhea for at least 12 months or any age with amenorrhea for al least 
6 months and a serum follicle stimulating honnonc lFSH] level >40 IU/L at 
Screening); or permanently sterilized (e.g .. 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 lnve tigator: one of 
the methods must be a barrier technique) from Screening through the end of study 
participation (Visit 9, Week 16/Day 11 2). 
4. Prior con finned diagnosis of RCD-11 defined by the following criteria: celiac disease 
confirmed by histology, endoscopy or serology; with persistent and recurrent symptoms 
(e.g .. diarrhea weight loss. abdominal pain): with abnormal small bowel histology; with 
aberrant intraepilhelial lymphocytosis of > 20% aberrant fELs vs total IELs (as 
determined by tlow cytometry (or >50% if determined by immunohistochemistry): 
despite adherence to a strict GFD for al least 6 months and after exclusion of other 
potential causes of symptomatic non-response (e.g., microscopic colitis, bacterial 
overgrowth. lactose intolerance, exocrine pancreatic insufficiency, hyperthyroidism. 
etc.) and intestinal histological abnormality (autoimmune entcropathy. giardiasis. 
immunodeficiency. collagenous sprue, Whipple's disease. etc.). 
NOTE: Subjects who have been treated for RCD-11 must continue to have 
increased aberrant I El s (>20% VS total I ELs vs total I EL by no .. v cytometry or 
>50% b)' IHC) and abnormal small bowel histology (Marsh "2'.: I) and must have 
had prior history of symptoms; however, symptoms are not required of 
previously treated subjects. or subjects being treated with steroids. at the time 
or study entry. 
5. 
Total attempted adherence to a GFD for at leasr 6 consecutive months prior to 
screening. Subjects must also agree to make no changes to lheir current GFD for the 
duration of study pa11 icipation. 
6. 
Anti-tissue transglutaminase (lgA and lgG) at screening <2 x the diagnostic level 
for cel iac disease (weak positive or negative). 
7. 
HLA-DQ typing compatible with celiac disease. provided or obtained prior lo 
baseline biopsy. 
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8. 
9. 
a) 
b) 
c) 
d) 
e) 
f) 
g) 
10. 
I I. 
12. 
9.2 
Life expectancy > 4 months. 
Laboratory values: 
Estimated CCr > 30 mL/min/ l .73m2 using the Cockcroft-Gauh equation 
Serum AP, ALT/SGPT. and AST/SGOT less chan 3x the ULN 
Total bilirubin of less than 2.5 x ULN 
Total WBC > 300/mm3 
Platelet count > 85,000/mm3 
IN R less than I .5 
Albumin of more than I 0 g/L (i.e .. I g/dL or 1.45 µmol/L) 
Subjects receiving syscemic steroids must be on a stable dose for at least 4 weeks 
prior lo randomization; the close should not exceed 20 mg of prednisonc. 
prednisolone or equivalent per day. Oral budesonide wi ll be accepted at a maximum 
dose of 9 mg per day. 
Willingness and ability to comply with study procedures and protocol stipulated 
concomitant medication guidelines. 
Willingness to return for all scheduled follow-up visits. 
EXCLUSION CRITERIA 
Subjects \.Viii be excluded from pa11icipation in the study if there is evidence of any or the 
following, ar screening and Visit I: 
I. 
Diagnosis of RCD-1 or EA TL (excluded by the site's standard imaging techniques 
for this purpose). 
2. 
Presence of any of the following related to infection: 
a) 
Active acute infection requiring systemic antibiotic. parenteral antifungal. or 
systemic antiviral treatments 
b) 
Severe infection within the 3 months prior to screening 
c) 
History of tuberculosis (TB) 
d) 
Positive IGRA test at screening OR known recent exposure (within 6 months 
prior lo screening) to a patient with active TB (subject can be enrolled if he or 
she has been successfully treated' ith appropriate chemoprophylaxis). 
e) 
History within the 3 years prior to screening of an opportunistic infection 
typical of those seen in immunocompromised subjects (e.g .. systemic candida 
infection, or systemic fu ngal infection). 
3. 
Current diagnosis or history of cancer in the past 5 years, except RCD-11. 
successfully treated basal cell or squamous cell carcinoma. cervical carcinoma-in-
situ, or early stage prostate cancer. 
4. 
History or presence of clinically significant disease that in the opinion or the 
Investigator. would confound the subject's participation and follow-up in the 
clinical trial or put the subject at unnecessary risk including but not limited to: 
Protocol CELIM-RCD-002 
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5. 
6. 
7. 
8. 
9. 
10. 
a) 
Cardiovascular disease [e.g., uncontrolled hypertension (office systolic blood 
pressure [BP] equal to or greater than 180 1111111 lg or office diastolic BP equal 
or greater than 11 0 mm/Hg), unstable angina. congestive heart failure worse 
than NYHA Class II. coronary angioplasty or myocardial infarction within the 
last 6 months. uncontrolled atrial or ventricular cardiac arrhythmias clinically 
b) 
c) 
a) 
b) 
significant pleural or pericardia! effusfon or ascitcs) 
Pulmonary disease (e.g .. severe chronic pulmonary disease) 
Renal. hematological. gastrointestinal. endocrine (e.g.. poorly controlled 
diabetes), immunologic, dermatologic, neurological, or psychiatric disease 
I Ii story of significant immune suppression: 
BMT or cladribine therapy less than 6 months prior to baseline. 
Potent systemic immune suppressants (e.g .. azathioprine) within the 3 months 
prior to baseline. 
History of alcohol or drug abuse that would interfere with the ability to comply with 
the study protocol. 
History of clinically significant hypersensitivity to the study drug or any related 
drugs or to any of the excipients. 
Positive Hep B. Hep C. or HIV test results at the time of screening. 
Females who are pregnant or planning to become pregnant during the study 
participation period of 6 months after last dose, or are currently breastfeeding. 
Participation in another investigational drug or device study or treatment with an 
investigational drug within 30 days or 5 half-lives. whichever is longer. prior to 
randomization. 
I I. 
Any additional reason, which in the opinion of the Investigator. would prevent the 
subject from safely participating in the study or complying with protocol 
requirements. 
10 
CONCOMITANT MEDLCATIONS 
10. I 
PROHIBITED MEDICATIONS 
The following medications are not allowed at the lime of randomization (Visit I. Week O/Day 
0) or throughout the study: 
• 
Systemic or intestinal immune suppressants. excluding steroids at a maximum dose of 
20 mg of prednisone. prednisolone or equivalent per day and/or oral budcsonide at a 
maximum dose of 9 mg/day. Systemic immune suppressants should not be used 
within the 3 months prior to randomization. Inhaled steroids for respiratory diseases 
such as asthma. and topical steroids are permitted. 
• 
Chronic or continuous oral and 1 V antibiotics (>2 weeks use). Topical antibiotic use 
is allowed. 
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• 
Systemic antivirals 
• 
Parenteral antifungals 
• 
Anticoagulants in the week prior to the protocol-indicated biopsies (alternatively, 
local guidelines for the prevention of bleeding during endoscopy can be fo llowed). 
• 
Live vaccines. 
• 
lnvestigational drugs or devices. 
Note: Arter randomization, use of any of these medications is permitted if required for 
treatment of an A E. These medications may be sta11ed 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 after treatment has been instinited to avoid classification as a protocol deviation. In 
the absence of discussion with the medical monitor, as described, starting these medications 
following randomization will be classified as a protocol deviation. If the prohibited 
concomitant medication is detem1ined to interfere with the results of the study, withdrawal of 
the subject shall occur at the discretion of the Investigator or the sponsor. 
Note: It is permitted to administer albumin if needed for the purpose of correcting excessive 
hypoalbuminemia in the context of protein-losing enteropathy. at the lnvestigator·s discretion. 
11 
STUDY ASSESSMENTS AND PROCEDURES 
All study procedures and their timing are summarized in the Schedule of Events (Table I). 
All visits. except the Follow-up Phone Call. Visit 2 (Week I /Day 7) and Visit 9 (Week 16/Day 
I 12) should be conducted within +/-3 days from the scheduled visit day relati ve to the 
randomization visit (unless otherwise indicated). The Follow-up Phone Call should be 
conducted within + I day from the randomization (Visit I; Week O/Day 0) visit date. The Visit 
1 {Week I /Day 7) study drug administration must be conducted on the scheduled visit date 
relative to the date of randomization. This visit cannot be conducted early and, shou ld it be 
conducted late, the visit schedule must be adjusted based on the actual date of Visit 2 (Week 
I/Day 7). The Visit 8 endoscopy and biopsy (not the visit, but the endoscopy and biopsy only) 
can be conducted within+/- 7 days of Visit 8, and Visit 9 (Week 16/Day 112) should be within 
+I-7 days from the original or adjusted scheduled visit date. 
All study visits occurring after randomization (Visit I. Week 0/Day 0) should be based on the 
Visit I study visit date. or the adjusted visit schedule in the event of a delayed Visit 2 (Weck 
I/Day 7). During the 12-week randomization period, subsequent to Visit 2 (Week I /Day 7). if 
a study visit occurs no more than a maximum of 4 days outside of the visit window (± 7) the 
study drug can be administered and the next visit scheduled in accordance with the original or 
adjusted visit calendar. If a late study visit should occur more than 4 days outside of the study 
visit window the study drug should not be administered and a protocol deviation recorded. 
Under no circumstances should any 2 doses of study drug be administered within fewer than 7 
days of each other. 
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l f' a subject misses 2 consecutive doses of study drug the subject should be terminated from the 
study after consultation with the Sponsor and should complete the Early Termination visit. The 
Final Study Visit should be conducted at least 6 weeks (+/- 7 days) after the last study 
administration of study drug. The Final Study Visit is not required if the last administration of 
study drug occurred 6 or more weeks prior to the Early Termination visit. 
11.l 
ASSESSMENTS AT EACH VISIT 
All subjects who sign an Informed 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 wi II be input 
into the Electronic Case Report form (eCRF). 
Retesting of screening evaluations is permitted once for each test without prior approval from 
the Sponsor. Additional retesting 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. 
11.1.J 
Screening Visit 
• 
Obtain informed consent. 
• 
Register the visit in the electronic data capture (EDC) system. 
• 
Review inclusion/exclusion criteria. For interpretation of hepatitis testing results. see 
Appendix F. 
• 
Document demographjcs and medical history. 
• 
Collect vital signs. 
• 
Measure height and weight. 
NOTE: Height will be measured at the Screening Visit only. Subjects will not 
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. 
• 
Document prior and concomitant medications (including prescription and over-the-
coumcr medications. nutritional supplements, and herbal preparations taken within 30 
days of screening). 
• 
Perfonn physical examination to include an examination of general appearance: head. 
eyes. ears, nose, throat (HEENT): lymph nodes: respiratory: cardiovascular: 
gastrointestinal; musculoskeletal: neurological, psychological and dermatological 
systems. 
• 
Perform 12-lead electrocardiogram (ECG). 
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NOTE: A 12-lead resting ECG wi ll be obtained from all subjects at the time of 
screening. ECGs will be recorded after the subject has been supine for 
approximately 5 minutes. Each 12-lead ECG will be evaluated by an 
appropriately qualified physician at the study site. ECG data wi ll be evaluated 
using the fol lowing categories: 
• 
Normal 
• 
Abnormal. not clinically significant 
• 
Abnonnal. clinically significant 
Any suspected cardiovascular AE should be followed with an additional ECG 
at the discretion of the Investigator. 
• 
Collect stool sample for iVYLISA GIP testing. 
• 
Collect blood and urine specimens for clinical laboratory testing (see Appendix B 
and/or Central Laboratory manual for the parameters). 
NOTE; HLA DQ typing is only required when this information is not already 
part of the subject's available existing medical record. 
• 
Collect blood for serum pregnancy test for FOCBP. 
• 
Begin assessment of AEs. 
• 
Schedule subject l'or endoscopy procedure. 
When the creening clinical laboratory test results are received, they must be re iewed by the 
Investigator or appropriate qualified dcsignee for clinically significant abnormalities. 
lf no clinically significant abnormalities or exclusions are found. the site should proceed with 
the scheduled endoscopy and biopsy (or proceed directly to the endoscopy and biopsy without 
having lab results if required due to logistical or clinical considerations). If clinically 
significant abnormalities are found. retesting of the subject shal I occur at the discretion of the 
Investigator or designee physician. Retesting is permitted one time for each laboratory 
parameter. Additional testing may be permitted after consultation with the Sponsor·s 
appropriate qualified dcsignee. If the clinically signi ficant abnormalities resolve, the subject 
can proceed with the scheduled endoscopy and biopsy. 
tl.2 
12-WEEK RANDOMlZATlON PERIOD 
I t.2.1 
Randomization and Dosing preparation 
The unblinded pharmacist or unblinded 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 i11 the EDC system at least 24 hours before the first dosing visit 
to obtain a randomized treatment assignment for the subject and subsequent vial distribution. 
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Study drug must be thawed overnight and prepared in advance of the study visit as per the 
guidance in Section 18 of this protocol. 
1 J .2.2 
Visit I (Week O/Day 0) 
• 
Review inclusion/exclusion criteria. 
• 
Document visit in the EDC system. 
• 
Allow subject to complete F-1 2 v. 2 and EQ-5D. 
• 
Assign e-diary and allow subject to complete the first weekly GSRS and daily CeD 
PRO. 
• 
Col lect vital signs. 
• 
Measure body weight. 
• 
Perfonn physical examination to include an examination of general appearance; 
HEENT: lymph nodes; respiratory: cardiovascular; gastrointestinal: musculoskeletal: 
neurological, psychological and dermatological systems. 
• 
Complete Physician Global Assessment (PGA). BEFORE study drug administration. 
• 
Allow the subject to complete the Patient Global Assessment of Disease (PtGA) 
BEFORE study drug administration. 
• 
Collect blood and urine for clinical laboratory testing. 
• 
Collect blood sample for PK, ADA and biomarkers BEFORE start of study drug 
administration. Record date and actual time of sampling. 
• 
Collect Whole Blood for Flow Cytomctry. 
• 
Collect blood cell pellet. 
• 
Collect iYY LISA GIP stool sample. The stool sample will be produced within 3 days 
prior to. or after. the scheduled study visit (±3 day window). 
• 
Perfonn urine pregnancy test on FOCBP. 
• 
Administer study medication. See section 18 for administration procedures. 
NOTE: Subject should remain in the dinic for a minimum of I hour after the 
end of study drug administration to monitor for new A Es and collect the second 
PK sample. 
• 
Assess AEs. 
• 
Monitor for changes to concomitant medications. 
• 
Dietitian assessment of the GFD. This assessment can be conducted by phone provided 
it is conducted within the allotted visit window. 
• 
Collect blood sample for PK I hour after END of infusion of study medication. Record 
date and actual time of infusion beginning, end and sampling. 
• 
Remind subjects to complete the BSFS at each occurrence of a bowel movement and 
the CeD PRO daily. 
• 
Remind subject to complete the weekly GSRS . 
• 
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t t.2.3 
Safety Phone Call (Week O/Day 1) 
• 
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 the weekly GSRS. 
11.2.4 
Visit 2 (Week I/Day 7) 
• 
Document visit in the EDC system. 
• 
Collect vital signs. 
• 
Measure body weight. 
• 
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. 
• 
Allow the s u~jecl to complete the Patient Global Assessment of Disease (PtGA). 
BEFORE study drug administration. 
• 
Perform urine pregnancy test on FOCBP. 
• 
Collect blood and urine for clinical laboratory testing. 
• 
Collect blood sample for PK and biomarkers BEFORE start of study drug 
administration. Record date and actual time of sampling. 
• 
Administer sLUdy medication. See section 18 for administration procedures. 
NOTE: Subject should remain in the clinic for a minimum of I hour after the 
end of study drug administration to monitor for new A Es. 
• 
Assess AEs. 
• 
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 the weekly GSRS. 
• 
Provide subject with iVYLISA GIP test kit and instructions for home collection. 
11.2.5 
Visit 3 (Week 2/Day 14) 
• 
Document visit in the EDC system. 
• 
Collect vital signs. 
• 
Measure body weight. 
• 
Perform physical examination to include an examination of general appearance: 
HEENT; lymph nodes: respiratory; cardiovascular; gastrointestinal; musculoskeletal; 
neurological. psychological and dermatological systems. 
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• 
Complete PGA BEFORE study drug administration. 
• 
Allow the subject to complete the Patient Global Ass\!ssment of Disease (PtGA) 
BEFORE study drug administration. 
• 
Collect blood and urine for clinical laborat0ry testing. 
• 
Collect blood sample for PK. ADA and biomarkers BEFORE start or study drug 
administration. Record date and actual time of sampling. 
• 
Collect stool for iYYLJSA GIP test. The stool sample will be produced within 3 days 
prior to, or after, the scheduled study visit. 
• 
Perform urine pregnancy test on FOCBP. 
• 
Administer study medication. ee section 18 for administration procedures. 
NOTE: Subject should remain in the dinic for a minimum of I hour after the 
end of study drug administration to monitor for new adverse events. 
• 
Assess AEs. 
• 
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 the weekly GSRS. 
• 
Provide subject with iVYLISA GIP test kit and instruction for home collection. 
11.2.6 
Visit 4 (Week 4/Day 28) 
• 
Document visit the EDC system. 
• 
Allow subject to complete SF- 12 v. 2 and EQ-5D. 
• 
Collect vital signs. 
• 
Measure body weight. 
• 
Collect vital signs. 
• 
Complete PGA BEFORE study drug administration. 
• 
Allow the subject to complete the Patient Global Assessment of Disease (PtGA) 
BEFORE study drug administration. 
• 
Collect blood and urine for clinical laboratory testing. 
• 
Collect blood sample for PK. ADA and biomarkers BEPORE start of study drug 
administration. Record date and actual time of sampling. 
• 
Collect Whole Blood for Flow Cytometry. 
• 
Collect stool for iYYLISA GIP test. The stool sample will be produced within 3 days 
prior to. or after. the scheduled study visit. 
• 
Perform urine pregnancy test on FOCBP. 
• 
Administer study medication .. ee section 18 for administration procedures. 
NOTE: Subject should remain in the clinic for a minimum of I hour after the 
end of study drug administration to monitor for new adverse events and to 
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collect the second PK sample. Collect blood sample for PK I hour after END 
of infusion of study medication. 
• 
Assess AEs. 
• 
Monitor for changes to concomitant medication. 
• 
Dietitian assessment of the GFD. This assessment can be conducted by phone. provided 
it is conducted within the a llotted visit window. 
• 
Remind subjects 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 iVYLISA G IP test kit and instructions from home collection. 
11.2.7 
Visit 5 (Week 6/Day 42) 
• 
Document visit in the EDC system. 
• 
Collect vita l signs. 
• 
Measure body weight. 
• 
Perform physical examination to include an examination of general appearance; 
HEENT: lymph nodes: respiratory: cardiovascular: gastrointestinal: musculoskelcta l: 
neurological, psychological and dermatological systems. 
• 
Perform urine pregnancy test on FOCBP. 
• 
Collect stool for iVYLISA GIP test. The stool sample will be produced within 3 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 the 
end of study drug administration to monitor for new adverse events. 
• 
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 the weekly GSRS. 
• 
Provide subject with iVYLISA GIP test kits and instructions from home collection. 
11.2.8 
Visit 6 (Week 8/Day 56) 
• 
Document visit in the EDC system. 
• 
Collect vital signs. 
• 
Measure body weight. 
• 
Collect blood sample for PK. ADA and biomarkers BEFORE start of study drug 
administration. Record date and actual time of sampling. 
• 
Complete PGA BEFORE study drug administration. 
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• 
Allow the subject to complete the Patient Global Assessment of Disease (PtGA), 
BEFORE ·tudy drug administration. 
• 
Collect blood and urine for clinical laboratory testing; including sample for biomarkers 
BEfORE study drug administration. 
• 
Collect Whole Blood for Flow Cytometry. 
• 
Perfonn urine pregnancy test on FOCBP. 
• 
Collect stool for iVYLISA GIP test. The stool sample will be produced within 3 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 the 
end of study drug administration to monitor for new adverse events. Collect 
blood sample for PK I hour after END of infusion of study medication. Record 
date and actual time of infusion beginning. end and sampling. 
• 
Assess A Es. 
• 
Monitor for changes to concomitant medications. 
• 
Dietitian assessment of the GFD. This assessment can be conducted by phone, provided 
it is conducted within the allotted visit window. 
• 
Remind subjects to complete the BSFS at each occurrence of a bowel movement and 
the CeD PRO daily. 
• 
Remind subject to complete the weekly GSRS. 
• 
Provide subjects with iVYLISA GIP test kit and instructions for home collection. 
11.2.9 
Visit 7 (Week 10/Day 70) 
• 
Document visit in the EDC system. 
• 
Collect vital signs. 
• 
Measure body weight. 
• 
Collect blood sample for PK and biomarkers BEFORE start of study drug 
administration. Record date and actual time of sampling. 
• 
Perform urine pregnancy test on FOCBP. 
• 
Collect stool for iVYLISA GIP test. The stool sample will be produced within J 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 after the 
end of study drug administration to monitor for new adverse events and to 
collect the second PK sample. 
• 
Assess AEs. 
• 
Monitor for changes to concomitant medications. 
• 
Remind subjects to complete the B FS at each occurrence of a bowel movement and 
the CeD PRO daily. 
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• 
Remind subject to complete weekly GSRS. 
• 
Provide subject with iYYLISA GIP test kit and instructions for home collections. 
11.2.JO 
Visit 8 (Week 12/0ay 84) 
NOTE: DO NOT ADMINISTER STUDY MEDICATION AT THIS VISIT 
• 
Document visit in the EDC system. 
• 
Allow subject to complete SF-12 v. 2 and EQ-SD. 
• 
Collect vital signs. 
• 
Measure body weight. 
• 
Perform physical examination to include an examination of general appearance~ 
H EENT; lymph nodes; respiratory; cardiovascular; gastrointestinal; musculoskeletal ; 
neurological. psychological and dermatological systems. 
• 
Complete PGA BEFORE study drug administration. 
• 
Allow the subject to complete the Patient Global Assessment of Disease (PtGA). 
BEFORE study drug administration. 
• 
Col lect blood and urine for clinical laboratory testing. 
• 
Collect blood sample for PK. ADA and biomarkcrs. Record date and actual time or 
sampling. 
• 
Collect Whole Blood for Flow Cytometry. 
• 
Perfonn serum pregnancy test on FOCBP. 
• 
Collect stool for iVYLJSA GIP testing. The stool sample will be produced within 3 
days pr ior to. or after, the scheduled visit. 
• 
Assess AEs. 
• 
Monitor for changes to concomitant medications. 
• 
Dietitian assessmenLofthe GFD. This assessment can be conducted by phone, pro ided 
it is conducted within the alloned visit window. 
• 
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 iYYLISA GIP test kit and instructions for home collection. 
• 
Pcrfonn endoscopy and collect biopsy specimens within 7 days of Visit 8. 
11.3 
FINAL STUDY VISIT 
11.3.1 
Visit 9 (Week 16/Day 112) or 6 Weeks After Last Study Drug Administration 
• 
Document visit in the EDC system. 
• 
Al low subject to complete SF-12 v. 2 and EQ-SD. 
• 
Collect vital signs. 
• 
Measure body weight. 
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• 
Complete PGA. 
• 
Allow the subject to complete the Patient Global Assessment of Disease (PtGA) 
BEFORE 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. 
• 
Collect blood and urine for clinical laboratory testing. 
• 
Collect blood sample for PK. ADA and biomarkers. Record date and actual time of 
sampling. 
• 
Collect Whole Blood for Flow Cytometry. 
• 
Perform urine pregnancy test on f.OCBP. 
• 
Collect stool for iYYLISA GIP resting. The stool sample will be produced within 3 
days prior to. or after. the scheduled visit. 
• 
Assess ne"v our ongoing A Es. 
• 
Monitor for changes to concomitant medications. 
• 
Collect eDiary and assure that any outstanding diaries have been entered. 
l 1.4 
EARLY TERMINATION (ET) 
Early Termination visits should be conducted for randomized subjects (subjects who received 
double-blind treatment) who discontinue participation in the study. Early termination visit 
procedures are not required for subjects who do not receive study drug and are rherefore 
considered screen failures. 
• 
Document visit in EDC system. 
• 
Collect vital signs. 
• 
Measure body weight. 
• 
Perform physical examination to include an examination of general appearance; 
HEENT: lymph nodes; respiratory; ca rdi ova sc ul ar ~ gastrointestinal; musculoskeletal: 
neurological. psychological and dermatological systems. 
• 
Collect blood and urine for clinical laboratory testing. 
• 
Collect blood sample for PK, ADA and biomarkers. Record date and actual lime of 
sampling. 
• 
Perfom1 scrum pregnancy test on FOCBP. 
• 
All attempts should be made to collect a final iVYLISA GIP stool sample, if the sample 
was not collected within 3 days prior to the scheduled Early Termination visit. 
• 
Assess AEs. 
• 
Monitor for changes to concomitant medications. 
• 
Allow subject to complete F-12 v. 2 and EQ-SD. 
• 
Complete PGA. 
• 
Allow the subject to complete the Patient Global Assessment of Disease (PtGA). 
BEFORE study drug administration. 
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• 
Perform endoscopy and collect biopsy specimens within 7 days of the Early 
Termination visit unless not indicated based on the subject's condition. at the Pl' 
discretion. 
• 
Schedule the Final Study Visit. The Final Study Visit is not required if the Early 
Termination visit occurs 6 or more weeks after the last study drug administration. 
12 
DEFINITlON OF END OF STUDY 
The end of study is defined as the last study visit (Visit 9: Week 16/Day 11 2. Final Study Visit) 
for the last subject randomized. 
13 
EFFICACY ASSESSMENTS 
13.J 
IMMUNOLOGICAL 
RESPONSE: 
ASSESSMENT 
OF 
ABERRANT 
INTRA£PITHELIAL LYMPHOCYTES 
The primary endpoint in this trial is the reduction in the % of aberranl intestinal IELs with 
respect to total I ELs as assessed by tlow-cytometry (Immunological Response 1 ). The first 
secondary endpoint is Immunological Response 2, the reduction in the % of aberrant intestinal 
I ELs with respect to intestinal epithelial cells. a composite endpoint calculated by multiplying 
the % of aberrant lEL vs total IELs (determined by tlow cytometry) by the% of total !EL vs 
intestinal epithelial cells. as assessed by immunohistochemistry. The secondary endpoint could 
be more representative of a benefit driven by functional impact rather than simple reduction in 
I EL numbers. 
Both endpoints address the core abnormality in RCD-11, an in situ small bowel T cell 
lymphoma in which aberrant lymphocytes are responsible for mucosa I damage and symptoms 
and for the progression to EA TL. Aberrant IE Ls are described as surface CD3-negative. 
intracellular CD3-posilive. The reduction in the proportion and number of aberrant 
lymphocytes is specific lo RCD-11. is analogous to a reduction in tumor size in a solid tumor 
cancer. and has been proposed as the most direct measurement of efficacy in RCD- 11 (as 
reviewed in van Wanrooij et nl. 20 14). 
This exploratory study, first industry-sponsored trial in RCD-11. will be considered positive for 
the purposes of Go-No decision-making if at least one of the two calculations of 
Immunological Response is found to be positive. 
Flow cytometry is the most accurate tool available to quantify aberrant I ELs (van Wanrooij el 
al. 20 14), and it is preferred over IHC, (less sensitive) and TcR rearrangement or clonality by 
polymerase chain reaction (PCR, less specific) (van Wanrooij el al, 20 14 ). Enumeration of 
total lELs will be done by JHC to calculate the secondary endpoint of% of aberrant IELs vs 
intestinal epithelial cells. Enumeration of aberrant (intracellular CD3) and abnormal (altered 
phenotype. such as overexpression of NKG2D) IELs by IHC and PCR will be performed as 
well, as exploratory endpoints. 
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Flow cytometry of IELs requires the acquisition of fragment(s) of small bowel tissue by 
endoscopy and biopsy. and the method to disperse, stain and analyze the IELs is described 
elsewhere (Leon. 2011 ). 
Flow cytomecry is the clinical-grade technique employed and validated in the routine 
phenotyping of hematological cancers such as leukemias and lymphomas. It is exquisitely 
quantitative(> I 0.000 single cells are quantified by laser beams per second based on multiple 
specific surface markers) (Leon 20 11, van Wanrooij et al. 2014). The large number of cells 
stained and analyzed. estimated to be between 0.5 million and 5 million per time point per 
patient. ensures low variabi lity and reproducibility. All sites will use the same procedure and 
experimental protocol. and technical validation\ ill be pcrfonned prior to study start. 
13.2 
HISTOLOC lC RESPONSE: SMALL BOWELL ENDOSCOPY, BIOPSY 
AND HISTOLOGY 
At each time point specified in Table I. small-bowel biopsies wi ll be collected in order to 
perfonn the aberrant IEL analysis and the histological assessment of mucosa) inflammation. 
The latter will provide the secondary endpoint of Histological Response. as measured by 
improvement from baseline in small intestinal VH:CD ratio assessed with a validated 
morphometric analysis (Taavela el al. 2013). Lack of Histological Response has been shown 
to correlate with long term outcomes including progression to EATL (Nijeboer el al, 2015 a. 
b). albeit the current Phase 2a study may be of insufficient dura1ion lo fully assess histological 
recovery (slower than immunologic resolution). In addition to the VI l:CD ratio. the second 
commonly used histological score. the Marsh-Oberhuber classification (Marsh, 1992. 
Oberhuber 2000). as well as the total IEL count (all IEL. not just aberrant) will also be 
calcula1ed as a secondary endpoint. 
Al each time point specified in Table I. approximately eleven to thirteen ( 11 -13) 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 collected 
from the 0 2 segment of the duodenum. Ulcerative lesions should be avoided. The location and 
macroscopic appearance of the tissue will be noted in rhe source documents. The potential 
presence of an) observable lesion uch as ulcerative jejunitis will be captured in the eCRF. 
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, and 
the I EL/LPL preparation method wi II be based on published methods by the Paris site. The 
fragments or specimens will be prioritized as fo llows: 
i. First five specimens collected, for now cytometry: Approximately S biopsy 
specimens will be used for tlow cytometry. done locally at each site with 
fresh tissue. 
11. Second three specimens collected, for histology and immunohistochemistry: 
Approximately three (3) biopsy specimens will be fixed in I 0% formalin or 
other fixative. with one (I) of them used for standard pathology at the site 
and two (2) of them embedded in pararfin wax after orientation for analysis 
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at the histology central laboratory. The Central Pathologist. blinded to 
treatment assignment. will assess villus height (VH, in micrometers) and 
crypt depth (CD, in micrometers) and their ratio. VH:CD ratio. Further. the 
Marsh-Oberhuber score will be given (MO, MI, M2. M3a. M3b, or M3c) and 
the density of CD3-positive IE Ls (cells/ I 00 epithelial cells) wil l be assessed. 
Histology and immunohistochemistry (I HC, e.g .. the determination or 
NKG2D on IEL) 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 readings 
using validated methods (Taavela et al, 2013). If it is not feasible to measure 
at least 3 villus-crypt units for a subject's given biopsies. even after re-cutting. 
the results will be considered not evaluable. 
111. Three specimens collected for experimental biomarkers: Approximately three 
(3) specimens wi ll be used for biomarker research. Two fragments will be 
placed in mRNA preservative for future mRNA analysis and one will be used 
for TcR clonality (fresh, frozen or embedded in paraffin). 
1v. Optionally, two fragments for functional experiments: Two specimens. if 
available. may be used fresh in select sites for analysis of I L-15 related 
functional biornarkers. Measurement of AMG 714 in the biopsies may be 
attempted. In Finland one or both optional specimens wi 11 be used in some 
patients for crypt cell ·'mini-gut'· in vitro cullllre at baseline and post-
treatment to study biomarkers of epithelial cell differentiation in the crypt-
vi llous axis. 
Every effort will be made to collect al l 11 to 13 specimens, but should this number not be 
reached. the specimens wi 11 be allocated in the order indicated. 
13.3 
CLINICAL RESPONSE: BRISTOL STOOL FORM SCALE (BSFS) AND 
GASTROINTESTINAL SYMPTOMS RATING SCALE (GSRS) 
Clinical Response, based on symptoms recorded with patient reported outcome (PRO) 
questionnaires, will be considered secondary endpoints. 
13.3.1 
Bristol Stool Form Test 
The Bristol Stool Form Scale (BSFS. Appendix C) is a pictorial aid to help subjects identify 
the shape and consistency of their bowel movements during the study (Riegler et al 200 I). 
Subjects will be asked to complete this form daily using an electronic diary at the time of each 
bowel movement from randomization through the Final Study Visit (Visit 9; Week 16/Day 
I 12). If no bowel movements were experienced by the subject on any given day. the subject 
should document this using the electronic diary. 
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13.3.2 
Gastrointestinal Symptom Rating Scale (GSRS) 
The GSRS (Appendix D) is a 15-question 7 scale questionnaire used to assess five dimensions 
or gastrointestinal syndromes: diarrhea. indigestion, constipation, abdominal pain and reflux 
( vedlund et al 1988). Whi le not specific for celiac disease. the GSRS is widely used in 
gastroenterology and has been used in several clinical trials of experimental medications in 
celiac disease. thus becoming a very useful tool with abundant existing reforencc data (Kelly 
el al 2013: Uihdeaho et al. 2011: Leffler el al, 2015). 
Subjects wi ll be asked to complete this questionnaire weekly, using an electronic diary. from 
the day of randomization through the Final tudy Visit. 
The analysis will include the full GSRS questionnaire as well as the subset of questions most 
closely related to celiac disease (termed "Celiac GSRS" or CeD-GSRs··) (Leffler el al. 2015). 
l 4 
EXPLORATORY ASSESSMENTS 
14.1 
PHARMACOKJNETICS/PHARMACODYNAMICS 
Pharmacokinetics of /\MG 714 in RCD-11 patients will be characterized using nonlinear 
mixed-effects modeling. including evaluation of effects of major covariates (weight or body 
mass index [BMI] and body surface area [BSA]. sex. biochemical parameters and disease 
characteristics at baseline) on AMG 7 14 exposure. 
Exploratory exposure-response analysis will be performed for efficacy, safety. and biomarker 
measures. 
The time and date of each PK sample must be carefully recorded and reported in the eCRFs, 
as well as the beginning and end or each investigational product infusion. 
14.2 
ASSESSMENT OF THE GLUTEN-FREE-DIET: JVYLISA GIP STOOL 
TEST AND DIETITIAN CONSULTATION 
In celiac disease, identification or gluten contamination is essential for the management or the 
disease and for the successful conduct of clinical trials. Contaminating gluten is a confounding 
factor in both diagnosis of RCD- 11 and in the evaluation of a potential therapeutic effect of any 
experimental medication. Histologic and clinical endpoints are heavily influenced by the 
presence of gluten in the diet. 
In addition to measuring symptoms through patient reported diaries, Celimmune plans to use 
the iVY LISA GI P-S gluten stool tcsL a gluten assay developed to detect inadvertent gluten 
consumption by measuring gluten immunogenic peptides (GIP) in feces (Comino el al. 20 12). 
The iVYLISA GI P-S test has a CE mark and is commercially available in Europe from 
8 iomedal SL (as a research test) and. at the time of this writing. from LA BCO (as a laboratory-
developcd test). iVYLISA GIP-S measures GIP in stools by immunoassay. a sandwich ELISA 
with antibody G12. specilic for an immunodominant epitope of gluten that is resistant to 
degradation in the intestine. The lower quantification limit of the assay is 0.16 µg of GI P/g of 
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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 corre lated with 
mucosa! atrophy 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 celiac study. 
This assay will be used in the CELIM-RCD-002 trial to assist with data interpretation by 
assessing if the subjects are compliant with the GFD before enrollment and during the study. 
Non-compliance information will aid understanding outliers and will be used in pre-specified 
subgroup analyses. 
The test detects gluten for up to four days after consumption. and testing will be done every 
two weeks - subjects should provide a stool sample collected up to 3 days before, or after, the 
visit to the sites. in order to have a good probability of identifying dietary transgressors to 
enable con-eel data interpretation. Testing will be done at a central lab. Stools may a lso be used 
for microbiome analysis. known lo affect gluten composition and the biology of IL-15. 
Tn addition to the glu1en stool test, adherence to the GFD will be assessed periodical ly (Table 
I ) by an expert dietitian who will counsel the subjects. The dietitian will fill out a questionnaire, 
provided by the Sponsor, to document the conversation and any detected dietary 
tTansgressions. This assessment can be conducted by phone, provided it is conducted within 
the allotted visit window. This information mc:ry be analyzed in an exploratory fashion. 
The questionnaire will address the following items: 
• 
Did the subject have nutritional counseling with an expert dietitian during the visit? 
Yes/No 
• 
Was a dietary transgression detected since the last visit? Yes/No 
• 
If Yes, please indicate the number of transgressions since the last visit. 
Patients will be provided a calendar or similar tool Lo note their dietary transgressions 
between visits. 
14.3 
PHYSICIAN GLOBAL ASSESSMENT OF DISEASE (PGA} AND 
PATIENT GLOBAL ASSESSMENT OF DISEASE (PTGA)/RATING Of 
CHANGE 
The PGA (Appendix E) is designed to be used by the Investigator or qualified designee to 
assess the subjects' disease activity at the time points specified in the study schedule of events 
(Table l ). An attempt should be made to use the same assessor at each specified time point. 
Part B of the PGA is designed to assess physician perception of change in disease activity. 
Part B should be completed as per the schedule of events (Table I) beginning after Visit I, 
Week O/Day 0. 
Assessments should be made prior to study drug administration using all tools available to the 
assessor including laboratory test results. 
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The PtGA {Appendix L) is deigned to be used by the subject to assess perception of disease 
activity that the time points listed in the Table I. Part B of the PtGA. is designed to assess 
subject perception of change in disease activity and should be administered as per the schedule 
of events (Table I) beginning after Visit I, Week O/Day 0. 
The PtGA should be completed by the subject prior 10 study drug administration. 
14.4 
QUALITY OF LIFE QUESTIONNAlRES: SF-12 V. 2 AND EQ-SD 
The SF-I 2v2 Health urvey is a shorter ersion of the SF-36v2 Health Survey uses just 12 
questions to measure functional health and well-being from the patient·s point of view. 
The Sf--I 2v2 covers the same eight health domains as the SF-36v2 with one or two questions 
per domain (Ware. et al. 2009). 
The EQ-50 is a simple. brief and standardized instrument for use as a measure of health 
outcome (http://www.euroqol.org/about-eq-5d.html). The SL version, available since 2009. 
will be used in the study. 
14.5 
BIOMARKERS OF DISEASE ACTIVITY 
Several biomarkers of disease activity wil l be analyzed in serum (e.g., CRP. IL-15. s1L- 15R), 
as exploratory indicators of disease activity and potential predictors of response to AMG 714. 
Flow cytometry will be perfonned with fresh whole blood and with intestinal mucosal cells 
(I EL and /amino proprio cells). Blood flow cytometry may be conducted on isolated pe.riphcral 
blood mononuclear cells and/or directly in whole blood. Flow cytometry will be used to 
Jescribc rhe phenotype of blood (including NK cells) and intestinal cells. including markers 
relevant to the enumeration (e.g., C03. CD I03) and function (e.g .. NKG20 ) of aberrant IELs. 
lmmunohistochemistry (IHC) will be performed in biopsy tissue to assess markers on IELs 
(e.g., NKG2D) and epithelial cells. 
Biomarkcrs of I L-15 biology may also be analyzed in fresh biopsies. if available at sites with 
the relevanr experimental capabilities. 
Jn addition, other exploratory biomarkers may be analyzed at a later time in stored samples. 
including serum (for proteins. RNA). blood cell pellet (for future biomarkers using gene 
expression profiling and possibly lymphoma mutational analysis), biopsy fragments (for 
mRNA. protein. and possibly lymphoma mutational analysis), stool (gluten. microbiomc). 
urine (gluten. metabolites). Future biomarker analysis wi ll solely be for the purpose of celiac 
disease or AMO 714 research and will be reported separately and not in the clinical study 
report. The sample retention timelines wil l be described in the infonned consent. 
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The DNA sample for HLA testing at screening, in subjects without pre-existing available HLA 
typing infonnation, will be used solely for that purpose and will be destroyed after the result 
is obtained. 
Blood samples for biomarkers must be obtained PRIOR to 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. 
Select safety biomarkers will be evaluated as well as exploratory indicators of possible clinical 
efficacy, such as BMT (derived from the weight measures at every visit), serum albumin 
(patient with albumin being provided exogenously will be excluded from this analysis), 
hemoglobin, hematocrit. 
14.6. IMMUNOGENIClTY 
A two tiered immunogenicity testing approach will be used in order to determine if a sample 
contains ADAs. Samples will be initially tested in an immunoassay (ELISA). Samples that test 
positive 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 of 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 Mesa cale Discovery (MSD) platform to potentially improve performance. The final 
method chosen will be described in the study manual and regulatory submissions 
14.7 
CELIAC DISEASE PATIENT REPORTED OUTCOME (CED PRO) 
Subjects will be asked to maincain a daily e-diary for the CeD PRO instrument (Appendix K) 
at times indicated on the Schedule of Events (Table I). This questionnaire was developed to 
assess symptom severity in cl inical trials in subjects with celiac disease. 
Items in the questionnaire were formulated based on one-on-one interviews with patients with 
celiac disease, thus they reflect 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-itcms 
asking participants about the severity of eeliac disease symptoms they may experience each 
day. Participants are 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. 
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15 
SAFETY ASSESSMENTS 
In addition LO AE monitoring (Section 21 ), 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 afety Monitoring Board 
(DSM B) will monitor safety (Section 22. I 0). 
The conduct or imaging tests is acceptable if required to evaluate the status of the lymphoma 
at any time during the conduct of the study. including during screening for the purpose of 
assessing eligibi lity criteria (e.g .. exclusion of EATL. which requires the use of the site's 
standard imaging techniques). These tests may include enteroscopy ( videocapsule and double 
balloon enteroscopy), entero CT scan. MRI (for size of mcsenteric lymph nodes; thickness of 
bm. el wall) and 18FDG-PETscan. The nature of the test and the results will be captured in the 
eC'RF. 
15.l 
VITAL SIGNS 
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. BMI and 
BSA will be obtained from measuremems of body weight and height. The calculation for BSA 
will be outlined in the study SAP. 
15.2 
PHYSICAL EXAM 
The Investigator or qualified designee will perform a complete physical exam at times 
indicated on the Schedule of Events (Table I). The physical exam should include ata 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 RE ULTS 
Laboratory parameters, as listed in Appendix B and the Central Laboratory Manual or 
equivalent document, will be obtained at times indicated on the Study Schedule of Study 
Procedures (Table L). Blood and urine samples collected at the Screening Visit will require a 
minimum 8-hour fast. 
A subject with a clinically significant laboratory finding identified at the Screening Visit 
should nor participate in the study. 
All clinically significant findings during the study should be fo llowed until resolution or until 
the finding is clinically stable. Subjects may be withdrawn from the tudy if the Investigator 
or ponsor deems the clinically significant fi nding compromising to the subject's safety. 
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Detailed info1rnation regarding the collection and handling of clinical laboratory specimens. 
including blood draw totals for each visit and instructions for re-testing of missing or 
compromised specimens. can be found in a separate Central Laboratory Manual or equivalent 
document supplied by the central clinical laboratory. 
15.3.1 
Pregnancy Testing 
A ll females of child bearing potential (FOCBP) will have urine or scrum pregnancy tests 
throughout the study as outlined in Schedule or Study Procedures (Table I ). Subjects who 
become pregnant during the study will be withdrawn from participation and the outcome of 
the pregnancy fo llmved. 
16 
CENTRAL LABORATORIES 
Detailed information about local and central laboratory activities will be provided in a separate 
Central Laboratory 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. 
• 
Subjects must be willing to rctum for all scheduled study visits and complete required 
study diaries 
• 
Subjects must refrain from illicit drug use and alcohol abuse throughout the duration 
of the study. 
18 
INVESTIGATIONAL PRODUCTS 
18.1 
DESCRIPTION OF INVESTIGATIONAL PRODUCT 
AMG 714 is a sterile solution for IV infusion will be administered at the study site by a 
qualified stafT member in a double-bl ind fashion. via a 120 minute IV infusion a total of 7 
limes for a maximum of I 0 weeks. 
Active clinical supply will be provided in glass vials as a frozen. clear. steri le protein solulion. 
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 
or the supplied vials will be described in the Investigator's Brochure (18). lnvestigational 
Product Manual. or equivalent document. The vials are intended for single-dose use only. 
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18.2 
PLACEBO 
Placebo will be administered at the study site by a qualified staff member in a double-blind 
fashion via a 120 minute IV infusion a total of? times for a maximum of I 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 level for the CELIM-RCD-002 study is based on a desire to strike the 
appropriate benefit/risk balance. striving for efficacy by testing an adequately high dose of 
AMG 714 in an at1empt to quickly alleviate the presumed effeccs of IL-1 5 on aberrant I ELs 
and on RCD-11 symptoms while using a dose that is similar to doses used in prior studies with 
tolerability comparable to placebo. The highest clinical dose of AMG 714 used chronically IV 
has been 8 mg/kg IV single dose fo llowed by 4 mg/kg IV q2w for 8 weeks. The proposed dose 
of 8 mg/kg IV for l 0 weeks. q2w with an extra dose at week l. is modestly higher in order to 
account for the presumed protein-losing enteropathy typical of RCD-11 (up to 40% protein loss 
can be expected based on albumin levels in RCD-11 patients) and for the larger target organ 
area (small bO\vel as compared to more localized joints). 
While exposure data at relevant IV doses are only available in healthy volunteers, the high 
bioavailability L)f 86.6% observed in healthy volunlccrs and the expected protein-losing 
enteropathy in RCD-11 suggest Lhal it is unlikely RCD-11 patients will present with 
meaningfully higher exposures than those srudied in healthy volunteers. 
Human studies to date. as well as model ing. support the dosing regimen of an IV in fusion of 8 
mg/kg AMG 714 a total or 7 times over I 0 weeks, over 120 minutes. The highest doses of 
AMG 7 14 studied in clinical trials are a single C dose of 700 mg. SC doses of 300 mg every 
two weeks for 12 weeks, and the aforementioned 8 mg/kg IV single dose followed by 4 mg/kg 
q2w for 8 weeks. all regimens with no safety signals identified to date. In addition. the 
ro osed stud regimen has ade uate safet margins based on toxicolog . 
The expected ranges provided by the dosing regimen are not only presumed to be tolerable. 
but also expected to be efficacious based on available mechanistic data. While there is no 
clinical experience with AMG 7 14 in RCD-11 nor any understanding of the potential PK/PD 
relationships in this disease. incubation of duodenal biopsies from RCD-11 patients with l 0 
µg/mL of AMG 714 for 48 hours effectively inhibited endogenous at:tivation or JAK3 and 
T /\TS (Malamut el al. 20 I 0). Serum concentrations in this study are predicted to always 
exceed 59 µg/mL. and following a dose at I week to exceed 96 µg/mL, even after accounting 
for possible leakage of protein in the intestine. Even if lm:al mucosa I tissue levels were lower 
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than serum levels. these serum values are several limes higher than the I 0 µg/111 L 
concentrations that were effective in the ex-vivo setting, and provide a reasonable expectation 
that the tissue levels achieved will be efficacious. 
Scrum exposure will be monitored with frequent PK sampling and with an unblinded interim 
analysis to be conducted by the DSMB. when the tenth patient reaches Weck 4. Tissue effects 
will be monitored with experimental biomarkers to be measured in the biopsies to be obtained 
in the study. 
18.4 
BLINDING 
This is a double-blind. placebo-controlled study. To maintain blinding, an assigned unblinded 
study staff member wi 11 be required to receive and prepare the study drug at each site. Due ro 
the difference in appearance between active study drug and placebo. only the unblinded study 
staff member should prepare the study medication for dosing. 
18.5 
UNBLINDl NG 
If there is a need to unblind a subject's treatment assignment for emergency medical 
management, the Investigator will contact the Medical Monitor. The 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 study personnel. 
18.6 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Subjects will be randomized at a 2: I allocation ratio to receive AMG 714 8 mg/kg or placebo 
a total of 7 times over I 0 weeks. The randomization wi II not be stratified as type II RCD is 
rare and the number of subjects in the study is small. For dosing times see the study Schedule 
of Events (Table 1 ). 
The unblinded pharmacist, or unblinded study staff designee, wil 1 be responsible for dispensing 
the study medication according to the treatment assignment provided by EDC. 
18.7 
DRUG SUPPLlES, DISPENSING, STORAGE AND ACCOUNTING 
In addition ro the information contained in this section of the study protocol, detailed 
infom1ation regarding the study drug will be provided in a separate 18, lnvcstigational Product 
Manual. or equivalent document. 
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18.7.1 
Packaging and Formulation 
AMG 714 will be manufactured and packaged by Amgen and distributed using the Sponsor or 
Sponsor representative·s clinical study drug distribution procedures. 
Active clinical supply will be provided in glass vials as a frozen, clear. sterile protein solution. 
with a light yel low color. The vials supplied are for single-dose use only. Volume and 
concentration will be provided in the 18. lnvestigational 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 71-l and placebo during the period of the 
study must be maintained and recorded (e.g .. daily and continuous freezer temperatures, date, 
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. Study site staff must notify 
the Sponsor 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 
P reparation and Ad ministration 
The unblinded study staff member responsible for receiving and preparing the study 
medication must obtain the treatment assignment via the EDC system a minimum of 24 hours 
prior to the scheduled randomization visit (Visit I: Week O/Day 0). This will al low for proper 
thawing and preparation of the study drug. Each subsequent visit should be documented in the 
EDC system in order to assure proper drug accountability. 
On the day before investigational product administration. AMG 714 must thaw overnight at 2 
to 8° C. Vials must continue to be protected from light during the thawing process. Once 
thawed. vials should be transferred to room temperature and gently swirled to ensure mixing. 
Avoid vigorous shaking or vortexing. Mixing may result in the formation of small bubbles. 
\.vhich is normal. Preparation of the clinical supplies should be performed using aseptic 
techniques. under sterile conditions. Prolonged exposure to light should be avoided. 
Please note that certain routine supplies and equipment \·Viii be provided by the study site. 
including but not limited to: 
I) IV bags (5% dextrose) 
2) Infusion pump 
3) IV Jine 
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The investigational product must be diluted using the following instructions: 
I) Withdraw the volume of the thawed investigational product needed for the weight of' 
the patient (8 mg per kg. calculating the volume needed given the concentration of 
investigational product of 100 mg/ml) and inject this volume directly into a I 00 mL 
5% dextrose IV bag using the injection port at the base of the bag. 
2) Gently inverse the IV bag a couple of times to ensure mixing and also ensure that there 
are no air bubbles remaining in the injection port. 
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. The prepared product (i.e., the diluted product in the IV bag) should 
be used immediately, and can be kept for a maximum of 12 hours at room temperature, including 
the administration time of 2 hours. 
All prepared IV bags must be labeled prior to administration with the fo llowing information: 
• 
Study number 
• 
Subject identi ft cation number (001-###-###) 
• 
Date and time of preparation 
• 
Initials of pharmacist 
• 
Initials of subject (if permitted by regulations) 
Once mixed with the investigational product prepared IV bags will not differ in color from the 
IV bags containing placebo. The product must continue to be protected from light using either 
foil or other light protective material. 
An experienced and qualified blinded study staff member must perform the placement of the 
TV catheter and subsequent TV administration. 
On any given day. if more than one subject is scheduled to receive study drug administration 
at the same research facility (which can only happen after the I 01h patit:nt has been dosed. sec 
Section 7), each dose administration must be given at least 15 minutes apart. 
18.7.4 
Supply and Return of Drug 
At study initiation, and as needed thereafter. AMG 714 will 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 or equivalent document. At the end of the study, or as directed by the 
Sponsor, all unused investigational product will be destroyed or returned. Used vials of study 
drug may be destroyed on site at the time of study drug preparation with preapproval from the 
study sponsor. Please reference the lnvestigational Product Manual for additional information 
regarding study drug destruction and return. 
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18.7.5 
lnvestigational Product Accountability 
An lnvestigational Product Accountability Record for AMG 714 must be kept current and 
should contain: 
• 
The dates and quantities of investigarional product received 
• 
Manufacturing batch numbers for product received 
• 
Subject's identification 
• 
Date and quantity of investigational product dispensed 
• 
The initials of 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 INVESTIGATIONAL PRODUCT OVERDOSE 
There is no information available on the effects of an overdose of AMG 714. Given the known 
safety profile. no spccitic recommendations can be issued at this time and Investigators shall 
use clinical judgment to rrcat this potential event. 
19 
STOPPING CRITERIA 
19.1 
INTERRUPTION OF DOSING IN AN INDIVfDUAL SUBJECT 
Due lo the current safety profile. no specific stopping rules have been identified for individual 
subjects. Investigators will exercise clinical judgment to assess whether an adverse event 
merits discontinuation of dosing in any given subject. 
Dose escalation or reduction is not allowed. 
19.2 
lNTERRUPTION OF DOSING FOR ALL SUBJECTS JN THE ENTIRE 
TRIAL 
ff any of the following occur: 
• 
Death of any subject 
• 
Anaphylactic reaction in any subject 
• 
A life-threatening adverse event in any subject 
The Sponsor will ask the DSMB Lo review the case. The committee and Sponsor will determine 
ira study wide interruption in dosing is required. 
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20 
SUBJECT COMPLETION AND WITHDRAWAL 
20.1 
SUBJECT COMPLETION 
Subjects will be considered study completers at Visit 8 (Week 12/Day 84). regardless of 
whether or not the Final Study Visit (Visit 9: Week 16/Day 112) is attended. 
Randomized subjects who withdraw and are not lost to follow-up\ ill complete the study at 
the ET V isit. 
Randomized subjects who withdraw and are considered to be lost to fo llow-up will complete 
the study at the last attended visit. 
20.2 
SUBJECT WIT HDRAWAL 
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 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. 
ln particular, subjects will be discontinued from the study if they develop severe 
complications of ccliac disease that require intensive treatment (EA TL. 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 
will report all such infonnalion on the cCRFs and decide. in accordance with the 
Sponsor. whether the subject is to be withdrawn). 
• 
Subject's decision to withdraw at any time. 
Subjects who withdraw prior to receiving the study drug are considered screen failures. 
20.2.l 
Withdrawal Procedures 
If for any reason a subject is withdrawn or discontinues before completing the final visit, the 
reason for termination must be recorded in the source documents and reported on the 
appropriate eCRF. All data gathered on the subject prior to termination will be made available 
to the Sponsor. 
Subjects discontinuing study drug should continue lo be fu lly evaluated per the protocol event 
schedule. when possible. for safety purposes. However. if the subject discontinues before 
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Weck 6, the second biopsy will not be collected. If a discontinuation occurs on or after Week 
6, the second biopsy will be obtained. 
2 J 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
21.1 
REPORTING RESPONSIBILITY 
The Investigator and study staff are responsible for detecting and recording AEs and SA Es. 
during scheduled safety evaluations and whenever such infomrntion is brought to their 
anentinn. This section of the protocol provides definitions and detailed procedure to be 
fo llowed. 
During each visit, the Investigator or qualified designee will assess adverse events using an 
open question that does not to influence the subject's answers. e.g .. "have you noticed any 
change in your healthT 
A II A Es occurring after signing of' the lnfonned Consent. and at or before the final visit must 
be reported regardless of suspected relationship to study drug. 
Al l AEs will be evaluated by the Investigator and intensity (severity) and relationships to study 
drug will 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). 
A Es and SA Es in possible subjects traveling to study sites from countries other than the study 
site country will be assessed and managed in the same fashion as those appearing in subjects 
from the study site countries. 
21.2 
DEFINITION OF AN AE 
An AE is any untoward medical occurrence (e.g .. sign. symptom. disease. syndrome. 
intercurrent illness) that occurs in a study subject, following the signing of informed consent. 
regardless of the suspected cause. Only subjects who have been exposed to study drug (active 
drug or placebo) can experience treatment emergent AEs. Untoward experiences occurring 
prior to initiation of first administration of study drug are considered non-treatment emergent 
A Es. 
21.3 
SEVERITY 
The term of severity is used to describe the intensity or a specific event. The event itself. 
however. may be of minor medical significance. This is not the same as serious. which is based 
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on outcome of the event. Seriousness. not intensity. serves as a guide for defining regulatory 
reporting obligations. 
For all A Es, severity wi ll 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 nonnal daily activity 
21.4 
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: 
or 
Related (definitely, possibly or probably): when there is a reasonable possibility 
that the study drug caused or contributed to the AE; this conclusion may be 
supported by the following observations, though these are not required for a 
determination of 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 lo the AE: 
Not related: when it is highly unlikely or impossible that the study drug caused 
or contributed to the AE; this conclusion may be suppo11ed by the following 
observations. though these are not required for a determination of not related: 
a) 
Another cause of the A E is evident and most plausible; 
b) 
The temporal sequence is inconsistent between the on et of the AE and 
study drug administration; 
c) 
A causal relationship is considered biologically implausible. 
21.5 
SERIOUS ADVERSE EVENTS 
An AE is serious if: 
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• 
it was fatal (i.e .. the AE caused or led to death) 
• 
it was life threatening (i.e .. the AE placed the subject at immediate risk of death; an 
AE that hypothetically might have caused death if 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 of 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 of the subject" s abi I ity to carry out normal Ii fe functions) 
• 
it resulted in a congenital anomaly/birth defect (i.e., an adverse outcome in a child or 
fetus of 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 ischemia. 
replacement of broken or malfunctioning device). 
21.6 
SPECIAL REPORTING SITUATIONS 
21.6.1 
Death 
Death is an outcome or an event. The AE that resulted in the death should be recorded and 
reported as the SAE. If an autopsy is performed. efforts should be made lo obtain the results. 
21.6.2 
Hospitalizations for Surgical or Diagnostic Procedures 
The AE leading lo the surgical or diagnostic procedure should be recorded and reported as the 
SAE. The procedure should be reported as an action in response to or treatment for the medical 
condition. 
21.6.3 
Pregnancy 
Any pregnancy that occurs during the study or within 6 monrhs of the last dose of study drug 
should be recorded on a Pregnancy Repo11 Fonn lo facilitate outcome follow-up. Pregnancy 
should be reported whether occurring in a female subject or the partner of a male subject. 
Spontaneous abortion shou Id be reported as an SI\ E. 
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 the pregnancy. 
Monitoring should continue until conclusion of the pregnancy. 
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21.6.4 
Inadvertent Exposure or Overdose 
Any inadvettent 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 reported of the appropriate eCRF forms. 
21.6.5 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
SUSA Rs shall be reported by the Sponsor to the regulatory authorities as applicable and to the 
relevant ethics committee to fulfill EU regulations ("Detailed guidance on the collection, 
verification 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 Eudra Vigilance 
database as soon as possible, however no later than within seven (7) days of the Sponsor being 
ihformed of fatal or life-threatening adverse reaction. 
Serious unexpected adverse reactions which are not life-threatening or fatal must be reported 
to the regulatory authority and EudraYigilance database as soon as possible and in any case 
within fifteen ( 15) days of the sponsor first being informed. 
Once a year, the Sponsor shall provide a list of all suspected serious adverse reactions which 
have occurred during the period in question (Annual Safety Report) to regulatory authotities 
as applicable or requii·ed. 
21.7 
PROCEDURES FOR REPORTING ADVERSE EVENTS 
Adverse events occurring after the subject has signed informed consent wi II 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 intensity or frequency, it should be reported as an A E. It is not necessary 
to complete an AE eCRF for fluctuations in the disease under study if: these fluctuations are 
adequately captured by the efficacy assessments, and the degree of variation in frequency or 
severity 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. 
Investigators should observe the following guidelines when recording AEs on the AE eCRF 
pages: use recognized medical tem1s: do not 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. 
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2 l.8 
PROCEDURES FOR REPORTING SERIOUS ADVERSE EVENTS 
SAEs and other specilied special reporting situations require expedited reporting to the 
Sponsor regardless of relationship to study drug. Tbe Investigator must report all 
SAEs to sponsor by phone AND by 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 event. Additional 
SAE pages may be submitted later as the case evolves or additional information becomes 
available. 
The SAE should be reported immediately to Sponsor at: 
+l 301 798 4988 
Or 
+40 723 676 900 
The completed SAE Report should be emailed immediately to the sponsor at: 
Email: (1luh<il S1\ I J 11hu'\ ti l hi ltc.:rn.c.:0111 
Additional relevant information or clinical follow-up should be emailed to the same comact as 
soon as it becomes available. 
21.9 
FOLLOW-UP FOR ADVERSE EVENTS AND SERfOUS ADVERSE 
EVENT 
All A Es will be followed until resolution or until the subject"s participation in the study ends. 
However, SA Es and non-serious AEs assessed by the Pl and the medical monitor as related co 
AMO 714 wi ll be fo llowed until resolution or until the Pl and the medical monitor assess them 
as .. chronic" or ·'stable; · even if this rt!quires extending follow-up beyond the usual duration 
of study participation. The Sponsor should be contacted regarding subjects who require fo llow 
up beyond the usual study duration. 
AE and SAE care and follow-up wil l be similar fix subjects traveling to the study site from 
countries other than the study site country. 
21 .10 
SAFETY REVIEW COMMJTTEE 
Safety \.viii be monitored throughout the study by the Sponsor and by a panel of independent 
experts. the DSMB. 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 safety. The DSMB will be formed before the start of study enrollment. The members 
of the DSMB will 110 1 be members of the AMO 714 study team. and' ill include at least one 
physician and one statistician. 
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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 empowered 
to recommend continuing enrollment, pausing of enrollment. ceasing dosing, changing the 
protocol and study assessments to enhance subject safety, or te1minating the study. as 
appropriate. If the investigation indicates with a high probabi I ity that the observed safety event 
was due to an identifiable cause other than the study drug. the DSMB may recommend 
continuation of study enrollment. 
A separate DSMB Charter, tinalized prior to the first DSMB meeting. outlines the specific 
guidelines for all DSMB activities. DSMB decisions will be communicated to the Investigators 
by the clinical study team. 
22 
DATA ANALYSIS AND STATISTICS 
In addition to this section of the study protocol, a stacistical analysis plan (SA P) and a PK 
analysis plan will 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: 
• 
Previous treatment for RCD-11 
• 
Dietary transgressions (gluten consumption) based on serial iVYLI A GIP testing 
and on the dietitian's assessment 
• 
Sex 
• 
Duration of disease 
• 
Age of onset 
• 
Site 
Non-evaluable subjects will include subjects missing one of the t\vo biopsies and subjects 
dropping out of the study before Week 6. If a discontinuation occurs on or after Week 6 the 
subject is considered evaluable. The non-evaluable subjects will be excluded from the PP 
population. 
The primary analyses will be based on the PP population. The PPpopulation is defined in 
Section 22.2. 
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22.1 
SAMPLE SIZE DETERMINATION 
The CELIM-RCD-002 study is an exploratory proof-of-concept (POC) study of an 
experimental medication, AMG 714. in RCD-JJ patients. While it will be the first such study 
sponsored by a pharmaceutical company, the straightforward design is based on several 
academic studies (Goerres et al, 2003: Brar et al, 2007: Tack et al. 20 11 a, 20 I I b) as well as 
on the nonclinical proof-of-principle signal obtained with AMG 714 in intestinal explants from 
patients with RCD-11 (Malamut et al. 20 I 0). 
The sample size is based on the size or previous academic studies. Pub I ished prospective 
academic srudies have ranged from 13 to 18 patients total (Tack et al. 20 I I a. 20 11 b) and 
CELIM-RCD-002 will be the largest prospective trial ever conducted in RCD-11, a very rare 
malignant disease. 
The sample size of approximately 24 subjects ( 16 subjects in AMG 714 arm and 8 subjects in 
placebo urm) has been calculated to achieve at least - 80% power to detect a 20 percentage 
point difference in the primary endpoint. the difference in the baseline-to-Week 12 reduction 
of% aberrant IELs vs total IELs between the AMG 714 arm and placebo arm. 
This sample size calculation was based on the following assumptions: 
• 
Two-sided type one error rate a = 0.1 
• 
Power 1-P = 0.8 
• 
Analysis method: one-way ANOVA by SAS® (proc power) 
• 
2: l allocation ratio between the AMG 714 and placebo arms 
• 
Common D = 17.4 for the baseline to Week 12 reduction in % aberrant I ELs 
as assessed by low-cytometry 
• 
Mean change of 20 percentage points and 0 percentage points in the baseline 
to Week 12 reduction in % aberrant I ELs in the AMG 714 and placebo arms. 
respectively 
• 
No drop-outs accounted (effo11s will be made to replace drop-outs before 
Week 6 and/or s u~ject s who do not provide the second biopsy) 
The standard deviation used for the sample size calculation is computed from the% aberrant 
I EL (obtained by now cytometry) data from 13 subjects treated with cladribine (subset of the 
patients reported in Tack et a I, 20 l I). 
22.2 
POPU LATIONS FOR ANALYSIS 
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The populations for analysis will be intention to treat (lTT, safety population who at least 
received one dose of investigational product) and the per protocol population (PP. efficacy. 
i.e., avai !able and evaluable pre- and post-biopsy information). 
PP Population: The PP population will exclude non-evaluable subjects and subjects with major 
protocol deviatjons thought lo impact the ability 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 wil I 
be speci fied in the SA P. 
ITT (Safety) 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 
they were randomized to. Subjects with only one measurement available will be excluded from 
the ITT population for all endpoints defined as change from baseline. The safety population is 
by definiti on the same as the ITT population. 
Main efficacy measures which require pre- and post-treatment biopsies will be based on the 
PP population (at least 2 biopsies, the second at least on Week 6 or later). Continuous variables 
will be analyzed based on the ITr population. Demographics and safety parameters will be 
analyzed using the ITT population. 
22.3 
MJSSING 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 
Week 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 imputation will be done. 
22.4 
STATISTICAL ANALYSES 
22.4.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 be tabulated. 
22.4.2 
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. 
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22.4.3 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics wi ll be summarized by treatment group and will be 
based on the ITT population. except for baseline variables ba ed on biopsy data where the PP 
population may be appropriate in addition to IIT. 
22.5 
EFFICACY ANALYSES 
22.5.l 
PRIMARY ENDPOINT 
The primary endpoint is the Immunological Response I: reduction at Weck 12 in % aberrant 
I ELs vs total IEL as assessed by flow-cytometry between the /\MG 714 and placebo arms. 
The primary endpoint will be tested as follows: 
Ho: µ AMG 714 =µplace/Jo 
against the alternative 
H,: µAMG 714 * llpracebo 
where l'-AMG 714 and µ11lace /Jodenote the mean baseline to Week 12 reduction in % aberrant 
I ELs vs total JELs as assessed by flow-cytometry in the AMG 7 14 and placebo arm 
respectively. The hypotheses will be tc tcd using a two-sided type I error level of 10%. 
The primary endpoint will be analyzed using analysis of covariance (ANCOVA) based on the 
per protocol population (PP), where baseline% aberrant I EL will be included as a covariate 
and treatment group as a fixed effect in the statistical model. The analysis wi II also include the 
percemage of patients with normal izalion of IEL counts by now cytometry (aberrant IE Ls < 
20% of total IEL). 
22.6 
SECONDARY ENDPOINTS 
Secondary endpoints will be described in the SAP and will include: 
• 
lmrnunological Response 2: Reduction from baseline in the % of aberrant IELs vs 
intestinal epithelial cells 
• 
Histological Response: improvement from baseline in small intestinal VH:CD ratio 
score. Marsh score and total I EL counts 
o 
VH:CD ratio by validated morphometry. Includes the % or patients with 
histological remission ( VH:CD > 2). 
o 
Marsh-Oberhuber classes. Marsh 0, I, 2. 3a-c. Grouping by converting the 
morphometric results into Marsh classes (Maki-Ji lab converter). Includes the% 
of pmients with histological remission (Marsh 0-l ). 
o 
IEL: for mucosa) innammation the density of IELs/100 epithelial cells will be 
calculated. The analysis will also include the percentage of patients with 
normalization of I EL counts vs. epithelial cells(% I ELs <50%). 
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• 
Clinical response: change from baseline in symptoms, 
o 
BSFS and number bowel movements by day and week 
o 
GSRS and CeD-GSRS, hy week 
In gemernl. efficacy measures which require pre- and post-treatment biopsies will be based on 
the PP population (at least 2 biopsies, the second at least on Week 6 or later). Continuous 
variables will be analyzed based on the ITT population. 
Change from baseline of Immunological Response 2. VH:CD and of total IEL counts will be 
analyzed using the same method as for the primary endpoint. 
The Marsh scores will be analyzed using a multinomial logistic regression model. where 
treatment group. baseline Marsh score. and a treatment group-by-baseline Marsh score 
interaction term will 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 wi ll also include 
treatment group, time (week) and their interaction. The change in lhe weekly BSFS scores will 
mainly be assessed with descriptive statistics, where change from the ·normal (mid-scale)" wi ll 
be explored. The GSRS and the CeD-GSRS will be analyzed using a linear mixed etTccts 
repeated measures model (MMRM) with the baseline value. treatment group. time point and a 
time point-by-treatment group interaction term as fixed effects with an underlying con-elation 
structure between the time points that results in the best fit for the model. Subject will be 
included as a random effect. 
22.7 
EXPLORATORY ENDPOINTS 
Exploratory endpoints will be described in the SAP and will include: 
• 
Reduction in aberrant and abnormal IELs by flow cytometry, immunohistochemistry 
and TcR clonality analyses (including% patients with normalization in IELs) 
• 
PGA and PtGA 
• 
Quality of Life Assessments: 
o 
SF- 12 v. 2 
o EQ-50 
• 
Biomarkers of disease activity 
• 
PK. PD. and PK/PO con-elations 
• 
CeD PRO 
The exploratory variables will be tabulated b) treatment group and time point (if feasible) 
using the ITT or PP populations as appropriate. 
The exploratory variable CeD PRO will be analyzed using the ame method as for the GSRS 
and CeD-GSRS. 
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Pharmacokinetics of AMG 714 in RCD-11 patients will also be characterized using nonlinear 
mixed-effects modeling, including evaluation of effects of major covariates (e.g .. weight or 
BMJ. B A. sex. biochemical parameters and disease characteristics al baseline) on AMG 714 
exposure. 
For PK/PD correlations. individual patients· exposure measures obtained from the PK analysis 
will be graphically assessed with select PD endpoints and if associations are observed wi ll be 
further elucidated with modeling and/or summaries by quartiles of exposure. 
Exploratory exposure-response analysis will be performed for efficacy. safety. and biomarkcr 
measures. These exploratory analyses will be assessed with appropriate descriptive statistics 
and graphical displays. 
Change from baseline (by time point) will also be presented for reduction in aberrant IELs by 
immunochemistry and TcR clonality analyses, PGA and quality of life assessments (SF- 12 v. 
2 and EQ-50). 
22.8 
SAFETY ANALYSES 
22.8.l 
Adverse Events 
All /\Es wi ll be coded using MedDRA. The AEs will be summarized by system organ class 
( OC). preferred term and separately by causality and severity. 
22.8.2 
Other Safety Assessments 
The fo llowing sa fety parameters will be assessed: 
o 
Clinical laboratory tests 
o 
Physical examination 
o 
Vital signs 
/\ II safety variables will be summarized by treatment group. Some of these variables will be 
tabulated by treatment and by visit. 
For the assessment or immunogenicity. the number and percent of subjects who developed 
binding antibodies and who developed neutralizing antibodies will be determined. 
In addition to the abovementioned safety assessments, all females wi II have urine or serum 
pregnancy tests throughout the study. 
All safet_ variables will be tabulated b_ treacment group and time point (if feasible) using the 
ITI population. 
22.8.3 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World I lealth Organization Drug 
Diccionar) (W HO DD). 
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23 
INTERIM ANALYSIS 
An interim analysis for safety and PK will be done when the tenth patient randomized reaches 
Visit 4 (Week 4/Day 28; subjects not replaced if dropped out). The interim analysis. to be pre-
specified in the DSMB charter, will be unblinded and conducted by an independent DSMB. 
which will also monitor unblinded safety data throughout the study. In addition to safety 
(including immunogenicity data if available) and PK, any other information available at the 
time of the analysis wi II be considered and a recommendation to stop, continue or modify the 
study will be made by the DSMB to the Sponsor. The recommendation and decision will be 
shared with the clinical sites and ethics committees. 
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24 
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Oberhuber G. Histopathology of celiac disease. Biomed Pharmacother. 2000: 54(7):368-72. 
Park CS. Yoon SO. Armitage RJ, et al. Follicular dendrilic cells produce I L- 15 that enhances 
germinal center B cell proliferation in membrane-bound form. J lmmunol. 
2004; 173( 11 ):6676-6683. 
Riddle MS. Murray JA. Porter CK. The incidence and risk of' ccliac disease in a healthy US 
adult population. Am./ Gasrroenterol. 2012: I 07: I 248-55 
Riegler G. Esposito L Bristol scale stool form. A still valid help in medical practice and 
clinical research. Tech Coloprocto/. 200 I Dec:5{3):163-4. 
Rubio-Tapia A, I lill ID, Kelly CP, et al. American College of Gastroenterology. ACG 
clinic.al guidelines: diagnosis and management of celiac disease. Am./ Gaslroe111erol. 
20 13: I 08:656-76. 
Schluns KS. 
toklasek T. Lefrancois L. The roles of interleukin-15 receptor alpha: 
transpresentation. receptor component, or both? Int J Biochem Cell Biol. 2005:37: 1567-1571 . 
rrotocol C ELIM-RCD-002 
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Shah S, Akbari M, Vanga R, el al. Patient perception of treatment burden is high in celiac 
disease compared with other common conditions. Am .J Gastroenterol. 20 14; I 09(9): 1304-11 . 
Sharaiha RZ, Lebwohl B, Reimers L, et al. lncreasing incidence of enteropathy-associated T-
eel I lymphoma in the United States, 1973-2008. Cancer. 2012; 11 8:3786-92. 
Svedlund, J, Sjodin. 1, Dotevall. G. GSRS-a clinical rating scale for gastrointestinal symptoms 
in patients with irritable bowel syndrome and peptic ulcer disease. Dig Dis Sci 1988;33: 129-
134 
Taavela .I, Koskinen 0 , Huhtala H, et al. Validation of morphometric analyses of small-
intestinal biopsy readouts in celiac disease. PLoS One. 20 I 3;8:e76 I 63. 
Tack GJ. Verbeek WH, Al-Toma A, et al. Evaluation of Cladribine treatment in refractory 
celiac disease type II. World J Gastroenterol 20 ll ;17:506-13. 
Tack GJ. Wondergem MJ, Al-Toma A. et al. Auto-Ser in refractory celiac disease type II 
patients unresponsive to cladribine therapy. Bone Marrow Tran.,planl 2011 ;46:840-6. 
Verbeek WH, Schreurs MW, Visser OJ, et al. Novel approaches in the management of 
refractory celiac disease. Experi Rev Clin Immunol 2008;4:205-19. 
van Wanrooij RL, MUiier DM, Neefjes-Borst EA. et al. Optimal strategies to identify aberrant 
intra-epithelial lymphocytes in refractory coeliac disease. J Clin Immunol 20 I 4;34:828-35. 
Ware J, Kosinski, M, Turner-Bowker D, Gandek B. User 's manual for the SF-12v2 Health 
Survey. 2009. 
Yokoyama S. Watanabe N, Sato N, et al. Antibody-mediated blockade of lL- 15 reverses the 
autoimmune intestinal damage in transgenic mice that overexpress [L-1 5 in enterocytes. Proc 
Nari Acad Sci US A. 2009; 106(37): 15849-54. 
Yokoyama S, Takada K. Hirasawa !VL er al. Transgenic mice that 
overexpress human lL-15 in enterocytes recapitulate both Band T cell-mediated pathologic 
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APPENDIX A. ADMINISTRATIVE, ETHICAL AND REG ULATORY 
POLICIES 
Celimmune is the Sponsor responsible for the entire conduct of the study. 
Study Initiation 
The Investigator is responsible for supplying at a minimum all of the required regulatory 
documentation specified below to Celimmunc or its designees prior to the start of the trial. 
The Investigator must complete all regulatory documentation as required by local and 
national regulations as appropriate; current signed and 
dated curricula vitae of the 
Investigator and all sub-investigators: complete financial disclosure 
fonns for the 
Investigator and all sub-investigators, if required by local regulatory authorities; Human 
Research Ethics Committee (HREC)/lndependent Ethics Committee (IEC) membership list 
and/or registration number by appropriate regulatory authority; written documentation of 
HREC/IEC approval of protocol: wrillen documentation of the HREC/IEC approval of the 
informed consent document: a copy of the HREC/IEC-approved informed consent form 
(ICF): the ICF must be reviewed and approved by Celimmune or its dcsignees as outline 
in the Section labeled ' Informed Consent' in Appendix A of this study protocol. Written 
documentation of HREC/IEC review and approval of any recruitment materials to be 
used for study recruitment. if applicable; any recruitment materials must be reviewed and 
approved by Celimmune or its designees prior to submission to the I IREC/IEC: current 
laboratory certification and analyte normal ranges for any local laboratory performing 
analyses to be recorded in the clinical trial database: a signed Clinical Research 
Agreement: a signed and dated protocol acceptance form; qualified translations or 
approved informed consent document or other documents to be read or completed by 
subjects (when applicable). Any additional contents or essential regulatory documents 
required in the trial master file by regional or local regulatory authorities must be filed at 
the investigator and ponsor sites before the start of the trial. 
Informed Consent Form 
An Informed Consent Form will be prepared and provided to Celimmune or its designecs to 
review prior to HREC/IEC submission. The final HR EC/IEC-approved informed ICF must 
be provided to Cclimmune for filing. 
The ICF must be signed and dated by the subject or the subject" s legally authorized 
representative before participation in the study. A copy or the signed ICF must be provided 
to the subject or the subject"s legally authorized representative. The source documentation 
and t! CRFs wi ll 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 vcri fication by study monitors at any time. 
Ir necessary, informed consent will be obtained in the subject's primary language using 
a qualified translation of the ICF into that language. 
Human Research Ethics Committee (HREC)/lodependent Ethics Committee (TEC) 
Approval 
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This protocol. the ICF. any anticipated recruitment materials and relevant supporting 
infonnation must be submitted to the HREC/IEC, by the Investigator or sponsor appointed 
designee, prior to study initiation. Investigator, or sponsor appointed designee, must obtain 
HREC/ECs written approval before being allowed to conduct and participate in the study 
The Investigator, or sponsor appointed designee, is responsible for keeping the HREC/IEC 
informed of amendments or changes to the protocol, and the progress of the study, as 
appropriate. Investigator is responsible for fulfilling any conditions of approval imposed by 
the HREC/JEC. The lnvestigatora, or sponsor appointed designee. is responsible for keeping 
rhe HREC/lEC informed of safety events. The Investigator, or sponsor appointed designee. 
must promptly forward to the HREC/IEC. as required, any written safety report or update 
provided by Celimmune (e.g., expedited safety report, I B safety amendment). The 
Investigator. or sponsor appointed designee, is are required to promptly notify the 
HREC/IEC. as required, of all AEs occurring at the site which are both serious and 
unexpected. This generally means SAEs that are not already identified in rhe 18 or protocol. 
and that are considered related to the study drug by the Investigator. Some HREC/IECs 
may have additional safety reporting requirements to which Investigators are expected to 
adhere. 
Case Report Forms 
Electronic CRFs as well as access to an eCRF system (including user names a passwords) will 
be suppl iecl by Cel immune or its designee. 
Instructions for eCRF completion will be provided in a separate eCRF Completion Guidel ine 
or equivalent document. 
The completed eCRF should be reviewed and the case book electronically signed, and dated 
by the Investigator. Instructions regarding e CRF completion should be followed by site 
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, will be maintained at the study site. The information on the eCRFs 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 of the Celimmune will periodically inspect study data. 
subjects' medical records, and eCRFs 
in 
accordance with current US 
and European 
community GCPs (JCH E6). 
The Investigator will permit authorized representatives of relevant national and local health 
authorities, as appropriate, to inspect facil ities and records pertaining to this study. 
Study Completion 
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The following data nnd materials are required before a study can be considered complete or 
tenninated. This includes but is not limited to clinical data, laboratory lest results and any 
special test results from Screening through the encl of study for all enrolled subjects, cCRFs 
(including correction forms) properly completed by appropriate study personnel and signed 
and dated by the Investigator. complete drug accountability records; a summary of the study 
prepared by the Investigator. all regulatory documents (e.g., curriculum vitae for Investigator 
and sub investigators): a signed and dated protocol amendment acceptance form and 
HREC/JEC approval/notification (i f applicable); updated financial disclosure forms for the 
Investigator and all sub-investigators (if required by local regulatory authorities). 
Study Med ication Accountability 
All study drugs will be provided by Amgen. Inc. The Investigator. with the help of an 
unblinded pharmacist or unblinded study staff member. is responsible for ensuring adequate 
accountabi lity or al l used and unused study drug. This includes the acknowledgment or 
receipt of each shipment of study product (quantity and condition) and subject dispensing 
records. Damaged supplies will be replaced. 
Accurate records of all 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. 
Oisclosu re of data 
Subject Confidentiality 
Subject medical information obtained by this study is confidential. and disclosure to third 
parties other than those noted below is prohibited. 
Data generated by this study must be available for inspection upon request by representatives 
of the Therapeutic Goods Administration (TGA), European Agency for the Evaluation of 
Medicinal Products (EMEA). FDA, other national or local health authorities, and the 
H REC/I EC. if appropriate. 
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 
of pa11icipating subjects. 
The Pl is responsible for compliance with other federal, local or institutional legislation and 
regulations related to subject privacy and confidentiality. 
Nondisclosure of Confidential Proprietary Information 
All investigators have completed Non-Disclosure Agreements with Celimmune. Any 
confidential proprietary information, including but not limited to. information on the study 
design. TB. efficacy or AE data, study doses. or method of admini tration should be 
disclosed on a need to know basis for the sole purpose of conducting the study. tr any 
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outside parties contact the study site regarding confidential information the study personnel 
are obligated to inform Investigator and Celimmune. 
Retention of Records 
Following the ICH E6 Guidance on GCP, the records and documents pc11aining to this 
study must be retained by the Investigator for 2 years after approval of the last marketing 
application for the study drug in an ICH region and until there are no pending or 
contemplated marketing applications. If no application is filed. these records musf be kept 
2 years after discontinuation of the study and notification to appropriate regulatory 
authorities. Celimmune will notify the Investigator in writing or these events. 
Records to be retained include. but are not limited to. consent forms. source documentation. 
laboratory test results, medication inventory records. and regulatory dm.:uments. 
Quality Assura nce 
The e CRFs will be reviewed for completeness by a clinical monitor or other representative 
of Ce I immune. Electronic Case Report Forms (eCRFs) will be used for data management and 
analysis. A clinical monitor will contact Investigator for corrections and/or clarifications of 
discrepant data. All data will be entered into a study database for analysis and reporting. A 
Clinical Monitoring and Data Management/Quality Plan that describes the quality checking to 
be performed on the data will be produced. Upon completion of data entry, the database wi ll 
be checked to ensure acceptable accuracy and completeness. 
Investigators and other individuals involved in study evaluations will be trained to perform 
the safety evaluations and activity measurements described in the protocol. Site staff will be 
trained on performance of study procedures. The training will be performed at 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 property of Celimmune, and shall be held in strict 
confidence along with all infonnation 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 Celimmune. 
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 joim 
publication by the lnvestigator(s) and appropriate Sponsor personnel. Authorship will be 
determined by mutual agreement. For mullicenter studies it is mandatory that the first 
publication is based on data from all centers. analyzed as stipulated in the protocol and not by 
individual Investigators. Investigators participating in multicenter studies agree not to present 
data gathered from one center or a small group of centers before the full publication, unless 
formally agreed to in writing. Written permission to the Investigator will be contingent on the 
review by the ponsor of the methodology and statistical analysis and any publication or 
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presentation will provide for nondisclosure of Celimrnune confidential or proprietary 
in formation. In all cases. the parties agree to submit all manuscripts or abstracts to all other 
parties at least 30 days prior to submission. This will enable all parties to protect proprietary 
in formation 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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APPENDIX B. LABORATORY PARAMETERS 
l ) crecning Visit (within 28 Days of Visit I) 
• 
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. Red Blood Cell (RBC) count. 
Platelet Count. WBC with Differential) 
• 
Anti-tissue transglutaminase antibodies (lgA and lgG) 
• 
I ILA-DQ (as needed) 
• 
HCV Antibodies 
• 
HBsAg 
• 
HIV Antibodies 
• 
Interferon Gamma Release Ass:iy (IGRA) 
• 
Urinalysis (Protein. Glucose, Ketones. Blood Cells) 
• 
Urine drug screen 
• 
Urine Pregnancy (all f OCBP) 
• 
IELs 
• 
VH:CD 
• 
Biopsy tlO\ -cytometry 
• 
Biopsy mRNA 
• 
Biopsy DNA for TCR clonality 
• 
iVYLISA GIP Stool Test 
• 
Serum Pregnancy (all FOCBP) 
2) Visit 1 (Randomization - Week O/Day 0) 
• 
Comprehensive Metabolic Panel (A lbumin, Alkaline Phosphatase. LOI I, ALT. AST, 
BUN. Calcium, Chloride, Creatinine, Glucose, Potassium. Sodium. Total bilirubin, 
Total protein) 
• 
Complete Blood Count (Hemoglobin. Hematocrit. RBC. Platelet Count. WBC with 
Differential) 
• 
Anti-tissue transglutaminase antibodies (lgA and lgG) 
• 
PK/PD/Biomarkers (including CRP) 
• 
Whole Blood flow cytometry 
• 
Anti-drug antibodies 
• 
Urinalysis (Protein. Glucose. Ketones. Blood Cells) 
• 
iVYLISA GIP Stool Test 
• 
Urine Pregnancy (all FOCBP) 
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3) Visit 2 (Week I/Day 7) 
• 
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, RBC. Platelet Count, WBC with 
Differential) 
• 
Urinalysis (Protein, Glucose, Ketones, Blood Cells) 
• 
iVYUSA GIP Stool Test 
• 
Urine Pregnancy (all FOCBP) 
4) Visit 3 (Week 2/Day 14) 
• 
Comprehensive Metabolic Panel (Albumin, Alkaline Phosphatase, LOH, ALT, AST, 
BUN. Calcium, Chloride, Creatininc, Glucose, Potassium, Sodium, Total bilirubin, 
Total protein) 
• 
Complete Blood Count (Hemoglobin. Hematocrit. RBC. Platelet Count, WBC with 
Differential) 
• 
PK/PD/Biomarkers (including CRP) 
• 
Anti-drug antibodies 
• 
Urinalysis (Protein. Glucose. Ketones. Blood Cells) 
• 
iVY LISA GIP Stool Test 
• 
Urine Pregnancy (all FOCBP) 
5) Visit 4 (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. Hematocrit. RBC, Platelet Count. WBC with 
Differential) 
• 
Anti-tissue transglutaminase antibodies (lgA and lgG) 
• 
PK/PD/Biomarkers (including CRP) 
• 
Whole Blood flow cytometry 
• 
Anti-drug antibodies 
• 
Urinalysis (Protein, Glucose. Ketones, Blood Cells) 
• 
iVYLISA GIP Stool Test 
• 
Urine Pregnancy (all FOCBP) 
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6) Visit 5 (Week 6f0ay 42) 
• 
iVYUSA GIP Stool Test 
• 
Urine Pregnancy (all FOCBP) 
7) Visit 6 (Week 8!Day 56) 
• 
Comprehensive Metabolic Panel (Albumin, Alkaline Phosphatase, LDH, ALT, AST. 
BUN. Calcium, Chloride. Creatinine, Glucose. Potassium. Sodium. Total bilirubih. 
Total protein) 
• 
Complete BJood Count (Hemoglobin, Hematocrit, RBC, Platelet Count, WBC with 
Differential) 
• 
Anti-tissue transglutaminase antibodies (lgA and lgG) 
• 
PK/PD/Biomarkers (including CRP) 
• 
Whole Blood flow cytometry 
• 
Anti-drug antibodies 
• 
Urinalysis (Protein, Glucose. Ketones. Blood Cells) 
• 
iVYLISA GIP Stool Test 
• 
Urine Pregnancy (all FOCBP) 
8) Visit 7 (Week 10/Day 70) 
• 
iVYLISA GIP Stool Test 
• 
PK 
• 
Urine Pregnancy (all FOCBP) 
9) Visit 8 (Week J 2/Day 84) OR Early Termination Visit 
• 
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, RBC, Platelet Count. WBC with 
Differential) 
• 
Anti-tissue transglutaminase antibodies (lgA and IgG) 
• 
PK/PD/Biomarkers (including CRP) 
• 
Whole Blood flow cytometry 
• 
Anti-drug antibodies 
• 
Urinalysis (Protein, Glucose, Ketones, Blood Cells) 
• 
iVYLISA GIP Stool Test 
• 
lELs 
• 
VH:CD 
• 
Biopsy flow-cytometry 
• 
Biopsy mRNA 
• 
Biopsy DNA for TCR clonality 
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• 
Serum Pregnancy (all FOCBP) 
NOTE: Ir conducting an Early Termination visit, an exit endoscopy wi II be collected 
unless indicated otherwise based on the subject"s condition and at the Pt's discre1ion. 
10) Visit 9 (Final Visit, Week 16/Day 112 
• 
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, RBC, Platelet Count. WBC with 
Di ITerential) 
• 
Anti-tissue transglutaminase antibodies (lgA and lgG) 
• 
PK/PD/Biomarkers (including CRP) 
• 
Anti-drug antibodies 
• 
Urinalysis (Protein. Glucose. Ketones. Blood Cells) 
• 
iVYLISA GIP Stool Test 
• 
Urine Pregnancy (all FOCBP) 
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APPENDIX C. BRISTOL STOOL FORM SCALE (BSFS) 
-:··· • .. 
-~ 
4:a• 
~ 
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Type 1 Separate hard lumps, like nuts 
Type 2 
Sausage-like but lumpy 
Type 3 
Like a sausage but with cracks in the surface 
Type 4 
Like a sausage or snake, smooth and soft 
Type 5 Soft blobs with clear-cut edges 
Type 6 
Fluffy pieces with ragged edges, a mushy stool 
Type 7 
Watery, no solid pieces 
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APPENDIX D. SAMPLE GASTROINTESTINAL SYMPTOM RATING 
SCALE (GSRS) 
Please read this first: 
Th is 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 fN YOUR UPPER 
ABDOMEN OR THE 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. 
I lave you been bothered by HEARTBURN during lhe past week? (13y heartburn we 
mean an unpleasant stinging or burning sensation in the chest.) 
D 
No discomfort at all 
D 
Minor discomfo11 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
Severe discomfort 
D 
Very severe discomfort 
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3. 
Have you been bothered by ACID REFLUX during the past week? (By acid renux 1,,ve 
mean the sensation of regurgitating small quantities of acid or llow of sour or bitter 
nuid from the stomach up to the throat.) 
D 
No discomfort at a ll 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
Severe discomfort 
D 
Very severe discomfort 
4. 
I lave you been bothered by HUNGER PAINS in the stomach during the past week? 
(This hollow fee ling in the stomach is associated with the need to cat between 
meals.) 
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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5. 
Have you been bothered by NAUSEA during the past week? (By nausea we mean a 
feeling of wanting to throw up or vomit.) 
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 
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 discomf0tt 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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7. 
Has your stomach felt BLOATED during the past week? (Feeling bloated refers to 
swelling often associated with a sensation of gas or air in the stomach.) 
D 
No discomfo11 at all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate di scorn fort 
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 al l 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfo11 
D 
Severe discomfort 
D 
Very severe discomfort 
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9. 
Have you been bothered by PASSING 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 all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
Severe discomfort 
D 
Very severe discomfort 
I 0. 
I lave you been bothered by CONSTIPATION during the past week? (Constipation 
refers to a reduced ability to empty the bowels.) 
D 
No discomfort at <\ll 
D 
Minor discomfo11 
D 
lild 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 discomfort 
D 
Moderately severe discomfo1t 
D 
Severe discomfort 
D 
Very severe discomfort 
12. 
Have you been bothered by LOOSE STOOLS during the 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 at all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
Severe discomforr 
D 
Very severe discomfort 
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13. 
Have you been bothered by HARD STOOLS during the past week? (Jf 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 all 
D 
Minor discomfort 
D 
Mi ld discomfort 
D 
Moderate discomfort 
D 
Moderately severe discomfort 
D 
Severe di scorn fo1t 
0 
Very severe discomfort 
14. 
Have you been bothered by an URGENT NEED TO HAVE A BOWEL MOVEMENT 
during the past week? (This urgent need to go to lhe toilet is often associated with a 
feeling that you are not in full control.) 
D 
No discomfort at all 
D 
Minor discomfort 
D 
Mild discomfort 
D 
Moderate discomfo11 
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 EMPTYING TH E BOWELS? (This feeling of incomplete 
empty ing means that you still feel a need to pass more stool despite having 
exerted yourself to do so.) 
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 
PLEASE CHECK THAT ALL QUESTlONS HAVE BEEN ANSWERED! 
THANK YOU FOR YOUR COOPERATION. 
Protocol CELIM-RCD-002 
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Con lident ial 

APPENDIX E. SAMPLE PHYSlCAN GLOBAL ASSESSMENT OF 
DISEASE/RA TING OF CHANGE 
Part A: To be completed by the physician al all required visits. 
Based on the information available. chose the box that best represents the subject"s current 
overall disease activity: 
D 
D 
Inactive 
Disease 
Protocol CELll\l-RCD-002 
Version 3. 11-.1 L-2016 
Page I 12 of1 34 
D 
Mild 
Disea e 
D 
D 
Moderate 
Disease 
D 
D 
evere 
Disease 
Confidential 

Symptoms & Signs 
Category Abdominal 
Inactive 
Disea~e 
Minimal or 
no 
symptoms 
thought to be 
related 
to 
RCD-11 
Mild Disease 
-
Mild 
recurring or 
persistent 
symptoms 
thought 10 b1i 
sccondal)' to 
RCD-11 
Moderate 
Disease 
-
Moderate or 
a 
combination 
or mild (lnd 
mod,ratt: 
recurring or 
persistent 
symptoms 
tl1ought to lx-
due to RCD-
11 
Severe 
Disease 
Severe or a 
combination 
of moderatc 
and 
severe 
recurring or 
persistent 
~-y mploms 
thought lo bt: 
related 
10 
RCD-11 
Pain 
Asymptomatic 
Mild 
pain 
secondary 
lo 
RDC-11 occurring 
several times a 
week 
Moderate 
abdominal 
pain 
tl1ought 
to 
bl: 
secondary 
to 
RCD-11 
Severe abdominal 
pain thought to be 
secondary 
to 
RCD-11 
Protocol CELIM-RCD-002 
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Page 113 of 134 
Diarrhea 
One 
or 
two 
episodes 
that 
resolve 
spontaneously 
Mild 
diarrhea 
thought 
to 
be 
secondary 
to 
RCD-11 
Moderate 
diarrhea 
thought 
to be secondary to 
RC'D-11 
Sig nificant 
diarrhea thought 
to be secondary lo 
RCD-11 
Fatigue 
Asymptomatic or 
symptoms felt to 
tic due to another 
disorder 
(i.e .. 
depression) 
Asymptomatic or 
mild 
symptoms 
tlmt 
resolved 
spontaneously 
Significant 
fatiguc thought 10 
be due to RDC-11 
Significant 
fatigue thought to 
be secondary to 
RCD-11 
Activity 
Asymptomatic or 
symptoms fell to 
be due to another 
disorder 
Asymptomatic or 
symptoms felt to 
be due 10 another 
disorder 
In 
ability 
10 
maintain normal 
activities due to 
fatigue or olher 
symptoms 
Severe 
impaim1cnt 
of 
nomial activities 
due to fatigue or 
other symptoms 
Lab Tests 
Normal 
or 
minimal 
abnom1alities 
Persistent 
and 
significant 
Jaboralol)• 
abnonnalities 
felt 
to 
be 
secondary to 
RCD-1 1 with 
no or mild 
associated 
symptoms 
Significant 
laboratory 
abnormalities 
felt 
to 
be 
secondary lO 
RCD-11 with 
mild 
or 
moderate 
associated 
symptoms 
Significant 
laboratory 
abnormalities 
tell 
10 
be 
SCC(llldary 
(O 
with 
moderate 
to 
severe 
associnted 
symptoms 
Confidential 

Part B: To be completed by the physician at all required visits after Visit I: Week O/Day 
0. 
Please choose one of' the following options that best describes rhe patient's overall change 
in their celiac symptoms since their baseline study visit: 
0 VERY MUCH BETTER 
0 MOO ERA TEL Y BETTER 
DA LITTLE BETTER 
0 NO CHANGE 
0 A LITTLE WORSE 
0 MOD ERA TEL Y WORSE 
0 VERY MUCH WORSE 
Protocol CELIM-RC0 -002 
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Con fidcnt ial 

APPENDIX F. INTERPRETATlON OF HEPATITIS RESULTS 
Subjects must undergo screening for hepatitis B virus (HBV). At a minimum, this includes 
testing for HBsAg (HBV surface antigen), anti-HBs (HBV surface antibody), and anti-I IBc 
total (HBV core antibody total): 
• 
Subjects who test negative for a ll HBV screening tests (ie, HBsAg-, anti-HBc-, and 
anti-HBs) are eligible for this study. 
• 
Subjects who test positive for surface antigen (HBsAg+ ) are not eligible for this study. 
regardless of the results of other hepatitis B tests. 
• 
Subjects who test negative for surface antigen (1 IBsAg-) and test positive for core 
ancibody (anti-HBc+) and surface antibody (anti-HBs+) are eligible for this study unless 
local guidelines require additional testing. 
• 
Subjects who test positive only for surface antibody (anti-HBs+ ) are eligible for this 
study unless local guidelines require additional testing. 
• 
ubjects who test positive only for core antibody (anti-HBc+ ) must undergo further 
testing for hepatitis B deoxyribonucleic acid (HBV DNA test). If the HBV DNA test is 
positive, the subject is not eligible for this study. If the HBV DNA test is negative, the 
subject is eligible for this study. In the event the H B V DNA test cannot be performed, the 
subject is 1101 eligible for this study. 
Protocol CELIM-RC0-002 
Version 3, I 1-JllL-2016 
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Confidential 

Eli!!ibilitv based 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* 
* If HBV DNA is detectable. exclude from clinical trial. If I IBV DNA testing cannot be perfonned. or there 
is evide11ce of chronic liver disease, exclude ITom clinical trial. 
**Local guidelines may require additional testing to rule out the presence of I IBV. 
Protocol C ELIM-RCD-002 
Version 3, 11-JUL-201 6 
Page 116of134 
Confidential 

APPENDIX G. PREDICTED EXPOSURE AND SAFETY MARGINS 
Table 4 shows predictions of exposure and safety margins calculated for proposed 8 mg/kg IV 
q2w dosing with an additional dose at Week I. 
Two sets of assumptions were used: a) that AMG 714 PK in RCD-1 1 patients is the same as in 
healthy subjects. and b) that AMG 714 clearance is higher in RCD-11 patients due to protein 
leakage in the intestine, and that the extent of the leakage is reflected in the serum albumin 
values. 
The data used in the calculations are described in Table 4. Calculations are described be low 
the tables. 
Table 4. Predicted Exposure and Safety Margins 
.. 
Protocol CELIM-RC0-002 
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• • .. • • • 
• • .. • • • 
Confidential 

Table 5. Data used for calculation of safety margins 
Parameter 
Protocol CELIM-RCD-002 
Version 3, 11-J L-2016 
Page 11 8 of 134 
Value 
• 
• 
• 
• 
• .. 
-
• 
Comment 
Confidential 

Protocol CELIM-RC D-002 
Version 3, t t-JUL-2016 
Page 119of134 
Confidential 

-
Protocol CELIM-RCD-002 
Version 3, 11-J L-2016 
Page 120 of 13.t 
Confidential 

APPENDIX H. SAMPLE INVESTIGATIONAL PRODUCT LABEL 
AMG 714: 
AMG 714100 m!}lml / 100 mg/ml 
2m Irr( 
Vslrv<tle' 
5 .c l~ ISC I 
IV. /~(IVI 
., __ 
-
•,T 
Nt.1·=~~ 
~1oorQSmvie@A.'T9'1l h; 
ThoosaOO Oal<s, CA9 IJ2().1799. IJS.\. 
Ce:nmre llOOdlh'tMIJ!a>: 
Lf£anon NJ 00833 
PLACEBO: 
Placebo 
t• _ _ 
llll l f't. >t l SJl.::-<llJ"e!l(SC) 
11
1~ 1M 
Vl31rur«-
'<OOl'.190 
f 
• 
Nl •·=-- ~ 
~ ·-~o:icrA:naen ~ 
~O...S CA913:1!).ll!'l liS>' • 
C<lr'mTe 110WC>ftMJyl.n l~ 
'<J L&lJ 
Protocol CELIM-RC 0 -002 
Version 3, J J-J UL-201 6 
Page 121 of134 
Fl t •• Palasnm:!ll Kil'ftY\11 iunev 
~ 
,ljrge!\ IA;, Tulsand ~ 
0.913"!).17!!9, l&, 
~ 
Gemnre. 110ad OrltNay llrle 
lfbral. NJ Cll833 
ES N:mero de 1'!Sila. 
EN 
Sf 
!·=~ tlesdtr 
H .eti!d 1:7 C6trm.re "'' ..m,en loc 
Tln.srd Qi!is CA 91:m 1 J!!l USA 
~rrm.ne llOOdDl'll.\11)'~ 
lbral NJ 00833 
FR 
~OeV'$IE-
F~im 
(A!IJrrmtt ;1'r "'11)!!r, '.IY. 
~Oll<s CA91321>17!!9 USA 
Ct*rntre l'OOl! Dr~~1 Lre Lbln NJCll83.'I 
Fatincaoo p.ya Gamnire!XJr 11119!'\ K. 
]Jwmj 000. CA 9132().' 'M, EE W 
Gelrmu>:. 110 Qd D1t•'a) !..ire. 
!.f!:elo1 Nlooa.tl 
SolW\ kt t,eaoo I SoWln 1:7 "'9cn 
~il!.l)-C: IO'c.(.20-Cto..!O'Cl 
~mlg'I 
.::AlJT10t Nwru,i l.mle<l t>tt.hledS!arelu • 
to~U;e 
~\:n.i.nrc<il7Cetmuieoy .ltrg:11 n:. 
Trosnl~ CA91:@ 1M 
~ 
Genmre 
l'OOd~A<!'1llrel!bnrl NJ0083'.l 
Hl' ~ 
iO' uie 9le ;:raooi 
A !•=""°"""""" 
~..,.,.....,~ 
"'*'-
~l'c ~ Ool.s C-" 9132ll-1M W 
~ 
~ 
110Clld~uno l~ 
>"1oes3l 
ES 
l~<ll>"""' 
=-~~00<1'"'P' K . 
Tl'O.lsnlCJal.s CASllZ'rl7ill EE.W 
S'E 
t • ~ PiOlr"ln 
9eoot. rr 
T._"ef>~l)f~ 'O'•/.mgen"' 
Tro.srd~, c;.~132: .. 1~. USA 
•:.MTmre 11 0 f).1~ ....na ~ 
~Q?.ilJ 
FR 
l~d< ~ 
=acn:;i..Ero.J'~ CW l-J"'l1!f'+
lr-<: 
~ !::als Cl-Sl~HS" W 
c,....,.._..,. 11; Cb C":'l"'1 UI"'@ ._.,,,. ·- ·~ 
tarntne 1tC Od~d'J-'1tt J!"....U rtJ \A!l! 
fN -ICr ~ I SotlX'l lt> ,,.."'°' 1517< .JC'C:: 1;i-c 
1·z:·cm ·.<O'Cl / f"""2<l'oo>lg'lt / f0'~"""'" ,..;mxri, 
~lllew0"3 •lrllalt:yV'Ald"""'°LM :C ~ll'A 1 
V~tlc.mnn@ty"""1"' he Trol.sroO..S C:. i l!<'}t'T?; 
t& ~ 
1 1J :JdC"'!fAQV Lr~ _!Ct.Y'O'" N,J cs;;,:,.: 
Confidential 

APPENDIX I. SAMPLE SF-12 V 2 
Your Health and Well-Being 
T his su1·wy asks for yonr ,iews about your health. This w fonn;ition will help 
keep track of how you feel and how well you are able to do ~·o a r usual acti,-ities-
Thauk you for co111pleti11g tit is sun·~ ·.' 
For each of the following questiom, please mark an 18] in the one box that best 
describes your· :lOswer. 
1. In gener:il, ~o uld you say~ our health is: 
faceUent 
Very good 
Good 
Frur 
Poor 
T 
T 
T 
T 
T 
0 
D-
o . 
o. 
o. 
2. The following questions are al.Jour actfrities you might do during a typical 
dar. Does vour health now limit m u in these acthities? If so, how 1nuch? 
Yes. 
!Ulllted 
a lor 
T 
Moderate acu>1t1cs. sucb as monng a table. pushing 
Yes. 
!united 
a little 
T 
Ko. not 
limited 
ar all • 
a ncrn.uu cleaner. bowling. or playmg golf······-···-··-... .. 0 '· ........... O . . 
0 , 
, C1unbmg se\·eral fughts of stairs 
o . ·-····o· 
SF·!!T:' Eae S-:in't\"~ !~ !~~~ ~tt:ll Or..:<l:ltl1Tru1u:.J~·Y.fl:l.( l:l:or;on:t.i .Al.::~:i:ws~ 
S.:·L!' a 1 rtp-!Et<l ;i~L oD!~ 
0.n::a::!H Tn:1: 
!SF-::!l-!' F..ull!I Sunn St1c.U:t. l"tr.f.i S!i!:ti rBipi.hn 
Protocol CELIM-RCD-002 
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o. 
Confidential 

3. During the past ~weeks, how much of the time han yon had any of the 
following problems with your work or other regula1· daily actfrities ~ 
result of Your phn ical health? 
All of 
rhe ume 
Most of 
che ame 
Some of 
A llnle of 
~one of 
the time 
che tune 
the time 
• 
Accompltshed less than you 
'vould like ...................................... O .............. O ; ............. 0 ............. 0 .............. 0 · 
Were lunired in the kind of 
work or other activities ........... ,. .... 0 , .......... . 0 ............. O " ............ 0 • ............ 0 ' 
4. During the past 4 weeks, how much of the time haw you had any of the 
following problems ";th your work or other regular daily acti,ities ~ 
result of anY emotional problems (such as feeling depressed or annous)? 
All of 
the time 
Most of 
the tune 
Some of 
:\ ltnle of 
~one of 
che time 
the rune 
the time 
. Accomplished les~ than you 
\Vould like ..................................... 0 1 ............. 0 , ............. O J. ............. 0 • ............. 0 · 
" 
Did \vork or other acuv1ties 
less carefully tl1an usual ................ 0 , ............. 0 ............. 0 '· .......... D ............. O . 
5. During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)? 
~or at all 
A linle bit 
Yloderarely 
Quite a blC 
Extremely 
... 
... 
... 
D 
D· 
D· 
SF-12\'l"'EN!ll! SIITT'ey Cl 1994 . 10~2 :\ledxal <;.nrc!lln Tro..'t acd Qu?.b:tyMemc Iucorpon:M All c~n reser.'ed 
SF-12• :> ~ reEJ~ 1r.1~ofM!dical Oatca:n.6 Trust 
($?-'. :!v}• F.ei!m Sll!";~y Star.d.ud. Ut.1tM S~tli (En~lllh)) 
Protocol C ELIM-RCD-002 
Version 3, 1 l-J UL-2016 
Page 123 of 134 
... 
o , 
Confidential 

6. These questions are about bow you feel and bow things h aYe been with yon 
rlnring the past 4 weeks. For each q u estion, please gi\·e the one answe1· tha r 
comes dosest to the way you h:we beeu feeling. How m uch of the time 
dw·ing the past 4 weeks ... 
Have you felt calm and 
All of 
the tune 
2\.1ost of 
lhe nwe 
T 
Some of 
A lmle of 
the wue 
tile ume 
T 
T 
~one of 
the ume 
peaceful'? 
.......................... O ............ 0 : ........ . .o . 
.o .......... . o . 
Did you have a lot of energy'? ... O '. 
0 .. 
o ......... o ........... o . 
Ha\-e vou felt downheaned 
and dipressed". . . . 
. .. .. . ..... . .O 
o . 
.. 0 ......... 0 .......... o . 
7. During the past-' weeks, h ow much of the time h as your· phYsical h ealth or 
em otional problem s int erfered with you1· social acthities (like Yi.siting with 
f1;ends. r·el:itfres. etc.)? 
All of 
we tune 
T 
0 
Mose of 
the rune 
T 
o . 
Some of 
the nroe 
.... 
o . 
A linlc of 
the rune 
T 
o. 
:'.'lone o f 
the time 
T /lank you for co111pleti11g tllese questions! 
s:-1~": ' P.....:~ s"""" c- 1;.s~ . ~on >t•uaJ <>-=""""' TNu • ...i Q\:.:.l;~ >hc>< Ix~:.i At ::Jh" ~ 
Sf· l~· a .& t•ps~ 
tra.dc:i:r.;a:rk o!~u:Ou.xom.H Tn:n 
(SF·:~·!" P.ul:tb Sun"t\' S1~-U. t:<.1:.d SQ:h tE:ip!lllH 
Protocol CELIM-RC0-002 
Version 3, 11 -JUL-2016 
Page 124 of 13.t 
Confidential 

APPENDIX J. SAMPLE EQ-5D QUESTIONNAlRE (SL VERSION) 
By placing a tick in one box in each group below, please indicate which 
statements best describe your own health state today. 
Mobility 
I have no problems in walking about 
I have some problems in walking about 
I am confined to bed 
Self-Care 
I have no problems with self-care 
I have some problems washing or dressing myself 
I am unable to wash or dress myself 
Usual Activities (e.g., work, study, housework, family or 
leisure activities) 
D 
D 
D 
D 
D 
D 
I have no problems with performing my usual activities 
D 
I have some problems with performing my usual activities 
D 
I am unable to perform my usual activities 
D 
© EuroQOL Group 1990 
Protocol CELIM-RC 0 -002 
Version 3, J 1-JUL-2016 
Page 125 of 134 
Ccinfidential 

Pain/Discomfort 
I have no pain or discomfort 
I have moderate pain or discomfort 
I have extreme pain or discomfort 
Anxiety/Depression 
I am not anxious or depressed 
I am moderately anxious or depressed 
I am extremely anxious or depressed 
IC'> EuroQOL Group 1990 
Protocol C ELll\1-RC D-002 
Version 3, l 1-J llL-201 6 
Page 126of 134 
0 
0 
0 
0 
0 
0 
Confidential 

To help people say how good or bad a health state is, we 
have drawn a scale (rather like a thermometer) on which 
the best state you can imagine is marked 100 and the 
worst state you can imagine is marked 0. 
We would 1 ike you to indicate on this scale how good 
or bad your own health is today, in your opinion. 
Please do this by drawing a line from the box below to 
whichever point on the scale indicates how good or 
bad your health state is today. 
© EuroQOL Group 1990 
Protocol CELIM-RCD-002 
Version J, l l-.JUL-2016 
Page 127of134 
Your O\Vll 
health state 
today 
Best 
imaginable 
health state 
100 
0 
Worst 
imaginable 
health state 
Confidential 

APPENDIX K. SAMPLE CELIAC DISEASE PATIENT REPORTED 
OUTCOME (CED PRO) 
Jnstrucrions: These questions ask about how you feel each day. Please complete the daily 
dimy every evening. at approximate~y the same lime. 
1. Thinking a bout 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 
~ 
.) 
4 
5 
6 
7 
8 
9 
10 
No 
Worst possible 
ubdominul 
abdomi.nal 
cramping 
b. How severe was your abdominal pain? 
0 
2 
3 
No 
abdominal 
pain 
c. How severe was your bloating? 
0 
Nu 
bloating 
Protocol CELJM-RC0 -002 
Version 3, 11-JUL-201<1 
Page 128 of134 
2 
3 
4 
4 
5 
6 
7 
8 
5 
6 
7 
9 
9 
cramping 
10 
Worst possible 
ubdomimtl pain 
10 
Worst possible 
bloating 
Confidential 

d. How severe was your diarrhea'? 
0 
No 
diarrhea 
2 
J 
e. How severe was your gas (flatulence)? 
0 
No 
gas 
3 
r. How severe was your loose stool? 
0 
No 
ll>OSC Slool 
2 
3 
g. I low severe was your nausea? 
0 
No 
\Omiting 
2 
3 
h. 
How severe was your headache(s)? 
0 
No 
hcadache(s) 
Protocol CELIM-RCD-002 
Version 3, I l-JUL-2016 
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3 
4 
4 
5 
6 
7 
5 
6 
7 
5 
6 
7 
5 
6 
7 
5 
6 
7 
8 
8 
8 
8 
8 
9 
9 
9 
9 
9 
10 
Worsi possible 
diurrhcn 
10 
Worst pos!>ibk 
gas 
10 
Wcm1 possible 
luos..: ~too l 
10 
\\'orst possible 
\t)mi1ing 
10 
Wors1 possible 
headache($) 
Confidential 

1. 
How severe was your tiredness? 
0 
No 
1ircdnes~ 
Protocol CELIM-llCD-002 
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Page 130of134 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worsi 
pos~iblc 
tiredness 
Confidential 

APPENDIX L. SAMPLE PATIENT GLOBAL ASSESSMENT OF 
DISEASE/RATING OF C HANGE 
Part A: (To be completed by the patient at all required visits) 
Please indicate your overall assessment of the severity of your celiac symptoms: 
0 NO CELIAC SYMPTOMS 
0 V ERY MILD 
D MILD 
0 MODERATE 
0 SEVERE 
0 VERY SEVERE 
Part B: (To be completed by the patient at all required visits after baseline Visit I; Week O/Day 
0) 
Please choose one of the fo llowing options that best describes the overall change in your ccliac 
symptoms since you began treatment in this study: 
0 VERY MUCH B ETI~ER 
0 MOD ERA TEL Y BETTER 
0 A UTILE BETTER 
O NO CHANGE 
0 A LITTLE WORSE 
0 MODERATELY WORSE 
0 VERY MUCH WORSE 
Protol'ol CELIM-RC0-002 
Version 3, I 1-JUL-2016 
Page 131 of 134 
Confidcnti:il 

APPENDIX M. PROTOCOL AMENDMENTS 
The protocol was modified to create version 3 on July l 1111 2016. The following changes 
and clarifications were made in the sections specified: 
1. To reduce burden on patients: 
( I ) , the rules for collection of stool samples have 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 IO; Section 11: Section 14.2). 
(2) The time of collection of the blood cell pellet has been changed to allow 
collection at any time during study (Table I , footnote 12). 
2. It has been clarified throughout the protocol that the DSMB is expected to review 
unblinded data, including during the interim analysis (Screening. Sections 6, 11. 
18, 2 I.I 0. 22 and 23). 
J. Clarification that simultaneous concomitant therapy with topical and systemic 
steroids is permissible, at or below the maximum doses indicated in the protocol. 
(Synopsis, Sections 6 and I 0.1 ). 
4. Clarification that, 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. And after preparation 
(once injected in the IV bag), it should be used immediately and can only be kept 
at room temperature for a maximum of 12 hours including the 2 hrs. of the IV 
administration. These instructions are in line with the study manual and have been 
correctly followed by the sites (Section 18.7.3). 
5. Clarification of the instructions to prepare the IV bag by withdrawing the volume 
of the thawed investigational product needed for the weight of the patient (8 rng 
per kg, calculating the volume needed given the concentration of investigational 
product of I 00 mg/ml) and injecting this volume directly into a I 00 mL 5% 
dextrose IV bag using the injection port at the base of the bag. These instructions 
are in I ine wilh the study manual and have been correctly followed by the sites 
(Section I 8.7.3). 
6. Clarification of the patient populations for analysis (Section 22.2 and throughout 
the protocol) and the statistical analysis method for the Marsh score (Synopsis and 
Section 22.6). The definitions and method are consistent with the Statistical 
Analysis Plan and will be used at completion of the study. 
Additional editoriaJ changes, corrections of typos and omissions. as well as minor clarifications 
were made throughout the protocol 
This protocol was modified to create version 2 on 01 February 2016. The following 
changes and clarifications were made in the sections specified: 
7. Addition of IND number (Page I). 
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Confidential 

8. Update of contact information for protocol vendors and responsible staff. 
9. Minor corrections to Schedule of St11dy Procedures (Table I): 
Addition of superscript to PK sample collection at Visit 6 (Week 8) Lo 
indicate that the sample for PK analysis at this visit should be collected 
before dosing starts. 
Clarification that the Visit 8 endoscopy and biopsy can be collected 7 days 
before or after Visit 8. 
3. Addition of rules to stagger the randomization and initial dosing of the first ten 
subjects (Synopsis and Section 7). 
4. Correct provision of iVYLISA GIP test kit and instructions for home collection from 
Visit I to Visit 2 in the Assessments at Each Visit section (Section 11.2). 
5. Removal of mandatory hood use for preparation of clinical supplies as Jong as 
preparation is perfonned using aseptic techniques, under sterile conditions (Section 
18.7.3). 
6. Corrections to the list of Laboratory Parameters (Appendix B) to match Schedule of 
Events (Table I): 
Clarification that "mRNA/DNA" at Screening and Visit 8 (Week 12) 
means "Biopsy mRNA., and .. Biopsy DNA for TCR clonality." 
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