Clinical trial NCT02762500
Conditions: Colitis, Ulcerative
Sponsor: Lycera Corp.
Start date: 2016-07-01; Completion date: 2018-05-01
Enrollment: 124 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the efficacy and safety of LYC-30937-EC given orally once daily in subjects with active ulcerative colitis (UC) defined as a total Mayo score (TMS) of 4-11 inclusive, with an endoscopic score of ≥ 2 and a rectal bleeding score of ≥ 1 at screening.

Detailed description:
Approximately 120 subjects will be randomized to receive either enteric-coated (EC) LYC-30937-EC 25 mg PO once daily (QD) or matching placebo PO QD for the duration of 8 weeks. Randomization will be stratified based on previous exposure to anti-tumor necrosis factor (TNF) agents such that at least 50% of the randomized subjects will be anti-TNF naïve .

The study will consist of 3 phases:

* screening phase: up to 4 weeks
* double-blind placebo-controlled phase treatment: 8 weeks
* post-treatment follow-up: 2 weeks

Eligible subjects will be randomized at Week 0 (Study Day 1) to either LYC-30937-EC 25 mg or placebo. Screening will occur from Study Days -28 to -1. Randomization and first dosing will occur at Week 0/Study Day 1. Double-blind study visits will occur at Weeks 2, 4, and 8, with the last dose at Week 8/Study Day 57. Subjects will return at Week 10 for a post-treatment safety follow-up visit.

Arms: arm 1: LYC-30937-EC 25 mg by mouth once daily for 8 weeks arm 2: Matching placebo by mouth once daily for 8 weeks
Interventions: intervention 1: LYC-30937-EC intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 


 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
LIST OF TABLES .........................................................................................................................6 
LIST OF ABBREVIATIONS .......................................................................................................7 
1.0 
PROTOCOL SUMMARY ..............................................................................................10 
2.0 
INTRODUCTION............................................................................................................15 
2.1 
Background ............................................................................................................15 
2.2 
Rationale for the Study ..........................................................................................16 
2.3 
Nonclinical Studies ................................................................................................17 
2.3.1 
Nonclinical Pharmacology .............................................................17 
2.3.2 
Nonclinical Pharmacokinetics .......................................................17 
2.3.3 
Safety Pharmacology and Toxicology ...........................................18 
2.4 
Previous Human Experience ..................................................................................19 
2.5 
Dose Selection Rationale .......................................................................................21 
2.6 
Risks and Benefits..................................................................................................22 
3.0 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................23 
3.1 
Study Objectives ....................................................................................................23 
3.1.1 
Primary Study Objective ................................................................23 
3.1.2 
Secondary Study Objectives ..........................................................23 
3.1.3 
Exploratory Objectives ..................................................................23 
3.2 
Endpoints ...............................................................................................................23 
3.2.1 
Efficacy Endpoints .........................................................................23 
3.2.2 
Safety Endpoint ..............................................................................24 
3.2.3 
PK and PD Endpoints ....................................................................24 
4.0 
STUDY DESIGN ..............................................................................................................25 
4.1 
Design Overview ...................................................................................................25 
4.2 
Number of Subjects and Sites ................................................................................26 
4.3 
Assignment of Subject Numbers ...........................................................................26 
4.4 
Subject Selection ....................................................................................................27 
4.4.1 
Inclusion Criteria ...........................................................................27 


 
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4.4.2 
Exclusion Criteria ..........................................................................28 
4.5 
Subject Withdrawals ..............................................................................................31 
5.0 
STUDY TREATMENTS .................................................................................................32 
5.1 
Description .............................................................................................................32 
5.2 
Treatment Regimen ................................................................................................32 
5.3 
Randomization .......................................................................................................33 
5.4 
Maintaining and Breaking the Blind ......................................................................33 
5.5 
Drug Supplies.........................................................................................................34 
5.5.1 
Packaging and Labeling .................................................................34 
5.5.2 
Product Accountability, Storage, Dispensing, and Return ............34 
5.5.3 
Treatment Compliance ...................................................................35 
5.6 
Concomitant Medications ......................................................................................35 
6.0 
STUDY PROCEDURES .................................................................................................36 
6.1 
Visit Timing ...........................................................................................................36 
6.2 
Schedule of Events .................................................................................................38 
6.2.1 
Screening Visit 1 ............................................................................41 
6.2.2 
Visit 2 (Randomization and Dosing) .............................................43 
6.2.3 
Visit 3 (Week 1) .............................................................................44 
6.2.4 
Visit 4 (Week 2) .............................................................................45 
6.2.5 
Visit 5 (Week 4) .............................................................................46 
6.2.6 
Visit 6 or Early Termination (Week 8) ..........................................47 
6.2.7 
Follow-up Visit 7 (Week 10) .........................................................49 
6.2.8 
Unplanned Visits ............................................................................49 
6.3 
Subject Diary .........................................................................................................49 
6.4 
Efficacy Assessments Performed ...........................................................................50 
6.4.1 
Ulcerative Colitis Disease Activity by Mayo Score ......................50 
6.5 
Safety Assessments Performed ..............................................................................52 
6.5.1 
Physical Examinations ...................................................................52 
6.5.2 
Medical and Surgical History ........................................................53 
6.5.3 
Vital Signs Measurements .............................................................53 


 
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6.5.4 
12-Lead ECG .................................................................................54 
6.5.5 
Laboratory Assessments ................................................................54 
6.5.6 
Inflammation monitoring ...............................................................55 
6.5.7 
Monitoring Subjects for Adverse Events of Special Interest .........56 
6.6 
Pharmacokinetic Assessments ...............................................................................58 
6.6.1 
Biological Samples ........................................................................58 
6.6.2 
Pharmacokinetic Parameters ..........................................................60 
6.7 
Exploratory Pharmacodynamic Assessments ........................................................60 
6.7.1 
Biological Samples for Pharmacodynamic Evaluations ................60 
6.7.2 
PD Parameters ................................................................................61 
7.0 
ADVERSE EVENTS AND SAFETY MONITORING ................................................62 
7.1 
Adverse Event Definition ......................................................................................62 
7.2 
Serious Adverse Events Definition ........................................................................62 
7.3 
Adverse Event Reporting .......................................................................................63 
7.4 
Assessment of Severity of Adverse Events ...........................................................64 
7.5 
Serious Adverse Event Reporting ..........................................................................65 
7.6 
Post-Week 10 Reporting of Serious Adverse Events ............................................66 
7.7 
Exposure in Utero ..................................................................................................66 
7.8 
Relationship/Causality of Adverse Events/Serious Adverse Events .....................67 
7.9 
Withdrawal Due to Adverse Events .......................................................................68 
7.10 
Medical Monitoring ...............................................................................................68 
7.11 
Data Safety Monitoring Board (DSMB) ................................................................69 
7.12 
Stopping Rules .......................................................................................................69 
7.12.1 
Suspension of Study .......................................................................69 
8.0 
STATISTICAL AND ANALYTICAL PLAN ...............................................................70 
8.1 
Sample Size Rationale ...........................................................................................70 
8.2 
Analysis Populations ..............................................................................................70 
8.2.1 
Full Analysis Set ............................................................................70 
8.2.2 
Safety Set .......................................................................................71 
8.2.3 
Other Population Sets ....................................................................71 


 
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8.3 
General Statistical Considerations .........................................................................71 
8.4 
Demographic and Subject Characteristics .............................................................71 
8.5 
Efficacy Analysis ...................................................................................................71 
8.5.1 
Primary Efficacy Endpoint Analysis .............................................71 
8.5.2 
Secondary Efficacy Endpoint Analyses .........................................72 
8.5.3 
Exploratory Efficacy Endpoint Analyses .......................................72 
8.6 
Safety Analysis ......................................................................................................73 
8.7 
Pharmacokinetic and Pharmacodynamic Analyses ...............................................73 
9.0 
ETHICAL CONSIDERATIONS ....................................................................................73 
9.1 
Basic Principles ......................................................................................................73 
9.2 
Institutional Review Board/Independent Ethics Committee..................................74 
9.3 
Informed Consent...................................................................................................74 
9.4 
Study Termination .................................................................................................74 
10.0 
DATA HANDLING AND RECORD KEEPING ..........................................................74 
10.1 
Study Monitoring ...................................................................................................74 
10.2 
Study Documentation.............................................................................................75 
10.3 
Record Retention ...................................................................................................76 
11.0 
CONFIDENTIALITY AND PUBLICATION PLAN...................................................77 
11.1 
Confidentiality .......................................................................................................77 
11.2 
Publication of Data and Protection of Intellectual Property ..................................77 
12.0 
REFERENCES .................................................................................................................78 
13.0 
APPENDICES ..................................................................................................................80 
13.1 
Appendix A:  Pharmacokinetic Measurements ......................................................80 
13.2 
Appendix B:  Total of Blood Volume....................................................................81 
13.3 
Appendix C:  Exploratory PD Biomarkers ............................................................82 
13.4 
Appendix D:  Biologic Medication Restriction .....................................................83 
14.0 
DOCUMENT HISTORY ................................................................................................84 
 


 
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LIST OF TABLES 
Table 1: 
Pharmacokinetics of Healthy Subjects in the Phase 1 Single Ascending 
Dose Study .......................................................................................................20 
Table 2: 
Pharmacokinetics of Healthy Subjects in the Phase 1 Multiple Ascending 
Dose Study .......................................................................................................20 
Table 3: 
Schedule of Events ...........................................................................................38 
 
 
 


 
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LIST OF ABBREVIATIONS 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
5-ASA 
5-aminosalicylic acid 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
ATPase 
mitochondrial ATP synthase enzyme 
AUC 
area under the plasma concentration-time curve 
AUC0-24 
area under the plasma (concentration-time) curve from time 0 to 24 hours post-dose  
BLQ 
below the limit of quantitation 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C. 
Clostridium 
CD 
Crohn’s Disease 
CFR 
Code of Federal Regulation 
Cmax 
maximum observed plasma concentration 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology for Adverse Events 
CYP 
Cytochrome P450  
DBP 
diastolic blood pressure 
DSMB 
Data Safety Monitoring Board 
EC 
enteric coated 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EIU 
exposure in utero  
ET 
early termination 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FE 
food effect 
FSH 
follicle-stimulating hormone 
GCP 
good clinical practice 


 
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GLP 
good laboratory practice 
GMP 
good manufacturing practice 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin  
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HEENT 
head, eyes, ears, nose and throat 
hERG 
human ether-a-go-go related gene 
HIV 
human immunodeficiency virus 
HPMC 
hydroxyl-propyl methyl-cellulose 
HR 
heart rate 
hsCRP 
high sensitivity C-reactive protein 
IBD 
inflammatory bowel disease 
IC50 
50% inhibitory concentration 
ICD 
informed consent document 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IWRS 
interactive web-based response system 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LLOQ 
lower limit of quantitation 
MAD 
multiple ascending dose 
MCH 
mean cell hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MMF 
mycophenolate mofetil 
MMS 
modified Mayo score 
NCI 
National Cancer Institute 
NOAEL 
no observed adverse effect level 
OLE 
open-label extension 
OXPHOS 
oxidative phosphorylation 
PD 
pharmacodynamics 
PGA 
Physician’s Global Assessment 


 
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PK 
pharmacokinetics 
PT 
prothrombin time 
PVSS 
Pharmacovigilance and Safety Services 
q.d. 
quaque Die, once daily 
RBC 
red blood cell  
ROS 
reactive oxygen species 
RR 
respiration rate 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SI 
international system units 
SUSAR 
suspected unexpected serious adverse reaction 
T 
temperature 
TEAE 
treatment emergent adverse event 
Tmax 
time at which maximum observed plasma concentration (Cmax)  
TMS  
total Mayo score 
TNBS 
trinitrobenzene sulfonic acid 
TNF 
tumor necrosis factor 
UC 
ulcerative colitis 
ULN 
upper limit of normal 
WBC 
white blood cell 
 


 
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1.0 
PROTOCOL SUMMARY 
Indication 
Ulcerative Colitis (UC) 
Study Rationale 
Inflammatory bowel disease (IBD) is a complex autoimmune disorder that consists of UC, 
Crohn’s Disease (CD), and nonspecific colitis that remains a disease of high unmet medical 
need.  Current therapies are limited by either low response rates or poor tolerability.  LYC-30937 
enteric-coated (EC) acts to induce apoptosis of chronically activated lymphocytes such as those 
thought to drive the inflammation of UC.  LYC-30937 demonstrated efficacy in animal models 
of IBD and selective induction of apoptosis in chronically activated human lymphocytes.  
LYC-30937-EC has also shown safety, tolerability, and a favorable pharmacokinetic (PK) profile 
in healthy subjects up to single doses of 300 mg and 7 days of daily dosing at 200 mg and in UC 
subjects in single doses of 25 and 100 mg.  The mechanism of action of selective induction of 
apoptosis in chronically activated lymphocytes, the demonstration of efficacy in IBD models, 
and the safety, tolerability, and PK profile demonstrated in the Phase 1 program supports the 
further of assessment of the efficacy LYC-30937-EC in inducing remission in subjects with 
active UC.   
Study Objectives 
The objective of this study is to evaluate the efficacy, safety, and tolerability of LYC-30937-EC 
compared to placebo in subjects with UC.  In addition, selected PK and pharmacodynamic (PD) 
parameters will be assessed.  Subjects who complete the double-blind portion of the trial through 
Week 8 will have the option of receiving open-label treatment with LYC-30937-EC in a separate 
open-label extension study (LYC-30937-2002) which will have the objective of collecting long-
term safety data on LYC-30937-EC in subjects with active UC.   
Primary Objectives 
The primary objective will be to assess the efficacy of LYC-30937-EC in inducing remission 
compared with placebo in subjects with active UC over a treatment duration of 8 weeks.   
Secondary Objectives 
The secondary objectives will be to evaluate the safety and tolerability of LYC-30937-EC 
compared with placebo in subjects with active UC.   


 
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Exploratory Objectives 
Exploratory objectives include determining plasma PK and the colon tissue exposure of 
LYC-30937-EC, assessment of endoscopic improvement at Week 8, evaluating PD biomarkers, 
and assessing efficacy in subjects with previous exposure to biologic (includes tumor necrosis 
factor [TNF]-alpha antagonist and integrin receptor antagonist agents) therapy.   
Study Population 
This study will include adult males and nonpregnant, nonlactating females with active UC.   
Study Design and Assessments 
All subjects who meet the eligibility criteria will be randomized in a 1:1 ratio to LYC-30937-EC 
25 mg or matching placebo.  The randomization will be stratified by previous treatment with 
biologic therapy such that at least 50% of the randomized subjects who have never received 
biologic therapy (ie, are biologic naïve).   
Assessments 
Safety assessments: 
Adverse events (AEs) will be collected from the time of signing the informed consent.  All 
subjects who are randomized will be monitored for AEs until the time they leave the study.   
Additional safety assessments:   
 Vital signs including body temperature 
 Physical examinations 
 Electrocardiograms (ECGs) 
 Clinical laboratory assessments 
 Monitoring of plasma LYC-30937 concentrations 
 AEs of special interest 


 
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Efficacy assessments:   
 Stool frequency 
 Rectal bleeding; 
 Disease severity assessed by endoscopy (either flexible sigmoidoscopy or colonoscopy) 
PK assessment:   
 Blood will be collected for determining plasma LYC-30937 concentrations and its metabolite 
LYC-53552. 
 Colon tissue will be collected for exploratory analysis of colon tissue concentrations of 
LYC-30937 and its metabolite.   
PD assessment (exploratory):   
 Blood, stool, and colon tissue analysis for PD parameters may be performed in consenting 
subjects where feasible and acceptable.   
Endpoints 
Primary Efficacy Endpoint:   
 The proportion of subjects who achieve a clinical remission at Week 8 using the modified 
Mayo score (MMS).  Clinical remission using MMS is defined as Mayo stool frequency 
subscore of ≤ 1, Mayo rectal bleeding subscore of 0 and Mayo endoscopy subscore of ≤ 1  
Secondary Efficacy Endpoints:   
 The proportion of subjects who achieve clinical remission at Week 8 using the total Mayo 
score (TMS). Clinical remission using TMS is defined as a TMS of ≤ 2, with no individual 
score > 1, and rectal bleeding score of 0 
 The proportion of subjects with a clinical response at Week 8, defined as a reduction from 
Baseline in MMS of ≥ 2 points and ≥ 25%, and a decrease from baseline in rectal bleeding 
subscore of ≥ 1 point or an absolute rectal bleeding subscore of ≤ 1 point 


 
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 The proportion of subjects with a clinical response at Week 8, defined as a reduction from 
Baseline in TMS of ≥ 3 points and ≥ 30%, and a decrease from baseline in rectal bleeding 
subscore of ≥ 1 point or an absolute rectal bleeding subscore of ≤ 1 point 
 The change from baseline TMS at Week 8 
 The change from baseline to Week 8 in fecal calprotectin 
Exploratory Efficacy Endpoint:  
 The proportion of subjects with endoscopic improvement at Week 8, defined by a Mayo 
endoscopic subscore of ≤ 1 point 
 The proportion of subjects with clinical remission, response, and endoscopic improvement at 
Week 8 who had previously received biologic therapy; who were refractory to biologic 
therapy (during their initial course of biologic treatment), or who lost response to biologic 
therapy or were intolerant of biologic therapy 
Safety Endpoint:   
 The incidence and type of AEs, serious AEs (SAEs), and AEs that led to discontinuation of 
treatment 
PK and PD Endpoints:   
 PK parameters will be derived from plasma concentrations of LYC-30937 (and its 
metabolite); colon tissue (exploratory) will be assayed for concentration of LYC-30937 and 
its metabolite; exploratory PD biomarkers will be assayed from blood, stool, and colon 
tissue.  
Anticipated Number of Subjects  
Approximately 120 subjects will be randomized into the study and dosed in a 1:1 ratio to 
LYC-30937-EC 25 mg or matching placebo. 
Anticipated Number of Sites 
Approximately 66 sites  


 
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First Subject Screened 
2nd quarter 2016 
End of Study 
Last subject last visit is expected to occur in approximately December 2017 
Study Countries 
The study is being conducted in North America (Canada, United States) and Europe (Czech 
Republic, Hungary, Netherlands, Poland, Serbia)  


 
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2.0 
INTRODUCTION 
2.1 
Background 
Inflammatory bowel diseases such as ulcerative colitis (UC), Crohn’s Disease (CD), and 
nonspecific colitis are chronic autoimmune diseases with significant unmet medical need.  
Manifestations of the disease are unpredictable and can be progressive and, in certain cases, may 
result in life-threatening complications.  Current small molecule therapies result in mainly 
symptomatic relief and current biologic therapies result in sustained remission in less than 25% 
of UC and 50% of CD patients, respectively.1,2  All treatment options are associated with 
significant safety concerns, notably increased infection risk due to sustained immune 
suppression.3  New treatment options are needed as surgical resection of the bowel remains a 
necessary intervention for a substantial portion of patients even after the introduction of biologic 
agents as treatments.  Since the introduction of newer agents (2003-2011), the rates of surgery 
for patients with CD and UC have decreased, but remained at ~20% and ~8%, respectively.4  
Thus, there is a need for novel oral treatment options that will result in induction of remission as 
well as maintenance of remission over long-term dosing, with a reduced risk for immune 
suppression.   
The rationale for assessing LYC-30937-EC starts with accumulating evidence that lymphocytes 
adopt a specific metabolic phenotype that supports their particular effector function.  Thus, the 
energy required for normal lymphocyte activation is driven by aerobic glycolysis, whereas 
chronically activated pathogenic lymphocytes make their adenosine triphosphate (ATP) 
primarily via oxidative phosphorylation (OXPHOS) occurring in the mitochondria.5,6  Oxidative 
phosphorylation is, in turn, dependent on the activity of the mitochondrial ATP synthase enzyme 
(F1F0-ATPase) that constitutes the final complex in the mitochondrial respiratory chain and is 
responsible for the formation of ATP.7,8  Modulation of the F1F0-ATPase (ATPase) with small 
molecule allosteric agents such as LYC-30937 (ATPase modulators) has demonstrated increases 
in reactive oxygen species and hyperpolarization of the mitochondrial membrane, changes that, 
together with other bioenergetic and redox abnormalities, result in apoptosis of susceptible cells.  
ATPase modulators, therefore, selectively deplete chronically activated pathogenic lymphocytes 
while sparing normal lymphocytic function based on the distinct role of the ATPase in the 
differential metabolism of these lymphocyte subsets.  In agreement with this mechanism of 
action, ATPase modulators have demonstrated efficacy in several preclinical rodent models of 
autoimmune disease (arthritis, lupus, psoriasis, graft-versus-host disease, and inflammatory 
bowel disease [IBD]) with no effect on normal immune responses (no effect on primary or 
secondary responses in murine T-Cell-Dependent Antibody Response and adoptive transfer 
immunization models).9,10,11,12  


 
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LYC-30937-EC is an orally administered EC small molecule ATPase modulator under 
development for treatment of IBD.  LYC-30937 acts as a potent immune modulator through 
induction of cell death in chronically activated pathogenic lymphocytes and demonstrates 
efficacy in acute and chronic rodent models of colitis.  Moreover, LYC-30937 distributes 
preferentially to the colon versus plasma at efficacious doses in these models and is therefore 
predicted to work predominantly through local effects in the gastrointestinal tract, with limited 
systemic exposure.   
In initial dosing in healthy subjects, the pharmacokinetic (PK) profile in single ascending doses 
(SAD) was consistent with post-pyloric delivery (due to enteric coating) and the systemic 
exposures did not exceed 5.1 ng/mL, which is 50-fold below the no observed adverse effect level 
(NOAEL) in the rat, the most sensitive species.  In the multiple ascending dose (MAD; 100 and 
200 mg dose groups) part of the study, the time at which maximum observed plasma 
concentration (Tmax) (> 4 hours) was also consistent with colonic delivery.  Furthermore, after 
multiple dosing, the area under the concentration-time curve from time 0 to 24 hours (AUC0-24) 
in the 100 mg dose group increased from 25.4 ng·h/mL at Day 1 to 99.5 ng·h/mL on Day 7, and 
from 62.7 ng·h/mL at Day 1 to 173 ng·h/mL at Day 7 in the 200 mg dose group.  The highest 
individual plasma concentration in the 200 mg dose group (maximum plasma concentration 
[Cmax]:  21.4 ng/mL; AUC0-24:  306 ng·h/mL) was still 10-fold below the NOAEL.  
In the Phase 1 study in UC subjects, the AUC and Cmax were very similar to healthy volunteers 
following a single administration of a single dose of 25 mg.  At a dose of 100 mg, exposures 
were higher in UC subjects; however, there were no safety findings and exposures remained at 
least 20-fold (based on Cmax and AUC) below the lowest NOAEL in the rat and monkey chronic 
toxicology studies. 
In summary, LYC-30937-EC is a first-in-class oral ATPase modulator with a novel mechanism 
of action that is anticipated to demonstrate clinical efficacy free from generalized immune 
suppression.  Overall, this profile could provide significant advantages for the treatment of IBD.   
2.2 
Rationale for the Study 
Inflammatory bowel disease is a complex autoimmune disorder that consists of UC, CD, and 
nonspecific colitis that remains a disease of high unmet medical need.  Current therapies are 
limited by either low response rates or poor tolerability.  LYC-30937-EC has a unique 
mechanism of action, which results in induction of apoptosis in chronically activated 
lymphocytes such as those thought to drive the inflammation of UC.  LYC-30937 demonstrated 
efficacy in animal models of IBD and selective induction of apoptosis in chronically activated 
human lymphocytes.  LYC-30937-EC has also shown safety, tolerability, and a favorable PK 


 
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profile in healthy male volunteers up to single doses of 300 mg and 7 days of daily dosing at 
200 mg and in UC subjects in single doses of 25 and 100 mg, which are the highest doses tested 
in humans to date.  The mechanism of action of selective induction of apoptosis in chronically 
activated lymphocytes, the demonstration of efficacy in IBD models and the safety, tolerability, 
and PK profile demonstrated in the Phase 1 program supports further study of the compound in 
humans with IBD.   
2.3 
Nonclinical Studies 
2.3.1 
Nonclinical Pharmacology 
LYC-30937 is an orally administered small molecule for the treatment of IBD.  It functions as an 
allosteric modulator targeting the mitochondrial ATP synthase, also known as the F1F0-ATPase.  
Compounds that modulate F1F0-ATPase activity increase superoxide formation and mediate 
apoptosis of susceptible cells via a well-characterized apoptotic signaling cascade.  Consistent 
with this mechanism of action, LYC-30937 slows the rate of ATP production in 
submitochondrial particles, increases reactive oxygen species (ROS) generation, and induces 
apoptosis in a lymphocyte cell line.  In addition, LYC-30937 induces apoptosis of gut-tropic 
T-cells from subjects with IBD.   
LYC-30937 and other ATPase modulator compounds are efficacious in acute and chronic rodent 
colitis models.  Oral administration of LYC-30937 in rodent models of IBD is associated with a 
reduction in clinical signs and improvements in histology.  LYC-30937 was selected for 
advancement based on its in vitro potency, in vivo immunomodulatory activity, and a PK profile 
characterized by high local tissue concentrations in the gastrointestinal tract.  In rodent efficacy 
studies, LYC-30937 was efficacious at doses where plasma drug levels were below 
concentrations anticipated to be efficacious based on biochemical and cellular assays.  In 
contrast, colonic drug levels exceeded the 50% inhibitory concentration (IC50) values in 
enzymatic and cellular assays.  These data suggest that efficacy was largely driven by drug in 
colon tissues rather than plasma.   
2.3.2 
Nonclinical Pharmacokinetics 
LYC-30937 has low aqueous solubility and exhibits moderate apparent permeability in a Caco-2 
cell model.  Following administration of single oral doses of LYC-30937 as an emulsion in a 
lipid-based formulation, bioavailability is low to moderate in monkeys, mice, and rats 
(10%-38%).  Plasma LYC-30937 exposures were similar in normal and trinitrobenzene sulfonic 
acid (TNBS)-treated rats indicating that colitis did not alter the PK of the drug.  When 
administered as a powder blend in an enteric-coated capsule (the intended clinical formulation) 
to monkeys, the AUC0-24 of LYC-30937-EC is approximately 10% of that achieved using a lipid-


 
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based formulation.  In mouse, rat, and monkey, LYC-30937 exhibits low to moderate plasma 
clearance, low to moderate volume of distribution, and a long terminal elimination half-life.  
Plasma protein binding is moderate in all species (13%-18% free).   
LYC-30937 is moderately stable in hepatocytes from rat and human, and poorly stable in 
hepatocytes from monkey.  Metabolite profiles are qualitatively similar across species and all 
human metabolites were produced in rat and monkey hepatocytes.  The major metabolic 
pathways included glucuronidation and hydroxylation.  In addition, a cyclodehydration product 
(LYC-53552) was observed that appears to be formed non-enzymatically.  Conversion of 
LYC-30937 to LYC-53552 also was observed in simulated gastric fluid, consistent with the 
compound’s known instability in the presence of acid.  LYC-30937 is not predicted to be a direct 
inhibitor of human cytochrome P450 enzymes (CYPs) but may be a weak time-dependent 
inhibitor of CYP 2D6.  LYC-30937 is unlikely to be associated with significant drug-drug 
interactions.   
2.3.3 
Safety Pharmacology and Toxicology 
LYC-30937 is not genotoxic and does not produce adverse central nervous system, pulmonary or 
cardiovascular effects in single dose safety pharmacology studies. In rats and monkeys dosed for 
up to 28 days with LYC-30937, there was no evidence of generalized immune suppression. 
In the rat 28-day good laboratory practice (GLP) toxicology study, an AUC of ≥ 5800 ng·h/mL 
was associated with sporadic instances of mortality.  In the rat 91-day GLP toxicology study, the 
NOAEL was 10 mg/kg with a plasma AUC of 7750 ng·h/mL (combined sex mean).  Since 
mortality was observed in previous studies at a lower AUC, the rat NOAEL across all studies 
was considered to be the mid dose in the 91-day study of 3 mg/kg with a Cmax of 257 ng/mL and 
an AUC of 3060 ng·h/mL.  In the 26-week chronic toxicology study, the NOAEL was also 
3 mg/kg and was associated with a mean steady state Cmax of 240 ng/mL and an AUC0-24 of 
3000 ng·h/mL. 
Due to the mitochondrial mechanism of action of LYC-30937, a study was conducted to explore 
uncoupling as a potential cause of mortality in rats at high plasma drug levels. As measured by 
indirect calorimetry, at doses ≥ 7 mg/kg, LYC-30937 produced dose-related increases in oxygen 
consumption and body temperature consistent with mitochondrial uncoupling. At a tolerated 
dose, measurable and reversible increases were observed for both parameters.   
In the 28-day GLP monkey toxicology study, an exposure of 6340 ng·h/mL in the male high 
dose group (30 mg/kg) was associated with dose-limiting emesis and diarrhea leading to 
euthanasia of the group following 16-18 days of dosing. In surviving animals, complete recovery 


 
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from these clinical signs occurred following a reversal period of 28 to 38 days. The NOAEL in 
the 28-day monkey study was 10 mg/kg/day associated with an AUC of 4820 ng·h/mL 
(combined sex mean).  In the 91-day GLP toxicology study, the NOAEL was 10 mg/kg with an 
AUC of 2580 ng·h/mL. Likewise, in the 39-week chronic toxicology study in monkeys, the 
NOAEL was 10 mg/kg and was associated with a mean Cmax of 281 ng/mL and a mean AUC0-24 
of 2760 ng·h/mL. 
Comparing plasma drug levels at the NOAELs in the chronic rat and monkey toxicology studies 
to the efficacious exposure in a chronic TNBS-induced colitis model following an oral dose of 
0.3 mg/kg, exposure ratios are > 20 based on Cmax and > 50 based on AUC. 
Additional information is provided in the Investigator’s Brochure (IB).   
2.4 
Previous Human Experience 
LYC-30937-EC has been studied in two Phase 1 studies. 
The Phase 1a study was comprised of a SAD, MAD, and food effect (FE) component. A total of 
57 healthy male subjects were randomized in the study, 34 subjects in the SAD component, 
16 subjects in the MAD component, and 7 subjects in the FE component. A total of 40 subjects 
received LYC-30937-EC treatment (SAD = 21, MAD = 12, FE = 7).  
A total of 52 treatment emergent adverse events (TEAEs) were reported. All TEAEs were of 
mild severity. There were no deaths or SAEs reported and no discontinuations due to AEs in any 
components of the study. A total of 6 TEAEs were considered by the investigator to be possibly 
related to study drug. All of these TEAEs were reported in the SAD component of the study, of 
which 5 TEAEs were reported by 3 placebo subjects and 1 TEAE (flatulence) by a subject 
receiving a single dose of 75 mg LYC-30937-EC. 
There were no clinically significant findings with respect to clinical laboratory, vital signs 
(including body temperature), ECGs, continuous cardiac monitoring, PE, respirometry, and 
tissue or pulse oximetry.  
In the SAD component of the study, the Cmax reached a plateau of 3 to 4 ng/mL at the 75 mg 
cohort (at least 60-fold below NOAEL in rat, the most sensitive species) and the AUC began to 
plateau at the 150-mg dose (Table 1).  In the MAD component of the trial, the mean Cmax and 
AUC values were 10.3 ng/mL and 173 ng·h/mL on Day 7 following oral administration of 
200 mg (Table 2). The extent of accumulation following multiple dosing was 3- to 4-fold.  


 
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Table 1: 
Pharmacokinetics of Healthy Subjects in the Phase 1 Single Ascending Dose 
Study 
Cohort a 
Dose (mg) 
Cmax (ng/mL) 
Tmax (hour) 
AUC0-last (ng·h/mL) 
1 
2 
0.3 (0.02) 
6.0 (2.0) 
1.1 (0.17) 
2 
8 
2.1 (0.34) 
4.0 (0.0) 
20.7 (4.9) b 
3 
25 
1.7 (1.08) 
12.0 (10.39) 
31.5 (7.4) 
4 
75 
3.0 (2.02) 
7.3 (4.16) 
50.3 (27.9) 
5 
150 
3.1 (1.09) 
13.0 (10.54) 
97.3 (56.4) 
6 
300 
4.2 (0.73) 
17.7 (15.96) 
134 (56.6) 
All data are presented as mean (SD) 
AUC = area under the plasma (concentration-time) curve; Cmax = maximum observed plasma concentration; 
SD = standard deviation; Tmax = time at which maximum observed plasma concentration Cmax 
a 
N = 3 healthy subjects per cohort except for N = 6 for the 300 mg cohort 
b 
Last measurable exposure at 36 or 48  hours (AUC0-36 and AUC0-48) 
Source:  LYC-30937-1001 Clinical Study Report Table 15.2.4  
 
Table 2: 
Pharmacokinetics of Healthy Subjects in the Phase 1 Multiple Ascending 
Dose Study  
Dose 
Day 
Cmax (ng/mL) 
Tmax (hour) 
AUCƮ (ng·h/mL) 
t1/2 (hours) 
100 mg 
1 
2.5 (1.75) 
11.3 (9.85) 
25.4 (12.1) 
- 
 
7 
6.3 (4.33) 
6.0 (3.10) 
99.5 (63.1) 
87.6 (27.4) 
200 mg 
1 
6.0 (2.3) 
5.67 (1.51) 
62.7 (20.6) 
- 
 
7 
10.3 (6.06) 
8.3 (2.94) 
173 (84.2) 
66.6 (10.2) 
All data are presented as mean (SD) 
N = 6 healthy subjects per dose group 
AUC = area under the plasma (concentration-time) curve; Cmax = maximum observed plasma concentration; 
SD = standard deviation; Tmax = time at which maximum observed plasma concentration 
Source: LYC-30937-1001 Clinical Study Report Table 15.2.4 
 
In the FE component of the study, administration of a single 100-mg dose under fed conditions 
resulted in a 15-fold increase in mean Cmax and a 6-fold increase in mean AUC versus the fasting 
exposures.  The highest individual exposure in a fed subject was 2- to 3- fold below the NOAEL 
in the rat, the most sensitive species.  
The Phase 1b study was an open-label, SAD study to evaluate the PK profile, safety, and 
tolerability in subjects with UC. A total of 6 subjects received LYC-30937-EC treatment at either 
25 mg (3 subjects) or 100 mg (3 subjects).  No AEs were reported for the study and exposures at 
the 25-mg dose were comparable to exposures in healthy volunteers.  At a dose of 100 mg, 


 
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exposures were higher in UC patients but there were not associated safety findings and exposures 
remained at least 20-fold (based on Cmax and AUC) below the lowest NOAEL in rat and monkey 
chronic toxicology studies.  
Overall, oral administration of LYC-30937-EC as a single dose up to 300 mg and as a daily dose 
up to 200 mg for 7 days was safe and well tolerated. Administration of a single, 100-mg dose 
under fed conditions in the FE component of the study demonstrated a significant food effect. 
The increased exposures were not associated with any safety findings.  
Additional information is provided in the IB. 
2.5 
Dose Selection Rationale 
The proposed dose to be studied in this Phase 2 proof of concept trial is 25-mg daily oral dose.  
The rationale for this is based on the exposures required to demonstrate efficacy in the chronic 
TNBS IBD model, and the safety margins for the both the fasted and fed states. 
From the SAD study, a dose of 25 mg was associated with a Cmax of 1.7 ng/mL and the AUC0-72 
was 31.5 ng·h/mL.  Projection of steady-state exposure was based on the average accumulation 
observed following doses of 100 or 200 mg and using linear regression in relation to other doses 
studied.  Using these methods, the steady state Cmax and AUC following daily doses of 25 mg are 
projected to be approximately 2 ng/mL and 40 ng·h/mL.  Both the Cmax and AUC values exceed 
the exposures achieved in the mouse chronic TNBS model at 0.03 mg/kg where Cmax was 
1 ng/mL and AUC0-24  was ≤ 10 ng·h/mL.  Furthermore, the colon tissue concentration of the 
compound is predicted to be at least 13-fold higher than in plasma, which will ensure adequate 
exposures at the site of action: chronically activated lymphocytes in the lamina propria.   
The dose is also to ensure safety.  Subjects in this trial will be instructed to take study drug in the 
fasted state.  In the fasting state, the Cmax and AUC are projected to be > 100-fold below and 
> 70-fold below the rat NOAEL, respectively.  In the fed state, where there is significantly 
increased systemic exposure, the mean plasma Cmax and AUC are projected to remain 10-fold 
below the NOAEL in the rat, the most sensitive species.   
Thus, the selection of 25-mg daily dose is made to provide the optimal benefit-to-risk profile.  
This is achieved by the mechanism of delivering drug to the site of action while minimizing the 
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2.6 
Risks and Benefits 
Based on the results from the first-in-human study described in Section 2.4, single doses of up to 
300 mg were proven to be safe and tolerable (in the SAD part of the study) and single-dose 
exposures observed with once-daily dosing for 7 days in 100 and 200 mg dose groups in the 
MAD part of the study were similar to those observed in the SAD part of the study.   
The EC capsule was developed to deliver study drug to luminal tissue in the ileum and colon.  In 
addition, LYC-30937 is sparingly soluble in water and distributes preferentially to the colon 
versus plasma.  It is therefore predicted to work predominantly through local effects in the 
gastrointestinal tract, with limited systemic exposure.  It should be noted that with any clinical 
study drug, there is a risk of AEs.  Based on the human exposures in the Phase 1 study in healthy 
subjects, there were no safety signals detected.  There were no clinically significant laboratory 
abnormalities and the subjects tolerated the drug well.   
In Phase 2, the subjects will be suffering from active UC and therefore will be a different subject 
population.  They will also be administered study drug for 8 weeks.  Subjects will be closely 
monitored for any potential AE or laboratory abnormality that may arise.  Because of the effect 
of a high fat meal on absorption, observed in the FE component of the Phase 1 study, subjects 
will be instructed to take their study drug upon awakening in the morning after fasting overnight. 
They should not eat until approximately 1 hour after taking study drug.  This will ensure that the 
systemic exposures are predictable and low.   
The colonoscopy/flexible sigmoidoscopy carries known risks including adverse reaction to the 
sedative, if used during the exam.  Other risks of the procedure itself may include perforation, 
bleeding or irritation of the lumen of the colon.  These risks are very small, especially in the 
hands of experts performing the procedures.   
The benefits of the drug in subjects with active UC are being evaluated in this study, therefore 
any benefit is theoretical.  There has not been an efficacy study yet.  The rationale to study this 
drug in subjects with UC is based on the mechanism of action and preclinical animal models of 
IBD.   


 
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3.0 
STUDY OBJECTIVES AND ENDPOINTS  
3.1 
Study Objectives 
3.1.1 
Primary Study Objective  
The primary objective will be to assess the efficacy of LYC-30937-EC in inducing remission 
compared with placebo in subjects with active UC over a treatment duration of 8 weeks.   
3.1.2 
Secondary Study Objectives  
The secondary objectives will be to evaluate the safety and tolerability of LYC-30937-EC 
compared with placebo in subjects with active UC.   
3.1.3 
Exploratory Objectives 
The exploratory objectives will be to determine plasma PK and the colon tissue exposure of 
LYC-30937-EC, evaluate pharmacodynamic (PD) biomarkers, assessment of endoscopic 
improvement at Week 8, and assessing efficacy in subjects with previous exposure to biologic 
therapy.   
3.2 
Endpoints 
3.2.1 
Efficacy Endpoints 
Primary Efficacy Endpoint:   
 The proportion of subjects who achieve a clinical remission at Week 8 using the modified 
Mayo score (MMS).  Clinical remission using the MMS is defined as a Mayo stool frequency 
subscore of ≤ 1, a Mayo rectal bleeding subscore of 0 and a Mayo endoscopy subscore 
of ≤ 1.   
Secondary Efficacy Endpoints:   
 The proportion of subjects who achieve a clinical remission at Week 8 using the total Mayo 
score (TMS).  Clinical remission using the TMS is defined as a TMS score of ≤ 2, with no 
individual score > 1, and rectal bleeding score of 0  


 
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 The proportion of subjects with a clinical response at Week 8, defined as a reduction from 
baseline MMS of ≥ 2 points and ≥ 25%, and a decrease from baseline in rectal bleeding 
subscore of ≥ 1 point or an absolute rectal bleeding subscore of ≤ 1 point 
 The proportion of subjects with a clinical response at Week 8, defined as a reduction from 
baseline TMS of ≥ 3 points and ≥ 30%, and a decrease from baseline in rectal bleeding 
subscore of ≥ 1 point or an absolute rectal bleeding subscore of ≤ 1 point 
 The change from baseline TMS at Week 8 
 The change from baseline to Week 8 in fecal calprotectin 
Exploratory Efficacy Endpoints:   
 The proportion of subjects with endoscopic improvement at Week 8, defined by an 
endoscopic subscore of ≤ 1 point 
 The proportion of subjects with clinical remission, response, and endoscopic improvement at 
Week 8 who had previously received biologic therapy; who were refractory to biologic 
therapy (during their initial course of biologic treatment), or who lost response to biologic 
therapy or were intolerant of biologic therapy 
3.2.2 
Safety Endpoint  
 The incidence and type of AEs, SAEs, and AEs that led to discontinuation of treatment 
3.2.3 
PK and PD Endpoints 
 PK parameters will be derived from measurements of plasma LYC-30937 concentrations, 
and its metabolite, using noncompartmental PK analyses. 
 Colon tissue concentrations of LYC-30937, and its metabolite, will be measured for 
exploratory analyses.  
 Where feasible and acceptable and in subjects who consent, biologic samples (blood, stool, 
colon tissue) will be assessed for a series of exploratory PD biomarkers aimed at helping 
understand the effects of LYC-30937-EC in subjects with active UC (see Appendix C).  
Biomarkers that may be assessed include:   


 
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 inflammatory proteins and cytokines 
 enumeration of lymphocytes subtypes 
 lymphocyte infiltration and metabolic remodeling 
 expression of proteins associated with gut-homing and lymphocyte activation  
 expression of small nucleotide polymorphism associated with UC;  
 transcriptional profiling for immune cell signatures 
 taxonomic composition of subject microbiomes 
4.0 
STUDY DESIGN 
4.1 
Design Overview 
This study is a Phase 2 multicenter, multinational, randomized, double-blind, placebo-controlled, 
parallel group study designed to evaluate the efficacy, PK, PD, safety, and tolerability of 
LYC-30937-EC in subjects with UC.  Male and female adult subjects with a previous diagnosis 
of UC will be screened to determine eligibility as per the inclusion and exclusion criteria (see 
Sections 4.4.1 and 4.4.2, respectively).  The screening period will be up to 28 days (4 weeks).   
There are 3 distinct phases of this study as outlined below:   
Screening:  The screening visit will take place up to 28 days (4 weeks) prior to randomization 
and the subject’s first dose of study drug.  Screening will take place over multiple days to 
complete and obtain results for all assessments.  Subjects who meet all eligibility requirements 
will return for the next phase of the study.   
Double-Blind Treatment Period:  Subjects meeting all entry criteria will be randomized in a 
1:1 ratio to LYC-30937-EC 25 mg once daily [q.d.] or placebo q.d.  Randomization will be 
stratified by previous treatment with biologic therapy such that at least 50% of randomized 
subjects are biologic naïve.  Subjects will receive their first dose of study drug at the clinic after 
randomization has occurred.  Subjects will return to the clinic at Weeks 1, 2, 4, and 8 for efficacy 
assessments, safety monitoring and study drug receipt.   


 
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Follow-Up:  There will be 1 follow-up visit performed at Week 10 for final safety monitoring 
purposes.   
All subjects will thus be followed for approximately 14 weeks, which includes up to 4 weeks 
between screening and Study Day 1 (first dose of study drug), 8 weeks for treatment and 2 weeks 
for follow-up.  Subjects will visit the clinic at Screening (Days -28 to -1), baseline (Day 1), 
Week 1 (Day 8), Week 2 (Day 15), Week 4 (Day 29), and Week 8 (Day 57) or at the Early 
Termination (ET) Visit.  In addition, a follow-up visit will be planned 2 weeks after the last 
administration of study drug (Week 10 [Day 71]).   
The assessments planned at each visit are detailed in the double-blind schedule of events 
(Table 3).   
After all subjects complete the Week 10 follow-up visit, the study database will be locked to 
allow for the analysis of data collected up through the Week 10 visit.   
The subjects, site personnel following the subject, and the Sponsor will remain blinded to 
treatment until after the database lock.   
Optional Open-Label Treatment:  An optional open-label extension study will be available to 
subjects under a separate protocol to subjects who complete the double-blind trial. The open-
label extension will allow up to 44 weeks of treatment with LYC-30937-EC.     
4.2 
Number of Subjects and Sites 
A total of approximately 120 subjects will be randomized into the study and treated at 
approximately 66 sites (refer to Section 8.1 for sample size estimation).   
4.3 
Assignment of Subject Numbers 
Subjects will be assigned a 6-digit unique identification number sequentially as they sign the 
informed consent document (ICD) and agree to participate in the study.  The first 3 numbers will 
identify the site number (eg, 200, 201, 202) and the next 3 numbers will be assigned 
consecutively starting with “001” then “002.”  Subject identification numbers will be captured on 
the electronic case report forms (eCRFs) and will serve as the primary method of identifying 
each subject on the eCRFs and on the site’s source documents throughout the study.  Each site 
will prepare and maintain a “Master List” of each subject participating in the study.   


 
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A randomization number will be assigned to each subject who has met entry criteria and is 
randomized into the study.  The treatment that the subject is assigned to receive will be linked to 
the randomization number.  A list of randomization numbers will be generated before enrollment 
begins.  The subject identification number and randomization number will be assigned by an 
interactive web-based (IWRS) response system.   
Rescreening of subjects, who previously failed screening, may be allowed once after consultation 
and approval by the study sponsor.  Depending on the timing of the rescreening, the subject may 
need to repeat certain screening assessments to confirm eligibility into the study.   
4.4 
Subject Selection 
The following entry criteria are designed to select subjects for the study for whom protocol 
treatment is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether this protocol is suitable for a particular subject.   
4.4.1 
Inclusion Criteria 
Each of the following inclusion criteria must be met for entry into the study.   
1. 
Consenting adults aged 18–75 years.   
2. 
Have had UC diagnosed at least 6 months prior to screening and with a minimum disease 
extent of ≥ 15 cm from the anal verge.  The diagnosis of UC must be confirmed by 
endoscopic and histologic evidence (histology may be confirmed at screening based on 
biopsy collection during the screening colonoscopy with histological evaluation done by 
the site).   
3. 
Have active UC defined as a TMS of 4–11 (inclusive) with endoscopic subscore of ≥ 2 and 
rectal bleeding subscore of ≥ 1 at screening.   


 
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4. 
Male and female subjects of childbearing potential must agree to use adequate birth control 
measures during the study.  Female subjects of childbearing potential must use 2 highly 
effective forms of contraception, unless surgically sterilized, partner has had a vasectomy, 
or they will be abstinent, during study participation and for 30 days after their last dose of 
study drug.  Highly effective methods of birth control in this study include:  intrauterine 
device, hormonal contraceptives (oral, patch, long acting injectable, implant), double -
barrier method (condom or diaphragm with spermicide).  (Postmenopausal defined as lack 
of menses for ≥ 6 months prior to screening confirmed with serum FSH > 25 mIU/mL at 
screening.)   
5. 
If currently receiving any of the following UC treatments, the duration and dose prior to 
the screening endoscopy must be as specified below and a stable dose should be 
maintained throughout the double-blind trial:  
a. 5-aminosalicylates (5-ASA) (eg, mesalamine, sulfasalazine, olsalazine, balsalazide) for 
≥ 6 weeks with the dose stable for ≥ 3 weeks prior to the screening endoscopy.   
b. Prednisone (dose ≤ 20 mg daily) or equivalent for ≥ 4 weeks and receiving a stable 
dose for ≥ 2 weeks prior to the screening endoscopy.  
c. Thiopurines (azathioprine or 6-mercaptopurine) provided the dose has been stable for 
≥ 8 weeks prior to screening endoscopy.  
6. 
If  5-ASA, or corticosteroids have been recently discontinued, they must have been stopped 
for ≥ 2 weeks prior to the screening endoscopy (eg, if recently tapered off corticosteroid).  
If a thiopurine has recently been discontinued, it  must have been stopped for ≥ 4 weeks 
prior to the screening endoscopy.   
7. 
Ability to provide written informed consent and to be compliant with the schedule of 
events, provided in Section 6.2 (Table 3).   
4.4.2 
Exclusion Criteria 
Subjects presenting with any of the following will not be randomized:   
1. 
Known mitochondrial disorder.   
2. 
History of CD or indeterminate colitis or the presence or history of a fistula consistent with 
CD.   


 
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3. 
History of bleeding disorders (eg, complement disorders, hemophilia, history of 
uncontrolled bleeding).   
4. 
Severe extensive disease that in physician judgment the subject is likely to require colonic 
surgery during the 8-week double-blind course (eg, fulminant colitis, toxic megacolon, 
bowel perforation, evidence of an acute abdomen).   
5. 
Positive test for Clostridium (C.) difficile, positive stool culture for enteric pathogens 
(eg, Salmonella, Shigella, Campylobacter), or presence of ova or parasites at screening.   
Note that C. difficile may be treated and the subject may be retested for screening after 
he/she completed this treatment.   
6. 
Any of the following laboratory abnormalities:   
a. liver function tests > 1.5 x the upper limit of normal (ULN) or direct bilirubin 
> 1.5 x ULN.   
b. hemoglobin < 8.5 g/dl (international system units [SI]:  < 85 g/L).   
c. neutrophils < 1500/mm3 (SI:  < 1.5 x 109/L).   
d. white blood cell (WBC) count < 3,000/mm3
 (SI:  < 3.0 x 109/L).   
e. Platelets < 80,000 mm3 (SI:  80 x 109/L).   
f. international normalized ratio (INR) > 1.5. 
g. serum creatinine > 1.4 mg/dL for women or > 1.6 mg/dL for men.   
7. 
Treatment with non-thiopurine immunosuppressant agents within 4 weeks prior to 
screening endoscopy (eg, cyclosporine, methotrexate, tacrolimus, sirolimus, or 
mycophenolate mofetil [MMF]).   
8. 
Pregnancy, lactation, or a positive serum beta human chorionic gonadotropin (hCG) at 
screening.  Female subjects should not be planning to become pregnant while enrolled in 
the trial.   


 
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9. 
Clinically relevant hepatic, neurological, pulmonary, ophthalmological, gastrointestinal,  
endocrine, psychiatric, or other major systemic disease making implementation of the 
protocol or interpretation of the study difficult or that would put the subject at risk by 
participating in the study.   
10. 
This criterion has been removed as part of the Amendment 4 revision.    
11. 
Current active or history of clinically significant, recurrent bacterial, viral, fungal, 
mycobacterial or other infections (including but not limited to tuberculosis and atypical 
mycobacterial disease and herpes zoster), human immunodeficiency virus, or any major 
episode of infection requiring hospitalization or treatment with intravenous antibiotics 
within 4 weeks prior to the screening visit and at any time during the screening period, up 
through the first dose of study drug.  Note that recurring urinary tract infections are 
allowed. 
12. 
History of cancer within the 5 years prior to screening including solid tumors and 
hematological malignancies, unless approved by the study medical monitor  (exception: no 
approval needed for basal cell and in situ squamous cell carcinomas of the skin that have 
been adequately treated with no re-occurrence for at least 1 year prior to screening).   
13. 
Presence of adenomatous colon polyps that have not been removed.   
14. 
History of alcohol or drug abuse within 1 year prior to randomization.   
15. 
History of or currently active primary or secondary immunodeficiency.   
16. 
Previous exposure to more than 2 biologic agents to treat UC and these treatments were 
considered not efficacious (eg, the subject was refractory to the therapies or they lost 
response to the therapies).  “Biologic agents” for this criterion includes approved biologics 
or biosimilars of approved biologics (either approved or in an investigational clinical trial; 
eg, TNF-alpha antagonist, integrin receptor antagonist).   
17. 
History of UC treatment with a biologic agent within 12 weeks or 5 elimination half-lives, 
whichever is shorter, prior to initiating the screening endoscopy (refer to Appendix D:  
Biologic Medication Restriction).   
18. 
Treatment with an investigational agent within 30 days prior to initiating screening 
procedures.   
19. 
Treatment with rectal steroids within 2 weeks of initiating screening procedures.  


 
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20. 
Treatment with a fecal transplant within 3 months of initiating screening procedures. 
4.5 
Subject Withdrawals 
Subjects will be encouraged to complete the study; however they may voluntarily withdraw at 
any point during the study without prejudice.  Lycera, or the designated contract research 
organization (CRO), must be notified immediately if a randomized subject is withdrawn from the 
study, and every effort should be made to inform Lycera prior to withdrawing the subject.   
Subjects may be withdrawn from the study for the following reasons:   
 screen failure:  subject does not meet entry criteria and was not randomized 
 occurrence of any AE (if the subject withdraws due to an AE the investigator should follow 
the subject until the AE resolve or stabilizes), concurrent illness, laboratory abnormality or 
other concern which, in the opinion of the investigator or Lycera, warrants the subject’s 
permanent withdrawal 
 subject noncompliance, defined as refusal or inability to adhere to the study schedule or 
procedures 
 at the request of the subject (withdraw consent) 
 at the request of the investigator, Lycera (sponsor), or regulatory authority(ies) for safety, 
behavioral, or administrative reasons  
 subject is lost to follow-up 
 If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject and/or the subject’s family.  This effort must be clearly documented.  
 other (eg, subject moved) 
If a subject withdraws before completing Visit 6 (Week 8) every effort should be made to have 
the subject undergo final visit procedures (Visit 6/Week 8) in order to document subject 
outcome, if possible.  The investigator or site staff should inquire about the reason for 
withdrawal and follow-up with the subject regarding any unresolved AEs.  The reason for the 
withdrawal will be documented in the source documents and in the appropriate eCRF.  If a 


 
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subject withdraws due to an AE or other safety reason, the subject should be asked to also return 
for follow-up Visit 7/Week 10 to have final safety assessments completed.   
If a subject withdraws from the study, and withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected.  Lycera may retain and continue to use any data collected before such withdrawal of 
consent.   
5.0 
STUDY TREATMENTS 
5.1 
Description 
 active Substance:  LYC-30937 
 activity:  Modulator of mitochondrial F1F0 ATPase 
 indication:  UC 
 strength:  25 mg 
 dosage Form:  oral, delayed release, enteric coated hydroxyl-propyl methyl-cellulose 
(HPMC) capsule 
 inactive placebo:  matching oral, enteric coated HPMC capsule containing the same inactive 
excipients as the LYC-30937 active treatment capsules  
 manufacturer:  QS Pharma (Boothwyn, USA) 
5.2 
Treatment Regimen 
The treatment (LYC-30937-EC or placebo) will be administered orally q.d. from Study Day 1 
through the end of the double-blind treatment phase (Visit 6/Week 8) for a total of 57 days of 
treatment.  The capsules must be administered in the morning upon awaking after fasting 
overnight.  Subject should not eat for approximately 1 hour (or more) after taking study drug.  
The exception to this is the Visit 2/randomization visit when the first dose of study drug is 
administered in the clinic.  Subjects may have eaten their morning meal prior to coming for this 
visit.  They should note the time they ate their last meal prior to this clinic visit and study drug 
should not be administered until at least 2 hours after that meal.   


 
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 LYC-30937-EC 25 mg q.d.:  one 25-mg capsule of LYC-30937-EC, administer upon 
awaking in the morning after fasting overnight and do not eat within the next approximately 
1 hour after dosing   
 placebo q.d.:  1 matching placebo capsule, administer upon awaking in the morning after 
fasting overnight and do not eat within the next approximately 1 hour after dosing   
At the clinic, the study drug supplies must be handled and stored safely and properly, and kept in 
a secured location to which only the investigator and authorized staff have access.   
5.3 
Randomization 
Subjects will be randomized on the same day (Visit 2) and just prior to the subject’s first dose of 
study drug.  The first dose of study drug will be taken while in the clinic under medical 
supervision.  Randomized subjects will receive LYC-30937-EC 25 mg or placebo in a 1:1 ratio.   
The randomization will be stratified by previous treatment with biologic therapy such that at 
least 50% of the randomized subjects are biologic naïve.   
5.4 
Maintaining and Breaking the Blind 
The 2 capsules developed for the trial (LYC-30937-EC 25 mg and placebo) are indistinguishable 
(identical in size, shape, color and appearance; all EC) and are packaged identically.   
To minimize the potential for bias, treatment information will be kept confidential and will not 
be available for release to the investigator, site staff, and Lycera until after database lock at the 
end of the double-blind study (Visit 7/Week 10).   
The study site will be instructed on the method for breaking the treatment blind prior to study 
start (ie, the actual treatment received by the subject).  The treatment blind is to be broken only 
in emergency situations when medical/supportive care cannot be provided without determining if 
the subject was treated with the study drug.  In the event that the treatment blind needs to be 
broken prior to the completion of the study, the investigator must contact Lycera or designee.  
The investigator will explain and document in writing why the blind was broken, how the blind 
was broken, and how the integrity of the remaining blinded subjects was maintained.   


 
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5.5 
Drug Supplies 
5.5.1 
Packaging and Labeling 
All study drug will be supplied in bottles.   
All manufacturing, packaging, and labeling operations will be performed according to Good 
Manufacturing Practices (GMP) for Medicinal Products and the relevant regulatory 
requirements.   
The study drug is to be dispensed according to the protocol.  The distribution will only occur 
after all required documentation is obtained including study approval by the Competent 
Authorities and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).   
Each bottle will be identified with a unique number.  The subject will be given bottles containing 
sufficient capsules for the subject until the next scheduled study visit.  The bottles will be labeled 
according to local requirements.   
5.5.2 
Product Accountability, Storage, Dispensing, and Return 
Upon receipt of the study drug, the investigator or authorized designee will inspect the amount 
and condition of the medication, review for appropriate language in the label, and acknowledge 
receipt and condition in the IWRS.  All study drug supplies will be stored in a locked and secure 
location accessible only to those authorized by the investigator to dispense the study drug.  The 
study drug supply will need to be stored under controlled room temperature conditions 
(15C-25°C/59F-77°F).  A detailed inventory log of study drug received and dispensed will be 
maintained by the investigator or authorized designee.   
The first dose of study drug will be taken while in the clinic under medical supervision.  
Subsequent dosing will take place at the subject’s home including on the days of study clinic 
visits (unless otherwise specified in Section 6.0).  Subjects are to take their study drug dose in 
the morning upon awaking after fasting overnight and they should not eat for approximately 
1 hour after taking study drug.  Selected subjects who provide blood samples for PK analysis and 
LYC-30937 plasma concentration monitoring may be instructed to not take their study drug at 
home the morning of specified clinic visit(s).  They instead will be asked to take their study drug 
in the clinic.  During each study visit, the subject will receive a new medication supply 
containing sufficient study drug for the period until the next visit.   


 
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A study drug accountability record will be maintained by the study site.  The investigator will 
not destroy unused study drug unless Lycera or designee provides written authorization.   
5.5.3 
Treatment Compliance 
For each study drug dose taken, the date, time, and number of capsules taken should be recorded 
in the subject’s electronic diary (see Section 6.3 for additional information).   
Subject compliance with taking study drug will be assessed by counting the number of returned 
capsules at each visit.  Subjects should take study drug as directed by the investigator without 
stopping or interrupting it on their own, unless they experience an adverse event (AE) and in this 
case they should be instructed to contact the investigator immediately.  The investigator (or 
designee) must complete the appropriate eCRF pages to document the data.   
Subjects will return any unused study drug and empty bottles at each study visit and/or early 
discontinuation visit (if applicable).  Missed doses of study drug should be discussed to try to 
ascertain the reason(s).  Every effort should be made to ensure proper subject dosing.   
All unused study drug and empty bottles will be returned to the study drug supplier/CRO depot 
as applicable at the closure of the study site or will be destroyed at the site, upon sponsor 
decision.   
5.6 
Concomitant Medications 
Subjects will not be permitted to use biologics or non-thiopurine immunomodulatory 
medications during the study.  Subjects are allowed to remain on 5-ASA products, oral 
corticosteroids, and thiopurines (azathioprine, 6-mercaptopurine)  as specified in Section 4.4.1 
(corticosteroid tapering is not allowed during this study).  They will not be permitted to use 
newly prescribed or increased dosages of these medications during the double-blind portion of 
the study.  Also, rectal preparations of corticosteroids are not permitted.  Inhaled or topical 
corticosteroids are permitted to be used as medically indicated.   
Apart from the above, subjects are allowed any medications necessary for the treatment of 
concomitant medical disorders as deemed necessary by the treating physician and according to 
standard practice guidelines.  No therapeutic interventions that the investigator feels are 
clinically indicated will be withheld, independent of whether those compounds, procedures, or 
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concomitant medications or any change in the dosage should be limited to those considered 
medically essential.  All concomitant medication administration should be recorded as specified 
on the eCRF.   
6.0 
STUDY PROCEDURES 
6.1 
Visit Timing 
The schedule of study assessments is described below (Table 3); however, a subject may be seen 
at any time for safety reasons.  Routine clinic visits outlined in the protocol should occur 
whenever possible at the same time of day throughout the study to decrease variation in 
assessments and procedures.  It’s recommended that study visits be scheduled in the morning.  
Morning visits will be necessary for subjects who participate in the safety PK exposure 
monitoring or serial PK substudies (refer to Section 6.6.1.1 and 6.6.1.2).  Prior to each clinic 
visit, subject activities should remain consistent with their normal routine (eg, meals, 
medications, caffeine ingestion).  Subjects should take prescribed and over-the-counter 
medications at the same time of the day throughout the study.   
 The day the subject receives the first dose of study drug is considered Study Day 1.  The 
timing of all study visits should be based on Study Day 1.   
 Study visit timing and windows are as follows:   
 screening (Visit 1) – approximately Study Day -28 to Day -1  
 randomization/treatment (Visit 2) – Study Day 1 
 Visit 3 (Week 1 – Study Day 8) – window ± 3 days  
 Visit 4 (Week 2 – Study Day 15) – window ± 3 days  
 Visit 5 (Week 4 – Study Day 29) – window ± 3 days  
 Visit 6 (Week 8 – Study Day 57) – window ± 4 days  
 Follow-up (Visit 7) (Week 10 – Study Day 71) – window ± 3 days 


 
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Unplanned visits may occur at any time for reasons of safety.  These visits and associated 
procedures must be documented on the eCRF.   


 
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6.2 
Schedule of Events 
Table 3: 
Schedule of Events  
Protocol Activity 
Screening Randomization 
and 1st Dose  
Treatment 
Follow-up 
 
 
Week 0 
Week 1 
Week 2 
Week 4 
Week 8/ 
ET 
Week 10 
Study Day   
-28 to -1 
1 
8 ± 
3 days 
15 ± 
3 days 
29 ± 
3 days 
57 ± 
4 days 
71 ± 
3 days 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
Informed consent 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Medical/surgical history a 
X 
 
 
 
 
 
 
Serology b 
X 
 
 
 
 
 
 
Prior UC medications 
X 
 
 
 
 
 
 
Serum pregnancy test 
(premenopausal females) 
X 
 
 
 
 
 
 
FSH (postmenopausal 
females) c 
X 
 
 
 
 
 
 
Assess protocol eligibility 
X 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Dispense study drug 
 
X 
X 
X 
X 
 
 
Administer study drug at 
the clinic 
 
X 
(X) n 
 
(X) o 
(X) n 
 
Review study drug 
compliance  
 
X s  
X 
X 
X 
X 
 
Mayo Score 
X 
 
 
 
 
X 
 
Stool frequency and rectal 
bleeding d 
X 
 
X 
X 
X 
X 
 
Physician’s Global 
Assessment 
X 
 
 
 
 
X 
 
Endoscopy and biopsy e, f 
X  
 
 
 
 
X  
 
Vital signs g 
X 
X 
X 
X 
X 
X 
X 
Body temperature 
collected by subjecth 
 
X 
 
 
 
 
 
Urine pregnancy test 
(women of childbearing 
potential only) 
 
X 
X 
X 
X 
X 
X 


 
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Table 3: 
Schedule of Events  
Protocol Activity 
Screening Randomization 
and 1st Dose  
Treatment 
Follow-up 
 
 
Week 0 
Week 1 
Week 2 
Week 4 
Week 8/ 
ET 
Week 10 
Study Day   
-28 to -1 
1 
8 ± 
3 days 
15 ± 
3 days 
29 ± 
3 days 
57 ± 
4 days 
71 ± 
3 days 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
Height 
X 
 
 
 
 
 
 
Weight 
X 
 
 
X 
X 
X 
X 
Physical examination 
X 
 
 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
 
X 
 
Chemistry panel i 
X 
 
 
X 
X 
X 
X 
Hematology panel j 
X 
 
 
X 
X 
X 
X 
Coagulation panel k 
X 
 
 
 
 
X 
 
Urinalysis l 
X 
 
 
 
 
X 
 
Stool collection m 
X 
 
 
X 
X 
X 
 
Safety PK exposure 
monitoring sub-study n   
 
 
X 
X 
X 
X 
 
Serial PK sub-study o 
 
 
 
 
X 
 
 
Plasma PK (all subjects 
who are NOT participating 
in safety PK exposure 
monitoring or serial PK 
substudies) p 
 
 
 
 
X 
 
 
Exploratory PD biomarker 
blood sample q 
X 
X 
 
X 
 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Assess AEs 
X r 
X 
X 
X 
X 
X 
X 
AE = adverse event; ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; LDH = lactate dehydrogenase; CPK = creatine phosphokinase; 
ECG = electrocardiogram; ET = early termination; FSH = follicle-stimulating hormone; HBsAg = hepatitis B 
surface antigen; HCV = hepatitis C; HDL = high-density lipoprotein; HIV = human immunodeficiency virus; 
hsCRP = high sensitivity C-reactive protein; LDL = low-density lipoprotein; MCH = mean cell hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PD = pharmacodynamic; 
PK = pharmacokinetics; PT = prothrombin time; RBC = red blood cell; TBD = to be determined; UC = ulcerative 
colitis; WBC = white blood cell. 
a 
Including smoking status, drug and alcohol consumption, and date of UC diagnosis. 
b 
HBsAg, HCV antibodies, and HIV 1/2 antibodies. 


 
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c 
Postmenopausal defined as no menses for ≥ 6 months prior to screening and serum FSH > 25 mIU/mL at 
screening. 
d 
Subject will collect rectal bleeding and stool frequency every day between clinic visits through Visit 6 (Week 8) 
in electronic diary.   
e 
Colon tissue samples are collected at screening and Visit 6 as part of the endoscopy procedures and will be 
analyzed for drug concentration levels and may be used for PD purposes.    
f 
This screening endoscopy will be a colonoscopy and it will be centrally read and used to determine eligibility.  
The Visit 6 endoscopy can be a colonoscopy or flexible sigmoidoscopy (left-sided disease only) and it will also 
be centrally read. 
g 
Vital signs will be collected after the subject has been sitting quietly for ≥ 5 minutes and include blood pressure 
(systolic and diastolic), heart rate, respiratory rate, and temperature. 
h 
At Days 1-7, subjects should take their body temperature at 4 and 8 hours after administration of the study drug.  
In case their temperature reading is > 101°F (or 38.3°C), they are to call the investigator for evaluation of 
possible infection.  After Day 7, subjects should report any elevated temperatures to the investigator (all 
elevated temperatures > 101°F (or 38.3°C) will be reported as AEs). 
i 
Chemistry panel includes:  glucose, calcium, sodium, albumin, total protein, potassium, bicarbonate, chloride, 
BUN, creatinine, lactate, LDH, ALT, AST, reflexive bilirubin (total, direct, indirect), ALP, cholesterol, 
triglycerides, CPK, hsCRP, HDL, and LDL.  
j 
Hematology Panel includes:  platelets, WBCs with differential if abnormal (% and absolute counts), hematocrit, 
RBCs, hemoglobin, MCV, MCHC, and MCH. 
k 
Coagulation Panel includes:  PT, fibrinogen and INR. 
l 
Urinalysis (dipstick) includes:  color, appearance, specific gravity, leukocyte esterase, pH, protein, glucose, 
ketones, blood, and nitrite.  Microscopic urinalysis will be performed on samples with abnormal blood, 
leukocyte esterase, protein, and nitrate.   
m 
Stool collected will be analyzed for fecal calprotectin and may be analyzed for PD biomarkers.  The stool 
collected at screening will also be tested for presence of pathogens and C. difficile. 
n 
A subset of up to 20 subjects will have blood collected at Visits 3, 4, 5, and 6 at the time points specified in 
Section 6.6.1.1.  At Visit 3 and at Visit 6 these subjects will take their study drug dose in the clinic after the pre-
dose blood draw. 
o 
A subset of up to 12 subjects will have 5 serial blood samples collected at Visit 5.  Samples will be collected 
pre-dose and 4, 6, 10, and 24 hours post-dose (± 30 minutes).  These subjects will have their daily study drug 
dose administered in the clinic at Visit 5.  See Section 6.6.1.2. 
p 
All subjects who are not participating in the safety PK exposure monitoring sub-study or the serial PK sub-
study will have 1 blood sample collected at Visit 5 (any time point) to measure plasma LYC-30937 
concentration.  See Section 6.6.1.3.  
q 
Optional PD Biomarker blood sample - collected where feasible and from subjects who consent to having this 
sample collected for exploratory PD assessments.  
r 
After informed consent is signed.  
s 
Telephone subject on Study Day 2 (the day following Visit 2) and again later during the week following Visit 2 
to ensure subject is compliant with taking study drug on an empty stomach (fasted overnight).  


 
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6.2.1 
Screening Visit 1 
No study-related procedures will be performed until each subject has been completely informed 
of the details of the study including its nature, risks, and procedures, and has signed and dated 
IRB/IEC-approved ICD.  A subject who satisfies all eligibility criteria during the screening visit 
may proceed to the next visit.   
A laboratory test (eg, alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
platelets) or procedure that does not meet eligibility criteria can be repeated once at the 
discretion of the investigator in order to determine eligibility.  A subject who does not satisfy all 
entry requirements that can be assessed during the screening phase will require no further visits 
and will be identified as a screen failure in the source documents and eCRFs.   
Re-screening of subjects initially not meeting all selection criteria may be allowed once after 
consultation with the sponsor (eg, subjects infected with C. difficile may be re-screened after 
completing treatment).   
Subject Screening will be divided over at least 2 days (all counted under Visit 1) with the 
recommendation that the easier and less invasive screening procedures be completed first to 
ensure subject meets these criteria prior to performing the more invasive endoscopy.  There will 
be at least 5 days between Part 1 and Part 2 (endoscopy visit) of the screening visit in order for 
the subject to collect baseline rectal bleeding and stool frequency information for use in 
calculation of the Mayo score.  If a subject meets the first set of eligibility criteria assessed at the 
first screening day, an endoscopy will be performed to complete the assessment of the subject’s 
eligibility.  (Sites should follow the scheduling practice at their site to determine timing of 
scheduling the endoscopy in order to complete the screening eligibility within the 28-day 
screening period). 
In the event that a potential study subject is already scheduled for a colonoscopy, it is acceptable 
to vary from the recommended screening procedure sequence and to consent the subject at the 
time of their colonoscopy visit and complete the rest of the screening procedures after this time 
point.   
Recommended processes and procedures occurring during Screening Visit 1 (Part 1) are detailed 
below:   
 Inform subject of the study details and obtain the subject’s signed ICD.   


 
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 Obtain Subject Identification Number through IWRS.   
 Obtain demographic information.   
 Obtain subject’s medical and surgical history including smoking status, drug and alcohol 
consumption and date of diagnosis for UC.   
 Obtain prior medication use for UC.   
 Provide subject with electronic diary and train on its use.  Instruct subject to begin recording 
stool frequency and rectal bleeding.  Subject’s should being collecting this information daily 
and they will bring their diary with them to all subsequent visits, including Part 2 of the 
screening visit.   
 Obtain vital signs after sitting quietly for at least 5 minutes (includes systolic and diastolic 
blood pressure [SBP and DBP], heart rate [HR], temperature [T], respiration rate [RR]).   
 Measure height and weight.   
 Conduct a physical examination.   
 Perform a 12-lead ECG.   
 Collect samples for serum chemistry, hematology, coagulation laboratory analysis as well as 
serology tests and follicle-stimulating hormone (FSH) measurement (in postmenopausal 
female subjects) and a urine sample for urinalysis.   
 Collect sample for serum pregnancy test (hCG) in premenopausal female subjects.   
 Collect exploratory PD biomarker sample in consenting subjects.   
 Collect a stool sample for fecal calprotectin and enteric pathogens.   
 Review and document concomitant medication use.  
 Assess for AEs (after informed consent has been signed) and/or determine if medical history 
should be updated.   
 Assess eligibility by carefully reviewing each inclusion/exclusion criteria.   


 
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Recommended processes and procedures occurring during Screening Visit 1 (Part 2) are detailed 
below:   
 Ensure rectal bleeding subscore ≥ 1 and that other eligibility criteria completed during 
screening visit Part 1 are met.   
 Perform a colonoscopy and biopsy collection (colonoscopy will be centrally read to 
determine eligibility).   
 Collect information on rectal bleeding, stool frequency, and Physician’s Global Assessment 
(PGA) in order to calculate the TMS and MMS.  
 Review and document any changes in concomitant medication use since the initial screening 
visit.   
 Assess for AEs (after informed consent has been signed) and/or determine if medical history 
should be updated occurring after the initial screening visit.   
 Assess eligibility by carefully reviewing each inclusion/exclusion criteria.   
6.2.2 
Visit 2 (Randomization and Dosing) 
Subjects who satisfy all inclusion/exclusion criteria assessed during the screening period will 
return to the clinic for Visit 2 for randomization and dosing.  Review all eligibility criteria and 
ensure the subject remains appropriate for study entry.   
Procedures completed at this visit are outlined below:   
 Assess protocol eligibility.   
 Obtain vital signs after sitting quietly for at least 5 minutes (includes SBP, DBP, HR, T, RR).   
 Review concomitant medication use.   
 Query for AEs.  
 Obtain urine sample for urine pregnancy test (women of childbearing potential only).   
 Collect exploratory PD biomarker sample in consenting subjects.   


 
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 Randomize subject.   
 Administer first dose of study drug at the clinic (dose should be taken at least 2 hours after 
last meal) and subject should wait approximately 1 hour before eating.   
 Dispense study drug and instruct subjects to take 1 capsule per day in the morning upon 
awaking (fasting overnight) and to wait for approximately 1 hour before eating; remind 
subject to record the time they take study drug in subject diary each day.   
 Remind the subject to measure his/her body temperature daily (at 4 and 8 hours after 
administration of the study drug) and record in the subject diary.  Body temperature may be 
measured using any method (eg, oral, temporal, etc.).  Instruct subject to measure their body 
temperature using the same method each time.   
 Post Visit 2 Telephone Follow-up with Subject – telephone the subject on Day 2 (the day 
following Visit 2) and a second time during the week following Visit 2 to remind the subject 
to take study drug on an empty stomach (fasted overnight) and to ensure they are completing 
their electronic diary. 
Randomization will be managed through IWRS.  Any subject failing to meet enrollment criteria 
prior to randomization will be considered a screen failure.   
All subjects who are randomized will be counted as part of the Full Analysis Set (FAS) 
population.   
6.2.3 
Visit 3 (Week 1) 
Subjects will return to the clinic for Visit 3, 1 week post Study Day 1.  Procedures completed at 
this visit are outlined below:   
 Obtain vital signs after sitting quietly for at least 5 minutes (includes SBP, DBP, HR, T, RR).   
 Collect information on rectal bleeding and stool frequency.   
 Obtain urine sample for urine pregnancy test (women of childbearing potential only).  
 Review concomitant medication use.   


 
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 Query for AEs.   
 Review study drug compliance.   
 Register visit in IWRS and dispense study drug and remind subjects to take 1 capsule per day 
in the morning upon awaking (fasting overnight), and to wait for approximately 1 hour 
before eating and remind subjects to record the time they take study drug in diary.   
 Remind the subject to report any increases in body temperature.   
 Note:  A selected subset of consenting subjects will provide blood samples to assess of 
plasma concentrations of LYC-30937 as part of the safety PK exposure monitoring sub-
study.  These subjects should have their study visit scheduled for the morning because they 
will take their dose of study drug in the clinic (not at home) after collection of a pre-dose 
blood sample.  A second blood sample will be collected 4-6 hours post-dose.  Refer to 
Section 6.6.1.1.   
6.2.4 
Visit 4 (Week 2) 
Subjects will return to the clinic for Visit 4 which occurs 2 weeks after Study Day 1.  Procedures 
completed at this visit are outlined below:   
 Obtain vital signs after sitting quietly for at least 5 minutes (includes SBP, DBP, HR, T, RR).   
 Measure weight.   
 Conduct a physical examination.   
 Collect a serum sample for chemistry and hematology laboratory analysis.   
 Collect exploratory PD biomarker sample in consenting subjects.   
 Obtain urine sample for urine pregnancy test (women of childbearing potential only).   
 Collect information on rectal bleeding and stool frequency.  
 Collect a stool sample for fecal calprotectin.   
 Review concomitant medication use.   


 
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 Query for AEs.  
 Review study drug compliance.   
 Register visit in IWRS and dispense study drug and remind subjects to take 1 capsule per day 
in the morning upon awaking (fasting overnight) and to wait for approximately 1 hour before 
eating and remind subjects to record the time they take study drug in diary.   
 Remind the subject to report any increases in body temperature.   
 Note:  A selected subset of consenting subjects will provide blood samples to assess of 
plasma concentrations of LYC-30937 as part of the safety PK exposure monitoring sub-
study.  A blood sample will be collected 4-6 hours after the subject has taken their daily 
study drug dose.  Refer to Section 6.6.1.1.   
6.2.5 
Visit 5 (Week 4) 
Subjects will return to the clinic for Visit 5, which occurs 4 weeks after Study Day 1.  Procedures 
completed at this visit are outlined below:   
 Collect information on rectal bleeding and stool frequency.  
 Obtain vital signs after sitting quietly for at least 5 minutes (includes SBP, DBP, HR, T, RR).   
 Measure weight.   
 Conduct a physical examination.   
 Collect a serum sample for chemistry and hematology analysis.   
 Obtain urine sample for urine pregnancy test (women of childbearing potential only).   
 Collect a stool sample for fecal calprotectin.   
 Collect serum sample for PK analysis – also see Section 6.6.1.3.  This sample will be 
collected from all subjects who are not participating in the safety PK exposure monitoring or 
serial PK substudies.   
 Review concomitant medication use.   


 
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 Query for AEs.   
 Review study drug compliance.   
 Register visit in IWRS and dispense study drug and remind subjects to take 1 capsule per day 
in the morning upon awaking (fasting overnight) and to wait for approximately 1 hour before 
eating and remind subjects to record the time they take study drug in diary.   
 Remind the subject to report any increases in body temperature.   
 Note:  A selected subset of consenting subjects will provide blood samples to assess of 
plasma concentrations of LYC-30937 as part of the safety PK exposure monitoring sub-
study.  A blood sample will be collected 4-6 hours after the subject has taken their daily 
study drug dose.  Refer to Section 6.6.1.1.   
 Note:  A subset of consenting subjects will provide serial blood samples to assess PK 
parameters as part of the serial PK sub-study.  These subjects should have their study visit 
scheduled for the morning.  Their dose of study drug will be taken in the clinic at this visit 
(not at home).  Blood samples will be collected pre-dose and at 4, 6, 10, and 24 hours post-
dose (± 30 minutes).  Refer to Section 6.6.1.2.   
6.2.6 
Visit 6 or Early Termination (Week 8) 
Subjects will return to the clinic for Visit 6 which occurs 8 weeks after Study Day 1.  Any 
subjects who terminate from the study prior to completing Week 8 should also complete the 
assessments required at this visit.  Procedures completed at this visit are outlined below: 
 Collect information on rectal bleeding, stool frequency, and PGA in order to calculate the 
TMS and MMS.   
 Perform an endoscopy and colon biopsy collection.   
 Obtain vital signs after sitting quietly for at least 5 minutes (includes SBP, DBP, HR, T, RR).   
 Measure weight.   
 Conduct a physical examination.   
 Conduct a 12-lead ECG.   


 
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 Collect a serum sample for chemistry, hematology, coagulation laboratory analysis and a 
urine sample for urinalysis.   
 Collect exploratory PD biomarker sample in consenting subjects.   
 Obtain urine sample for urine pregnancy test (women of childbearing potential only).   
 Collect a stool sample for fecal calprotectin.   
 Review concomitant medication use.   
 Query for AEs.   
 Review study drug compliance.   
 Collect electronic diary.   
 Remind the subject to report any increases in body temperature.   
 Note:  A selected subset of consenting subjects will provide blood samples to assess plasma 
concentrations of LYC-30937 as part of the safety PK exposure monitoring sub-study.  These 
subjects should have their study visit scheduled for the morning because they will take their 
dose of study drug in the clinic (not at home) after collection of a pre-dose blood sample.  A 
second blood sample will be collected 4-6 hours post-dose.  Refer to Section 6.6.1.1.   
 Subjects may elect to participate in the optional open-label extension (OLE) study 
LYC-30937-2002.  Refer to that protocol for details of the OLE study.  Subjects who enter 
the OLE upon completion of Visit 6 (Week 8) procedures and prior to follow-up Visit 7 
(Week 10) will not return for the Visit 7 (Week 10).  Subjects who elect to participate in the 
OLE study but who do not start OLE treatment prior to Visit 7 (Week 10) must return for 
Visit 7 (Week 10).  Subjects who will not enter the OLE study will return for follow-up 
Visit 7 (Week 10).   
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6.2.7 
Follow-up Visit 7 (Week 10) 
Subjects returning for Visit 7 (Week 10) will undergo the following procedures:   
 Obtain vital signs after sitting quietly for at least 5 minutes (includes systolic and diastolic 
BP, HR, T, RR.   
 Measure weight.   
 Conduct a physical examination.   
 Collect a serum sample for chemistry and hematology laboratory analysis.   
 Obtain urine sample for urine pregnancy test (women of childbearing potential only).   
 Review concomitant medication use.   
 Query for AEs.   
6.2.8 
Unplanned Visits 
Unplanned visits may occur at any time for reasons of safety.   
6.3 
Subject Diary  
Subjects will be given and instructed on the use of an electronic diary at screening to record the 
following:   
 From Day 1 through Day 57 (or ET), subjects will be asked to record the date and time study 
drug is ingested.   
 From Day 1 through Day 7 (or ET), subjects will be asked to record their body temperature 
(measured 4 and 8 hours post dosing).  The method of taking body temperature is optional 
(eg, oral, temporal, etc.) but subjects should use the same method for the duration of this 
trial.   
 From screening Visit 1 to Visit 8 (or ET), subjects will be asked to record daily their stool 
frequency and rectal bleeding.  This stool frequency and rectal bleeding information will be 
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Information recorded in the diary will be reviewed by site personnel before or at each study visit. 
Subjects will enter diary information daily throughout the study in order to encourage 
consistency in diary recording.   
6.4 
Efficacy Assessments Performed 
6.4.1 
Ulcerative Colitis Disease Activity by Mayo Score 
At the time points indicated in the double-blind schedule of events (Table 3), the subject will be 
asked to record their stool frequency and rectal bleeding and the Investigator will be asked to 
complete the PGA.   
A colonoscopy will be performed at screening to assess disease severity.  Depending upon 
disease extent, either a flexible sigmoidoscopy or colonoscopy will be performed at end of 
double-blind treatment visit (Visit 6/Week 8).  The screening colonoscopy will image the entire 
colon to determine areas of inflammation and demarcation. If the inflammation identified at 
screening is left-sided disease, defined as extending ≥ 15 cm from anal verge and with clear 
demarcation at not higher than 5 cm below the splenic flexure, then the Week 8 endoscopy can 
be a flexible sigmoidoscopy instead of a colonoscopy.  All endoscopies performed will be based 
on the investigative site’s standard practice including bowel preparation.  The endoscopies 
(either colonoscopy or flexible sigmoidoscopy) will be performed at the site and the endoscopy 
video recording will be sent to the central reader for evaluation. The Mayo endoscopy subscore 
component will be assigned based on review by a central reader.  Central readers are experienced 
at reviewing and scoring endoscopies and they will receive study-specific training prior to their 
reading endoscopies for this trial. This training will include ensuring their understanding that the 
presence of “friability” is not considered consistent with remission and therefore, if present, the 
Mayo endoscopic subscore must be at least 2.  Additional details for performing and submitting 
endoscopy images for the central read will be described in a separate imaging manual.   
Based on these parameters, the subject’s Mayo score will be calculated.   
The TMS is a scoring system for the assessment of UC activity calculated based on 4 parameters 
(PGA, endoscopy findings, rectal bleeding, and stool frequency).  The MMS is calculated based 
on 3 parameters (all aforementioned parameters apart from the PGA).   


 
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 stool frequency a (expressed in relation to the subject’s “normal” baseline number of stools 
when not having a flare and this will be documented at screening):  
0 = normal number of stools for the subject 
1 = 1-2 more stools than normal 
2 = 3-4 stools more than normal 
3 = 5+ stools more than normal 
 rectal bleeding b: 
0 = no blood seen 
1 = streaks of blood < 50% of the time 
2 = obvious blood with stool most of the time 
3 = passes blood without stool 
 PGA c:  
0 = normal 
1 = mild disease 
2 = moderate disease 
3 = severe disease 
 endoscopic findings:  
0 = normal or inactive disease 
1 = mild disease (erythema, decreased vascular pattern) 
2 = moderate disease (marked erythema, absent vascular pattern, friability, erosions) 
3 = severe disease (spontaneous bleeding, ulcerations) 
a  
Each subject serves as their own control to establish the degree of abnormality of stool frequency.  
b  
The daily bleeding score represents the most severe bleeding of the day. 
c  
The PGA acknowledges the three other criteria, the subject’s recollection of abdominal discomfort and general 
sense of well-being, and other observations, such as physical findings and the subject’s performance status. 
 
Each of these individual scores will be summed to give a MMS of 0-9 or a TMS of 0-12.   
Mayo scores are calculated using the stool frequency and rectal bleeding data obtained from the 
subjects via their direct daily diary entries. Stool frequency and rectal bleeding data from the 


 
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most recent consecutive 3-day period prior to the study visit will be used for the Mayo score, 
excluding: 
a. The day medications for constipation, diarrhea, or bowel irregularity are taken 
b. The day(s) of a procedure or preparation for a procedure (eg, enemas, laxative, clear 
liquid diet) that would affect bowel frequency or blood content of stool 
c. The 48 hours following the use of anti-motility medication (eg, loperamide) 
d. The 48 hours following endoscopy. 
The investigator (or designee) will select the most recent consecutive 3-day period and the stool 
frequency scores over those 3 days will be totaled and the average calculated.  This average 
score will be used to calculate the Mayo score.  Similarly the rectal bleeding scores over the 
3-day period will be averaged and this average score will be used to calculate the Mayo score.    
Note that in order to be eligible for the study, a subject must have a TMS of 4-11 inclusive at 
screening with an endoscopy subscore of ≥ 2 and a rectal bleeding subscore of ≥ 1.   
6.5 
Safety Assessments Performed  
6.5.1 
Physical Examinations 
A physical examination will be conducted at the time points indicated in the schedule of events 
(Table 3).   
Standard physical examination will be performed by the Investigator or by an appropriately 
trained individual and will include a review of body systems outlined below.  
 general appearance 
 head, eyes, ears, nose, and throat (HEENT) 
 respiratory examination 
 circulatory system 
 abdominal examination 


 
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 musculoskeletal 
 neurological examination to record the presence of abnormalities in mental status, motor, and 
sensory function (includes reflexes) 
 any additional assessments necessary to establish baseline status or evaluate symptoms or 
adverse experiences 
Every effort should be made to have the same examiner perform each physical exam for a given 
subject to minimize variability in the examinations.  Clinically significant changes from 
screening should be noted as AEs.  
6.5.2 
Medical and Surgical History 
Medical history will be obtained and reviewed to ensure the subject is appropriate for study 
entry.  During the Screening period, site personnel may become aware of additional events or 
procedures which should be added to medical or surgical history.   
6.5.3 
Vital Signs Measurements 
Vital signs will be measured at the time points indicated in the schedule of events (Table 3).   
Vital signs measurements consist of SBP, DBP, HR, RR, and T.  Subjects should sit quietly with 
feet flat on the floor or be supine (lying down) for at least 5 minutes prior to measurements.   
 Subject must remain seated or lying down for the entire measurement.   
 The use of automated devices for measuring BP and HR is acceptable.  If done manually, HR 
must be measured in the brachial/radial artery for at least 30 seconds.   
 BP determinations must be performed using calibrated and appropriately maintained 
equipment and the same equipment should be used on the same subject throughout the study 
as much as possible.   
 The same size BP cuff, which has been properly sized and calibrated, will be used to measure 
BP each time.   
 Subject’s arm must be at the same height (at the level of the heart) during each BP 
measurement.   


 
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6.5.4 
12-Lead ECG 
A 12-lead ECG will be conducted at the time points indicated in the schedule of events (Table 3).   
A standard 12-lead ECG will be performed after 5 minutes of rest in the supine position using a 
standardized automated device.  The following ECG parameters will be recorded by the study 
site: HR, PR-interval, QRS-duration, QT and QTc intervals, and the investigator’s assessment of 
the ECG profile (note that QTcF, the QT interval corrected for heart rate according to 
Fredericia’s formula, will be programmatically calculated and the site does not need to calculate 
this value).  Clinically significant changes from screening should be recorded as AEs.   
6.5.5 
Laboratory Assessments 
Serum samples for laboratory assessments and urine samples for urinalysis will be collected at 
the time points indicated in the schedule of events and be analyzed by a central laboratory 
(Table 3).  The details on the serum and urine sampling procedures will be described in a 
separate laboratory manual.   
The investigator at the site must assess the clinical significance of all laboratory values outside 
the laboratory reference ranges.  All laboratory abnormalities considered to be clinically 
significant by the investigator should be repeated.  Confirmed, clinically significant laboratory 
abnormalities should be further evaluated by the investigator and captured as an AE.   
Chemistry Panel Sample 
The chemistry panel includes:  glucose, calcium, sodium, albumin, total protein, potassium, 
bicarbonate, chloride, blood urea nitrogen (BUN), creatinine, lactate, ALT, AST, reflexive 
bilirubin (total, direct, indirect), alkaline phosphatase (ALP), high sensitivity C-reactive protein 
(hsCRP), creatine phosphokinase (CPK), cholesterol, triglycerides, high density lipoprotein 
(HDL), low density lipoprotein (LDL), lactate dehydrogenase (LDH).   
Hematology Panel Sample 
The hematology panel includes:  platelets, WBCs with differential if abnormal (% and absolute 
counts), hematocrit, red blood cells (RBCs), hemoglobin, mean corpuscular volume (MCV), 
mean corpuscular hemoglobin concentration (MCHC), and mean cell hemoglobin (MCH).   


 
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Coagulation Panel Sample 
The coagulation panel includes: prothrombin time (PT), fibrinogen, and INR.   
Urine Sample (Dipstick) 
The urinalysis test includes:  color, appearance, specific gravity, leukocyte esterase, pH, protein, 
glucose, ketones, blood, and nitrites.  Microscopic urinalysis will be performed on samples with 
abnormal blood, leukocyte esterase, protein, and nitrite.  This test will be evaluated by dipstick at 
the central laboratory.   
Childbearing Potential Evaluation and Pregnancy Tests 
Serum FSH in postmenopausal female subjects and a serum hCG (pregnancy test) in 
premenopausal females will be evaluated at the central laboratory at screening.  At Visits 2 
through 7, urine pregnancy tests will be performed in women of childbearing potential. 
Stool Sample 
Stool samples will be collected at the time points indicated in the schedule of events (Table 3).  
These samples will be analyzed for the presence of fecal calprotectin, a marker of bowel 
inflammation.  Fecal calprotectin is being assessed as a secondary efficacy endpoint.  
Additionally, the screening stool sample will be evaluated for the presence of C. difficile and 
enteric pathogens.   
6.5.6 
Inflammation monitoring 
Subjects are to take their body temperature at the time points indicated in the schedule of events 
(Table 3) (ie, 4 and 8 hours after taking the study drug on Days 1-7).  The subject should 
complete their temperature reading in the electronic diary.   
If the subject’s temperature reading is > 101°F (or 38.3°C) they must call their investigator and 
this should be recorded as an AE.   
If a subject calls with an elevated body temperature, the subject is to present to the clinic and be 
evaluated for a possible bacterial or viral infection.  This assessment is to be completed per the 
investigator’s best clinical judgment (eg, if there is suspicion of a urinary tract infection, then the 
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upper respiratory tract infection, then the subject can be treated symptomatically without being 
evaluated).   
If there are no signs or symptoms of infection, then the subject is to present to the clinic.  The 
study drug should be withheld and the subject should be evaluated for other sources of increased 
temperature as medically indicated.  Study drug may be re-started if study drug has been 
interrupted for no more than 3 days and the source of the elevated temperature is determined, or 
it resolves, and in the clinical judgement of the investigator and Study Medical Monitor it is safe 
for the subject to continue study drug. If the subject is off drug for more than 3 days the 
investigator should withdraw the subject from the study.  
6.5.7 
Monitoring Subjects for Adverse Events of Special Interest 
Subjects will be monitored throughout the study for the occurrence of AEs and for abnormal 
clinical laboratory values.   
AEs of special interest include those that may be related to LYC-30937’s mechanism of action of 
mitochondrial modulation and those AEs which may indicate hepatotoxicity. Investigators 
should be particularly mindful of these AEs, which include vomiting, abdominal pain, elevated 
lactate, and abnormal liver function tests indicative of possible hepatotoxicity (AST, ALT, total 
bilirubin, ALP, LDH). Guidance for monitoring for these AEs of special interest is outlined 
below: 
Vomiting or Abdominal Pain: 
If a subject exhibits repeated episodes of vomiting or persistent abdominal pain above the 
severity and/or frequency they experience as part of their underlying UC, they must contact their 
investigator.  [It’s understood that subjects will experience these symptoms as part of their UC.  
It is therefore very important to understand and document at screening the “normal” severity and 
frequency of these symptoms experienced by the subject].  They should present to the clinic as 
soon as possible to be evaluated for potential source of the symptom and liver function testing 
should be performed.  The study medical monitor should be contacted. If a source is not readily 
identified then study drug should be withheld and the subject should continue to be evaluated for 
the source and managed as medically indicated.  Study drug may be re-started if it has been 
interrupted for no more than 3 days and the source of the vomiting or abdominal pain is 
determined, or if these symptoms resolve, and in the clinical judgement of the investigator and 


 
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study medical monitor it is safe for the subject to continue study drug.  If the subject is off drug 
for more than 3 days the investigator should withdraw the subject from the study. 
Monitoring Lactate and Liver Function: 
If a subject exhibits any of the following elevations, study drug should be withheld at least until 
evaluation of the subject:   
 ALT or AST > 8 x ULN 
 ALT or AST > 5 x ULN for more than 2 weeks 
 ALT or AST > 3 x ULN and total bilirubin > 2 x ULN (or INR > 1.5) 
 ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash and/or eosinophilia (> 5%) 
 ALP > 1.5 x ULN 
 Lactate ≥ 3 mmol/L 
 LDH > 2 x ULN 
If any of the above occur the investigator must contact the subject to request they stop taking 
study drug and  report to the clinic as soon as possible for evaluation (do not wait for the next 
scheduled study visit).  As dehydration and heavy physical exertion can cause elevations (eg, of 
blood lactate levels), the clinical lab should be repeated with the subject instructed to ensure 
hydration and avoid heavy physical activity.  The study medical monitor should be contacted to 
discuss the subject.  If the elevation is confirmed by the repeat lab and neither dehydration nor 
heavy physical exertion explains the elevation, study drug must continue to be withheld.  Close 
observation of the subject should be initiated.  Repeat liver enzyme and serum bilirubin testing 
should be performed 2 to 3 times weekly until the values return to baseline.  Frequency of this 
retesting can decrease to once per week or less if abnormalities stabilize or the study drug has 
been discontinued and the subject is asymptomatic.  The investigator should obtain a detailed 
history of symptoms, prior or concurrent diseases, concomitant drug use, alcohol use, 
recreational drug use, special diets, and exposure to environmental chemical agents.  Evaluation 
should be performed to rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or 
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disease. Obtain additional tests to evaluate liver function as appropriate (eg, INR, direct 
bilirubin).  Consider gastroenterology or hepatology consults.  If a source of the abnormal value 
is not readily identified the subject should continue to be evaluated for the source and managed 
as medically indicated.  Study drug may be re-started if study drug has been interrupted for no 
more than 3 days and the source of the abnormal value(s) is determined, or if upon repeating the 
clinical lab the value returns to normal, and in the clinical judgement of the investigator and 
study medical monitor it is safe for the subject to continue study drug.  If study drug cannot be 
ruled out as the cause of the abnormal value then study drug should be permanently 
discontinued.  Additionally, if study drug is interrupted for more than 3 days, then study drug 
should be permanently discontinued.  
6.6 
Pharmacokinetic Assessments 
6.6.1 
Biological Samples 
Blood samples for plasma PK analysis will be collected as outlined in the schedule of events and 
as specified below.  Because PK results would unblind investigators, this data will not be 
reported to sites or to Lycera during the double-blind portion of the trial (except as noted in 
Section 6.6.1.1).   
6.6.1.1 
Safety Pharmacokinetic Exposure Monitoring Sub-study Sample Collection 
Up to 20 consenting subjects will have blood samples collected for determination of plasma 
concentrations of LYC-30937.  These samples will be collected at the following visits and time 
points:   
 Visit 3* (Week 1):  fasting pre-dose and 4-6 hours post-dose  
 Visit 4 (Week 2):  4-6 hours post-dose 
 Visit 5 (Week 4):  4-6 hours post-dose 
 Visit 6* (Week 8):  fasting pre-dose and 4-6 hours post-dose 
* Note that in preparation for Visit 3 and Visit 6, subjects will be asked to come to these study 
clinic visits after having fasted overnight and they will be instructed not to take their study 
drug that morning.  Study drug will be administered in the clinic after having the pre-dose 


 
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blood sample collected.  They will wait approximately 1 hour after administration of their 
study drug before they eat.   
PK samples from these subjects will be collected, sent to the central clinical laboratory for 
evaluation and will be available for Data Safety Monitoring Board (DSMB) review.  
6.6.1.2 
Serial Pharmacokinetic Sub-study Sample Collection 
Up to 12 consenting subjects will participate in a PK sub-study to assess LYC-30937 plasma PK 
parameters (and PK parameters of its metabolite).  These subjects will have 5 serial blood 
samples collected at Visit 5 (Week 4).  Blood samples will be collected at:   
 Visit 5 (Week 4):  pre-dose (fasted) and post-dose at 4, 6, 10, and 24 hours (window 
± 30 minutes at each time point).   
These subjects will take their study drug dose on the day of Visit 5 at the clinic and not at home.  
They will come to the clinic for Visit 5 assessments after having fasted overnight and will have 
their pre-dose blood sample collected before taking their daily dose of study drug.  They will 
then take their study drug dose and have the other study visit procedures performed.  Note: they 
should not eat for approximately 1 hour after taking their study drug dose.  Additional blood 
samples will be collected at 4, 6, and 10 hours post-dose.  They will return to the clinic the 
following day to have a 24-hour blood post-dose sample collected after fasting overnight and 
prior to taking their daily dose of study drug.  After the 24-hour blood sample is collected, they 
will take their study drug dose and they will be able to eat after waiting approximately 1 hour 
after taking study drug.  These serial PK blood samples may be collected ± 30 minutes from the 
specified collection times.   
6.6.1.3 
Plasma Pharmacokinetic Sample Collection 
All subject who are not participating in either the safety PK exposure monitoring sub-study 
(Section 6.6.1.1) or the serial PK sub-study (Section 6.6.1.2) will have a single blood draw at 
Visit 5 (Week 4).  This sample will be assessed for plasma concentration of LYC-30937 and its 
metabolite.   
6.6.1.4 
Exploratory Colon Tissue Concentration 
In addition, colon tissue biopsies will be collected to determine the tissue concentration of 
LYC-30937 and its metabolite and for exploratory PD assessments (see Section 6.7).  These 


 
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tissue biopsies will be collected at screening and at Visit 6 (Week 8) from all subjects as part of 
the endoscopy procedures performed at these visits.  At screening tissue biopsies will be 
collected from segments in which disease is present, with 3 biopsies collected from each of these 
segments.  These will be mucosal biopsies collected from the most inflamed areas of 
inflammation (avoid ulcerated mucosa).  At Visit 6, 3 mucosal biopsies will be collected from 
the same segments that were biopsied at screening.   
At selected sites, an additional 3 mucosal biopsies will be collected at Visit 6 from the ileocecal 
junction to assess LYC-30937 tissue concentrations.   
The details on the plasma and colon tissue PK sampling and processing procedures will be 
described in a separate laboratory manual.   
6.6.2 
Pharmacokinetic Parameters 
The PK parameters to be calculated from the plasma and colon tissue concentration data for 
LYC-30937 and its metabolite are outlined in Appendix A.  The study drug concentration 
measurements in plasma and colon tissue will be performed by a validated method.   
6.7 
Exploratory Pharmacodynamic Assessments 
6.7.1 
Biological Samples for Pharmacodynamic Evaluations 
Where feasible and acceptable and in subjects who consent, exploratory PD analysis will be 
performed on biologic samples collected in the study.  This aspect of the trial is optional and 
subjects may participate in this trial even if they don’t consent to have their biologic tissue used 
for the PD evaluation.  Evaluation of these exploratory PD biomarkers will aid in understanding 
the effects of LYC-30937 in subjects with active UC.  Because these are exploratory, the 
samples may be evaluated in batches by the central lab or by Lycera and the results will not be 
reported to the study sites during the study.   
Biologic samples, including blood, stool, and colon biopsy tissue, will be collected at the time 
points indicated in the schedule of events (Table 3).  Refer to Appendix C for biomarker analyses 
that may be performed.  
Collection of approximately 12 mL of blood for exploratory PD assessments will be collected 
from consenting subjects as noted in the schedule of events (Table 3) at screening and at Visits 2, 
4, and 6.   


 
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Colon tissue biopsies will be collected (required for study participation) as noted in the schedule 
of events (Table 3).  Colon biopsy tissue will used to assess for LYC-30937 PK concentrations.  
If biopsy tissue is available after assessment of drug levels, this tissue may be used for assessing 
exploratory PD biomarkers.   
Stool samples will be collected (required for study participation) as noted in the schedule of 
events (Table 3).  Stool will be used to assess for fecal calprotectin, an intestinal inflammatory 
marker.  Additionally, stool collected at screening will be used to assess for enteric pathogens 
(for eligibility).  Stool remaining after these required evaluations may be used for PD 
assessments.   
6.7.2 
PD Parameters 
Refer to Appendix C for exploratory PD biomarker parameter analyses that may be performed.   
Serum from blood will be used to assess for inflammatory proteins; cells will be analyzed by 
flow cytometry for enumeration of lymphocyte subtypes and expression of proteins associated 
with gut homing and lymphocyte activation; expression of small nucleotide polymorphism 
associated with UC will be assessed.   
Stool samples will be processed to determine the presence of inflammatory cytokines, and 
transcriptional profiling for immune cell signatures and taxonomic composition of subject 
microbiomes.   
Colon biopsy tissue available after measurement of LYC-30937 tissue concentrations will be 
processed to assess for inflammatory proteins, transcriptional profiling, and assessment of 
lymphocyte infiltration and metabolic remodeling.   


 
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7.0 
ADVERSE EVENTS AND SAFETY MONITORING 
7.1 
Adverse Event Definition 
Defined by 21 Code of Federal Regulation (CFR) 312.32(a) and consistent with International 
Council for Harmonisation (ICH) E2A guidance, an AE means untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related.  An AE can 
be any unfavorable or unintended sign (eg, an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, without any judgment about causality.  Examples of 
AEs include but are not limited to:   
 abnormal test findings 
 clinically significant symptoms and signs 
 changes in physical examination findings 
 hypersensitivity 
 progression/worsening of underlying disease 
Events related to the underlying disease(s), which have not worsened in intensity (severity) or 
frequency since screening, are not AEs.   
7.2 
Serious Adverse Events Definition 
Defined by 21CFR 312.32(a) and consistent with ICH E2A guidance, an AE is considered 
“serious” if, in the view of either the investigator or Sponsor, it results in any of the following 
outcomes:   
 death 
 life threatening (ie, in the view of either the investigator or sponsor, its occurrence places the 
subject at immediate risk of death.  It does NOT include an event, that had it occurred in a 
more severe form, might have caused death.) 
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 persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
 congenital anomaly/birth defect 
 other medically significant events that, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above (eg, an allergic bronchospasm requiring intensive treatment in an 
emergency room or home, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency) 
7.3 
Adverse Event Reporting 
Adverse events, both serious and nonserious, should be collected on source documents from the 
time the subject has signed informed consent through last subject visit.  The investigator is to 
collect all directly observed AEs and all AEs spontaneously reported by the study subject.  In 
addition, each study subject will be questioned about AEs.  For all randomized subjects, AEs 
should be recorded on case report forms (CRFs) from the time the subject has signed informed 
consent.  For subjects not randomized, only SAEs and AEs leading to screen failure will be 
collected on the CRFs from the time the subject has signed informed consent.   
Each AE is to be assessed to determine if it meets the criteria for SAE, see Section 7.2 above.  If 
an SAE occurs, expedited reporting will follow local and international regulations, as 
appropriate.   
AEs should be reported using concise medical terminology on the CRFs.   
Diagnostic and therapeutic noninvasive procedures should not be reported as AEs.  However, the 
medical condition for which the procedure was performed should be reported if it meets the 
definition of an AE and procedure would be the treatment and recorded as “action taken” of the 
AE.   
For all AEs, the investigator must pursue and obtain information adequate both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Lycera or its designated representative.  For all AEs, 
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All AEs that occur from the time of informed consent, regardless of whether the particular event 
is expected and regardless of relatedness, will be recorded as an AE.   
7.4 
Assessment of Severity of Adverse Events 
The investigator or blinded physician will assess subjects at each visit for the occurrence of AEs.  
In order to avoid bias in eliciting AEs, subjects should be asked the following nonleading 
questions:  “How are you feeling?”  All AEs (serious and nonserious) reported by the subject 
must be recorded on the CRFs regardless whether a causal relationship to the study drug is 
suspected. 
Severity of AEs will be graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) v4.03. 
Adverse events that are not included in the NCI CTCAE lists will be graded according to the 
NCI CTCAE general guideline for grades as follows: 
Grade 1 
Mild, asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate, minimal, local intervention, or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL), eg, 
preparing meals, shopping for groceries or clothes, using the telephone, managing 
money. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL, eg, bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily a serious event.  For example, a headache may be severe (interferes significantly with 
subject’s usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed in Section 7.2.   


 
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7.5 
Serious Adverse Event Reporting 
All observed or volunteered SAEs regardless of treatment group or suspected causal relationship 
to the study drug will be reported as described below.   
If an SAE occurs, ICON Pharmacovigilance and Safety Services (PVSS) is to be notified within 
24 hours of awareness of the event by the investigator or subinvestigator.  The initial SAE report 
form should be completed and faxed to ICON PVSS using one of the following: 
North America: 
Email: icon-mads@iconplc.com 
Facsimile: +1-215-616-3096 
Telephone: +1-888-723-9952 
Europe: 
Email: icon-safety-centralreceipt@iconplc.com 
Facsimile: +44 (0)208 100 5005 
In particular, if the SAE is fatal or life threatening, notification must be made immediately, 
irrespective of the extent of available AE information.   
This timeframe also applies to additional new information (follow-up) on previously forwarded 
SAE reports as well as to the initial and follow-up reporting of exposure in utero (EIU) cases.  
The investigator should continue to report any significant follow-up information to ICON PVSS 
up to the point of resolution.   
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient trial subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and the document the time 
of his/her first awareness of the SAE.   
The study sponsor medical monitor will perform final medical review of SAEs.  Full details of 
the SAE processing and review procedures will be documented in a safety management plan and 
medical monitoring plan.  Serious adverse events, including any deemed as suspected 
unexpected serious adverse reactions (SUSAR) will be reported according to timeframes as per 
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(FDA) within 15 calendar days of ICON PVSS notification and within 7 calendar days if the 
SUSAR is considered life threatening or resulted in death.  Non-SUSAR SAEs will be reported 
to country regulatory authorities annually as per regulatory guidance.  
For all SAEs, the investigator is obligated to pursue and provide information to Lycera or 
designee in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Lycera to obtain specific additional follow-up information in 
an expedited fashion.  In general, the SAE form will include a description/narrative of the event 
in sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality.  Information on other possible causes of the event, such as 
concomitant medications and illnesses must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Lycera or its 
designated representative.  Expedited safety reports on all unexpected SAEs that are at least 
possibly related to study procedures will be provided to the FDA.   
Subjects with unresolved previously reported SAEs, or new SAEs identified on the last 
scheduled visit, should be followed by the investigator until the events are satisfactorily resolved.  
Resolution means the subject has returned to the baseline state of health, the investigator does 
not expect any further improvement or worsening of the AE, or upon agreement with Lycera or 
designee.   
7.6 
Post-Week 10 Reporting of Serious Adverse Events 
Any SAEs reported by the subject to the investigator that occur after the last visit  and are 
determined by the investigator to be associated with the use of LYC-30937-EC or with 
associated study procedures (biopsies), should be reported to Lycera or designee.   
7.7 
Exposure in Utero  
For investigational products within clinical trials, an EIU occurs if:   
 A female becomes, or is found to be, pregnant after receiving the study drug (eg, after Study 
Day 1).   
If any study subject becomes pregnant during their participation in the study, the subject will 
stop study drug and withdraw from the study.  The investigator must submit this information to 
Lycera or designee on EIU Form.  This must be done irrespective of whether an AE has occurred 


 
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and within 24 hours of awareness of the pregnancy.  The information submitted should include 
the anticipated date of delivery (see below for information related to an induced termination of 
pregnancy).   
Follow-up is conducted to obtain pregnancy outcome information on all EIU reports with an 
unknown outcome.  The investigator will follow the pregnancy until completion or until 
pregnancy termination (ie, induced abortion) and then notify Lycera or designee of the outcome.  
The investigator will provide this information as a follow up to the initial EIU Form.  The 
reasons(s) for an induced abortion should be specified.  An EIU report is not created when an 
ectopic pregnancy report is received since this pregnancy is not usually viable.   
If the pregnancy outcome meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including resulting in an 
aborted fetus, stillbirth or neonatal death]), the investigator should follow the procedures for 
reporting SAEs.   
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth (ie, 
no minimum follow-up period of a presumably normal infant is required before an EIU Form can 
be completed).  The “normality” of an aborted fetus can be assessed by gross visual inspection, 
unless pre-abortion test findings are suggestive of a congenital anomaly.   
Additional information about pregnancy outcomes that are classified as SAEs follows:   
 “Spontaneous abortion” includes miscarriage and missed abortion.   
 All neonatal deaths that occur within 1 month of birth should be reported, without regards to 
causality as SAEs.  In addition, any infant death after 1 month that the investigator assesses 
as possibly related to the in utero exposure to the investigational medication should be 
reported.   
7.8 
Relationship/Causality of Adverse Events/Serious Adverse Events 
The investigator’s assessment of causality must be provided for all AEs (serious and nonserious).  
The causality assessment is the determination of whether there exists a reasonable possibility that 
the study drug itself (eg, LYC-30937-EC or placebo) caused or contributed to an AE.   
If the final determination of causality is unknown and the investigator does not know whether the 
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reporting purposes.  If the investigator’s causality assessment is “unknown, but not related to 
study drug”, this should be clearly documented on study records.   
Relationship of an AE to the study drug will be assessed as follows: 
Unrelated [Not Related or Unlikely Related]:  There is not a temporal or causal relationship to 
the study drug.  If the AE is “unrelated” to the study drug, the investigator must assess whether 
the event is thought to be related to the disease under study, concomitant medication, 
exacerbation of pre-existing condition, other illness, or unknown.   
Related [Definite]:  There is reason to conclude that the study drug caused the AE.   
Suspected [Possible or Probable]:  There is evidence to suggest a causal relationship between 
the study drug and the AE.   
7.9 
Withdrawal Due to Adverse Events 
Withdrawal due to AEs must be recorded on the appropriate AE CRF page.   
When a subject withdraws due to an SAE, the SAE must be reported in accordance with the 
reporting requirements as defined.   
7.10 
Medical Monitoring 
Medical monitoring of the study will be performed by Lycera or designee in cooperation with the 
investigator(s) at the participating sites.  Review of laboratory data, AEs, vital signs, physical 
exam data, and ECG data will be at regular intervals throughout the study.  When additional 
information is required, Lycera or designee will contact the investigator or designee.   
The sponsor Medical Monitor for the trial is: 
H. Jeffrey Wilkins, MD 
Lycera Corp. 
Plymouth Meeting, Pennsylvania USA 
Office:  +1-484-243-6222 
Mobile:  +1-610-457-5095 
Facsimile:  +1-734-207-3178 


 
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7.11 
Data Safety Monitoring Board (DSMB) 
A DSMB, independent of the sponsor, will be established to review safety data as specified in 
the DSMB charter.  The DSMB will be comprised of a pharmacokineticist, a therapeutic expert 
and a statistician.  The DSMB’s initial planned review will take place when the first 30 subjects 
treated have completed at least 4 weeks of treatment.  Accumulated safety data (AEs, AEs of 
special interest, SAEs, withdrawals due to AEs, vital signs, body temperature AEs) and plasma 
PK data will be available for this initial review.  Frequency of DSMB meetings will be specified 
in the charter.  The DSMB may recommend changes to the trial due to safety concerns based on 
their review.  Any necessary blinding plan to assure the study data remains blinded to sponsor 
personnel and others involved in the trial, and additional relevant details of DSMB review 
activities will be provided in the DSMB charter.   
7.12 
Stopping Rules 
The sponsor has the right to terminate the study prematurely for safety or administrative reasons. 
In all cases, necessary measures will be taken to ensure appropriate safety follow-up of all 
subjects in the trial.   
Individual subjects may interrupt or stop study drug at the discretion of the investigator or 
medical monitor any time for safety reasons.  Individual subjects must discontinue if they 
experience a study drug-related Grade 3 (CTCAE version 4.0) AE of special interest – see 
Section 6.5.7 for list of AEs of special interest.   
ECGs are scheduled to be performed at baseline and end of study.  An additional ECG should be 
performed if a subject reports symptoms of recurrent palpitations, recurrent, persistent 
lightheadedness or faintness, or any symptom that the investigator deems for cause.  Subjects 
should report these symptoms to the investigator immediately and return to the clinic as soon as 
possible for evaluation including an ECG.  Subjects will discontinue study drug if marked 
QT/QTc prolongation of > 500 ms or > 60 ms over baseline is present (a repeat ECG should be 
performed within 24 hours to confirm the QT/QTc prolongation). 
7.12.1 
Suspension of Study 
The study will be suspended if any subject experiences a drug-related AE that meets Grade 4 
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Grade 3 AE of the same type.  Adverse event reports will be submitted to regulatory agencies 
and clearance received before any further dosing takes place.  
The study will be suspended if 50% of subjects experience clinically important drug-related AEs 
with a determined intensity of CTCAE Grade 2.  The clinical data must be unblinded and 
reviewed by the unblinded medical monitor for safety before proceeding with the study.    
8.0 
STATISTICAL AND ANALYTICAL PLAN 
8.1 
Sample Size Rationale 
A total of approximately 120 subjects will be randomized into the study and using a 
1:1 randomization ratio of LYC-30937-EC 25 mg or placebo.   
A sample size of 60 subjects per group will achieve approximately an 88% power to detect 
superiority in the remission rate of the active treatment group compared to the placebo treatment 
group.  The placebo treatment group remission rate is assumed to be 6.7%.  The power was 
computed for the case when the actual treatment group remission rate is 25% for a delta of 
18.33%.  The test statistic used is the one-sided Z test (pooled).  The alpha level of the test was 
targeted at 0.05.  Additionally, a sample size of 54 subjects per group excluding dropouts will 
achieve approximately a 78% power to detect non-inferiority in the remission rate of the active 
treatment group compared to the placebo treatment group where the placebo treatment group 
remission rate is assumed to be 7.41% and the actual treatment group remission rate is 25.92% 
for a delta of 18.51%.   
Assuming a dropout rate of 10%, the study will enroll 120 subjects in order to complete 108.   
8.2 
Analysis Populations 
8.2.1 
Full Analysis Set  
The FAS is defined as all randomized subjects.  Subjects will be included in the treatment group 
to which they were randomized, regardless of the treatment they actually received.  All efficacy 
analyses will be performed on the FAS.   


 
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8.2.2 
Safety Set 
The Safety Set is defined as all randomized subjects.  For summaries/listings where treatment 
group is included, subjects will be included in the treatment group to which they were actually 
treated.  All safety analyses will be performed on the Safety Set.   
8.2.3 
Other Population Sets 
Other population sets for the PK and PD analyses will be defined in the statistical analysis plan 
(SAP).   
8.3 
General Statistical Considerations 
Baseline will be defined as the last observation prior to dosing unless otherwise specified.   
Continuous endpoints will be summarized using at least mean, standard deviation, median, 
minimum, and maximum.  Categorical endpoints will be summarized by the number and percent 
of subjects in each category.  Additional details of the statistical analyses will be detailed in the 
SAP.   
8.4 
Demographic and Subject Characteristics 
Demographic information and subject characteristics such as gender, race, age, baseline weight, 
baseline Mayo score, and subjects with and without previous biologic therapy will be 
summarized by treatment group and overall.   
8.5 
Efficacy Analysis 
8.5.1 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint, ie, the proportion of subjects who achieve a clinical remission at 
Week 8 of treatment using the MMS, defined as a Mayo stool frequency subscore of ≤ 1, a Mayo 
rectal bleeding subscore of 0, and a Mayo endoscopy subscore of ≤ 1, will be reported for the 
LYC-30937-EC and placebo treatment arms.  Statistical comparisons between the 
LYC-30937-EC treatment arm and placebo will be done using a one-sided Pearson chi-square 
test.  The difference in proportion of subjects who achieve a clinical remission at Week 8 of 
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estimated.  Subjects who are missing the Week 8 Mayo score assessment will be assumed to 
have not achieved clinical remission.   
8.5.2 
Secondary Efficacy Endpoint Analyses 
The following secondary efficacy endpoints will be summarized and compared between the 
LYC-30937-EC treatment arm and placebo:   
 the proportion of subjects who achieve a clinical remission at Week 8 using the TMS, 
defined as a TMS score of ≤ 2, with no individual score > 1 and rectal bleeding score of 0 
 the proportion of subjects with a clinical response at Week 8, defined as a reduction from 
baseline MMS of ≥ 2 points and ≥ 25%, and a decrease from baseline in rectal bleeding 
subscore of ≥ 1 point or an absolute rectal bleeding subscore of ≤ 1 point 
 the proportion of subjects with a clinical response at Week 8, defined as a reduction from 
baseline in TMS of ≥ 3 points and ≥ 30%, and a decrease from baseline in the rectal bleeding 
subscore of ≥ 1 point or an absolute rectal bleeding subscore of ≤ 1 point 
 the change from baseline in TMS at Week 8 
 the change from baseline to Week 8 in fecal calprotectin 
8.5.3 
Exploratory Efficacy Endpoint Analyses 
The following exploratory efficacy endpoint will be summarized and compared between the 
LYC-30937-EC treatment arm and placebo:   
 the proportion of subjects with endoscopic improvement at Week 8, defined by a Mayo 
endoscopic subscore of ≤ 1 point 
 the proportion of subjects with clinical remission, response, and endoscopic improvement at 
Week 8 who had previously received biologic therapy; who were refractory to biologic 
therapy (during their initial course biologic treatment), or who lost response to biologic 
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8.6 
Safety Analysis 
AE collection begins after the subject signs the ICD and continues until Week 10 or ET.  For all 
randomized subjects, AEs should be recorded on CRFs from the time the subject has signed 
informed consent through Week 10.  For subjects not randomized, only SAEs and AEs leading to 
screen failure will be collected from the time the subject has signed informed consent through 
screen failure.  Treatment-emergent AEs (TEAEs) are defined as AEs that start after study drug 
administration (LYC-30937-EC or placebo).  AEs that occur in subjects who screen fail will only 
be listed if they were the reason the subject was a screen failure.   
AEs and SAEs will be summarized by system organ class, by severity, and by relationship; this 
will be done by treatment group and overall.  SAEs resulting in death will be listed and 
summarized separately.  TEAEs and treatment-emergent SAEs will also be summarized by 
system organ class, by severity, and by relationship; this will be done by treatment group and 
overall.   
Other safety data, such as physical examinations, vital signs, ECGs, clinical laboratory data, and 
body temperature will be summarized by study visit and treatment group.  Where appropriate, 
change from baseline in safety data will also be summarized by study visit and treatment group.   
8.7 
Pharmacokinetic and Pharmacodynamic Analyses 
Pharmacokinetic concentrations in plasma and colon tissue for LYC-30937 and its metabolite 
will be listed and summarized by time point for the active treatment group.  Pharmacokinetic 
parameters calculated from the plasma concentrations for LYC-30937 and its metabolite outlined 
in Appendix A will be listed and summarized for the active treatment group.  The handling of 
concentrations that are missing or below the limit of quantitation (BLQ) will be described in the 
SAP.  
Pharmacodynamic markers will be listed and summarized by treatment group using descriptive 
statistics. 
9.0 
ETHICAL CONSIDERATIONS 
9.1 
Basic Principles 
The study will be performed in accordance with the protocol, ICH good clinical practice (GCP) 
guidelines, and applicable local regulatory requirements and laws.   


 
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9.2 
Institutional Review Board/Independent Ethics Committee  
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, eg, 
advertisements, if applicable from the IRB or IEC.  All correspondence with the IRB/IEC should 
be retained in the Investigator File.  Copies of IRB/IEC approvals should be forwarded to Lycera 
or designee.   
9.3 
Informed Consent 
Written informed consent is to be obtained prior to the subject entering the study (before 
initiation of protocol-specified procedures).  The investigators, or other study personnel, explain 
the nature, purpose, and risks of the study to each subject.  Each subject is to be informed that 
he/she could withdraw from the study at any time and for any reason.  Each subject is to be given 
sufficient time to consider the implications of the study before deciding whether to participate.  
Subjects who chose to participate will sign an ICD.   
9.4 
Study Termination 
Premature termination of this study or part of the study may occur because of a regulatory 
authority decision, change in opinion of the IRB/IEC, safety problems, or at the discretion of 
Lycera.  In addition, Lycera retains the right to discontinue development of LYC-30937-EC at 
any time.   
If a study is prematurely terminated or discontinued, Lycera will promptly notify the 
investigator.  After notification, the investigator must notify all subjects currently participating in 
the study within a specific timeframe designated by Lycera.  As directed by Lycera, study 
materials will be collected and all CRFs completed to the greatest extent possible. 
10.0 
DATA HANDLING AND RECORD KEEPING 
10.1 
Study Monitoring 
The investigator will allow representatives of Lycera (or their designee) to periodically monitor 
all CRFs, source documents, informed consent documents, and clinical laboratory records for 
each subject.  The purpose of the monitoring visits will be to: 
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 verify the accuracy and completeness of the CRFs 
 verify the signed informed consent document, the Regulatory binder, and study drug  storage 
and records 
 resolve any inconsistencies in the study records 
 ensure that all protocol requirements are being fulfilled  
 ensure GCPs are being followed 
The study site may be subject to review by the IRB/IEC, and/or to quality assurance audits 
performed by Lycera (or designee), and/or to inspection by appropriate Regulatory Authorities.   
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.   
10.2 
Study Documentation 
Electronic CRFs are required and should be completed for all subjects signing informed consent.  
Subjects who screen fail will have demographic and disposition CRF with the reason for screen 
fail (if they screen fail due to an adverse event, the AE CRF will also be collected).  For this trial, 
the CRFs are an electronic data record.  The completed original CRFs are the sole property of 
Lycera and should not be made available in any form to third parties, except for authorized 
representatives of Lycera or appropriate regulatory authorities, without written permission from 
Lycera.   
It is ultimately the investigator’s responsibility to ensure completion and to review and approve 
all CRFs. Individual CRFs may be signed by the investigator or by an authorized staff member 
(and may be an electronic signature).  A final CRF must be signed by the investigator to attest 
that the information contained on the CRF is true.  At all times, the investigator has final 
personal responsibility for the accuracy and authenticity of all clinical and laboratory data 
entered on the CRFs. Subject source documents are the investigator’s subject records maintained 
at the study site.  In most cases, the source documents will be the hospital’s or the investigator’s 
chart.  In cases where the source documents are the hospital or the investigator’s chart, the 
information collected on the CRFs must match those charts.   


 
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The CRF for questionnaires may serve as the source document.   
10.3 
Record Retention  
Food and Drug Administration/ICH regulations require all investigators participating in clinical 
drug studies to maintain detailed clinical data for one of the following periods:   
FDA/ICH 
 A period of at least 2 years following the date on which a marketing application (eg, 
biological license application) is approved by the FDA 
 A period of 2 years after Lycera notifies the investigator that no further application is to be 
filed with the FDA. 
ICH 
 Subject identification codes must be retained for at least 15 years following the completion or 
discontinuation of the study. 
To enable evaluations and/or audits from regulatory authorities or Lycera, the investigator agrees 
to keep records, including the identity of all participating subjects (sufficient information to link 
records, eg, CRFs and hospital records), all original signed informed consent forms, copies of all 
CRFs, SAE forms, source documents, and detailed records of treatment disposition (at the end of 
the study).  The records should be retained by the investigator according to ICH, local 
regulations, or as specified in the Clinical Study Agreement, whichever is longer.   
If the investigator relocates, retires, or for any reason withdraws from the study, Lycera should 
be prospectively notified.  The study records must be transferred to an acceptable designee, such 
as another investigator, another institution, or to Lycera.  The investigator must obtain Lycera’s 
written permission before disposing of any records, even if retention requirements have been 
met.   


 
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11.0 
CONFIDENTIALITY AND PUBLICATION PLAN 
11.1 
Confidentiality 
Subject’s medical information obtained as a result of this study is considered confidential, and 
disclosure to third parties other than those noted below is prohibited.  All reports and 
communications relating to subjects in this study will identify subjects only by subject number.  
Medical information resulting from a subject’s participation in this study may be given to the 
subject’s personal physician or to the appropriate medical personnel responsible for the subject’s 
welfare.  Data generated in this study are to be available for inspection on request by the FDA or 
other government regulatory agency inspectors, and the IRB/IEC but should otherwise remain 
confidential.   
11.2 
Publication of Data and Protection of Intellectual Property 
Any information about the study drug and company operations at Lycera is confidential, and 
shall remain the sole property of Lycera.  The investigator agrees to use this information only in 
conducting this study, and to not use it for other purposed without prior written consent from 
Lycera.   
The information developed in this clinical study will be used by Lycera in the clinical 
development of its compound and therefore, may be disclosed by Lycera, as required, to other 
clinical investigators, pharmaceutical companies, the FDA, and other government agencies.   


 
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12.0 
REFERENCES 
1. 
Peyrin-Biroulet L, Lemann M. Review article: remission rates achievable by current 
therapies for inflammatory bowel disease. Aliment Pharmacol Ther. 2011;33:870-9. 
2. 
Feagen BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. 
Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl 
J Med. 2013;369(8):699-710. 
3. 
Viget N, Vernier-Massouille G, Salmon-Ceron D, Yazdanpanah Y, Colombel JF. 
Opportunistic infections in patients with inflammatory bowel disease: prevention and 
diagnosis. Gut. 2008;57(4):549-58. 
4. 
Rungoe C, Langholz E, Andersson M, Basit S, Nielsen NM, Wohlfahrt J, et al. 
Changes in medical treatment and surgery rates in inflammatory bowel disease: a 
nationwide cohort study. Gut. 2014;63(10):1607-16. 
5. 
Fox CJ, Hammerman PS, Thompson CB. Fuel feeds function: energy metabolism and 
the T-cell response. Nat Rev Immunol. 2005;5:844-52. 
6. 
Frauwirth KA, Thompson CB. Regulation of T lymphocyte metabolism. 
J Immunology. 2004;172:4661-5. 
7. 
Nelson D, Cox M, Lehninger principles of biochemistry, 6th ed. New York: 
W. H. Freeman and Company; 2012. 
8. 
Berg J, Tymoczko J, Stryker L. Biochemistry, 7th ed. New York: W. H. Freeman and 
Company; 2010. 
9. 
Bednarski J, Warner R, Rao T, Leonetti F, Yung R, Richardson BC, et al. Attenuation 
of autoimmune disease in Fas-deficient mice by treatment with cytotoxic 
benzodiazepine. Arthritis Rheum. 2003;48(3):757-66 
10. 
Gatza E, Wahl D, Opipari A, Sundberg T, Reddy P, Lui C, et al. Manipulating the 
bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-
versus-host disease. Sci Transl Med. 2011;3(67);67ra8. 


 
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11. 
Bhagavathula N, Nerusu K, Hanosh A, Aslam M, Opipari A, Johnson K, et al. 
Bz-423, a benzodiazepine, suppresses keratinocyte proliferation and has anti-psoriatic 
activity in human skin-SCID mouse transplant model. J Pharmacol Exp Ther. 
2008;324:938-47. 
12. 
Franchi L, Monteleone I, Morgan R, Opipari A, Carter L, Click G, et al. Modulation 
of the F1F0-ATPase induces apoptosis of mouse and human lamina propria T-cells 
and is efficacious in models of IBD [Abstract 593]. Gastroenterology. 2014;146(5) 
Suppl 1:s112. 
 


 
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13.0 
APPENDICES 
13.1 
Appendix A:  Pharmacokinetic Measurements  
Pharmacokinetic (PK) parameters that may be calculated from the plasma concentration data and 
colon tissue for LYC-30937-EC and its metabolite (LYC-53552) are outlined below:  
Cmax 
Maximum observed plasma concentration 
Tmax 
Time at which maximum observed plasma concentration Cmax 
AUC0-t 
AUC up to time t using linear-log trapezoidal rule, where t is the last time point 
with concentrations above the lower limit of quantitation (LLOQ) 


 
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13.2 
Appendix B:  Total of Blood Volume 
The table below displays the approximate number and approximate volume of blood that will be 
collected per subject throughout the study.  
Total Blood Volume by Assessment 
Assessment 
Maximum # 
Samples 
mL of Blood 
per Sample 
Total Volume 
of Blood (mL) 
Lab to Analyze 
Safety, PK, and PD 
 
 
 
 
Hematology 
6 
3 
18 
Central Lab 
Chemistry 
6 
4 
24 
Central Lab 
Coagulation 
2 
3 
6 
Central Lab 
Serology 
1 
5 
5 
Central Lab 
 
 
 
 
 
PK of -30937 and Metabolite -53552 
(subjects not participating in Safety 
PK or Serial PK substudies)  
1 
6 
6 
Central Lab 
Optional Exploratory PD 
4 
12 
48 
Central Lab/Lycera/ 
Specialty Lab 
TOTAL 
 
 
107 
 
 
 
 
 
 
Additional samples collected from a 
subset of subjects: 
 
 
 
 
Safety PK exposure monitoring sub-
study (up to  20  subjects treated) 
6 
6 
36 
Central Lab 
Serial PK sub-study (up to 
12 subjects) 
5 
6 
30 
Central Lab 
PD = pharmacodynamic; PK = pharmacokinetic. 


 
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13.3 
Appendix C:  Exploratory PD Biomarkers 
The table below lists PD biomarkers by biologic sample type that may be selected for 
investigation from the biologic samples collected in this trial.  The ultimate selection of 
biomarkers for evaluation may involve a review of feasibility and also may be based on relevant 
information regarding these biomarkers that emerge during the course of this study. 
Sample Type 
Sample 
Biomarker Analysis 
Blood 
Whole blood or PBMC 
Leukocyte characterization by flow cytometry: including but 
not limited to α4β7, Treg, PD-1, Annexin V, CD62L, 
glucose/fatty acid uptake 
Plasma  
Cytokine profile by immunocapture assays: including but not 
limited to IL8, IL10, IFN γ, IL17, IL6, IL1β 
Stool 
Soluble fraction 
Cytokine profile by immunocapture assays: including but not 
limited to IL8, IL10, IFN γ, IL17, IL6, IL1β 
RNA  
gene chip or nanostring analysis  
DNA 
sequencing for microbiome characterization  
Biopsy 
Lysate from whole biopsy 
Cytokine profile by immunocapture assays: including but not 
limited to IL8, IL10, IFN γ, IL17, IL6, IL1β 
RNA  
gene chip analysis  
Formalin fixed 
H&E and Immunohistochemistry: including but not limited 
to CD3, PD-1, CD62L,  Annexin V 
CD3 = cluster of differentiation 3 protein complex; CD62L = L-selectin; IL = interleukin; IFN gamma = interferon 
gamma; PBMC = peripheral blood mononuclear cells; PD-1 = programmed cell death protein 1; Treg = regulatory 
T cells. 
 


 
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13.4 
Appendix D:  Biologic Medication Restriction  
Biologic medications to treat UC are not to be used during this study.  They should not be used 
within 5 elimination half-lives or within 12 weeks prior to the initiation of screening procedures, 
whichever time period is shorter.  Biologic medications and the time period prior to screening for 
which they should be stopped are listed below.  This list is not exhaustive.  If you have questions 
regarding these or biologic medications not listed below, please contact the Medical Monitor. 
Infliximab (Remicade) 
≥ 6 weeks (based on 5 half-lives) 
Adalimumab (Humira) 
≥ 12 weeks 
Golimumab (Simponi) 
≥ 11 weeks (based on 5 half-lives) 
Certolizumab (Cimzia) 
≥ 11 weeks (based on 5 half-lives)  
Vedolizumab (Entyvio) 
≥ 12 weeks 
Natalizumab (Tysabri, Antegren) 
≥ 12 weeks 
Ustekinumab (Stelara) 
≥ 12 weeks 
Rituximab (Rituxan) 
≥ 12 weeks 
 
 


 
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14.0 
DOCUMENT HISTORY 
 
Summary of Changes 
Document 
Version Date 
Description of Change 
Rationale 
Original Protocol 
01 March 2016 
N/A 
N/A 
Amendment 1 
09 May 2016 
 
Revised Section 6.5.7:  Monitoring Subjects 
for AEs of Special Interest; 
 
Revised Section 7.12:  Stopping Rules and 
added Section 7.12.1:  Suspension of Study; 
 
Reduce LFT exclusion to 1.5 x ULN;  
 
New Lycera facsimile number added to cover 
page; 
 
Minor revisions/clarifications throughout 
 
FDA request that safety monitoring and 
stopping rules for hepatotoxicity be consistent 
with recommendations as described in FDA’s 
industry guidance on drug-induced liver 
injury.  
 
FDA request to reduce LFT exclusion criteria 
level. 
 
New facsimile number received. 
 
Minor revisions and clarifications determined 
as useful to include since protocol was to be 
amended for other reasons.  
Amendment 2 
22 June 2016 
 
Exploratory efficacy endpoint referencing 
“mucosal healing” changed throughout to 
“endoscopic improvement” since histologic 
evaluation of mucosa to validate healing will 
not be performed in this trial.;  
 
Revised per FDA guidance regarding labeling 
requirement for “mucosal healing.”   
 
 
 
Secondary efficacy endpoint Week 8 TMS 
clinical remission definition revised 
throughout to include rectal bleeding score 
of 0; 
 
Occurrences in the protocol of this endpoint 
definition were not consistent.  Therefore 
revised to ensure consistency. 
 
 
 
Section 4.4.1:  Inclusion criteria 4 revised to 
require that women of childbearing potential 
use 2 highly effective forms of birth control; 
 
Inclusion criteria 4 revised to align with FDA 
guidance related to including women of 
childbearing potential in trials prior to 
completion of reproductive toxicity studies. 


 
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Summary of Changes 
Document 
Version Date 
Description of Change 
Rationale 
 
 
 
Section 4.4.2:  Exclusion criteria 6 revised to 
add elevated serum creatinine as an exclusion 
to exclude patients with renal impairment; 
 
Revised based on FDA request. FDA felt 
current data provided at this time did not 
adequately support including subjects with 
impaired renal function. 
 
 
 
Section 6.4.1 revised to add definition of left-
sided disease to clarify which subjects can 
have a flexible sigmoidoscopy at week 8 
based on demarcation of inflammation 
observed in screening colonoscopy; 
 
Revised to clarify/define subjects who may 
have Week 8 sigmoidoscopy instead of a full 
colonoscopy based on demarcation of disease 
at screening. 
 
 
 
Section 6.4.1 revised to clarify that endoscopy 
video recording will be provided for central 
reading and clarified that central readers will 
have study specific training, which will 
include that Mayo endoscopic score of 0 or 1 
cannot include any degree of “friability” as 
this is not consistent with remission; 
 
Clarification to align with FDA guidance that 
endoscopic finding of friability is not 
consistent with Mayo endoscopy subscores of 
“0” or “1.” Also revised to clarify that central 
readers will receive study-specific training and 
will use endoscopy videos for their review and 
assessment of endoscopy subscores. 
 
 
 
Section 6.4.1 revised to clarify that stool 
frequency and rectal bleeding data for Mayo 
scoring will be obtained from the diary 
completed by the subjects. Also clarified that  
the average stool frequency and average rectal 
bleeding score will be calculated from the 
individual 3 consecutive days will be used for 
the Mayo score; 
 
Revised to specify that the Mayo score will be 
calculated using the stool frequency and rectal 
bleeding subscores obtained from patients 
through their daily diary entries. 
 
 
 
Section 6.5.7 revised to state that study drug 
will be withheld in subjects who exhibit any 
of the listed lab elevations in liver biochemical 
parameters and lactate; 
 
Revised per FDA request. 


 
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Summary of Changes 
Document 
Version Date 
Description of Change 
Rationale 
 
 
 
Section 7.5 revised to add SAE reporting 
information including time frame for reporting 
SAEs to US FDA; 
 
Revised to provide detail of the SAE reporting 
process. 
 
 
 
Section 6.6.1.2 revised to clarify serial PK 
sub-study blood sample collection; 
 
Minor revisions to provide clarity. 
 
 
 
Section 7.10 revised to add sponsor medical 
monitor name and contact information; 
 
Medical Monitor contact information added 
for completeness. 
 
 
 
Section 7.12 revised to add individual subject 
stopping criteria based on abnormal ECG 
findings of prolonged QT/QTc interval; 
 
Revised per FDA request. 
 
 
 
Section 11.1 revised to remove statement that 
subjects will be identified by their initials. 
Subject initials are not being collected. 
 
Revised due to error in protocol. 


 
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Summary of Changes 
Document 
Version Date 
Description of Change 
Rationale 
Amendment 3 
07 December 2016 
 
Throughout protocol: revised all references to 
“anti-TNF” therapy to state “biologic” 
therapy; 
 
Section 1.0 revised to add countries 
participating in trial and the estimated last 
subject last visit;  
 
Throughout protocol: revised to clarify that 
both anti-integrin and anti-TNF agents are 
included in the “biologic” definition; 
 
Section 1.0 revised for clarity;  
 
 
 
Sections 1.0 - 2.5 updated and reorganized; 
 
Sections 1.0 - 2.5 updated based on recently 
finalized toxicology and phase 1 data; also  
reorganized for clarity and conciseness; 
 
 
 
Section 4.1 revised language related to open-
label extension protocol; 
 
Section 4.1 Updated based on revised duration 
of open-label extension of up to 44 weeks; 
 
 
 
Section 4.4.1 Inclusion criteria #2 revised to 
add clarity to histological evaluation if done at 
screening; 
 
Section 4.4.1 IC #2 revised to add clarity 
based on site feedback; 
 
 
 
Section 4.4.1 Inclusion criteria #4 revised to 
add clarity to effective birth control; 
 
Section 4.4.1 IC #4 revised to add clarity 
based on site feedback; 
 
 
 
Section 4.4.1 Inclusion criteria #5 revised to 
add clarity; 
 
Section 4.4.1 Inclusion criteria #6 revised to 
add clarity; 
 
Section 4.4.2 Exclusion criteria #3 revised for 
clarity regarding bleeding disorders; 
 
Section 4.4.2 Exclusion criteria #10 revised to 
define history of uveitis; 
 
Section 4.4.2 Exclusion criteria #12 revised to 
define type of colon polyp being referenced; 
 
Section 4.4.2 Exclusion criteria #19 revised to 
 
Section 4.4.1 IC #5 revised to add clarity 
based on site feedback; 
 
Section 4.4.1 IC #6 revised to add clarity 
based on site feedback; 
 
Section 4.4.2 EC #3 revised to add clarity 
based on site feedback; 
 
Section 4.4.2 EC #10 revised to provide 
clarity based on site feedback; 
 
Section 4.4.2 EC #12 revised provide clarity 
based on site feedback; 
 
Section 4.4.2 EC #19 revised due to error; 


 
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Summary of Changes 
Document 
Version Date 
Description of Change 
Rationale 
remove reference to use of “topical” 5-ASA 
and steroids; 
 
Section 5.5.2-5.5.3 revised to add clarity 
related to IWRS and compliance; 
 
Section 5.6 revised to be consistent with other 
sections of protocol and to specify that 
corticosteroid taper is not allowed during trial; 
 
Section 6.2.1 revised wording related to 
timing for screening procedures when a 
subject is already scheduled for a 
colonoscopy; 
 
Section 6.5.4 revised to clarify calculation of 
QTcF will not be done by sites; 
 
Section 6.5.7 revised to specify that baseline 
abdominal pain and vomiting should be 
carefully assessed; 
 
Section 7.4 revised to include the CTCAE 
criteria for assessment of AE severity; 
 
Section 7.12.1 study suspension criteria 
revised to state that if 50% of subjects 
experience clinically important drug-related 
AEs (instead of TESAEs) with severity of 
CTCAE grade 2; 
 
Appendix B revised: hepatitis blood sample 
removed. 
 
 
 
Section 5.5.2-5.5.3 revised to add clarity; 
 
 
Section 5.6 revised for consistency and to add 
clarity based on site feedback; 
 
 
Section 6.2.1 revised to provide flexibility to 
screening visit based on site feedback; 
 
 
 
Section 6.5.4 revised to clarify based on site 
feedback; 
 
Section 6.5.7 revised based on site feedback 
and based on patient population under study; 
 
 
Section 7.4 revised per FDA request to assess 
AE severity using CTCAE criteria; 
 
Section 7.12.1 revised because previous 
language (referencing TESAEs) was in error; 
 
 
Appendix B revised to remove hepatitis blood 
sample because this sample is included in the 
“serology” blood sample. 


 
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Summary of Changes 
Document 
Version Date 
Description of Change 
Rationale 
Amendment 4 
05 June 2017 
 
Section 4.4.1 Inclusion criteria #5 revised to 
allow inclusion of subjects on concomitant 
thiopurine UC treatment and to allow subjects 
on no UC treatment. 
 
Section 4.4.1 IC #5:  
In recruiting the trial, it has been learned that 
some patients are either intolerant of or 
frustrated with current first line UC therapies.  
Thus, this change allows for the fact that 
patients may be on a baseline first line 
therapy; but does not require it.  Therefore, 
those patients who were intolerant of or 
resistant to 5-ASA or steroid products and 
those with poorly controlled UC will be 
eligible for the trial. Safety data from the 
Phase 2 study, completed Phase 1 studies and 
preclinical data support the use of LYC-
30937-EC without concomitant UC treatment.  
It was also learned that many patients are 
symptomatic despite being on azathioprine or 
6-mercaptopurine. Safety data from this Phase 
2 study, previously completed Phase 1 studies 
and preclinical data demonstrates no evidence 
of immune suppression with the study drug. 
Additionally, the completed in vitro 
interaction studies (cyps, transporters) 
demonstrate that there is little chance for 
interaction with 5-ASA products, 
corticosteroids and azathioprine or 
mercaptopurine based upon the very low 
systemic exposures achieved (Cmax of 
approximately 0.004 µM following a single 25 
mg dose). 


 
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Summary of Changes 
Document 
Version Date 
Description of Change 
Rationale 
 
 
 
Section 4.4.1 Inclusion criteria #6 revised to 
include thiopurine. 
 
Section 4.4.1 IC #6 revised in conjunction 
with the revision of IC #5. 
 
 
 
Section 4.4.2 Exclusion criteria #7 revised to 
remove reference to thiopurines and to reduce 
the washout of other immunomodulatory 
medications to 4 weeks prior to the screening 
endoscopy. 
 
Section 4.4.2 EC #7 – This revision will allow 
sufficient time for washout of 
immunosuppressant medications without 
making it onerous for patients to be off UC 
treatments.  The new timing is supported by 
safety data from this Phase 2 study, completed 
Phase 1 studies and preclinical data which 
demonstrate no evidence of immune 
suppression with the study drug.  It also 
considers that the time from screening to 
randomization is ~2-4 weeks. 
 
 
 
Section 4.4.2 Exclusion criteria #10 removed 
(history of uveitis). 
 
Section 4.4.2 EC #10 – This criterion removed 
because comorbid uveitis is not a safety 
concern with respect to the study drug 
mechanism and therefore subjects with uveitis 
may be included in the trial. 
 
 
 
Section 4.4.2 Exclusion criteria #12 revised to 
allow subjects with a history of cancer that is 
in remission for  5 years and excludes  
subjects with cancer diagnosed within the past 
5 years unless approved by the study medical 
monitor. 
 
Section 4.4.2 EC #12 - Cancer in remission 
for 5 years or more has low probability of 
recurrence therefore these subjects may be 
considered for the trial.  Subjects with cancer 
diagnosed within the past 5 years are excluded 
unless approved by the study medical monitor 
based on the cancer, its treatment and clinical 
course. 


 
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Summary of Changes 
Document 
Version Date 
Description of Change 
Rationale 
 
 
 
Section 4.4.2 Exclusion criteria #17 biologic 
washout period determination revised and 
Appendix D added. 
 
Section 4.4.2 EC #17 – This criterion revised 
to use specific biologic elimination half-life to 
determine washout period for some biologics. 
 
 
 
Section 4.4.2 Exclusion criteria #19 revised to 
allow use of rectal 5-ASA medications. 
 
 
Section 4.4.2 EC #19 – This criterion revised 
because rectal 5-ASA pharmacokinetics and 
pharmacodynamics are similar to those of oral 
5-ASA medications. 
 
 
 
Section 5.6 revised to allow concomitant use 
of a stable dose of thiopurines. 
 
Section 6.2.6 revised to specify that the Visit 6 
date is the date of study completion. 
 
Section 5.6 revised in accordance with the 
Section 4.4.1 IC #5 revision. 
 
Section 6.2.6 revised to clarify the study 
completion date. 
 
 
 
Section 6.6.1.1, Table 3 footnote and 
Appendix B revised to specify that up to 
20 subjects will participate in the safety PK 
sub-study. 
 
Section 6.6.1.1 safety PK sub-study 
participation is optional for sites and subjects 
therefore allowance is made in case fewer than 
20 subjects consent to participate. 
 
 
 
Section 6.6.1.2, Table 3 footnote and 
Appendix B revised to specify that up to 
12 subjects will participate in the serial PK 
sub-study. 
 
Section 6.6.1.2 serial PK sub-study 
participation is optional for sites and subjects; 
therefore, allowance is made in case fewer 
than 12 subjects consent to participate. 
 
 
 
Section 7.12 revised to specify that a repeat 
ECG should be performed if QT/QTc 
prolongation stopping criteria are noted for 
confirmation. 
 
Section 7.12 revised to request a 2nd ECG to 
confirm QT/QTc prolongation and that this 
repeat ECG be performed within 24 hours. 
 

SAP_001.pdf: 
LYC-30937-2001 
 
Statistical Analysis Plan, V1.0 
 
 
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Confidential and Proprietary 
Page 1 of 27 
 
 
 
 
 
Statistical Analysis Plan (SAP) 
 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
PARALLEL GROUP STUDY TO ASSESS THE EFFICACY AND SAFETY 
OF INDUCTION THERAPY WITH LYC-30937-EC IN SUBJECTS WITH 
ACTIVE ULCERATIVE COLITIS 
 
 
Protocol LYC-30937-2001 
SAP Version 1.0 (Final) 
 
 
 
 
______________________________________________________________________ 
 
 
 
 
 
 
 
This document contains confidential and proprietary information, and is not to be distributed 
to any third party. 
 
 
 
 
 




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Statistical Analysis Plan, V1.0 
 
 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................5 
1 
INTRODUCTION ....................................................................................................................6 
2 
STUDY OVERVIEW ...............................................................................................................6 
2.1 
Study Population ..................................................................................................................6 
2.2 
Study Design ........................................................................................................................6 
2.3 
Assessments .........................................................................................................................7 
2.4 
Anticipated Number of Subjects ..........................................................................................7 
3 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................7 
3.1 
Objectives ............................................................................................................................7 
3.2 
Efficacy Measures ................................................................................................................8 
4 
ANALYSIS PLAN OVERVIEW ...........................................................................................10 
5 
ANALYSIS SETS ..................................................................................................................10 
5.1 
Full Analysis Set (FAS) .....................................................................................................10 
5.2 
Per Protocol Population (PP) .............................................................................................10 
5.3 
Safety Set ...........................................................................................................................11 
5.4 
PK and PD Set ...................................................................................................................11 
5.5 
Protocol Deviations and Treatment Misallocation ............................................................11 
6 
STATISTICAL ANALYSES .................................................................................................11 
6.1 
Statistical Power and Sample Size Considerations ............................................................11 
6.2 
Baseline, Endpoint and Missing Value Definitions ...........................................................12 
6.2.1 
Baseline Definition ......................................................................................................12 
6.2.2 
Subgroups ....................................................................................................................12 
6.2.3 
Visit Windows .............................................................................................................13 
6.2.4 
Replicate Data ..............................................................................................................14 
6.2.5 
Missing Data ................................................................................................................14 
6.2.6 
Change From Baseline .................................................................................................15 
6.3 
Statistical Analyses ............................................................................................................15 
6.3.1 
Subject Baseline Characteristics ..................................................................................15 
6.3.2 
Subject Disposition ......................................................................................................16 
6.3.3 
Interim Analysis ...........................................................................................................17 
6.3.4 
Treatment Compliance and Exposure ..........................................................................17 
6.3.5 
Efficacy Endpoint Analyses .........................................................................................18 
 
Primary Endpoint Efficacy Analysis .....................................................................18 
6.3.5.1
 
Additional Analyses of the Primary Efficacy Endpoint ........................................19 
6.3.5.2
 
Secondary Efficacy Endpoints Analyses ...............................................................19 
6.3.5.3


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Exploratory Efficacy Endpoints Analyses .............................................................20 
6.3.5.4
6.3.6 
Safety Analyses ............................................................................................................20 
 
Adverse Events ......................................................................................................20 
6.3.6.1
 
Other Safety Data ...................................................................................................20 
6.3.6.2
6.3.7 
Exploratory Analyses ...................................................................................................22 
7 
APPENDICES ........................................................................................................................24 
7.1 
Appendix 1. Prior and Concomitant Medication Start/Stop Date Imputation ...................24 
7.2 
Appendix 2. Adverse Event Start/Stop Date Imputation ...................................................25 
7.3 
Appendix 3. Ulcerative Colitis Disease Assessment by Mayo Score ................................26 
 
LIST OF TABLES 
Table 1. 
Visit Windows for Assessments Done at Baseline and Weeks 1, 2, 4, and 8 or 
Baseline and Weeks 1, 2, 4, 8, and 10 ...................................................................13 
Table 2. 
Visit Windows for Assessments Done at Baseline and Weeks 2, 4, and 8  or 
Baseline and Weeks 2, 4, 8, and 10 .......................................................................14 
Table 3. 
Visit Windows for Assessments Done at Baseline and Week 8 ............................14 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
 
 
AE 
adverse event 
5-ASA 
5-aminosalicylic acid 
CD 
cluster of differentiation 
DSMB 
Data Safety Monitoring Board 
EC 
enteric coated 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
IFN-γ 
interferon gamma 
IL 
Interleukin 
MMS 
modified Mayo score 
PD 
Pharmacodynamics 
PGA 
physician’s global assessment 
PK 
Pharmacokinetic 
PP 
Per Protocol 
SAE 
serious adverse event 
TEAE 
Treatment-emergent adverse event 
TMS 
Total Mayo Score 
UC 
ulcerative colitis 
ULN 
upper limit of normal 


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1 INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to summarize the study design and 
objectives, and provide details of the outcome and statistical methods required for the statistical 
analysis of data from Protocol LYC-30937-2001.  The statistical plan described is an a priori 
plan and no unblinded analysis prior to the preparation of this plan has been conducted.  
2 STUDY OVERVIEW 
2.1 
Study Population 
The study will include adult males and non-pregnant non-lactating females age 18-75 years 
(except Czech Republic where upper age is 65 years) with active ulcerative colitis (UC) 
diagnosed at least 6 months prior to Screening with a minimum disease extent of ≥ 15 cm from 
the anal verge (diagnosis confirmed by both endoscopic and histologic evidence).  They will 
have active UC defined as a Total Mayo Score (TMS) of 4-11 inclusive, and Mayo endoscopic 
subscore of ≥ 2 and a Mayo rectal bleeding subscore of ≥ 1.  They may be receiving as treatment 
for UC, stable doses of oral aminosalicylates and/or thiopurines and/or corticosteroids prior to 
entering the trial.  
2.2 
Study Design  
This study is a randomized, double-blind, placebo-controlled, parallel group Phase 2 study 
comparing LYC-30937-enteric coated (EC) 25 mg and placebo in subjects with active UC.  All 
subjects who meet eligibility criteria will be randomized 1:1 to receive either LYC-30937-enteric 
coated (EC) 25 mg or placebo.  Study drug will be administered as an oral capsule to be taken 
once daily.  Approximately 120 subjects will be randomized in the trial. 
Subject randomization will be stratified across treatment groups by type of biologic therapy 
(subjects that have received biologic therapy (e.g. anti-tumor necrosis factor (anti-TNF), 
anti-integrin) and those that are naïve to biologic therapy).  The randomization will be stratified 
to ensure that at least 50% of subjects included in the study are biologic therapy naïve and that 
these subjects are assigned evenly between the 2 arms. 
Subjects who complete the double-blind portion of the trial through Week 8 will have the option 
of receiving open-label treatment with LYC-30937-EC in a separate open-label extension study 
(LYC-30937-2002) which will have the objective of collecting long-term safety data on LYC-
30937-EC in subjects with active UC.  


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2.3 
Assessments 
All subjects who are randomized will be monitored for adverse events (AEs) and serious (SAEs) 
from the time the subject signs informed consent through last subject visit.  Assessments will 
include: 
 Safety assessments:  clinical laboratory tests; monitoring of AEs, medical history, and 
concomitant medications and procedures; vital signs including body temperature; physical 
examinations; Electrocardiograms (ECGs); monitoring of plasma LYC-30937 concentrations 
and compliance. 
 Efficacy assessments:  Mayo subscores of stool frequency, rectal bleeding, endoscopic 
evaluation, and physicians global assessment (PGA); fecal calprotectin. 
 PK/PD assessments:  plasma pharmacokinetic (PK) parameters; colon tissue PK parameters; 
and exploratory pharmacodynamics (PD) biomarkers.   
2.4 
Anticipated Number of Subjects  
Approximately 120 subjects will be randomized into the study in a 1:1 ratio to LYC-30937-EC 
or placebo. 
3 STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Objectives  
Primary Objective 
The primary objective will be to assess the efficacy of LYC-30937-EC in inducing remission 
compared with placebo in subjects with active UC over treatment duration of 8 weeks.   
Secondary Objectives 
The secondary objectives will be to evaluate the safety and tolerability of LYC-30937-EC 
compared with placebo in subjects with active UC.   
Exploratory Objectives 
The exploratory objectives will be to assess the plasma PK of LYC-30937-EC and its metabolite, 
determine the colon tissue exposure of LYC-30937-EC, evaluate PD biomarkers, and assess 
endoscopic improvement at Week 8 in subjects with active UC; and assess efficacy in a subset of 
subjects with previous exposure to biologic therapy. 


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3.2 
Efficacy Measures 
The individual Mayo subscore components will be summed to give a modified Mayo score 
(MMS) of 0-9 or a total Mayo score (TMS) of 0-12 with higher scores indicating more active 
disease.  Endoscopy finding, stool frequency, and rectal bleeding will be summed to calculate 
MMS.  PGA will not be used to calculate MMS.  All 4 subscores including PGA, endoscopy 
finding, stool frequency, and rectal bleeding will be summed to calculate TMS.  Efficacy will be 
assessed using both TMS and MMS. 
Primary Efficacy Endpoint  
The primary efficacy endpoint is Clinical remission at Week 8 using MMS.  
A responder for the Clinical remission using MMS is defined as any subject that has a Mayo 
stool frequency subscore of ≤ 1, a Mayo rectal bleeding subscore of 0 and a Mayo endoscopy 
subscore of ≤ 1.  Subjects with a missing Week 8 response will be considered non-responders.  
The Mayo score (total and modified) will use the Mayo endoscopy score assessed by the 
independent central reader.  In the case that a centrally read endoscopic Week 8 result is missing, 
the Week 8 endoscopic subscore assessed by the investigator will be used.  
Calculation of the Week 8 MMS for efficacy endpoints requires that the endoscopy score be 
available.  In other words, if the endoscopy score is missing, the MMS will be considered 
missing. If the stool frequency score and/or the rectal bleeding score is missing at Week 8, these 
scores may be carried forward from the most recent post-baseline previous visit for which the 
score is available.   
The primary endpoint will be analysed using the Full Analysis Set (FAS).  An additional Per 
Protocol (PP) population analysis will be completed.  FAS and PP are as defined in Sections 5.1 
and 5.2. 
Secondary Efficacy Endpoints 
The secondary efficacy outcome is Clinical remission at Week 8 using TMS.  A responder for 
the clinical remission using TMS is defined as any subject that has a TMS score of ≤ 2, with no 
individual score > 1 and with a rectal bleeding score of 0. 
Calculation of the Week 8 TMS for efficacy endpoints requires that the PGA subscore and 
endoscopic subscore be available. In other words, if either the PGA score or endoscopic score is 
missing, the TMS will be considered missing. If the stool frequency score and/or rectal bleeding 
score is missing at Week 8, these scores may be carried forward from the most recent post-
baseline previous visit for which the subscore is available.   


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The secondary endpoint of Clinical remission at Week 8 using TMS will be analysed using the 
Full Analysis Set (FAS) and Per Protocol (PP) populations as defined in Sections 5.1 and 5.2. 
Other secondary endpoints include: 
 Clinical response at Week 8 using MMS.  This is defined as a reduction from baseline MMS 
of ≥ 2 points and ≥ 25%, and a decrease from baseline in rectal bleeding subscore of ≥ 1 
point or an absolute rectal bleeding subscore of ≤ 1 point. 
 Clinical response at Week 8 using TMS.  This is defined as a reduction from baseline TMS 
of ≥ 3 points and ≥ 30%, and a decrease from baseline in rectal bleeding subscore of ≥ 1 
point or an absolute rectal bleeding subscore of ≤ 1 point. 
 Change from baseline in TMS at Week 8. 
 Change from baseline in MMS at Week 8. 
 Change from baseline in fecal calprotectin at Week 8. 
Change from baseline is defined in Section 6.2.6.  For efficacy endpoints using the change from 
baseline, if the baseline value or Week 8 value is missing, the subject will be excluded from the 
analysis. 
Exploratory Efficacy Endpoints  
Additional exploratory efficacy endpoints will be considered, including the following: 
Endoscopy 
 Endoscopic improvement at Week 8, where a responder is defined as any subject with an 
endoscopic subscore of ≤ 1 point. 
 Endoscopy subscore of 0 at Week 8. 
As a post-hoc analysis, and dependent on the number of subjects in each randomized stratum an 
additional endpoint of endoscopic improvement at Week 8 by previous biologic therapy status 
might be considered. 
TMS 
 Clinical remission at Week 8 using TMS by previous biologic therapy status.  
 Clinical response at Week 8 using TMS by previous biologic therapy status.  
 Clinical remission at Week 8 using TMS by subgroup (subgroups defined in Section 6.2.2). 
As a post-hoc analysis, and dependent on the number of subjects in each randomized stratum an 
additional endpoint of Change from baseline in TMS at Week 8 by previous biologic therapy 
status might be considered. 
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 Absolute and percent change from baseline in MMS at Week 8.  
 Absolute and percent change from baseline in Mayo subscores at Week 8.  
Safety Endpoints 
 The incidence and type of AEs, SAEs, and AEs that led to discontinuation of study treatment 
PK and PD Endpoints 
 PK parameters will be derived from measurements of plasma LYC-30937 concentrations, 
and its metabolite. 
 Colon tissue concentrations of LYC-30937 and its metabolite.  
 PD biomarkers in subjects who consent to biologic samples (blood, stool, colon tissue).  
Biomarkers that may be assessed where feasible and acceptable include:   
o inflammatory proteins and cytokines 
o enumeration of lymphocytes subtypes 
o lymphocyte infiltration and metabolic remodeling 
o expression of proteins associated with gut-homing and lymphocyte activation  
o expression of small nucleotide polymorphism associated with UC 
o transcriptional profiling for immune cell signatures 
o taxonomic composition of subject microbiomes 
4 ANALYSIS PLAN OVERVIEW 
The final analysis will be performed after official database lock, once the last subject has 
completed the Week 10 follow-up visit.  No adjustments will be made for multiplicity. 
The analysis of safety, PK and PD endpoints will be limited to descriptive statistics. 
5 ANALYSIS SETS 
5.1 
Full Analysis Set (FAS) 
The FAS is defined as all randomized subjects.  Subjects will be included in the treatment group 
to which they were randomized, regardless of the treatment they actually received.  All efficacy 
analyses will be performed on the FAS. 
5.2 
Per Protocol Population (PP) 
The PP is defined as all randomized subjects who are at least 80% compliant with taking study 
medication and who completed the Week 8 efficacy assessments.  Subjects will be included in 
the treatment group to which they were treated.  The PP population will exclude those subjects 
who had specific major protocol violations that would impact the assessment of efficacy and 
these will be finalized before database lock.  The patients excluded from the PP population will 


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be fully defined and documented in a separate memo with reasons for exclusion prior to database 
lock.  Primary and key secondary efficacy analyses will also be performed on the PP.  The FAS 
will be primary. 
5.3 
Safety Set 
The Safety Set is defined as all randomized subjects who received at least one dose of study 
drug.  For summaries/listings where treatment group is included, subjects will be included in the 
treatment group to which they were actually treated.  All safety analyses will be performed on 
the Safety Set. 
5.4 
PK and PD Set 
The Safety PK Set is defined as up to 20 randomized and LYC-30937-EC treated subjects who 
have at least one blood sample collection at Visit 3, 4, 5 or 6. 
The Serial PK Set is defined as a subset of up to12 randomized and LYC-30937-EC treated 
subjects with sufficient serial blood sample collections at Visit 5 to derive at least 1 PK 
parameter. 
The Plasma PK Set is defined as all randomized and LYC-30937-EC treated subjects who are 
not in the Safety PK Set or the Serial PK Set and have one blood sample collection at Visit 5. 
The PD Set is defined as all randomized and LYC-30937-EC treated subjects who consent to 
biologic samples (blood, stool, colon tissue) and have at least one colon tissue concentration or 
PD biomarker endpoint measurement.  All PD analyses will be performed on the PD Set. 
5.5 
Protocol Deviations and Treatment Misallocation 
Key and non-key protocol deviations will be listed.  Protocol deviations will be used to assess 
the quality of study conduct but there are no plans to use them to define an additional population 
for analyses.  Decisions to exclude patients or data from any statistical analyses will be decided 
on a case-by-case basis before database lock and without knowledge of treatment assignment and 
reasons will be documented. Treatment misallocation will be handled as described in the analysis 
set definitions in Sections 5.1 through 5.3.  
6 STATISTICAL ANALYSES 
6.1 
Statistical Power and Sample Size Considerations 
A total of approximately 120 subjects will be randomized into the study and using a 1:1 
randomization ratio of LYC-30937-EC 25 mg or placebo.   


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A sample size of 60 subjects per group will achieve approximately an 88% power to detect 
superiority in the remission rate of the active treatment group compared to the placebo treatment 
group.  The placebo treatment group remission rate is assumed to be 6.7%.  The power was 
computed for the case when the actual treatment group remission rate is 25% for a delta of 
18.33%.  The test statistic used is the one-sided Z test (pooled).  The alpha level of the test was 
targeted at 0.05.  Additionally, a sample size of 54 subjects per group excluding drop-outs will 
achieve approximately a 78% power to detect non-inferiority in the remission rate of the active 
treatment group compared to the placebo treatment group where the placebo treatment group 
remission rate is assumed to be 7.41% and the actual treatment group remission rate is 25.92% 
for a delta of 18.51%.  All sample size calculations were performed using the Power Analysis & 
Sample Size (PASS), version 11 software. 
Assuming a drop-out rate of 10%, the study will enroll approximately 120 subjects in order to 
complete 108. 
6.2 
Baseline, Endpoint and Missing Value Definitions 
6.2.1 
Baseline Definition 
Baseline for demographics; height; weight; body mass index (BMI); physical examination (PE); 
electrocardiogram (ECG); laboratory results (including chemistry, hematology, and coagulation 
panels, and urinalysis); stool (including fecal calprotectin); Mayo Score; stool frequency and 
rectal bleeding; physician's global assessment (PGA); and endoscopy and biopsy is defined as 
those assessments from Screening. 
Baseline for vital signs; body temperature; and PD biomarkers is defined as those assessments 
from prior to drug administration at Week 0 / Study Day 1 / Visit 2.  If a subject is missing a 
pre-dose assessment from Visit 2 then a previous measurement (from Visit 1 / Screening or an 
unscheduled visit, for vital signs or PD biomarkers) will be used as baseline, if available.  If no 
previous measurement is available, then the baseline will be missing.  If there are multiple 
assessments prior to Week 0 / Study Day 1 / Visit 2, then the measurement closest to Week 0 / 
Study Day 1 / Visit 2 will be used. 
6.2.2 
Subgroups 
The following subgroup variables will be used for efficacy analyses:  
 Age at baseline (<65, >=65 years) 
 Sex (Male, Female) 
 Race (White, Non-White) 
 Region ((Europe:  Czech Republic, Hungary, Netherlands, Poland, and Serbia versus North 
America) 


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 Weight (<55, 55-<70, 70-<85, 85-<100, >=100 kg) 
 Baseline TMS Score (4-6, 7-9, >-10) 
 Duration of disease (<2, 2-<5, 5-<10, >=10 years) 
 Concomitant use of corticosteroids at baseline (yes, no) 
 Previous biologic therapy status (yes, no) 
 Previous use of immunosuppressants (yes, no) 
6.2.3 
Visit Windows 
Data at scheduled visits will be assigned to analysis visits as defined in this section and in the 
Visit Window tables below which are provided based on how frequently the assessments are 
done.  To ensure that all visits have the possibility to be included in the summaries, the visit 
window will also classify all unscheduled and early termination visits.  The analysis visits will be 
derived in terms of study days since the first dose of study treatment.  These analysis visits will 
be utilized in the summary and analyses of efficacy and safety endpoints. 
If a subject has more than 1 assessment in a visit window, only the assessment that is closest to 
the Scheduled Visit Day will be used for analysis.  In case where 2 assessments have the same 
distance from the Scheduled Visit Day, the later assessment will be used for analysis.  The early 
termination visit will be assigned to an analysis visit based on the window below. 
The Week 8 efficacy endpoints will use the visit window for summarization of Day ≥ 44.  The 
Week 8 safety assessments will use the window of Day 44 – Day 64, except for assessments 
which have only 1 scheduled post-baseline assessment, (eg, ECG) which will use the window of 
Day ≥ 2.   
Table 1. Visit Windows for Assessments Done at Baseline and Weeks 1, 2, 4, and 8 or 
Baseline and Weeks 1, 2, 4, 8, and 10 
Analysis Visit 
Scheduled Visit Day 
Visit Window for Summarization 
Baseline 
Day -28 to 1 
≤ Day1 
Week 1 
Day 8 
Day 2 – Day 11 
Week 2 
Day 15 
Day 12  – Day 22 
Week 4 
Day 29 
Day 23 – Day 43 
Week 8 
Day 57 
Day 44 – Day 64 
Week 10 
Day 71 
Day ≥ 65 
 


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Table 2. Visit Windows for Assessments Done at Baseline and Weeks 2, 4, and 8  or 
Baseline and Weeks 2, 4, 8, and 10 
Analysis Visit 
Scheduled Visit Day 
Visit Window for Summarization 
Baseline 
Day -28 to 1 
≤ Day1 
Week 2 
Day 15 
Day 2 – Day 22 
Week 4 
Day 29 
Day 23 – Day 43 
Week 8 
Day 57 
Day 44 – Day 64  
Week 10 
Day 71 
Day ≥ 65 
 
Table 3. Visit Windows for Assessments Done at Baseline and Week 8 
Analysis Visit 
Scheduled Visit Day 
Visit Window for Summarization 
Baseline 
Day -28 to 1 
≤ Day1 
Week 8  
Day 57 
Day ≥ 2 
 
6.2.4 
Replicate Data  
For each parameter, if two or more non-missing values are in the same visit window, then the 
one collected on the day that is closest to the target day will be used in the analysis irrespective 
of whether the data came from a planned or unplanned visit.  If there are 2 study visits that are 
equally close to the target visit day, then the later assessment will be used.  All data will be 
provided in the data listings. 
6.2.5 
Missing Data 
For efficacy analyses the primary time point of interest is Week 8.  For efficacy endpoints using 
the proportion of responders, subjects with a missing Week 8 response will be considered non-
responders (this includes subjects who discontinue early).  For efficacy endpoints using the 
change from baseline, if the baseline value or Week 8 value is missing, the subject will be 
excluded from the analysis.  
The Mayo score (total and modified) will use the Mayo endoscopy score assessed by the 
independent central reader.  In the case that a centrally read endoscopic Week 8 result is missing, 
the Week 8 endoscopic subscore assessed by the investigator will be used.  
Calculation of the TMS for efficacy endpoints requires that the PGA subscore and endoscopic 
subscore be available.  If the stool frequency score and/or rectal bleeding score is missing, these 
scores may be carried forward from the most recent previous visit for which the subscore is 
available.  If either the PGA score or endoscopic score is missing, the TMS will be considered 
missing. 


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Calculation of the MMS for efficacy endpoints requires that the endoscopy score be available.  If 
the stool frequency score and/or the rectal bleeding score is missing, these scores may be carried 
forward from the most recent previous visit for which the score is available.  If the endoscopy 
score is missing, the MMS will be considered missing. 
Missing PK concentrations and PD data will be treated as missing in the calculation of summary 
statistic.  For serial PK sampling, missing concentrations will be treated as missing in the 
calculation of PK parameters and concentrations below the lower limit of quantification (LLOQ) 
will be treated as zero or missing in the calculation of PK parameter and zero in the calculation 
of summary statistics. 
6.2.6 
Change From Baseline 
Absolute change from baseline is defined as: 
Value of parameter post-treatment – Value of parameter at baseline 
Percent change from baseline is defined as: 
(Value of parameter post-treatment – Value of parameter at baseline) / Value of parameter at 
baseline * 100 
If the baseline value is missing for a subject, then change from baseline will not be calculated for 
that subject.  The subject will not be included in the summarization / analysis of that parameter. 
6.3 
Statistical Analyses  
The following general comments apply to all statistical analyses and data presentations.  
 Summaries will include frequency, percentages, and missing for categorical data; and non-
missing subjects, mean, standard deviation, and median, minimum and maximum for 
continuous data.   
 Individual subject listings of all data represented on the electronic case report forms (eCRFs) 
will be provided to facilitate the investigation of tabulated values and to allow for the clinical 
review of all efficacy and safety parameters. 
 Version 9.3 (or higher) of SAS® statistical software package will be used to provide all 
summaries, listings, graphs, and statistical analyses. 
6.3.1 
Subject Baseline Characteristics 
Demographic information and baseline subject characteristics include: 
 Age at baseline (years) defined as screening date year – birth year.  
 Age at diagnosis (years) defined as diagnosis date year – birth year. 


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 Sex 
 Ethnicity 
 Race 
 Region (Europe:  Czech Republic, Hungary, Netherlands, Poland, and Serbia versus North 
America)  
 History of tobacco, drug abuse, alcohol (Never, Current, Former) 
 Baseline height, weight, BMI 
 Biologic therapy status at baseline 
 Baseline TMS and MMS score  
 Duration of disease (years) – defined as screening date year – UC diagnosis date year. 
 Baseline C-Reactive protein and C-Reactive protein categories (< 5, ≥ 5 mg/L) 
 Baseline fecal calprotectin and fecal calprotectin categories (≤ 250, > 250 - ≤ 500, 
> 500 µg/g) 
 Concomitant Medication Use at baseline (None, 5-ASA, Corticosteroids, Thiopurines, 
5-ASA + Corticosteroids, 5-ASA + Thiopurines, 5-ASA + Corticosteroids + Thiopurines, 
Other) 
Demographic information and baseline subject will be summarized by treatment group and 
overall. 
Medical History 
Subjects with reported medical history will be listed by treatment group. 
Prior and Concomitant Medications and Procedures 
Medications will be coded using World Health Organization Drug Dictionary Enhanced (WHO 
DDE) (Version MAR2016 or higher). Medications are considered concomitant if the medication 
start date is prior to the first dose of study drug.  Both UC and non-UC medications are 
summarized by Anatomical Therapeutic Chemical Classification (ATC) level 3 (third level 
indicates the therapeutic/pharmacologic subgroup) and generic medication name. Concomitant 
procedures will be listed.  
6.3.2 
Subject Disposition 
The overall number of subjects screened and screen failures will be presented.  Screen failure 
reasons will be listed.  A listing, grouped by randomized strata, will be provided that indicates 
the subject's date and time of informed consent and randomization, randomized treatment 
assignment, randomization number, first and last dose date.  A listing will be provided of 


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randomized subjects who did not meet all inclusion/exclusion criteria, and which criteria were 
not met.   
The number of subjects included in each of the analysis populations (ie, randomized, FAS, 
Safety, PP) will be listed and summarized by treatment group. Reasons for exclusion from each 
population will be documented in a memo that indicates each subject’s inclusion in/exclusion 
from the populations and the reason for exclusion from each of the populations.   Number of 
subjects entering the open-label extension study will be summarized. 
The number and percentage of subjects completing the study will be presented for each treatment 
group and overall for the randomized subjects.  Reasons for premature discontinuation of the 
study, as recorded on the eCRF will be summarized (number and percentage) by treatment group 
and overall.  A listing of all FAS subjects who prematurely discontinued the study will be 
presented, and the primary reason for discontinuation of not completing the study will be 
provided.   
6.3.3 
Interim Analysis 
There is no plan to conduct an interim analysis. 
However, a Data Safety Monitoring Board (DSMB), independent of the sponsor, will be 
established to review safety data as specified in the DSMB charter.  The DSMB will be 
comprised of a pharmacokineticist, a therapeutic expert and a statistician.  The DSMB’s initial 
planned review will take place when the first 30 subjects treated have completed at least 4 weeks 
of treatment.  Accumulated safety data (AEs, AEs of special interest, SAEs, withdrawals due to 
AEs, vital signs, body temperature) and available plasma PK data will be included for this initial 
review.  Frequency of DSMB meetings will be specified in the DSMB charter.  The DSMB may 
recommend changes to the trial due to safety concerns based on their review.  Any necessary 
blinding plan to assure the study data remains blinded to sponsor personnel and others involved 
in the trial, and additional relevant details of DSMB review activities will be provided in the 
DSMB charter. 
More detail related to the DSMB is contained in the DSMB Charter. 
6.3.4 
Treatment Compliance and Exposure 
Exposure summary by treatment group and overall will be presented for the Safety population.  
The distribution of subjects by the total number of days on treatment (≤ 1, 2 - 8, 9 - 15, 16 - 29, 
30 - 57 and ≥ 58 days) will be presented as will descriptive statistics for the duration of 
treatment.  Duration of treatment is calculated (in days) as last dose date – first dose date +1. 
Drug interruptions are expected to be minimal and will not be accounted for in the duration of 
treatment definition.  


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Drug compliance is calculated as (number of capsules taken)/(number of scheduled capsules) 
× 100.  For a patient who drops out early, the number of scheduled tablets is the number the 
patient should have taken until the time subject dropped out. The compliance is only calculated 
for patients who had returned all the dispensed bottles. The percentage of subjects who were < 
80%, 80% - < 100%, 100% - < 120%, and ≥ 120% compliant will be summarized for the Safety 
population. 
6.3.5 
Efficacy Endpoint Analyses 
Mayo scores; subscores including stool frequency, rectal bleeding, PGA, and endoscopic 
findings; and fecal calprotectin will be listed and summarized by treatment group and scheduled 
visit window.  TMS, MMS, and fecal calprotectin will be summarized descriptively in both 
continuous and categorical manner by treatment group and scheduled visit window.  Line graphs 
will be produced to present mean MMS and TMS at baseline and Week 8.   
A listing of individual outcomes for each of the efficacy endpoints will also be presented by 
treatment group.  Listings will include a flag to designate subjects with and without prior 
biologic therapy exposure.  Summaries of efficacy data will also be presented by prior biologic 
therapy exposure and by treatment group.  The definition for subjects with prior biologic therapy 
exposure is described in Section 2.2. 
 
Primary Endpoint Efficacy Analysis 
6.3.5.1
The primary efficacy analyses will be based on the FAS population.  The statistical test will be a 
one-sided hypothesis test performed at the 5% level of significance.  The primary efficacy 
outcome is the percentage of subjects who achieve a clinical remission at Week 8 of treatment 
using MMS.  The number and percentage of subjects in each treatment group will be tabulated.  
The null and alternative hypotheses are as follows: 
𝐻0: 𝑝1 ≤𝑝2 and, 𝐻𝑎: 𝑝1 > 𝑝2 
where p1 is the proportion of subjects who achieve clinical remission with LYC-30397-EC and p2 
is the proportion of subjects who achieve clinical remission with placebo.  
To test the null hypothesis a Pearson chi-square test will be used.  In addition, the difference in 
proportion of subjects who achieve a clinical remission at Week 8 of treatment (LYC-30937 
minus placebo) and corresponding 90% confidence interval will also be estimated. 
The following SAS code will be used: 
PROC FREQ; 
  TABLES TREATMENT*MREMISS / CHISQ RISKDIFF ALPHA=0.1; 
RUN; 


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Where TREATMENT=1 for LYC-30937-EC and =0 for placebo; MREMISS='Y' for subjects 
who achieve a clinical remission and ='N' for subjects who do not achieve a clinical remission.   
 
Additional Analyses of the Primary Efficacy Endpoint 
6.3.5.2
The above analysis will also be conducted on the PP population.  
 
As a post-hoc analysis, an additional Cochran-Mantel-Haenszel statistical analysis might be 
considered to test the association between treatment and clinical remission at Week 8 using 
MMS after adjusting for the randomization strata (biologic therapy status).  
  
 
Secondary Efficacy Endpoints Analyses 
6.3.5.3
The following secondary efficacy endpoints:  Clinical Remission using TMS, Clinical Response 
using MMS and Clinical Response using TMS will be summarized and analysed using the same 
statistical methodology as the primary endpoint described in section 6.3.5.1. Clinical remission at 
Week 8 using TMS will also be presented by subgroup, where subgroups are as defined in 
section 6.2.2.  
Change from Baseline in MMS and TMS 
The change from baseline in MMS and TMS at Week 8 will be summarized using descriptive 
statistics by treatment group.  The change from baseline in TMS will be analysed using an 
analysis of covariance (ANCOVA) with a factor for treatment and a covariate for baseline 
scores.  The difference in the change from baseline in TMS (LYC-30937 minus placebo) and 
corresponding 90% confidence interval will also be estimated.  The following SAS code will be 
used: 
PROC GLM; 
  CLASS TREATMENT; 
  MODEL tmschg = TMSBASE treatment; 
  ESTIMATE 'lyc-pLA' -1 1 / CL ALPHA=0.1; 
RUN; 
Where TREATMENT=1 for LYC-30937-EC and =0 for placebo; TMSBASE is the baseline 
TMS; and TMSCHG is the change from baseline TMS at Week 8.  Subjects who are missing the 
baseline or Week 8 TMS will be excluded from the analysis. 
Change from Baseline in fecal calprotectin 
The change from baseline in fecal calprotectin at Week 8 will be summarized and analysed using 
the same statistical methodology as the change from baseline in TMS described above.   


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Exploratory Efficacy Endpoints Analyses 
6.3.5.4
The exploratory efficacy endpoints that are categorical will be summarized and analysed using 
the same statistical methodology as the primary endpoint described in Section 6.3.2.  The 
continuous exploratory efficacy endpoints will be summarized and analysed using the same 
statistical methodology as the secondary efficacy endpoint change from baseline in TMS 
described above.   
6.3.6 
Safety Analyses 
 
Adverse Events 
6.3.6.1
Verbatim descriptions of AEs will be coded using Version 19.0 or higher of MedDRA.  
Treatment-emergent adverse events (TEAEs) are defined as adverse events (AEs) that first 
occur, or worsen, after the first dose of study medication and within 14 days after the permanent 
discontinuation of the study medication.  AEs that occur in subjects who fail screening will only 
be listed if they were the reason the subject was a screen failure. 
An overall summary of AEs will include the number of subjects who experienced at least one AE 
of the following categories:  any AE, any TEAE, any related TEAE, any severe TEAE, any 
serious TEAE, any related SAE, any serious TEAE leading to death, any TEAE leading to 
withdrawal of study treatment, any TEAE leading to premature discontinuation from the study, 
any TEAE leading to dose interruption of test article, and any serious TEAE leading to 
withdrawal of study treatment.  Subjects who die will also be summarized. 
The number and percentage of subjects reporting a TEAE in each treatment group will be 
tabulated by system organ class and preferred term; by system organ class, preferred term, and 
severity (National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v.4.03).  The incidence of TEAEs will be summarized by preferred term and treatment 
group, for all TEAES, related TEAEs, serious TEAEs and TEAEs leading to treatment 
discontinuation.  For all analyses of TEAEs, if the same AE (based on preferred term) is reported 
for the same subject more than once, the AE is counted only once for that preferred term and at 
the highest severity and strongest relationship to test article.  Should there be any SAEs resulting 
in death, these will be listed and summarized separately. 
 
Other Safety Data 
6.3.6.2
Laboratory Values 
Summaries of laboratory data will include hematology, chemistry, urinalysis and coagulation 
parameters.  Descriptive statistics (based on standard international (SI) units) for chemistry, 
hematology and coagulation values will be summarized by treatment group at each time point.  


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Box-plots for chemistry and hematology laboratory values by visit and treatment group will be 
provided.  
Subjects with chemistry and hematology laboratory values above 2 standard deviations (SD) of 
ULN will be listed. Laboratory abnormal values of special interest will be determined based on 
the criteria below.  Any subjects meeting the criteria at any time post-baseline will be 
summarized by treatment group. 
Chemistry 
Alanine Aminotransferase (ALT) > 3x ULN a) 
Aspartate Amino transferase (AST) > 3x ULN b) 
Alkaline phosphatase (ALP) > 400 U/L 
Lactate ≥ 2x baseline value and >25 mg/dL 
Total Bilirubin >34.2 mmol/L 
Hematology 
Leukocytes < 2x10^9/L 
a) 
is the upper limit of the normal range (55 U/L) 
b) 
is the upper limit of the normal range (34 U/L) 
Vital Signs 
Seated blood pressure (systolic and diastolic), temperature, respiratory rate and heart rate will be 
summarized using descriptive statistics.  Descriptive statistics of the absolute change from 
baseline to each post-baseline visit window will also be provided.  For change from baseline, a 
subject must have a baseline measurement and a measurement at that visit window to be 
included in the summaries.   
Electrocardiogram (ECGs)  
The QTc interval will be presented by using the Fridericia (QTcF = QT/(RR)⅓) correction (RR = 
heart rate/60).  The QTcF values and absolute changes from baseline to Week 8 will be 
summarized using descriptive statistics. For change from baseline, a subject must have a baseline 
measurement and a measurement at Week 8 to be included in the summaries. All other ECG 
parameters will be listed.  
By-subject listings of vital signs, ECG, lab data, physical examination, and abnormal findings on 
the physical examination will be provided. 
Special safety topics of interest 
Certain safety topics of special interest will be specifically evaluated and will be discussed in the 
Clinical Study Report (CSR). These include but are not limited to: 
 
Repeated episodes of vomiting -  above the severity and/or frequency of the baseline 
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 
Persistent abdominal pain that - above the severity and/or frequency of the baseline 
ulcerative colitis symptoms 
 
Elevated body temperature 
 
Elevations in liver related clinical lab parameters: alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, alkaline phosphatase (ALP) 
 
Lactate and lactate dehydrogenase elevations 
These topics will be assessed using existing listings and tables as relevant.  
6.3.7 
Exploratory Analyses 
Plasma PK Data 
Listings of LYC-30937 and metabolite concentrations will be generated for the Safety PK Set, 
the Serial PK Set and the Plasma PK Set separately by analyte and scheduled timepoint and/or 
visit window.  LYC-30937 and metabolite concentrations will also be summarized by number of 
subjects, mean, standard deviation, median and minimum and maximum values by PK set, 
analyte, and scheduled timepoint and/or visit window. 
For serial PK concentrations, individual concentration versus time plots will be produced using 
actual time from Visit 5 drug administration on a linear and semi log scale.  Mean (±SD) 
concentration versus nominal time plots will also be produced for the Serial PK Set using a linear 
and semi log scale. 
The following PK parameters for LYC-30937 and its metabolite will be derived for the Serial PK 
Set: 
Cmax 
Maximum observed plasma concentration 
Tmax  
Time at which maximum observed plasma concentration Cmax 
AUC0-t 
AUC up to time t using linear-log trapezoidal rule, where t is the last time point with concentrations 
above the lower limit of quantitation (LLOQ) 
 
The PK parameters will be summarized by number of subjects, mean, standard deviation, median 
and minimum and maximum values by analyte. 
Colon Tissue Concentrations 
Individual LYC-30937 and metabolite concentrations from the 3 biopsies at Visit 6 (Week 8) 
from each colon segment (rectum, sigmoid, descending, transverse, ascending and in selected 
subjects the ileocecum) where disease is present will be listed by analyte and biopsy site for 
subjects in the PD Set.  The LYC-30937 and metabolite concentrations from the 3 biopsies will 
also be averaged at each biopsy site and the average concentrations will be listed by analyte and 
biopsy site for subjects in the PD Set.  If < 3 or > 3 biopsies are collected from a given site, all 


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biopsies collected will be averaged.  The average LYC-30937 and metabolite concentrations in 
colon tissue will also be summarized by number of subjects, mean, standard deviation, median, 
minimum, and maximum values by analyte, biopsy site, and scheduled visit window. 
PD Biomarkers 
Listings of PD biomarkers from blood, stool, or colon tissue biopsy will be generated for 
subjects in the PD Set by treatment group and scheduled visit window.  The PD biomarkers may 
also be summarized by biomarker, treatment group, and scheduled visit window. 
The table below lists PD biomarkers by biologic sample type that may be selected for 
investigation from the biologic samples collected in this trial.  The ultimate selection of 
biomarkers for evaluation may involve a review of feasibility and also may be based on relevant 
information regarding these biomarkers that emerge during the course of this study. 
Sample type 
Sample 
Biomarker Analysis 
Blood 
Whole blood or PBMC 
Leukocyte characterization by flow cytometry: including but not 
limited to α4β7, Treg, PD-1, Annexin V, CD62L, glucose/fatty acid 
uptake 
Plasma 
Cytokine profile by immunocapture assays: including but not 
limited to IL8, IL10, IFN γ, IL17, IL6, IL1β 
Stool 
Soluble fraction 
Cytokine profile by immunocapture assays: including but not 
limited to IL8, IL10, IFN γ, IL17, IL6, IL1β 
RNA 
gene chip or nanostring analysis 
DNA 
Sequencing for microbiome characterization 
Biopsy 
Lysate from whole 
biopsy 
Cytokine profile by immunocapture assays: including but not 
limited to IL8, IL10, IFN γ, IL17, IL6, IL1β 
RNA 
gene chip analysis 
Formalin fixed 
H&E and Immunohistochemistry: including but not limited to CD3, 
PD-1, CD62L, Annexin V 
CD3 = cluster of differentiation 3 protein complex; CD62L = Lselectin; IFN gamma = interferon gamma; 
IL = interleukin; PBMC = peripheral blood mononuclear cells; PD-1 = programmed cell death protein 1; 
Treg = regulatory T cells, DNA = deoxyribonucleic acid,; RNA = ribonucleic acid. 
 
 
 


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7 APPENDICES 
7.1 
Appendix 1. Prior and Concomitant Medication Start/Stop Date Imputation 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date  
D only 
M and Y same as M and Y of first dose 
of study drug 
Date of first dose of study 
drug 
M and/or Y not same as date of first 
dose of study drug 
First day of month 
M and D 
Y same as Y of first dose of study drug 
Date of first dose of study 
drug 
Y not same as Y of first dose of study 
drug 
Use Jan 01 of Y 
M, D, and Y 
None - date completely missing 
Day prior to date of first 
dose of study drug 
Stop date  
D only 
M and Y same as M and Y of last dose 
of study drug 
Date of last dose of study 
drug 
M and/or Y not same as date of last 
dose of study drug 
Last day of month 
M and D 
Y same as Y of last dose of study drug 
Date of last dose of study 
drug 
Y not same as Y of last dose of study 
drug 
Use Dec 31 of Y 
M, D, and Y 
None - date completely missing and 
NOT ongoing 
Date of last dose of study 
drug 
Note:  In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day 
month. 
 
 
 


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7.2 
Appendix 2. Adverse Event Start/Stop Date Imputation 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for AEs 
D 
M and Y same as M and Y of first dose 
of study drug 
Date of first dose of study 
drug 
M and/or Y not same as date of first 
dose of study drug 
First day of month 
D and M 
Y same as Y of first dose of study drug 
Date of first dose of study 
drug 
Y prior to Y of first dose of study drug 
but same as Y of screening date 
Date of screening date 
D, M, Y 
None - date completely missing 
Date of first dose of study 
drug 
Stop date for AEs 
D 
M and Y same as M and Y of last dose 
of study drug 
Date of last dose of study 
drug 
 
M and/or Y not same as date of last 
dose of study drug 
Use last day of month 
 
D and M 
Y same as Y of last dose of study drug 
Date of last dose of study 
drug 
 
Y not same as Y of last dose of study 
drug 
Use Dec 31 of Y 
 
D, M, Y 
None - date completely missing 
No imputation, but 
assume ongoing 
Note:  AE = Adverse Event 
Note:  In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day 
month. 


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7.3 
Appendix 3. Ulcerative Colitis Disease Assessment by Mayo Score 
The TMS is a scoring system for the assessment of UC activity calculated based on 4 parameters 
(PGA, endoscopy findings, rectal bleeding, and stool frequency).  The MMS is calculated based 
on 3 parameters (all the aforementioned parameters apart from the PGA).   
The 4 components are described and scored as follows: 
 stool frequency a (expressed in relation to the subject’s “normal” baseline number of 
stools when not having a flare and this will be documented at screening):  
0 = normal number of stools for the subject 
1 = 1-2 more stools than normal 
2 = 3-4 stools more than normal 
3 = 5+ stools more than normal 
 rectal bleeding b: 
0 = no blood seen 
1 = streaks of blood < 50% of the time 
2 = obvious blood with stool most of the time 
3 = passes blood without stool 
 PGA c:  
0 = normal 
1 = mild disease 
2 = moderate disease 
3 = severe disease 
 endoscopic findings:  
0 = normal or inactive disease 
1 = mild disease (erythema, decreased vascular pattern) 
2 = moderate disease (marked erythema, absent vascular pattern, friability, erosions) 
3 = severe disease (spontaneous bleeding, ulcerations) 
a  
Each subject serves as their own control to establish the degree of abnormality of stool frequency.  
b  
The daily bleeding score represents the most severe bleeding of the day. 
c  
The PGA acknowledges the three other criteria, the subject’s recollection of abdominal discomfort and general 
sense of well-being, and other observations, such as physical findings and the subject’s performance status. 
 
Each of these individual scores will be summed to give a MMS of 0-9 or a TMS of 0-12.   
Subjects were requested to enter all stools and associated rectal bleeding daily in their diary 
starting at Screening.  Mayo scores are calculated using the stool frequency and rectal bleeding 
data obtained from the subjects daily diary entries. Stool frequency and rectal bleeding data from 
the most recent 3 days prior to the study visit (consecutive 3 days is preferred or non-consecutive 


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are used, if the most recent 3 days are not consecutive).  If 3 days of diary data were not 
available, data from the 2 most recent days prior to the study visit were used. Data were not to  
be used from the following days: 
a. The day medications for constipation, diarrhea, or bowel irregularity are taken 
b. The day(s) of a procedure or preparation for a procedure (eg, enemas, laxative, clear 
liquid diet) that would affect bowel frequency or blood content of stool 
c. The 48 hours following the use of anti-motility medication (eg, loperamide) 
d. The 48 hours following endoscopy. 
Stool frequency subscore calculation: The number of stools each of the 3 days is totaled 
individually. The subject’s normal number of stools is subtracted from each daily stool total. The 
Mayo subscore is assigned to each days “normalized” stool total. These Mayo subscores are 
totaled for the 3 days and averaged (rounded to the nearest integer). This average is used to 
calculate the Mayo score.  
Rectal bleeding subscore:  The worst bleeding score from each of the 3 days is selected, totaled 
and averaged (rounded to the nearest integer). This average is used to calculate the Mayo score.   
The PGA was completed by the Investigator (or designee) at Screening and at Week 8.   
A colonoscopy was performed at screening to assess disease severity.  Depending upon disease 
extent, either a flexible sigmoidoscopy or colonoscopy was performed at Week 8.  The screening 
colonoscopy was to image the entire colon to determine areas of inflammation and demarcation. 
If the inflammation identified at screening was determined to be left-sided disease, defined as 
extending ≥ 15 cm from anal verge and with clear demarcation at not higher than 5 cm below the 
splenic flexure, then the Week 8 endoscopy could be a flexible sigmoidoscopy instead of a 
colonoscopy.  All endoscopies performed were conducted using the investigative site’s standard 
practice including bowel preparation.  The endoscopies (either colonoscopy or flexible 
sigmoidoscopy) were performed at the site and the endoscopy video recording was sent to the 
ICON Medical Imaging for blinded, independent central reader review and assignment of the 
Mayo endoscopy subscore.  Central readers are experienced at reviewing and Mayo scoring 
endoscopies and they received study-specific training prior to their reading endoscopies for this 
trial. This training included ensuring their understanding that the presence of “friability” is not 
considered consistent with remission and therefore, if present, the Mayo endoscopic subscore 
must be at least 2.