Clinical trial NCT02872285
Conditions: Psoriasis
Sponsor: Lycera Corp.
Start date: 2016-12-05; Completion date: 2017-06-22
Enrollment: 33 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this Phase 2 trial is to determine the efficacy and safety of LYC-30937-EC in patients with moderate plaque-type psoriasis.

Detailed description:
Approximately 30 subjects will be enrolled in this double-blind, placebo-controlled study. The randomization will be stratified 2:1 into the LYC-30937-EC cohort (2) or the placebo cohort (1). The active cohort will receive LYC-30937-EC 25 mg once daily, which demonstrated safety and tolerability in Phase I trials.

The study is designed for patients with previously diagnosed moderate chronic plaque-type psoriasis and consists of the following:

* Screening period (initials assessment and eligibility scoring)
* Day 1: confirm eligibility, baseline efficacy assessments (PASI, IGA), randomize and initiate dosing
* Week 2: safety assessments including vital signs, body temperature, physical exam, clinical labs will be performed
* Week 4: efficacy (PASI, IGA) and safety assessments including vital signs, body temperature, physical exam, and clinical labs will be performed
* Week 8: efficacy (PASI, IGA) and safety assessments including vital signs, body temperature, physical exam, and clinical labs will be performed
* Week 12: final efficacy assessments (PASI, IGA), safety assessments including vital signs, body temperature, physical exam, ECG, and clinical labs will be performed
* Week 14: final safety assessments including vital signs, body temperature, and clinical labs

Arms: arm 1: LYC-30937-EC 25 mg by mouth once daily for 12 weeks arm 2: Placebo enteric coated (EC) by mouth once daily for 12 weeks
Interventions: intervention 1: Drug: LYC-30937-EC intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
30 Aug 2016


 
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INVESTIGATOR STATEMENT 
I have read and understand the protocol and agree to conduct this study as detailed herein, in 
compliance with current Good Clinical Practice (GCP) and the applicable regulatory 
requirements, and will make every reasonable effort to complete the study within the time 
designated. 
I will provide adequate protocol training to my associates, colleagues, and employees assisting in 
the conduct of the study.  The protocol and all relevant information on the study drug relating to 
pre-clinical and prior clinical experience, which was furnished by the sponsor, will be made 
available to all physicians, nurses and other personnel who participate in the conduct of this 
study.  I will discuss this material with them to assure that they are fully informed regarding the 
drug(s) and the conduct of the study. 
I will obtain approval from, the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) for the protocol and Informed Consent Document (ICD) before enrollment of subjects in 
the study.  I understand that any modifications to the protocol made during the course of the 
study must first be approved by the IRB except when such modification is made to remove an 
immediate hazard to the patient. 
I will ensure that a fully executed ICD is obtained from each patient before initiation of any 
study procedures. 
I will report any serious adverse event (SAE) that occurs during the course of the study in 
accordance with the procedures described in Section 7.5 of the protocol. 
I will allow the sponsor, Lycera Corp. (Lycera) and its agents, as well as the United States Food 
and Drug Administration (US FDA) and other regulatory agencies, to inspect study facilities and 
pertinent records at reasonable times and in a reasonable manner, ensuring patient 
confidentiality.  If I am notified that this study is to be inspected by a regulatory agency, I will 
notify Lycera as soon as possible thereafter. 
This document contains information that is privileged or confidential.  As such, it may not be 
disclosed unless specific prior permission is granted in writing by Lycera or such disclosure is 
required by federal or other laws or regulations.  Persons to whom any of this information is to 
be disclosed must first be informed that the information is confidential.  These restrictions on 


 
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disclosure will apply equally to all future information supplied, which is indicated as privileged 
or confidential. 
Lycera will have access to any source documents from which Case Report Form (CRF) 
information may have been generated.  The CRF and other data pertinent to this study are the 
sole property of Lycera, which may utilize the data in various ways, such as for submission to 
government regulatory authorities, or in publication of the results of the study. 
 
Signature of principal investigator: 
 
 
 
______________________________________ 
_________  
ADD NAME 
ADD DATE (DD MMM YYYY) 
ADD AFFILIATION 
 
 


 
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TABLE OF CONTENTS 
INVESTIGATOR STATEMENT ................................................................................................2 
TABLE OF CONTENTS ..............................................................................................................4 
LIST OF TABLES .........................................................................................................................7 
LIST OF ABBREVIATIONS .......................................................................................................8 
1.0 
PROTOCOL SUMMARY ..............................................................................................11 
2.0 
INTRODUCTION............................................................................................................14 
2.1 
Disease Background...............................................................................................14 
2.2 
Product Background...............................................................................................15 
2.3 
Nonclinical Studies ................................................................................................16 
2.3.1 
Nonclinical Pharmacology .............................................................16 
2.3.2 
Nonclinical Pharmacokinetics .......................................................17 
2.3.3 
Safety Pharmacology and Toxicology ...........................................17 
2.4 
Previous Human Experience ..................................................................................18 
2.5 
Dose Selection Rationale .......................................................................................19 
2.6 
Risks and Benefits..................................................................................................20 
3.0 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................21 
3.1 
Study Objectives ....................................................................................................21 
3.2 
Endpoints ...............................................................................................................21 
4.0 
STUDY DESIGN ..............................................................................................................22 
4.1 
Design Overview ...................................................................................................22 
4.2 
Number of Subjects and Sites ................................................................................23 
4.3 
Assignment of Subject Numbers ...........................................................................23 
4.4 
Subject Selection ....................................................................................................24 
4.4.1 
Inclusion Criteria ...........................................................................24 
4.4.2 
Exclusion Criteria ..........................................................................25 
4.5 
Subject Withdrawals ..............................................................................................27 
5.0 
STUDY TREATMENTS .................................................................................................28 
5.1 
Description .............................................................................................................28 
5.2 
Treatment Regimen ................................................................................................28 


 
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5.3 
Randomization .......................................................................................................29 
5.4 
Maintaining and Breaking the Blind ......................................................................29 
5.5 
Drug Supplies.........................................................................................................30 
5.5.1 
Packaging and Labeling .................................................................30 
5.5.2 
Product Accountability, Storage, Dispensing, and Return ............30 
5.5.3 
Treatment Compliance ...................................................................31 
5.6 
Concomitant Medications ......................................................................................31 
6.0 
STUDY PROCEDURES .................................................................................................32 
6.1 
Visit Timing ...........................................................................................................32 
6.2 
Schedule of Events .................................................................................................33 
6.2.1 
Visit Procedure Guidelines ............................................................35 
6.3 
Efficacy Assessments Performed ...........................................................................35 
6.3.1 
Psoriasis Area and Severity Index (PASI) and Body Surface 
Area (BSA) ....................................................................................35 
6.3.2 
Static Investigator’s Global Assessment (static IGA) ...................36 
6.4 
Safety Assessments Performed ..............................................................................37 
6.4.1 
Physical Examinations (PE) ...........................................................37 
6.4.2 
Vital Signs Measurements .............................................................38 
6.4.3 
12-Lead ECG .................................................................................39 
6.4.4 
Laboratory Assessments ................................................................39 
6.4.5 
Body Temperature monitoring .......................................................40 
6.4.6 
Monitoring Subjects for Adverse Events of Special Interest .........40 
7.0 
ADVERSE EVENTS AND SAFETY MONITORING ................................................42 
7.1 
Adverse Event Definition ......................................................................................42 
7.2 
Serious Adverse Events Definition ........................................................................43 
7.3 
Adverse Event Reporting .......................................................................................43 
7.4 
Assessment of Severity of Adverse Events ...........................................................44 
7.5 
Serious Adverse Event Reporting ..........................................................................45 
7.6 
Post-Week 14 Reporting of Serious Adverse Events ............................................47 
7.7 
Exposure in Utero ..................................................................................................47 


 
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7.8 
Relationship/Causality of Adverse Events/Serious Adverse Events .....................48 
7.9 
Withdrawal Due to Adverse Events .......................................................................48 
7.10 
Medical Monitoring ...............................................................................................49 
7.11 
Study Hold or Stopping Criteria ............................................................................49 
7.11.1 
Suspension of Study .......................................................................49 
8.0 
STATISTICAL AND ANALYTICAL PLAN ...............................................................50 
8.1 
Sample Size Calculation ........................................................................................50 
8.2 
Analysis Populations ..............................................................................................50 
8.2.1 
Full Analysis Set ............................................................................50 
8.2.2 
Safety Set .......................................................................................50 
8.3 
Demographic and Subject Characteristics .............................................................51 
8.4 
General Statistical Considerations .........................................................................51 
8.5 
Efficacy Analysis ...................................................................................................51 
8.5.1 
Primary Efficacy Endpoint Analysis .............................................51 
8.5.2 
Secondary Efficacy Endpoint Analyses .........................................52 
8.6 
Safety Analysis ......................................................................................................52 
9.0 
ETHICAL CONSIDERATIONS ....................................................................................54 
9.1 
Basic Principles ......................................................................................................54 
9.2 
Institutional Review Board/Independent Ethics Committee..................................54 
9.3 
Informed Consent...................................................................................................54 
9.4 
Study Termination .................................................................................................54 
10.0 
DATA HANDLING AND RECORD KEEPING ..........................................................55 
10.1 
Study Monitoring ...................................................................................................55 
10.2 
Study Documentation.............................................................................................55 
10.3 
Record Retention ...................................................................................................56 
11.0 
CONFIDENTIALITY AND PUBLICATION PLAN...................................................57 
11.1 
Confidentiality .......................................................................................................57 
11.2 
Publication of Data and Protection of Intellectual Property ..................................57 
12.0 
REFERENCES .................................................................................................................58 
13.0 
APPENDICES ..................................................................................................................60 


 
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13.1 
The PASI Scoring System .....................................................................................60 
14.0 
DOCUMENT HISTORY ................................................................................................63 
 
LIST OF TABLES 
Table 1: 
Schedule of Events ...........................................................................................33 
 
 
 


 
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LIST OF ABBREVIATIONS 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transferase 
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 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 
Cave 
average concentration 
CFR 
Code of Federal Regulation 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRO 
contract research organization 
CYP 
cytochrome P450 enzyme 
EC 
enteric coated 
EC50 
effective concentration 50% (concentration at which 50% maximal response occurs) 
ECG 
electrocardiogram 
EIU 
exposure in utero 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FE 
food effect 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
hCG 
human chorionic gonadotropin 
HDL 
high density lipoprotein 
HEENT 
head, eyes, ears, nose, and throat 


 
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HIV 
human immunodeficiency virus 
HPMC 
hydroxyl-propyl-methyl-cellulose 
HR 
heart rate 
hsCRP 
high sensitivity C-reactive protein 
IB 
investigator’s brochure 
IC50 
50% inhibitory concentration 
ICD 
informed consent document 
ICH 
International Council for Harmonization 
IEC 
independent ethics committee 
IGA 
Investigator’s Global Assessment 
IL 
interleukin 
IRB 
institutional review board 
IRT 
interactive response technologies 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
MAD 
multiple ascending dose 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
NCI CTCAE 
National Cancer Institute common terminology criteria for adverse events 
NOAEL 
no observed adverse effect level 
NSAID 
nonsteroidal anti-inflammatory drug 
PASI 
Psoriasis Area and Severity Index 
PE 
physical examination 
PI 
principal investigator 
PK 
pharmacokinetics 
PT 
prothrombin time 
q.d. 
quaque die, once daily 
QTcF 
QT interval corrected for heart rate according to Fridericia’s formula 
RBC 
red blood cell 
ROS 
reactive oxygen species 
RR 
respiratory rate 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


 
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SI 
international system units 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TNBS 
trinitrobenzene sulfonic acid 
TNF 
tumor necrosis factor 
UC 
ulcerative colitis 
ULN 
upper limit of normal 
US 
United States 
UV 
ultraviolet 
WBC 
white blood cell 
 
 
 


 
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1.0 
PROTOCOL SUMMARY 
Indication 
Chronic Plaque-type Psoriasis 
Study Rationale 
Chronic plaque-type psoriasis is an autoimmune disorder that manifests as a chronic 
inflammatory skin disease.  The features of the underlying inflammation are erythema of the skin 
with associated induration, scaling, and plaque formation, often in the extensor surfaces.  It 
affects 1–3% of the world’s population and can result in significant morbidity and diminished 
quality of life of individuals with the disease.[1] 
Pathologic chronically activated T lymphocytes are crucial in the development of chronic 
plaque-type psoriasis.[2], [3]  These abnormal lymphocytes cause chronic inflammation and the 
resultant clinical manifestations of the disease.  There is increasing evidence that these 
chronically activated lymphocytes traffic to skin from highly immune-rich areas of the body – 
“immune hubs” – like the intestines.[4], [5]  This is further supported by evidence of correlation of 
systemic autoimmune diseases and bacterial presence in the gut [6], [7], [8] and the detection of 
upregulated gut-tropic CCR9+ immune cells in inflamed end organs.[9] 
LYC-30937-enteric coated (EC) is an allosteric modulator of F1F0 adenosine triphosphate 
synthase enzyme  (F1F0-ATPase) that acts on chronically activated lymphocytes locally in the 
lumen of the gut due to limited systemic absorption.  The mechanism of LYC-30937-EC is to 
induce apoptosis of chronically activated lymphocytes such as those thought to drive the 
pathogenesis of plaque-type psoriasis.  In preclinical experiments, LYC-30937 has been shown 
to differentially affect chronically activated lymphocytes versus normal lymphocytes because of 
the metabolic differences between the cells.  LYC-30937 has demonstrated efficacy in animal 
models of psoriasis and other models of systemic inflammation like collagen-induced arthritis 
despite very low systemic exposure.  It has also been studied in healthy subjects up to a 300 mg 
daily dose and 200 mg daily dose over 7 days with very low systemic absorption and a very low 
incidence of adverse events (AEs).   
With the low systemic exposure of LYC-30937-EC, the good tolerability demonstrated in 
healthy subjects, the growing scientific support that chronically activated lymphocytes traffic 
from immune-rich areas of the body to chronically inflamed tissue, and the efficacy of gut-
directed F1F0-ATPase modulators demonstrated in systemic autoimmune models (psoriasis and 
collagen-induced arthritis) despite very low systemic exposures, it is proposed that LYC-30937-


 
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EC may provide a favorable benefit to risk profile in patients with moderate chronic plaque-type 
psoriasis .   
Study Objectives 
The objective of this study is to assess the efficacy, safety, and tolerability of LYC-30937-EC 
compared to placebo in subjects with chronic plaque-type psoriasis.    
Primary Objective 
The primary objective will be to assess the efficacy of LYC-30937-EC in inducing a reduction 
from baseline in Psoriasis Area and Severity Index (PASI) compared with placebo in subjects 
with chronic plaque-type psoriasis over the treatment duration of 12 weeks. 
Secondary Objectives 
The secondary objectives will be to evaluate the overall efficacy, safety and tolerability of 
LYC-30937-EC compared with placebo in subjects with chronic plaque-type psoriasis. 
Exploratory Objectives 
The exploratory objectives will be to assess concentration of LYC-30937 in plasma and in skin 
tissue.  Skin biopsies are optional and will be collected in a subset of approximately 6 consenting 
study subjects to assess LYC-30937 concentrations in skin.  
Endpoints 
Primary Efficacy Endpoint 
The primary endpoint of the study will be the mean percent change from baseline to Week 12 in 
PASI. 
Secondary Efficacy Endpoint 
The secondary efficacy endpoints of the study will be: 
 The proportion of subjects who achieve a ≥ 75% reduction from baseline in PASI at 
Week 12. 
 The mean percent change from baseline to Week 12 in body surface area (BSA). 


 
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 The proportion of subjects who achieve “cleared” (score = 0) or “minimal” (score = 1) on 
the static Investigator’s Global Assessment (IGA) at Week 12. 
 The proportion of subjects who achieve a 2 step reduction on the static IGA at Week 12.  
Secondary Safety Endpoint 
The secondary safety endpoint of the study will include AEs and their causality assessments by 
investigators, physical examinations (PE), vital signs measurements, 12-lead electrocardiogram 
(ECG), and laboratory assessments. 
Exploratory Endpoint 
Concentration of LYC-30937 will measured in plasma and in skin as an exploratory endpoint. 
Study Population 
This study will include adult males and non-pregnant, non-lactating females with moderate 
chronic plaque-type psoriasis.   
Study Design 
This is a phase 2a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study designed to evaluate the efficacy, safety and tolerability of LYC-30937-EC treatment in 
subjects with chronic plaque-type psoriasis.  
All subjects who meet the eligibility criteria will be randomized 2:1 into the LYC-30937-EC or 
placebo group. 
Assessments 
Efficacy Assessments 
The following efficacy assessments will be performed in this study: 
 
PASI 
 
Static IGA  
Safety Assessments 


 
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All subjects who are randomized will be monitored for AEs until they leave the study. 
Additional safety assessments include:   
 
PE 
 
vital sign measurements including systolic and diastolic blood pressure (BP), heart rate 
(HR), respiratory rate (RR), and body temperature 
 
12-lead ECG 
 
laboratory assessments including chemistry, hematology,  and urinalysis 
Anticipated Number of Subjects  
Approximately 30 subjects will be enrolled into the study and dosed in a 2:1 ratio of 
LYC-30937-EC or placebo. 
Anticipated Number of Sites 
Approximately 6 sites are planned to be included in the study. 
First Subject Screened 
The study is planned to start in the 4th quarter of 2016. 
Study Countries 
United States 
 
2.0 
INTRODUCTION 
2.1 
Disease Background 
Psoriasis is an autoimmune disorder, manifesting in the skin, joints, or both.[10]  The disease is 
characterized by inflammation accompanied by hyperkeratosis resulting in inflamed, raised 
plaques, usually on the extensor surfaces of the body.  Psoriasis provides many challenges 
including high prevalence, chronicity, disfiguration, disability, and associated comorbidities 


 
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(such as arthritis, depression, inflammatory bowel disease, and cardiovascular diseases).[10], [11], 
[12]   
The prevalence of psoriasis in the US was estimated to be 7.4 million in 2013.  The estimated 
total financial burden of psoriasis was estimated as 35.2 billion dollars.[13]   
The current treatment options for psoriasis are determined by the severity of the disease.  For 
patients with severe disease that affects a large percentage of BSA, there has been robust efficacy 
demonstrated by biologics that block the effect of key cytokines that drive the inflammation like 
anti-tumor necrosis factor (TNF) α, anti-interleukin (IL) 12/23 and anti-IL-17.[14]  Patients with 
moderate plaque psoriasis are either treated with topical agents (eg, corticosteroids, retinoids, 
vitamin D analogs), for minimal BSA involvement, ultraviolet (UV) light (with or without 
psoralen), or oral drugs that aim to reduce inflammation through systemic effects on the immune 
system (eg, methotrexate and apremilast).  These treatments are limited in demonstrating robust 
efficacy or have safety issues through local effects on the skin or systemic effects on the immune 
system.  The current study with LYC-30937-enteric coated (EC) aims to assess the efficacy and 
safety of an agent that works locally in the gut with limited systemic exposure to address this 
continued unmet medical need.   
2.2 
Product Background 
LYC-30937-EC is an orally administered small molecule  modulator of the mitochondrial F1F0-
ATPase, being developed for the treatment of inflammatory diseases such as ulcerative colitis 
(UC) and chronic plaque-type psoriasis.  It is formulated with an enteric coating that allows for 
drug delivery beyond the stomach at a pH of 5.8 – 6.8.  The properties of the study drug are such 
that systemic absorption is low as demonstrated in a healthy volunteer trial where LYC-30937-
EC was administered up to a 300 mg single dose and 200 mg daily dose over one week.  In the 
multiple ascending dose (MAD) trial in which 200 mg capsules were dosed once daily for one 
week, the maximum concentration (Cmax) seen was 21.4 ng/mL (mean 10.3 ng/mL) and the 
maximum area under the curve (AUC) seen was 306 ng·h/mL (mean 173 ng·h/mL).  
The LYC-30937-EC mechanism of action is the selective induction of apoptosis in metabolically 
sensitive lymphocytes such as those chronically activated by skin antigens and thought to drive 
the inflammation of chronic plaque-type psoriasis.  Gut-directed ATPase modulators have 
demonstrated efficacy in animal models of autoimmune disease like psoriasis and collagen 
induced arthritis despite very low systemic exposure.  These data support the hypothesis that 
delivering drug to the immune-rich bowel may have an effect on active skin inflammation thus 
supporting study of the compound in humans with chronic plaque-type psoriasis. 


 
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Based on its mechanism of action and distribution profile, LYC-30937-EC is anticipated to 
demonstrate clinical efficacy free from generalized immune suppression in subjects with chronic 
plaque-type psoriasis.  
2.3 
Nonclinical Studies 
2.3.1 
Nonclinical Pharmacology 
LYC-30937 is an orally administered small molecule that functions as an allosteric modulator of 
the mitochondrial ATPase, 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 sub-mitochondrial particles, increases reactive 
oxygen species (ROS) generation, and induces apoptosis of a lymphocyte cell line.   
Recent literature on autoimmune disease pathogenesis proposes that chronically activated 
lymphocytes traffic through immune-rich hubs, such as the gut, prior to infiltrating distal 
inflamed tissues like the skin. Because LYC-30937 and related molecules have significantly 
higher exposure in the gut then in plasma, this may allow local targeting of pathogenic cells in 
the gut. In support of this hypothesis,  LYC-30937 and other ATPase modulator compounds are 
efficacious in rodent models of systemic autoimmune disease despite very low systemic 
exposures.  For instance, efficacy was demonstrated by LYC-30937 in a collagen induced 
arthritis model at an average concentration (Cave) of 0.9 ng/mL (2nM) and an area under the 
plasma (concentration-time) curve from time 0 to 24 hours (AUC0-24h) of 22 ng·h/mL which is 
below the effective concentration to achieve 50% of the maximal response (EC50) based on 
biochemical (27 nM) and cellular assays (59 nM).  Another ATPase modulator in the chemical 
series, LYC-51661, demonstrated efficacy in the imiquimod-induced ear swelling rodent model.  
It demonstrated this efficacy at 30 mg/kg which is comparable to exposures above as LYC-
51661 is approximately 100-fold less potent than LYC-30937.  LYC-30937 was selected for 
advancement based on its in vitro potency, in vivo immunomodulatory activity, and a 
pharmacokinetic (PK) profile characterized by high local tissue concentrations in the 
gastrointestinal tract.   
In rodent inflammatory bowel disease 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.  It is in the gut where it is 


 
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hypothesized that chronically activated lymphocytes traffic prior to infiltrating distal inflamed 
areas like the skin. 
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%).    
When administered as a powder blend in an EC capsule (the intended clinical formulation) to 
monkeys, the AUC0-24 of LYC-30937-EC is approximately 10% of that achieved using a lipid-
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 (CNS), 
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 
immunosuppression.  
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.  The NOAEL was 2 mg/kg/day with plasma 
AUC values of 1690 ng∙h/mL in male rats and 1040 ng∙h/mL in female rats. In the rat 91-day 
GLP toxicology study, the no observed adverse event level (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 of 3 mg/kg with a Cmax of 257 ng/mL and an AUC of 3060 ng∙h/mL.  


 
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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 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.  
2.4 
Previous Human Experience 
LYC-30937-EC has been studied in two Phase 1 studies. 
The Phase 1a study was comprised of a single ascending dose (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. 
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 
dose cohort (64-fold below the NOAEL in rats, the most sensitive species) and the AUC began 
to plateau at the 150 mg dose. 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. 
The extent of accumulation following multiple dosing was 3- to 4-fold.  


 
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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.  
Overall, oral administration of LYC-30937-EC as single dose up to 300 mg and as once 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 can be found in the current LYC-30937 Investigator’s Brochure (IB) and 
in Addendum #1. 
2.5 
Dose Selection Rationale 
The proposed dose to be studied in this Phase 2a study is 25 mg once daily (q.d.) oral dose.  The 
rationale for this is based on the exposures required to demonstrate efficacy in models of 
autoimmune disease, 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 an AUC0-72 
of 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, respectively.  Both the Cmax and AUC 
values exceed the exposures achieved in the collagen-induced arthritis model where Cave was 0.9 
ng/mL (2nM) and AUC was 22 ng·h/mL.  Exposures were comparable in an imiquimod-induced 
ear swelling model when those exposures are extrapolated for the 100-fold less potent ATPase 
modulator.  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 trafficking in the gut.   
The 25 mg dose is also to ensure safety.  Subjects in this study 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 


 
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significantly increased systemic exposure, exposures are projected to remain 10-fold below the 
lowest exposure associated with mortality in rats, the most sensitive species.   
Thus, the selection of the 25 mg daily dose is intended 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 systemic exposures.   
2.6 
Risks and Benefits 
The rationale for the clinical study is that current systemic therapies for tissue-specific 
autoimmune diseases are often associated with  immune suppression.  The selective action of 
LYC-30937-EC, on metabolically sensitive, chronically activated lymphocytes coupled with the 
minimal systemic exposure suggest a possible benefit to patients of an efficacious drug without 
immunosuppression and systemic adverse events.  The benefit of LYC-30937-EC is that it 
intended to fulfill the existing unmet needs in the treatment of chronic plaque-type psoriasis. 
Based on the results from the first-in-human study described in Section 2.4, single doses of up to 
300 mg were shown to be safe and well tolerated (in the SAD component of the study) and single 
dose exposures in the 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.  In the Phase 1 study in healthy subjects and in the Phase 1b 
study in subjects with active UC, no safety signals were detected.  There were no clinically 
significant laboratory abnormalities and the subjects tolerated the drug well.   
In Phase 2, the subjects will have an active autoimmune disease (chronic plaque-type psoriasis) 
and therefore will be a different study population.  These subjects will be administered study 
drug once daily for 12 weeks and will be closely monitored for any AE or other safety 
parameters during the course of the study.  Because a high fat meal increased absorption 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.     
The efficacy of LYC-30937-EC in subjects with chronic plaque-type psoriasis is being evaluated 
in this study, therefore any benefit is theoretical at this time.  This is the first study to evaluate 
efficacy in this population.  


 
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3.0 
STUDY OBJECTIVES AND ENDPOINTS  
3.1 
Study Objectives 
The objective of this study is to assess the efficacy, safety, and tolerability of LYC-30937-EC 
compared to placebo in subjects with chronic plaque-type psoriasis.   
 
Primary Study Objective  
The primary objective will be to assess the efficacy of LYC-30937-EC in inducing a 
reduction from baseline in PASI compared with placebo in subjects with chronic plaque-type 
psoriasis over the treatment duration of 12 weeks. 
 Secondary Study Objectives  
The secondary objectives will be to evaluate the overall efficacy, safety and tolerability of 
LYC-30937-EC compared with placebo in subjects with chronic plaque-type psoriasis. 
 Exploratory Objectives  
The exploratory objectives will be to assess concentration of LYC-30937 in plasma and in 
skin tissue.  Skin biopsies are optional and will be collected in a subset of approximately 6 
consenting study subjects to assess LYC-30937 concentrations in skin.  
3.2 
Endpoints 
 
Primary Endpoints (Efficacy) 
The primary efficacy endpoint of the study will be the mean percent change from baseline to 
Week 12 in PASI. 
 
Secondary Endpoints (Efficacy) 
The secondary efficacy endpoints of the study will be: 
 
The proportion of subjects who achieve a ≥ 75% reduction from baseline in PASI at 
Week 12. 
 
The mean percent change from baseline to Week 12 in BSA. 


 
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 
The proportion of subjects who achieve “cleared” (score = 0) or “minimal” (score = 1) 
on the static IGA at Week 12. 
 
The proportion of subjects who achieve a 2 step reduction on the static IGA at Week 12.  
 
Secondary Safety Endpoint  
The secondary safety endpoint of the study will include AEs, PE, vital sign measurements, 
12-lead ECG, and laboratory assessments. 
 
Exploratory Endpoint  
Concentration of LYC-30937 will measured in plasma and in skin as an exploratory 
endpoint. 
4.0 
STUDY DESIGN 
4.1 
Design Overview 
This is a phase 2a multi-center, randomized, double-blind, placebo-controlled, parallel-group 
study designed to evaluate the efficacy, safety and tolerability of LYC-30937-EC treatment in 
subjects with chronic plaque-type psoriasis.  
After signing an informed consent, all eligible subjects will be followed for approximately 
16 weeks, which includes up to 2 weeks between screening and Study Day 1 (first dose of 
treatment), 12 weeks for treatment, and 2 week for follow-up.   
There are 3 distinct phases of this study outlined below: 
Screening:  The screening visit will take place up to 2 weeks prior to randomization and 
subject’s first dose of LYC-30937-EC (or matching placebo).  Subjects who meet all eligibility 
requirements will return for the next phase of the study. 
Treatment Period:  Subjects meeting all entry criteria will be randomized in a 2:1 ratio to active 
treatment (LYC-30937-EC 25 mg q.d.) or matching placebo.  Subjects will receive their first 
dose of study drug at the investigational site after randomization has occurred.  Subjects will 
return to the investigational site at Weeks 2, 4, 8, and 12 for efficacy assessments, safety 
monitoring, and study drug receipt (at Weeks 2, 4, 8).   


 
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Follow-Up:  There will be 1 follow-up visit performed at Week 14 for final safety monitoring 
purposes.  
After completion of all follow-up visits, the study database will be locked to allow for the 
analysis of data collected up through Week 14.  
The subjects, site personnel following the subject, and the sponsor will remain blinded to 
treatment until after the database lock. 
4.2 
Number of Subjects and Sites 
A total of approximately 30 subjects will be randomized into the study and treated at 
approximately 6 sites (refer to Section 8.1 Sample Size Calculation). 
4.3 
Assignment of Subject Numbers 
Subjects will be assigned a 6-digit unique identification number sequentially as they sign the 
informed consent document and agree to participate in the study.  The first 3 numbers will 
identify the site number (e.g., 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 CRFs and will serve as the primary method of identifying each subject on the CRFs 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. 
Each subject meeting entry criteria will be assigned a randomization number.  The treatment 
assignment for the subject will be linked to the randomization number.  Before enrollment 
begins, the randomization numbers list will be generated.  The subject identification number and 
randomization number will be assigned by an interactive response technologies (IRT) system.   
Rescreening of subjects who previously failed screening may be allowed depending on the 
reason for the screen fail and 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 and this determination will be made through discussion with the 
Sponsor on a case-by-case basis.  


 
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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 
Subjects must meet the following inclusion criteria to participate in the study.   
1. 
Consenting adult aged 18 – 75 years at screening.   
2. 
Have a diagnosis of plaque-type psoriasis for ≥ 6 months prior to screening. 
3. 
Must have chronic plaque-type psoriasis of moderate severity confirmed at both Screening 
and Baseline visits. Moderate severity is defined as: 
 PASI > 7 with BSA involvement of 5 – 15% inclusive, and 
 overall lesion severity of moderate or marked, where: 
o moderate = moderate plaque elevation (= 0.75mm); moderate red 
coloration; coarse scale predominates;  
o marked = moderate plaque elevation (= 1mm); bright red coloration; 
thick, non-tenacious scale predominates. 
4. 
Female subjects of childbearing potential must use two 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 contraception (oral, patch, injectable, implant) or double-barrier method 
(condom or diaphragm with spermicide).  This contraception must be continued during the 
study and for 30 days after taking the last dose of study drug. (Post-menopausal defined as 
lack of menses for ≥ 6 months prior to screening confirmed with serum follicle stimulating 
hormone (FSH) > 25 mIU/mL at screening.)   
5. 
Male subjects with partners of childbearing potential must take appropriate precautions to 
avoid fathering a child while participating in the study and use appropriate barrier  
contraception or abstinence during the study and for 30 days after their last dose of study 
drug.   


 
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6. 
Agree to avoid prolonged sun exposure and avoid tanning booths or UV light sources 
during the study.   
7. 
Ability to provide written informed consent and to be compliant with the schedule of 
events.   
4.4.2 
Exclusion Criteria 
Subjects presenting with any of the following will not participate in the study:   
1. 
Non-plaque-type psoriasis (eg, pustular, erythrodermic, and guttate psoriasis).   
2. 
Drug-induced psoriasis (ie, new onset or current exacerbation from beta-blockers, calcium 
channel blockers, or lithium).   
3. 
Spontaneously improving or rapidly deteriorating plaque psoriasis.  
4. 
Comorbid psoriatic arthritis not amenable to treatment with nonsteroidal anti-inflammatory 
drugs (NSAIDs). 
5. 
Treatment with any biologic agent for plaque psoriasis.  
6. 
Failed 2 or more systemic treatments for plaque psoriasis. 
7. 
Received phototherapy or prolonged sun exposure or use of tanning booth or other 
ultraviolet light source within 4 weeks prior to initiating screening procedures. 
8. 
Received systemic drug therapy  (non-biologic) for plaque psoriasis or any other systemic 
medications that could affect psoriasis or its evaluation (PASI or static IGA), including but 
not limited to oral or injectable corticosteroids, retinoids, sulfasalazine, within 4 weeks of 
initiating screening procedures.  
9. 
Received topical medication that could affect psoriasis or its evaluation (PASI or static 
IGA), including but not limited to corticosteroids, retinoids, topical vitamin D derivatives, 
pimecrolimus, tacrolimus, calcipotriene, within 2 weeks of initiating screening procedures.   
10. 
Received immunosuppressant agents (eg, cyclosporine, azathioprine, methotrexate) within 
8 weeks of initiating screening procedures.   


 
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11. 
Known mitochondrial disorder.   
12. 
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 < 3000/mm3 (SI:  < 3.0 x 109/L)   
e 
platelets < 80000/ mm3 (SI:  80 x 109/L)   
f 
serum creatinine > 1.4 mg/dL for women or > 1.6 mg/dL for men 
13. 
Pregnancy, lactation, or a positive serum beta human chorionic gonadotropin (hCG) 
measured at screening.  Female subjects should not be planning to become pregnant while 
enrolled in the study.   
14. 
Clinically relevant hepatic, neurological, pulmonary, dermatological, 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. 
15. 
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 (HIV), 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. 
16. 
History of cancer, including solid tumors and hematological malignancies (except 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). 


 
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17. 
History of alcohol or drug abuse within 1 year prior to randomization. 
18. 
History of or currently active primary or secondary immunodeficiency. 
19. 
History of treatment with an investigational agent within 30 days prior to initiating 
screening procedures.   
20. 
In the opinion of the investigator, the subject is not a suitable candidate for this study. For 
example, a medical condition that may put the subject at increased risk, likely not to be  
cooperative with study procedures or with completion of the study, or the inability to 
communicate reliably with the investigator.   
4.5 
Subject Withdrawals 
All subjects have the right to withdraw at any point during the study without prejudice.  Lycera 
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 who are 
withdrawn may be replaced at the discretion of Lycera on a case-by-case basis.   
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 resolves or stabilizes), concurrent illness, or laboratory abnormality 
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, or regulatory authority(ies) for safety, behavioral, 
or administrative reasons  


 
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 subject 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) 
The subject will be asked to undergo final visit procedures (Visit 6/Week 12) 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. 
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:  chronic plaque-type psoriasis  
 strength:  25 mg 
 dosage form:  oral, delayed release, EC hydroxyl-propyl-methyl-cellulose (HPMC) capsule 
 inactive placebo:  matching oral, EC HPMC capsule containing the same inactive excipients 
as the LYC-30937-EC active treatment capsules 
 manufacturer:  QS Pharma (Boothwyn, US) 
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 12) for a total of 84 days of 
treatment.  The capsules must be administered in the morning upon awaking after fasting 


 
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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.   
 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.:  one 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 either LYC-30937-EC or placebo in a 2:1 ratio.  
5.4 
Maintaining and Breaking the Blind 
The 2 capsules developed (LYC-30937 EC 25 mg and placebo) are indistinguishable (identical 
in size, shape, color, appearance, and both are EC) and 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 study (Visit 7/Week 14).   
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 Practice (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 IRB.   
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 medication, the principal investigator (PI) or authorized designee will 
inspect and count the study drug.  All study drug supplies for the study will be stored in a locked 
and secure location accessible only to those authorized by the PI to dispense the study drug.  The 
study drug supply is to be stored under controlled room temperature conditions (15-25°C).  A 
detailed inventory log will be maintained by the PI or authorized designee.  
The first dose of study drug will be taken in the clinic under medical supervision.  Subsequent 
dosing will take place at the subject’s home including on the days of study clinic visits.  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.  The subject will receive a new 
medication supply containing sufficient study drug for the period until the visits specified in 
Table 1.   
Lycera (or designee) will retrieve all partially used or unused treatments.  A detailed log of the 
returned study drug will be established.  The PI will not destroy unused study drug unless Lycera 
provides written authorization.  


 
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5.5.3 
Treatment Compliance 
Subject compliance with taking the treatment will be assessed by counting the number of 
returned capsules at each visit.  The investigator (or designee) must complete the appropriate 
CRF 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/ contract 
research organization (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 use biologics intended for treatment for plaque psoriasis during the study. They 
will not use immunomodulatory medications during the study. 
Other limitations of concomitant medications during the study are:  
 No topical therapy for psoriasis 
 No new systemic therapy for psoriasis 
 No use of phototherapy, tanning booths, prolonged sun exposure or other ultraviolet (UV) 
light sources 
 No use of any investigational drug  
 Patients may use Eucerin cream for excessively dry skin, but these should not be used with 
24 hours of study visits.  No oil-based gels are to be used 
 No topical or oral corticosteroids are permitted; patients may use inhaled corticosteroids or 
nasal corticosteroids                  
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 
therapies were excluded in the eligibility criteria.  Following randomization, addition of 


 
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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 CRF.   
6.0 
STUDY PROCEDURES 
6.1 
Visit Timing 
The schedule of study procedures is below (Table 1); 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.  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 defined as Study Day 1.  The 
timing of all study visits are based on Study Day 1.   
 Study visit timing and windows are as follows:   
 Screening (Visit 1) – approximately Study Day -14 to Day -1  
 Randomization/treatment (Visit 2) – Study Day 1 
 Visit 3 (Week 2 – Study Day 15) – window ± 2 days  
 Visit 4 (Week 4 – Study Day 29) – window ± 2 days  
 Visit 5 (Week 8 – Study Day 57) – window ± 3 days  
 Visit 6 (Week 12 – Study Day 85) – window ± 3 days  
 Follow-up (Visit 7) (Week 14 - Study Day 99) – window ± 3 days 
Unplanned visits may occur at any time for reasons of safety.  These visits and associated 
procedures must be documented on the CRF. 


 
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6.2 
Schedule of Events 
Table 1: 
Schedule of Events  
Protocol Activity 
Screening Randomization 
and Dosing  
Treatment 
Follow-up 
 
 
 
Week 2 
Week 4 
Week 8 
Week 12/ 
ET 
Week 14 
Study Day   
-14 to -1 
1 
15 ± 
2 days 
29 ± 
2 days 
57 ± 
3 days 
85 ± 
3 days 
99 ± 
3 days 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
Informed consent 
X 
 
 
 
 
 
 
Demography a 
X 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
Serology b 
X 
 
 
 
 
 
 
Prior psoriasis treatments 
X 
 
 
 
 
 
 
Serum pregnancy test 
(pre-menopausal female 
subjects) 
X 
 
 
 
 
 
 
FSH (post-menopausal 
female subjects) c 
X 
 
 
 
 
 
 
Vital signs d 
X 
X 
X 
X 
X 
X 
X 
Assess protocol 
eligibility l 
X 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Dispense study drug 
 
X 
X 
X 
X 
 
 
Administer study drug at 
the clinic 
 
X 
 
 
 
 
 
Telephone reminder to 
subject regarding taking 
study drug after fasting 
overnight 
 
X m 
 
 
 
 
 
Review study drug 
compliance 
 
 
X 
X 
X 
X 
 
PASI and % BSA 
X 
X 
 
X 
X 
X 
 
Static IGA 
X 
X 
 
X 
X 
X 
 
Photographs j 
 
X 
 
 
 
X 
 


 
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Table 1: 
Schedule of Events  
Protocol Activity 
Screening Randomization 
and Dosing  
Treatment 
Follow-up 
 
 
 
Week 2 
Week 4 
Week 8 
Week 12/ 
ET 
Week 14 
Study Day   
-14 to -1 
1 
15 ± 
2 days 
29 ± 
2 days 
57 ± 
3 days 
85 ± 
3 days 
99 ± 
3 days 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
Skin biopsy k 
 
 
 
 
X 
 
 
Urine pregnancy test 
(female subjects of 
childbearing potential) 
 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
X 
 
Physical examination 
X 
 
X 
X 
X 
X 
 
12-Lead ECG 
X 
 
 
 
 
X 
 
Chemistry panel e 
X 
 
X 
X 
X 
X 
X 
Hematology panel f 
X 
 
X 
X 
X 
X 
X 
Urinalysis g 
X 
 
 
 
 
X 
 
Plasma PK sample 
collectionh 
 
 
 
 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Assess AEs i 
X 
X 
X 
X 
X 
X 
X 
AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CPK = creatine phosphokinase; CRP = C-reactive protein; ECG = electrocardiogram; FSH = follicle 
stimulating hormone; HbsAG = hepatitis B surface antigen; HCV = hepatitis C virus; HDL = high density lipoprotein; 
HIV = human immunodeficiency virus; hsCRP = high sensitivity C-reactive protein; IGA = Investigator’s Global Assessment; 
LDH = lactate dehydrogenase; LDL = low density lipoprotein; MCH = mean cell hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; PASI = Psoriasis Area and Severity Index; 
PD = pharmacodynamics; PK = pharmacokinetics; PT = prothrombin time; RBC = red blood cell; WBC = white blood cell 
a 
Demography includes smoking status, drug and alcohol consumption, and date of chronic plaque-type psoriasis diagnosis. 
b 
HbsAG, HCV antibodies, and HIV-1/2 antibodies. 
c 
Post-menopausal is defined as having no menses for ≥ 6 months prior to screening and a serum FSH level > 25 mIU/mL at 
screening. 
d 
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. 
e 
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.  


 
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f 
Hematology Panel includes:  platelets, WBCs with differential if abnormal (% and absolute counts), hematocrit,  RBCs, 
hemoglobin, MCV, MCHC, and MCH. 
g 
Urinalysis (dipstick) 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 
nitrate.   
h 
All subjects will have one blood sample collected at Week 8 (any time post study drug dose) to measure plasma LYC-
30937 concentration.  
i 
AEs will be assessed after the informed consent is signed.  
j 
Photographs will be taken at randomization (pre-dosing) and at Week 12 in a subset of subjects.  
k 
Optional skin biopsy will be collected at Week 8 in a subset of approximately 6 consenting subjects. Biopsy collection 
instructions will be included in a separate document. This tissue will be assayed for concentration of LYC-30937. 
l 
Note that confirmation of moderate plaque-type psoriasis is determined at both Screening and Visit 2 (baseline, prior to 
first dose).  
m 
Site will telephone subjects the day after randomization visit to remind them to take study drug in the morning after fasting 
overnight and to wait approximately 1 hour before eating a meal. 
 
6.2.1 
Visit Procedure Guidelines 
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 informed consent document (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 CRFs.   
Re-screening of subjects initially not meeting all selection criteria may be allowed once after 
consultation with the sponsor.    
6.3 
Efficacy Assessments Performed 
6.3.1 
Psoriasis Area and Severity Index (PASI) and Body Surface Area (BSA) 
The PASI[17], a widely used index to express the severity of chronic plaque-type psoriasis, will 
be assessed at the time points indicated in the schedule of events (Table 1).  The PASI is a 
quantitative rating score for measuring the severity of psoriatic lesions based on area coverage 
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The index combines the assessment of severity of the lesions (erythema, induration/thickness, 
and desquamation/scaling) and percentage of affected area into a single score ranging from 0 (no 
disease) to 72 (maximal disease).   
The index is calculated as follows (also see Appendix A):  
 
The subject’s body is divided into 4 regions (head, upper extremities, trunk, and lower 
extremities).  Each of these 4 regions is first scored by itself and then all 4 scores are 
combined into the final PASI.   
 
For each region, the percent of area of skin involved (0 to 100% BSA), is estimated using 
the palm (including fingers) and % BSA is totaled for the whole body.  Additionally the % 
BSA in each of the 4 body regions is transformed into a grade from 0 (0%) to 6 (90-100%) 
for the PASI calculation.  
 
Within each of the 4 body regions, the severity of chronic plaque-type psoriasis is estimated 
by the evaluation of 3 clinical signs:  erythema (redness), induration (thickness), and 
desquamation (scaling).  Severity parameters are measured on a scale of 0 (none) to 4 (very 
severe). 
 
The sum of all 3 severity parameters for each region of skin is then multiplied by the area 
score for that area and multiplied by a different factor for each region (0.1 for head, 0.2 for 
upper extremities, 0.3 for trunk and 0.4 for lower extremities).   
The investigator will collect the components necessary to calculate the PASI and these 
components will be entered into the CRF where the PASI score will be calculated. To be eligible 
for study participation, the subject must have a PASI score of greater than 7 at both the screening 
visit and the randomization visit, with total BSA involvement of 5-15%, inclusive.    
The PASI scoring system is described further in Appendix A. 
6.3.2 
Static Investigator’s Global Assessment (static IGA) 
The static IGA[15] is used to measure psoriasis severity in clinical trials. The static IGA used in 
this trial will be a 6-point scale and will be evaluated at the time points indicated in the schedule 
of events (Table 1). The scoring is based on response to treatment measured by lesion erythema, 
induration, and scale. The static IGA scoring and descriptors are as follows: 


 
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Score Short Descriptor 
Detailed descriptor 
0 
Cleared 
No plaque elevation, erythema or scaling; hyperpigmentation may 
be present 
1 
Minimal 
Minimal plaque elevation (=0.25mm); faint erythema; minimal 
scaling, with occasional fine scale over < 5% of lesion 
2 
Mild 
Mild plaque elevation (=0.5mm); light red coloration; fine scale 
predominates 
3 
Moderate 
Moderate plaque elevation (=0.75mm); moderate red coloration; 
coarse scale predominates 
4 
Marked  
Moderate plaque elevation (=1mm); bright red coloration; thick, 
non-tenacious scale predominates 
5 
Severe 
Severe plaque elevation (≥1.25mm); dusky to deep red coloration; 
very thick, tenacious scale predominates 
 
6.4 
Safety Assessments Performed  
6.4.1 
Physical Examinations (PE) 
A standard PE will be performed by the PI or by an appropriately trained individual at the time 
points indicated in the schedule of events (Table 1) and will include a review of body systems 
outlined below.   
 general appearance 
 head, eyes, ears, nose, and throat (HEENT) 
 respiratory examination 


 
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 circulatory system 
 abdominal examination 
 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 PE for a given subject to 
minimize variability in the examinations.  Clinically significant changes from screening should 
be noted as AEs.   
6.4.2 
Vital Signs Measurements 
Vital signs measurements will be performed at the time points indicated in the schedule of 
assessments (Table 1) and will consist of BP (systolic and diastolic), HR, RR, and temperature.  
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 as per site standard procedures.   
 Blood pressure 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 should be at the same height (at the level of the heart) during each BP 
measurement.  Clinically significant changes from baseline should be recorded as AEs. 


 
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6.4.3 
12-Lead ECG 
A standard 12-Lead ECG will be performed after 5 minutes of rest in the supine position using a 
standardized automated device at the time points indicated in the schedule of assessments 
(Table 1).  The following ECG parameters will be recorded:  HR, PR-interval, QRS-duration, 
QT-interval, QT interval corrected for HR according to Fridericia’s formula (QTcF)-interval and 
the PI’s assessment of the ECG profile.  Clinically significant changes from screening should be 
recorded as AEs. 
6.4.4 
Laboratory Assessments 
Laboratory assessments will be performed at the time points indicated in the schedule of 
assessments (Table 1) and will be evaluated by a central laboratory. 
The PI 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 PI should be repeated.  Confirmed, clinically significant laboratory abnormalities should 
be further evaluated by the PI 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, lactate dehydrogenase 
(LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), reflexive bilirubin 
(total, direct, indirect), alkaline phosphatase (ALP), cholesterol, triglycerides, creatine 
phosphokinase (CPK), high sensitivity C-reactive protein (hsCRP), high density lipoprotein 
(HDL), and low density lipoprotein (LDL).   
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 hematocrit concentration (MCHC), and mean corpuscular hematocrit (MCH).   
   


 
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Urine Sample (Dipstick) 
The urinalysis test includes:  color, appearance, specific gravity, leukocyte esterase, pH, protein, 
glucose, ketones, blood, and nitrates.  Microscopic urinalysis will be performed on samples with 
abnormal blood, leukocyte esterase, protein, and nitrate.  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 lab at screening.   
Urine pregnancy tests for female subjects of childbearing potential will be performed at the time 
points indicated in the schedule of assessments (Table 1). 
6.4.5 
Body Temperature monitoring 
Subjects’ body temperature will be measured at clinic visits (Table 1).  Use the same type 
thermometer throughout the study (eg, oral, axillary, etc.) 
If the temperature reading is > 101°F (or 38.3°C), the subject is to 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 subject is to have a 
urinalysis performed; if the subject has signs and symptoms of a classic viral upper respiratory 
tract infection, then the subject can be treated symptomatically without being evaluated).   
If there are no signs or symptoms of infection, the study drug is to be withheld and the subject 
should be evaluated for other sources of increased temperature as medically indicated.  Study 
drug may be re-started if it has not been interrupted for 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 study drug for more than 3 days the investigator should withdraw the subject from 
the trial.  
6.4.6 
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.   


 
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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 they must 
contact their investigator.  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 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  
 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 the stop taking 
study drug and report to the clinic as soon as possible for evaluation (do not wait for the next 


 
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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 case.  If the elevation is confirmed by repeat lab and neither dehydration nor 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 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 alcoholic 
hepatitis; nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease. 
Obtain additional tests to evaluate liver function as appropriate (eg, international normalized 
ratio, 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.  
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 on Harmonization (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 


 
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 clinically significant symptoms and signs 
 changes in PE 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.)   
 in-subject hospitalization or prolongation of existing hospitalization   
 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 non-serious, should be collected on source documents from the 
time the subject has signed informed consent through last subject visit.  The investigator is to 


 
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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 enrolled/randomized subjects, 
AEs should be recorded on 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.  The diagnosis should 
be recorded on the CRF, rather than recording individual signs and symptoms.  For example, 
congestive heart failure should be recorded rather than low ejection fraction, pedal edema, rales 
and dyspnea. However, if a diagnosis is known and there are other signs or symptoms that are 
not generally part of the diagnosis, the diagnosis and each sign or symptom not part of the 
diagnosis should be recorded separately, for example: congestive heart failure and conjunctivitis 
should recorded as separate AEs.  
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, 
sufficient information should be obtained to determine the causality of the AE.   
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 non-leading 
questions:  “How are you feeling?”  All AEs (serious and non-serious) reported by the subject 
must be recorded on the CRFs regardless whether a causal relationship to the study drug is 
suspected.   


 
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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.   
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, Lycera or designee is to 
be notified within 24 hours of awareness of the event by the investigator or designee.  
All SAEs and follow-up information must be reported to Lycera or designee within 1 business 
day or 24 hours of awareness of the event as required by your local requirements by emailing a 
completed SAE report form to following email address:  
SAE Email: LyceraDrugSafety@mmsholdings.com 


 
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In particular, if the SAE is fatal or life threatening, notification to Lycera or designee 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 Lycera or 
designee 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 study 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 to U.S. FDA within 15 calendar 
days of notification and within 7 calendar days if the SUSAR is considered life-threatening or 
resulted in death.  A serious adverse reaction is considered “unexpected” if it’s not listed in the 
LYC-30937 IB or is not listed at the specificity or severity that has been observed.  Non-SUSAR 
SAEs will be reported 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.   


 
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7.6 
Post-Week 14 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 studies, 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 the EIU Form.  This must be done irrespective of whether an AE has 
occurred 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, however such 
events should be considered as SAEs and the investigator should follow the procedures for 
reporting SAEs.   
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.   


 
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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 non-
serious).  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 
study drug caused the event, then the event will be handled as “related to study drug” for 
reporting purposes.  If the investigator’s causality assessment is “unknown, but not related to 
study drug”, this should be clearly documented on study records and will be categorized as “not 
related to study drug” for reporting purposes.   
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, other 
illness, other, 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. For analysis purposes, “Suspected [Possible or Probable]” events are 
categorized as “Related.”  
7.9 
Withdrawal Due to Adverse Events 
Withdrawal due to AEs must be recorded on the appropriate AE CRF page.   


 
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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, PE 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, PA USA 
Office: +1-484-243-6222 
Mobile: +1-610-457-5095 
Facsimile: +1-734-207-3178 
7.11 
Study Hold or Stopping Criteria 
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) severity AE of special interest – see Section 
6.4.6 for list of AEs of special interest.   
ECGs are scheduled to be performed at Week 12 (end of treatment). 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.  
7.11.1 
Suspension of Study 
The study will be suspended if any subject experiences a drug-related adverse event that meets 
grade 4 or 5 CTCAE severity criteria or if 2 or more subjects experience the same type of grade 


 
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2 study drug-related adverse event and/or meets the serious criteria as defined in Section 7.2. The 
unblinded medical reviewer will review these cases to determine treatment assignment.  Adverse 
event reports will be submitted to regulatory agencies and clearance received before any further 
dosing takes place.  
8.0 
STATISTICAL AND ANALYTICAL PLAN 
8.1 
Sample Size Calculation 
A total of approximately 30 subjects will be randomized into the study and using a 2:1 
randomization ratio of LYC-30937-EC 25 mg or placebo daily.   
A sample size of 30 subjects (20 LYC-30937-EC and 10 placebo) will achieve approximately an 
80% power to detect difference in the mean percent change from baseline in PASI at Week 12 in 
the LYC-30937 treatment group compared to the placebo treatment group.  The mean percent 
change from baseline in PASI at Week 12 in the placebo treatment group is assumed to be 16.7% 
with SD=32.0.[16]  The power was computed assuming the mean percent change from baseline in 
PASI at Week 12 in the LYC-30937-EC treatment group is at least 52.7% (SD=32.0) for a mean 
difference of at least 36.0%.  The test statistic used is the two-sided t-test.  The alpha level of the 
test was targeted at 0.05. 
8.2 
Analysis Populations 
8.2.1 
Full Analysis Set 
The full analysis set (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.   
8.2.2 
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. 


 
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8.3 
Demographic and Subject Characteristics 
Demographic information and subject characteristics such as gender, race, age, and baseline vital 
signs, baseline PASI score, baseline % total BSA involvement, and baseline static IGA will be 
summarized by treatment group and overall.   
8.4 
General Statistical Considerations 
For safety and efficacy endpoints, baseline will be defined as the last observation prior to dosing.   
Continuous safety and efficacy endpoints will be summarized using mean, standard deviation, 
median, minimum, and maximum.  Discrete safety and efficacy endpoints will be summarized by 
the number and percent of subjects in each category.  Continuous efficacy endpoints will be 
analyzed using an analysis of covariance model with treatment as a factor and baseline value as a 
covariate.  Discrete variables will be analyzed using a chi-square test.  There will be no 
adjustments for multiplicity.  Additional details of the statistical analyses will be described in the 
statistical analysis plan (SAP).   
8.5 
Efficacy Analysis 
8.5.1 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is the mean percent change from baseline in PASI score at 
Week 12.  The endpoint will be calculated by taking the Week 12 PASI score and subtracting the 
baseline PASI score then dividing by the baseline PASI score and multiplying by 100 to get the 
percentage.  The mean percent change from baseline in PASI scores will be compared between 
the LYC-30937-EC treatment group and placebo using analysis of covariance with treatment as a 
factor and baseline as a covariate to assess the null hypothesis that the LYC-30937-EC arm mean 
percent change equals the placebo arm mean percent change  The mean difference (LYC-30937-
EC versus placebo) will also be estimated along with the 95% confidence interval of the 
difference. If the confidence interval does not contain 0 the null hypothesis will be rejected and 
the mean percent change from baseline in PASI score at Week 12 will be considered different 
due to treatment arm.  


 
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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 ≥ 75% reduction from baseline in PASI at Week 12 
will be calculated by taking the number of subjects who achieve a ≥ 75% reduction from 
baseline in PASI at Week 12 divided by the total number of subjects in each treatment arm.  
The proportion of subjects in each treatment arm will be compared using a chi-square test. 
 The mean percent change from baseline to Week 12 in the BSA will be calculated by taking 
the Week 12 BSA and subtracting the baseline percent BSA then dividing by the baseline 
percent BSA and multiplying by 100 to get the percentage of baseline.  The mean percent 
change in each treatment arm will be compared using the same methodology for the primary 
efficacy endpoint. 
 The proportion of subjects who achieve “cleared” (score = 0) or “minimal” (score = 1) on the 
static IGA at Week 12 will be calculated by taking the number of subjects who achieve 
“cleared” (score = 0) or “minimal” (score = 1) on the static IGA at Week 12 divided by the 
total number of subjects in each treatment arm.  The proportion of subjects in each treatment 
arm will be compared using a chi-square test. 
 The proportion of subjects who achieve at least a 2 step reduction on the static IGA at Week 
12 will be calculated by taking the number of subjects who achieve at least a 2 step reduction 
on the static IGA at Week 12 (ie, a score of 5 at baseline to a score of 3 or less at Week 12) 
divided by the total number of subjects in each treatment arm.  The proportion of subjects in 
each treatment are will be compared between treatment arms using a chi-square test.   
8.6 
Safety Analysis 
Adverse event collection begins after the subject signs the informed consent document and 
continues until Week 14.  For all randomized subjects, AEs should be recorded on CRFs from 
the time the subject has signed informed consent through Week 14.  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 are 
defined as AEs that start after study drug administration (LYC-30937-EC or placebo) and 
include worsening of conditions that existed prior to study drug administration.  Adverse events 


 
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that occur in subjects who screen fail will only be listed if they were the reason the subject was a 
screen failure.   
Adverse events and SAEs will be summarized by system organ class, by severity, and by 
relationship; this will be done by treatment group and overall.  Serious adverse events resulting 
in death will be listed and summarized separately. 
Other safety data, such as vital signs and clinical laboratory data will be summarized by study 
visit and treatment group.  Where appropriate, change from baseline in safety data will also be 
summarized  for each study visit, for end of treatment visit, and for “worse value” by treatment 
group. 


 
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9.0 
ETHICAL CONSIDERATIONS 
9.1 
Basic Principles 
The study will be performed in accordance with the protocol, ICH GCP guidelines, and 
applicable local regulatory requirements and laws.   
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. 


 
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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: 
 evaluate the progress of the study 
 verify the accuracy and completeness of the CRFs 
 verify the signed ICD, 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 
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 study, 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 


 
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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.   
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 documents, 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 initials and 
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] Jacobson CC, Kumar S, Kimball AB. Latitude and psoriasis prevalence. J Am Acad 
Dermatol. 2011;65(4):870-3. 
[2] Sa SM, Valdez PA, Wu J, Jung K, Zhong F, Hall L, et al. The effects of IL-20 subfamily 
cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate 
defense and pathogenic adaptive immunity in psoriasis. J Immunol. 2007;178(4):2229-40. 
[3] Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 
2007;445(7130):866-73. 
[4] Steinman L. Weighing in on autoimmune disease: ‘Hub-and-spoke’ T cell traffic in 
autoimmunity. Nat Med. 2013;19(2):139-41. 
[5] Odoardi F, Sie C, Streyl K, Ulaganathan VK, Schläger C, Lodygin D, et al. T cells become 
licensed in the lung to enter the central nervous system. Nature 2012;488(7413):675-9. 
[6] Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, et al. Expansion of 
intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife 
2013;2:e01202 
[7] Vaahtovuo J, Munukka E, Korkeamäki M, Luukkainen R, Toivanen P. Fecal microbiota in 
early rheumatoid arthritis. J Rheumatol. 2008;35(8):1500-5. 
[8] Wu HJ, Ivanov II, Darce J, Hattori K, SHima T, Umesaki Y, et al. Gut-residing segmented 
filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 
2010;32(6):815-27. 
[9] Morton AM, Sefik E, Upadhyay R, Weissleder R, Benoist C, Mathis D. Endoscopic 
photoconversion reveals unexpectedly broad leukocyte trafficking to and from the gut. Proc 
Natl Acad Sci U S A 2014;111(18):6696-701. 
[10] Boehncke WH, Schön MP. Psoriasis. Lancet 2015;386(9997):983-94. 
[11] Oliveira Mde F, Rocha Bde O, Duarte GV. Psoriasis:classical and emerging comorbidities. 
An Bras Dermatol 2015;90(1):9-20. 


 
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[12] Torres T, Bettencourt N. Psoriasis: the visible killer. Rev Port Cardiol. 2014;33(2):95-9. 
[13] Vanderpuye-Orgle J, Zhao Y, Lu J, Shrestha A, Sexton A, Seabury S, et al. Evaluating the 
economic burden of psoriasis in the United States. J Am Acad Dermatol. 2015;72(6):961-7. 
[14] Papp KA, Langley RG, Sigurgeirsson B, Abe M, Baker DR, Konno P, et al. Efficacy and 
safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis; a randomized 
double-blind, placebo-controlled phase II dose-ranging study. Br J Dermatol. 
2013;168(2):412-21. 
[15] Langley RGB, Feldman SR, Nyirady J, van de Kerkhof  P, Papavassilis C. The 5-point 
Investigator’s Global Assessment (IGA) scale: a modified tool for evaluating plaque 
psoriasis severity in clinical trials. J Dermatological Treatment 2015;26(1):23-31. 
[16] Papp K, Reich K, Leonardi CI, Kircik L, Chimenti S, Langley RGB, et al. Apremilast, an 
oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque 
psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial 
Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1).  J Am Acad Dermatol. 
2015;73(1):37-49. 
[17] Fredriksson T and Pettersson U. Severe psoriasis – oral therapy with a new retinoid. 
Dermatologica 1978;157:138-244 
 
 
 


 
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13.0 
APPENDICES 
13.1 
The PASI Scoring System 
Body Region 
Erythema (E) 
Thickness (I)  
(plaque elevation, 
induration) 
Scaling (S) 
(desquamation) 
Area score % (A) 4 
Head (H) 1 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=0% 
1=1-9% 
2=10-29% 
3=30-49% 
4=50-69% 
5=70-89% 
6=90-100% 
Trunk (T) 2 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=0% 
1=1-9% 
2=10-29% 
3=30-49% 
4=50-69% 
5=70-89% 
6=90-100% 
Upper extremities 
(U) 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=0% 
1=1-9% 
2=10-29% 
3=30-49% 
4=50-69% 
5=70-89% 
6=90-100% 


 
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Lower extremities 
(L) 3 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=0% 
1=1-9% 
2=10-29% 
3=30-49% 
4=50-69% 
5=70-89% 
6=90-100% 
1 Neck is evaluated as part of the head (H). 
2 Axillae and groin are evaluated as part of the Trunk (T). 
3 Buttocks are evaluated as part of the Lower extremities (L).  
4 Degree of involvement as a percentage for each body region affected. 
 
In the PASI the body is divided into 4 regions: head (H), trunk (T), upper extremities (U) and 
lower extremities (L). Each region is considered to account for the following % of total BSA, 
head = 10% (0.1), trunk = 30% (0.3), upper extremities = 20% (0.2) and lower extremities = 40% 
(0.4).   
 
Estimation of the % body area affected by psoriatic plaque in each region is done by the trained 
clinician using the palm (fingers included) and then converted the corresponding numeric score 
(0 to 6) as indicated in column 5 in the above table.   
 
Each region is also evaluated separately for signs of disease (erythema (E), thickening (I), and 
scaling (D), which are rated and given a score (0 to 4), as indicated in the above table.  
 
The PASI generates a numeric score that can range from 0 (no signs of psoriasis) to 72. 
 
Scores from the 4 regions are combined to get the PASI score using the PASI formula: 
PASI = 0.1(EH + IH = SH)AH  + 0.3(ET + IT + ST)AT + 0.2(EU + IU + SU)AU + 0.4(EL + IL + SL)AL 
 
The investigator will be responsible for collecting the components (E, I, S) and the total regional 
area. These components will be entered into the CRF and calculation of the PASI score will done 
in the CRF.  
 
 
 


 
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SAMPLE: PASI Scoring Worksheet 
Plaque Characteristics 
Lesion Score 
Head 
Upper 
extremities 
Trunk 
Lower 
Extremities 
Erythema (E) 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
 
 
 
 
Induration/Thickness (I) 
 
 
 
 
Scaling (S) 
 
 
 
 
Add together each of the 3 scores for each body region to give 4 separate sums (A) 
Lesion Score Sum (A) 
 
 
 
 
 
 
Percentage body 
surface area affected 
Area Score 
Head 
Upper 
extremities 
Trunk 
Lower 
Extremities 
Area Score (B) 
Degree of involvement 
as a percentage for each 
body region affected 
(each region given a 
score of 0 to 6) 
0 = 0% 
1 = 1 - 9% 
2 = 10 - 29% 
3 = 30 - 49% 
4 = 50 - 69% 
5 = 70 - 89% 
6 = 90 - 100% 
 
 
 
 
Multiply each Lesion Score Sum (A) by Area Score (B), for each body region, to give the 4 individual 
subtotals 
Subtotals (C) 
 
 
 
 
Multiply each of the Subtotals (C) by amount of body surface area represented by that region, i.e., x 0.1 
for head, x 0.2 for upper extremities, x 0.3 for trunk, and x 0.4 for lower extremities. 
Body Surface Area 
x 0.1 
x 0.2 
x 0.3 
x 0.4 
Totals (D) 
 
 
 
 
Add together each of the scores for each body region to give the total PASI Score. 
 
Total PASI Score = _____________ 


 
LYC-30937 
Clinical Protocol LYC-30937-2003 
Issue Date: 30 August 2016 
 
Confidential and Proprietary 
 
Page 63 of 63 
 
 
14.0 
DOCUMENT HISTORY 
 
Summary of Changes 
Document 
Version 
Date 
Description of Change 
Rationale 
 
 
 
 
Original 
Protocol 
30AUG 
2016 
NA 
NA 
 
 
 
 
 

SAP_001.pdf: