Clinical trial NCT02976129
Conditions: Crohn's Disease
Sponsor: VHsquared Ltd.
Start date: 2016-12-01; Completion date: 2019-03-08
Enrollment: 125 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of V565 in participants with active Crohn's Disease (CD).

Detailed description:
This study will be a multiple-site, double-blind, placebo-controlled, parallel-group study in approximately 126 subjects with a confirmed diagnosis of CD for at least three months and have CD involving the ileum and/or colon. Following a screening period of up to 28 days, subjects will be randomly allocated into one of two treatment arms: either V565 or placebo using a 2:1 active:placebo ratio for a treatment period of 6 weeks.

Subjects will be treated with study drug as an add-on to any permitted stable medications already being taken for CD.

Arms: arm 1: V565 three times a day (TID) PO for 6 weeks arm 2: Placebo TID PO for 6 weeks
Interventions: intervention 1: V565 intervention 2: Placebo
Intervention descriptions: intervention 1: Daily dosing of V565 three times a day orally for 6 weeks intervention 2: Daily dosing of placebo three times a day orally for 6 weeks

Protocol documents:
Prot_000.pdf: 
VHsquared Ltd 
 
1 
Protocol V56502 
Drug Name: V565 
02 December 2016 
 
Confidential 
 
 
Clinical Study Protocol 
Protocol Title:  
A Phase 2 study to investigate the efficacy, safety, and 
tolerability of six weeks treatment with V565 in subjects 
with active Crohn’s disease 
Protocol Number: 
V56502 
Date of Protocol: 
24 August 2016 
Date of Protocol Amendment: 
02 December 2016 
Version: 
Version 1.3 
Product: 
V565 
IND No.: 
130643 
EudraCT No.: 
2016-002939-15 
Study Phase: 
Phase 2  
Sponsor: 
VHsquared Ltd. 
1 Lower Court, Copley Hill Business Park 
Cambridge Road, Babraham,  
Cambridge, CB22 3GN, United Kingdom 
 
Confidentiality Statement 
This protocol is the confidential property of VHsquared Ltd., and is intended solely for the 
guidance of this clinical investigation. This protocol may not be disclosed to parties not 
associated with the clinical investigation or used for any other purpose without the prior 
written consent of VHsquared Ltd. The confidential information in this document is provided 
to you as an Investigator or consultant for review by you, your staff, and the applicable 
Institutional Review Board/Independent Ethics Committee. Your acceptance of this 
document constitutes agreement that you will not disclose the information contained herein to 
others without written authorisation from the Sponsor. 


VHsquared Ltd 
 
2 
Protocol V56502 
Drug Name: V565 
02 December 2016 
 
Confidential 
Signatures 
PROTOCOL TITLE: 
A Phase 2 study to investigate the efficacy, safety, and 
tolerability of six weeks treatment with V565 in subjects with active Crohn’s disease 
 
PROTOCOL NO: V56502 
Version 1.3  02 December 2016  
___________________________________  
 
________________________ 
Suhail Nurbhai, MBChB MRCP (UK) 
 
 
Date 
Chief Medical Officer 
VHsquared Ltd 
1 Lower Court, Copley Hill Business Park 
Babraham Road, Cambridge 
CB22 3GN, United Kingdom 
___________________________________  
 
________________________ 
Daniel Szabo, MD, EDA 
 
 
 
 
Date 
Medical Monitor 
QuintilesIMS 
Medical Director 
Immunology & Internal Medicine 
Medical Strategy & Science 
Therapeutic Science & Strategy Unit 
Budafoki u. 91-93.Budapest, 1117 - Hungary 
 


VHsquared Ltd 
 
3 
Protocol V56502 
Drug Name: V565 
02 December 2016 
 
Confidential 
SYNOPSIS 
Name of Sponsor/Company: 
VHsquared Ltd. 
Name of Finished Product: 
V565 
Name of Active Ingredient: 
V565 
Title of Study: 
A Phase 2 study to investigate the efficacy, safety, and tolerability of six weeks 
treatment with V565 in subjects with active Crohn’s disease 
Primary 
Investigator:   
Multiple sites 
Protocol No: 
V56502 
Study site(s): 
Proposed sites: Approximately 76  
Proposed territories:  North America, European Union (EU) (including West, Central 
and East EU countries).  
Study duration: The study consists of six site visits over approximately 12 weeks. 
The duration of treatment is 42 days (six weeks repeat dose administration).  
Phase: 2 
 
Objectives: 
Primary Objective: 
To evaluate the efficacy of V565 555 mg three times a day (TID) in subjects with active Crohn’s disease 
(CD) measured by the proportion of subjects achieving response to therapy. Response is defined as reduction 
in the Crohn's Disease Activity Index (CDAI) scores and in inflammatory markers (C-reactive protein [CRP] 
or faecal calprotectin [FCP] at Day 42.  
Secondary Objectives: 
 
To further characterise the efficacy of V565 in subjects with active CD assessed by changes in 
CDAI scores and/or inflammatory markers  
 
To assess the effects of V565 based on changes in Abdominal Pain and Stool Frequency instrument 
(PRO-2) scores 
 
To assess safety and tolerability of V565 
Pharmacokinetic Objectives: 
 
To determine the concentration of V565 in serum and urine 
Exploratory Objectives: 
 
To assess the proportion of subjects achieving CRP or FCP levels within normal limits  
 
To assess changes in CDAI scores and CRP or FCP levels over time 
 
To determine changes in anti-V565 antibody titre  
 
To evaluate the frequency of loose or watery stools, assessed using the Bristol Stool Form Scale 
(BSFS) 
 
To evaluate changes in abdominal pain using the Numeric Pain Scale (NPS) 
 
To evaluate changes in faecal urgency 
Exploratory Endoscopy Substudy Objectives: 
 
To investigate the effect of V565 on changes in endoscopic mucosal appearance, evaluated with an 
overall assessment and the Simple Endoscopic Score for Crohn's Disease (SES-CD), as determined 
by a central reader  


VHsquared Ltd 
 
4 
Protocol V56502 
Drug Name: V565 
02 December 2016 
 
Confidential 
Methodology: This study will be a multiple-site, double-blind, placebo-controlled, parallel-group 
proof-of-concept study in approximately 126 subjects with active CD. This study will include subjects who 
have a confirmed diagnosis of CD for at least three months and have CD involving the ileum and/or colon. 
Inclusion and exclusion criteria are described in detail in subsequent sections.  
The duration of treatment will be 42 days (six weeks); each subject’s participation in the study will be 
approximately 12 weeks. This includes a screening period of up to 28 days, a treatment period of 42 days and 
a follow-up period of 14 days after the last dose of study drug.  
Subjects will be randomised into two treatment arms: either V565 or placebo using a 2:1 active: placebo 
ratio. Randomisation will be stratified to ensure treatment groups have similar rates of prior anti-tumour 
necrosis factor alpha (TNFα) therapy.  
Subjects will receive three V565 185 mg capsules three times daily or matching placebo, for 42 days. The 
total daily V565 dose is 1665 mg. 
Subjects will be treated with study drug as an add-on to any permitted stable medications already being taken 
for CD. No alteration of background CD medication will be permitted for the duration of the study.  
There are six study visits. Two screening visits to assess eligibility will occur during Days -28 to Day -1; 
these are Visit 1 (start of screening), and Visit 2 (eligibility ileocolonoscopy). Additional study visits will 
occur on Day 1 (randomisation and initiation of treatment), Day 14 (Interim Visit), Day 42 (End of 
Treatment Visit), and Day 56 (Follow up Visit).  
Collection of subject-reported variables of the CDAI will be via diaries given to the subject at Visit 1. Prior 
to Visit 2, the subject-reported variables will be combined with the variables collected at the site on Visit 1 
and the CDAI score will be calculated. In order to have an ileocolonoscopy, eligible subjects must have 
sufficient diary entries to calculate a CDAI score, a CDAI score ≥220 to ≤450 and a CRP ≥5 mg/L (or if CRP 
is normal, FCP ≥250 µg/g) prior to Visit 2.  
A previous ileocolonoscopy conducted within 12 weeks before Visit 1 may be substituted for the Visit 2 
ileocolonoscopy provided it is forwarded to the central reader and was performed in such a way as to enable 
evaluation by the central reader.  
The Visit 2 ileocolonoscopy will be evaluated by a central reader for to assess the overall appearance of the 
mucosa for the presence of active disease and scored using the SES-CD. Active disease must be confirmed 
by the central reader for the subject to proceed to Visit 3 and to be randomised on Day 1.   
The efficacy of V565 will be evaluated by assessing CDAI scores, biomarkers (CRP or FCP), and the 
PRO-2.  
Exploratory efficacy measures include changes in CDAI scores, changes in CRP (or FCP) values over time, 
the frequency of loose or watery stools as measured by the BSFS, the degree of abdominal pain as measured 
by the NPS, and changes in faecal urgency. This study will also evaluate the immunogenicity of V565.  
In an exploratory endoscopy substudy, subjects with more severe disease at the Visit 2 ileocolonoscopy 
(a SES-CD ≥7, if ileum and colon are involved or ≥4 if only the ileum is involved) will undergo a second 
ileocolonoscopy at the end of treatment (Day 42) to evaluate changes in the mucosa. 
Pharmacokinetic (PK) evaluations will be based on concentrations of V565 measured in serum and urine.   
Safety will be assessed through evaluations of adverse events (AEs), clinical laboratory results, vital signs, 
physical examinations, electrocardiograms (ECGs) and concomitant medications.  
Planned number of subjects: 
Approximately 126 randomised to receive study drug in a 
2:1 active:placebo ratio (84:42)  
Approximately 114 to complete (76:38) based on an estimated dropout 
rate of 10% during treatment 


VHsquared Ltd 
 
5 
Protocol V56502 
Drug Name: V565 
02 December 2016 
 
Confidential 
Diagnosis and 
main criteria for inclusion: 
This study will enrol adult subjects with active CD. The main criteria for 
inclusion are:  
1. History of CD (confirmed by ileocolonoscopy) of at least three 
months duration prior to Visit 1 
2. CDAI score of ≥220 to ≤450 during Screening   
3. CRP ≥5 mg/L (or, if CRP is normal, FCP ≥250 µg/g) at 
Screening 
4. Active CD of ileum and/or colon as determined by the baseline 
ileocolonoscopy  
5. Female subjects must not be pregnant and male and female 
subjects must agree to use effective contraception throughout 
the study and for 90 days after the last dose of study drug.  
6. Subject must have failed or experienced intolerance to at least 
one of the following: aminosalicylates, corticosteroids; 
immunosuppressants (e.g., azathioprine [AZA], 
6-mercaptopurine [6-MP], or methotrexate [MTX]). 
In addition, in order to participate in the exploratory endoscopy substudy, 
subjects must have a SES-CD ≥7 (if ileum and colon are involved) or ≥4 
(if only the ileum is involved) at the baseline ileocolonoscopy.  
 
The main criteria for exclusion are:  
1. CD of mouth, stomach, oesophagus or duodenum which, in the 
opinion of the Investigator, is likely to be causing symptoms  
2. Known history of or suspicion of ulcerative colitis, 
indeterminate colitis, microscopic colitis, ischaemic colitis or 
radiation-induced colitis, based on medical history, endoscopy 
and/or histological findings. 
3. Any gastrointestinal (GI) manifestations of CD that might affect 
the evaluation of efficacy 
4. Prior primary efficacy failure of or secondary loss of response to 
anti-TNFα therapy, or any contraindication to anti-TNFα 
therapy 
5. The use of medications prior to the study or during the study 
with the potential to affect the evaluation of efficacy 
6. Recent changes in background CD medications.  
7. History or recurrent infections, a current infection with a GI 
pathogen or an increased risk of infection  
Test product, dose and mode 
of administration: 
V565 Oral capsule  
Dose: 185 mg/capsule  
Regimen: Three capsules, three times daily, for 42 days 
Reference therapy, dose, and 
mode of administration: 
Matching placebo capsules administered in the same manner as test 
product. 


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Protocol V56502 
Drug Name: V565 
02 December 2016 
 
Confidential 
Criteria for evaluation: 
Primary Efficacy Endpoint: 
 
Proportion of responders at Day 42, defined as subjects achieving both CDAI ≥70-point reduction 
from Baseline OR CDAI score <150, AND a reduction of ≥40% from the baseline value of CRP or 
FCP 
Secondary Efficacy Endpoints: 
 
Proportion of subjects achieving a ≥100-point reduction in CDAI score and a concomitant reduction 
of 50% in CRP or FCP at Day 42 
 
Proportion of subjects achieving a ≥70-point reduction in CDAI score at Day 42 
 
Proportion of subjects achieving a ≥100-point reduction in CDAI score at Day 42 
 
Proportion of subjects achieving a CDAI score of <150 CDAI at Day 42  
 
Changes from Baseline in scores for PRO-2 at Day 14 and Day 42  
Safety Endpoints:   
 
Evaluations of AEs, clinical laboratory results, physical examination findings, ECGs and vital signs 
throughout the study 
Pharmacokinetic Endpoint: 
 
Serum and urine concentration of V565 prior to first administration of study drug and at Day 14, 
Day 42, and Day 56. In addition, On Day 1, a post-dose urine sample will be obtained at the site 
4 to 8 hours after the first dose of study drug.   
Exploratory Endpoints: 
 
Proportion of subjects achieving CRP or FCP levels within normal limits at Day 14 and Day 42 
 
Changes from Baseline in CDAI score over time  
 
Changes from Baseline in CRP or FCP levels over time  
 
Change from Baseline in anti-V565 antibody titre at Day 14, Day 42, and Day 56 
 
Changes from Baseline in the frequency of loose or watery stools (Type 6 or Type 7) as measured 
by the BSFS  
 
Changes from Baseline in the abdominal NPS  
 
Changes from Baseline in faecal urgency 
Exploratory Endoscopy Substudy Endpoints:  
 
Changes from Baseline in endoscopic mucosal appearance after 42 days treatment evaluated by 
changes in overall mucosal appearance and changes in SES-CD as determined by a central reader. 
Note: this substudy will be limited to subjects with a baseline SES-CD ≥7 (if ileum and colon are 
involved) or ≥4 (if only ileum is involved).  
Statistical methods: 
Determination of sample size: 
The sample size is based on being able to claim superiority of V565 over placebo; the primary endpoint is 
defined as a response rate, based on CDAI reduction/remission and CRP or FCP results.  
It is assumed that the proportion of subjects assigned to placebo treatment who respond is 0.15. A clinically 
important response rate on V565 is defined as 0.4. A 2:1 (V565:placebo) allocation, 80% power and 5% 
statistical significance rate estimate 76:38 evaluable subjects will be required for this study. With a 10% 
estimated non-evaluable rate, it is planned to assign 126 subjects (84:42) to randomised treatment. 
Sample size estimates are based on a Pearson chi-square test for two proportions and generated using SAS 
Power and Sample Size v13.2. 
A subgroup of subjects will be assessed by endoscopy for changes in overall mucosal appearance and 
changes in SES-CD. However, the study is not powered to show a difference in these endpoints. 
Statistical Analysis: 
As appropriate, variables will be summarised descriptively (frequency and percentage will be summarised for 
categorical variables; mean, standard deviation [SD], median, minimum, and maximum will be presented for 
continuous variables) by study visit and by treatment group. All study data will be listed by subject. 
A detailed Statistical Analysis Plan (SAP) including dictionaries used for coding and software used will be 
finalised prior to the initial unblinding of the study. 


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7 
Protocol V56502 
Drug Name: V565 
02 December 2016 
 
Confidential 
Efficacy 
The primary endpoint will be analysed using a logistic regression model with treatment as the fixed effect 
and prior anti-TNFα therapy, baseline CDAI score, baseline CRP and baseline FCP values as covariates. For 
the active treatment versus placebo comparison, the results will be presented in terms of an odds ratio 
together with its associated 95% confidence interval (CI) and 2-sided p-value. Two-sided 95% CIs for the 
odds ratio will be provided. 
Unless otherwise specified, the proportions of subjects fulfilling the relevant requirements will be presented 
with 95% CIs for all the primary and secondary endpoints.  
Safety 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and will be tabulated 
in incidence tables by System Organ Class (SOC) and Preferred Term. 
AEs will be summarised by SOC, Preferred Term, and treatment group. AEs will be further summarised by 
maximum severity and relationship to study medication. Prior and concomitant medications will be 
summarised by treatment. Other routine safety assessments such as vital signs, ECG and safety laboratory 
tests will be summarised by treatment group using statistics for continuous or categorical data, as appropriate.  
Pharmacokinetics 
The drug concentration results in serum and urine will be summarised by planned sampling time and 
treatment group. 


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8 
Protocol V56502 
Drug Name: V565 
02 December 2016 
 
Confidential 
TABLE OF CONTENTS 
SIGNATURES..........................................................................................................................2 
1.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................12 
2.0 
INTRODUCTION......................................................................................................15 
2.1 
Background Information ..............................................................................15 
2.2 
Rationale .........................................................................................................17 
2.3 
Hypothesis .......................................................................................................18 
2.4 
Risk Assessment and Management of Risk .................................................18 
2.4.1 
Potential Risks Associated with V565 ..............................................18 
2.4.2 
Potential Risks Associated with Underlying Disease and 
Study Design .....................................................................................19 
2.4.3 
Risk-benefit Analysis ........................................................................19 
2.5 
Administrative Structure ..............................................................................20 
3.0 
STUDY OBJECTIVES AND ENDPOINTS ............................................................22 
3.1 
Study Objectives.............................................................................................22 
3.1.1 
Primary Objective ..............................................................................22 
3.1.2 
Secondary Objectives ........................................................................22 
3.1.3 
Pharmacokinetic Objectives ..............................................................22 
3.1.4 
Exploratory Objectives ......................................................................22 
3.1.5 
Exploratory Endoscopy Substudy Objectives ...................................22 
3.2 
Study Endpoints .............................................................................................23 
3.2.1 
Primary Endpoint ...............................................................................23 
3.2.2 
Secondary Endpoints .........................................................................23 
3.2.3 
Safety Endpoints ................................................................................23 
3.2.4 
Pharmacokinetic Endpoints ...............................................................23 
3.2.5 
Exploratory Endpoints .......................................................................23 
3.2.6 
Exploratory Endoscopy Substudy Endpoints ....................................23 
4.0 
INVESTIGATIONAL PLAN ...................................................................................24 
4.1 
Summary of Study Design .............................................................................24 
4.2 
Description of Study Periods.........................................................................29 
4.2.1 
Screening: Visit 1 and Visit 2 (Ileocolonoscopy) (Day -28 
to Day -1) ...........................................................................................29 
4.2.2 
Treatment Period ...............................................................................29 
4.2.3 
Follow-up: Day 56 .............................................................................30 
4.2.4 
30-day Post-treatment ........................................................................30 
4.2.5 
Early Termination Visit .....................................................................30 
4.2.6 
Unscheduled Visits ............................................................................30 
4.3 
Discussion of Study Design ............................................................................31 
4.4 
Selection of Study Population .......................................................................32 
4.4.1 
Inclusion Criteria ...............................................................................32 


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Protocol V56502 
Drug Name: V565 
02 December 2016 
 
Confidential 
4.4.2 
Exclusion Criteria ..............................................................................33 
4.5 
Subject Withdrawal .......................................................................................35 
4.6 
Lost to Follow-up ...........................................................................................36 
5.0 
STUDY TREATMENTS ...........................................................................................37 
5.1 
Treatments Administered .............................................................................37 
5.2 
Identity of Investigational Product(s) ..........................................................37 
5.3 
Storage ............................................................................................................38 
5.4 
Supply, Packaging and Labelling .................................................................38 
5.5 
Accountability ................................................................................................38 
5.6 
Method of Assigning Subjects to Treatment Group ...................................38 
5.7 
Selection of Doses in the Study .....................................................................39 
5.8 
Selection and Timing of Dose for Each Subject ..........................................39 
5.9 
Blinding ...........................................................................................................39 
5.10 
Prior and Concomitant Treatments .............................................................39 
5.10.1 
Prior and Concomitant Medications ..................................................39 
5.10.2 
Permitted Medications .......................................................................40 
5.10.3 
Prohibited Medications ......................................................................40 
5.11 
Medical Care of Subjects after End of Study ..............................................41 
5.12 
Treatment Compliance ..................................................................................41 
5.13 
Study Drug Accountability............................................................................41 
6.0 
EFFICACY, 
PHARMACOKINETIC, 
SAFETY, 
HEALTH 
OUTCOME, AND PHARMACOGENOMIC ASSESSMENTS ...........................42 
6.1 
Efficacy Assessment .......................................................................................42 
6.1.1 
Subject Diary .....................................................................................42 
6.1.2 
Crohn’s Disease Activity Index .........................................................42 
6.1.3 
Biomarkers of Inflammation .............................................................43 
6.1.4 
Abdominal Pain and Stool Frequency Instrument (PRO-
2) ........................................................................................................44 
6.1.5 
Ileocolonoscopy .................................................................................44 
6.1.6 
SES-CD .............................................................................................45 
6.1.7 
Exploratory Efficacy Measures .........................................................45 
6.1.7.1 
Bristol Stool Form Scale .................................................45 
6.1.7.2 
Numeric Pain Scale .........................................................45 
6.1.7.3 
Faecal Urgency ................................................................46 
6.2 
Safety Assessments .........................................................................................46 
6.2.1 
Adverse Events ..................................................................................46 
6.2.1.1 
Monitoring of Adverse Events ........................................49 
6.2.1.2 
Recording of Adverse Events ..........................................49 
6.2.1.3 
Reporting of Serious Adverse Events ..............................50 
6.2.1.4 
Reporting of Serious Adverse Events to 
Regulatory Authorities and Investigators ........................51 
6.2.1.5 
Follow-Up of Adverse Events .........................................51 
6.2.1.6 
Pregnancy ........................................................................51 
6.2.2 
Contraception ....................................................................................52 
6.2.3 
Clinical Laboratory Evaluations ........................................................53 


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Protocol V56502 
Drug Name: V565 
02 December 2016 
 
Confidential 
6.3 
Vital 
Signs, 
Physical 
Examination 
and 
Other 
Safety 
Assessments ....................................................................................................54 
6.3.1 
Vital Signs .........................................................................................54 
6.3.2 
Physical Examination, Height and Weight ........................................55 
6.3.3 
Electrocardiogram .............................................................................55 
6.3.4 
Medical History .................................................................................56 
6.4 
Immunogenicity..............................................................................................56 
6.5 
Pharmacokinetics ...........................................................................................56 
6.5.1 
Blood .................................................................................................57 
6.5.2 
Urine ..................................................................................................57 
6.6 
Pharmacogenetics ..........................................................................................57 
6.7 
Appropriateness of Measurements ...............................................................58 
7.0 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................59 
7.1 
Monitoring ......................................................................................................59 
7.2 
Data Management/Coding ............................................................................60 
7.3 
Quality Assurance Audit ...............................................................................61 
8.0 
STATISTICS ..............................................................................................................62 
8.1 
Determination of Sample Size .......................................................................62 
8.2 
Statistical Methods .........................................................................................62 
8.2.1 
Primary Efficacy Analysis .................................................................63 
8.2.2 
Secondary Efficacy Analyses ............................................................63 
8.2.3 
Exploratory Analyses ........................................................................63 
8.2.4 
Pharmacokinetic Analysis .................................................................64 
8.2.5 
Safety Analyses .................................................................................64 
8.2.5.1 
Adverse Events ................................................................64 
8.2.5.2 
Safety Laboratory Tests ...................................................65 
8.2.5.3 
Vital Signs and 12-lead ECG ..........................................65 
8.2.5.4 
Physical Examinations .....................................................65 
8.2.5.5 
Concomitant Medications ................................................65 
8.2.6 
Data To Be Analysed .........................................................................65 
8.2.7 
Analysis Populations .........................................................................66 
8.2.8 
Missing Data ......................................................................................66 
8.2.9 
Subgroup Analysis .............................................................................66 
8.3 
Interim Analyses ............................................................................................66 
9.0 
ETHICS ......................................................................................................................67 
9.1 
Institutional Review Board or Independent Ethics Committee ................67 
9.2 
Ethical Conduct of the Study ........................................................................67 
9.3 
Subject Information and Informed Consent ...............................................68 
9.4 
Subject Data Protection .................................................................................68 
10.0 
STUDY ADMINISTRATION ..................................................................................69 
10.1 
Administrative Structure ..............................................................................69 
10.2 
Data Handling and Record Keeping ............................................................69 
10.3 
Direct Access to Source Data/Documents ....................................................69 


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Protocol V56502 
Drug Name: V565 
02 December 2016 
 
Confidential 
10.4 
Investigator Information ...............................................................................70 
10.4.1 
Investigator Obligations ....................................................................70 
10.4.2 
Protocol Signatures ............................................................................70 
10.4.3 
Publication Policy ..............................................................................70 
10.5 
Financing and Insurance ...............................................................................70 
11.0 
REFERENCES ...........................................................................................................71 
12.0 
APPENDICES ............................................................................................................74 
12.1 
Sample Crohn’s Disease Activity Index (CDAI) Score ..............................74 
12.2 
Sample Bristol Stool Chart ...........................................................................75 
12.3 
Signature of Investigator ...............................................................................76 
12.4 
Protocol Amendment 1.3 Summary of Changes .........................................77 
 
LIST OF TABLES 
Table 1: Administrative Structure ............................................................................................20 
Table 2: Schedule of Events ....................................................................................................26 
Table 3: Components of V565 Drug Product ..........................................................................37 
Table 4: Clinical Laboratory Testing .......................................................................................54 
 
LIST OF FIGURES 
Figure 1: Study Diagram ..........................................................................................................25 
 


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Protocol V56502 
Drug Name: V565 
02 December 2016 
 
Confidential 
1.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF 
TERMS 
Abbreviation 
Definition 
5-ASA 
5-aminosalicylic acid 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase  
ALT 
Alanine aminotransferase 
Anti-HBc, Total 
Hepatitis B core total antibody 
Anti-HBs 
Hepatitis B surface antibody 
Anti-HCV 
Hepatitis C antibody 
APTT 
Activated partial thromboplastin time  
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AZA 
Azathioprine  
BMI 
Body mass index 
β-hCG 
Beta human chorionic gonadotropin 
BP 
Blood pressure 
BSFS 
Bristol Stool Form Scale 
CD 
Crohn's Disease 
CDAI 
Crohn's Disease Activity Index  
CI 
Confidence Interval 
CHMP 
Committee for Medicinal Products for Human Use  
CRO 
Contract Research Organisation 
CRP 
C-reactive protein 
CTFG 
Clinical Trial Facilitation Group  
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ET 
End of treatment 
EU 
European Union 
FCP 
Faecal calprotectin  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 


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Protocol V56502 
Drug Name: V565 
02 December 2016 
 
Confidential 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice   
HBsAg 
Hepatitis B surface antigen 
HCT 
Haematocrit  
HDPE 
High-density polyethylene  
HIV 
Human immunodeficiency virus 
HPMC 
Hydroxypropyl methylcellulose   
IB 
Investigator’s Brochure 
IBD 
Inflammatory bowel disease 
ICF 
Informed consent form  
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IM 
Intramuscular  
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
IWRS 
Interactive Web Activated Response System  
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures  
6-MP 
6-Mercaptopurine  
MTX 
Methotrexate  
NPS 
Numeric Pain Scale 
NSAID 
Non-steroidal anti-inflammatory drug 
PK 
Pharmacokinetics 
PP 
Per Protocol  
PRO-2 
Abdominal Pain and Stool Frequency Instrument 
QTcF 
QTc using the Fridericia correction  
SAE 
Serious adverse event 
SAF 
Safety (Population) 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SES-CD 
Simple Endoscopic Score for Crohn's Disease  
SOC 
System Organ Class 
SOP 
Standard operating procedure 


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SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis  
TEAE 
Treatment-emergent adverse event 
TID 
Three times a day (ter in die) 
TNFα 
Tumour necrosis factor alpha 
ULN 
Upper limit of normal 
U.S. 
United States of America 
VHH 
Variable heavy chain antibody 


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2.0 INTRODUCTION 
2.1 
Background Information 
Inflammatory bowel disease (IBD) includes both Crohn’s disease (CD) and ulcerative colitis 
as well as other less prevalent, destructive diseases of the gastrointestinal (GI) tract. Crohn’s 
disease is characterised by a chronic, relapsing, progressive course of intestinal inflammation 
and damage and generally begins in young adulthood. The incidence and prevalence of CD is 
increasing worldwide with current incidence of 6 to 15/100,000 and prevalence estimated at 
50 to 200/100,000 [1]. The highest incidences of CD have been reported in northern Europe, 
the UK and North America suggesting common etiological factors, but the rate of growth is 
increasing rapidly in other parts of the world [2].  
The aetio-pathogenesis of CD is not fully understood but genetic and environmental factors 
interact to promote an excessive and poorly controlled mucosal inflammatory response 
against components of gut micro-flora. The excessive production of proinflammatory 
cytokines within mucosal and sub-mucosal tissues drives chronic inflammatory processes 
within the gut wall that are responsible for development of the disease immunopathology. 
Evidence from clinical studies with systemically delivered anti-tumour necrosis factor alpha 
(TNFα) antibodies has clearly established that blocking the biological effects of TNFα is 
beneficial in the treatment of CD and has confirmed the central importance of this master 
proinflammatory cytokine as a mediator of disease pathogenesis. 
If disease control is inadequate, the chronic inflammation leads to significant inflammatory, 
infectious and structural complications. The complications result in an increased need for 
hospitalisation and surgery, impaired quality of life, and disease-related mortality. For 
example, in CD approximately half of all patients will experience an intestinal complication 
within 20 years, often leading to the need for surgical intervention [3]. Moreover, persistent 
and extensive intestinal inflammation increases the risk of developing small bowel and 
colorectal carcinoma [4].  
The traditional goal of treatment in IBD is to first induce, and then to maintain, clinical 
remission. Therapeutic decisions tend to be driven by the absence of clinical symptoms but 
accumulating data show that achieving this goal does not necessarily determine the 
subsequent clinical course of the disease or prevent the damaging long-term sequelae [5, 6]. 
The goal for therapy has thus shifted to include achieving healing of the gut mucosa with a 
view to reducing disability and bowel damage. The conventional strategy adopted for 
treatment (stepwise, sequential introduction of therapies starting with the least expensive and 
least systemically active medications and then gradually intensifying therapy) is being 
challenged because it is associated with lower efficacy, disease progression, a potentially 
higher risk of infections and, in moderate to severe disease, increased mortality. The use of 


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this conventional treatment strategy increases the likelihood that structural complications will 
develop before therapies proven to prevent such complications are introduced.  
Parenterally administered TNFα monoclonal antibodies such as infliximab, adalimumab and 
certolizumab pegol have been validated as transformative CD therapies that can affect disease 
progression and improve long-term outcomes. They are utilised for induction of a clinical 
response, remission, prevention of relapse, corticosteroid sparing and mucosal healing in 
patients with moderate to severely active CD. Data have accumulated to support the case for 
earlier intervention with these systemic TNFα biologics. Observational, subgroup analyses 
and randomised control trial data, both in adults and in paediatric populations, indicate that 
TNFα antagonists are much more effective when given to patients within 1 to 2 years of 
initial diagnosis and that early intervention prior to prolonged steroid administration 
improves clinical outcomes [6, 7, 8].  
Therefore, the goal of therapy has expanded from just the control of symptoms to include the 
prevention of disease. Further, the indications are that the earlier a potent, safe, disease 
modifying TNFα antagonist therapy can be provided to patients, the better the outcomes. 
However, the only biological agents to date that have been shown to be capable of achieving 
this goal are severely restricted to patients who have either failed or not responded to 
conventional therapy. Only a minority of patients with CD currently receive systemic 
anti-TNFα therapy and they are generally used as second or third line agents. Two major 
barriers to expanded use across a wider spectrum of patients with CD are cost and safety 
concerns. In addition, immunogenicity is a major issue that affects the durability of response 
seen with systemic anti-TNFα biologics. This may result in both primary and secondary loss 
of response and lead to cycling between different products. 
VHsquared Ltd. (hereinafter, the “Sponsor”) is developing an orally active, protease 
stabilised, engineered domain antibody against TNFα that may deliver significant advantages 
over current systemically administered anti-TNFα agents. The enhanced safety profile 
provided by local targeting and minimal systemic exposure and the expected low 
immunogenicity has the potential to provide the proven efficacy benefits of anti-TNFα 
therapy to a wider spectrum of patients. It may allow earlier intervention in the disease 
course, thus potentially maximising the clinical benefit of TNFα inhibition. The minimal 
systemic exposure would promote use in paediatrics and pregnancy, areas where parenteral 
administration and lack of a safe potent oral formulation are currently problematic. 
The multi-particulate V565 oral formulation planned for further clinical use has been 
evaluated in a toxicology programme with dosing up to six weeks, and a Phase 1 clinical 
study including 49 healthy volunteers and subjects with dosing up to 14 days. Results from 
these studies support further investigation of V565 as a potential therapy for CD. 
The Phase 1 study was conducted in four parts: 


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In Part 1 (n=29) 19 healthy volunteers received a single dose of V565 at a dose of either 
62 mg (n=4), 185 mg (n=4), 555 mg (n=3), 1665 mg (n=4), 4995 mg (n=4), or placebo 
(n=10) in a conventional single ascending dose design. 
In Part 2 (n=10) eight healthy volunteers received multiple doses of V565 (1665 mg three 
times a day [TID]) and two received placebo TID for 14 days. The objectives were to assess 
safety and tolerability of multiple doses of V565, and to investigate potential immunogenicity 
following multiple dosing. 
In Part 3 (n=4) otherwise healthy subjects with a terminal ileostomy received a single dose of 
V565 1665 mg to evaluate V565 luminal concentrations at the terminal ileum. 
Part 4 (n=6) was a single ascending dose study that investigated systemic exposure in 
subjects with mild to moderate CD. Two subjects received a single 555 mg dose and, 
following review by the Safety Review Committee, a further four subjects received a single 
1665 mg dose. This was considered important as patients with CD have increased intestinal 
permeability compared to healthy volunteers, which could potentially lead to increased 
systemic exposure. In addition, in this part of the study, urine collections were scheduled as 
an indirect method of assessing systemic exposure in case V565 was not detectable in serum 
samples.  
The results of the Phase 1 study are summarised below: 
 V565 has been administered to 37 human subjects in single doses up to 4995 mg 
and in multiple doses up to 1665 mg TID for 14 days. V565 was safe and well 
tolerated. There were no deaths, no serious adverse events (SAEs) and no adverse 
events (AEs) leading to withdrawal or change of dose. Almost all AEs were mild, 
with the only severe AE being a report of tonsillitis with initial symptoms starting 
approximately three hours after a 62 mg dose.   
 V565 was not detectable in any serum sample in any part of the study.  
 V565 was detected in the urine collection taken four to eight hours after dosing of 
one subject with CD in Part 4, confirming that active V565 passes across the 
lamina propria. 
 No neutralising anti-drug antibodies were detected in any subject. 
 High concentrations of active V565 were detected in ileal fluid and faeces.  
Additional non-clinical information is provided in the current version of the V565 
Investigator's Brochure (IB).  
2.2 
Rationale 
There is a medical need for a targeted anti-TNFα therapy that would minimise systemic 
exposure (and the side effects associated with systemic exposure), while providing effective 
treatment to the affected portions of the GI tract. Data from the Phase 1 study suggest that, 
relative to other anti-TNFα products (which are given parenterally and result in systemic 


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exposure), orally administered V565 results in a very low level of systemic exposure. 
Therefore, V565 may be expected to have a better safety profile than other anti-TNFα 
products. In addition, orally administered V565 provides a more convenient route of 
administration than the parenteral route used for other anti-TNFα products. This proof-of-
concept Phase 2 study will evaluate the efficacy, safety, pharmacokinetics (PK), and 
immunogenicity in subjects who receive V565 in combination with any ongoing, permitted 
background treatment for CD. Permitted background treatments (those that will not interfere 
with the evaluation of the efficacy of V565) are described in Section 5.10.2. 
2.3 
Hypothesis 
The hypothesis of this study is that the proportion of subjects at Day 42 achieving both  
 Crohn’s Disease Activity Index [CDAI] ≥70-point reduction from Baseline OR a 
CDAI score <150 
AND 
 A reduction of ≥40% from baseline value of C-reactive protein [CRP] or faecal 
calprotectin [FCP])  
will be higher in subjects who receive V565 than in subjects who receive placebo when used 
in combination with their permitted background CD medications. 
2.4 
Risk Assessment and Management of Risk 
2.4.1 
Potential Risks Associated with V565 
The safety profile of parenteral anti-TNFα therapy is well-established [9]. Because of the low 
level of systemic exposure associated with V565, it is anticipated that the potential adverse 
effects of anti-TNFα therapy will be minimised.  
V565 was not associated with any treatment-related adverse effects in non-clinical toxicology 
studies. V565 was safe and well tolerated in the Phase 1 study and there were no deaths, no 
SAEs and no AEs leading to withdrawal. Most AEs were mild.  
Based on the mode of action of anti-TNFα therapy there may be an increased risk of GI and 
other infections. This risk is being mitigated by excluding subjects with a high risk of 
infections (such as those with tuberculosis [TB], infection with GI pathogens, current 
infection, or history of recurrent infections). During the study, subjects will be closely 
monitored for the occurrence of GI and other infections.  
No reproductive toxicity studies have been carried out to date. While there is post-marketing 
data on the outcome of pregnancies in women taking TNFα inhibitors, women of 
childbearing potential must not enter this study if they are pregnant or breastfeeding, and both 
male and female study subjects must take adequate precautions to prevent pregnancy. 


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No data exist on the effects of overdose with V565. Preclinical assessment has revealed no 
adverse effects at high levels of systemic exposure. The No Observed Adverse Effect Level 
(NOAEL) is defined as at least 75 mg/kg/day when administered by intravenous (IV) 
infusion to monkeys for 6 weeks. This resulted in a maximum concentration (Cmax) of 317 
µg/mL after 6 weeks treatment. To date, 37 human subjects have received oral doses of V565 
up to 4995 mg in a single dose and 1665 mg TID for 14 days. V565 was not detectable in any 
serum sample. No subject has had a serum concentration above the lower limit of 
quantification (62.5 ng/mL) at any dose administered. 
In the unlikely event of overdose, it is recommended that supportive measures are taken and 
further doses are withheld.  
2.4.22.3.1 Potential Risks Associated with Underlying Disease and Study Design 
Lack of Efficacy: The subjects in this study will remain on their allowed background therapy 
for the treatment of CD. Therefore, using V565 or placebo as an “add-on” therapy to the 
subject’s pre-existing CD treatment regimen provides the subject with their minimal therapy.  
A rescue strategy has not been implemented because the study is only 6 weeks treatment 
duration, which is a short time from a CD perspective. However, if there are any concerns, 
the subjects are free to discontinue treatment at any time.  
There is no guarantee that the study drug will have the expected efficacy; however, the 
relatively short duration of treatment (six weeks) minimises the amount of time the subject 
might be at risk of treatment with an ineffective study drug. All subjects will be closely 
monitored during the study. If a subject’s condition worsens, and/or they require prohibited 
medications for the control of CD, they will be withdrawn from the study and treated as 
considered appropriate by their physician. Finally, the study excludes individuals who have 
failed to respond to anti-TNFα therapy in the past and who therefore might be at risk of 
failing to respond to oral V565.  
Study-related Procedures: The procedures used in this study are consistent with those used in 
the evaluation of CD as part of the Committee for Medicinal Products for Human Use 
(CHMP) guideline [10]. While ileocolonoscopy is an invasive procedure, it is routinely 
conducted in patients with CD to inform decision making for the appropriate therapy for the 
patient. The risks associated with all procedures will be explained to subjects as part of the 
informed consent process.  
2.4.32.3.2 Risk-benefit Analysis 
Crohn’s disease is a serious, progressive, and lifelong disease for which there is an unmet 
medical need for effective therapy. Anti-TNFα therapies are recognised as effective and 
important treatments for patients with CD, but they are given by parenteral administration. 
Therefore, treatment with these products results in systemic suppression of the activity of 
TNFα throughout the body for prolonged periods.  


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V565 is an engineered domain antibody to TNFα selected to be resistant to GI proteases, and 
formulated for oral administration. The formulation is designed to release active compound 
such that it is available to the ileum and colon, the regions of the GI tract most commonly 
affected by CD. In addition, preclinical and clinical data show that when administered orally, 
minimal V565 reaches the systemic circulation. This profile represents a potential benefit for 
the treatment of patients with CD, maximising delivery to the site of TNFα production in the 
lamina propria, and minimising anti-TNFα exposure to other parts of the body.  
This study has been designed to minimise potential risks to subjects. The exclusion criteria 
and screening procedures were designed to exclude subjects who may be at undue risk if they 
participate in the study.  
As this is a proof-of-concept study, there may be no benefit from participation in the study to 
an individual subject. However, there is the expectation that subjects treated with V565 will 
experience improvements in the symptoms of their underlying disease.  
In summary, the assessment of potential risks associated with V565 in non-clinical and 
clinical studies conducted to date support further evaluation in humans. 
This study will be performed in compliance with the protocol, International Council for 
Harmonisation (ICH), Good Clinical Practice (GCP), and applicable regulatory requirements. 
2.52.4 Administrative Structure 
VHsquared Ltd. is the Sponsor for this study. Details concerning the administrative structure 
of the study are presented in Table 1. 
Table 1: Administrative Structure 
Sponsor 
VHsquared Ltd. 
1 Lower Court, Copley Hill Business Park, 
Cambridge Road, Babraham,  
Cambridge, CB22 3GN, United Kingdom 
 
 
Contract Research Organisation 
Quintiles 
Green Park, 500 Brook Dr,  
Reading RG2 6UU, United Kingdom 
Contract Research Organisation Services: 
Data Management, Biostatistics, Medical Monitoring 
Medical Writing, Study Monitoring 
Investigational Medicinal Product Supply 
Quay Pharmaceuticals Ltd. 
Quay House, 28 Parkway, Deeside Industrial Park, 
Deeside, Flintshire, CH5 2NS 
United Kingdom 
Bioanalysis 
LGC Ltd. 
Newmarket Road, Fordham,  
Cambridgeshire, CB7 5WW 
United Kingdom 
Safety Reporting 
Emas Pharma 
63-65 Knowl Piece, Hitchin 
Hertfordshire SG4 OTY 
United Kingdom  
Ileocolonoscopy Central Reading 
BioClinica, Inc. 
100 Overlook Center 
Princeton, NJ 08540 
United States 


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Clinical Safety Laboratory: Europe 
Q2 Solutions  
The Alba Campus, Rosebank Livingston, EH54 
7EG, United Kingdom 
Clinical Safety Laboratory: North America 
Q2 Solutions, LLC 
27027 Tourney Road, Suite 2E, Valencia, CA 91355 
United States 
 


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3.0 STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 
Primary Objective  
The primary objective is to evaluate the efficacy of V565 555 mg TID in subjects with active 
CD measured by the proportion of subjects achieving response to therapy. Response is 
defined as reduction in the Crohn's Disease Activity Index (CDAI) scores and in 
inflammatory markers CRP or FCP at Day 42. 
3.1.2 
Secondary Objectives 
Secondary objectives are:  
 To further characterise the efficacy of V565 in subjects with active CD assessed 
by changes in CDAI scores and/or inflammatory markers  
 To assess the effects of V565 based on changes in Abdominal Pain and Stool 
Frequency Instrument (PRO-2) scores 
 To assess safety and tolerability of V565 
3.1.3 
Pharmacokinetic Objectives 
The PK objectives are to determine the concentration of V565 in serum and urine.  
3.1.4 
Exploratory Objectives 
The exploratory objectives are to:  
 To assess the proportion of subjects achieving CRP or FCP levels within normal 
limits  
 To assess changes in CDAI scores and CRP or FCP levels over time 
 To determine changes in anti-V565 antibody titre  
 To evaluate the frequency of loose or watery stools, assessed using the Bristol 
Stool Form Scale (BSFS) 
 To evaluate changes in abdominal pain using the Numeric Pain Scale (NPS) 
 To evaluate changes in faecal urgency 
3.1.5 
Exploratory Endoscopy Substudy Objectives 
 To investigate the effect of V565 on changes in endoscopic mucosal appearance, 
evaluated with an overall assessment and the Simple Endoscopic Score for 
Crohn's Disease (SES-CD), as determined by a central reader   


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3.2 
Study Endpoints 
3.2.1 
Primary Endpoint  
 Proportion of responders at Day 42, defined as subjects achieving both CDAI 
≥70-point reduction from Baseline OR CDAI score <150, AND a reduction of 
≥40% from the baseline value of CRP or FCP 
3.2.2 
Secondary Endpoints 
 Proportion of subjects achieving a ≥100-point reduction in CDAI score and a 
concomitant reduction of 50% in CRP or FCP at Day 42 
 Proportion of subjects achieving a ≥70-point reduction in CDAI score at Day 42 
 Proportion of subjects achieving a ≥100-point reduction in CDAI score at Day 42 
 Proportion of subjects achieving a CDAI score of <150 CDAI at Day 42  
 Changes from Baseline in scores for PRO-2 at Day 14 and Day 42  
3.2.3 
Safety Endpoints 
 Evaluations of AEs, clinical laboratory results, physical examination findings, 
electrocardiograms (ECGs) and vital signs throughout the study 
3.2.4 
Pharmacokinetic Endpoints 
 Serum and urine concentration of study drug prior to first administration of study 
drug, and at Day 14, Day 42, and Day 56. In addition, on Day 1, a post-dose urine 
sample will be obtained at the site 4 to 8 hours after the first dose of study drug.   
3.2.5 
Exploratory Endpoints 
 Proportion of subjects achieving CRP or FCP levels within normal limits at 
Day 14 and Day 42 
 Changes from Baseline in CDAI score over time  
 Changes from Baseline in CRP or FCP levels over time  
 Change from Baseline in anti-V565 antibody titre at Day 14, Day 42, and Day 56 
 Changes from Baseline in the frequency of loose or watery stools (Type 6 or 
Type 7) as measured by the BSFS  
 Changes from Baseline in the abdominal NPS  
 Changes from Baseline in faecal urgency 
3.2.6 
Exploratory Endoscopy Substudy Endpoints 
 Changes from Baseline in endoscopic mucosal appearance after 42 days treatment 
evaluated by changes in overall mucosal appearance and changes in SES-CD as 
determined by a central reader. Note: this substudy will be limited to subjects with 
a baseline SES-CD ≥7 (if ileum and colon are involved) or ≥4 (if only ileum is 
involved).. 


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4.0 INVESTIGATIONAL PLAN 
4.1 
Summary of Study Design 
This study will be a multiple-site, double-blind, placebo-controlled, parallel-group 
proof-of-concept study in approximately 126 subjects with active CD. This study will include 
subjects who have a confirmed diagnosis of CD for at least three months and have CD 
involving the ileum and/or colon. Inclusion and exclusion criteria are described in detail in 
Section 4.4.  
The duration of treatment will be 42 days (six weeks); each subject’s participation in the 
study will be approximately 12 weeks. This includes a screening period of up to 28 days, a 
treatment period of 42 days and a follow-up period of 14 days after the last dose of study 
drug.  
Subjects will be randomised into two treatment arms: either V565 or placebo using a 2:1 
active:placebo ratio. Randomisation will be stratified to ensure treatment groups have similar 
rates of prior anti-TNFα therapy.  
Subjects will receive three V565 185 mg capsules three times daily or matching placebo, for 
42 days (six weeks). The total daily V565 dose is 1665 mg. 
Subjects will be treated with study drug as an add-on to any permitted stable medications 
already being taken for CD. Permitted CD medications are described in Section 5.10.2. No 
alteration of background CD medication will be permitted for the duration of the study.  
There are six study visits. Two screening visits to assess eligibility will occur during Days -
28 to Day -1; these are Visit 1 (start of screening), and Visit 2 (eligibility ileocolonoscopy). 
Additional study visits will occur on Day 1 (randomisation and initiation of treatment), Day 
14 (Interim Visit), Day 42 (End of Treatment Visit), and Day 56 (Follow up Visit). 
Collection of subject-reported variables of the CDAI will be via the diaries given to subjects 
at Visit 1. Prior to Visit 2, the subject-reported variables will be combined with the variables 
collected at the site on Visit 1 and the CDAI score will be calculated. In order to have an 
ileocolonoscopy, eligible subjects must have sufficient diary entries to calculate a CDAI 
score, a CDAI score ≥220 to ≤450 and a CRP ≥5 mg/L (or if CRP is normal, FCP ≥250 µg/g) 
prior to Visit 2.  
A previous ileocolonoscopy conducted within 12 weeks before Visit 1 may be substituted for 
the Visit 2 ileocolonoscopy provided it is forwarded to the central reader and was performed 
in such a way as to enable evaluation by the central reader.   
The Visit 2 ileocolonoscopy will be evaluated by a central reader for to assess the overall 
appearance of the mucosa for the presence of active disease and scored using the SES-CD. 


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Active disease must be confirmed by the central reader for the subject to proceed to Visit 3 
and to be randomised on Day 1. 
The efficacy of V565 will be evaluated throughout the study by assessing changes in CDAI 
scores and changes in inflammatory markers (CRP or FCP). Efficacy will also be evaluated 
with the PRO-2.  
Exploratory efficacy measures include changes in CDAI scores, changes in CRP (or FCP) 
values over time, the frequency of loose or watery stools as measured by the BSFS, the 
degree of abdominal pain as measured by the NPS, and changes in faecal urgency. This study 
will also assess the immunogenicity of V565.  
In an exploratory endoscopy substudy, subjects with more severe disease at the Visit 2 
ileocolonoscopy (a SES-CD ≥7, if ileum and colon are involved or ≥4 if only the ileum is 
involved) will undergo a second ileocolonoscopy at the end of treatment (Day 42) to evaluate 
changes in mucosal appearance. 
The PK evaluations will be based on V565 concentrations measured in serum and urine to 
evaluate systemic exposure (serum) and determine the levels of active V565 in urine samples. 
Safety will be assessed through evaluations of AEs, clinical laboratory results, vital signs, 
physical examinations, ECGs and concomitant medications.  
A study diagram in presented in Figure 1. The Schedule of Events is presented in . 
Figure 1: Study Diagram 
 
 


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Table 2: Schedule of Events  
Visit  
1 
2 [a, b] 
3 [c] 
4 
5/ET visit 
Unscheduled [d] 
6 
 
Screening 
Randomisation 
 
End of Week 2 
End of 
Treatment or 
Early 
Termination 
Visit 
 
Week 8  
Follow up 
Visit Window  
(relative to Day 1) 
Day -28 to  
Day -1 
Day 1 
Day 14  
(-3/+1 days) 
Day 42  
(-3/+1 days) 
 
Day 56  
(±3 days) 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
X 
 
 
 
 
Randomisation 
 
 
X 
 
 
 
 
Assess compliance with study drug 
 
 
 
X 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
Dispense subject diary [e] 
X 
 
 
 
 
 
 
Discuss diary with subject and review 
compliance with data entry 
X[f]  
X 
X 
X [g] 
 
 
Dispense study drug  
 
 
X [h] 
X 
 
 
 
Medical History 
 
 
 
 
 
 
 
General medical history 
X 
 
 
 
 
 
 
CD history [i] 
X 
 
 
 
 
 
 
Extra-intestinal manifestation of IBD 
X 
 
 
 
 
 
 
Prior anti-TNFα therapy 
X 
 
 
 
 
 
 
Previous IBD treatment history 
X 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
Serum -hCG (women of CBP) 
X 
 
 
 
 
 
 
Urine β-hCG (women of CBP) 
 
 
X 
 
X [o] 
 
X [o] 
TB Screen 
X 
 
 
 
 
 
 
Hepatitis B + Hepatitis C screen [j] 
X 
 
 
 
 
 
 
Activated partial thromboplastin time 
X 
 
 
 
 
 
 
Test stool sample for C. difficile  
X 
 
 
 
 
 
 


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Visit  
1 
2 [a, b] 
3 [c] 
4 
5/ET visit 
Unscheduled [d] 
6 
 
Screening 
Randomisation 
 
End of Week 2 
End of 
Treatment or 
Early 
Termination 
Visit 
 
Week 8  
Follow up 
Visit Window  
(relative to Day 1) 
Day -28 to  
Day -1 
Day 1 
Day 14  
(-3/+1 days) 
Day 42  
(-3/+1 days) 
 
Day 56  
(±3 days) 
Test stool sample for other enteric 
pathogens (Shigella, Salmonella, 
Yersinia, Campylobacter, parasites or 
parasitic ova) 
X 
 
 
 
 
 
 
Complete physical exam [k] 
X 
 
 
 
X 
 
 
Brief physical exam [k] 
 
 
X 
X 
 
X 
X 
Weight 
X 
 
X 
X 
X 
X 
X 
Height, BMI 
X 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
X 
X 
X 
X 
Vital signs (BP, HR, body temperature)  
X 
 
X 
X 
X 
X 
X 
Haematology 
X 
 
X 
X 
X 
X 
X 
Clinical chemistry 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
X 
X 
X 
X 
SAE/AE assessment  
X 
X 
X 
X 
X 
X 
X 
Prior or concomitant medication  
X 
X 
X 
X 
X 
X 
X 
Efficacy Assessments 
 
 
 
 
 
 
 
CRP sample 
X 
 
 
X 
X 
 
X 
FCP sample [l] 
X 
 
 
X [l] 
X [l] 
 
X[l] 
Ileocolonoscopy [m] 
 
X 
 
 
X [n] 
 
 
CDAI and PRO-2 
X 
 
 
X 
X 
 
 
Faecal urgency 
 
 
X 
X 
X 
 
 
Subject-reported entries of the CDAI, 
BSFS, and NPS 
Completed daily from Visit 1 to the end of the treatment period 
 
 
Pharmacokinetics 
 
 
 
 
 
 
 
Blood (serum) samples [p] 
 
 
X 
X 
X 
 
X 
Urine samples [q]  
 
 
X 
X 
X 
 
X 


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Visit  
1 
2 [a, b] 
3 [c] 
4 
5/ET visit 
Unscheduled [d] 
6 
 
Screening 
Randomisation 
 
End of Week 2 
End of 
Treatment or 
Early 
Termination 
Visit 
 
Week 8  
Follow up 
Visit Window  
(relative to Day 1) 
Day -28 to  
Day -1 
Day 1 
Day 14  
(-3/+1 days) 
Day 42  
(-3/+1 days) 
 
Day 56  
(±3 days) 
Immunogenicity 
 
 
 
 
 
 
 
Serum sample for anti-V565  
antibody [r] 
 
 
X 
X 
X 
 
X 
Pharmacogenomics 
 
 
 
 
 
 
 
Serum sample for storage  
 
 
X 
 
 
 
 
AE: adverse event; β-hCG: beta human chorionic gonadotropin; BMI: body mass index; BP: blood pressure; BSFS: Bristol Stool Form Scale; CBP: childbearing potential; CD: Crohn’s disease; CDAI: Crohn's Disease 
Activity Index; CRP: C-reactive protein; ECG: electrocardiogram; ET: end of treatment; FCP: faecal calprotectin; HR: heart rate; IBD: inflammatory bowel disease; NPS: Numeric Pain Score: PRO-2: Abdominal Pain 
and Stool Frequency; SAE: serious adverse event; TB: tuberculosis, TNFα: Tumour necrosis factor alpha 
a) 
The timing of Visit 2 is flexible but ileocolonoscopy must not occur until the subject has sufficient diary entries to calculate the CDAI score, meets the criteria for CDAI score and meets the criteria for CRP (or 
FCP) levels. The Visit 2 ileocolonoscopy must be evaluated by a central reader and active disease must be confirmed before randomisation on Day 1.   
b) 
All assessments scheduled for Visit 2 should be done prior to the ileocolonoscopy.  
c) 
All baseline procedures on Day 1 must occur prior to taking the first dose of study drug (except for post-dose urine sample).  
d) 
The assessments indicated for unscheduled visits are for subjects who return to the site for safety reasons. Other safety assessments may be done at the Investigator’s discretion. These assessments are not 
required for subjects who return to the site for administrative reasons (e.g., to pick up additional study drug).   
e) 
Subjects will complete the diary daily throughout the study. The diary will contain the subject-reported entries of the CDAI, as well as the BSFS and the NPS.    
f) 
During Screening, subjects must have sufficient diary entries to calculate a CDAI score.   
g) 
Diaries will be collected at Day 42 visit. 
h) 
Subjects will take their first dose of study drug at the site on Day 1.  
i) 
Including date of diagnosis, disease severity, disease duration, disease location, extra-intestinal manifestations, associated complications, and hospitalisations. Information should also be obtained concerning 
prior CD therapy.   
j) 
Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody (Anti-HBs), Hepatitis B core total antibody (Anti-HBc, Total), and Hepatitis C Antibody (Anti-HCV) 
k) 
Full physical exam at Visit 1 and Day 42 and brief physical exam for Day 1, Day 14 and Day 56 
l) 
FCP will be used as the eligibility test if CRP results are < 5mg/L. During the treatment and follow up phase of the study, FCP will only be evaluated in subjects whose screening CRP was < 5mg/L, and who 
qualified for the study based on their screening FCP value. 
m) 
Ileocolonoscopy may be scheduled during Screening after the subject has met the inclusion/exclusion criteria including meeting the criteria for the CDAI scores and CRP (or FCP) levels. However, an 
ileocolonoscopy performed within the previous 12 weeks and declared evaluable by the central reader is acceptable in place of the ileocolonoscopy scheduled for Visit 2.  
n) 
A Visit 5/ET ileocolonoscopy will only be done for subjects in the exploratory ileocolonoscopy substudy.  
o) 
A positive result should be confirmed with a serum pregnancy test. 
p) 
Blood samples for determination of V565 concentrations in serum will be collected prior to first dose on Day 1 and at the same time as the serum sample for anti-V565.  
q) 
Subjects will be asked to void their bladder prior to the first dose of V565; this void will be used as predose (blank) sample. The subjects will provide a post-dose sample at the site 4 to 8 hours after taking their 
study drug. During the Day 14 and Day 42 visits, subjects will be asked to provide complete urine voids prior to leaving the clinic. The date and time of the urine sample and time in relation to the most recent 
dose of study drug should be recorded. 
r) 
The date and time in relation to the most recent dose of study drug should be recorded 


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4.2 
Description of Study Periods 
4.2.1 
Screening: Visit 1 and Visit 2 (Ileocolonoscopy) (Day -28 to Day -1) 
The subjects will be screened during the 28-day period prior to randomisation using the 
procedures outlined in  to ensure that all eligibility criteria are fulfilled. Screening may be a 
maximum of 28 days but may be shorter depending on the amount of time required to 
determine that the subject is eligible for the study.   
In order to have an ileocolonoscopy, eligible subjects must have sufficient diary entries to 
calculate a CDAI score, a CDAI score ≥220 to ≤450 and a CRP ≥5 mg/L (or if CRP is 
normal, FCP ≥250 µg/g) prior to Visit 2. 
When it is determined that the subject is eligible for the Visit 2 ileocolonoscopy, the site will 
contact the subject, confirm the date and instruct the subject in the use of the preparation for 
the ileocolonoscopy according to local practice. All assessments scheduled for Visit 2 should 
be done prior to the ileocolonoscopy. 
A previous ileocolonoscopy conducted within 12 weeks before Visit 1 may be substituted for 
the Visit 2 ileocolonoscopy provided it is forwarded to the central reader and was performed 
in such a way as to enable evaluation by the central reader.  
Active disease must be confirmed by the central reader in order for the subject to proceed to 
Visit 3 and to be randomised on Day 1. 
Assessments conducted at Visits 1 and 2 may be repeated once if they are out of range or 
unacceptable, providing that they are completed and that the results known within the 
screening period. The re-test value(s) will supersede the original values for the evaluation of 
the subject’s eligibility.  
If a subject cannot be declared eligible within the 28-day screening period and the 
Investigator wishes to re-screen the subject, the Investigator must contact the Quintile’s 
Medical Advisor for permission to re-screen. Requests for re-screening will be handled on a 
case-by-case basis. A re-screening can be allowed once only for an individual subject, 
regardless of the reason. The subject will be allocated a new screening number.  
4.2.2 
Treatment Period  
During the treatment period, the subject will attend three site visits (Day 1, Day 14 and 
Day 42). If possible, site visits will be scheduled for the morning. The window for the Day 14 
and Day 42 visits is -3 days to +1 day.  
On Day 1, subject compliance with diary completion will be reviewed to confirm that diary 
compliance is still acceptable. If all eligibility requirements have been met (including those 
based on the results of the ileocolonoscopy), the subject will be randomised. If not, the 
subject will be considered a screen failure and the reason for the screen fail will be recorded. 


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Eligible subjects will be randomly assigned to receive one of two oral regimens: V565 555 
mg TID or placebo.  
The Day 1 assessments and procedures presented in  will be completed prior to starting 
treatment with study drug. Treatment will begin on Day 1 at the site and continue to Day 42. 
Additional information on dosing is available in Section 5.8. 
Subjects will continue to fill out their diaries daily throughout the treatment period. At each 
visit, site personnel will review the diaries and assess compliance with study drug 
administration and with the use of the diary.  
Pharmacokinetic samples (blood and urine) will be collected at each study visit. On Day 1, 
subjects will be asked to provide a pre-treatment sample and an additional sample 4 to 8 
hours after the first dose of study drug.  
The subjects take their last dose of study drug on Day 42. The subjects will return to the site 
on Day 42 for the assessments and procedures indicated in . The subject diaries will be 
collected at this time. Subjects participating in the endoscopy substudy will have their second 
ileocolonoscopy performed on Day 42.  
4.2.3 
Follow-up: Day 56 
The subject will return to the site for a follow-up visit at Day 56, approximately two weeks 
after the last dose of study drug. The procedures performed during the follow-up visit are 
presented in .  
4.2.4 
30-day Post-treatment  
Serious adverse events reported spontaneously will be collected for 30 days after the last dose 
of study drug.  
4.2.5 
Early Termination Visit 
A subject will have an Early Termination Visit if they discontinue treatment with study drug 
or withdraw from the study. If a subject withdraws from the study, or is discontinued from 
treatment with study drug, every effort should be made to complete an Early Termination 
Visit with the same assessments as scheduled for Day 42. The Early Termination Visit should 
be scheduled as soon as possible after it has been decided that the subject will be permanently 
discontinued from treatment with study drug. In addition to the Early Termination Visit, the 
Follow-up Visit should be performed on Day 56 if possible. Details describing subject 
withdrawal are presented in Section 4.5. 
4.2.6 
Unscheduled Visits 
Unscheduled visits, if needed, may occur at any time as deemed necessary by the Investigator 
or site staff. If a subject returns to the site for an unscheduled visit due to a safety reason, 
assessments indicated in  should be performed. In addition, the Investigator may do other 


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safety assessments as deemed necessary. These assessments are not required for subjects who 
return to the site for administrative reasons (e.g., to pick up additional study drug). 
4.3 
Discussion of Study Design 
This study has been designed to provide an initial evaluation of the clinical efficacy of V565 
in subjects with active CD. In this proof-of-concept study, the effect of V565 (555 mg TID 
for 6 weeks) will be compared to placebo. A double-blind, parallel-group, placebo-controlled, 
randomised design was chosen to minimise bias. Concurrent therapies for the treatment of 
CD are permitted at stable doses during the study.  
The dose selected for this clinical proof-of-concept study is based on the 
safety/tolerability/PK profile elicited from the previous non-clinical and Phase 1 clinical 
studies, the known extensive safety database of systemic anti-TNFα therapy, and the 
necessity to provide doses likely to be therapeutically useful to patients with CD. 
V565 was not detected in the serum of any subject in the Phase 1 study given a single dose of 
either 555 mg or 1665 mg, including six subjects with CD who likely have greater GI 
permeability than that of healthy volunteers. Dose selection was therefore based not on 
systemic exposure, but on the requirement to use a feasible dose which would be expected to 
deliver potentially therapeutically useful concentrations and which is not associated with 
adverse findings. Preclinical modelling has predicted that a dose around 500 mg TID would 
provide the required luminal concentration of V565 to provide potential benefit in CD. In 
addition, 555 mg delivered suitable faecal concentrations of V565 in both healthy volunteers 
and subjects with CD in the Phase 1 study, and did not present adverse safety or tolerability 
findings. Therefore, the proposed dose for clinical testing is 555 mg TID, a total daily dose of 
1665 mg. 
The primary endpoint is based on changes in CDAI score and CRP (or FCP) biomarkers. The 
CDAI is well established as a standard scale for the evaluation of clinical outcome in CD. 
Published data do not explicitly clarify the relevant reduction in CRP associated with a 
clinical response in CD. However, in 2012, Reinisch reported that the mean % reduction from 
baseline CRP associated with maintenance of a clinical response was 40% [11]. In this proof 
of concept study, a 40% reduction from Baseline has therefore been defined as a CRP 
response. The same definition will be applied to reduction in FCP. While a number of studies 
use normalisation of CRP as a criterion, given the wide range of potential elevated CRP 
values in active CD patients this results in an unrealistically high hurdle for “relevant 
improvement” for inclusion in the primary endpoint in those patients with higher baseline 
values. Normalisation of CRP will, however, be investigated as an exploratory endpoint in 
this study. 
The 6-week treatment period is considered sufficient to evaluate clinical efficacy in this 
proof-of-concept study. The CHMP guidelines for new products for the treatment of CD 
describe 4 to 8 weeks of therapy as sufficient for the evaluation of CD [10].  


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4.4 
Selection of Study Population 
4.4.1 
Inclusion Criteria  
Subjects who meet these inclusion criteria will be eligible to enrol in the study:  
1. Male or female subjects aged 18 to 80 years, inclusive at Visit 1 
2. Willing and able to provide written informed consent 
3. Willing and able to attend study visits and follow study procedures 
4. History of Crohn’s disease (confirmed by ileocolonoscopy) of at least three months 
duration prior to Visit 1 
5. CDAI score of ≥220 to ≤450 during Screening 
6. CRP ≥5 mg/L (or, if CRP is normal, FCP ≥250 µg/g) at Screening 
7. Active CD of ileum and/or colon as determined by the baseline ileocolonoscopy  
8. Subjects for the exploratory endoscopy substudy must have a SES-CD ≥7 (if ileum 
and colon are involved) or ≥4 (if only the ileum is involved) at the baseline 
ileocolonoscopy.  
9. Subject must have failed or experienced intolerance to at least one of the following: 
aminosalicylates, corticosteroids; immunosuppressants (e.g., azathioprine [AZA], 
6-mercaptopurine [6-MP], or methotrexate [MTX]). 
10. Permitted CD medication regimen expected to remain stable during the period of the 
study 
11. Females of childbearing potential must have a negative serum pregnancy test at Visit 
1 and agree to use effective contraception from signing informed consent and for at 
least 90 days after the last dose of study drug. Males who are sexually active with a 
female partner of childbearing potential must be willing to use effective contraception 
from signing informed consent and for 90 days after the study.   
a. Females of childbearing potential include any female who has experienced 
menarche and who has not undergone successful surgical sterilisation 
(hysterectomy, bilateral tubal ligation, salpingectomy, or bilateral 
oophorectomy) or is not postmenopausal. Postmenopausal is defined as no 
menses for ≥12 months without an alternative medical cause. Females with 
questionable menopausal history (e.g., irregular menstrual periods and age >40 
years) are considered to be of childbearing potential.  
b. Females of childbearing potential: Females of childbearing potential must use 
acceptable highly effective (according to Clinical Trial Facilitation Group 
[CTFG] recommendations) methods of birth control in this study. These 
include:  
i. Combined (oestrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation (oral, 
intravaginal, transdermal) 
ii. Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, implantable) 
iii. Intrauterine device  
iv. Intrauterine hormone-releasing system  
v. Bilateral tubal occlusion  
vi. Vasectomised partner  
vii. Sexual abstinence (see definition in Section 6.2.2) 


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12. Fertile males who are sexually active with a female partner of childbearing potential 
must agree to use contraception (condom plus spermicide or partner using acceptable 
highly effective method) from signing informed consent and for 90 days after last 
dose.  
13. Fertile males should be instructed that they are not to donate sperm during the study 
or up to 90 days the last dose of study drug.   
14. In regards to contraception, subjects must follow the strictest applicable local 
requirement as specified by the Regulatory Agency or Ethics Committee approving 
the trial.  
4.4.2 
Exclusion Criteria 
Subjects who meet any of these criteria are not eligible to enrol in this study.  
1. Crohn’s disease of mouth, oesophagus, stomach or duodenum which, in the opinion 
of the Investigator, is likely to be causing symptoms  
2. Known history of or suspicion of ulcerative colitis, indeterminate colitis, microscopic 
colitis, ischaemic colitis or radiation-induced colitis, based on medical history, 
endoscopy and/or histological findings 
3. Any GI manifestations of CD that might affect the evaluation of efficacy: 
a. Prior significant GI resection 
b. Current abscess or symptomatic stricture 
c. Abdominal, enterocutaneous or pelvic active fistulas or fistula likely to require 
surgery during the study. Non active/non draining fistulas (including seton 
drained fistulas) are allowed. 
d. History of short bowel syndrome  
e. Presence of ileostomy or colostomy 
4. Isolated disease confined to the recto-sigmoid colon (approximately the last 25 cm) 
5. Any abdominal surgery within the six months before Visit 1 that required entering 
peritoneal cavity  
6. Planned surgery or likely need for surgery during the study period  
7. Any history of GI tract dysplasia or neoplasia 
8. Any history of lymphoproliferative disease 
9. Required enteral or parenteral feeding within 6 months before Visit 1 (oral 
supplements are acceptable) 
Exclusion Criteria Related to Medications 
10. Prior primary efficacy failure of or secondary loss of response to anti-TNFα therapy, 
or any contraindication to anti-TNFα therapy 
11. History of sensitivity to any of the study drug, components, or a history of drug or 
other allergy that, in the opinion of the Investigator or Medical Monitor, 
contraindicates participation in the study 
12. Prior use of any other biological therapy other than anti-TNFα therapy for IBD 
13. Any live, attenuated, recombinant vaccine vaccination during the study, or inoculation 
with such vaccines within four weeks prior to Visit 1. 
14. Use of any investigational product within 30 days prior to Visit 1, or five half-lives or 
twice the duration of the biological effect of the product (whichever is longer) 
15. Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) is prohibited within 
four weeks of Visit 1 (except low dose aspirin [<325 mg/day] for cardioprotection 
which must have been used at stable dose for at least 4 weeks prior to Visit 1 


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16. Use of the following medications as shown below: 
a. Corticosteroids administered IV, intramuscularly (IM), subcutaneously (SC) 
or rectally within 2 weeks prior to Visit 1 (Topical use [e.g., inhaled, nasal, 
aural or ocular] of corticosteroids is allowed) 
b. Oral corticosteroids at the following doses: prednisone >20 mg/day or 
equivalent, or budesonide >6 mg/day – 4 weeks prior to Visit 1 
c. Parenteral antibiotics – 2 weeks prior to Visit 1 
d. Local use (enema or suppository) of 5-aminosalicylic acid (5-ASA) within 
4 weeks prior to Visit 1 
e. Chronic opioid use – 4 weeks prior to Visit 1 
f. Immunosuppressant use (other than those permitted as per Section 5.10.2) 
including, but not limited to, cyclosporine, tacrolimus, sirolimus or 
mycophenolate mofetil and/or apheresis) – 8 weeks prior to Visit 1 
g. Anti-TNFα therapy – 12 weeks prior to Visit 1 
17. Changes in dose of the following medications during the time periods shown below: 
a. Oral corticosteroids (change in dose) – 4 weeks prior to Visit 1 
b. Oral corticosteroids (discontinuation) – 2 weeks prior to Visit 1 
c. Oral aminosalicylates (change in dose or discontinuation) – 2 weeks prior to 
Visit 1 
d. Probiotic therapy (change in dose or discontinuation) – 4 weeks prior to 
Visit 1 
e. Methotrexate (change in dose or discontinuation) – 8 weeks prior to Visit 1 
f. Azathioprine/6-MP (change in dose or discontinuation) – 12 weeks prior to 
Visit 1 
Exclusion Criteria Related to Medical Conditions and Laboratory Results 
18. History of a clinically significant infection within two weeks prior to Visit 1 or during 
the screening period which may, in the opinion of the Investigator or Medical 
Monitor, compromise the subject’s safety, interfere with the evaluation of study drug 
or reduce the subject’s ability to participate in the study. A clinically significant 
infection is one requiring treatment with parenteral (IV or IM) antibiotic, antiviral, or 
antifungal medication or any major infection requiring hospitalisation. 
19. History of recurrent, clinically significant bacterial, viral, fungal, mycobacterial or 
other infections or any major episode of infection requiring hospitalisation or 
treatment with parenteral medication 
20. Known varicella, herpes zoster, or other severe viral infection within six weeks prior 
to Visit 1 
21. A history of TB or latent TB infection, in the absence of documented adequate 
therapy for the disease. 
22. Positive result of TB surveillance as determined (at a minimum) by the 
QuantiFERON-TB Gold Test (performed at the central lab). The subject may also be 
evaluated for the presence of TB with any additional test required by local practice.  
23. Unable to refrain from travelling to countries with a high prevalence of infectious 
disease until the end of the study. 
24. Congenital or acquired immunodeficiency (including known human 
immunodeficiency virus [HIV]) or a history of chronic or recurrent opportunistic 
infections 


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25. Current evidence of, or recent (within the past five years) treatment for a malignancy 
other than localised basal cell, squamous cell skin cancer, cervical dysplasia, or 
cancer in situ that has been resected 
26. Evidence of previous or present Hepatitis B or C infection by testing Hepatitis B 
surface antigen (HBsAg), Hepatitis B surface antibody (Anti-HBs), Hepatitis B core 
total antibody (Anti-HBc, Total) and Hepatitis C antibody (Anti-HCV)  
27. Stool positive for C. difficile or positive for any other enteric pathogen (e.g., Shigella, 
Salmonella, Yersinia, Campylobacter, parasites or parasitic ova) 
28. Evidence of hepatic dysfunction, or elevations in serum alanine aminotransferase 
(ALT) and/or aspartate aminotransferase (AST) values >2 times the upper limit of 
normal (ULN), or a total bilirubin value >1.5 times ULN; alkaline phosphatase (ALP) 
>2 times ULN; current or chronic history of liver disease or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) 
29. White blood cell count ≤3.0109/L or >18.0109/L, serum creatinine >1.5 mg/dL, 
haemoglobin <9 g/dL, activated partial thromboplastin time (APTT) ≥1.5 times ULN 
30. QTc using the Fridericia correction (QTcF) ≥450 msec for males or ≥470 msec for 
females  
31. Concurrent illness or disability that, in the opinion of the Investigator or 
Sponsor/designee, may affect the interpretation of clinical data, or otherwise 
contraindicates participation in this clinical study (e.g., an unstable cardiovascular, 
autoimmune, renal, hepatic, pulmonary, endocrine, metabolic, GI, haematological, or 
neurological condition or mental study impairment) 
Other Exclusion Criteria 
32. History of alcohol or drug abuse within the last two years 
33. Lactating women 
34. If male, planning to donate sperm during or up to 90 days after study 
4.5 
Subject Withdrawal 
All subjects are free to withdraw from participation in the study at any time, for any reason, 
specified or unspecified, and without prejudice to further treatment. In addition, subjects will 
be withdrawn from study drug and from the study in the following circumstances: 
 The Investigator decides that the subject should be withdrawn. If this decision is 
made because of an intolerable AE or a clinically significant laboratory value, the 
study drug is to be discontinued and appropriate measures are to be taken. The 
Medical Monitor is to be notified immediately.  
 The subject is unwilling to continue in the study.  
 Noncompliance or protocol violations that in the opinion of the Investigator or 
Sponsor/designee necessitates the subject being removed. The decision to 
withdraw the subject should be taken in consultation with the Medical Monitor. 
 Pregnancy 
 Events that require emergency unblinding 
 Has infectious complications that require stopping or reduction of 
immunosuppressive therapy 


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 Requires any abdominal surgery or surgery for fistula or abscesses; the decision to 
withdraw the subject should be taken in consultation with the Medical Monitor.  
 The Investigator or the Sponsor, for any reason, stops the study.  
In general, before the decision is made to withdraw the subject, consultation with the Medical 
Monitor is recommended. 
If a subject chooses to withdraw from the study (permanently stop taking the study drug), 
they will be encouraged to return to the site for safety reasons to complete the assessments 
planned for Visit 5 (Day 42) during an Early Termination Visit and for the Follow-up Visit 
(Day 56). 
The Investigator should ensure that all reasonable attempts (telephone calls, contact with 
primary care physician, certified letter) are made to obtain follow-up safety information on 
subjects who do not return to the site for study visits or are lost to follow-up. 
Subjects who are withdrawn from the study after randomisation and who receive at least one 
dose of study drug will not be replaced. These subjects cannot be rescreened.  
Subjects who withdraw from the study after dosing should be advised by the Investigator to 
continue contraception restrictions for 90 days after the last administration of study drug. 
The Investigator will ensure that the reasons for withdrawal are documented on the subject’s 
medical records (source documents) and in the electronic Case Report Form (eCRF). If the 
subject withdraws due to an AE, the details of the AE must be entered on the AE section of 
the eCRF. If the reason for subject withdrawal is not known, every effort must be made to 
contact the subject to establish the reason for withdrawal. 
4.6 
Lost to Follow-up 
Subjects will be considered lost to follow-up when they fail to attend study visits without 
stating an intention to withdraw from the study. The Investigator should show due diligence 
by documenting in the source documents the steps taken to contact the subject through at 
least three telephone calls and/or emails and one registered letter. The subject should be 
recorded as “lost to follow-up” in the eCRF if all reasonable attempts made to contact the 
subject have failed. 


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5.0 STUDY TREATMENTS 
5.1 
Treatments Administered 
The subjects in this study will receive either V565 (three 185-mg capsules for a dose of 
555 mg TID, for a total daily dose of 1665 mg) or an equal number of matching placebo 
capsules (TID) for 42 days (six weeks).  
5.2 
Identity of Investigational Product(s) 
V565 is a 115 amino acid 12.6 kDa single domain variable heavy chain antibody (VHH), 
active against human TNFα. The antibody is manufactured in Saccharomyces cerevisiae.  
The drug substance is formulated into 3 mm round mini-tablets. The mini-tablets are coated 
with a polymer sub-coat and a Eudragit® enteric coat is applied to engender release in the 
required area of the GI tract. Once coated, the mini-tablets are encapsulated in hydroxypropyl 
methylcellulose (HPMC) capsules.  
The formulation is engineered to release the mini-tablets from the capsules in the stomach. 
The size of the mini-tablets enables them to escape through the pylorus and migrate through 
the GI tract. The mini-tablet coating releases active molecule at a pH designed to ensure 
delivery of high concentrations of V565 to the ileum and distal parts of the GI tract. 
The components of the V565 drug product are presented in Table 1.  
There is one dose strength for V565 active capsules. The V565 dose per capsule is 185 mg. 
Each 185 mg Size 00 pink opaque HPMC capsule contains 15 mini-tablets. Placebo HPMC 
capsules are identical to capsules containing V565 and contain an equivalent number of 
mini-tablets of identical size, shape, and colour. The placebo mini-tablets are made of the 
same components as in Table 1 but contain no active V565. 
Table 1: Components of V565 Drug Product 
Component 
Purpose 
Mini-tablet Cores 
 
V565 
Active ingredient 
Mannitol 
Compression aid 
Microcrystalline cellulose 
Compression aid 
Croscarmellose sodium 
Super disintegrant 
Magnesium stearate 
Lubricant 
Sub-coat 
 
Hydroxypropylmethyl cellulose 
Polymer coat 
Enteric Coat 
 
Eudragit®  
Enteric polymer coat 
Triethyl citrate 
Plasticiser 
Talc 
Anti-tacking agent 
Sodium lauryl sulphate 
Surfactant 


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5.3 
Storage 
All study drug will be stored below 25°C in an adequate storage area, which is a secure, 
temperature controlled, locked environment with restricted access. Study drug must not be 
refrigerated or frozen. 
No special procedures for the safe handling of V565/placebo are required.  
The Sponsor and their authorised representatives such as study monitors or auditors as well as 
regulatory inspectors will be permitted, upon request, to audit the supplies, storage and 
dispensing procedures and records in accordance with applicable regulatory requirements, 
provided that the blind of the study is not compromised. 
Once study drug has been dispensed to study subjects, it should be stored in accordance with 
the instructions on the label. 
5.4 
Supply, Packaging and Labelling 
Bulk V565/placebo will be manufactured and supplied by Quay Pharmaceuticals Ltd.  
Capsules will be packed into Duma special high-density polyethylene (HDPE) containers 
fitted with a low-density polyethylene tamper evident cap in compliance with EU Good 
Manufacturing Practice (GMP) conditions and labelled in accordance with local regulations 
(Duma Handycap manufactured by Gerresheimer Pharmasystems). Matching placebo will 
also be supplied.  
Study drug will be labelled with multi-language booklets in accordance with GMP and 
country-specific regulations as required by the regulatory bodies in the countries where the 
study is conducted.  
5.5 
Accountability 
In accordance with GCP, the Investigational Site will account for all supplies of 
V565/placebo. Details of receipt, storage, assembly, and return will be recorded.  
All unused supplies of V565/placebo will be returned to the Sponsor at the end of the study in 
accordance with instruction by the Sponsor. The study drug may be destroyed at the site with 
the consent of the Sponsor.  
5.6 
Method of Assigning Subjects to Treatment Group 
Once the subject provides an informed consent and meets inclusion and exclusion criteria, the 
study site will request the study drug assignment using the Interactive Web Activated 
Response System (IWRS). Approximately 126 subjects will be randomised in a 2:1 ratio 
(84 subjects in the V565 arm and 42 subjects in the placebo arm). Randomisation will be 
stratified to ensure treatment groups have similar rates of prior anti-TNFα therapy. 


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5.7 
Selection of Doses in the Study 
Dose selection is discussed in Section 4.3.  
5.8 
Selection and Timing of Dose for Each Subject 
Each dose will consist of three capsules of V565 (three 185-mg capsules, total dose 555 mg) 
or placebo. Study drug will be administered orally TID. The subjects will be instructed to 
take the capsules with sufficient fluid one hour before meals and at least two hours after the 
previous meal.  
No dose adjustments are permitted.  
5.9 
Blinding 
This is a randomised, double-blind, placebo-controlled study with limited access to the 
randomisation code. Study drug and placebo capsules will be identical in physical 
appearance. The treatment each subject will receive will not be disclosed to the Investigator, 
study site staff, subject, Sponsor, designee or contracting clinical safety laboratories.  
Investigators are strongly discouraged from requesting the blind be broken for an individual 
subject, unless there is a subject safety issue that requires unblinding and would change 
subject management.  
The decision to break the blind in an emergency situation remains the responsibility of the 
treating physician, which will not be delayed or refused by the Sponsor. However, the 
Investigator may contact the Medical Monitor prior to breaking the blind to discuss 
unblinding. The Investigator should promptly notify the Medical Monitor of the emergency 
unblinding and the reason for breaking the blind, which should be clearly documented. 
Emergency unblinding should only be performed by the Investigator through the IWRS. In 
case of unblinding, the subject should be withdrawn from the study (permanently stops the 
study drug, but attends the Early Termination Visit and Follow-up Visit if possible). 
5.10 Prior and Concomitant Treatments 
All medications (prescription and non-prescription), treatments, and therapies taken by the 
subject from the time consent is signed throughout their entire participation in the study, 
including those initiated prior to the start of the study, must be recorded on the subject’s 
source document and on the appropriate page of the eCRF. The dose, unit, frequency, route, 
indication, date the medication was started, and date the medication was stopped (if not 
ongoing) must be recorded. 
5.10.1 
Prior and Concomitant Medications 
The use of medications in the 12 weeks prior to Visit 1 should be reported in the eCRF, 
indicating the dose, frequency, indication and start and stop dates. The use of some prior 
medication or therapy more than 12 weeks prior to Visit 1 may affect a subject’s eligibility 


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for enrolment. These medications are listed in the exclusion criteria (see Section 4.4). Details 
about medications prohibited during the study are presented in Section 5.10.3.  
5.10.2 
Permitted Medications  
Medications considered necessary for the safety and well-being of the subject may be 
permitted during the study at the discretion of the Investigator provided they are not listed as 
a prohibited medication in Section 5.10.3.  
 Background CD Therapy: Subjects will remain on their background CD therapy 
throughout the study. It should be noted that the doses of background concomitant 
medications given for the treatment of CD may not be changed during the study. 
No new background CD therapy may be added to the subject’s treatment regimen 
after Visit 1.  
 Oral Corticosteroids: The dose must be ≤20 mg/day prednisolone or equivalent, 
remain unchanged for at least four weeks prior to Visit 1 and remain stable for the 
duration of the study. The dose of budesonide must be ≤6 mg/day, remain 
unchanged for at least four weeks prior to Visit 1, and remain stable for the 
duration of the study. 
 Oral Aminosalicylates: The dose must have been unchanged for at least two 
weeks prior to Visit 1 and remain stable for the duration of the study.  
 Methotrexate: The dose must have been unchanged for at least 8 weeks prior to 
Visit 1 and remain stable for the duration of the study.  
 Azathioprine/6-MP: The dose must have been unchanged for at least 12 weeks 
prior to Visit 1 and remain stable for the duration of the study. 
 Oral Antibiotics:  
 NSAIDs such as low dose aspirin [<325 mg/day] may be continued at an 
unchanged dose.  
 Probiotics may be continued at an unchanged dose. 
5.10.3 
Prohibited Medications 
The use of the following medications either alone or in combination for the treatment of CD 
is prohibited during the study.  
 Local use (enema or suppository) of 5-ASA  
 Corticosteroid administered IV, IM, SC or rectally. (Note: topical use [e.g., 
inhaled, nasal, aural or ocular] of corticosteroid is allowed during the study.)   
 Use of other immunosuppressant agents (other than those permitted as per 
Section 5.10.2) or therapy (e.g., apheresis) including, but not limited to, 
cyclosporine, tacrolimus, sirolimus or mycophenolate mofetil 
 Anti-TNFα therapy other than the study drug. 
 Any other biological therapy for IBD. 


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 Parenteral or enteral nutrition therapy. 
 Chronic use of NSAIDs other than for cardioprotection (as detailed in 
Section 5.10.2). 
 Chronic use of opioids (e.g., codeine, fentanyl, tramadol, etc.).  
 Vaccination with live, attenuated, or recombinant vaccines. 
Note:  Subjects should not discontinue prohibited pre-existing background CD medications 
prior to Visit 1 in order to qualify for the study.  
The use of any prohibited medication is considered a protocol deviation and the details 
including the starting date and its dosage should be recorded in the eCRF. Subjects should be 
withdrawn from the study if any prohibited medications are taken or if background CD 
therapy is changed during the study. 
5.11 Medical Care of Subjects after End of Study 
The Sponsor will not provide any additional care to subjects after they leave the study. 
Subjects will return to the care of their personal physician.  
5.12 Treatment Compliance  
It is the Investigator’s responsibility to ensure that subjects are instructed in the proper use of 
study drug and that the subjects are fully compliant with their assigned dosage regimen, as 
well as the timing for taking the study drug relative to meals (see Section 5.8). 
The prescribed dosage, timing, and mode of study drug administration may not be changed. 
Any departures from the intended regimen must be recorded in the eCRF.  
At Day 14 and Day 42, previously dispensed study drug will be retrieved by the Investigator 
and compliance assessed. Subjects will be asked to return all unused medication at each visit.  
Adequate compliance is defined as taking between 80% and 120% of dispensed study drug. 
Compliance problems (e.g., missing 2 or more consecutive full days [at least 6 doses] or 
taking less than 80% or more than 120% of the doses between study visits) should be 
discussed with the Medical Monitor to determine if the subject may continue in the study.  
5.13 Study Drug Accountability 
The Investigator, a member of the investigational staff, or a hospital pharmacist must 
maintain an adequate record of the receipt and distribution of all study drug using the Drug 
Accountability Form. These forms must be available for inspection at any time. 
All study drug supplies should be accounted for at the termination of the study and a written 
explanation provided for discrepancies. All unused study drug supplies and packaging 
materials are to be inventoried and returned by the Investigator as instructed by the Sponsor. 
The study drug may be destroyed at the site with the consent of the Sponsor. 


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6.0 EFFICACY, PHARMACOKINETIC, SAFETY, HEALTH 
OUTCOME, AND PHARMACOGENOMIC 
ASSESSMENTS 
6.1 
Efficacy Assessment 
6.1.1 
Subject Diary 
During Visit 1, a diary will be given to each subject. Subjects will be trained how to complete 
the diary and instructed in the use of the diary. The importance of completing the diary daily 
throughout the study will be stressed. The subject will complete the diary daily throughout 
the study until Day 42 (the End of Treatment Visit). The diary will be used to record the 
subject-reported variables of the CDAI, the BSFS, and the NPS.  
Site personnel will assess the subject’s compliance with the use of the diary throughout the 
study.  
During the screening period, subjects must have entered sufficient diary data to allow 
calculation of the CDAI score (see Section 6.1.2). Subjects with poor compliance completing 
the diary during screening will be considered screen failures. Subjects with poor compliance 
completing the diary during the treatment period may be withdrawn from the study. 
The data obtained from the subject diary will be used for calculation of the subject-reported 
variables of the CDAI and other efficacy outcomes measures such as the PRO-2, BSFS and 
NPS.  
The subject will record the following information in the subject diary to assess CD activity: 
1. Number of liquid or very soft stools  
2. Abdominal pain/cramps 
3. General well-being 
4. Fever over 100°F (37.8°C) 
5. Use of anti-diarrheal drugs (e.g., loperamide, diphenoxylate, or opiates) 
6.1.2 
Crohn’s Disease Activity Index   
Crohn’s Disease Activity Index (CDAI) is the most commonly used measure of clinical 
activity in patients with CD [12, 13, 14]. Some of the data used to calculate the CDAI is 
obtained from the subject diary (see Section 6.1.1) and some is obtained at site visits. The 
CDAI will be calculated at the time points identified in . 
The CDAI consists of eight variables: 
1.  Total number of liquid or very soft stools (total for previous 7 days) 
2. Abdominal pain/cramps rating (total for previous 7 days) 


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3. Subjective general well-being rating (total for previous 7 days) 
4. Total number of listed categories the subject has experienced during the last 7 days 
(Note: all of these are assessed by the Investigator with the exception of fever, which 
is obtained from the subject diary.) 
a. Arthritis or arthralgias 
b. Iritis/uveitis, erythema nodosum, or pyoderma gangrenosum 
c. Aphthous ulcers  
d. Anal fissures, fistulae, or abscess  
e. Other fistula (specified by site personnel) 
f. Fever higher than 100°F or 37.8°C during previous week  
5. Use of anti-diarrheal drugs (e.g., loperamide, diphenoxylate, or opiates) 
6. Presence of abdominal mass  
7. Anaemia based on haematocrit (HCT) value entered into formula: 
a. For men = 47 – HCT value 
b. For women = 42 – HCT value 
8. Body weight in kilograms (kg) entered into formula: 
a. ([standard weight in kg – actual weight kg] / [standard weight in kg]) x 100% 
The responses are scored numerically and weighted. Total CDAI scores range from 
0 to approximately 600 points; a higher score indicates a more active disease. A CDAI score 
of <150 points denotes remission, a score between 150 to 219 points denotes mildly active 
disease, a score of ≥220 to ≤450 points denotes moderately active disease, and a score of 
>450 points denotes severe disease. 
During the study, the CDAI will be calculated from the scores obtained from the 
subject-reported variables of the CDAI and the results recorded at the site. Haematocrit 
values will be extracted from the central laboratory results and used for the calculation of the 
CDAI score. 
Subjects who prematurely discontinue treatment prior to Day 42 will be asked to continue to 
record CDAI data until the Early Termination Visit. 
Instructions for recording the CDAI score will be given at Visit 1 (see Section 6.1.1). Data 
should be reviewed at each study visit, including unscheduled visits. 
A sample of a CDAI score worksheet is provided in the Appendix (Section 12.1) 
6.1.3 
Biomarkers of Inflammation 
The collection of CRP and/or FCP will occur at the time points indicated in . 
C-reactive protein is an acute-phase reactant produced in the liver and is an easily measured 
non-specific marker of inflammation. It is a widely used marker of inflammation in CD and 
elevations in CRP have been associated with endoscopic inflammation in CD [15, 16]. 


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C-reactive protein will be analysed in blood samples. If CRP values are normal, FCP will be 
assessed in the faecal samples. FCP will be used as the eligibility test if CRP results are 
<5 mg/L. During the treatment and follow up phase of the study, FCP will only be evaluated 
in subjects whose screening CRP was <5 mg/L, and who qualified for the study based on 
their screening FCP value. 
Calprotectin is abundant in the cytosol of activated neutrophils. The amount of FCP is 
directly proportional to neutrophil influx into the intestinal tract and is a reliable non-specific 
marker of intestinal inflammation [17, 18, 19]. While currently endoscopy with biopsy is 
considered the gold standard for evaluating the extent and location of inflammatory mucosal 
lesions, studies have shown that FCP may also be a useful marker of intestinal inflammation.  
On Day 1, the faecal sample for FCP should be collected prior to administration of the first 
dose of study drug. The subject may also provide a sample from faeces passed one day prior 
to the scheduled visits. These samples will be collected in sterile containers (to be provided to 
the subjects) and refrigerated at home. At each sampling time point, approximately 2 g to 5 g 
of faeces will be collected.  
6.1.4 
Abdominal Pain and Stool Frequency Instrument (PRO-2) 
PRO-2 will be calculated at the time points indicated in . 
The PRO-2 is a composite score that measures abdominal pain and soft stool frequency 
averaged over seven days [20]. The data for the total PRO-2 score is extracted from selected 
subject-reported variables of the CDAI included in the subject diary. These data are the 
entries for the number of liquid or soft stools/day and abdominal pain (rated on a scale of 0-3) 
assessed over the course of seven days.  
6.1.5 
Ileocolonoscopy  
It is important to confirm that subjects are eligible for the ileocolonoscopy prior to Visit 2. 
During the screening period, subjects must have entered sufficient diary data to allow 
calculation of the CDAI score, have CDAI scores ≥220 to ≤450 and CRP level ≥5 mg/L [or if 
CRP is normal, FCP level ≥250 µg/g]). The timing of the Visit 2 is flexible but the 
ileocolonoscopy must not be done until it has been documented that the subject is eligible for 
the ileocolonoscopy.  
It should be noted that subjects who have had an ileocolonoscopy within 12 weeks of Visit 1 
do not require an ileocolonoscopy at Visit 2 provided it is forwarded to the central reader 
and was performed in such a way as to enable evaluation by the central reader.  
Video images of all endoscopic procedures will be captured and sent to a qualified central 
reader.  
The images will be examined to determine the central reader’s overall impression of the state 
of mucosa to assess eligibility for randomisation and to calculate the SES-CD (see 


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Section 6.1.6). Active disease must be confirmed by the central reader in order for the subject 
to proceed to Visit 3 and randomisation on Day 1.  
6.1.6 
SES-CD 
The SES-CD assesses the mucosal appearance of the intestine in subjects with CD [21]. It 
includes four variables: ulcer size, the extent of ulcerated surface, extent of affected surface, 
and stenosis.   
Each of these four components are assessed in the five segments of the ileum and colon: 
ileum, right colon, transverse colon, left colon (descending and sigmoid), and rectum. The 
SES-CD is the sum of the individual scores of each of the components across the five 
segments. For the SES-CD, a higher score indicates more severe disease.  
In addition to obtaining baseline information on the condition of the mucosa, changes in 
overall mucosal appearance and changes in the SES-CD in response to treatment will be 
evaluated in an exploratory endoscopy substudy. This substudy will include subjects with a 
baseline SES-CD  ≥7 (if ileum and colon are involved) or ≥4 (if the lesions are confined to 
the ileum). These subjects will have an additional ileocolonoscopy at Day 42.  
6.1.7 
Exploratory Efficacy Measures 
6.1.7.1 
Bristol Stool Form Scale 
The BSFS [22, 23] is used to monitor change in intestinal function and transit time, by 
classifying the form of faeces into 7 categories: 
 Type 1: Separate hard lumps, like nuts (hard to pass)  
 Type 2: Sausage-shaped, but lumpy  
 Type 3: Like a sausage but with cracks on its surface  
 Type 4: Like a sausage or snake, smooth and soft  
 Type 5: Soft blobs with clear-cut edges (passed easily)  
 Type 6: Fluffy pieces with ragged edges, a mushy stool 
 Type 7: Watery, no solid pieces, entirely liquid 
This scale will be included in the subject diary and will be completed daily. The Bristol Stool 
Chart is included in the Appendix (Section 12.2).  
6.1.7.2 
Numeric Pain Scale 
Abdominal pain will be evaluated with an 11-point NPS.  
The NPS is an 11-point numeric scale ranging from 0 to 10, with 0 as no pain and 10 as worst 
pain imaginable [24, 25]. 


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The subjects are asked to rate their abdominal pain by recording the number that best 
describes their pain, on average, in the preceding 24 hours. Subjects will record the score 
daily in the subject diary.  
6.1.7.3 
Faecal Urgency 
The degree of faecal urgency will be evaluated by asking the subject if they experienced 
faecal urgency in the 24 hours prior the site visits on Day 1 (Baseline), Day 14 and Day 42. 
Faecal urgency evaluates the subjects need to rush to the toilet for a bowel movement.  Faecal 
urgency will be scored using the following scale:  
 0 = No urgency 
 1 = Mild urgency 
 2 = Moderate urgency 
 3 = Severe urgency 
 4 = Very severe urgency/didn’t make it to toilet on time 
If the subject had more than one bowel movement in the 24 hours prior to the study visit, the 
event with the most urgency will be recorded.  
6.2 
Safety Assessments 
Safety will be monitored during the study as detailed in . Safety variables include evaluations 
of AEs, laboratory evaluations, vital signs, physical examinations, ECGs and concomitant 
medications.  
6.2.1 
Adverse Events  
Definition of AE: An AE is any untoward medical occurrence in a subject enrolled in this 
study (i.e., that occurs after the informed consent form [ICF] is signed), regardless of its 
causal relationship to study drug. 
An AE can therefore be any unfavourable and unintended sign (including a clinically 
significant abnormal laboratory finding), symptom, or disease. 
An AE includes a/an: 
 Exacerbation of a pre-existing condition or disease. 
 Increase in frequency or intensity of a pre-existing condition. 
 Continuous persistent pre-existing disease or symptoms that worsen after the 
subject provides informed consent. 
If a clinically significant abnormal laboratory finding or other abnormal test result meets the 
definition of an AE or SAE, then the AE eCRF page or SAE eCRF page must be completed, 
as appropriate. Clinically significant laboratory results include those that: 
 Result in discontinuation from the study. 


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 Require treatment or any other therapeutic intervention. 
 Require further diagnostic evaluation (excluding a repetition of the same 
procedure to confirm the abnormality). 
 Are associated with clinical signs or symptoms judged by the Investigator to have 
a clinically significant impact. 
A diagnosis (if known), or clinical signs and symptoms (if diagnosis is unknown), rather than 
the clinically significant abnormal laboratory finding or test result, should be entered on the 
AE or SAE eCRF page. If no diagnosis is known and clinical signs and symptoms are not 
present, then the clinically significant abnormal finding should be recorded as an AE. 
An AE does not include a/an: 
 Medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, 
transfusion); the condition that leads to the procedure is an AE. Any complication 
of the procedure is also considered to be an AE. 
 Pre-existing disease or conditions present or detected at the start of the study that 
do not worsen. 
 Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalisations for cosmetic elective surgery, social and/or convenience 
admissions). 
 The disease or disorder being studied or sign or symptom associated with the 
disease or disorder, unless more severe or frequent than expected for the subject’s 
condition. 
Any medical condition that is present prior to informed consent should be recorded as 
medical history and not be reported as an AE. 
Treatment-emergent Adverse Event: A TEAE is defined as  
1. A new event that occurs during or after treatment with study drug or  
2. Any event present at Baseline that worsens in either intensity or frequency after 
exposure to study drug.  
Definition of Serious Adverse Event:  
An SAE, experience or reaction, is any untoward medical occurrence (whether considered to 
be related to study drug or not), that, at any dose: 
 Results in death – the death was an outcome of an AE. 
 Is life-threatening (the subject is at a risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were more 
severe). 
 Requires inpatient hospitalisation or prolongation of existing hospitalisation: 
Hospital admissions and/or surgical operations planned before or during a study 


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are not considered AEs if the illness or disease existed before the subject was 
enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study. 
 Results in persistent or significant disability/incapacity, i.e., the AE resulted in a 
substantial disruption of a person’s ability to conduct normal life functions, i.e., 
the AE resulted in a significant, persistent or permanent change, impairment, 
damage or disruption in the subject’s body function/structure, physical activities 
and/or quality of life  
 Is a congenital abnormality/birth defect in the offspring of a subject who received 
drug – it is suspected that exposure to study drug prior to conception or during 
pregnancy may have resulted in an adverse outcome in the child. 
 Other:  Medically significant events, which do not meet any of the criteria above, 
but may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the other serious outcomes listed in the definition above. Examples 
of such events are blood dyscrasias (e.g., neutropenia or anaemia requiring blood 
transfusion, etc.) or convulsions that do not result in hospitalisation. 
Other Adverse Event Definitions: 
An Adverse Drug Reaction (ADR) is defined as all noxious and unintended responses to a 
medicinal product related to any dose.  
An Unexpected ADR is defined as any adverse reaction, the nature of which is not consistent 
with the applicable product information and is unexpected. An adverse reaction is 
‘unexpected’ if its nature and severity are not consistent with the information about the 
medicinal product in question set out in Section 7 of the IB.  
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is an adverse reaction, the 
nature or severity of which is not consistent with the applicable product information (e.g., for 
applicable product information, include the IB for an unapproved investigational product or 
the package insert/summary of product characteristics for an approved product). Therefore, if 
a treatment-related SAE occurs and it was not mentioned in the applicable product 
information, then it will be reported as a SUSAR.  
Definitions of Severity 
The severity of the AE will be characterised as “mild, moderate or severe” according to the 
following definitions: 
 Mild events are usually transient and do not interfere with the subject’s daily 
activities. 
 Moderate events introduce a low level of inconvenience or concern to the subject 
and may interfere with daily activities. 
 Severe events interrupt the subject’s usual daily activity. 


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Definitions of Relationship 
Causal relationship must be assessed by the Investigator answering the following question: 
‘Is there a reasonable possibility that the drug caused the event?’ 
Yes 
There is a reasonable or strong temporal relationship, and the events are unlikely 
attributed to other drugs, underlying diseases or other factors. 
No 
There is no strong temporal relationship, and/or use of other drugs, underlying 
diseases, or other factors provide plausible explanations for the occurrence of the 
event. 
6.2.1.1 
Monitoring of Adverse Events 
The Investigator is responsible for recording all AEs observed during the study (screening, 
treatment, and follow-up periods). At each visit, the subject will be asked if they have 
experienced any untoward occurrence since the last trial visit. In addition, subjects will be 
instructed to contact the study site at any time after the ICF is signed if any symptoms 
develop. 
All AEs/SAEs should be recorded individually in the study subject’s own words (verbatim) 
unless, in the opinion of the Investigator, the AEs/SAEs constitute components of a 
recognised condition, disease, or symptom. The Investigator should attempt to establish a 
diagnosis of the event based on signs, symptoms, and/or other clinical information. In such 
cases, the diagnosis should be documented as the AE and/or SAE rather than the individual 
signs/symptoms. 
All AEs will be recorded on the eCRFs and include a description of the event, severity, time 
of occurrence, and duration. In addition, any action (e.g., treatment and follow-up tests) and 
the outcome should be provided along with the Investigator’s assessment of the relationship 
to the investigational drug. 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure 
is considered as the AE rather than the procedure itself. 
In cases in which the subject dies, the cause of death should be recorded as an SAE; death is 
considered the outcome of the SAE.  
Adverse events should be followed until recovery to the normal state has been achieved. In 
the event of a subject not returning to the study site, the outcome of this event will be 
recorded as unknown. 
6.2.1.2 
Recording of Adverse Events 
All AEs that occur after the subject has signed consent (regardless of severity and/or 
perceived relationship to study drug) are to be recorded on the appropriate AE sections (either 


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‘serious’ or ‘non-serious’) in the eCRF. Spontaneously reported SAEs that occur for up to 30 
days after the last dose of study drug will also be recorded. The Investigator should complete 
all the details requested including dates of onset, severity, action taken, outcome, relationship 
to study drug. Each event should be recorded separately. 
6.2.1.3 
Reporting of Serious Adverse Events  
In the case of an SAE (including SUSARs), the Investigator must complete, sign and date the 
SAE pages from the eCRF, and check that the data are consistent.  
Any SAE, including death due to any cause, which occurs during this study, whether or not 
related to the study drug, must be reported immediately (within 24 hours of the study site’s 
knowledge of the event) by sending a completed, separate SAE Report Form by fax or email 
to Emas Pharma as displayed below:: 
Contact Method 
Fax 
+44(0)1462 600 456 
Email 
drug.safety@emaspharma.com 
The report will contain all available information concerning the SAE to enable the Sponsor 
(or an authorised representative) to file a report, which satisfies regulatory reporting 
requirements. These timelines apply to initial reports of SAEs and to all follow-up reports.  
All SAEs will be recorded on the SAE Report Form, the Adverse Events Form in the eCRF, 
and source documents. Criteria for documenting the relationship to study drug as well as 
severity and outcome will be the same as those previously described.  
SAEs considered causally related to study treatment that are spontaneously reported to the 
Investigator more than 30 days after a subject’s last dose of study drug should also be 
collected and reported as described previously, regardless of the time after the trial. 
The information must include at least the following: 
 Name, address, and telephone number of the reporting Investigator 
 Investigational product and study code. 
 Subject identification number, sex, and date of birth (recorded as permitted by 
local authorities). 
 Description of the AE, measures taken and outcome. 
 Preliminary classification of causal relationship by the Investigator  
Additional follow-up information should be completed on an SAE Form with a copy sent to 
Emas Pharma and the original included in the SAE section of the eCRF. 


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6.2.1.4 
Reporting of Serious Adverse Events to Regulatory Authorities and 
Investigators 
Investigators will be notified of all SAEs that require prompt submission to their Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC). Investigators should provide 
written documentation of IRB/IEC notification for each report to the Sponsor or Quintiles. 
Emas Pharma will ensure that all applicable SAEs are reported to the appropriate regulatory 
authorities on behalf of the Sponsor. In countries where the sponsor is responsible for IEC 
submissions of applicable SAEs, this will be performed by Emas Pharma.  
6.2.1.5 
Follow-Up of Adverse Events 
Any AEs observed from Screening/randomisation up to the final study visit will be followed 
up to resolution. Resolution means that the subject has returned to a baseline state of health or 
the Investigator does not expect any further improvement or worsening of the AE.  
6.2.1.6 
Pregnancy 
Females of childbearing potential will have a serum pregnancy test performed at Screening 
and a urine pregnancy test at Day 1 to ensure the exclusion of pregnant women from the 
study. Female subjects will be instructed to inform the site if they become pregnant during 
the study. Male subjects will be instructed to inform the site if their partner becomes pregnant 
during the study. 
Female subjects of childbearing potential will have an additional test for pregnancy at Day 42 
(the end of the study) and at Day 56 (the Follow-up Visit). In addition, a pregnancy test will 
be performed at the Early Termination Visit, if a female of childbearing potential 
discontinues the study prior to Day 42.  
Any known or suspected pregnancy that occurs during the study (either in female subjects or 
female partners of male subjects) must be reported to Emas Pharma within 24 hours of the 
time the Investigator becomes aware of the event, using the Pregnancy Report Form. 
Suspected pregnancies in subjects will be confirmed with a pregnancy test. Pregnant females 
will be discontinued from the study.  
The Sponsor/designee has a responsibility to monitor the outcome of all pregnancies reported 
during the study. The Investigator must follow up and document the course and the outcome 
of all pregnancies even if the subject withdraws consent or the study has finished. 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of contraceptive medications or a suspected AE is 
associated with pregnancy. 
Elective abortions without complications should not be regarded as AEs, unless they were 
therapeutic abortions (see below). Hospitalisation for normal delivery of a healthy new-born 
should not be considered an SAE. 


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All outcomes of pregnancy must be reported by the Investigator to Emas Pharma on the 
Pregnancy Outcome Report Form within 30 days after he/she has gained knowledge of the 
normal delivery or elective abortion. The Investigator must follow up and document the 
course and the outcome of all pregnancies even if the subject was withdrawn from the study 
or if the study has finished. The pregnancy will be followed up to delivery; the Investigator 
must report any complications that occur even though the study has finished. 
Any SAE that occurs during pregnancy must be recorded on the SAE Report Form 
(e.g., maternal serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, 
neonatal death, congenital anomaly, birth defect) and reported within 24 hours in accordance 
with the procedure for reporting SAEs (see Section 6.2.1.3).  
6.2.2 
Contraception 
The need to avoid pregnancy and acceptable methods of contraception should be discussed 
with male subjects and female subjects of childbearing potential prior to the administration of 
study drug. 
Females of childbearing potential must have a negative serum pregnancy test at Visit 1, a 
negative urine test at Day 1, and agree to use effective contraception from signing informed 
consent and for at least 90 days after the last dose of study drug. Males who are sexually 
active with a female partner of childbearing potential must be willing to use effective 
contraception from signing informed consent and for 90 days after the study.  
1. Females of childbearing potential include any female who has experienced menarche 
and who has not undergone successful surgical sterilisation (hysterectomy, bilateral 
tubal ligation, salpingectomy, or bilateral oophorectomy) or is not postmenopausal. 
Postmenopausal is defined as no menses for ≥12 months without an alternative 
medical cause. Females with questionable menopausal history (e.g., irregular 
menstrual periods and age >40 years) are considered to be of childbearing potential.  
2. Females of childbearing potential must use acceptable highly effective (according to 
Clinical Trial Facilitation Group [CTFG] recommendations) methods of birth control 
in this study. These include:  
 Combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation 
o oral 
o intravaginal 
o transdermal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation 
o oral 
o injectable 


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o implantable  
 Intrauterine device  
 Intrauterine hormone-releasing system  
 Bilateral tubal occlusion  
 Vasectomised partner (provided that partner is the sole sexual partner of the 
female of childbearing potential trial participant and that the vasectomised partner 
has received medical assessment of the surgical success.) 
 Sexual abstinence must be true sexual abstinence defined as refraining from 
heterosexual intercourse as part of the preferred and usual lifestyle of the subject. 
This behavior must cover the entire period of risk associated with the study 
treatment, which includes at least the time of screening up to at least 90 days after 
the end of treatment. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study. Periodic abstinence (e.g., calendar ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of exposure to study drug, and withdrawal are not acceptable methods of 
contraception. 
3. Fertile males who are sexually active with a female partner of childbearing potential 
must agree to use contraception (condom plus spermicide or partner using acceptable 
highly effective method) from signing informed consent and for 90 days after last 
dose.  
4. Fertile males should be instructed that they are not to donate sperm during the study 
or up to 90 days the last dose of study drug.  
5. Subjects must follow the strictest applicable local requirement in regards to 
contraception as specified by the Regulatory Agency or Ethics Committee approving 
the trial. 
6.2.3 
Clinical Laboratory Evaluations 
Blood will be drawn and urine samples will be collected from each subject at each study visit. 
The clinical laboratory parameters used as screening tests, efficacy outcomes or for safety 
monitoring are presented in Table 2. 
Clinical laboratory tests will be reviewed for results of potential clinical significance 
throughout the study (see Section 6.2.1 for definition of clinically significant laboratory 
results). If the Investigator determines a laboratory abnormality to be clinically significant, it 
is considered a laboratory AE. However, if possible, the underlying condition causing the 
laboratory abnormality, rather than the abnormality itself, should be reported as the AE. 
Clinically significant laboratory results will be followed to resolution or until the Investigator 
considers the abnormality chronic and/or the subject to be stable. 


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A central laboratory designated by the Sponsor will be used for all laboratory assessments 
during the trial. Urine pregnancy testing will be done by dipsticks (supplied by the central 
laboratory). 
If an immediate result is required, a sample should be sent to both the local and central 
laboratory. 
Table 2: Clinical Laboratory Testing  
Haematology: 
White blood cell count (differential, percentages and 
absolute count)   
Haemoglobin  
Haematocrit  
Red blood cell count  
Mean corpuscular volume  
Mean corpuscular haemoglobin  
Mean corpuscular haemoglobin concentration  
Red cell distribution width  
Platelet count  
 
Urinalysis: 
Colour  
Clarity/Appearance  
Specific gravity  
pH  
Protein  
Blood  
Glucose  
Ketones  
Bilirubin  
Urobilinogen  
Nitrite  
Leukocyte esterase  
Microscopy 
 
Additional Tests (Screening only): 
Activated partial thromboplastin time 
Hepatitis B surface antigen  
Hepatitis B surface antibody  
Hepatitis B core total antibody  
Hepatitis C antibody  
C. difficile toxin and presence of other enteric 
pathogens 
QuantiFERON-TB Gold Test 
Serum Chemistry: 
Sodium  
Potassium  
Blood urea nitrogen/Urea  
Creatinine  
Glucose  
Calcium  
Phosphorus  
Total protein  
Albumin   
Aspartate aminotransferase  
Alanine aminotransferase  
Total bilirubin 
Alkaline phosphatase 
 
Additional Tests (Females of childbearing potential): 
Serum pregnancy test (at Visit 1) 
Urine pregnancy at Day 1, Day 42 and Day 56 
If the urine pregnancy test gives equivocal results at 
these visits, or is positive, a serum pregnancy test 
will be performed to determine if the subject is 
pregnant. 
 
Biomarkers 
C-reactive protein 
Faecal calprotectin 
 
6.3 
Vital Signs, Physical Examination and Other Safety Assessments 
6.3.1 
Vital Signs 
Vital signs include systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate 
(HR), and body temperature. These data will be collected at the visits indicated in . 


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Blood pressure (measured after at least five minutes in the sitting position) and HR (measured 
after at least five minutes in the sitting position) will be recorded at every study visit. 
Automatic or manual devices may be used, but the same device should be used for any given 
subject throughout the study wherever possible. The same arm should be used for all 
measurements, if possible. Blood pressure and HR should be measured after the subject has 
rested (sitting quietly) for at least five minutes, and more than 10 minutes after any blood 
draw. 
Temperature will be measured as per local standard of care.  
6.3.2 
Physical Examination, Height and Weight  
A full physical examination will be performed at the time points indicated in . Physical 
examinations will be performed by a physician. The complete physical examination 
performed at Visit 1 and Day 42 will include the examination of the following:  
 General appearance 
 Eyes 
 Ears, nose, throat 
 Chest/respiratory 
 Heart/cardiovascular 
 Gastrointestinal/liver musculoskeletal/extremities 
 Dermatological/skin 
 Thyroid/neck 
 Lymph nodes 
 Neurological/psychiatric 
At other time points (Day 1, Day 14 and Day 56), a brief physical examinations will include 
assessments of the skin, lungs, cardiovascular system, abdomen (liver and spleen) and other 
symptom-directed assessments as appropriate.  
Weight (without shoes and in normal street clothes) will be measured at each study visit.  
Height (without shoes) and body mass index (BMI) will be measured at Baseline. 
6.3.3 
Electrocardiogram 
Electrocardiograms will be evaluated at the time points indicated in . Electrocardiogram 
recordings will be obtained after the subject has been supine and at rest for at least five 
minutes. ECG results will be evaluated at the investigational site to monitor safety during the 
trial. The Investigator or designee will review, sign, and date each ECG reading. The 
Investigator or designee will determine if any abnormal results are of clinical significance. 
The ECG will be repeated if any results are considered by to be clinically significant. 


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6.3.4 
Medical History 
Medical history (including CD history) will be collected at Visit 1.  
A complete medical history will include evaluation (past or present) of the following:   
 General  
 Head and neck  
 Eyes, ears, nose, throat 
 Chest/respiratory  
 Heart/cardiovascular  
 Gastrointestinal/liver 
 Gynaecological/urogenital 
 Musculoskeletal/extremities 
 Skin 
 Neurological/psychiatric 
 Endocrine/metabolic 
 Haematologic/lymphatic 
 Allergies/drug sensitivities  
 Past surgeries  
 Substance abuse  
 Any other diseases or disorders  
A detailed history of CD, including date of diagnosis, disease severity, disease duration, 
disease location, associated complications, hospitalisations and extra-intestinal manifestations 
will be collected during Screening. The subject’s CD drug history will also be recorded.  
6.4 
Immunogenicity 
Blood samples will be evaluated for the presence of anti-V565 antibody at the time points 
indicated in . Samples will be collected, labelled, stored, and shipped as detailed in the 
Central Laboratory Manual. Samples will be processed by LGC Ltd, Fordham, UK.  
6.5 
Pharmacokinetics 
The concentration of V565 will be determined in serum, and urine at the time points indicated 
in . Samples will be collected, labelled, stored, and shipped as detailed in the Central 
Laboratory Manual. Samples will be processed by LGC Ltd, Fordham, UK. 


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6.5.1 
Blood 
Samples will be obtained for the determination of V565 in serum. The following information 
will be captured for blood sample collection in each subject’s eCRF: 
1. Subject’s study number and initials 
2. Time and date of first V565 dose administration on Day 1 and time and date of the 
most recent V565 dose prior to PK sampling on Day 14 and 42. 
3. Time and date of each blood sample collected for PK analysis 
4. Time and date of subject’s most recent ingestion of food prior to dose administration 
Samples will be collected, processed, labelled, stored, and shipped as detailed in the 
Central Laboratory Manual. 
6.5.2 
Urine 
Urine samples for analysis of V565 in urine will be collected as follows: 
1. Prior to administration of the first dose of V565 on Day 1. Date/time of urine 
collections will be captured in each subject’s eCRF. 
2. Post-dose on Day 1, 4 to 8 hours after the first dose of study drug, prior to leaving the 
clinic 
3. During the Day 14 and Day 42 visits, complete urine voids will be collected prior to 
the subject leaving the clinic. The weight (g) or volume (mL) and pH of the urine void 
along with the date/time of urine collections will be captured in each subject’s eCRF. 
Date and time of the last dose prior to urine collection will also be captured in the 
eCRF. 
Aliquots of the respective urine sample will be frozen and stored until determination of V565 
concentration as outlined in the Central Laboratory Manual. 
6.6 
Pharmacogenetics 
A blood sample for exploratory genetic research will be obtained from consenting subjects 
pre-dose, at Visit 3 (Day 1). Although genotype is a stable parameter, sample collection prior 
to the first dose on Day 1 is preferred to avoid introducing bias through excluding subjects 
who may withdraw due to an AE; it is important to include such subjects in any genetic 
analysis. If the sample is not drawn at Visit 3 (Day 1), it may be taken at any visit until the 
last study visit. Only one sample should be collected per subject for possible genetic analysis. 
Samples will be collected, labelled, stored, and shipped as detailed in the Central Laboratory 
Manual. 
Participation in this optional genetic research is voluntary. A separate ICF will be used for 
subjects who elect to contribute samples for pharmacogenetic analyses. This sample may be 


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analysed only for genes involved in the drug metabolism, safety, and clinical efficacy of 
V565. These samples may provide information on how individuals metabolise and react to 
the study drug.  
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality. Samples will be stored for a maximum of 15 
years from the date of the last subject’s last visit, after which they will be destroyed. Samples 
will be stored and used until no further analyses are possible or the maximum storage time 
has been reached. 
For all samples, irrespective of the type of coding used, the DNA will be extracted from the 
blood sample. The DNA sample will be assigned a unique number replacing the information 
on the sample tube. Thereafter, the DNA sample will be identifiable by the unique DNA 
number only. No personal details identifying the individual will be available to any person.  
6.7 
Appropriateness of Measurements 
All efficacy, safety, and tolerability assessments used in this study are standard and generally 
accepted as appropriate for this type of study. 


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7.0 QUALITY CONTROL AND QUALITY ASSURANCE 
According to the Guidelines of Good Clinical Practice (CPMP/ICH/135/95), the Sponsor is 
responsible for study drug documentation and maintaining quality assurance and quality 
control systems with written Standard Operating Procedures (SOPs).  
Quality control will be applied to each stage of data handling.  
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
 Investigator meeting(s) 
 Central laboratories for clinical laboratory parameters 
 Site Initiation visit 
 Early site visits post-enrolment 
 Routine site monitoring 
 Ongoing site communication and training 
 Data management quality control checks 
 Continuous data acquisition and cleaning 
 Internal review of data 
 Quality control check of the final clinical study report 
In addition, the Sponsor and/or Quintiles Clinical Quality Assurance Department may 
conduct periodic audits of the study processes, including, but not limited to study site, site 
visits, central laboratories, vendors, clinical database, and final clinical study report. When 
audits are conducted, access must be authorised for all study related documents including 
medical history and concomitant medication documentation to authorised Sponsor’s 
representatives and regulatory authorities. 
7.1 
Monitoring 
The Sponsor has engaged the services of a contract research organisation (CRO), Quintiles, 
to perform all monitoring functions within this clinical study. Quintiles’ monitors will work 
in accordance with Quintiles’ SOPs. Monitors will establish and maintain regular contact 
between the Investigator and the Sponsor. 
Monitors will evaluate the competence of each study site, informing the Sponsor about any 
problems relating to facilities, technical equipment, or medical staff. During the study, 
monitors will check that written informed consent has been obtained from all subjects 
correctly and that data are recorded correctly and completely. Monitors are also entitled to 
compare entries in eCRFs with corresponding source data and to inform the Investigator of 
any errors or omissions. Monitors will also control adherence to the protocol at the study site.  


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Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards. Regular monitoring visits will be made to each site while subjects are enrolled in 
the study. The monitor will make written reports to the Sponsor on each occasion contact 
with the Investigator is made, regardless of whether it is by phone or in person. 
During monitoring visits, entries in the eCRFs will be compared with the original source 
documents (source data verification). 
7.2 
Data Management/Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of 
the Data Management and Biostatistics departments of Quintiles.  
Electronic Data Capture (EDC) will be used for this study, meaning that all eCRF data will 
be entered in electronic forms at the study site. Data collection will be completed by 
authorised study site staff designated by the Investigator. Appropriate training and security 
measures will be completed with the Investigator and all authorised study site staff prior to 
the study being initiated and prior to any data being entered into the system for any study 
subjects. 
All data must be entered in English. The eCRFs should always reflect the latest observations 
on the subjects participating in the study. Therefore, the eCRFs are to be completed as soon 
as possible during or after the subject’s visit. To avoid inter-observer variability, every effort 
should be made to ensure that the same individual who made the initial baseline 
determinations completes all efficacy and safety evaluations. The Investigator must verify 
that all data entries in the eCRFs are accurate and correct. If some assessments are not done, 
or if certain information is not available or not applicable or unknown, the Investigator 
should indicate this in the eCRF. The Investigator will be required to sign off electronically 
on the clinical data.  
The monitor will review the eCRFs and evaluate them for completeness and consistency. The 
eCRF will be compared with the source documents to ensure that there are no discrepancies 
between critical data. All entries, corrections, and alterations are to be made by the 
responsible Investigator or his/her designee. The monitor cannot enter data in the eCRFs. 
Once clinical data of the eCRF have been submitted to the central server, corrections to the 
data fields will be audit trailed, meaning that the reason for change, the name of the person 
who performed the change, and the time and date of the change will be logged. Roles and 
rights of the site staff responsible for entering the clinical data into the eCRF will be 
determined in advance. If additional corrections are needed, the responsible monitor or Data 
Manager will raise a query in the EDC application. The appropriate study site staff will 
answer queries sent to the Investigator. This will be audit trailed by the EDC application, 
meaning that the name of investigational staff, time and date stamp are captured. 
The eCRF is essentially considered a data entry form and should not constitute the original 
(or source) medical records unless otherwise specified. Source documents are all documents 


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and sources of information used by the Investigator or hospital that relate to the subject’s 
medical history, that verify the existence of the subject, the inclusion and exclusion criteria 
and all records covering the subject’s participation in the study. They include laboratory 
notes, ECG results, memoranda, pharmacy dispensing records, subject files, etc. 
The Investigator is responsible for maintaining source documents. These will be made 
available for inspection by the study monitor at each monitoring visit. The Investigator must 
submit a completed eCRF for each subject who receives study drug, regardless of duration. 
All supportive documentation submitted with the eCRF, such as laboratory or hospital 
records, should be clearly identified with the study and subject number. Any personal 
information, including subject name, should be removed or rendered illegible to preserve 
individual confidentiality. 
eCRF records will be automatically appended with the identification of the creator by means 
of their unique UserID. Specified records will be electronically signed by the Investigator to 
document his/her review of the data and acknowledgement that the data are accurate. This 
will be facilitated by means of the Investigator’s unique UserID and password; date and time 
stamps will be added automatically at time of electronic signature. If an entry on an eCRF 
requires change, the correction should be made in accordance with the relevant software 
procedures. All changes will be fully recorded in a protected audit trail, and a reason for the 
change will be required. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary and Anatomical Therapeutic Chemical (ATC) system. Concomitant 
diseases/medical history will be coded using MedDRA.  
7.3 
Quality Assurance Audit 
Study sites, the study database and study documentation may be subject to Quality Assurance 
audit during the course of the study by the Sponsor or Quintiles on behalf of the Sponsor. In 
addition, inspections may be conducted by regulatory bodies at their discretion.  


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8.0 STATISTICS 
8.1 
Determination of Sample Size 
The sample size is based on being able to claim superiority of V565 over placebo; the 
primary endpoint is defined as a response rate, based on CDAI reduction/remission and CRP 
or FCP results.  
It is assumed that the proportion of subjects assigned to placebo treatment who respond is 
0.15. A clinically important response rate on V565 is defined as 0.4. 
A 2:1 (V565:placebo) allocation, 80% power and 5% statistical significance rate estimate 
76:38 evaluable subjects will be required for this study. With a 10% estimated non-evaluable 
rate, a total of 126 subjects (84:42) are planned to be randomised to treatment. 
Sample size estimates are based on a Pearson chi-square test for two proportions and are 
generated using SAS Power and Sample Size v13.2.  
A subgroup of subjects will be assessed by endoscopy for changes in overall mucosal 
appearance and changes in SES-CD. However, the study is not powered to show a difference 
in these endpoint. 
8.2 
Statistical Methods 
The default summary statistics for continuous variables include number of contributing 
observations [n], mean, standard deviation (SD), median, minimum, and maximum.  
For categorical variables, the number and percentage (the percentage of subjects in each 
category relative to the total number of subjects in the relevant analysis population or relative 
to the total number of subjects in the relevant analysis population, with assessments available 
[where appropriate]) in each category will be the default summary presentation.  
Unless otherwise specified, “Baseline” is defined as the last observed value of the parameter 
of interest prior to the first intake of study medication (this includes unscheduled visits). For 
numerical variables, change from Baseline will be calculated as the difference between the 
value of interest and the corresponding baseline value. 
Unless otherwise specified, all formal statistical tests will be two-sided at the 5% significance 
level. Point estimates of treatment differences will be accompanied with two-sided 95% 
confidence intervals (CIs) where applicable.  
In the case of normality assumption violations, appropriate non-parametric methods will be 
used for analysis.  
All data will be presented in by-subject listings. 
The statistical analysis will be performed using SAS® Version 9.2 or higher. 


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8.2.1 
Primary Efficacy Analysis 
The primary clinical efficacy endpoint of the study is the proportion of subjects at Day 42 
that have both CDAI ≥70-point reduction from Baseline or CDAI <150, and a reduction of 
≥40% from the baseline value of CRP or FCP. 
The primary endpoint will be analysed using a logistic regression model with treatment as the 
fixed effect and prior anti-TNFα therapy, baseline CDAI score, baseline CRP and baseline 
FCP values as covariates. For the active treatment versus placebo comparison, the results will 
be presented in terms of an odds ratio together with its associated 95% CI and 2-sided p-
value. Two-sided 95% CIs for the odds ratio will be provided. 
Possible effects of any other covariates may also be investigated. Details of such analyses 
will be described in the Statistical Analysis Plan (SAP). Missing data handling and possible 
sensitivity analysis will be described in the SAP. Details of specific alternative statistical 
methods in the event model assumptions are violated will be documented in the SAP.  
8.2.2 
Secondary Efficacy Analyses 
The secondary endpoints below will be analysed using the same model as used in the primary 
endpoint analysis.  
 Proportion of subjects achieving a ≥100-point reduction in CDAI score and a 
concomitant reduction of 50% in CRP or FCP at Day 42 
 Proportion of subjects achieving a ≥70-point reduction in CDAI score at Day 42 
 Proportion of subjects achieving a ≥100-point reduction in CDAI score at Day 42 
 Proportion of subjects achieving a CDAI score of <150 CDAI at Day 42  
For the PRO-2 score assessments, the changes in total scores from Baseline to Day 14 and 
Day 42 will be analysed using a Mixed Model for Repeated Measures (MMRM) with 
treatment as the fixed effect, prior anti-TNFα and baseline scores as covariates. 
8.2.3 
Exploratory Analyses 
The exploratory endpoint evaluating the proportion of subjects achieving CRP (or FCP) 
levels within normal limits at Day 14 and Day 42 will be summarised using frequency and 
percentage.  
The endpoints evaluating changes in CDAI score over time and changes in CRP (or FCP) 
results over time will be summarised using descriptive statistics.  
The anti-V565 antibody responses will be summarised and listed for the safety (SAF) 
population.  
Changes from Baseline in the frequency of loose or watery stools (BSFS Type 6 and Type 7) 
and changes in NPS scores (both averaged over 7 consecutive days) will be summarised 


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using descriptive statistics. The proportion of subjects with various degrees of faecal urgency 
at Day 1, Day 14 and Day 42 will be summarised using frequency and percentage to evaluate 
changes from baseline in faecal urgency. Details will be presented in the SAP.  
In the exploratory endoscopy substudy, changes in the central reader’s overall assessment and 
changes in SES-CD from Baseline to Day 42 will be summarised using descriptive statistics. 
Summary statistics presentation will be separated for subjects with ileum and colon 
involvement and for subjects with only ileal mucosal lesions.  
Any additional analyses or data presentation details will be described in the SAP. 
8.2.4 
Pharmacokinetic Analysis 
Samples for analysis of concentrations of study drug will be collected as specified on the 
Schedule of Events (). Individual PK blood sample collection dates/times, urine sample 
collection dates/times/sample volume and the associated V565 concentrations will be listed. 
Serum V565 concentrations will be summarised using descriptive statistics by planned 
sampling time. 
The amount of V565 excreted in each urine collection will be determined as 
V565 concentration × urine volume of the urine sample and listed for each subject by visit.  
8.2.5 
Safety Analyses 
All safety data will be provided in by-subject listings. 
8.2.5.1 
Adverse Events  
Treatment-emergent Adverse Event: A TEAE is defined as:  
 A new event that occurs during or after treatment with study drug or  
 Any event present at Baseline that worsens in either intensity or frequency after 
exposure to study drug.  
Only TEAEs will be summarised.  
The number and percentage of subjects experiencing TEAEs and serious TEAEs will be 
summarised by treatment group, and by MedDRA System Organ Class (SOC) and Preferred 
Term. The TEAEs will also be summarised by maximum severity and relationship to study 
medication in addition to SOC, Preferred Term and treatment group. Summaries will also be 
presented for serious TEAEs and for TEAEs leading to permanent discontinuation. 
Medical history will be coded using the MedDRA latest version and listed for all subjects. 
8.2.5.2 
Safety Laboratory Tests 
The results of safety laboratory tests will be summarised for each laboratory parameter and 
planned visit time point.  


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Continuous laboratory parameters will be summarised by visit time point using the number of 
subjects with non-missing data, mean, SD, median, minimum and maximum. Actual values 
as well as changes from Baseline will be summarised. 
Categorical parameters will be summarised by the number and percentage of subjects within 
each category, relative to the total number of subjects in the SAF, with data available. In the 
event of missing test results, a “missing” category showing the number of subjects with 
missing test results at each level of summarisation will be presented. 
Shift tables for specific time points versus baseline status will be presented for both 
continuous (categorised in accordance with study-specific reference ranges as Low, Normal, 
High) and categorical (using appropriate categories such as Normal, Abnormal) laboratory 
parameters. “Time point” in these tables may be either a specific visit, a final study visit or 
the entire study duration on-treatment. 
8.2.5.3 
Vital Signs and 12-lead ECG 
Vital signs statistics will be presented in a similar way to the laboratory variables.  
All ECG data results (normal/abnormal) will be summarised using frequency counts and 
percentages. Clinically significant abnormalities will be presented in by-subject listings.  
8.2.5.4 
Physical Examinations 
Physical examination results will be summarised using frequency tables for normal/abnormal 
results per visits.  
8.2.5.5 
Concomitant Medications 
All medications will be coded using the WHO Drug Dictionary and ATC system. Each 
medication will be classified as prior medication if it is stopped prior to the first dose of study 
medication, or as concomitant medication if it is ongoing at the time of the first dose or is 
started after the first dose of study medication. Prior and concomitant medications (other than 
permitted medications for the treatment of CD) will be summarised by treatment group by 
ATC level 2 categories and preferred name. 
Permitted medications for the treatment of CD will be summarised separately. 
8.2.6 
Data To Be Analysed 
All details regarding the statistical analysis and the preparation of tables, listings and figures 
will be described in the SAP prepared by Quintiles and approved by the Sponsor before 
database lock. 


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8.2.7 
Analysis Populations 
Intent-to-Treat (ITT) population: The ITT population will include all randomised subjects. In 
this population, treatment will be assigned based upon the treatment arm to which subjects 
were randomised regardless of which treatment they actually received. 
Per Protocol population (PP): The PP population will include all subjects who do not have 
major protocol violations that would affect the evaluation of the primary efficacy endpoint.  
Safety population (SAF): The SAF population will include all randomised subjects who 
receive at least one dose of study drug. In this population, treatment will be assigned based 
upon the treatment subjects actually received, regardless of the treatment to which they were 
randomised.  
Pharmacokinetic population (PK): The PK population will include all subjects in the SAF 
population who receive at least one dose of study drug and who have at least one post dose 
sample of serum and urine who do not have events or protocol deviations with the potential to 
affect PK concentrations.  
8.2.8 
Missing Data 
Missing data handling and possible sensitivity analysis will be described in the SAP.  
8.2.9 
Subgroup Analysis 
No subgroup analyses are planned.  
8.3 
Interim Analyses 
No interim analysis for efficacy or safety is planned. 


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9.0 ETHICS 
9.1 
Institutional Review Board or Independent Ethics Committee 
An ethics committee should approve the final protocol, including the final version of the ICF 
and any other written information and/or materials to be provided to the subjects. The 
Investigator will provide the Sponsor or Quintiles with documentation of IRB/IEC approval 
of the protocol and informed consent before the study may begin at the study site(s). The 
Investigator should submit the written approval to Sponsor or representative before enrolment 
of any subject into the study. 
Sponsor or representative should approve any modifications to the ICF that are needed to 
meet local requirements. 
The Investigator will supply documentation to the Sponsor or Quintiles of required 
IRB/IEC’s annual renewal of the protocol, and any approvals of revisions to the informed 
consent document or amendments to the protocol. 
The Investigator will promptly report any new information that may adversely affect the 
safety of subjects or the conduct of the study to the IRB/IEC. Similarly, the Investigator will 
submit written summaries of the study status to the IRB/IEC annually, or more frequently if 
requested by the IRB/IEC. Upon completion of the study, the Investigator will provide the 
IRB/IEC with a brief report of the outcome of the study, if required. 
Sponsor or representative will provide Regulatory Authorities, ethics committees and 
Investigators with safety updates/reports according to local requirements, including SUSARs, 
where relevant. 
Each Investigator is responsible for providing the IRB/IEC with reports of any serious and 
unexpected adverse drug reactions from any other study conducted with the study drug. The 
Sponsor or representative will provide this information to the Investigator so that he/she can 
meet these reporting requirements. 
9.2 
Ethical Conduct of the Study 
This study will be conducted, and the informed consent will be obtained, according to the 
ethical principles stated in the Declaration of Helsinki (64th WMA General Assembly, 
Fortaleza, Brazil, October 2013), the applicable guidelines for good clinical practice (GCP) 
(CPMP/ICH/135/95), or the applicable drug and data protection laws and regulations of the 
countries where the study will be conducted. 
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human subjects. The study 
will be conducted in compliance with GCP and the applicable national regulations to assure 


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that the rights, safety and wellbeing of the participating study subjects are protected 
consistent with the ethical principles that have their origin in the Declaration of Helsinki. 
9.3 
Subject Information and Informed Consent 
The ICF will be used to explain the risks and benefits of study participation to the subject in 
simple terms before the subject will be entered into the study. The ICF contains a statement 
that the consent is freely given, that the subject is aware of the risks and benefits of entering 
the study, and that the subject is free to withdraw from the study at any time. Written consent 
must be given by the subject and/or legal representative, after the receipt of detailed 
information on the study. 
The Investigator is responsible for ensuring that informed consent is obtained from each 
subject or legal representative and for obtaining the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures and prior to 
the administration of study drug. The Investigator will provide each subject with a copy of 
the signed and dated consent form.  
A separate ICF will be used for subjects who elect to contribute samples for pharmacogenetic 
analyses.  
9.4 
Subject Data Protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
The Sponsor or representative will not provide individual genotype results to subjects, any 
insurance company, any employer, their family members, general physician or any other third 
party, unless required to do so by law. 
Extra precautions will be taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the subject. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a subject. For 
example, in the case of a medical emergency, a Sponsor or representative physician or an 
Investigator might know a subject’s identity and also have access to his or her genetic data. In 
addition, regulatory authorities may require access to the relevant files. 


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10.0 STUDY ADMINISTRATION 
10.1 Administrative Structure 
The administrative structure of this study is presented in . 
10.2 Data Handling and Record Keeping 
It is the Investigator’s responsibility to maintain essential study documents (protocol and 
protocol amendments, completed eCRFs, signed ICFs, relevant correspondence, and all other 
supporting documentation). The study site should plan to retain such documents for 
approximately 15 years after study completion. The study site should retain such documents 
until at least two years after the last approval of a marketing application in an ICH region and 
until there are no pending or contemplated marketing applications in an ICH region or at least 
two years after the formal discontinuation of clinical development of the investigational 
product. These documents should be retained for a longer period if required by the applicable 
regulatory requirements or the hospital, institution, or private practice in which the study is 
being conducted. Subject identification codes (subject names and corresponding study 
numbers) will be retained for this same period. These documents may be transferred to 
another responsible party, acceptable to Sponsor, who agrees to abide by the retention 
policies. Written notification of transfer must be submitted to Sponsor. The Investigator must 
contact Sponsor prior to disposing of any study records.  
The U.S. Food and Drug Administration (FDA) regulations (21 CFR §312.62[c]) and the ICH 
Guideline for GCP (see Section 4.9 of the guideline) require that records and documents 
pertaining to the conduct of this study and the distribution of study drug (including eCRFs, 
consent forms, laboratory test results, and medication inventory records), must be retained by 
the Principal Investigator for 15 years after the last marketing application approval in an ICH 
region or after at least 15 years have elapsed since formal discontinuation of clinical 
development of the investigational product. The Sponsor will notify the Principal Investigator 
of these events.  
No records should be disposed of without the written approval of the Sponsor.  
For studies conducted outside the United States under a U.S. Investigational New Drug (IND) 
application, the Principal Investigator must comply with U.S. FDA IND regulations and with 
those of the relevant national and local health authorities. 
10.3 Direct Access to Source Data/Documents 
The Investigator will prepare and maintain adequate and accurate source documents to record 
all observations and other pertinent data for each subject randomised into the study.  


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The Investigator will allow the Sponsor, Quintiles, and authorised regulatory authorities to 
have direct access to all documents pertaining to the study, including individual subject 
medical records, as appropriate. 
10.4 Investigator Information 
10.4.1 
Investigator Obligations 
This study will be conducted in accordance with the ICH Harmonised Tripartite Guideline for 
GCP (GCP, 1997); the U.S. CFR Title 21 parts 50, 56, and 312; and European Legislation; 
and the ethical principles that have their origin in the Declaration of Helsinki.  
The Investigator agrees to conduct the clinical study in compliance with this protocol after 
the approval of the protocol by the IEC/IRB in compliance with local regulatory 
requirements. The Investigator and the Sponsor will sign the protocol to confirm this 
agreement. 
10.4.2 
Protocol Signatures 
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative (see the Appendix, Section 12.3). By 
signing the protocol, the Investigator confirms in writing that he/she has read, understands 
and will strictly adhere to the study protocol and will conduct the study in accordance with 
ICH Tripartite Guidelines for GCP and applicable regulatory requirements. The study will 
not be able to start at any site where the Investigator has not signed the protocol. 
10.4.3 
Publication Policy  
The data generated by this study are confidential information of the Sponsor. The Sponsor 
will make the results of the study publicly available. The publication policy with respect to 
the Investigator and study site will be set forth in the Clinical Trial Agreement. 
10.5 Financing and Insurance  
The Sponsor will obtain liability insurance that covers this study as required by local law 
and/or national regulations and/or ICH guidelines whichever is applicable. The terms of the 
insurance will be kept in the study files. 


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11.0 REFERENCES 
1. Cosnes J, Gower–Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of 
inflammatory bowel diseases. Gastroenterology. 2011;140(6):1785-94. 
2. Ng S. Emerging leadership lecture: Inflammatory bowel disease in Asia: emergence of a 
"Western" disease. J Gastroenterol Hepatol. 2015;30(3):440-5. 
3. Thia KT, Sandborn WJ, Harmsen WS, Zinsmeister AR, Loftus EV Jr. Risk factors 
associated with progression to intestinal complications of Crohn's disease in a population-
based cohort. Gastroenterology. 2010;139(4):1147-55. 
4. Nielsen OH, Ainsworth MA. Tumor necrosis factor inhibitors for inflammatory bowel 
disease. N Engl J Med. 2013;369(8):754-62. 
5. Allen PB, Peyrin-Biroulet L. Moving towards disease modification in inflammatory 
bowel disease therapy. Curr Opin Gastroenterol. 2013;29(4):397-404. 
6. Peyrin-Biroulet L, Fiorino G, Buisson A, et al. First line therapy in adult Crohn’s disease: 
who should receive anti-TNF agents? Nat Rev Gastroenterol Hepatol. 2013;1096:345-51. 
7.  Schreiber S, Colombel JF, Bloomfield R, Nikolaus S, Schölmerich J, Panés J, et al. 
Increased response and remission rates in short-duration Crohn's disease with 
subcutaneous certolizumab pegol: an analysis of PRECiSE 2 randomized maintenance 
trial data. Am J Gastroenterol. 2010;105(7):1574-82. 
8. Schreiber S, Reinisch W, Colombel JF, Sandborn WJ, Hommes DW, Robinson AM, et al. 
Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates 
through 3 years for adalimumab-treated patients with early Crohn's disease. J Crohns 
Colitis. 2013;7(3):213-21. 
9. Antoni C, Braun J. Side effects of anti-TNF therapy: Current knowledge. Clin Exp 
Rheumatol 2002; 20 (Suppl. 28): S152-S157. 
10. EMA Guideline on the development of new medicinal products for the treatment of 
Crohn’s Disease (CHMP/EWP/2284/99 Rev. 1). London. 2008 
11. Reinisch W, Wang Y, Oddens BJ, Link R. C‐reactive protein, an indicator for maintained 
response or remission to infliximab in patients with Crohn's disease: a post‐hoc analysis 
from ACCENT I. Alimentary pharmacology & therapeutics. 2012;35(5):568-76. 
12. Best WR, Becktel JM, Singleton JW, Kern F. Development of a Crohn's disease activity 
index. Gastroenterology. 1976;70(3):439-44. 
13. Best WR, Becktel JM, Singleton JW. Rederived values of the eight coefficients of the 
Crohn's Disease Activity Index (CDAI). Gastroenterology 1979;77:843–846. 


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14. Sandborn WJ, Feagan BG, Hanauer SB, Lochs H, Löfberg R, Modigliani R, Present DH, 
Rutgeerts P, Schölmerich J, Stange EF, Sutherland LR. A review of activity indices and 
efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease. 
Gastroenterology. 2002;122(2):512-30. 
15. Solem CA, Loftus EV, Tremaine WJ, Harmsen WS, Zinsmeister AR, Sandborn WJ. 
Correlation of C‐reactive protein with clinical, endoscopic, histologic, and radiographic 
activity in inflammatory bowel disease. Inflammatory Bowel Diseases. 
2005;11(8):707-12.  
16. Jones J, Loftus EV, Panaccione R, Chen LS, Peterson S, McConnell J, Baudhuin L, 
Hanson K, Feagan BG, Harmsen SW, Zinsmeister AR. Relationships between disease 
activity and serum and fecal biomarkers in patients with Crohn's disease. Clinical 
Gastroenterology and Hepatology. 2008;6(11):1218-24. 
17. Erbayrak, M, et al. The role of fecal calprotectin in investigating inflammatory bowel 
diseases. Clinics (Sao Paulo). 2009;64(5):421–425. 
18. Gisbert JP, McNicholl AG. Questions and answers on the role of faecal calprotectin as a 
biological marker in inflammatory bowel disease. Digestive and Liver Disease. 
2009;41(1):56-66. 
19. Burri E, Beglinger C. Faecal calprotectin–a useful tool in the management of 
inflammatory bowel disease. Swiss Med Wkly. 2012;142:w13557 
20. Levesque BG, Sandborn WJ, Ruel J, Feagan BG, Sands BE, Colombel JF. Converging 
goals of treatment for inflammatory bowel disease from clinical trials and practice. 
Gastroenterology 2015;148(1):37-51. 
21. Daperno M, D'Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, Sostegni R, 
Rocca R, Pera A, Gevers A, Mary JY. Development and validation of a new, simplified 
endoscopic activity score for Crohn's disease: the SES-CD. Gastrointestinal Endoscopy. 
2004;60(4):505-12. 
22. Saad RJ, Rao SS, Koch KL, Kuo B, Parkman HP, McCallum RW, Sitrin MD, Wilding 
GE, Semler JR, Chey WD. Do stool form and frequency correlate with whole-gut and 
colonic transit? Results from a multicenter study in constipated individuals and healthy 
controls. Am J Gastroenterol. 2010 Feb;105(2):403-11. 
23. FDA. Guidance for industry Irritable Bowel Syndrome – clinical evaluation of drugs for 
treatment. May 2012. 
24. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann 
Acad Med. 1994;23(2):129-38. 


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25. Turk DC, Dworkin RH, Allen RR, Bellamy N, Brandenburg N, et al. Core outcome 
domains for chronic pain clinical trials: IMMPACT recommendations. Pain. 
2003;106(3):337-45. 


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12.0 APPENDICES 
12.1 Sample Crohn’s Disease Activity Index (CDAI) Score 
 
Factor 
Number of liquid or soft stools each day for 7 days 
×2 
Abdominal pain (0-3 on severity) each day for 7 days 
×5 
Subjective general well-being (0=well to 4=terrible for each day for 7 
days 
×7 
Presence of complications* 
×20 
Taking diphenoxylate or opiates for diarrhoea  
×30 
Presence of an abdominal mass (0=none; 2=questionable; 5=definite) 
×10 
Absolute deviation of haematocrit from 47% in men and 42% in women 
×6 
Percentage deviation from standard weight 
×1 
*One point each is added for each set of complications 
 The presence of joint pain (arthralgia) or frank arthritis 
 Inflammation of the iris or uveitis 
 Presence of erythema nodosum, pyoderma gangrenosum or aphthous ulcers 
 Anal fissures, fistulae or abscesses 
 Other fistulae 
 Fever (>37.8°C) during the previous week 
Reference: Monteleone, G, Neurath MF, Ardizzone S, Di Sabatino A, Fantini, MC et al. 
Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease. N Engl J Med. 
2015;372(12):1104-1113. 
 
 
 
 


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12.2 Sample Bristol Stool Chart 
 
Reference: Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. 
Scand J Gastroenterol. 1997;32(9):920-924. 
 


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12.3 Signature of Investigator 
PROTOCOL TITLE:  A Phase 2 study to investigate the efficacy, safety, and tolerability of 
six weeks treatment with V565 in subjects with active Crohn’s disease 
PROTOCOL NO: 
V56502 
Version 1.3  02 December 2016 
This protocol is a confidential communication of VHsquared Ltd. I confirm that I have read 
this protocol, I understand it, and I will work according to this protocol. I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki 
and that are consistent with good clinical practices and the applicable laws and regulations. 
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from 
VHsquared Ltd.  
Instructions to the Investigator:  Please SIGN and DATE this signature page. PRINT your name, title, and the 
name of the site in which the study will be conducted. Return the signed copy to Quintiles.   
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:      
__________________________            Date:  ________ 
Printed Name:                                ___________________________ 
Investigator Title:                           ___________________________ 
 
Name/Address of Site:               
___________________________ 
 
___________________________ 
 
___________________________ 
 
 
 


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12.4 Protocol Amendment 1.3 Summary of Changes 
The following non-substantial changes were implemented with Protocol Version 1.3: 
1. Inclusion criterion 11(vii) amended to include reference to Section 6.2.2. 
2. Section 6.2.2 additional detail provided for vasectomised partners and detailed 
definition of sexual abstinence. 
3. Table 2: Activated partial thromboplastin time added to Safety Assessments. 
4. Table 4: Activated partial thromboplastin time added to Additional Tests 
(Screening Only). 
 

SAP_001.pdf: 
 
 
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STATISTICAL ANALYSIS PLAN 
 
 
V56502 
A PHASE 2 STUDY TO INVESTIGATE THE EFFICACY, SAFETY, AND TOLERABILITY OF SIX 
WEEKS TREATMENT WITH V565 IN SUBJECTS WITH ACTIVE CROHN’S DISEASE 
 
 
 
 
 
AUTHOR: SHARMILA AGARWAL 
VERSION NUMBER AND DATE: FINAL V1.012MAR2019  
 


 
 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V1.0(Dated 12MAR2019) for Protocol V56502 
 
 
Name 
Signature 
Date 
Author: 
Sharmila Agarwal  
 
 
 
Position: 
Manager, Biostatistics 
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
Susmita Sanyal 
 
 
 
Position: 
Stat Scientist 
 
Company: 
IQVIA 
 
Approved By: 
Suhail Nurbhai 
 
 
 
Position: 
Chief Medical Officer 
 
Company: 
VHsquared Ltd 


 
 
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reproduction is strictly prohibited. 
MODIFICATION HISTORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
V1.0 
12MAR2019 
Sharmila 
Agarwal 
Not Applicable – First Version 


 
 
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reproduction is strictly prohibited. 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................................. 9 
2. 
STUDY OBJECTIVES .......................................................................................................... 9 
2.1. 
Primary Objective ........................................................................................................................................9 
2.2. 
Secondary Objectives ..................................................................................................................................9 
2.3. 
Pharmacokinetic Objectives ........................................................................................................................9 
2.4. 
Exploratory Objectives .............................................................................................................................. 10 
2.5. 
Exploratory Endoscopy Substudy Objectives ............................................................................................. 10 
3. 
STUDY DESIGN................................................................................................................. 10 
3.1. 
General Description ................................................................................................................................... 10 
3.2. 
Schedule of Events..................................................................................................................................... 11 
3.3. 
Changes to Analysis from Protocol ............................................................................................................ 11 
4. 
PLANNED ANALYSES ..................................................................................................... 12 
4.1. 
Data Monitoring Committee (DMC) ........................................................................................................... 12 
4.2. 
Interim Analysis ......................................................................................................................................... 12 
4.3. 
Final Analysis ............................................................................................................................................. 12 
5. 
ANALYSIS SETS ................................................................................................................ 12 
5.1. 
Intent-to-Treat (ITT) population ................................................................................................................ 12 
5.2. 
Per Protocol population (PP) ..................................................................................................................... 12 
5.3. 
Safety population (SAF) ............................................................................................................................. 13 


 
 
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reproduction is strictly prohibited. 
5.4. 
Pharmacokinetic population (PK) .............................................................................................................. 13 
5.5. 
Endoscopy Substudy population ................................................................................................................ 14 
5.6. 
Immunogenicity Population ...................................................................................................................... 14 
6. 
GENERAL CONSIDERATIONS ...................................................................................... 14 
6.1. 
Reference Start Date and Study Day .......................................................................................................... 15 
6.2. 
Baseline ..................................................................................................................................................... 15 
6.3. 
Derived Timepoints ................................................................................................................................... 16 
6.4. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 16 
6.5. 
Windowing Conventions ............................................................................................................................ 16 
6.6. 
Statistical Tests .......................................................................................................................................... 17 
6.7. 
Common Calculations ................................................................................................................................ 17 
6.8. 
Software Version ....................................................................................................................................... 17 
7. 
STATISTICAL CONSIDERATIONS ............................................................................... 17 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................... 17 
7.2. 
Multicenter Studies ................................................................................................................................... 18 
7.3. 
Missing data .............................................................................................................................................. 18 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 18 
7.5. 
Examination of Subgroups ......................................................................................................................... 18 
8. 
OUTPUT PRESENTATIONS .......................................................................................... 18 
9. 
DISPOSITION AND WITHDRAWALS ......................................................................... 18 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................... 19 


 
 
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reproduction is strictly prohibited. 
11. DISEASE AND MEDICAL HISTORY ............................................................................. 20 
12. PREVIOUS IBD TREATMENT/THERAPY HISTORY .............................................. 20 
13. MEDICATIONS .................................................................................................................. 20 
14. STUDY DRUG COMPLIANCE ........................................................................................ 21 
14.1. Derivations ................................................................................................................................................ 21 
15. EFFICACY OUTCOMES ................................................................................................... 22 
15.1. Primary Efficacy ......................................................................................................................................... 22 
15.1.1. 
Primary Efficacy Variable & Derivations ...................................................................................................22 
15.1.2. 
Missing Data Methods for Primary Efficacy Variable ...............................................................................23 
15.1.3. 
Primary Analysis of Primary Efficacy Variable(s) ......................................................................................23 
15.1.4. 
Sensitivity Analysis of Primary Efficacy Variable .......................................................................................24 
15.2. Secondary Efficacy ..................................................................................................................................... 24 
15.2.1. 
Secondary Efficacy Variables & Derivations .............................................................................................24 
15.2.1.1. 
Proportion of subjects achieving a ≥100-point reduction in CDAI score and a concomitant 
reduction of at least 50% in CRP or FCP at Day 42 ...............................................................................................24 
15.2.1.2. 
Proportion of subjects achieving a ≥70-point reduction in CDAI score at Day 42 ............................25 
15.2.1.3. 
Proportion of subjects achieving a ≥100-point reduction in CDAI score at Day 42 ..........................25 
15.2.1.4. 
Proportion of subjects achieving a CDAI score of <150 at Day 42 ....................................................25 
15.2.1.5. 
Change from baseline in PRO-2 ........................................................................................................25 
15.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s) .......................................................................25 
15.2.3. 
Analysis of Secondary Efficacy Variables ..................................................................................................26 
15.3. Exploratory Efficacy ................................................................................................................................... 26 
15.3.1. 
Exploratory Variables & Derivations .........................................................................................................26 
15.3.1.1. 
Proportion of subjects achieving CRP or FCP levels within protocol defined normal limits at Day 14 
and Day 42 26 
15.3.1.2. 
Changes from Baseline in CDAI score over time ...............................................................................26 
15.3.1.3. 
Changes from Baseline in CRP or FCP levels over time .....................................................................26 
15.3.1.4. 
Changes from Baseline in the frequency of loose or watery stools (Type 6 or Type 7) as measured 
by the BSFS 27 
15.3.1.5. 
Changes from Baseline in the abdominal NPS ..................................................................................27 
15.3.1.6. 
Changes from Baseline in faecal urgency .........................................................................................27 
15.3.1.7. 
Changes in Endoscopic Mucosal Appearance – endoscopic sub study patients only.......................27 
15.3.1.8. 
Changes in Endoscopic Score for Crohn's Disease (SES-CD) – endoscopic sub study patients only .27 
15.3.2. 
Missing Data Methods for Exploratory Variable(s) ...................................................................................27 


 
 
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15.3.3. 
Analysis of Exploratory Variables..............................................................................................................28 
15.3.3.1. 
The proportion of subjects achieving CRP (or FCP) levels within protocol defined normal limits at 
Day 14 and Day 42 ................................................................................................................................................28 
15.3.3.2. 
The endpoints evaluating changes in CDAI score over time and changes in CRP (or FCP) results 
over time 
28 
15.3.3.3. 
Changes from Baseline in day 7, 14, 21, 28, 35 and 42 in the frequency of loose or watery stools 
(BSFS Type 6 or Type 7) ........................................................................................................................................28 
15.3.3.4. 
Changes in NPS scores (averaged over 7 consecutive days) .............................................................28 
15.3.3.5. 
Proportion of subjects with various degrees of faecal urgency at Day 1, Day 14 and Day 42 .........28 
15.3.3.6. 
Overall mucosal appearance ............................................................................................................28 
15.3.3.7. 
Change from baseline of SES-CD .......................................................................................................28 
16. PHARMACOKINETIC ANALYSIS ................................................................................. 29 
17. SAFETY OUTCOMES ....................................................................................................... 29 
17.1. Adverse Events .......................................................................................................................................... 29 
17.1.1. 
All TEAEs ...................................................................................................................................................30 
17.1.1.1. 
Severity .............................................................................................................................................30 
17.1.1.2. 
Relationship to Study Drug ...............................................................................................................30 
17.1.2. 
TEAEs Leading to Discontinuation of Study Drug .....................................................................................30 
17.1.3. 
Serious Adverse Events .............................................................................................................................30 
17.1.4. 
Adverse Events Leading to Death .............................................................................................................30 
17.2. Laboratory Evaluations .............................................................................................................................. 30 
17.2.1. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ..............................................................31 
17.3. ECG Evaluations ......................................................................................................................................... 31 
17.4. Vital Signs .................................................................................................................................................. 32 
17.4.1. 
Vital Signs Specific Derivations .................................................................................................................32 
17.5. Physical Examination ................................................................................................................................. 32 
17.6. Other safety assessments .......................................................................................................................... 33 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS .................................. 33 
IQVIA Output Conventions .................................................................................................................................... 33 
Dates & Times ....................................................................................................................................................... 33 
Spelling Format ..................................................................................................................................................... 33 


 
 
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Presentation of Treatment Groups ....................................................................................................................... 34 
Presentation of Visits ............................................................................................................................................ 34 
Listings .................................................................................................................................................................. 34 
APPENDIX 2. PARTIAL DATE CONVENTIONS ................................................................. 35 
Algorithm for Treatment Emergence of Adverse Events: ...................................................................................... 35 
Algorithm for Prior / Concomitant Drugs: ............................................................................................................. 37 
APPENDIX 3. SAMPLE SAS CODE ......................................................................................... 39 
SAS code for logistic regression ............................................................................................................................. 39 
SAS code for MMRM ............................................................................................................................................. 39 
sas code for Mann-whitney u statistic ................................................................................................................... 40 
 
 


 
 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy, 
pharmacokinetics (PK) and safety data for Protocol V56502. It describes the data to be summarised and analysed, 
including specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version 1.3, dated 24 August 2016 and amendment 02 
December 2016. 
2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective is  
 
To evaluate the efficacy of V565 555 mg three times a day (TID) in subjects with active Crohn’s 
disease (CD) measured by the proportion of subjects achieving response to therapy. Response is 
defined as reduction in the Crohn's Disease Activity Index (CDAI) scores and in inflammatory 
markers C-reactive protein [CRP] or faecal calprotectin [FCP] at Day 42. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives are 
 
To further characterise the efficacy of V565 in subjects with active CD assessed by changes in CDAI 
scores and/or inflammatory markers 
 
To assess the effects of V565 based on changes in Abdominal Pain and Stool Frequency instrument 
(PRO-2) scores 
 
To assess safety and tolerability of V565 
2.3. 
 PHARMACOKINETIC OBJECTIVES 
The pharmacokinetic (PK) objective is  
 
To determine the concentration of V565 in serum and urine 


 
 
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2.4. 
EXPLORATORY OBJECTIVES 
The exploratory objectives are  
 
To assess the proportion of subjects achieving CRP or FCP levels within normal limits 
 
To assess changes in CDAI scores and CRP or FCP levels over time 
 
To determine changes in anti-V565 antibody titre 
 
To evaluate the frequency of loose or watery stools, assessed using the Bristol Stool Form Scale  
(BSFS) 
 
To evaluate changes in abdominal pain using the Numeric Pain Scale (NPS) 
 
To evaluate changes in faecal urgency 
2.5. 
EXPLORATORY ENDOSCOPY SUBSTUDY OBJECTIVES 
 
To investigate the effect of V565 on changes in endoscopic mucosal appearance, evaluated with an 
overall assessment and the Simple Endoscopic Score for Crohn's Disease (SES-CD), as determined by 
a central reader 
3. STUDY DESIGN 
3.1. 
GENERAL DESCRIPTION 
This study will be a multiple-site, double-blind, placebo-controlled, parallel-group proof-of-concept study in 
approximately 126 subjects with active CD. This study will include subjects who have a confirmed diagnosis of CD 
for at least three months and have CD involving the ileum and/or colon. 
 
The duration of treatment will be 42 days (six weeks); each subject’s participation in the study will be 
approximately 12 weeks. This includes a screening period of up to 28 days, a treatment period of 42 days and a 
follow-up period of 14 days after the last dose of study drug. 
 
Subjects will be randomised into one of two treatment arms: either V565 or placebo using a 2:1 active:placebo 
ratio. Randomisation will be stratified to ensure treatment groups have similar rates of prior anti-tumour necrosis 
factor alpha (TNFα) therapy. 
  
Subjects will receive three V565 185 mg capsules three times daily or matching placebo, for 42 days (six weeks). 
The total daily V565 dose is 1665 mg. 


 
 
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Figure 1: Study Diagram 
 
3.2. 
SCHEDULE OF EVENTS 
Schedule of events can be found in Table 2 of the protocol. 
3.3. 
CHANGES TO ANALYSIS FROM PROTOCOL 
In the protocol section 8.2.1 it is mentioned that the baseline CRP and baseline FCP results will be included as 
covariates in the statistical model for logistic regression. CRP or FCP will be used to determine inflammation status 
at baseline. Some subjects may appear ‘normal’ on the basis of their CRP result however the FCP measurement 
reveals the presence of inflammation. As FCP will be measured for subjects only if CRP is <5 mg/L, FCP will be 
missing for many subjects.  In addition, the CRP result for subjects who entered on the basis of inflammation 
measured by a FCP result => 250 ug/g will not be meaningful as a reflection of inflammation status. For these 
reasons neither FCP nor CRP will be incorporated into the primary model fit. However, if a subject is enrolled in the 
study based on the baseline result of CRP the definition of response will incorporate a 40% reduction in CRP. If a 
subject is enrolled in the study based on the baseline result of FCP the definition of response will incorporate a 40% 
reduction in FCP. 
 
  


 
 
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4. PLANNED ANALYSES 
4.1. 
DATA MONITORING COMMITTEE (DMC)  
There is no DMC planned for this study. 
4.2. 
INTERIM ANALYSIS  
No interim analysis for efficacy or safety is planned for this study. 
4.3. 
FINAL ANALYSIS  
The final analyses identified in this SAP will be performed by IQVIA Biostatistics following Sponsor Authorisation of 
this SAP, Database Lock, and Sponsor Authorisation of Analysis Sets and unblinding of Treatment. 
5. ANALYSIS SETS 
Agreement and authorisation of subjects included/excluded from each analysis set will be conducted prior to the 
unblinding of the treatment allocations. A blinded data review plan will be created and further details related to 
analysis sets and major protocol deviations will be described in this plan. 
5.1. 
INTENT-TO-TREAT (ITT) POPULATION 
The ITT population will include all randomised subjects irrespective of whether any study medication was ingested. 
In this population, treatment will be assigned based upon the treatment arm to which subjects were randomised 
regardless of which treatment they actually received. 
5.2. 
PER PROTOCOL POPULATION (PP) 
The PP population will include all randomised subjects who do not have major protocol deviations that would affect 
the evaluation of the primary efficacy endpoint.  
A major protocol deviation that is considered to affect the primary efficacy endpoint will lead to exclusion of 
subjects from the PP population. Major protocol deviations considered to affect the primary analysis include, but 
are not limited to, the following;  
1. 
Violations of the inclusion/exclusion criteria 
a. 
The following inclusion criteria should be fulfilled: 


 
 
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i. Inclusion criterion 2: CDAI score of ≥220 to ≤450 during Screening 
ii. Inclusion criterion 3: CRP ≥5 mg/L (or, if CRP is normal, FCP ≥250 μg/g) at screening. 
iii. Inclusion criterion 4: Active CD of ileum and/or colon as determined by the baseline 
ileocolonoscopy 
b. 
The following exclusion criteria should be absent in the data for the subjects: 
i. Exclusion criterion 3: Any gastrointestinal (GI) manifestations of CD that might affect the 
evaluation of efficacy. 
ii. Exclusion criterion 5: Prior primary efficacy failure of or secondary loss of response to anti-
TNFα therapy, or any contraindication to anti-TNFα therapy 
iii. Exclusion criterion 6: The use of medications prior to the study or during the study with the 
potential to affect the evaluation of efficacy. 
 
2. Mishandling of the study drug which could have impacted the integrity of the study data such as non-
allowable temperature deviations during storage or dispensing of study drug to the wrong subject 
3. 
Non-compliance rate of <80% or >120% with study treatment. 
4. 
Use of prohibited concomitant medications. 
5. 
Study procedures done outside protocol-specified window period that are judged to affect study efficacy data. 
6. 
Assessments for primary endpoint not done. 
Protocol deviations will be reviewed prior to unblinding and individual subjects having protocol deviations will be 
evaluated for inclusion in the PP population. Any additional deviations not listed above will be documented at this 
time. 
5.3. 
SAFETY POPULATION (SAF) 
The SAF population will include all randomised subjects who receive at least one capsule of V565/placebo. In this 
population, treatment will be assigned based upon the treatment subjects actually received, regardless of the 
treatment to which they were randomised. 
5.4. 
 PHARMACOKINETIC POPULATION (PK) 
The PK population will include all subjects in the SAF population who receive at least one capsule of V565 and who 
have at least one pre dose sample of serum or urine and who do not have events or protocol deviations with the 
potential to affect serum PK or urine PK concentrations. 
Changes to the procedures or events, which may impact the quality of the PK data will be described within the 
clinical study report body text. These changes or events will include any circumstances that will alter the evaluation 
of the PK.  Examples include, but may not be limited to,   
1. 
sample processing errors that lead to inaccurate bioanalytical results,  
2. 
inaccurate dosing on the day of PK sampling due to administration incidents or lack of compliance with 


 
 
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the protocol, 
3. 
dosing date/time not available 
4. 
blood/urine sampling date and time not available. 
Affected data will be evaluated by the pharmacokineticist to determine whether or not they can be included in the 
PK analysis. Other changes to the procedures or events which do not impact the quality of the PK data will not be 
considered significant protocol deviations.  A common example of a non-significant protocol deviation is a missed 
blood sample or deviations from blood collection times. 
Protocol deviations will be reviewed prior to unblinding and individual subjects having protocol deviations with the 
potential to affect PK concentrations will be evaluated during the blinded data review meeting for inclusion in the 
PK population. 
5.5. 
ENDOSCOPY SUBSTUDY POPULATION 
The endoscopy substudy population will include the subjects  who undergo ileocolonoscopy at both the visits: Visit 
2 and Visit 5 (Day 42).  
 
5.6. 
IMMUNOGENICITY POPULATION 
The immunogenicity population will include all subjects in the SAF population who receive at least one capsule of 
V565/placebo and who have at least one pre dose sample of serum and who do not have events or protocol 
deviations with the potential to affect immunogenicity. 
6. GENERAL CONSIDERATIONS 
The following descriptive statistics will be presented in summary tables: 
 
Continuous variables: number (non-missing cases), mean, median, standard deviation (SD), 
minimum, and maximum 
 
Categorical variables: will be summarised by treatment group using frequency tables (frequencies 
and percentages). Percentages are routinely based on the total category count excluding the missing 
category if not otherwise mentioned. Missing category with zero count will not be presented 
In general, the number of decimal places displayed for each statistic will be determined as follows with a maximum 
of three decimal places: 
 
Mean and median: one more than the number of decimal places allotted in the raw data received 
from data management 
 
SD: two more than the number of decimal places allotted in the raw data 


 
 
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 
Minimum and maximum: equal to the number of decimal places allotted in the raw data  
 
Confidence Intervals (CIs) will be presented using the number of decimal places plus one as the 
parameters (e.g. mean) as appropriate 
 
P-values greater than or equal to 0.0001, in general, will be presented to four decimal places. P-
values less than 0.0001 will be presented as “<0.0001” and p-value greater than “>0.9999” will be 
presented as 1.0000 
 
Percentages will be reported to one decimal place 
In the case of normality assumption violations, appropriate non-parametric methods will be used for analysis as 
mentioned in section 15.2.3 
Coding of adverse events and medications data (i.e. by Medical Dictionary for Regulatory Activities [MedDRA 19.1] 
or World Health Organization [WHO]-drug dictionary 01Sep2016E) will be included in the datasets. 
6.1. 
REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/ stop day of assessments 
and events.  
Reference start date is defined as the day of the first dose of study drug, (Day 1 is the day of the first dose of study 
drug)and will appear in every listing except medical history where an assessment date or event date appears.  
 
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1 
 
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference date) 
In the situation where the event date is partial or missing, the date will appear partial or missing in the listings, and 
Study Day, and any corresponding durations will be presented based on the imputations specified in appendix 2; 
Partial Date Conventions. 
6.2. 
BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to first 
administration of study drug (including unscheduled assessments). In the case where the last non-missing 
measurement and the reference start date coincide, that measurement will be considered pre-baseline, but 
Adverse Events (AEs) and concomitant medications commencing on the reference start date will be considered 
post-baseline. 
For the endpoints of CRP and FCP, the baseline score is the last non-missing measurement taken prior to Day 1 
(including unscheduled assessments).  


 
 
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For the endpoints CDAI score and PRO-2, the screening score will be considered as baseline. 
For the endpoint frequency of loose or watery stools (BSFS Type 6 and Type 7) the baseline is defined as 
the averaged  non-missing total number of loose or watery stools for same 7 days  used to calculate the screening 
CDAI score.  The missing number of loose or watery stools should be missing and not considered as zero. 
 
For Abdominal Pain NPS scores the baseline is defined as the averaged  non-missing total of abdominal pain score 
for same 7 days used to calculate the screening CDAI score.  The missing NPS score should be missing and not 
considered as zero. 
Listings will include scheduled and unscheduled data. 
6.3. 
DERIVED TIMEPOINTS  
Last observation carried forward (LOCF) method will be used for primary analysis. If any of the element ( Patient 
reported data or Physician reported data or Haematocrit value ) of primary endpoint is missing at Day 42, LOCF will 
be applied and that element will be carried forward from last available post-baseline visit. 
Also, LOCF will be performed as part of sensitivity analysis for the primary and secondary efficacy endpoints. The 
missing CDAI scores, CRP and FCP will be carried forward from the last available post-baseline measurements.   
In addition, the worst observation carried forward (WOCF) will also be performed as part of sensitivity analysis for 
the missing CDAI scores, CRP and FCP from the available baseline, post-baseline and the unscheduled assessments. 
The descriptive summaries of derived timepoints provided for the primary efficacy variables will be summarised and 
named as “Day 42 (LOCF)” and “Day 42 (WOCF)”. 
6.4. 
RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION 
DATA 
For by-visit summaries, data recorded at the nominal visit will be presented. Last non-missing value for a particular 
parameter will be included in by-visit summaries and listings.  as well where unscheduled measurements will also 
be considered.  
Subjects who prematurely discontinue from the study for any reason, will be scheduled for an Early Termination 
(ET) visit, at which time all of the assessments listed for that visit will be performed. 
In by-visit summaries of all study objectives the Day 42 or ET visit will be summarised as follows “Day 42/Early 
Termination”. 
Additionally, in by-visit summaries for primary efficacy variables CDAI score, CRP and FCP values “Day 42 (LOCF)” 
and “Day 42 (WOCF)” will also be summarised.  
6.5. 
WINDOWING CONVENTIONS  
No visit windowing will be performed for this study. 


 
 
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6.6. 
STATISTICAL TESTS 
The default significance level will be (5%); confidence intervals will be 95% and all tests will be two-sided, unless 
otherwise specified in the description of the analyses. 
Two-sided CIs will be assessed at the 5% significance and two-sided p-value will be reported. 
6.7. 
COMMON CALCULATIONS 
For quantitative measurements,  
 
change from baseline will be calculated as Test value at Day x – Baseline Value 
 
percent change from baseline will be calculated as  
(Test value at Day x –  Test value at Baseline)
Test value at baseline
 𝑋 100 
6.8. 
SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4. 
 
7. STATISTICAL CONSIDERATIONS  
7.1. 
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
The following covariates and factors are used in the analyses. For details of their inclusion in the models, see the 
specific analysis in Section 15. 
 
Treatment 
 
Prior anti-TNFα therapy 
 
Baseline CDAI score 


 
 
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7.2. 
MULTICENTER STUDIES  
This study will be conducted by multiple investigators at multiple sites and the summaries will not be presented by 
site. Randomisation to treatment arms is not stratified by center. 
7.3. 
MISSING DATA 
Missing safety data will not be imputed while missing dates will be imputed as per appendix 2. 
Missing efficacy data will be handled as described in section 15.1.2 of this analysis plan.  
7.4. 
MULTIPLE COMPARISONS/ MULTIPLICITY 
All statistical comparisons will be made at the 5% level. No adjustment will be made for multiple comparisons. 
Interpretation of the results should consider this 
7.5. 
EXAMINATION OF SUBGROUPS 
No subgroup analyses are planned for this study. 
8. OUTPUT PRESENTATIONS 
The templates provided with this SAP describe the presentations for this study and the format and content of the 
summary tables and listings to be provided by IQVIA Biostatistics. 
Tables will be presented by V565, Placebo and Total unless otherwise specified. For efficacy outputs, Total column 
will not be presented. 
9. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this study.  
Subject disposition including number and percentage of subjects screened, screen failures including reason as 
entered in “Eligibility” eCRF, randomised, treated, completed the study, discontinued early (including primary 
reason of discontinuation as mentioned in Disposition Study page of eCRF) will be tabulated by treatment group 
and Total. 
Summaries for overview of disposition will be based on ITT subjects. 
Number and percentage of subjects in each population and excluded subjects and the reason for exclusion from 
each population will also be summarised. Percentages for population exclusion will be based on ITT population. 
Subjects who are excluded and reason for exclusion from safety, ITT, PP, PK and Immunogenicity population will be 


 
 
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listed. 
Protocol deviations captured by the Clinical Trials Management System (CTMS) will be summarised and listed on ITT 
population. Percentages will be based on ITT population for protocol deviation summary. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the ITT, SAF and PP populations. 
No statistical testing is planned for demographic or other baseline characteristics. 
Summaries for continuous and categorical variables (as described in section 6) will be presented for each treatment 
and Total. 
Demographics and baseline characteristics will be presented in a listing by subject. 
The following demographic and other baseline characteristics will be reported for this study  
 
Age (years) at screening as collected from eCRF  
 
Sex 
 
Race  
 
Ethnicity 
 
Body Weight (kg) at screening  
 
Height (cm) at screening as collected from eCRF 
 
BMI (kg/m2) at screening as collected from eCRF 
 
Prior Anti-TNF Therapy 
 
Childbearing potential for female subjects 
 
Disease duration (months) 
 
Baseline CDAI score 
 
Baseline CRP for patients qualifying on CRP 
 
Baseline FCP for patients qualifying on FCP 
 
Baseline SES-CD score 
 
Prior CD medication use 


 
 
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11. DISEASE AND MEDICAL HISTORY 
Disease and Medical History information will be presented for the ITT and PP population.  
 
For Crohn’s Disease History the parameters disease severity, disease location, associated 
complications, Other Manifestations (Including Extra-Intestinal), number of subjects hospitalised 
due to CD within the previous 12 months will be summarised by counts and percentage of subjects 
and number of times hospitalised since CD diagnosis will be summarised using descriptive statistics 
by treatment and Total. The disease history will also be listed. 
 
Number of subjects according to MedDRA will be summarised using counts and percentage of 
subjects for each medical history. Medical history details will also be listed. The summaries will be 
presented by primary system organ class (SOC) and preferred term (PT) for each treatment group 
and Total for all subjects in ITT population. A subject will be counted only once within the SOC and 
PT if the subject has multiple medical conditions within the same SOC and PT. 
12. 
PREVIOUS IBD TREATMENT/THERAPY HISTORY 
The previous IBD treatment and therapies as captured in the eCRF will be summarised by counts and percentages of 
subjects and also be listed on ITT population. 
Medications will be presented for the ITT population and coded using WHO Drug dictionary 01Sep2016E. Frequency 
and percentage of concomitant medications use will be presented by Anatomical Therapeutic Chemical (ATC) level 
2 and preferred name.  Tables will also show the Total number and percentage of subjects receiving at least one 
treatment of a particular preferred name. Subject receiving multiple medications within the same preferred names 
will be counted only once under that preferred name. 
13. MEDICATIONS  
Medications will be presented for the ITT population and coded using WHO Drug dictionary 01Sep2016E. See 
appendix 2 for handling of partial dates for medications  
Frequency and percentage of concomitant medications use will be presented by ATC level 2 and preferred name. 
Tables will also show the Total number and percentage of subjects receiving at least one treatment of a particular 
preferred name. Subjects receiving multiple medications within the same preferred names will be counted only 
once under that preferred name. Classification of Prior and concomitant medications will be based on medications 
start date and stop date as entered in prior and concomitant medications page of eCRF. 
 
 ‘Prior’ medications are medications which started and stopped prior to the first capsule of study 
drug  
 
‘Concomitant’ medications are medications which:  


 
 
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started prior to, on or after the first capsule of study drug or started before the end of study drug, 
and ended on or after the date of first dose of study drug or were ongoing at the end of the study 
drug  
 
‘Post treatment’ medications are medications which are started after the last capsule of study drug 
and at or before the follow up visit 
Concomitant medications will be summarised by ATC level 2 and preferred term based on ITT population. 
Summary will be presented for each treatment and Total. 
 
Details of prior, concomitant and post treatment medications will be listed. 
 
The following permitted medications based on the preferred term will be summarised by ATC level 2 and 
preferred term based on ITT population. 
 
 
Oral Corticosteroids 
 
Oral Aminosalicylates 
 
Methotrexate 
 
Azathioprine/6-MP 
 
Oral Antibiotics 
 
NSAIDs such as low dose aspirin [<325 mg/day]  
 
Probiotics at an unchanged dose 
14. STUDY DRUG COMPLIANCE   
Compliance to study drug will be presented for the SAF population. 
14.1. 
DERIVATIONS 
Compliance with study drug based on the drug accountability data will be calculated as the number of capsules 
taken (total dispensed – total returned) divided by the prescribed number of capsules expressed as a percentage, 
see calculations below.  
A table consisting of summary statistics for percent compliance along with the number and percent of subjects with 
compliance in each of the following groups: <80%, =>80% - <=120% and >120% as well as the Total number and 
percentage of subjects compliant for each treatment group and Total will be produced across the whole study on 
SAF population.  


 
 
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A listing of drug accountability will be presented on SAF population to account for all drug distributed to each 
subject, including the container number, total number capsules dispensed, returned, percentage compliance and 
compliant (yes/no).   
       The percent compliance per visit will be calculated as follows:  
 
Percentage Compliance  at Day 14 =
{([୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ ୈୟ୷ ଵ] ି [୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ ୈୟ୷ ଵସ])}
([ୈୟ୲ୣ ୭୤ ୈୟ୷ ଵସ] ି [ୈୟ୲ୣ ୭୤ ୈ୧ୱ୮ୣ୬ୱ୧୬୥ ୟ୲ ୈୟ୷ ଵ]ାଵ)∗ Ө
∗100  
 
Percentage Compliance  at Day 42 =
{([୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ ୈୟ୷ ଵସ] ି [୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ ୈୟ୷ ସଶ])}
([ୈୟ୲ୣ ୭୤ ୈୟ୷ ସଶ] ି [ୈୟ୲ୣ ୭୤ ୈ୧ୱ୮ୣ୬ୱ୧୬୥ ୟ୲ ୈୟ୷ ଵସ]ାଵ )∗ Ө
*100 
 
Overall Percentage Compliance =
൜൬[୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ ୈୟ୷ ଵ] ି [୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ ୈୟ୷ ଵସ]ା
[୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ ୈୟ୷ ଵସ] ି [୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ ୈୟ୷ ସଶ]൰ൠ
([ୈୟ୲ୣ ୭୤ ୈୟ୷ ସଶ] ି [ୈୟ୲ୣ ୭୤ ୈ୧ୱ୮ୣ୬ୱ୧୬୥ ୟ୲ ୈୟ୷ ଵ]ାଵ)∗ Ө
*100 
 
 
Where Ө = 9, Number of capsules required to be taken per day. 
For subjects who discontinued from the study, the “Date of Day x” will be replaced by the date of study 
discontinuation where x= 14 and 42. 
 
Each subject will be considered non-compliant if taking less than 80% or more than 120% of the expected capsules.  
15. EFFICACY OUTCOMES  
15.1. 
PRIMARY EFFICACY  
15.1.1. 
PRIMARY EFFICACY VARIABLE & DERIVATIONS 
The primary efficacy variable is Responders at Day 42 
A Responder is defined as subjects achieving both CDAI ≥70-point reduction from Baseline OR CDAI score <150, and 
a reduction of ≥40% from the baseline value of CRP (where CRP at baseline => 5mg/dL) or FCP (where CRP at 
baseline <5mg/dL and FCP at baseline =>250 ug/g) 
 
The CDAI score is calculated as sum of the following scores obtained from the subject-reported 
variables of the CDAI obtained from the subject diary and the physician / lab assessments. Non-
screening CDAI score will use the most recent 7 days with completed Evening Diaries excluding the 
day of clinic visit, and omit data based on the date of colonoscopy and omit the day before 
colonoscopy when bowel preparation was being taken. 
o 
Number of liquid or soft stools each day for 7 days ×2 
o 
Abdominal pain (0-3 on severity) each day for 7 days ×5 


 
 
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o 
Subjective general well-being (0=well to 4=terrible) for each day for 7 days ×7 
o 
Presence of complications ×20 
o 
Taking diphenoxylate or opiates for diarrhoea ×30 
o 
Presence of an abdominal mass (0=none; 2=questionable; 5=definite) ×10 
o 
Absolute deviation of haematocrit from 47% in men and 42% in women ×6  
o 
Percentage deviation from standard weight ×1 
 
[1 – (body weight/ iBW)] *100 
 
Where ideal Body Weight (iBW) is calculated using Lemmen’s formula  
 
iBW = H x H x 22; H is the height in meters and 22 is the recommended BMI to 
use 
 
 Negative number if body weight is greater than standard weight. Use this negative 
number up to a value of -10. (Values less than -10 should be reported as -10) 
Change from baseline for CDAI score and percent change from baseline for CRP or FCP at day 42 are 
calculated using the formulae mentioned in section 6.7 
15.1.2. 
MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE 
Missing responder will be defined if at any visit either CDAI score or CRP/FCP values are missing. The missing 
responder status will then be imputed. 
Missing primary efficacy data will be imputed using a LOCF method based on the following criteria - 
CDAI score will be considered as missing for a visit if any one of the following elements of CDAI is missing, for that 
visit;  and will be imputed using LOCF,where missing element at Day 42 will be carried forward from last available 
post baseline (being it scheduled or unscheduled visit)  value: 
 Patient reported data: Loose stools, Abdominal pain, General wellbeing and Anti Diarrhoeal use  
Physician reported data: Extra intestinal manifestation, Abdominal mass and Body weight 
Haematocrit value 
CRP/FCP valueTo assess the sensitivity of the results for the primary efficacy endpoint any missing CDAI score will 
be imputed in two methods. 
LOCF: In this method last available post baseline observation will be carried forward. 
WOCF: In this method any previous highest  score observation (being it baseline,scheduled post-baseline  or 
unscheduled postbaseline visit) will be carried forward.  
. 
15.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
The primary objective is to evaluate the efficacy of V565 555 mg TID in subjects with active CD measured by the 


 
 
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proportion of subjects achieving response to therapy. 
The hypothesis of this study is that 
Null hypothesis (H0): Proportion of responders at day 42 on V565 <= Proportion of responders at day 42 on Placebo 
Alternative hypothesis (H1): Proportion of responders at day 42 on V565 > Proportion of responders at day 42 on 
Placebo 
The primary efficacy analysis will be performed on ITT population. The primary endpoint will be analysed using a 
logistic regression model with treatment as the fixed effect and prior anti-TNFα therapy and baseline CDAI score as 
covariates. For the active treatment versus placebo comparison, the results will be presented in terms of an odds 
ratio together with its associated 95% CI and 2-sided p-value. Two-sided 95% CIs for the odds ratio will be provided. 
The SAS® procedure GENMOD that will be used is given in appendix 3The CDAI score, FCP, CRP results along with 
the change from baseline values will also be listed and summarised for the ITT population. 
15.1.4. 
SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The same primary efficacy analysis logistic regression model will be repeated using LOCF and WOCF on the ITT 
population.  
The same primary efficacy analysis logistic regression model used for the ITT population will be repeated on the PP 
population.  The same model used for primary efficacy will be used. 
For details, refer section 15.1.2. 
15.2. 
SECONDARY EFFICACY 
The secondary efficacy analyses will be performed and also be listed on ITT population. 
15.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS 
The secondary efficacy variables are  
15.2.1.1. Proportion of subjects achieving a ≥100-point reduction in CDAI score and a concomitant 
reduction of at least 50% in CRP or FCP at Day 42 
Where subject achieving >=100 point reduction of CDAI score from baseline and a reduction of >=50% from the 
baseline value of CRP or FCP 
 
CDAI score is calculated as defined in the section 15.1.1 
 
Change from baseline for CDAI score and percent change from baseline for CRP or FCP are 
calculated using the formulae mentioned in section 6.7 


 
 
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15.2.1.2. Proportion of subjects achieving a ≥70-point reduction in CDAI score at Day 42 
Where subject achieving >=70 point reduction of CDAI score from baseline  
 
CDAI score is calculated as defined in the section 15.1.1 
 
Change from baseline for CDAI score is calculated using the formulae mentioned in section 6.7 
15.2.1.3. Proportion of subjects achieving a ≥100-point reduction in CDAI score at Day 42 
Where subject achieving >=70 point reduction of CDAI score from baseline  
 
CDAI score is calculated as defined in the section 15.1.1 
 
Change from baseline for CDAI score is calculated using the formulae mentioned in section 6.7 
15.2.1.4. Proportion of subjects achieving a CDAI score of <150 at Day 42 
 Where subject’s CDAI score at day 42 is < 150  
 
CDAI score is calculated as defined in the section 15.1.1 
 
Change from baseline for CDAI score is calculated using the formulae mentioned in section 6.7 
15.2.1.5. Change from baseline in PRO-2 
 
the total PRO-2 score is extracted from selected subject-reported variables of the CDAI included in 
the subject diary 
 
PRO-2 will be calculated at Day 14 and 42  
( 𝐴𝑣𝑒𝑟𝑎𝑔𝑒 𝑜𝑓 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑙𝑖𝑞𝑢𝑖𝑑 𝑜𝑟 𝑠𝑜𝑓𝑡 𝑠𝑡𝑜𝑜𝑙𝑠 𝑒𝑎𝑐ℎ 𝑑𝑎𝑦 𝑜𝑣𝑒𝑟 7 𝑑𝑎𝑦𝑠 × 2) +
(𝐴𝑣𝑒𝑟𝑎𝑔𝑒 𝑜𝑓 𝑎𝑏𝑑𝑜𝑚𝑖𝑛𝑎𝑙 𝑝𝑎𝑖𝑛 (0 −3 𝑜𝑛 𝑠𝑒𝑣𝑒𝑟𝑖𝑡𝑦)𝑒𝑎𝑐ℎ 𝑑𝑎𝑦 𝑜𝑣𝑒𝑟 7 𝑑𝑎𝑦𝑠 × 5)  
 
Change from baseline at Day 14 and 42 are calculated using the formula mentioned in section 6.7 
15.2.2. 
MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S)  
Imputation of secondary efficacy variables will also follow the same procedure as primary efficacy 
variables. 
For imputation methods refer Section 15.1.2. 


 
 
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15.2.3. 
ANALYSIS OF SECONDARY EFFICACY VARIABLES 
 
The endpoints mentioned in 15.2.1.1 to 15.2.1.4 will be analysed using the same model as used in 
the primary endpoint analysis on ITT population 
 
For the PRO-2 score assessments, the changes in total scores from Baseline to Day 14 and Day 42 
will be analysed using a Mixed Model for Repeated Measures (MMRM) with treatment as the fixed 
effect, prior anti-TNFα and baseline scores as covariates 
i. 
An unstructured covariance matrix will be used for the analyses. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. Residual/restricted 
maximum likelihood (REML) method will be used to estimate parameters. 
ii. 
The SAS® procedure MIXED will be used given in appendix 3 
iii. 
The residuals from the MMRM analyses are to be checked for normality and homogeneity of 
variance. Normality is to be examined by normal probability plots, while homogeneity of 
variance is to be assessed by plotting the residuals against the predicted values for the model. 
iv. 
If the data are not normally distributed then the appropriate non-parametric Mann-Whitney 
U test will be used to analyse data 
15.3. 
EXPLORATORY EFFICACY  
15.3.1. 
EXPLORATORY VARIABLES & DERIVATIONS 
15.3.1.1. Proportion of subjects achieving CRP or FCP levels within protocol defined normal limits at Day 14 
and Day 42 
15.3.1.2. Changes from Baseline in CDAI score over time 
 
CDAI score is calculated at baseline, Day 14 and Day 42 as defined in the section 15.1.1 
 
Change from baseline at Day 14 and 42 are calculated using the formula mentioned in section 6.7 
15.3.1.3. Changes from Baseline in CRP or FCP levels over time 
 
Change from baseline at Day 14 and 42 are calculated using the formula mentioned in section 6.7 


 
 
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15.3.1.4. Changes from Baseline in the frequency of loose or watery stools (Type 6 or Type 7) as measured 
by the BSFS 
 
Average is calculated using the total number of loose or watery stools for non-missing days in the 
previous 7 consecutive days at day 7, 14, 21, 28, 35 and 42 as collected from the evening diary data 
 
Change from baseline at day 7, 14, 21, 28, 35 and 42 are calculated using the formula mentioned in 
section 6.7 
15.3.1.5. Changes from Baseline in the abdominal NPS 
 
Average is calculated using the total of abdominal pain score for the non-missing days in the 
previous 7 consecutive days at day 7, 14, 21, 28, 35 and 42 as collected from the evening dairy data 
 
Change from baseline at day 7, 14, 21, 28, 35 and 42 are calculated using the formula mentioned in 
section 6.7 
15.3.1.6. Changes from Baseline in faecal urgency 
 
The degree of faecal urgency at Days 14 and 42 will be evaluated using the scale as collected in the 
eCRF 
o 
0 = No urgency 
o 
1 = Mild urgency 
o 
2 = Moderate urgency 
o 
3 = Severe urgency 
o 
4 = Very severe urgency/didn’t make it to toilet on time  
15.3.1.7. Changes in Endoscopic Mucosal Appearance – endoscopic sub study patients only 
 
Change from baseline at Day 42 in overall Mucosal Appearance assessed as Markedly Better, Slightly 
Better, No Difference, Slightly Worse, Markedly Worse, Cannot be Determined 
15.3.1.8. Changes in Endoscopic Score for Crohn's Disease (SES-CD) – endoscopic sub study patients only 
 
Change from baseline in SES-CD at day 42 for the subjects with an SES-CD ≥7, or ≥4 if only the ileum 
is involved using the formula mentioned in section 6.7 
15.3.2. 
MISSING DATA METHODS FOR EXPLORATORY VARIABLE(S) 
Imputation of secondary efficacy variables will also follow the same procedure as primary efficacy 
variables. 
 


 
 
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15.3.3. 
ANALYSIS OF EXPLORATORY VARIABLES 
15.3.3.1. The proportion of subjects achieving CRP (or FCP) levels within protocol defined normal limits at 
Day 14 and Day 42  
 
will be summarised using frequency and percentage and listed by subject for the ITT population 
15.3.3.2. The endpoints evaluating changes in CDAI score over time and changes in CRP (or FCP) results 
over time  
 
will be summarised using descriptive statistics and listed by subject for the ITT population 
15.3.3.3. Changes from Baseline in day 7, 14, 21, 28, 35 and 42 in the frequency of loose or watery stools 
(BSFS Type 6 or Type 7)  
 
will be summarised by using descriptive statistics and listing by subject on Type 6 or Type 7 for the 
ITT population 
15.3.3.4. Changes in NPS scores (averaged over 7 consecutive days)  
 
will be summarised by visit using descriptive statistics and will be listed by subject for the ITT 
population. 
15.3.3.5. Proportion of subjects with various degrees of faecal urgency at Day 1, Day 14 and Day 42  
 
will be summarised using frequency and percentages and shift table and will be listed by subject for 
the ITT population. 
 
Mean urgency score at Day 1 , Day 14 and Day 42 for each treatment group  
15.3.3.6. Overall mucosal appearance  
 
The number and proportion of subjects in each of the categories defined in section 15.3.1.8 will be 
summarised for each treatment group at Day 42  
15.3.3.7. Change from baseline of SES-CD  
 
will be summarised using descriptive statistics at Day 42   
 
Based on the number of subjects having second, post treatment endoscopy, the SES-CD change 
from baseline scores will be analysed using ANCOVA model as appropriate with treatment as the 
fixed effect, prior anti-TNFα use and baseline scores as covariates. 


 
 
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16. PHARMACOKINETIC ANALYSIS 
Individual PK serum blood sample collection dates/times, and the associated V565 concentrations will be listed by 
visit for each subject.  
The PK urine sample collection dates/times and V565 excreted will be listed by visit for each subject. The amount 
excreted will be determined as V565 concentration × urine volume of the urine sample at the visit.   
Serum and urine V565 concentrations will be summarized using descriptive statistics by visit on the PK population. 
17. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the Safety Analysis Set.  
There will be no statistical comparisons between the treatment groups for safety data.  
17.1. 
ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA Version 19.1.  
Treatment emergent adverse events (TEAEs) are defined as:  
1. A new event that occurs during or after treatment with study drug or 
2. Any event present at Baseline that worsens in either intensity or frequency after exposure to 
study drug. 
See appendix 2 for handling of partial dates for AEs. 
An AE is any untoward medical occurrence in a subject enrolled in this study (i.e., that occurs after the informed 
consent form [ICF] is signed), regardless of its causal relationship to study drug. 
An AE can therefore be any unfavourable and unintended sign (including a clinically significant abnormal laboratory 
finding), symptom, or disease. 
An AE includes a/an: 
Exacerbation of a pre-existing condition or disease. 
Increase in frequency or intensity of a pre-existing condition. 
Continuous persistent pre-existing disease or symptoms that worsen after the subject provides informed consent. 
An overall summary of number of subjects within each of the categories described in the sub-section below, will be 
provided as specified in the templates.  
Listings will include TEAEs and Non-TEAEs. 


 
 
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17.1.1. 
ALL TEAES  
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and also broken down 
further by maximum severity and relationship to study drug. 
17.1.1.1. Severity 
Severity is classed as mild/ moderate/ severe (increasing severity). TEAEs starting after the first dose of study drug 
with a missing severity will be classified as severe. If a subject reports a TEAE more than once within that SOC/ PT, 
the AE with the worst case severity will be used in the corresponding severity summaries. 
17.1.1.2. Relationship to Study Drug 
Relationship, as indicated by the Investigator, is classed as Yes/No. TEAEs with a missing or ‘Unknown’ relationship 
to study drug will be regarded as “Yes” to study drug. If a subject reports the same AE more than once within that 
SOC/ PT, the AE with the worst case relationship to study drug will be used in the corresponding relationship 
summaries.  
17.1.2. 
TEAES LEADING TO DISCONTINUATION OF STUDY DRUG 
For TEAEs leading to discontinuation of study drug, summaries of incidence rates (frequencies, percentages and 
events) by SOC and PT will be prepared. 
17.1.3. 
SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as ”Serious” on the Adverse Events page of the eCRF. A 
summary of serious TEAEs by SOC and PT will be prepared. 
17.1.4. 
ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as ”Fatal” on the Adverse Events page of the eCRF. A 
summary of TEAEs leading to death by SOC and PT will be prepared. 
17.2. 
LABORATORY EVALUATIONS 
Results from the Q2 central laboratory will be included in the reporting of this study for Haematology, Chemistry 
and Urinalysis. All laboratory assessments will be included in the outputs.  
Presentations will use SI Units. 
The following summaries will be provided for laboratory data: 
 
Actual and change from baseline by visit (for quantitative measurements) 


 
 
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 
Shift from baseline according to normal range criteria (for quantitative measurements and 
categorical measurements) 
 
Listing of subjects meeting markedly abnormal criteria 
17.2.1. 
LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in SI units 
and categorized as: 
 
Low: Below the lower limit of the laboratory reference range.  
 
Normal: Within the laboratory reference range (upper and lower limit included). 
 
High: Above the upper limit of the laboratory reference range. 
17.3. 
ECG EVALUATIONS 
Results from the Electrocardiogram (ECG) as collected from eCRF will be included in the reporting of this study.  
The following ECG parameters will be reported for this study: 
 
PR Interval (msec) 
 
RR Interval (msec) 
 
QRS Interval (msec) 
 
QTcF Interval (msec)  
 
HR (bpm) 
 
Overall assessment of ECG (Investigator’s judgment): 
o 
Normal 
o 
Abnormal, Clinically Significant (ACS) 
o 
Abnormal, Not Clinically Significant (ANCS) 
 
The following summaries will be provided for ECG data on SAF population: 
 
Actual and change from baseline by visit (for quantitative measurements) 
 
Number and percentage of subjects with Normal, clinically significant and not clinically significant 


 
 
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 
Number and percentage of subjects shift from baseline to day 42 according to normal, clinically 
significant and not clinically significant 
 
Listing of subjects with ECG data 
17.4. 
VITAL SIGNS 
The following Vital Signs measurements as collected from eCRF will be reported for this study on SAF population: 
 
Systolic Blood Pressure (mmHg) 
 
Diastolic Blood Pressure (mmHg) 
 
Heart Rate (beats/min) 
 
Body Temperature (⁰C) 
 
Weight (kg) 
 
BMI (kg/m2) 
The following summaries will be provided for vital signs data: 
 
Actual and change from baseline by visit  
 
Listing of subjects having vital signs data  
17.4.1. 
VITAL SIGNS SPECIFIC DERIVATIONS 
 
height (m) = height (cm) * 0.010 
 
BMI (kg/ m2) = weight (kg)/ height (m)2 
 
Weight (kg) = 0.45359237 * weight (lb) 
 
(⁰C) = (°F -  32) x 5/9  
17.5. 
PHYSICAL EXAMINATION 
Physical examination findings as collected in eCRF and abnormalities associated, along with clinical significance will 
be tabulated and presented in the listings on SAF population. 
Following summary will be presented: 


 
 
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Number and percentage of subjects shift from baseline to day 42 for complete physical examination according to 
normal, clinically significant and not clinically significant 
Number and percentage of subjects shift from baseline to day 42 for brief physical examination according to 
normal, clinically significant and not clinically significant 
17.6. 
OTHER SAFETY ASSESSMENTS 
 
The serum pregnancy test performed at Screening and a urine pregnancy test at Day 1, Day 42 (the 
end of the study) and at Day 56 (the Follow-up Visit) or ET visit will only be listed on SAF population 
 
The safety parameters Activated partial thromboplastin time, the Serology laboratory assessments 
(Hepatitis B surface antigen, Hepatitis B surface antibody, Hepatitis B core total antibody, Hepatitis C 
antibody), C. difficile toxin and presence of other enteric, pathogens and QuantiFERON-TB Gold Test 
collected at screening visit as collected in eCRF will only be listed on SAF population 
 
The Pharmacogenetics sample data as collected in eCRF will only be listed on SAF population 
 
Titre values for anti drug antibodies for  will be listed for all subjects both V565 and placebo at Day 1 
(pre dose) and for V565 subjects only at Days, 14, 42 and 56. Results  will be listed for each subject 
by visit and treatment on SAF population. Subjects who test positive for anti- drug antibodies will be 
tested to confirm whether the antibodies are neutralising.      
 
 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA OUTPUT CONVENTIONS 
Outputs will be presented according to the following:  
DATES & TIMES 
Depending on data available, dates and times will take the form dd-mmm-yyyy hh:mm:ss. 
SPELLING FORMAT 
English UK   


 
 
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PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment 
Group 
For Tables and Graphs 
For Listings (include if different 
to tables) 
V565 
V565 
V565 
Placebo 
Placebo 
Placebo 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows as applicable in the tables and listings and in that order: 
 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
 
Treatment 
 
Subject ID 
 
date (where applicable), 
 
 
Long Name (default) 
Screening  
Baseline  
Day 1 
Day 14 
Day 42/Early Termination 
Day 42 (LOCF) 
Day 42 (WOCF) 
Day 56 


 
 
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APPENDIX 2. 
PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If start date < study drug start date, then not TEAE 
If start date >= study drug start date, then TEAE 
 
Partial 
If start date < study drug start date, then not TEAE 
If start date >= study drug start date, then TEAE 
 
Missing 
If start date < study drug start date, then not TEAE 
If start date >= study drug start date, then TEAE 
 
 
 
Partial, but known 
components show 
that it cannot be on 
or after study med 
start date 
Known 
Not TEAE 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on 
or after study med 
start date 
Known 
If stop date < study drug start date, then not TEAE 
If stop date >= study drug start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day 
of month if day unknown or 31st December if day 
and month are unknown), then: 
If stop date < study drug start date, then not TEAE 
If stop date >= study drug start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study drug start date, then not TEAE 


 
 
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START DATE 
STOP 
DATE 
ACTION 
If stop date >= study drug start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day 
of month if day unknown or 31st December if day 
and month are unknown), then: 
If stop date < study drug start date, then not TEAE 
If stop date >= study drug start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
 
 
 
 
 
 


 
 
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ALGORITHM FOR PRIOR / CONCOMITANT DRUGS:  
START 
DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If stop date < study drug start date, assign as prior  
If stop date >= study drug start date and start date <= end of treatment, 
assign as concomitant  
If stop date >= study drug start date and start date > end of treatment, 
assign as post study  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study drug start date, assign as prior 
If stop date >= study drug start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study drug start date and start date > end of treatment, 
assign as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior drug 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date < study drug start date, assign as prior 
If stop date >= study drug start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study drug start date and start date > end of treatment, 
assign as post treatment 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown) and impute stop 
date as latest possible date (i.e. last day of month if day unknown or 31st 
December if day and month are unknown), then: 
If stop date < study drug start date, assign as prior 
If stop date >= study drug start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study drug start date and start date > end of treatment, 
assign as post treatment 


 
 
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START 
DATE 
STOP 
DATE 
ACTION 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior drug 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < study drug start date, assign as prior 
If stop date >= study drug start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study drug start date, assign as prior 
If stop date >= study drug start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant 
 


 
 
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APPENDIX 3. 
SAMPLE SAS CODE 
SAS CODE FOR LOGISTIC REGRESSION 
proc genmod data=<data_set_name> desc; 
class treatment prior_anti_TNFα_therapy; 
model response=treatment prior_anti_TNFα_therapy baseline_CDAI_score 
/dist=bin link=logit; 
lsmeans treatment/ diff cl om exp; 
ods output lsmeans=lsmeans diffs=estimates; 
           output out=pred_resp reschi=resid;  
run; 
 
where  
 
response = binary response variable (Responder and Non-responder) 
treatment = treatment group (V565 and Placebo) 
prior_anti_TNFα_therapy = prior anti- TNFα therapy (yes/no) 
baseline_CDAI_score = CDAI score value at baseline 
 
SAS CODE FOR MMRM 
 
proc mixed data=<data_set_name> method=reml; 
    class subject treatment visit prior_anti_TNFα_therapy; 
    model response = treatment visit prior_anti_TNFα_therapy 
baseline_score treatment*visit prior_anti_TNFα_therapy*visit 
baseline_score*visit /outp=outp ddfm=kr residual; 
    repeated visit /type=un subject=subject; 
    lsmeans treatment treatment*visit/ cl diff om slice=visit; 
    ods output lsmeans=lsmeans diffs=diffs; 
run; 
Where 
response = change from baseline of PRO-2 assessments 
treatment = treatment group (V565 and Placebo) 
visit = visit at Day 14 and 42 
prior_anti_TNFα_therapy = prior anti- TNFα therapy 


 
 
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baseline_score = PRO-2 assessment score at baseline 
 
Programming Note: In case if model doesn’t converge change the 
covariance structure from type=UN to the below order  
 
1. type = AR(1); if AR(1) doesn’t converge then use 
2. type = CS 
SAS CODE FOR MANN-WHITNEY U STATISTIC  
proc npar1way data=<data_set_name> wilcoxon; 
by visit; 
class treatment; 
var response; 
run; 
 
where  
 
response = change from baseline of PRO-2 assessments 
visit = visit at Day 14 and 42 
treatment = treatment group (V565 and Placebo)