Clinical trial NCT02597712
Conditions: Barrett's Esophagus
Keywords: acid reflux intragastric pH gastrin hypergastrinemia
Sponsor: Trio Medicines Ltd.
Start date: 2013-05-15; Completion date: 2017-12-27
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A phase 2, randomised, double-blind, out-patient trial to determine if YF476 is a safe and effective treatment in patients with Barrett's esophagus.

Detailed description:

Arms: arm 1: Patients will take 25 mg YF476 once daily for 12 weeks arm 2: Patients will take matching placebo once daily for 12 weeks
Interventions: intervention 1: YF476 intervention 2: YF476 placebo
Intervention descriptions: intervention 1: gastrin receptor antagonist intervention 2: placebo

Protocol documents:
Prot_000.pdf: 
YF476 in Barrett’s esophagus 
 
Trial code: 10-505 (T-016) 
Protocol Version 24 
26 April 2018 
Page 1 of 66 
TRIO 
 
Trio Medicines Limited 
Trial protocol 
Confidential 
 
Trial title 
Randomized, placebo-controlled trial of YF476, a gastrin 
receptor antagonist, in Barrett’s esophagus 
Short title 
YF476 and Barrett’s esophagus 
Version and date of protocol 
Version 24, 26 April 2018 
HMR code  
10-505 
Sponsor code  
T-016 
IND# 
IND 107354 
EudraCT number 
2014-002418-22 
Trial medication 
YF476 
Phase of trial 
Phase II 
Place of trial 
Columbia University 
 
Division of Digestive & Liver Diseases 
622 W 168th Street 
PH 7W-318 
New York, NY  10032 
USA 
 
 
National Institute for Health Research 
Clinical Investigation Ward 
 
Cambridge University Hospitals NHS Foundation Trust 
Cambridge Biomedical Campus 
Hills Road 
Cambridge  CB2 0QQ 
 
UK 
 
 


YF476 in Barrett’s esophagus 
 
Trial code: 10-505 (T-016) 
Protocol Version 24 
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Sponsor 
TRIO Medicines Ltd 
PO Box 53346 
London, NW10 7XU 
England 
 
Chief investigator, and  
principal investigator at  
Columbia University 
Julian A. Abrams  MD  MS 
Columbia University 
 
Division of Digestive & Liver Diseases 
622 W 168th St 
 
PH 7W-318 
New York, NY   10032 
 
USA 
 
Tel: +1 (212) 342-0476 
Fax: +1 (212) 342-5759 
E-mail: ja660@columbia.edu 
Co-investigator at 
Columbia University 
Charles J Lightdale  MD 
Columbia University 
Division of Digestive & Liver Diseases 
180 Ft. Washington Avenue 
Harkness Pavilion, 7th Floor 
New York, NY  10032 
USA 
 
Tel: +1 (212) 305-4398 
E-mail: cjl18@columbia.edu 
Co-investigator at 
Columbia University 
John M. Poneros  MD 
Columbia University 
Division of Digestive & Liver Diseases 
622 W 168th Street 
PH 7W-318 
New York, NY  10032 
USA 
 
Tel: +1 (212) 342-3171 
E-mail: jmp14@columbia.edu 


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Trial code: 10-505 (T-016) 
Protocol Version 24 
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Co-investigator at 
Columbia University 
Timothy Wang  MD 
Columbia University 
Division of Digestive & Liver Diseases 
1130 St. Nicholas Avenue 
Herbert Irving Cancer Center, Room 923 
New York, NY  10032 
USA 
 
Tel: +1 (212) 851-4581 
E-mail: tcw21@columbia.edu 
Co-investigator at 
Columbia University 
Antonia Sepulveda  MD 
Columbia University 
Department of Pathology 
630 W 168th Street 
Vanderbilt Clinic, 14-212 
New York, NY  10032 
USA 
 
Tel: +1 (212) 305-3623 
E-mail: as4400@columbia.edu 
Principal investigator at  
University of Cambridge 
Professor Rebecca Fitzgerald 
 
MRC Cancer Unit 
University of Cambridge 
Hutchison/MRC Research Centre (Box 197) 
Cambridge Biomedical Campus 
Cambridge 
United Kingdom 
CB2 0XZ 
Study biostatistician 
Bin Cheng, PhD 
Columbia University 
722 W 168th Street 
Room 631 
New York, NY  10032 
 
Tel: +1 (212) 342-1238 
Fax: +1 (212) 342-1232 
E-mail: bc2159@columbia.edu 


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Protocol Version 24 
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Sponsor’s medical representative 
Malcolm Boyce  BSc  FRCP  FFPM  FBPharmacolS 
Hammersmith Medicines Research (HMR) 
Cumberland  Avenue 
London, NW10 7EW 
England 
 
Tel:  +44 (0) 20 8961 4130 
 
Mobile: +44 (0) 7850 510 572 
Fax: +44 (0) 20 8961 8665 
Email:  mboyce@hmrlondon.com 
Sponsor’s statistician 
Toni Mitchell   BSc  MSc  CStat 
Head of Statistics and Data Management 
HMR 
 
Tel:  +44 (0) 20 8961 4130 
Fax: +44 (0) 20 8961 8665 
Email:  tmitchell@hmrlondon.com 
Planned dates of trial 
February 2012 – December 2016 




YF476 in Barrett’s esophagus 
 
Trial code: 10-505 (T-016) 
Protocol Version 24 
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1 
Summary 
1.1 
Background 
Barrett’s Esophagus (BE) is the precursor lesion for the development of esophageal 
adenocarcinoma (EAC).  BE is defined as the presence of intestinal metaplasia in the 
distal esophagus, and is associated with a 25-30 times increased risk of 
EAC.1    Unfortunately, the prognosis of esophageal cancer is poor, with 5-year survival 
rates of 16.5% in the US.2 
The development of BE is thought to be caused in part by acid reflux.  The change in 
esophageal lining presumably develops as a result of chronic exposure to refluxed 
stomach acid and bile, leading to recurrent mucosal injury.3 
Current management of BE patients consists of endoscopic surveillance and acid 
suppression.4  In theory, gastric acid suppression reduces chronic inflammation within 
the BE segment, which in turn may reduce the risk of progression to EAC. 
By inhibiting acid secretion and increasing intragastric pH, proton pump inhibitors 
(PPIs) at therapeutic doses can cause secondary hypergastrinemia.  Gastrin exerts 
trophic effects in BE via cholecystokinin-2 receptor (CCK2R) activation5, and there is 
some evidence that hypergastrinemia is associated with an increased risk of progression 
to high grade dysplasia and cancer.6  
YF476 is a potent, orally active, highly selective, competitive antagonist of CCK2 
receptors.7  The primary hypothesis for this study is that administration of YF476 to 
patients with BE will result in a significant decrease in cellular proliferation in the 
Barrett’s mucosa. 
1.2 
Trial medication 
YF476 (25 mg) or matching placebo: one capsule to be taken by mouth once daily for 12 
weeks.  Study medication will be taken with breakfast except on clinic visit days, when 
patients will fast overnight and take study medication after completion of study 
procedures. 
1.3 
Objectives 
Primary: 
The primary objective of this study is to determine if administration of YF476 (a 
CCK2R antagonist) to patients with Barrett’s esophagus (BE) decreases tissue Ki67 
expression, a marker of cellular proliferation. 


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Trial code: 10-505 (T-016) 
Protocol Version 24 
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Secondary: 
 
The secondary objectives are to assess the effects of YF476 on:  
• Biomarkers potentially associated with esophageal adenocarcinoma, in particular, 
cyclooxygease-2 (COX-2), p53, CCK2R and DCAMKL1; and 
• fasting serum gastrin, a marker of gastric acid suppression, and plasma chromogranin 
A (CgA), a marker of ECL cell hyperplasia. 
We also aim to determine whether YF476 is safe in patients with BE. 
1.4 
Type of trial 
Phase II, randomised, double-blind, out-patient trial. 
1.5 
Trial population 
a 
Total  20 patients completing the trial.  
b 
Inclusion criteria 
1. 
Aged ≥18 years, with histologically confirmed diagnosis of BE without dysplasia.  
A prior endoscopy with biopsies read as indefinite for dysplasia is permitted if 
biopsies from the most recent endoscopy prior to study entry demonstrated BE 
without dysplasia. 
2. 
Minimum of 1 cm circumferential Barrett’s mucosa on endoscopy or at least 2 cm 
maximal contiguous extent of Barrett’s mucosa. (Prague criteria C≥1, any M or 
any C, M≥2). 
3. 
Proton pump inhibitor use at least once daily, for at least twelve months prior to 
enrollment, and stable dose of PPI for the three months before enrollment. Any 
PPI, dose, and frequency are allowable. 
4. 
ECOG performance status ≤2 and Karnofsky ≥60%; see Appendix A. 
5. 
Normal organ and marrow function, defined as white blood cells (WBC) ≥3 x 
109/L, absolute neutrophil count ≥1.5 x 109/L, platelets ≥100 x 109/L, 
creatinine ≤1.5 mg/dL, total bilirubin ≤1.5 mg/dL, AST ≤100 U/L, ALT ≤100 U/L. 
6. 
Use of adequate contraception during the study as follows.   
• Pre-menopausal women must use a highly effective method of contraception 
(≤1% failure/year when used correctly), including:  
o intrauterine device (IUD); 
o bilateral tubal occlusion; 
o vasectomised partner – must have had medical assessment of successful 
surgery; 
o intrauterine hormone-releasing system (IUS); 


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o progestogen-only hormonal contraception implants associated with 
inhibition of ovulation; or 
o hormonal contraception associated with inhibition of ovulation 
(combined or progestogen-only – includes oral, intravaginal, transdermal 
and injections).  
• To prevent pregnancy, men with partners of childbearing potential must use a 
condom or have had a vasectomy (with a medical assessment of successful 
surgery).  Partners who are not of childbearing potential are defined as:  men; 
post-menopausal women (no menstrual periods for at least 1 year); or women 
who have no uterus, ovaries or fallopian tubes.   
• Women classed as post-menopausal (no menstrual periods for at least 1 year) 
are not required to use contraception. 
7. 
Willingness to comply with all treatment and follow-up procedures. 
8. 
Ability to understand and the willingness to sign a written informed consent 
document. 
9. 
Up to date with all age-appropriate cancer screening tests (based on national 
guidelines. 
d 
Exclusion criteria 
1. 
Histologically confirmed BE with high-grade dysplasia. 
2. 
Histologically confirmed diagnosis of invasive carcinoma of the esophagus. 
3. 
Histologically confirmed BE with low-grade dysplasia that has been diagnosed by 
at least two expert gastrointestinal pathologists.  
4. 
Prior endoscopic therapy for Barrett’s esophagus. 
5. 
A relevant history of esophageal or gastric surgery that, in the investigator’s 
opinion, could compromise the objectives of the trial. 
6. 
History of atrophic gastritis, pernicious anemia, or Zollinger-Ellison syndrome. 
7. 
Participation in a trial of an IMP within the previous 28 days. 
8. 
Prolonged QTc interval >450 msec  
9. 
History of allergic reactions attributed to compounds of similar chemical 
composition to YF476. 
10. 
History or baseline findings of: 
• diabetes mellitus requiring insulin therapy; 
• pancreatitis (baseline amylase and/or lipase ≥ 2.0 x ULN); 
• hepatitis B or hepatitis C; 


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• HIV, unless, at the discretion of the PI, with at least 120 days on stable 
antiretroviral therapy (ART) with undetectable HIV viral load and CD4 >350 
cells/mm3; 
• malabsorption syndrome or inability to swallow or retain oral medicine; 
• major surgery ≤28 days prior to enrollment; 
• ECOG performance status ≥2; or 
• another cancer within 3 years except for basal carcinoma of the skin or 
cervical carcinoma in-situ. 
• Also, any clinically significant and uncontrolled major morbidity including 
but not limited to: serious cardiac disease (unstable angina, s/p myocardial 
infarction ≤1 month); respiratory disease (advanced COPD or pulmonary 
fibrosis); uncontrolled hypertension; active systemic infection; or psychiatric 
illness/social situations that would limit compliance with study requirements. 
11. 
Certain medicines and herbal remedies (see Appendix B) taken during the 7 days 
before the start of study drug. 
12. 
A history of cancer >3 years from the time of enrollment, and the patient is not up 
to date with surveillance for that cancer (based on national guidelines), or has 
evidence of cancer at the time of enrollment. 
1.6 
Trial design and methods 
Patients will be randomised (1:1 ratio) to receive either 25 mg YF476  or matching 
placebo.  They will attend the clinic 4 or 5 times, and will take up to 18 weeks to 
complete the trial. 
At Visit 1, patients will sign the Informed Consent form. Patients will undergo 
assessment of eligibility, physical examinations, ECG, urine pregnancy test (pre-
menopausal women only) and safety tests of blood and urine. 
Visit 2 can take place on the same day as visit 1, or up to 2 weeks later.  At Visit 2, 
patients will undergo ECG, safety tests of blood and urine, including urine pregnancy 
test (pre-menopausal women only), unless Visit 2 is on the same day as Visit 1.  All 
patients will have baseline biomarker assessments, baseline 
esophagogastroduodenoscopy (EGD) and biopsies.  If they meet all the eligibility 
criteria, they will be given a bottle of study medication (25 mg YF476 or placebo) 
capsules to take once daily, with breakfast, starting the next day.  Patients will complete 
a diary card throughout the treatment period. 
The Week 6 visit will be 6 weeks after starting study treatment.  Patients will fast before 
the visit, and will bring their dose of study medication to the clinic, to take after fasting 
blood tests.  First, patients will have safety tests of blood and urine, ECG, and blood 
taken for biomarkers and trough YF476 concentration.  Patients will then take their 
study medication, and 1 h afterwards will have blood taken for peak YF476 


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concentration.  Patients will be asked about any adverse events and concomitant 
medications, and will return their study medication bottle for assessment of compliance.  
They will receive their next bottle of study medication. 
The Week 12 visit will be 12 weeks after starting study treatment.  Patients will fast 
before the visit, and will bring their dose of study medication to the clinic, to take after 
fasting blood tests.  First, patients will have safety tests of blood and urine, ECG, and 
blood taken for biomarkers and trough YF476 concentration, before undergoing EGD 
assessments and biopsies.  Patients will then take their study medication, and 1 h 
afterwards will have blood taken for peak YF476 concentration.  
Follow-up visit will be 4 weeks after the patients have stopped taking study medication.  
Patients will have safety tests of blood and urine, ECG, and blood tests for biomarkers.  
Patients will be asked about any adverse events.     
1.7 
Methods 
• Esophagogastroduodenoscopy (EGD), to enable taking of biopsies for assessment of 
the primary endpoint, Ki67 expression levels; 
• blood sampling for assay of biomarkers and serum for storage; 
• diary card for patients to record adverse events, concomitant medication and 
compliance; and 
• physical examination, ECG and safety tests of blood and urine. 
1.8 
Primary variable 
Efficacy: 
change in Ki67 expression between baseline (Visit 2) and the 
Week 12 visit 
1.9 
Secondary variables 
Biomarkers:   
change from baseline at Week 12 in biomarkers potentially 
associated with esophageal adenocarcinoma, in particular, 
cyclooxygenase-2 (COX-2), P53, CCK2R and DCAMKL1, and in 
fasting serum gastrin and plasma CgA  
Safety: 
vital signs, ECG, physical examination, laboratory safety tests: 
blood tests: red blood cells (RBC), haemoglobin, haematocrit, 
platelets, white blood cells (WBC, differential: neutrophils, bands, 
lymphocytes, monocytes, eosinophils, basophils), sodium, 
potassium, magnesium, chloride, bicarbonate, creatinine, serum 
glucose, blood urea nitrogen (BUN), alkaline phosphatase, lactate 
dehydrogenase (LDH), serum glutamic-oxaloacetic 


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transaminase/aspartate amino transferase (SGOT/AST), serum 
glutamic-pyruvic transaminase/ alanine aminotransferase 
(SGPT/ALT), total bilirubin, total protein, albumin, calcium, 
amylase, lipase; and urine tests: pH, specific gravity, protein, 
glucose, ketones, blood, and change in histology. 
Tolerability: 
adverse events 
Pharmacokinetics: 
trough and peak concentrations of YF476 


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STUDY DIAGRAM 
 
Randomized, placebo-controlled trial of a gastrin  
receptor antagonist, YF476, in Barrett’s esophagus 
 
 
Barrett’s esophagus without dysplasia 
Proton pump inhibitor use at least once daily, for at least 12 months prior to enrollment, and 
stable dose of PPI for the 3 months before enrollment 
 
 
Informed consent 
 
 
Baseline data collection [history + physical, endoscopy + biopsy, blood (safety tests, pregnancy 
test (pre-menopausal women only) biomarkers), urine] 
 
 
Randomization: 1:1 ratio between patients on 25 mg YF476 daily and patients on placebo daily, 
for 12 weeks 
 
 
Follow-up data collection [endoscopy + biopsy, blood (safety tests, biomarkers, YF476 PK), 
urine, compliance, AEs, SAEs] 
 
 
Primary Endpoint – Ki67 expression 
Secondary endpoints – expression of other biomarkers (including COX-2, p53, CCK2R, 
DCAMKL1), serum gastrin, plasma CgA and safety. 
 


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Table of contents 
Signatures 
5 
1 
Summary 
6 
1.1 
Background 
6 
1.2 
Trial medication 
6 
1.3 
Objectives 
6 
1.4 
Type of trial 
7 
1.5 
Trial population 
7 
1.6 
Trial design and methods 
9 
1.7 
Methods 
10 
1.8 
Primary variable 
10 
1.9 
Secondary variables 
10 
Table of contents 
13 
List of Abbreviations 
16 
2 
Objectives 
19 
2.1 
Primary objective 
19 
2.2 
Secondary objectives 
19 
3 
Background 
19 
3.1 
Barrett’s esophagus 
19 
3.2 
YF476 
20 
3.2.1 
Non-clinical studies 
20 
3.2.2 
Phase 1 studies 
21 
3.3 
Rationale 
22 
4 
Summary of study plan 
23 
4.1 
Study design 
23 
4.2 
Discussion of study design 
24 
4.3 
Risk-benefit analysis 
25 
5 
Patient selection 
26 
5.1 
Inclusion criteria 
26 
5.2 
Exclusion criteria 
27 
5.3 
Inclusion of women and minorities 
28 
5.4 
Recruitment and retention plan 
28 
6 
Administration of study medication 
29 
6.1 
Dose regimen and dose groups 
29 
6.2 
YF476 administration 
29 
6.3 
Run-in procedures 
29 


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6.4 
Contraindications 
29 
6.5 
Concomitant medications 
30 
6.6 
Dose modification 
30 
6.7 
Compliance 
30 
7 
Pharmaceutical information 
32 
7.1 
Active pharmaceutical ingredient (API):  YF476 
32 
7.2 
Formulated intermediate:  spray-dried YF476 
32 
7.3 
Final formulation 
33 
7.4 
Packaging and labelling 
33 
7.5 
Storage, accountability and dispensing of study medication 
33 
7.6 
Registration and randomization 
34 
7.7 
Blinding and unblinding methods 
34 
7.8 
YF476 destruction/disposal 
35 
8 
Clinical evaluations and procedures 
36 
8.1 
Schedule of events 
36 
8.2 
Baseline testing and pre-study evaluation 
37 
8.3 
Evaluations during study treatment 
38 
8.4 
Evaluations at completion of study treatment 
38 
8.5 
Post-treatment follow-up period 
39 
8.6 
Flexibility of study days 
39 
8.7 
Withdrawal of patients from the trial 
39 
8.7.1 
Termination of study medication 
39 
8.7.2 
Termination of study participation 
40 
8.8 
Study termination 
40 
9 
Criteria for evaluation and endpoint definition 
40 
9.1 
Primary endpoint 
40 
9.2 
Secondary endpoints 
40 
10 
Methods 
41 
10.1 
Methods for clinical procedures 
41 
10.2 
Rationale for laboratory methods 
42 
10.3 
Laboratory methods 
43 
10.3.1 Laboratories 
43 
10.3.2 Collection and handling procedures 
43 
11 
Reporting adverse events 
45 
11.1 
Adverse events (AEs) 
45 
11.2 
Serious adverse events (SAEs) 
47 
11.2.1 Definition 
47 
11.2.2 Reporting SAEs 
48 


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12 
Data management and quality assurance 
49 
12.1 
Data and safety monitoring plan 
49 
12.2 
Sponsor or regulatory monitoring 
50 
12.3 
Record retention 
50 
12.4 
Clinical Trial Agreement 
50 
13 
Statistical methods 
50 
13.1 
Analysis Sets 
50 
13.2 
General Statistical Considerations 
51 
13.3 
Study Population Data 
51 
13.4 
Efficacy Analyses 
51 
13.5 
Pharmacokinetic Analyses 
52 
13.6 
Safety Analyses 
53 
13.6.1 Adverse Event Analyses 
53 
13.6.2 Analyses of Clinical Laboratory Tests 
53 
13.6.3 Electrocardiogram Analyses 
53 
13.7 
Determination of sample size 
53 
14 
Ethical and regulatory considerations 
54 
14.1 
Columbia University Medical Center, New York, US 
54 
14.1.1 Form FDA 1572 
54 
14.1.2 Other required documents 
54 
14.1.3 Institutional Review Board (IRB) approval 
55 
14.2 
National Institute for Health Research Clinical Investigation Ward, Cambridge, 
UK 
55 
14.3 
Informed consent 
56 
15 
Financing, expenses, and/or insurance 
56 
16 
Obligations of the sponsor and investigator 
56 
16.1 
Publication 
56 
16.2 
Archiving 
57 
16.3 
Premature termination of the trial 
57 
17 
References 
58 
Appendix A – performance status criteria 
60 
Appendix B – drug interactions 
61 
Appendix C – medications card (CUMC) 
65 


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List of Abbreviations 
ACG 
American College of Gastroenterology 
ADL 
activities of daily living 
AE 
adverse event 
API 
active pharmaceutical ingredient 
ART 
antiretroviral therapy 
AUC 
area under the curve 
BE 
Barrett’s esophagus 
CAP 
College of American Pathologists 
CCK2R 
cholecystokinin 2 receptor 
CDE 
Common Data Elements 
CgA 
chromogranin A 
CI 
confidence interval 
CIW 
CLIA 
Clinical Investigation Ward 
Clinical Laboratory Improvement Amendments 
cm 
centimetre 
Cmax 
peak concentration 
COX-2 
cyclooxygenase-2 
CRF 
case report form 
CTA 
clinical trial authorisation 
CTCAE 
Common Terminology Criteria for Adverse Events 
CUMC 
Columbia University Medical Centre 
CV 
Curriculum Vitae 
CYP 
cytochrome P450 enzyme 
DCAMKL-1 
doublecortin- and Ca2+/calmodulin-dependent protein kinase-like 
protein 1 
DCP 
Division of Cancer Prevention 
DSMB 
Data Safety Monitoring Board 
EAC 
esophageal adenocarcinoma 
ECL 
enterochromaffin-like 


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EGD 
esophagogastroduodenoscopy 
FDA 
Food and Drug Administration 
FWA 
Federal-wide assurance 
g 
gram 
GCP 
Good Clinical Practice 
GERD 
gastro-esophageal reflux disesase 
GI 
gastrointestinal 
GMP 
Good Manufacturing Practice 
GRA 
gastrin receptor antagonist  
h 
hour 
H2RA 
histamine-2 receptor antagonist 
hERG 
human ether-à-go-go related gene 
HGD 
high grade dysplasia 
HIPAA 
health insurance portability and accountability act 
HMR 
Hammersmith Medicines Research 
HPMC 
hydroxypropylmethylcellulose 
IC50 
concentration of a drug causing 50% inhibition of a response 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use  
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LGD 
low grade dysplasia 
mg 
milligram 
MHRA 
Medicines and Healthcare products Regulatory Agency 
mL 
millilitre 
mm Hg 
millimetres of mercury 
NCI 
National Cancer Institute 
NDA 
new drug application 
NIHR 
National Institute for Health Research 


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NOAEL 
no observable adverse effect level 
NSAID 
non-steroidal anti-inflammatory drug 
ºC 
degrees celsius 
OHRP 
office for human research protections 
OR 
odds ratio 
p53 
tumour protein 53 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic 
pH 
negative logarithm to base 10 of the hydrogen ion concentration 
PI 
principal investigator 
PK 
pharmacokinetic 
PPI 
proton pump inhibitor 
QA 
quality assurance 
qRT-PCR 
quantitative RT-PCR 
QTc 
interval of the ECG corrected for heart rate 
REC 
Research ethics committee 
RT-PCR 
reverse transcriptase polymerase chain reaction 
SAB 
SAE 
Scientific Advisory Board 
serious adverse event 
SAS 
statistical analysis software 
SD 
standard deviation 
SUSAR 
serious unexpected serious adverse reaction 
T1/2 
half-life 
Tmax 
time of peak concentration 
ΔKi67 
change in Ki67 expression 
μg 
microgram 
μmol 
micromole 


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2 
Objectives 
2.1 
Primary objective 
The primary objective of this study is to determine if administration of YF476 (a 
CCK2R antagonist) to patients with Barrett’s esophagus (BE) decreases tissue Ki67 
expression, a marker of cellular proliferation. 
2.2 
Secondary objectives  
The secondary objectives are to assess the effects of YF476 on:  
• biomarkers potentially associated with esophageal adenocarcinoma, in particular, 
cyclooxygease-2 (COX-2), p53, CCK2R and DCAMKL1; and 
• fasting serum gastrin, a marker of gastric acid suppression, and plasma chromogranin 
A (CgA), a marker of ECL cell hyperplasia. 
We also aim to determine whether YF476 is safe in patients with BE. 
3 
Background 
3.1 
Barrett’s esophagus 
Barrett’s esophagus (BE) is the precursor lesion for the development of esophageal 
adenocarcinoma (EAC).  BE is defined as the presence of intestinal metaplasia in the 
distal esophagus, and is associated with a 25–30 fold increased risk of EAC.1  The 
incidence of EAC has increased five-fold in the past three decades in the United States 
(US), with similar patterns of incidence observed in most developed western countries.8  
Unfortunately, the prognosis of esophageal cancer is poor, with 5-year survival rates of 
16% in the US.2 
The development of BE is thought to be caused in part by acid reflux.  The change in 
esophageal lining presumably develops as a result of chronic exposure to refluxed acid 
and bile from the stomach leading to recurrent mucosal injury.3  The esophageal injury is 
accompanied by inflammation and, ultimately, a cellular change (metaplasia) to a 
specialized columnar epithelium.  BE-associated intestinal metaplasia can ultimately 
progress to low grade (LGD) and high grade dysplasia (HGD), states that are associated 
with elevated risk of progressing to EAC. 
Current management of BE patients consists of endoscopic surveillance and acid 
suppression.4  For example, current American College of Gastroenterology (ACG) 
guidelines recommend periodic upper endoscopy with random biopsies of the Barrett’s 
segment in order to assess for the presence of LGD, HGD, or EAC.  The purpose of 
surveillance is to allow for early detection, which may lead to improved patient 
outcomes.  ACG guidelines for the management of BE also recommend gastric acid 
suppression with proton pump inhibitors (PPIs).  In theory, gastric acid suppression 


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reduces chronic inflammation within the BE segment, which in turn may reduce the risk 
of progression to EAC.   
3.2 
YF476 
Details of YF476 are in the Investigator’s Brochure (Trio Medicines Ltd)7, so only a 
summary is provided here. 
3.2.1 
Non-clinical studies 
Non-clinical studies have shown YF476 to be a potent, highly selective, and competitive 
antagonist of gastrin receptors in vitro and in vivo.9-11 
Toxicology studies of YF476 consisted of: single- and/or repeat-dose toxicity studies in 
rats and dogs; toxicokinetics in rats and dogs; and embryo-foetal toxicity studies in rats 
and rabbits.  Other non-clinical studies consisted of: safety pharmacology studies in rats, 
mice and dogs; genotoxicity studies in vivo and in vitro; studies of metabolism by 
cytochrome P450 in human liver microsomes in vitro; a study to determine the extent of 
YF476 protein binding in normal human serum in vitro; a study of the effect of YF476 
on the hERG ion channel in human embryonic kidney cells in vitro: and a study to 
compare the metabolism of 14C-YF476 in rat, dog and human cells in vitro. 
In acute toxicity studies in beagle dogs, 100 and 500 mg/kg/day resulted in similar 
plasma concentrations of YF476, and caused no adverse effects.  Therefore, 10, 30 and 
100 mg/kg/day were tested in a 13-week toxicity study.  Changes in pancreas weight and 
histopathology were observed in some animals, and serum amylase was elevated in one 
low-dose male.  Although the histological findings resemble nesidioblastosis, a 
spontaneous finding in laboratory beagles, an effect of YF476 cannot be excluded, so the 
study did not clearly establish a NOAEL. 
A 13-week toxicity study of YF476 doses 100, 300 and 1000 mg/kg/day was done in 
rats.  At 300 and 1000 mg/kg/day, some animals had minor, reversible changes in 
enzyme activities and heart weight, and discoloured urine and pale faeces.  Also, there 
were minor histopathological lesions in the heart and pancreas of four treated animals 
and one control animal.  The NOAEL was deemed 100 mg/kg/day.   
In the 13-week study in dogs, YF476 had no effect on the ECG, and no effect on the 
ECG intervals, including QTc.  A concentration of YF476 about four times the highest 
Cmax in a human subject to date did not affect the hERG channel in vitro.  Because 
∼84% of YF476 is bound to serum protein in vivo, that represents 25-fold safety cover.   
Embryo-foetal studies were done in the rat and rabbit, using YF476 doses of 100, 300 
and 1000 mg/kg/day.  YF476 had no effect on embryo-foetal survival, growth or 
development in rabbits.  There was slight delay in foetal development in rats given 
1000 mg/kg/day, so the NOAEL was deemed 300 mg/kg/day. 
The metabolism of parent 14C-YF476 was most efficiently catalysed by human > dog > 
rat hepatocytes in vitro.  Phase I and II metabolites were formed.  There was no evidence 


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for formation of unique major human metabolites, although the main metabolite was 
different from that formed by rat and dog.  Thus, the rat and dog are appropriate species 
to assess the potential toxicity of YF476 in humans. 
YF476 caused some reversible inhibition of CYP2C8 and CYP3A4 in vitro.  The 
likelihood of a drug-drug interaction via those enzymes in trials in patients is remote or 
possible, respectively, at the proposed doses of YF476. 
Non-clinical studies support administration of YF476 to humans for up to 13 weeks.  
The treatment period for this clinical trial will be 12 weeks. 
3.2.2 
Phase 1 studies 
Trio has completed 11 studies of YF476 in healthy men and women.7  184 subjects 
received YF476: single doses up to 400 mg; up to 25 mg daily for 14 days; 100 mg 
twice daily for 7 days; 100 mg YF476 daily, either alone or with 20 mg rabeprazole, for 
6 weeks; and 25 mg YF476 daily for 14 days either alone or with 40 mg esomeprazole.  
The outcome measures were: safety; tolerability; pharmacokinetics; and 
pharmacodynamics (24-h gastric pH; pentagastrin-induced gastric acid secretion; serum 
gastrin; and markers of ECL-cell hyperplasia).  The comparators were placebo, 
ranitidine, omeprazole and rabeprazole. 
Safety and tolerability 
In all studies, YF476 was well tolerated.  Adverse events were minor, transient, occurred 
in subjects given placebo or comparators as well as YF476, and were not YF476-dose 
dependent.  YF476 affected neither vital signs, ECG, nor safety tests of blood and urine.   
Pharmacodynamics  
Single doses caused dose-dependent increases in 24-h gastric pH.  The effect lasted 
much longer than that of a single dose of ranitidine.  However, the effect of YF476 on 
24-h gastric pH was mostly lost after repeated doses, whereas that of omeprazole 
persisted.  Single doses of YF476 also caused dose-dependent inhibition of pentagastrin-
induced falls in gastric pH and increases in gastric volume and H+ output.  Again, the 
effect on gastric pH was mostly lost after repeated doses of YF476.  But, the effects on 
volume and H+ output persisted.  So, gastrin receptors must still be blocked after 
repeated doses of YF476.  In a study of YF476 and rabeprazole, alone and in 
combination for 6 weeks, YF476:  
• was as effective as the PPI in reducing gastric volume and H+ activity;  
• was as effective as the PPI in increasing serum gastrin;  
• did not increase plasma chromogranin A (CgA), a biomarker for ECL-cell 
activity, whereas the PPI increased it;  
• abolished the PPI-induced increase in CgA;  


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• augmented gastric acid suppression by the PPI without reducing the increase 
in gastric pH induced by the PPI; and  
• prevented the rebound increase in H+ activity induced by the PPI.   
In conclusion, the combination was more effective than either the PPI or YF476 alone in 
suppressing gastric acid production.  YF476 prevented stimulation of ECL cells and 
rebound hyperacidity, both of which are caused by PPI-induced hypergastrinaemia.  
Overall, the effects of YF476 are consistent with antagonism of gastrin receptors. 
Pharmacokinetics 
The pharmacokinetic profile of YF476 varied among the 1996, 2001, 2005 and 2009 
capsule formulations.  The 2001 and 2005 formulations were crystalline, and the 1996 
and 2009 formulations were spray-dried. The spray-dried formulations had the most 
favourable profile.  In a single-dose study of 50–400 mg of the current (2009) 
formulation of YF476, absorption was rapid, Tmax was 1.5–2 h, T½ varied with dose, and 
Cmax and AUC0-24 were not proportional to dose.  T½ after 100 mg YF476 was about 7 
h.  Food increased Cmax and AUC0–24 by 1.9 and 1.6-fold, respectively.  The absolute 
bioavailability was about 16% in a study of 100 mg ‘cold’ YF476 by mouth after fasting 
and 15 µg 14C-YF476 intravenously.  Protein binding in human serum was about 84%.  
In a 7-day study of 100 mg YF476 twice daily of the 1996 formulation, YF476 reached 
steady state by Day 3 and did not accumulate by Day 7.  Even though the crystalline 
formulations were much less bioavailable than the spray-dried formulations, the 
pharmacodynamic results were still favourable, which suggests that YF476 is a potent 
gastrin antagonist in man.   
3.3 
Rationale 
As described above, clinical guidelines for the management of BE include gastric acid 
suppression with chronic PPI therapy.  Acid reflux appears to have an important causal 
role in the development of BE, and a history of reflux symptoms is associated with 
EAC.12  However, data are inconclusive with regard to acid suppression and EAC risk.  
In a retrospective study of veterans with BE, PPI compared with histamine-H2 
antagonists or no acid suppression was associated with a lower risk of progression to 
dysplasia.13  In contrast, other studies suggest that PPIs may be associated with an 
increased risk for developing EAC,14 and Feagins et al reported anti-proliferative effects 
of acid exposure in non-dysplastic BE cells.15 
By inhibiting acid secretion, PPIs at therapeutic doses can cause secondary 
hypergastrinemia.  Gastrin exerts trophic effects in BE via CCK2R activation.5 There is 
increased expression of CCK2R in BE compared to squamous epithelium, and gastrin 
can stimulate proliferation, anti-apoptosis, COX-2 expression, and loss of cell-cell 
adhesion in BE cells.5, 16  The chief investigator’s group recently reported that BE 
patients with high serum gastrin levels had significantly increased odds of a history of 
high grade dysplasia (HGD) or EAC.6  In that cross-sectional study, they enrolled 95 


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patients with BE (with and without dysplasia or EAC) and GERD controls on chronic 
PPI therapy.  Subjects in the highest serum gastrin quartile had significantly increased 
odds of a history of advanced neoplasia (adjusted OR 5.46, 95% CI 1.20–24.8).  The 
group also analyzed 19 samples from non-dysplastic Barrett’s epithelium, and found 
marked elevations in Ki67 expression, with a mean Ki67 index of 48.3% (SD 16.0%).  
They also found a moderate correlation between serum gastrin and tissue Ki67 index 
(r=0.64, p=0.05) in a subset of ten patients 17. 
Those studies support the notion that gastrin may promote carcinogenesis in BE, and 
that these potentially pro-neoplastic effects occur via activation of the CCK2 receptor.  
We therefore propose the following clinical trial to analyze the effects of a CCK2 
receptor antagonist in patients with BE.  The primary hypothesis is that administration of 
YF476, a CCK2 receptor antagonist, in patients with BE will result in a significant 
decrease in cellular proliferation in the Barrett’s mucosa. 
4 
Summary of study plan 
4.1 
Study design 
We propose a randomized, double-blind, placebo-controlled pilot study of YF476, a 
cholecystokinin-2 receptor antagonist, in patients with Barrett’s esophagus without 
dysplasia.  Patients will take YF476 or placebo for 12 weeks.   
There are 2 research sites, Columbia University and the University of Cambridge.  We 
aim for 20 patients to complete the study.  Patients will be randomized (1:1 ratio) to 
treatment with YF476 or placebo.   
Patients will make up to 5 visits to the research site (Visits 1 and 2 may be combined, or 
up to 2 weeks apart.  See schedule of events in Section 8.1.): 
• Registration (Visit 1) 
• Baseline (Visit 2 – start of treatment phase) 
• Study treatment (6 weeks after the start of the treatment phase). 
• End of study treatment (after 12 weeks’ treatment) 
• Follow-up (4 weeks after the end of treatment). 
After giving informed consent (Visit 1) and after the initial endoscopy (Visit 2), patients 
will be given one bottle of YF476 or placebo. They will be given a study bottle again at 
the Week 6 visit.   
The primary endpoint of the study (Ki67 expression) will be assessed using endoscopic 
biopsies taken at baseline and at 12 weeks.  
Esophageal tissue from endoscopic biopsies will be evaluated for Ki67 expression 
(primary endpoint) and expression of additional markers potentially associated with 


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esophageal neoplasia (secondary endpoints).   Expression of these markers will be 
assessed by RNA sequencing (RNA-Seq), immunohistochemistry (IHC) and reverse 
transcriptase-PCR (RT-PCR), as appropriate. 
Blood samples will be taken at Visit 2, the Week 6 visit and the Week 12 visit for 
measurement of serum gastrin and plasma CgA, and at the Week 6 and Week 12 visits 
for trough and peak YF476 concentrations. 
Safety tests and pregnancy tests (pre-menopausal women only) will be done at each 
visit.  Patients will complete a diary card daily to record study drug, concomitant 
medication and adverse events.  Adverse events will be assessed 6 and 12 weeks after 
starting study medication, and 4 weeks after finishing study medication.  Blood and 
urine samples will also be collected at these visits to assess for hematologic, metabolic, 
or other disturbances that may be due to study drug.  The duration of the study for each 
individual patient will be between 16 and 18 weeks. 
4.2 
Discussion of study design 
Patient population 
In this first trial of YF476 in patients with BE, we will study only those without 
dysplasia.  BE patients without dysplasia are all placed on PPIs for acid suppression and 
undergo lifelong endoscopic surveillance.  Therefore, this population will be most 
vulnerable to any long-term adverse effects of increased gastrin exposure, and represents 
the group of patients who could potentially benefit the most from a gastrin receptor 
antagonist. The standard of care for patients with high grade dysplasia (HGD) at the 
study institutions consists of endoscopic ablative therapy and not continued endoscopic 
surveillance. The diagnosis of low grade dysplasia (LGD) is confounded by extremely 
poor interobserver reliability, even among expert pathologists.  Additionally, ablative 
therapy is also frequently recommended for LGD patients. Therefore, BE patients with 
LGD and HGD are not ideal candidates for chemoprevention studies in BE.  
Dose regimen 
The dose regimen of 25 mg YF476 or matching placebo once daily has been chosen 
based on a previous study of YF476 (T-013), which showed that a dose as low as 5 mg 
YF476 suppressed the increase in CgA, a marker of ECL-cell activity, induced by PPI 
treatment, in healthy subjects.  The patients in the proposed T-016 study will have had 
prolonged hypergastrinaemia, so a dose of 25 mg YF476 is appropriate.  A placebo-
controlled design is appropriate for this study as there is no alternative treatment known 
to reduce the levels of Ki67 expression in patients with BE. 
Efficacy tests 
We will use Ki67 index as the primary endpoint, as it is a reliable and reproducible 
marker of ongoing cellular proliferation.  Quantitative assessment of the number of 
proliferating (Ki67+) epithelial cells is easiest and most reliable in 


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immunohistochemistry (IHC).  We will also take blood samples to assay fasting serum 
gastrin and plasma CgA, and trough and peak YF476 concentrations. 
4.3 
Risk-benefit analysis 
What are the potential risks of harm to the trials patients from YF476 and from the trial 
procedures, and how might they be mitigated? 
Reported adverse events and potential risks 
In all studies in healthy volunteers, YF476 was well tolerated.  Adverse events were 
minor, transient, occurred in subjects given placebo or comparators as well as YF476, 
and were not YF476-dose dependent.  YF476 did not affect:  vital signs; ECG; or safety 
tests of blood and urine.  There was no evidence of effect on QT interval in human 
studies, but in vitro studies showed that YF476 has a low potential for prolonging QT 
interval (See Section 3.2.1).  So, until we have more information about YF476, patients 
with prolonged QT interval are excluded from clinical trials. 
The adverse effects that occurred at a frequency of 10% or greater were:  abdominal 
distention, diarrhea, abdominal pain, nausea, and headache.  None of these adverse 
effects were observed with greater frequency as compared to placebo or comparators. 
Because of the pancreatic findings in the 13-week toxicology study of dogs (Section 
3.2.1), serum amylase and lipase will be monitored at each visit.  Also, any patient who 
complains of abdominal discomfort at any time during the study will be seen 
immediately by the investigator or delegate and evaluated with history, physical 
examination, and laboratory tests, including serum amylase and lipase, and other 
appropriate tests, including radiological investigations. 
Risk from concomitant medications 
In vitro studies have shown that the likelihood of a drug-drug interaction in patients in 
vivo is: 
• 
CYP2C8:  possible for 50–400 mg YF476  
• 
CYP3A4 (testosterone):  remote for 50 & 100 mg YF476, and possible for 200 & 
400 mg 
• 
CYP3A4 (midazolam):  remote for 50 mg YF476, and possible for 100–400 mg. 
Although YF476 caused some irreversible inhibition of CYP3A4, the degree of 
inhibition makes a drug-drug interaction in patients in vivo unlikely.  And, a clinical 
study (T-007) of YF476 and midazolam (a substrate of CYP3A4) alone and in 
combination showed that neither medicine affects the pharmacokinetics of the other (see 
YF476 Investigator’s brochure for further details). 
Many medicines are metabolised via CYP3A4/5. Very few are metabolised via 
CYP2C8.  Examples of the main types of medicine that are metabolised by CYP3A4/5 


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and CYP2C8 are listed in Appendix B.  Guidance about assessing the risk and managing 
drug-drug interactions is also provided in Appendix B.  All medications (prescription 
and over-the-counter), vitamin and mineral supplements, and/or herbs taken by the 
patient will be documented in the CRF at baseline, and the patient will record any new 
concomitant medications in the diary card, which will be checked at each visit. 
Risk from study procedures: endoscopy 
Patients who take part in the trial must undergo endoscopy at baseline and at the 
Week 12 visit.  All patients in the study will have had at least one endoscopy before the 
trial.  Most gastroscopies are done without any problem.  Some people have a sore throat 
for a day or so afterwards.  Patients may feel tired or drowsy for several hours after 
sedation.  There is a slightly increased risk of developing a chest infection after 
endoscopy.  Rarely, the endoscope damages the esophagus, causing bleeding or 
infection.  Patients will be given information on how to prepare for their endoscopy 
according to local procedures. 
Overall, the potential benefits to the trial patients of taking part in the trial greatly 
outweigh the risks of any harm. 
5 
Patient selection 
5.1 
Inclusion criteria 
1. Aged ≥ 18 years, with histologically confirmed diagnosis of BE, defined as 
endoscopically-suspected BE with intestinal metaplasia present on esophageal 
biopsies, without dysplasia.  A prior endoscopy with biopsies read as indefinite for 
dysplasia is permitted if biopsies from the most recent endoscopy prior to study entry 
demonstrated BE without dysplasia.  The most recent endoscopy documenting BE 
must have been performed no more than three (3) years from the time of enrollment. 
2. Minimum of 1 cm circumferential Barrett’s mucosa on endoscopy or at least 2 cm 
maximal contiguous extent of Barrett’s mucosa. (Prague criteria C≥1, any M or any 
C, M≥2). 
3. Proton pump inhibitor use at least once daily, for at least twelve months prior to 
enrollment, and stable dose of PPI for the three months before enrollment. Any PPI, 
dose, and frequency are allowable. 
4. ECOG performance status ≤2 and Karnofsky  ≥60%; see Appendix A. 
5. Participants must have normal organ and marrow function, defined as white blood 
cells (WBC) ≥3 x 109/L, absolute neutrophil count  ≥1.5 x 109/L, 
platelets ≥100 x 109/L, creatinine ≤1.5 mg/dL, total bilirubin ≤1.5 mg/dL, 
AST ≤100 U/L, ALT ≤100 U/L. 


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6. The effects of YF476 on the developing human fetus at the recommended therapeutic 
dose are unknown.  All patients must agree to use adequate contraception for the 
duration of study participation as follows.      
• Pre-menopausal women must use a highly effective method of contraception 
(≤1% failure/year when used correctly), including:  
o intrauterine device (IUD); 
o bilateral tubal occlusion; 
o vasectomised partner – must have had medical assessment of successful 
surgery; 
o intrauterine hormone-releasing system (IUS); 
o progestogen-only hormonal contraception implants associated with 
inhibition of ovulation; or 
o hormonal contraception associated with inhibition of ovulation 
(combined or progestogen-only – includes oral, intravaginal, transdermal 
and injections).  
• To prevent pregnancy, men with partners of childbearing potential must use a 
condom or have had a vasectomy.  Partners who are not of childbearing 
potential are defined as:  men; post-menopausal women (no menstrual periods 
for at least 1 year); or women who have no uterus, ovaries or fallopian tubes.   
• Women classed as post-menopausal (no menstrual periods for at least 1 year) 
are not required to use contraception. 
7. Willingness to comply with all treatment and follow-up procedures. 
8. Ability to understand, and the willingness to sign, a written informed consent 
document. 
9. Up to date with all age-appropriate cancer screening tests (based on national 
guidelines. 
5.2 
Exclusion criteria 
1. 
Histologically confirmed BE with high-grade dysplasia. 
2. 
Histologically confirmed diagnosis of invasive carcinoma of the esophagus. 
3. 
Histologically confirmed BE with low-grade dysplasia that has been diagnosed by 
at least two expert gastrointestinal pathologists.  
4. 
Prior endoscopic therapy for Barrett’s esophagus, including (but not limited to) 
mucosal resection, radiofrequency ablation, and photodynamic therapy. 
5. 
A relevant history of esophageal or gastric surgery that, in the investigator’s 
opinion, could compromise the objectives of the trial. 
6. 
History of atrophic gastritis, pernicious anemia, or Zollinger-Ellison syndrome. 
7. 
Participation in a trial of an IMP within the previous 28 days. 


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8. 
Prolonged QTc interval (>450 msec)  
9. 
History of allergic reactions attributed to compounds of similar chemical 
composition to YF476. 
10. 
History or baseline findings of: 
• diabetes mellitus requiring insulin therapy; 
• pancreatitis (baseline amylase and/or lipase ≥ 2.0 x ULN); 
• hepatitis B or hepatitis C; 
• HIV, unless, at the discretion of the PI, with at least 120 days on stable ART 
with undetectable HIV viral load and CD4 >350 cells/mm3; 
• malabsorption syndrome or inability to swallow or retain oral medicine; 
• major surgery ≤28 days prior to enrollment; 
• ECOG performance status ≥2; or 
• cancer within 3 years except for basal carcinoma of the skin or cervical 
carcinoma in-situ. 
• Also, any clinically significant and uncontrolled major morbidity including 
but not limited to: serious cardiac disease (unstable angina, s/p myocardial 
infarction ≤1 month); respiratory disease (advanced COPD or pulmonary 
fibrosis); uncontrolled hypertension; active systemic infection; or psychiatric 
illness/social situations that would limit compliance with study requirements. 
11. 
Certain medicines and herbal remedies (see Appendix B) taken during the 7 days 
before the start of study drug. 
12. 
A history of cancer >3 years from the time of enrollment, and the patient is not up 
to date with surveillance for that cancer (based on national guidelines), or has 
evidence of cancer at the time of enrollment. 
5.3 
Inclusion of women and minorities 
Men and women of all races and ethnic groups are eligible for this trial.  However, the 
described epidemiology of Barrett’s esophagus is such that the majority of study patients 
are likely to be white males. 
5.4 
Recruitment and retention plan 
There will be 2 study sites: Columbia University Medical Center (CUMC), New York, 
US, and the National Institute for Health Research (NIHR) Clinical Investigation Ward 
(CIW), Cambridge University Hospitals, Cambridge, UK.  Eligible patients will be 
recruited from the clinical practices of the study investigators (JAA, CJL, JMP, RF). All 
of the study investigators see a large volume of patients referred for management and 
treatment of Barrett’s esophagus.  We aim for 20 patients to complete the trial.  
Recruitment progress will be assessed on an ongoing basis.  Screening and enrollment 
logs will be regularly reviewed by the investigators.  Patient withdrawals will be 


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carefully monitored. Methods for patient retention will be implemented, including the 
maintenance of regular contact with study patients.  The study staff will meet regularly 
to review issues related to recruitment and retention, identify areas of improvement, and 
implement appropriate strategies to address any deficiencies.  Additional recruitment 
methods such as advertising may be performed by each individual site with the approval 
of that site’s Institutional Review Board or REC. 
Withdrawals will be replaced at the discretion of the investigator.  
6 
Administration of study medication 
Study medication will be dispensed on an outpatient basis, and self-administered by 
patients.  Reported adverse events and potential risks are described in Section 4.3.   
6.1 
Dose regimen and dose groups 
• 
Patients will take 25 mg YF476 (1 x 25 mg capsule) or matching placebo capsules, 
by mouth once daily. 
• 
The treatment period for this trial will be 12 weeks. 
6.2 
YF476 administration 
• 
Each study patient will self-administer the YF476 or placebo.  
• 
The study medication will be dispensed into bottles: 46 capsules of 25 mg YF476 
or placebo per bottle.  1 bottle will be dispensed to participants at the baseline visit 
(Visit 2) and at the Week 6 visit. 
• 
Study medication should be taken once daily, in the morning, with breakfast. But, 
if a patient takes the study medication without food, or at a different time of the 
day, it will not be recorded as a protocol deviation.  Missed doses will be recorded 
as protocol deviations. 
6.3 
Run-in procedures 
No run-in phase is planned for this study.   
6.4 
Contraindications 
Contraindications to taking YF476 include prolonged QTc interval, pregnancy or 
breastfeeding.  Patients with prolonged QTc interval (>450 msec) are excluded.  Women 
of childbearing potential will be included in the study only if they are using adequate 
contraception and will be advised by the recruiting physician and in the information and 
consent form about the risks of becoming pregnant while taking part in the study.  
Pregnancy tests will be done at each visit. 


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6.5 
Concomitant medications 
All study patients will take proton pump inhibitors at least once daily.  Any formulation 
of PPI is permitted during the study period. 
All medications (prescription and over-the-counter), vitamin and mineral supplements, 
and/or herbs taken by the participant will be documented on the concomitant medication 
CRF and will include: 1) start and stop date, dose and route of administration, and 
indication. Medications taken for a procedure (eg: biopsy) should also be included. 
CYP 450 enzymes 
Studies were done to assess the potential of YF476 to inhibit cytochrome P450 enzymes 
in vitro.  For details, see Appendix B – drug interactions, and the YF476 Investigator’s 
Brochure. The likelihood of a drug-drug interaction in patients in vivo is: 
• 
CYP2C8:  possible for 50–400 mg YF476  
• 
CYP3A4 (testosterone):  remote for 50 & 100 mg YF476, and possible for 200 & 
400 mg 
• 
CYP3A4 (midazolam):  remote for 50 mg YF476, and possible for 100–400 mg. 
Although YF476 caused some irreversible inhibition of CYP3A4 in vitro, the degree of 
inhibition makes a drug-drug interaction in patients in vivo unlikely.  And, a clinical 
study (T-007) of YF476 and midazolam (a substrate of CYP3A4) alone and in 
combination showed that neither medicine affects the pharmacokinetics of the other.  
For details, see the Netazepide (YF476) Investigator’s Brochure. 
Many medicines are metabolised via CYP3A4/5. Very few are metabolised via 
CYP2C8.  Examples of the main types of medicine that are metabolised by CYP3A4/5 
and CYP2C8 are listed in Appendix B.  Guidance about assessing the risk and managing 
drug-drug interactions is also provided in Appendix B. 
Drugs that are substrates for, or inhibitors or inducers of CYP3A4/5 and CYP2C8 are 
not prohibited, but the patients must be monitored carefully, and the investigator must be 
informed of any new concomitant medications via the patient’s diary card.  Midazolam 
may be used during endoscopy.  It was used safely before gastroscopy in a study of 
YF476 in healthy subjects. 
6.6 
Dose modification 
Dose modifications of study drug will not be performed.  If drug-related toxicity is 
suspected, then treatment will be discontinued. 
6.7 
Compliance 
• 
All randomized patients will be eligible for statistical analysis.  Patients will be 
analyzed on an intent-to-treat basis, and also per protocol. 


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• 
Compliance will be measured by capsule counts at the Week 6 and Week 12 visits, 
and by review of patient diary cards. 


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7 
Pharmaceutical information 
YF476 (IND # 107354, IND Sponsor: Trio Medicines Ltd)   
7.1 
Active pharmaceutical ingredient (API):  YF476 
International non-proprietary name (INN):  netazepide 
Structural formula: 
 
Chemical formula: (R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5- 
(2-pyridyl)-1H -1,4-benzodiazepin-3-yl]-3-(3-methylaminophenyl)urea   
Molecular formula:  C28H30N6O3 
Molecular weight:  498.58 
Description: white crystalline powder 
Purity: 99.9% 
Optical rotation: [α]D20 = +124 ° (Acetone, 0.5%) 
Acid dissociation constant (pKa): 2.53, 4.59 
Hygroscopicity: <0.3% at room temperature, and 93% relative humidity (7 days) 
Stability: Chemically stable for at least 9.5 years at room temperature, protected from 
light.  
7.2 
Formulated intermediate:  spray-dried YF476  
YF476 and hydroxypropylmethylcellulose (HPMC) (YF476:HPMC ratio 1:3.5) were 
dissolved in dichloromethane/isopropanol (7:2 v/v).  The solution was spray-dried, and 
at all stages of production, the solution and resulting spray-dried powder were shielded 
from light.  The formulated intermediate was characterised as follows. 
Description: white to off-white powder 
Structural configuration:  amorphous by x-ray powder diffraction 
YF476 purity:  ≥95% of the theoretical purity (adjusted for water) 
Water content:  ≤7.5% 


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Residual dichloromethane:  ≤2000 ppm 
Residual isopropanol:  ≤10000 ppm 
Stability:  Chemically and physically stable at 2–8 °C for at least 4 years.  Stability 
studies are ongoing.   
7.3 
Final formulation 
The co-formulation of spray-dried YF476 and HPMC is blended with starch, and placed 
into hard gelatine capsules at the Hammersmith Medicines Research (HMR) Pharmacy.  
Each capsule contains 25 mg YF476.  Matching placebo capsules, containing starch 
only, will also be prepared.  The sponsor will provide a certificate of analysis for the test 
product.  
7.4 
Packaging and labelling 
For the CUMC, HMR Pharmacy will provide bulk supplies of investigational medicinal 
product (IMP) in accordance with The Rules Governing Medicinal Products in the 
European Union, Volume 4:  Good Manufacturing Practice (GMP) 19, and with HMR’s 
Manufacturing Authorisation for IMPs (MIA(IMP)).  The trial medication will be 
dispensed and labelled by the site pharmacy in accordance with United States Code of 
Federal Regulations governing labelling of investigational new drugs (21CFR 312.6).   
For NIHR CIW, the trial medication will be packaged and labelled by the HMR 
Pharmacy, in accordance with The Rules Governing Medicinal Products in the European 
Union, Volume 4:  Good Manufacturing Practice (GMP)19], and with HMR’s 
Manufacturing Authorisation for IMPs (MIA(IMP)).  The IMP labels will include the 
information required by Annex 13 to GMP.  
7.5 
Storage, accountability and dispensing of study medication 
The HMR Pharmacy will dispatch the study medication to the site Pharmacy by secure 
temperature-controlled courier after ethical and regulatory approvals of the trial have 
been obtained.  The site Pharmacy will record and acknowledge in writing the receipt of 
all supplies of study medication.  The study medication will be stored securely at 2 to 
8°C, protected from moisture and light, accessible only to those individuals authorised 
by the investigator to dispense the IMP.   
Each site pharmacy will dispense study drug (or placebo) for trial patients in accordance 
with the randomization code.  The labels on bottles given to trial patients will not 
indicate whether the capsules are study drug or placebo, so as to maintain blindness 
among the study investigators and study patients.   
The site Pharmacy will maintain a careful record of the inventory and disposition of all 
medication received from the HMR Pharmacy. The site Pharmacy will maintain 
adequate records of receipt, dispensing and final disposition of YF476 and placebo. The 
receipt record will include from whom the study medication was received and to whom 


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study medication was distributed, date, quantity and batch or lot number. The dispensing 
record will be blinded, and will include quantities and the dates YF476 or placebo was 
dispensed to and returned by each participant. Dr. Julian A. Abrams will be responsible 
for study medication accountability for participants at CUMC and Prof. Rebecca 
Fitzgerald will be responsible for study medication accountability for participants at 
NIHR CIW. 
At the end of the trial, all unused study medication supplies will be returned to the HMR 
Pharmacy. 
7.6 
Registration and randomization 
• 
A member of the HMR Statistics and Data Management Department will generate 
a randomization list for each site.  Patient numbers will be allocated to eligible 
patients immediately before the EGD and biopsy at Visit 2 (Baseline).  Patients 
enrolled at CUMC will be allocated patient numbers 01–24.  Patients enrolled at 
NIHR CIW will be allocated patient numbers 1001–1024.  The lists are 
independent of each other.  At both sites, patients on PPI once daily will be given 
the next available number from the top of the list, and patients on PPI twice daily 
will be given the next available number from the bottom of the list.   
• 
At each site, the site coordinators will maintain a site-specific list of participants, 
including patient codes, start date, and duration of treatment.  Every time a patient 
is recruited at one of the sites, the coordinator for that site will inform the chief 
investigator (if applicable) and the coordinator for the other site.  It is the chief 
investigator’s responsibility to ensure that the total number of study patients does 
not exceed the target. 
The randomization list will specify whether the patient receives a dose of YF476 or 
placebo.  Fixed allocation randomization will be performed, with equal allocation (1:1) 
between the 25 mg YF476 and placebo groups. Blocked randomization will be used. 
Randomization will be stratified by PPI dose and by site.  The site pharmacy will 
dispense YF476 or placebo according to the randomization list.  The study investigators 
and the study patients will remain blinded.  
7.7 
Blinding and unblinding methods 
• 
Bottles containing study medication for individual patients will not be labelled 
with any information to indicate whether the capsules are YF476 or placebo. 
• 
Patients will be blinded to study treatment.  
• 
One member of the HMR Statistics and Data Management Department will not be 
blinded.  That person will generate the randomization code. The Columbia 
University biostatistician will be blinded. 
• 
All Investigators will be blinded to study treatment.  


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• 
For each site, there will be a blinded monitor and an unblinded monitor.  The 
unblinded monitor will review dispensing records at the site Pharmacy. 
• 
Pharmacy staff will not be blinded. 
• 
The Data and Safety Monitoring Board will not be blinded. 
• 
The blind will be broken by the investigator or delegate in the following 
circumstances: 
o 
If unblinding is required in the interest of the safety of a subject, an 
investigator will discuss the matter with the sponsor before opening the 
individual code-break envelope for that subject.  In a medical emergency, the 
principal investigator or delegate may open the individual code-break 
envelope for that subject without prior consultation with the sponsor.  In that 
event, the principal investigator or delegate will notify the sponsor as soon as 
possible that the randomisation code has been broken for the subject. 
o 
The blind will be broken for the entire study population at the completion of 
the study, after the statistical analysis plan (SAP) has been signed and the 
database has been locked. 
7.8 
YF476 destruction/disposal 
At the completion of investigation, the site Pharmacy will return all unused YF476 and 
placebo capsules to the HMR Pharmacy.  


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8 
Clinical evaluations and procedures 
8.1 
 Schedule of events 
 
Baseline Testing/ 
Prestudy Evaluation 
Study treatment 
Follow-up period 
 
Visit 11 
Visit 2 
Week 6 
visit  
Week 12 
visit  
Follow–up 
Evaluation/ Procedure 
Registration 
Randomization, 
& Endoscopy 
Week 6 
Week 12 
Follow Up Visit 4 weeks after 
stopping treatment 
Informed consent 
X 
 
 
 
 
Assess eligibility 
X 
 
 
 
 
Central pathology review2 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Physical exam 
X 
 
 
 
 
Vital signs 
X 
X5 
X 
X 
X 
Height and weight/ 
waist circumference 
X 
 
 
 
 
Smoking history 
X 
 
 
 
 
Medication history 
X 
 
 
 
 
Blood and urine collection 
for safety tests 
X 
X5 
X 
X 
X 
Urine pregnancy test4 
X 
X5 
X 
X 
X 
ECG 
X 
X5 
X 
X 
X 
Blood for YF476 assay3 
 
 
X 
X 
 
Blood for assay of fasting 
serum gastrin and plasma 
CgA, and serum for storage 
 
X 
X 
X 
X 
EGD (Upper GI endoscopy) 
 
X 
 
X 
 
Biopsies 
 
X 
 
X 
 
Concomitant medication 
assessment 
 
X 
X 
X 
 
Dispense study medication 
 
X 
X 
 
 
Collect study medication 
 
 
X 
X 
 
Compliance assessment 
 
 
X 
X 
 
AE assessment 
 
X 
X 
X 
X 
1. There may be up to a 2-week gap between Visits 1 and 2. 
2. Review of patient’s history to obtain histological confirmation of the patient’s eligibility to participate in the trial. 
3. Plasma YF476 assay: patients fast overnight.  For the Week 6 and 12 visits, patients bring their container of study 
medication with them, and take study medication only after collection of blood samples for trough YF476, fasting serum 
gastrin and CgA levels, and endoscopy (if applicable).  Patients stay for 1 h after dosing for collection of a blood sample 
for peak YF476 level.  
4. Pre-menopausal women only. 
5. These tests may be omitted if Visit 2 occurs on the same day as Visit 1. 


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8.2 
Baseline testing and pre-study evaluation 
Visit 1: registration 
Patients will attend the clinic and complete the informed consent form.   The investigator 
will complete the following evaluation for each patient, and enter the data from this 
visit, and all subsequent visits, on the appropriate page of the CRF: 
• review of most recent endoscopy (within 3 years) to confirm diagnosis of Barrett’s 
esophagus with no dysplasia; 
• review of medication history to determine that participants meet the inclusion 
criteria (daily PPI use for at least the most recent 12 months before study entry, and 
stable PPI dose for at least the most recent 3 months before study entry); 
• medical history, physical examination, ECG and vital signs; 
• blood and urine samples for laboratory safety tests; and 
• urine pregnancy test (pre-menopausal women only).  
Visit 2: baseline 
Visit 2 may occur on the same day or up to 2 weeks after Visit 1.  The patient will fast 
for 6 hours before the study visit.  The investigator will complete the following 
evaluation for each patient, and enter the data from this visit, and all subsequent visits, 
on the appropriate page of the CRF.  If Visits 1 and 2 are combined, only 1 blood sample 
(safety tests, fasting serum gastrin, plasma CgA and serum for storage) and 1 urine 
sample will be taken, and ECG, vital signs and pregnancy tests will be done only once. 
• blood and urine samples for laboratory safety tests, urine pregnancy test (pre-
menopausal women only), ECG and vital signs; 
• blood samples for fasting serum gastrin, plasma CgA and serum for storage; 
• endoscopy and biopsies; and 
• randomization to 25 mg YF476 or placebo, and dispensing of study medication (a 
42-day supply, plus overage: 1 bottle of 25 mg YF476 or placebo containing 
46 capsules). 
The investigator will then: 
• give the patient a diary card; 
• tell the patient to start taking their study medication the day after Visit 2; 
• remind the patient to fast before the Week 6 visit (6 weeks after starting study 
medication); and 
• remind the patient not to take their study medication at home on the day of the 
Week 6 visit, but instead to bring their container of study medication with them to 
the visit, and take their dose at the clinic, after the fasting blood tests.  


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8.3 
Evaluations during study treatment 
Week 6 visit: after 6 weeks of study treatment 
The investigator will: 
• check that the patient has fasted; 
• collect the diary card, and issue a new one; 
• check the diary card for compliance with treatment, and for adverse events and 
concomitant medication; 
• collect the study medication bottle and assess compliance; 
• do an ECG and vital signs; 
• take blood and urine for laboratory safety tests and urine pregnancy testing 
(pre-menopausal women only); 
• take blood samples for fasting serum gastrin, plasma CgA, trough YF476 
concentration and serum for storage; 
• after taking the fasting blood samples, give the patient their dose of study 
medication, wait 1 h, then collect blood for assay of peak concentration of YF476; 
• issue a new container of study medication, to be taken as before; 
• remind the patient to fast before the next visit; and 
• remind the patient not to take their study medication at home on the day of the 
Week 12 visit, but instead to bring their container of study medication with them to 
the visit, and take their dose at the clinic, after the fasting blood tests and 
endoscopy.  
8.4 
Evaluations at completion of study treatment 
Week 12 visit: after 12 weeks of study treatment   
The investigator will: 
• check that the patient has fasted; 
• collect the diary card; 
• check the diary card for compliance with treatment, and for adverse events and 
concomitant medication; 
• collect the study medication bottle and assess compliance; 
• do an ECG and vital signs; 
• take blood and urine for laboratory safety tests and urine pregnancy testing (pre-
menopausal women only); 


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• take blood samples for fasting serum gastrin, plasma CgA, trough YF476 
concentration and serum for storage; 
• do an endoscopy and biopsies; and 
• after the endoscopy, give the patient their dose of study medication, wait 1 h, then 
collect blood for assay of peak concentration of YF476.  
8.5 
Post-treatment follow-up period 
Follow-up: 4 weeks after stopping study treatment  
The patient will return 4 weeks after the end of the treatment period.  The investigator 
will: 
• assess the patient for any delayed adverse events; 
• do an ECG and vital signs; 
• take blood and urine for laboratory safety tests and urine pregnancy testing (pre-
menopausal women only); and 
• take blood samples for fasting serum gastrin, plasma CgA, and serum for storage. 
8.6 
Flexibility of study days 
There will be a ±4 day window for clinic visits.   
8.7 
Withdrawal of patients from the trial 
 
Termination of study medication 
8.7.1
Patients may stop taking study medication for the following reasons.  
• 
When a patient has completed the protocol-prescribed treatment, we will not 
provide any further study medication. 
• 
If a patient has an adverse event, grade 2 or greater (see section 11.1), the patient 
or investigator may choose to terminate study treatment. 
• 
A patient might be non-compliant and stop taking the protocol-prescribed 
treatment; or the investigator may choose to terminate study treatment.  
• 
The investigator may terminate study treatment because of a medical 
contraindication. 
• 
The investigator may terminate study treatment because of evidence of serious 
interactions with medications metabolized by CYP3A4/5 or CYP2C8, (see 
Appendix B for list of relevant medications).  
In all cases listed above, patients will continue to be followed, if possible, for safety 
reasons and in order to collect endpoint data according to the schedule of events.  


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Termination of study participation 
8.7.2
Patients may go ‘off-study’ (ie leave the study with no follow-up possible) for the following 
reasons.  
• 
The protocol treatment and any protocol-required follow-up period is completed.  
• 
If a patient has an adverse event, grade 2 or greater (see section 11.1), the patient 
may choose to terminate study participation.  
• 
A patient might be lost to follow-up, if the investigator is unable to establish 
contact with him or her. 
• 
A patient might be non-compliant and not attend the clinic visits (including the 
follow-up visit).  
• 
The investigator may terminate study participation because of a medical 
contraindication. 
• 
A patient may withdraw his or her consent to participate in the study.  
• 
Determination of ineligibility, not discovered before enrollment.  In particular; 
patients will be withdrawn from the study if their baseline endoscopy (Visit 2): 
o does not show any intestinal metaplasia; or 
o biopsies are read as indefinite for dysplasia, low grade dysplasia, high grade 
dysplasia, or adenocarcinoma. 
• 
Death.  
8.8 
Study termination 
Enrollment of patients onto the study will be terminated when at least 20 participants 
have completed 12 weeks of treatment, undergone a post-treatment endoscopy, and 
returned for the follow-up visit (4 weeks after stopping study medication).  The study 
will end when the analysis of all biopsy samples is complete.  
9 
Criteria for evaluation and endpoint definition 
9.1 
Primary endpoint 
• 
Change in Ki67 expression (∆Ki67) between baseline (Visit 2) and the Week 12 
visit 
9.2 
Secondary endpoints 
• 
Biomarkers 
o 
Change from baseline at Week 12 in biomarkers potentially associated with 
esophageal adenocarcinoma, in particular:   
 Change in CCK2R mRNA levels  
 Change in DCAMKL1 expression  


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 Change in DCAMKL1 mRNA levels Change in COX-2 mRNA levels 
 Change in p53 expression  
o 
Gene expression will be measured using RNA-Seq. Further examination of 
any changes in expression from baseline may be done using qRT-PCR and 
IHC.  
o 
Reduction in PPI-induced increase in plasma CgA 
o 
Increase in PPI-induced hypergastrinaemia 
• 
Safety 
o 
Vital signs, ECG, physical examination, laboratory safety tests: blood tests: 
red blood cells (RBC), haemoglobin, haematocrit, platelets, white blood cells 
(WBC, differential: neutrophils, bands, lymphocytes, monocytes, 
eosinophils, basophils), sodium, potassium, magnesium, chloride, 
bicarbonate, creatinine, serum glucose, blood urea nitrogen (BUN), alkaline 
phosphatase, lactate dehydrogenase (LDH), serum glutamic-oxaloacetic 
transaminase/aspartate amino transferase (SGOT/AST), serum glutamic-
pyruvic transaminase/ alanine aminotransferase (SGPT/ALT), total bilirubin, 
total protein, albumin, calcium, amylase, lipase; and urine tests: pH, specific 
gravity, protein, glucose, ketones, blood. 
o 
Change in histology 
• 
Tolerability:  assessment of adverse events. 
• 
Pharmacokinetics:  through and peak concentration of YF476 
10 
Methods 
10.1 
Methods for clinical procedures 
Upper endoscopy with biopsies will be performed at baseline (Visit 2) and at the 
Week 12 visit, after 12 weeks’ treatment with study medication.  Patients will fast before 
the endoscopy, and will need to come accompanied to the site endoscopy suite, 
according to hospital practice and regulations.  Upon arrival at the endoscopy suite, a 
peripheral intravenous line will be inserted.  Informed consent will be obtained for the 
endoscopy prior to starting the procedure.  In the procedure room, a local anaesthetic 
(xylocaine) will be sprayed in the back of the mouth to diminish the gag reflex.  
Subsequently, intravenous medication (specifically, midazolam, fentanyl, and/or 
propofol) will be administered in order to achieve moderate sedation.  Once the patient 
has been sedated, the upper endoscope will be inserted into the esophagus and advanced 
to the second portion of the duodenum.  The following represents standard clinical care 
for Barrett’s esophagus: 1) the area of Barrett’s esophagus will be carefully inspected for 
any focal nodules or mucosal irregularities that could represent the presence of 
dysplasia; 2) if any such abnormalities are noted, then targeted biopsies of these areas 
will be taken; 3) irrespective of the presence of such abnormalities, random 4-quadrant 
biopsies will be taken every 1–2 cm along the length of BE.  For study purposes, 6 
additional biopsies will be taken and snap frozen for RNA-Seq and qRT-PCR analyses: 
GE junction (top of the gastric folds; 2 biopsies); mid-Barrett’s segment (2 biopsies); 


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normal-appearing esophageal mucosa (2 cm above the maximal extent of BE; 2 
biopsies).  
10.2 
Rationale for laboratory methods 
In general, it is desirable to perform quantitative analyses of biomarkers, as achieved by 
using quantitative real-time PCR (qRT-PCR), in contrast to qualitative or 
semi-quantitative immunhistochemical analyses (IHC).  Quantitative analysis allows for 
detection of small differences between different tissue samples.  However, qRT-PCR 
does not discriminate between different cell types within a particular tissue sample, 
whereas IHC allows for visual assessment of the type and location of cells that express a 
biomarker of interest. We will also employ RNA-Seq (RNA sequencing) to identify 
changes in gene expression caused by treatment with netazepide in Barrett’s esophagus 
tissue.   
• 
IHC for Ki67 is a robust marker of ongoing proliferation, and has been reliably 
and reproducibly used to evaluate cell type-specific evaluation.  Quantitative 
assessment of the number of proliferating (Ki67+) epithelial cells is easiest and 
most reliable in IHC. 
• 
For the assessment of CCK2R expression in human esophageal tissue, qRT-PCR 
seems to be the best method, as IHC with various antibodies has proven to be 
unreliable and non-specific.  
• 
Biologically relevant COX-2 expression can be quantitatively assessed using 
qRT-PCR, but cannot be detected by IHC.  
• 
DCAMKL-1 is a putative marker of intestinal stem cells.  In order to analyze 
expansion of these putative stem cells in the development of Barrett’s esophagus, 
it is important to get an impression of the precise location of these cells.  
Therefore, both qRT-PCR and IHC will be used to analyze DCAMKL-1 
expression. 
• 
Changes in the levels of p53 protein expression can be detected best with IHC, as 
mRNA levels of p53 do not differ very much despite altered protein expression.  
The function of p53 is more likely determined by protein stability.  
• 
RNA-Seq is an untargeted approach to studying changes in gene expression; this is 
particularly valuable in the current study, as the effects of gastrin receptor 
antagonism in Barrett’s esophagus tissue with regard to esophageal 
adenocarcinoma prevention are unknown.   
In order to identify other key pathways impacted by gastrin receptor antagonism in BE, 
we will do RNA-Seq to assess the difference in gene expression between the netazepide 
and placebo groups.  In addition to the original focus aimed at assessing expression of a 
very limited number of genes, this analysis will serve to identify affected pathways in 


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the progression from Barrett’s esophagus to esophageal adenocarcinoma, potential 
prognostic markers, and possible new chemopreventive targets. 
All the above described methods have been performed in previously published studies 
(by the chief investigator’s group and others) as well as in Dr. Timothy Wang’s 
laboratory in a new mouse model of Barrett’s esophagus and adenocarcinoma.  
Therefore, the investigators will be able to compare the achieved data with previously 
published and unpublished results from the chief investigator’s laboratory and other 
groups.  
10.3 
Laboratory methods 
 Laboratories 
10.3.1
All tissue biomarker analyses will be performed in the laboratory of Dr. Timothy Wang 
(Columbia University, New York, NY).  Histological review of specimens, including 
IHC assessment of Ki67, p53, and DCAMKL1 expression, will be performed by Dr. 
Antonia Sepulveda (Columbia University, New York, NY).  Routine testing of blood 
and urine specimens will be performed locally. 
 Collection and handling procedures 
10.3.2
• 
Collection and analysis of tissue for RNA-Seq, IHC and qRT-PCR 
RNA-Seq and qRT-PCR.  Routine endoscopic biopsies (4 quadrant biopsies every 2 cm 
along the length of BE) will be taken for clinical purposes and placed in formalin.  The 
formalin-fixed biopsies taken at CUMC will be submitted to the Columbia University 
Department of Pathology (CUDP).  The formalin-fixed biopsies taken at NIHR CIW will 
be stored there; slides of the biopsies will be sent by courier to CUDP at the end of the 
study, or as agreed between the investigators and sponsor.  The respective Departments of 
Pathology will store the paraffin-embedded samples as per usual practice. Histologic 
analysis of biopsies from both study sites will be done at CUDP.  As per clinical practice, 
these biopsies will be reviewed to assess the presence of dysplasia.  Six additional 
biopsies (from each endoscopy; 2 biopsies each from GE junction, mid-Barrett’s segment, 
and normal esophagus) will be taken for study purposes, placed in Qiagen Allprotect™ 
tissue reagent, and then stored at –80°C for future RNA-Seq and qRT-PCR analysis. The 
freezers for storing these samples are located in the laboratory of Dr. Timothy Wang at 
Columbia University.  Samples taken at Cambridge University will be stored in freezers 
in Prof. Rebecca Fitzgerald’s laboratory at the MRC Cancer Unit, University of 
Cambridge, until dispatch to Columbia University. 
IHC analyses.  Additional sections will be cut from paraffin-embedded endoscopic 
biopsies for study purposes.  Slides from NIHR CIW will be sent by courier to Columbia 
University at the end of the study, or as agreed between the investigators and sponsor. 


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Ki67 expression will be assessed by IHC from esophageal biopsies of Barrett’s 
esophagus.  Paraffin-embedded biopsies from the most distal esophageal biopsies 
containing intestinal metaplasia will be immunostained for Ki67.  Ki67 index will be 
calculated as:  (# crypt epithelial cells with positive nuclear staining for Ki67) / (# BE 
crypt cells counted).  Five representative crypts with goblet cells will be evaluated from 
five separate fields at 100x magnification.  ∆Ki67 for YF476 and placebo arms will be 
compared.  The pathologist evaluating Ki67 staining will be blinded to both treatment arm 
and timing of endoscopy (ie pre- or post-treatment). 
• 
Collection and processing of blood samples for laboratory safety tests: 
20 mL of blood will be collected.  10 mL (one purple top, one gold top tube) will be 
used for routine measurements.  The other 10 mL (one purple top, one gold top tube) 
will be processed for separate storage of serum, plasma, and Buffy coats at –80°C.  
o 
Safety tests: 
 haematology:  Hb, RBC, haematocrit, WBC and differential, and 
platelets;   
 biochemistry: creatinine,  total bilirubin, BUN, LDH,  total protein, 
albumin, alkaline phosphatase, AST, ALT, glucose, potassium, sodium, 
calcium, magnesium, chloride, amylase and lipase. 
Blood specimens will be collected when the patient is fasting.  If the blood collection 
occurs on the day of the endoscopy, the blood will be collected prior to the endoscopy.   
• 
Collection of urine for laboratory safety tests 
A routine urine sample will be collected for standard urinalysis: dipstick test:  protein, 
blood, ketones, glucose, specific gravity, pH; microscopy if the result of the dipstick test 
for protein or blood is abnormal; and pregnancy test (pre-menopausal women only).  
• 
Collection and processing of blood samples for serum gastrin and stored serum 
Venous blood for serum gastrin assay and stored serum (2 × 2.5 mL) will be collected 
into polypropylene tubes and will be allowed to clot at room temperature for at least 
20 min.  After clotting, the tubes will be centrifuged at about 1500 G for 10 min at 4°C, 
and the serum transferred to smaller tubes in equal aliquots then stored at –80°C before 
shipment to the HMR Analytical Laboratory, Cumberland Avenue, Park Royal, London, 
NW10 7EW.  Shipment of serum samples for gastrin assay and storage will be agreed 
between the investigator and sponsor.  Serum will be stored by the HMR laboratory for 
assay of trial-related markers only, which will be decided on at a later date.   
• 
Collection and processing of plasma for CgA assays 
4 mL venous blood will be collected into an EDTA tube and centrifuged at about 
1500 G for 10 minutes at 4°C.  2 equal aliquots of plasma will be transferred to 
polypropylene tubes, and stored at –80°C, before shipment to the HMR Analytical 
Laboratory, Cumberland Avenue, Park Royal, London, NW10 7EW.  Shipment of 


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plasma samples for CgA assay will be agreed between the investigator and sponsor.  All 
sample handling materials will be provided by the HMR Analytical Laboratory. 
• 
Gastrin and CgA assays   
Serum gastrin and plasma CgA will be measured by the HMR Analytical Laboratory 
using commercially available assays.  The analytical laboratory may not analyse samples 
collected from patients with HIV.  
• 
Collection and processing of blood samples for YF476 PK 
YF476 is light sensitive, so blood samples (4 mL) will be taken into foil-wrapped or 
amber lithium heparin tubes and immediately placed on ice.  Samples will be 
centrifuged at about 1500 G for 10 minutes at 4°C.  Plasma will be transferred to foil-
wrapped or amber polypropylene storage tubes.  Plasma samples will be stored at –80°C 
within 90 minutes after collection, and stored in darkness until dispatch.  Samples will 
be sent to the HMR laboratory, Cumberland Avenue, London, NW10 7EW for 
reconciliation before being sent to Analytical Services, St George’s Hospital for analysis 
of YF476 by the method of Redrup et al 2002.18 
• 
All specimens will be labelled with a code assigned to the study patient.  
• 
A separate tracking sheet will be maintained for each study patient.  All specimens 
will be logged on these sheets, including date and time of collection. 
• 
Samples will be kept in storage for the duration of the study.  Unused samples will 
be kept in storage for an additional three years prior to disposal. 
The analytical laboratory may not analyse samples collected from patients with HIV. 
11 
Reporting adverse events 
Definition:  an adverse event (AE) is any untoward medical occurrence in a study 
participant.  An AE does not necessarily have a causal relationship with the treatment or 
study participant.  An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with participation in a study, whether or not related to that participation.  This includes 
any deaths that occur while a participant is on a study. 
A list of adverse events that have occurred or might occur can be found in Section 4.3, 
and in the Investigator Brochure.   
11.1 
Adverse events (AEs) 
• 
Reportable adverse events 
All adverse events that occur after the informed consent is signed will be recorded 
on the adverse event CRF whether or not related to study medication. 


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• 
AE data elements  
o 
AE reported date 
o 
AE Verbatim Term 
o 
SOC (System Organ Class from MedDRA) 
o 
Common Terminology for Adverse Events v4.0 (CTCAE) AE term 
o 
Event onset date and event ended date 
o 
Severity grade 
o 
Attribution to study medication (relatedness) 
o 
Whether or not the event was reported as a Serious Adverse Event (SAE) 
o 
Whether or not the patient dropped due to the event 
o 
Action taken with the study medication 
o 
Outcome of the event 
o 
Comments 
• 
Severity of AEs 
Adverse events will be identified using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0.  The CTCAE provides descriptive 
terminology and a grading scale for each adverse event listed.  A copy of the 
CTCAE can be found 
at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc
_40 
AEs will be assessed according to the CTCAE grade associated with the AE term.  
AEs that do not have a corresponding CTCAE term will be assessed according to 
the general guidelines for grading used in the CTCAE v4.0. as stated below.  
• 
CTCAE v4.0 general severity guidelines  
(from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-
15_QuickReference_8.5x11.pdf) 


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Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental 
ADL*. 
3 
Severe 
Severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care 
ADL**. 
4 
Life-
threatening 
Life-threatening consequences; urgent intervention 
indicated. 
5 
Fatal 
Death related to AE. 
• 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden. 
• 
Assessment of relationship of AE to treatment 
The possibility that the adverse event is related to study medication will be 
classified as one of the following:  not related, unlikely, possible, probable, 
definite.  
• 
Follow-up of AEs 
All AEs, including abnormalities that in the opinion of the investigator are 
clinically significant, will be followed according to good medical practices and 
documented as such. 
11.2 
Serious adverse events (SAEs) 
 Definition 
11.2.1
ICH Guideline E2A and Fed. Reg. 62, Oct. 7, 1997 define serious adverse events as 
those events, occurring at any dose, which meet any of the following criteria: 
• 
Results in death.  


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• 
Is life threatening (Note: the term life-threatening refers to an event in which the 
patient was at 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 hospitalization or prolongation of existing hospitalization.  
• 
Results in persistent or significant disability/incapacity.  
• 
Is a congenital abnormality/birth defect.  
• 
Events that may not meet these criteria, but which the investigator finds very 
unusual and/or potentially serious, will also be reported in the same manner. 
  Reporting SAEs 
11.2.2
• 
The investigators will report SAEs on the SAE form.  
• 
The Sponsor representative and the Data Safety Monitoring Board (DSMB) 
representative will be contacted within 24 hours of knowledge of the event.   
• 
The following information will be included when informing the Sponsor and the 
DSMB representative: 
o 
when the SAE occurred 
o 
when the SAE report will be available 
o 
Name of reporter 
o 
Call back phone number (if primary contact is by phone) 
o 
Protocol number 
o 
Description of the SAE, including attribution to drug  
• 
The investigators will FAX (or email a scan of) written SAE reports to the Sponsor 
and DSMB within 48 hours of learning of the event using the paper SAE form. 
• 
The Sponsor will determine which SAEs require submission to the competent 
authorities. 
• 
The Lead Organization and all Participating Organizations will comply with 
applicable regulatory requirements related to reporting SAEs to the IRB and/or 
REC.  
• 
Follow-up of SAE:  site staff will send follow-up reports as requested when 
additional information is available.  Additional information will be entered on the 
SAE form in the appropriate format.  Follow-up information will be sent to the 
Sponsor and DSMB as soon as available. SAEs will be followed by the study staff 
until resolved. 


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12 
Data management and quality assurance 
Patient data will be collected using protocol-specific case report forms (CRF).  These 
will be designed and produced by HMR.  The final version will be approved by the 
sponsor.  All data will be entered legibly in black or blue ink with a ball-point pen.  If an 
error is made, the error will be crossed through with a single line in such a way that the 
original entry can still be read.  The correct entry will then be clearly inserted and the 
alterations will be initialled and dated by the person making the alteration.  Overwriting 
or use of correction fluid is not permitted. 
To preserve confidentiality, the CRFs will not bear the subject’s name.  The subject’s 
initials, date of birth, and subject number will be used for identification. 
It will be the responsibility of the investigator to ensure the accuracy of all data entered 
in the CRFs. 
The data will be securely stored by the investigator.  After the CRFs have been signed 
off by the principal investigator, the original NCR copies will be sent to the Data 
Management department at HMR, where they will be securely stored on behalf of the 
sponsor. 
Data will be double-entered into a clinical database management system (ClinPlus 
Version 3.3), which is based on SAS® Version 9.2.  Edit checks and generation of 
queries will be done in ClinPlus.  Tabulations and listings will be produced using 
validated, trial-specific SAS® programs. 
Data will be checked by the HMR Quality Assurance (QA) Department.  In addition, the 
HMR QA Department will audit the trial report; that audit will include checks to ensure 
that statistical output is correctly reproduced in the report. 
Source documents.  Before the start of the study, the sponsor and investigator(s) will 
sign an agreement listing the source documents to be used in this trial.  The CRF will be 
source for the following datapoints: heart rate and blood pressure. 
12.1 
Data and safety monitoring plan 
The Data Safety Monitoring Board (DSMB) will review all SAE forms as well as all 
AEs.  If additional information is required, the DSMB will request that information from 
the PI.  The DSMB will review reported AEs at regular meetings and provide written 
reports to the PI.  The reports will contain written information regarding findings for the 
trial as a whole related to cumulative toxicities observed and any relevant 
recommendations related to continuing, changing, or terminating the trial.  
Members of the DSMB are as follows: 
Benjamin Lebwohl (Columbia University, Division of Digestive & Liver Diseases) 
Lorna Dove (Columbia University, Division of Digestive & Liver Diseases) 
Zhezhen Jin (Columbia University, Department of Biostatistics) 
Hugo Ford (Cambridge University, Cancer Services) 


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12.2 
Sponsor or regulatory monitoring 
Trio Medicines, Ltd. (or their designee) or the relevant regulatory authorities may 
monitor/audit various aspects of the study. These monitors will be given access to 
facilities, databases, supplies and records to review and verify data pertinent to the 
study.  
12.3 
Record retention 
The sponsor and both principal investigators will keep the following in a trial master 
file. 
• All the essential documents required by GCP 
• All data generated during the study 
All documents will be stored such that they are readily available for inspection at the 
request of the sponsor or a regulatory authority.  Any transfer of ownership of the 
investigator’s data or documents will be documented, and the sponsor will be informed. 
For at least 15 years after the end of the study, and at least 2 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 have elapsed 
since the formal discontinuation of clinical development of the study medication: 
• HMR will ensure that the sponsor’s master file and original copies of CRFs will be 
archived in a secure place; and 
• the investigators will ensure that the investigator’s master file, and original source 
documents (other than CRFs) will be archived in a secure place.   
12.4 
Clinical Trial Agreement  
The sponsor and the investigators will sign an agreement outlining each party’s 
obligations with respect to the trial. 
Each party will allow the other 30 days to comment before any results are submitted for 
publication, or 10 days prior to an abstract presentation.  Authorship should reflect work 
done by the investigators and personnel of the sponsor, in accordance with generally 
recognized principles of scientific collaboration. 
13 
Statistical methods 
13.1 
Analysis Sets 
The safety analysis set will include all patients who are randomized and receive at least 
one dose of study medication.  In this population, treatment will be assigned based upon 
the treatment patients actually receive regardless of the treatment to which they were 
randomized. 
The pharmacokinetic analysis set will include all patients who receive at least one dose 
of study medication, and yield at least one plasma concentration for YF476. 


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The Intent-to-Treat (ITT) analysis set will include all randomized patients who receive 
at least one dose of study medication and have at least one post-baseline assessment.  In 
this population, treatment will be assigned based upon the treatment to which patients 
were randomized regardless of which treatment they actually received. 
A per-protocol analysis will also be completed. 
13.2 
General Statistical Considerations 
The null hypothesis is that there is no difference between YF476 and placebo in the 
treatment of patients with Barrett’s esophagus, the alternative hypothesis is that there is 
a difference between the treatments.  Statistical significance will be defined as p≤0.05. 
Statistical analysis will be done by HMR.  The statistical package SAS (version 9.2) will 
be used to produce all summary tables and data listings. 
For the data analysis, missing or dropout data will not be imputed; analyses will be 
performed only on observed data.  In this study, there will be no significance level 
adjustment for multiplicity. 
Quantitative data will be tabulated with descriptive summary statistics: arithmetic mean, 
standard deviation, median, minimum and maximum values, and number of 
observations.  Geometric mean and geometric CV% will be provided for Cmax and 
Ctrough.   For categorical data, frequency tables will be provided. 
A detailed Statistical Analysis Plan (SAP) describing the methodology to be used in the 
final analysis will be prepared by the HMR Statistics and Data Management Department 
after completion of the final protocol.  Any deviations from the planned statistical 
analyses in the protocol will be fully described in the SAP. 
13.3 
Study Population Data 
The safety population will be summarized for demographic characteristics, and will be 
presented.  Continuous demographic variables (age, weight, height, and BMI) will be 
summarised with descriptive statistics.  Categorical demographic variables (gender, race, 
and ethnicity) will be summarised with frequency counts and corresponding percentages. 
13.4 
Efficacy Analyses 
All efficacy analyses, summaries and listings will be generated using the efficacy 
analysis set. 
Primary efficacy variables are: 
• 
Change in Ki67 expression (∆Ki67) 
Secondary efficacy variables are:  


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• 
Changes in gene expression in BE tissue (measured by RNA-Seq).  
• 
Change in CCK2R mRNA levels (measured by qRT-PCR) 
• 
Change in DCAMKL1 expression (measured by IHC) 
• 
Change in DCAMKL1 mRNA levels (measured by qRT-PCR) 
• 
Change in COX-2 mRNA levels (measured by qRT-PCR) 
• 
Change in p53 expression (measured by IHC) 
• 
Change in serum gastrin and plasma CgA between baseline and Visit 5 
For all efficacy variables listed above, individual values will be presented by patient and 
summarised by visit.   
The primary endpoint (Change from baseline (Visit 2) in Ki67 expression (∆Ki67)) will 
be summarised using descriptive statistics.  The primary analysis for the primary 
endpoint will use two sample t-tests comparing between treatment groups.  Nominal 
p-value and 95% confidence intervals for treatment difference will be reported.   
To evaluate the robustness of the primary analysis, the following sensitivity analysis will 
also be performed:  
Baseline Adjusted Analysis: this sensitivity analysis will use an analysis of covariance 
model with the primary endpoint as the dependent variable, treatment group as a factor 
and baseline (Visit 2) as a covariate.  Adjusted least square means and corresponding 
95% confidence interval will be reported. 
Serum gastrin and chromogranin A (CgA) will be measured at baseline (Visit 2) and at 
Weeks 6 and 12.  Analyses will be performed to determine whether there is a correlation 
between baseline gastrin and subsequent ∆Ki67.  YF476 assays will be performed at 
Weeks 6 and 12. 
Analysis of the secondary endpoints will be similar to the primary analysis. No 
sensitivity analysis is planned for these endpoints.  
13.5 
Pharmacokinetic Analyses 
The statistical analysis of pharmacokinetic parameters will be done by the HMR 
Statistics and Data Management Department. 
All pharmacokinetic analyses, summaries, and listings will be generated using the 
pharmacokinetic analysis set. 
The pharmacokinetic parameters will be listed in tables of individual values and 
aggregated in summary tables.  Descriptive statistics (sample size, mean, standard 
deviation, coefficient of variation [%CV], standard error of the mean, minimum, 
maximum, and median) will be calculated at each evaluation timepoint for plasma 
concentrations of YF476. 


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Individual, mean and median plasma concentration-time data will be presented 
graphically. 
The relationship between PK concentrations and plasma CgA concentration or serum 
gastrin concentration will be examined using a graphical approach. 
13.6 
Safety Analyses 
Summaries and listings of safety data will be generated using the safety analysis set. 
 Adverse Event Analyses 
13.6.1
Adverse events (AEs) will be coded using the version of the Medical Dictionary for 
Regulatory Activities (MedDRA) that is current when the database is locked.  All AEs 
including serious AEs will be mapped to system organ class and preferred term, and will 
be listed in the data listing. 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment, having been absent pre-treatment, or that worsens relative to the pre-treatment 
state.   
The number and percentage of patients reporting TEAEs will be tabulated for the safety 
analysis set by MedDRA preferred term and system organ class, and further by 
relationship to study drug administered and by severity.   
Listings of deaths, SAEs, and AEs that lead to discontinuation of a patient will be 
presented. 
 Analyses of Clinical Laboratory Tests 
13.6.2
Standard haematology, biochemistry and urinalysis at each planned assessment, and 
change from baseline at each planned post-baseline assessment, will be summarized.    
 Electrocardiogram Analyses 
13.6.3
The ECG variables (PR, RR, QRS, QT, QTcB, and QTcF) and heart rate (HR) at each 
planned assessment will be summarised.  The QT intervals will be corrected for heart 
rate by the Bazett’s and Fridericia’s formula (QTcB = QT/[RR]1/2 and QTcF = 
QT/[RR]1/3).  The incidence of outliers in absolute QT, QTcF and QTcB intervals (>450, 
>480, and >500 msec), and the change from time-matched baseline in QT, QTcF and 
QTcB intervals (>30 and >60 msec) will be summarised. 
13.7 
Determination of sample size 
Based on our preliminary data, we estimate a mean baseline Ki67 index of 45–50%, 
with a common SD of 14–18%. Assuming a two-sided type I error rate of 0.05, a sample 
size of 20 (10 per arm) has 98% power to detect a 30% absolute difference in ΔKi67 
between the two arms if the common SD is 16%, and 97% power for a 25% difference 
with a 14% common SD (see Table 1).   


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Table 1.  Power calculations based on 20 patients (10 per arm) 
 
ΔKi67YF – ΔKi67pl 
SD 
0.25 
0.30 
0.35 
0.14 
97% 
99% 
>99% 
0.16 
91% 
98% 
>99% 
0.18 
84% 
94% 
98% 
14 
Ethical and regulatory considerations 
This trial will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP), and the applicable regulatory requirements. 
14.1 
Columbia University Medical Center, New York, US 
 Form FDA 1572 
14.1.1
Prior to initiating this study, the Chief Investigator and the Principal Investigator at the 
Participating Organization(s) will provide a signed Form FDA 1572 stating that the 
study will be conducted in compliance with regulations for clinical investigations and 
listing the investigators that will participate in the protocol. 
 Other required documents 
14.1.2
• 
Signed and dated current (within two years) CV or short biography for all 
investigators listed on the Form FDA 1572 for the Lead Organization and all 
Participating Organizations.  
• 
Current medical licenses for all investigators listed on Form FDA 1572 for the 
Lead Organization and all Participating Organizations. 
• 
Laboratory certification (eg, CLIA, CAP) and laboratory normal ranges for all labs 
listed on Form FDA 1572 for the Lead Organization and all Participating 
Organizations. 
• 
IRB Membership list/letter from IRB for the Lead Organization and all 
Participating Organizations. 
• 
Documentation of training in “Protection of Human Research Subjects” for all 
investigators listed on the FDA Form 1572 for the Lead Organization and all 
Participating Organizations. 
• 
Documentation of Federal-wide Assurance (FWA) number for the Lead 
Organization and all Participating Organizations. 
• 
Signed receipt of Investigator Brochure 


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• 
Delegation of Responsibility form 
• 
FDA Form 3455 Financial Disclosure Form 
• 
Evidence of submission of this protocol to the FDA 
 Institutional Review Board (IRB) approval 
14.1.3
Prior to initiating the study and receiving study medication, the Investigators at the Lead 
Organization and the Participating Organization(s) will obtain written approval to 
conduct the study from the appropriate IRB. Should changes to the study become 
necessary, protocol amendments will be submitted to the respective institutional IRBs.  
14.2 
National Institute for Health Research Clinical Investigation Ward, 
Cambridge, UK  
The trial protocol will be reviewed by a recognised REC, the Scientific Advisory Board 
(SAB) at Addenbrooke’s Clinical Research Centre, and by the MHRA.  The trial will 
not proceed in the UK unless the sponsor obtains from the MHRA a clinical trial 
authorisation (CTA), and the main REC and SAB approves the trial.  The trial will not 
proceed until the local National Health Service Trust has approved it. 
The trial will be done in compliance with EU Directives 2001/20/EC and 2005/28/EC, 
The Medicines for Human Use (Clinical Trials) Regulations 2004 and current 
amendments, the Declaration of Helsinki (South Africa Revision, 1996), GMP, the 
standard operating procedures issued by NRES for RECs in the UK, and Good Clinical 
Practice. 
The sponsor will ensure that the MHRA and the REC are informed promptly of 
suspected serious adverse reaction (SUSARs), and that any new reports of SUSARs 
from other ongoing trials of the IMP under investigation in this trial are notified to the 
MHRA, and to the REC, if applicable.  The sponsor will provide the investigator, the 
REC and the MHRA with annual safety reports of each IMP under investigation, and 
listings of all SSAR reports.   
The investigator will promptly inform the sponsor and chief investigator of any SAE that 
occurs during this trial.  The principal investigator will in turn inform the REC, if 
applicable.  The principal investigator will provide the REC with annual progress reports 
of the trial, if it lasts longer than a year. 
The principal investigator will report to the sponsor and chief investigator any protocol 
deviation that is, in his or her opinion, of clinical significance.  The principal 
investigator will also inform the sponsor and chief investigator in the event of several 
deviations which, although of no clinical significance, cause inconvenience and/or 
discomfort to the volunteers.  The principal investigator will in turn promptly inform the 
REC. 


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The sponsor will notify the MHRA and REC of any serious breach of Good Clinical 
Practice (for example, the investigator puts subjects’ safety at risk, falsifies data, or 
persistently fails to comply with this protocol or Good Clinical Practice).  
Within 90 days after the end of the trial, the sponsor will ensure that the REC and the 
MHRA are notified that the trial has finished.  If the trial is terminated prematurely, 
those reports will be made within 15 days after the end of the trial. 
The sponsor will supply a summary report of the clinical trial to the MHRA and REC 
within 1 year after the end of the trial.  
14.3 
Informed consent 
All potential study participants will be given a copy of the IRB- or REC-approved 
information and consent form (ICF) to review. The investigator will explain all aspects 
of the study in lay language and answer all questions regarding the study. If the patient 
decides to participate in the study, he/she will be asked to sign and date the ICF. The 
study medication will not be released to a patient who has not signed the Informed 
Consent document. Patients who refuse to participate or who withdraw from the study 
will be treated without prejudice. 
Prior to study initiation, the site-specific ICFs will be reviewed and approved by the IRB 
or REC, as appropriate.  Prior to implementation, any changes to the ICF for Columbia 
University will be approved by the IRB, and any substantial changes to the ICF for 
Cambridge University will be approved by the REC. 
15 
Financing, expenses, and/or insurance 
The baseline endoscopy and biopsies are considered standard of care for eligible study 
patients, so the cost of those procedures will not be covered by the trial.  At CUMC, the 
baseline endoscopy and biopsies will be billed to the study patients’ insurance.  All 
additional tests and procedures, including the endoscopies and biopsies at the Week 12 
visit, will be covered by the trial. The YF476 and placebo capsules will be provided free 
of charge. If the participant is injured and requires medical treatment as a direct result of 
taking part in this study, the study sponsor will pay reasonable medical costs (doctor’s 
fees and medical expenses) needed to treat the injury.  The treatment must be authorized 
by the investigator except in the event of an emergency in which case the investigator 
should be notified as soon as possible.  
16 
Obligations of the sponsor and investigator 
16.1 
Publication 
Each party will allow the other 30 days to comment before any results are submitted for 
publication, or 10 days prior to an abstract presentation.  Authorship should reflect work 


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done by the investigators and personnel of the sponsor, in accordance with generally 
recognized principles of scientific collaboration. 
16.2 
Archiving 
The sponsor and both principal investigators will keep the following in a trial master 
file. 
• All the essential documents required by GCP 
• All data generated during the study 
All documents will be stored such that they are readily available for inspection at the 
request of the sponsor or a regulatory authority.  Any transfer of ownership of the 
investigator’s data or documents will be documented, and the sponsor will be informed. 
For at least 15 years after the end of the study, and at least 2 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 have elapsed 
since the formal discontinuation of clinical development of the study medication: 
• HMR will ensure that the sponsor’s master file and original copies of CRFs will be 
archived in a secure place; and 
• the investigators will ensure that the investigator’s master file, and original source 
documents (other than CRFs) will be archived in a secure place.    
16.3 
Premature termination of the trial 
The sponsor and investigator reserve the right to terminate this trial should serious or 
severe AEs or any other safety issue occur during the trial.  In addition, the sponsor may, 
at any time for any reason, terminate the trial by halting further recruitment of patients.  
If the trial is terminated prematurely, the investigator will return all CRFs to the sponsor, 
and the sponsor or investigator, as appropriate, will provide a written statement of the 
reasons for termination.  The sponsor will ensure that the IRB, REC and competent 
authorities are notified. 


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17 
References 
1. Shaheen NJ. Advances in Barrett's esophagus and esophageal adenocarcinoma. 
Gastroenterology 2005;128:1554-66. 
2. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71-96. 
3. Shaheen N, Ransohoff DF. Gastroesophageal reflux, barrett esophagus, and esophageal cancer: 
scientific review. JAMA 2002;287:1972-81. 
4. Wang KK, Sampliner RE. Updated guidelines 2008 for the diagnosis, surveillance and therapy 
of Barrett's esophagus. Am J Gastroenterol 2008;103:788-97. 
5. Haigh CR, Attwood SE, Thompson DG, et al. Gastrin induces proliferation in Barrett's 
metaplasia through activation of the CCK2 receptor. Gastroenterology 2003;124:615-25. 
6. Wang JS, Varro A, Lightdale CJ, et al. Elevated serum gastrin is associated with a history of 
advanced neoplasia in Barrett's esophagus. Am J Gastroenterol 2010;105:1039-45. 
7. Boyce M. Investigator's Brochure: YF476. In: Trio Medicines, Ltd.; 2009. 
8. Brown LM, Devesa SS, Chow WH. Incidence of adenocarcinoma of the esophagus among 
white Americans by sex, stage, and age. J Natl Cancer Inst 2008;100:1184-7. 
9. Semple G, Ryder H, Rooker DP, et al. (3R)-N-(1-(tert-butylcarbonylmethyl)-2,3-dihydro-2-
oxo-5-(2-pyridyl)-1H-1, 4-benzodiazepin-3-yl)-N'-(3-(methylamino)phenyl)urea (YF476): a 
potent and orally active gastrin/CCK-B antagonist. J Med Chem 1997;40:331-41. 
10. Takemoto Y, Yuki H, Nishida A, et al. Effects of YF476, a potent and selective 
gastrin/cholecystokinin-B receptor antagonist, on gastric acid secretion in beagle dogs with 
gastric fistula. Arzneimittelforschung 1998;48:403-7. 
11. Takinami Y, Yuki H, Nishida A, et al. YF476 is a new potent and selective 
gastrin/cholecystokinin-B receptor antagonist in vitro and in vivo. Aliment Pharmacol Ther 
1997;11:113-20. 
12. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a 
risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340:825-31. 
13. El-Serag HB, Aguirre TV, Davis S, Kuebeler M, Bhattacharyya A, Sampliner RE. Proton 
pump inhibitors are associated with reduced incidence of dysplasia in Barrett's esophagus. Am J 
Gastroenterol 2004;99:1877-83. 
14. Garcia Rodriguez LA, Lagergren J, Lindblad M. Gastric acid suppression and risk of 
oesophageal and gastric adenocarcinoma: a nested case control study in the UK. Gut 
2006;55:1538-44. 
15. Feagins LA, Zhang HY, Hormi-Carver K, et al. Acid has antiproliferative effects in 
nonneoplastic Barrett's epithelial cells. Am J Gastroenterol 2007;102:10-20. 
16. Ferrand A, Wang TC. Gastrin and cancer: a review. Cancer Lett 2006;238:15-29. 


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17. Green DA, Mlynarczyk CM, Vaccaro BJ, et al. Correlation between serum gastrin and 
cellular proliferation in Barrett's esophagus. Therap Adv Gastroenterol 2011 (in press). 
18. Redrup MJ, Leaf FC, Miyashita A, et al. Validation of a liquid chromatographic-tandem mass 
spectrometric method for the measurement of (R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2-
pyridyl)-1H-1,4-benzodiazep in-3-yl]-3-(3-methylaminophenyl)urea (YF476) in human plasma. J 
Chromatogr B Analyt Technol Biomed Life Sci 2002;772:317-25. 
19. The Rules Governing Medicinal Products in the European Union, Volume 4 – Good 
Manufacturing Practice, incorporating Directive 2003/94/EC. 
 
 


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Appendix A – performance status criteria 
 
ECOG performance status scale 
Karnofsky performance scale 
Grade 
Descriptions 
Percent Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (eg, light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead 
0 
Dead 
 
 


YF476 in Barrett’s esophagus 
 
Trial code: 10-505 (T-016) 
Protocol Version 24 
26 April 2018 
Page 61 of 66 
Appendix B – drug interactions 
Non-clinical studies support administration of the study medication (YF476) to humans for up to 
13 weeks.  In vitro studies showed that YF476 inhibited CYP2C8 and CYP3A4/5.  Specific 
notation will be made of any regular concomitant medications metabolized via CYP2C8 or 
CYP3A4/5.  These medications do not need to be discontinued, although specific monitoring for 
side effects and toxicities will be performed during the study period. 
CYP 450 enzymes 
In tests for reversible inhibition of CYP 450 enzymes, the IC50 of YF476 was 3.52, 8.37 and 12.1 
µM for CYP2C8, CYP3A4 (midazolam) and CYP3A4 (testosterone), respectively.  But, YF476 
did not inhibit CYP2C9 at doses up to 25 µM.  In tests for irreversible inhibition, 0.5 µM YF476 
did not cause significant inhibition of CYP3A4 (midazolam).  However, 5 µM YF476 caused 
43.9% irreversible inhibition of CYP3A4 (midazolam), which was reduced to 30.2% when 
corrected for vehicle control.  Neither CYP3A4 (testosterone) nor CYP2C9 was inhibited by 
5 µM YF476. For further details of the in vitro studies, see the YF476 Investigator’s Brochure. 
To assess the likelihood of CYP2C8 and CYP3A4 inhibition in patients in vivo, [I]/Ki ratios 
(where Ki = IC50/2, and I = Cmax for YF476) were calculated from IC50 values for reversible 
inhibition by YF476 and Cmax for total (bound and unbound) plasma concentrations of YF476 
from a study of single doses of 50, 100, 200 and 400 mg in healthy subjects (Table 2.  T–011; see 
Investigators’ Brochure).  FDA guidelines (2006) state that an interaction is likely if the ratio is 
greater than 1, possible if between 1 and 0.1, and remote if less than 0.1.   
Table 2: [I]/Ki ratios calculated with total (bound plus unbound) plasma concentrations of 
YF476.  
 Isoform 
IC50 (µM) 
Ki 
[I1]/Ki 
[I2]/Ki 
[I3]/Ki 
[I4]/Ki 
CYP2C8  
3.52 
1.76 
0.184 
0.302 
0.584 
0.803 
CYP3A4 
(testosterone) 
12.1 
6.05 
0.054 
0.088 
0.170 
0.233 
CYP3A4 
(midazolam) 
8.37 
4.185 
0.077 
0.127 
0.246 
0.338 
Where Ki = IC50/2, and I1, I2, I3 and I4 = Cmax for 50, 100, 200 & 400 mg YF476, respectively, in fasting subjects. 
Therefore, the likelihood of a drug-drug interaction in patients in vivo is: 
• 
CYP2C8:  possible for 50–400 mg YF476  
• 
CYP3A4 (testosterone):  remote for 50 & 100 mg YF476, and possible for 200 & 
400 mg 
• 
CYP3A4 (midazolam):  remote for 50 mg YF476, and possible for 100–400 mg. 
Although YF476 caused some irreversible inhibition of CYP3A4, the degree of inhibition makes 
a drug-drug interaction in patients in vivo unlikely. 


YF476 in Barrett’s esophagus 
 
Trial code: 10-505 (T-016) 
Protocol Version 24 
26 April 2018 
Page 62 of 66 
Many medicines are metabolised via CYP3A4/5 (Dressler et al 2000). Very few are metabolised 
via CYP2C8.  Examples of the main types of medicine that are metabolised by CYP3A4/5 and 
CYP2C8, and guidance about assessing the risk and managing drug-drug interactions is provided 
here. 
The Table 3 lists drugs with effects on the human cytochrome P450 system. There is evidence, 
for drugs in this table, that these are metabolized, at least in part, via that isoform. This does not 
indicate that changes in the rate of that metabolic reaction will largely affect the drug’s 
pharmacokinetics. 
Table 3: Drug Interactions with cytochrome P450 system 
 
CYP2C8 
CYP3A4/5 
 
 
Substrates 
paclitaxel 
torsemide 
amodiaquine 
cerivastatin 
repaglinide 
Macrolide antibiotics: 
clarithromycin 
erythromycin (not 
3A5) 
NOT azithromycin 
telithromycin 
HMG CoA Reductase 
Inhibitors: 
atorvastatin 
cerivastatin 
lovastatin 
NOT pravastatin 
Simvastatin 
Immune Modulators: 
cyclosporine 
tacrolimus (FK506) 
 
 
Anti-arrhythmics: 
quinidine_3OH (not 
3A5) 
Steroid 6beta-OH: 
estradiol 
hydrocortisone 
progesterone 
testosterone 
HIV Antivirals: 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
 
 
Benzodiazepines: 
alprazolam 
diazepam_3OH 
midazolam 
triazolam 
Prokinetic: 
Cisapride 
Calcium Channel 
Blockers: 
amlodipine 
diltiazem 
felodipine 
lercanidipine 
nifedipine2 
nisoldipine 
nitrendipine 
verapamil 
Antihistamines: 
astemizole 
chlorpheniramine 
terfenadine 


YF476 in Barrett’s esophagus 
 
Trial code: 10-505 (T-016) 
Protocol Version 24 
26 April 2018 
Page 63 of 66 
 
CYP2C8 
CYP3A4/5 
 
 
 
 
Miscellaneous: 
alfentanyl 
aprepitant 
aripiprazole 
buspirone 
cafergot 
caffeine_TMU 
cilostazol 
cocaine 
codeine- 
Ndemethylation 
dapsone 
dexamethasone 
dextromethorphan 
docetaxel 
domperidone 
eplerenone 
fentanyl 
finasteride 
gleevec 
haloperidol 
irinotecan 
LAAM 
lidocaine 
methadone 
nateglinide 
ondansetron 
pimozide 
propranolol 
quetiapine 
quinine 
 
risperidone 
NOT rosuvastatin 
salmeterol 
sildenafil 
sirolimus 
tamoxifen 
taxol 
terfenadine 
trazodone 
vincristine 
zaleplon 
ziprasidone 
zolpidem 
Inhibitors gemfibrozil 
trimethoprim 
glitazones 
montelukast 
quercetin 
HIV Antivirals: 
indinavir 
nelfinavir 
ritonavir 
aprepitant 
erythromycin 
fluconazole 
grapefruit juice 
verapamil 
diltiazem 
 
 
clarithromycin 
itraconazole 
ketoconazole 
nefazodone 
saquinavir 
telithromycin 
cimetidine  
diethyldithiocarbamate 
fluvoxamine 
gestodene 
imatinib 
mibefradil 
mifepristone 
 
 
norfloxacin 
norfluoxetine 
star fruit 
voriconazole 
amiodarone 
NOT azithromycin 
chloramphenicol 
ciprofloxacin 
delaviridine 


YF476 in Barrett’s esophagus 
 
Trial code: 10-505 (T-016) 
Protocol Version 24 
26 April 2018 
Page 64 of 66 
 
CYP2C8 
CYP3A4/5 
 
 
Inducers 
rifampin 
HIV Antivirals: 
efavirenz 
nevirapine 
barbiturates 
carbamazepine 
efavirenz 
pioglitazone 
glucocorticoids 
modafinil 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
rifabutin 
rifampin 
St. John's wort 
troglitazone 
 
Source: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.asp. 
Accessed 04/22/10 


YF476 in Barrett’s esophagus 
 
Trial code: 10-505 (T-016) 
Protocol Version 23 
                                                                                                13 May 2016 
 
Page 65 of 66 
 
Appendix C – medications card (CUMC) 
 
 


YF476 in Barrett’s esophagus 
 
Trial code: 10-505 (T-016) 
Protocol Version 23 
                                                                                                13 May 2016 
 
Page 66 of 66 
 
 
 

SAP_001.pdf: 
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Page 1 of 46 
Statistical Analysis Plan 
Clinical trial protocol title:  
Randomized, placebo-controlled trial of YF476, a 
gastrin receptor antagonist, in Barrett’s esophagus 
HMR code: 
10-505 
Sponsor code: 
T-016 
EudraCT no: 
2014-002418-22 
CRO details: 
Hammersmith Medicines Research 
Cumberland Avenue 
London NW10 7EW 
Sponsor details: 
 
 
Trio Medicines Ltd 
Hammersmith Medicines Research 
Cumberland Avenue 
London 
NW10 7EW 
 
Issued:  
10 January 2019 
Version:  
1 
Based on: 
Protocol version 24, 26 April 2018 
Number of pages:  
46 
Prepared by:  
Stephen Sah 


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Table of contents 
1 
LIST OF ABBREVIATIONS .............................................................................4 
2 
SIGNATURES ......................................................................................................6 
3 
INTRODUCTION ................................................................................................7 
4 
STUDY OBJECTIVES AND ENDPOINTS ......................................................7 
4.1 
Study Objectives ........................................................................................7 
4.1.1 
Primary Objective ............................................................................................... 7 
4.1.2 
Secondary Objectives ......................................................................................... 7 
4.2 
Study Endpoints .........................................................................................8 
4.2.1 
Primary Endpoints .............................................................................................. 8 
4.2.2 
Secondary Endpoints .......................................................................................... 8 
4.3 
Statistical Hypotheses ................................................................................8 
5 
STUDY DESIGN ..................................................................................................9 
6 
TIME AND EVENTS TABLE ..........................................................................10 
7 
PLANNED ANALYSES ....................................................................................11 
7.1 
Interim Analyses ......................................................................................11 
7.2 
Final Analysis ..........................................................................................11 
7.2.1 
Persons responsible for analysis ....................................................................... 11 
8 
SAMPLE SIZE CONSIDERATIONS .............................................................11 
8.1 
Sample Size Assumptions .......................................................................11 
9 
ANALYSIS POPULATIONS ...........................................................................12 
9.1 
Analysis Datasets .....................................................................................12 
10 
TREATMENT COMPARISONS .....................................................................13 
11 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ........................13 
11.1 
Data Display Treatment and Other Subgroup Descriptors ......................13 
11.2 
Conventions for Summary Statistics and Data Displays .........................13 
12 
DATA HANDLING CONVENTIONS ............................................................14 
12.1 
Premature Withdrawal and Missing Data ................................................14 
12.2 
Derived and Transformed Data ...............................................................14 
12.3 
Assessment Windows ..............................................................................14 
12.4 
Values of Potential Clinical Importance ..................................................15 
13 
STUDY POPULATION ....................................................................................15 
13.1 
Disposition of Patients .............................................................................15 
13.2 
Protocol Deviations .................................................................................15 
13.3 
Baseline Characteristics and Concomitant Medication ...........................15 


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13.4 
Treatment Compliance ............................................................................16 
14 
SAFETY ANALYSES .......................................................................................16 
14.1 
Extent of Exposure ..................................................................................16 
14.2 
Adverse Events ........................................................................................16 
14.3 
Deaths, Serious Adverse Events and Other Significant Adverse Events 17 
14.4 
Adverse Events Leading to Withdrawal from the Study .........................17 
14.5 
Clinical Laboratory Evaluations ..............................................................17 
14.6 
Other Safety Measures .............................................................................17 
14.6.1 Vital signs ......................................................................................................... 17 
14.6.2 ECG .................................................................................................................. 17 
15 
EFFICACY ANALYSES ...................................................................................18 
16 
PHARMACOKINETIC ANALYSES ..............................................................18 
16.1 
Pharmacokinetic Concentration Data ......................................................19 
17 
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSIS
 
19 
18 
REFERENCES ...................................................................................................19 
19 
ATTACHMENTS ..............................................................................................20 
19.1 
Table of Contents for Data Display Specifications .................................20 
19.2 
Data Display Specifications .....................................................................24 
19.2.1 Table Outlines .................................................................................................. 24 
19.2.2 Figure Outlines ................................................................................................. 35 
19.2.3 Listing Outlines ................................................................................................ 37 
APPENDIX A: SAMPLE PAGE LAYOUT ...............................................................46 
 


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1 
List of abbreviations 
AE 
Adverse Event 
BE 
Barrett’s esophagus 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
CCK2R 
CI 
Cholecystokinin 2 receptor 
Confidence Interval 
CgA 
Chromogranin A 
Cmax 
Peak Plasma Concentration 
Ctrough 
Trough Plasma Concentration 
CRF 
COX-2 
Case Report Form 
Cyclooxygenase-2 
CSR 
Clinical Study Report 
CV 
DCAMKL1 
Coefficient of variance 
Doublecortin- and Ca2+/calmodulin-dependent protein kinase-like 
protein 1 
       ECG 
Electrocardiogram 
ECL 
Enterochromaffin-like 
HMR 
Hammersmith Medicines Research 
HR 
Heart Rate 
ICH 
IHC 
International Conference on Harmonization 
Immunohistochemistry 
ITT 
Intent-to-treat  
LDH 
Lactase dehydrogenase 
MedDRA 
mRNA 
Medical Dictionary for Regulatory Activities 
Messenger RNA 
N 
Number of patients 
N 
p53 
Number of observations used in analysis 
Tumour protein 53 
PK 
Pharmacokinetic(s) 
PP 
PPI 
Per protocol 
Proton pump inhibitor 
PR 
Portion of the ECG from the beginning of the P wave to the beginning of the 
QRS complex, representing atrioventricular node function. 
Q1 
Lower quartile 
Q3 
Upper quartile 
QRS 
 
qRT-PCR 
The QRS complex of the ECG reflects the rapid depolarization of the right 
and left ventricles. 
Quantitative RT-PCR 
QT 
Portion of the ECG between the onset of the Q wave and the end of the T 
wave, representing the total time for ventricular depolarization and 
repolarization. 
QTc 
Corrected portion of the ECG between the onset of the Q wave and the end 
of the T wave, representing the total time for ventricular depolarization and 
repolarization. 
QTcB 
QTc interval with Bazett's correction method 
QTcF 
QTc interval with Fridericia's correction method 
RBC 
Red blood cells 


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RNAseq 
RNA sequencing 
RR 
 
RT-PCR 
Portion of the ECG between consecutive R waves, representing the 
ventricular rate 
Reverse transcriptase polymerase chain reaction 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SGOT/AST 
Serum glutamic-oxaloacetic transaminase/aspartate amino transferase 
SGPT/ALT 
Serum glutamicpyruvic transaminase/ alanine aminotransferase 
TEAE 
Treatment Emergent Adverse Event 
WBC 
White blood cells 
∆Ki67 
Change in Ki67 expression 
 
 
 




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3 
Introduction 
This Statistical Analysis Plan (SAP) is based on the current trial protocol (version 24, 26 
April 2018.  Where statistical methods differ substantially between this SAP and the protocol, 
that will be identified in this document. 
This SAP describes the datasets and the statistical methods to be used for the reporting and 
analysis of all data collected during the trial except the efficacy data  which will be reported 
separately.  Serum gastrin and plasma CgA data will be included in this SAP.  
The randomisation code will not be broken before this SAP is finalised.  If a future protocol 
amendment necessitates a substantial change to the statistical analysis of the trial data, this 
SAP will be amended accordingly.  If, after database lock, additional analyses are required to 
supplement the planned analyses described in this SAP, those unplanned analyses will not be 
described in an amended SAP, but they will be identified in the integrated clinical study 
report (CSR).  Any deviations from this SAP will be documented in the CSR. 
This SAP has been written in consideration of the following guidelines:   
 International Conference on Harmonization (ICH) E9, Guidance for Industry:  Statistical 
Principles for Clinical Trials (ICH E9 1998)1; and  
 ICH E3, Guidance for Industry: Structure and Content of Clinical Study Reports (ICH E3 
1995)2. 
Statistical analysis will be done using SAS 9.3 on a Windows PC. 
4 
Study Objectives and Endpoints 
4.1 
Study Objectives 
4.1.1 Primary Objective 
The primary objective of this study is to determine if administration of netazepide (a CCK2R 
antagonist) to patients with Barrett’s esophagus (BE) decreases tissue Ki67 expression, a 
marker of cellular proliferation. 
4.1.2 Secondary Objectives 
The secondary objectives are to assess the effects of netazepide on: 


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Page 8 of 46 
• 
biomarkers potentially associated with esophageal adenocarcinoma, in particular, 
cyclooxygease-2 (COX-2), p53, CCK2R and DCAMKL1; and 
• 
fasting serum gastrin, a marker of gastric acid suppression, and plasma chromogranin 
A (CgA), a marker of ECL cell hyperplasia. 
We also aim to determine whether netazepide is safe in patients with BE. 
4.2 
Study Endpoints 
4.2.1 Primary Endpoints 
Change in Ki67 expression (ΔKi67) between baseline (Visit 2) and the Week 12 visit 
4.2.2 Secondary Endpoints 
• 
Biomarkers 
o Change from baseline at Week 12 in biomarkers potentially associated with 
esophageal adenocarcinoma, in particular: 
 Change in CCK2R mRNA levels (measured by qRT-PCR) 
 Change in DCAMKL1 expression (measured by IHC) 
 Change in DCAMKL1 mRNA levels (qRT-PCR) 
 Change in COX-2 mRNA levels (qRT-PCR) 
 Change in p53 expression (IHC) 
o Gene expression will be measured using RNA-Seq. Further examination of any 
changes in expression from baseline may be done using qRT-PCR and IHC 
o Reduction in PPI-induced increase in plasma CgA 
o Increase in PPI-induced hypergastrinaemia 
• 
Safety 
o Vital signs, ECG, physical examination, laboratory safety tests: blood tests: red 
blood cells (RBC), haemoglobin, haematocrit, platelets, white blood cells 
(WBC, differential: neutrophils, bands, lymphocytes, monocytes, eosinophils, 
basophils), sodium, potassium, magnesium, chloride, bicarbonate, creatinine, 
serum glucose, blood urea nitrogen (BUN), alkaline phosphatase, lactate 
dehydrogenase (LDH), serum glutamic-oxaloacetic transaminase/aspartate 
amino transferase (SGOT/AST), serum glutamicpyruvic transaminase/ alanine 
aminotransferase (SGPT/ALT), total bilirubin, total protein, albumin, calcium, 
amylase, lipase; and urine tests: pH, specific gravity, protein, glucose, ketones, 
blood. 
o Change in histology 
• 
Tolerability: assessment of adverse events. 
• 
Pharmacokinetics: trough and peak concentration of netazepide 
4.3 
Statistical Hypotheses 
No formal statistical testing will be done 


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5 
Study Design 
A randomized, double-blind, placebo-controlled pilot study of netazepide, a cholecystokinin-2 
receptor antagonist, in patients with Barrett’s esophagus without dysplasia.  Patients will take 
netazepide or placebo for 12 weeks.   
There are 2 research sites, Columbia University and the MRC Cancer Unit at the University 
of Cambridge.     
Patients will be randomised (1:1 ratio) to receive either 25 mg netazepide or matching 
placebo. 
 


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6 
Time and Events Table  
 
Baseline Testing/ 
Prestudy Evaluation 
Study treatment 
Follow-up period 
 
Visit 11 
Visit 2 
Week 6 
visit  
Week 12 
visit  
Follow–up 
Evaluation/ Procedure 
Registration 
Randomization, 
& Endoscopy 
Week 6 
Week 12 
Follow Up Visit 4 weeks after 
stopping treatment 
Informed consent 
X 
 
 
 
 
Assess eligibility 
X 
 
 
 
 
Central pathology review2 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Physical exam 
X 
 
 
 
 
Vital signs 
X 
X5 
X 
X 
X 
Height and weight/ 
waist circumference 
X 
 
 
 
 
Smoking history 
X 
 
 
 
 
Medication history 
X 
 
 
 
 
Blood and urine collection 
for safety tests 
X 
X5 
X 
X 
X 
Urine pregnancy test4 
X 
X5 
X 
X 
X 
ECG 
X 
X5 
X 
X 
X 
Blood for YF476 assay3 
 
 
X 
X 
 
Blood for assay of fasting 
serum gastrin and plasma 
CgA, and serum for storage 
 
X 
X 
X 
X 
EGD (Upper GI endoscopy) 
 
X 
 
X 
 
Biopsies 
 
X 
 
X 
 
Concomitant medication 
assessment 
 
X 
X 
X 
 
Dispense study medication 
 
X 
X 
 
 
Collect study medication 
 
 
X 
X 
 
Compliance assessment 
 
 
X 
X 
 
AE assessment 
 
X 
X 
X 
X 
1. There may be up to a 2-week gap between Visits 1 and 2. 
2. Review of patient’s history to obtain histological confirmation of the patient’s eligibility to participate in the trial. 
3. Plasma YF476 assay: patients fast overnight.  For the Week 6 and 12 visits, patients bring their container of study 
medication with them, and take study medication only after collection of blood samples for trough YF476, fasting 
serum gastrin and CgA levels, and endoscopy (if applicable).  Patients stay for 1 h after dosing for collection of a 
blood sample for peak YF476 level.  
4. Pre-menopausal women only. 
5. These tests may be omitted if Visit 2 occurs on the same day as Visit 1. 
 


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7 
Planned Analyses 
7.1 
Interim Analyses 
No interim analyses are planned. 
 
7.2 
Final Analysis 
The database will be locked once all patients have completed the study, data have been 
entered and all queries resolved.  The final analysis will be carried out following database 
lock and unblinding. 
7.2.1 Persons responsible for analysis 
Steven Whaley  (HMR) 
Statistician 
Nick Jackson  (HMR) 
SAS Programmer 
Jyoti Ambhir  (HMR) 
Data Manager 
 
8 
Sample Size Considerations 
8.1 
Sample Size Assumptions 
Based on preliminary data, a mean baseline Ki67 index of 45–50%, with a common SD of 
14–18% was estimated. Assuming a two-sided type I error rate of 0.05, a sample size of 20 
(10 per arm) has 98% power to detect a 30% absolute difference in ΔKi67 between the two 
arms if the common SD is 16%, and 97% power for a 25% difference with a 14% common 
SD (see Table 1).   
 


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Table 1.  Power calculations based on 20 patients (10 per arm) 
 
ΔKi67YF – ΔKi67pl 
SD 
0.25 
0.30 
0.35 
0.14 
97% 
99% 
>99% 
0.16 
91% 
98% 
>99% 
0.18 
84% 
94% 
98% 
 
9 
Analysis Populations 
The following populations will be identified: 
Screened Population:  
All patients screened for the study. 
Safety Population:  
All patients who are randomised and received at least one 
dose of the study drug. In this population, treatment will be 
assigned based upon the treatment patients actually receive 
regardless of the treatment to which they were randomized. 
Intent-to-Treat (ITT) Population: All randomised patients who receive at least one dose of 
study medication and had at least one post-baseline 
assessment. In this population, treatment will be assigned 
based upon the treatment to which subjects were 
randomised regardless of which treatment they actually 
received. 
Per Protocol (PP) Population: 
All randomized patients who receive at least one dose of 
study medication and had at least one post-baseline 
assessment and did not have any major protocol deviations. 
In all populations (apart from ITT) treatment will be assigned based upon the treatment 
patients actually receive regardless of the treatment to which they were randomised. 
The primary endpoint will be analysed using the ITT population. 
 
 
9.1 
Analysis Datasets 
All analysis datasets will be based on observed data, except as outlined in Section 12.2. 


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10 
Treatment Comparisons 
The treatment comparison of interest is active (netazepide) versus placebo. 
11 
General Considerations for Data Analyses 
11.1 Data Display Treatment and Other Subgroup Descriptors 
The sort order for treatment groups will be placebo, then study treatment.  When a total 
column is included, it immediately follows the treatment groups which it aggregates. 
Listings of data will be sorted and displayed by treatment group, patient number, and also by 
date and time if applicable.   
The treatment descriptions to be used on all tables and listings are:  
Treatment Groups  
Placebo 
Netazepide  25 mg  
 
11.2 Conventions for Summary Statistics and Data Displays 
The minimum set of summary statistics for numeric variables will be: n, mean, standard 
deviation (or standard error), median, minimum, and maximum. 95% confidence intervals 
will be presented where appropriate for data interpretation.  
Categorical data will be summarised in frequency tables with n and percentage.  Summaries 
of a categorical variable will include all recorded values. 
The minimum and maximum values will be presented with the same number of decimal 
places as the raw data collected on the CRF (or to 3 significant figures for derived parameters 
less than 100 and as integers for values more than 99). The mean and percentiles (e.g. median, 
Q1, and Q3) will be presented using one additional decimal place. The standard deviation and 
standard error will be presented using two additional decimal places.  


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12 
Data Handling Conventions 
12.1 Premature Withdrawal and Missing Data 
All patients who withdraw prematurely from the study or study drug will be included in the 
statistical analyses.  
If a patient completes the treatment period but has missing data, then this will be made 
apparent in the patient listings. Missing data will not be imputed except for as outlined in 
Section 12.2.   
If the study is prematurely discontinued, all available data will be listed and a review will be 
carried out to assess which statistical analyses are still considered appropriate. 
Data collected at unscheduled time points during the study will not be used in the summaries 
or data analyses.  They will be included in the listings. 
If time information (i.e. hours and/or minutes) for adverse events or concomitant medication 
is missing, but the day is present, then the time will be calculated in days.    If date 
information is partial or missing, then any derived times (e.g. AE start time from last study 
medication) will be listed as missing.  
12.2 Derived and Transformed Data 
Baseline will be considered to be the latest value obtained before study drug administration 
(e.g. Visit 2; or Visit 1 if not recorded elsewhere).   
Laboratory data will be reported in standard units.  Out-of-range laboratory tests may be 
repeated.  If a test is out-of-range at a baseline timepoint and repeated before dosing, the latest 
repeat value before dosing will be used as baseline.  However, if a test is out-of-range and 
repeated at any other time during the study, the out-of-range value (not the repeat value) will 
be included in statistical summaries. 
12.3 Assessment Windows 
There is a +/- 4 day window for clinic visits.  Visit 2 can take place on the same day as visit 1, 
or up to 2 weeks later.  
For the safety and ITT populations, all data will be analysed as recorded (regardless of the 
assessment windows). 


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12.4 Values of Potential Clinical Importance 
Laboratory results identified as ‘clinically significant’ in the CRF will be considered to be 
potentially clinically important. 
QT, QTcB or QTcF > 450 msec  and increases in QT, QTcB or QTcF from baseline (Visit 2) 
of > 30 msec will be considered to be potentially clinically important.   
13 
Study Population 
13.1 Disposition of Patients 
The disposition of all patients in the safety population will be summarised (by site and 
overall) including number of patients randomised, number completing the study by treatment, 
and number withdrawn from the study.  The number of screen failures will also be 
summarised and listed. 
All patients who withdraw or are withdrawn from the study will be listed by treatment, with 
the reason for withdrawal.  
A listing of analysis populations will be provided. 
 
13.2 Protocol Deviations 
Before closing the database, data listings will be reviewed to identify any significant 
deviations and determine whether the data should be excluded from any analysis populations.   
Major protocol deviations include patients who: 
 Entered the study even though they did not satisfy the entry criteria. 
 Met the criteria for withdrawal from the study but were not withdrawn. 
 Received the wrong treatment or incorrect dose. 
 Received an excluded concomitant therapy. 
 Received investigational product(s) past the expiration date. 
 Had their treatment assignment unblinded. 
 Visits outside of assessment windows 
 
13.3 Baseline Characteristics and Concomitant Medication 
Demographic and baseline characteristics (e.g. , vital signs and ECGs) will be listed and 
summarised.  


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Patients who take concomitant medication will be listed and summarised.  
Proton Pump Inhibitor use data will be listed. 
Medical history including history of Barrett’s Esophagus data will be listed and summarised 
13.4 Treatment Compliance 
The percentage treatment compliance at each visit will be listed and summarised. 
14 
Safety Analyses 
Summaries and listings of safety data will use the safety population.  
14.1 Extent of Exposure 
The dates and times of first and last treatment dosing will be listed to indicate exposure to the 
study medication. 
14.2 Adverse Events 
Adverse events will be coded using the version  of the Medical Dictionary for Regulatory 
Activities (MedDRA) which is current at the time of database lock (version 20.1 or higher).   
All adverse events will be listed. 
The number of patients with at least one treatment-emergent adverse event (TEAE) will be 
tabulated by actual treatment and MedDRA system organ class.  A treatment-emergent 
adverse event is defined as an event emerging during treatment having been absent pre-
treatment or having worsened relative to pre-treatment1.  
For each of the following, the number of adverse events and number of patients with adverse 
events will be summarised by treatment: 
• 
TEAEs by system organ class and preferred term 
• 
Drug-related (“possibly”, “probably” or “definitely” as recorded by the Investigator) 
TEAEs by system organ class and preferred term 
Patients with more than one TEAE will be counted only once, at the greatest severity or 
causality, for each system organ class/preferred term.  Multiple TEAEs in a patient will be 


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counted once per system organ class and preferred term.  Adverse events with missing 
severity and/or causality will be treated as severe and definitely related, respectively. 
Summaries will be sorted by system organ class and decreasing total incidence of preferred 
term. 
14.3 Deaths, Serious Adverse Events and Other Significant Adverse 
Events 
Deaths and serious adverse events will be listed separately (fatal events separate from non-
fatal events).  Other significant adverse events, as identified by the investigator in the CRF, 
will be listed separately. 
14.4 Adverse Events Leading to Withdrawal from the Study 
Adverse events leading to withdrawal will be listed separately.   
14.5 Clinical Laboratory Evaluations 
Data from haematology, clinical chemistry and urinalysis will be summarised by treatment 
group.  
All laboratory values of potential clinical importance will be listed and all related laboratory 
results (i.e. haematology or clinical chemistry) for patients with values of potential clinical 
importance will be listed, separately.  Frequencies of laboratory values of potential clinical 
importance will be summarised. 
 
Urinalysis parameters will also be listed. 
 
14.6 Other Safety Measures 
14.6.1 Vital signs 
Vital signs evaluation at each planned visit, and change in vital signs from baseline (Visit 2 or 
Visit 1 if not recorded elsewhere) at each planned post-baseline visit, will be summarised by 
treatment group.  
14.6.2 ECG 
QT interval data will be presented using Bazett's (QTcB) and Fridericia's (QTcF) corrections.   


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ECG data will be summarised by treatment and  visit.  Differences from baseline (Visit 2) will 
be summarised by treatment and visit.   
The number of patients with a potentially clinically important ECG value will be summarised 
by actual treatment and visit, giving the numbers of patients with QT, QTcB or QTcF > 450 
msec, > 480 msec and > 500 msec, and the numbers of patients with increases in QT, QTcB 
or QTcF from baseline of > 30 msec and > 60 msec3.  A supporting listing of all patients with 
an ECG value of potential clinical importance and a separate listing of ECG findings 
classified as abnormal by the Investigator will also be provided. 
15 
Efficacy Analyses  
Efficacy data (serum gastrin and CgA) will be summarised using the ITT and PP populations.  
Summaries based on the PP population will only be produced if there is a difference between 
the ITT and PP populations 
Serum gastrin and plasma CgA data at each planned visit, and change in Serum gastrin and 
plasma CgA from baseline at each planned post-baseline visit, will be summarised by 
treatment group and visit. Individual values will be presented by patient  
Mean profile plots for serum gastrin and CgA will also be produced.  Each plot will contain 
all results for all subjects in the active and placebo arms 
16 
Pharmacokinetic Analyses 
Analytics Services International Ltd. will measure the plasma concentrations of netazepide.  
The pharmacokinetic analysis will be done by HMR.   
PK data will be summarised using the safety population for patients who received netazepide  
25 mg.  
For all variables N (number of patients receiving the treatment in the population),  n (number 
of observations), arithmetic mean, median, minimum, maximum, SD, %CV, and the 95% 
confidence interval for the arithmetic mean will be provided.   


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16.1 Pharmacokinetic Concentration Data 
The peak (Cmax) and trough (Ctrough) plasma concentration will be listed, presented graphically 
and summarised by treatment.   
We will produce scatterplots to examine the relationship between peak PK concentrations and 
plasma CgA concentration or serum gastrin concentration.  
17 
Changes from the Protocol Specified Statistical Analysis 
After the study was submitted to the regulatory authorities and ethics committee the following 
changes were made to the analyses: 
 Section 13.1 Analysis  Sets of the protocol states “The pharmacokinetic analysis set 
will include all patients who receive at least one dose of study medication, and yield at 
least one plasma concentration for netazepide.”  This definition is not included in the 
SAP as the population is not required. 
18 
References 
1. International Conference on Harmonization, 1998.  Statistical Principles for Clinical 
Trials - ICH Harmonised Tripartite Guideline. Guidance for Industry, E9, FDA federal 
register, Vol 63, 1998, p49583.  Available at: http://www.fda.gov/cder/guidance. 
2. International Conference on Harmonization, 1995.  Structure and Content of Clinical 
Study Reports - ICH Harmonised Tripartite Guideline. Guidance for Industry, E3, FDA 
federal register, Vol 61, 1996, p37320.  Available at: http://www.fda.gov/cder/guidance. 
3. International Conference on Harmonisation, 2005.  Clinical Evaluation of QT/QTc 
Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.  
Concept paper, Guidance for Industry, E14, Center for Drug Evaluation and Research 
(CDER).  Available at:  http://www.fda.gov/cder/guidance/6922fnl.htm. 
 
 
 
 
 


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19 
ATTACHMENTS 
19.1 Table of Contents for Data Display Specifications 
For overall page layout refer to Appendix B. 
The numbering  in the tables below will take precedence over the numbering in the shells. 
The following tables and figures will be produced (templates provided in Section 19.2.1 and 
19.2.2):


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Table 
Description 
Population 
Source 
Listing 
Template 
(Shells below) 
10.1   
Summary of patient disposition 
Safety 
16.2.1.2   
16.2.3.1 
T_SD1 
10.2.1 
Summary of concomitant medications 
Safety 
16.2.4.2 
T_CM1 
10.2.2 
Summary of medical history: barrett’s esophagus 
Safety 
16.2.4.3 
T_MH1 
10.2.3 
Summary of treatment compliance 
Safety 
16.2.5.1 
T_COMP1 
14.1  
 DEMOGRAPHIC DATA 
 
 
14.1 
Summary of demographic characteristics 
Safety 
16.2.4  
T_DM1 
14.2  
 PHARMACOKINETIC and EFFICACY 
 
 
 
14.2.1 
Summary of netazepide plasma peak and trough concentration data 
Safety 
16.2.6.1 
T_PK1 
14.2.2.1 
Summary of serum gastrin and plasma CgA data (ITT) 
ITT 
16.2.6.2 
T_EG2 
14.2.2.2* 
Summary of serum gastrin and plasma CgA data (PP) 
PP 
16.2.6.2 
T_EG2 
14.3  
 SAFETY DATA 
 
 
14.3.1.1 
Summary of treatment-emergent adverse events 
Safety 
16.2.7.1 
T_AE1 
14.3.1.2 
Summary of drug-related treatment-emergent adverse events 
Safety 
16.2.7.1 
T_AE1 
14.3.2.1 
Listing of fatal adverse events 
Safety 
16.2.7.1 
L_AE1_PG  
14.3.2.2 
Listing of non-fatal serious adverse events 
Safety 
16.2.7.1 
L_AE1_PG  
14.3.2.3 
Listing of other significant adverse events 
Safety 
16.2.7.1 
L_AE1_PG  
14.3.3   
Narratives of deaths, other serious and significant adverse events 
Safety 
- 
- 
14.3.4   
Summary of laboratory values of potential clinical importance 
Safety 
16.2.8.1, 
16.2.8.3 
T_LB1  
14.3.5.1 
Summary of chemistry laboratory values 
Safety 
16.4 
T_LB2  
14.3.5.2 
Summary of haematology laboratory values 
Safety 
16.4 
T_LB2  
14.3.5.3 
Summary of urinalysis results 
Safety 
16.4 
T_UR1 
14.3.6.1 
Summary of vital signs 
Safety 
16.4 
T_VS1 
14.3.7.1 
Summary of ECG values 
Safety 
16.4 
T_EG2 
14.3.7.2 
Summary of ECG values and changes in ECG values of potential clinical 
importance  
Safety 
16.4 
T_EG3 
 
 


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Figure 
Description 
Population 
Source 
Listing 
Template 
(Shells below) 
14.3 
SAFETY AND EFFICACY DATA 
 
 
 
14.3.1 
Individual netazepide plasma concentration plots  
Safety 
16.2.6.1 
F_PK1 
14.3.2.1.1 
Mean ± SD serum gastrin – time plot (ITT) 
ITT 
16.2.6.2 
F_PK4 
14.3.2.1.2* 
Mean ± SD serum gastrin – time plot (PP) 
PP 
16.2.6.2 
F_PK4 
14.3.2.2.1 
Mean ± SD plasma CgA – time plot (ITT) 
ITT 
16.2.6.2 
F_PK4 
14.3.2.2.2* 
Mean ± SD plasma CgA – time plot (PP) 
PP 
16.2.6.2 
F_PK4 
 
*Only produce if there is a difference between ITT and PP populations 
 
The following listings will be produced (templates found in section 19.2.3) 
 
Listing 
Description 
Template (Shells 
below) 
16.2.1  
 Study dates & disposition of patients 
 
16.2.1.1 
Listing of study dates 
L_SD1_PG 
16.2.1.2 
Listing of reasons for withdrawal 
L_SD2_PG 
16.2.1.3 
Listing of screen failures 
L_SD3_PG 
16.2.2  
 Protocol deviations 
 
16.2.2.1 
Listing of patients with inclusion/exclusion criteria deviations 
L_DV1_PG 
16.2.2.2 
Listing of patients with other protocol deviations 
L_DV2_PG 
16.2.3  
 Analysis sets, including patients excluded from analysis 
 
16.2.3.1 
Listing of analysis populations 
L_AN1_PG 
16.2.4  
 Demographic data & concomitant medication 
 
16.2.4.1 
Listing of demographic characteristics 
L_DM1_PG  
16.2.4.2 
Listing of concomitant medications 
L_CM1_PG  
16.2.4.3 
Listing of medical history: barrett’s esophagus 
L_MH1_PG 
16.2.4.4 
Listing of proton pump inhibitor use 
L_PP1_PG 


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Listing 
Description 
Template (Shells 
below) 
16.2.5  
 Study drug administration 
 
16.2.5.1 
Listing of study drug administration and treatment compliance 
L_EX_PG  
16.2.6  
 Pharmacokinetic and Efficacy data 
 
16.2.6.1 
 Listing of netazepide plasma pharmacokinetic data  
L_PK1_PG  
16.2.6.2 
 Listing of serum gastrin and plasma CgA data 
L_PK4_PG 
16.2.7  
 Adverse events 
 
16.2.7.1 
Listing of all adverse events 
L_AE1_PG  
16.2.7.2 
Listing of serious adverse events 
L_AE1_PG 
16.2.7.3 
Listing of adverse events leading to withdrawal from study 
L_AE1_PG  
16.2.8  
 Laboratory values 
 
16.2.8.1 
Listing of clinical chemistry abnormalities of potential clinical importance  
L_LB1_PG 
16.2.8.2 
Listing of all clinical chemistry laboratory data for patients with PCI abnormalities 
L_LB2_PG 
16.2.8.3 
Listing of haematology abnormalities of potential clinical importance 
L_LB1_PG 
16.2.8.4 
Listing of all haematology laboratory data for patients with PCI abnormalities 
L_LB2_PG 
16.2.8.5 
Listing of urinalysis results 
 
16.2.9  
 ECG variables 
 
16.2.9.1 
Listing of ECG values of potential clinical importance 
L_EG1_PG  
16.2.9.2 
Listing of abnormal ECG findings  
L_EG2_PG  
 
Complete listings of all data collected in this study will also be produced. 
 
 


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19.2 Data Display Specifications 
19.2.1 Table Outlines 
Template T_SD1 
Table   10.1 
Summary of Patient Disposition 
Population 
Status 
Reason for Withdrawal 
Treatment 1 
Etc 
All Patients 
 
 
 
Columbia 
Cambridge 
All Sites 
 
Columbia 
Cambridge 
All Sites 
 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
Screened 
Included 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
Safety  
Included 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
Completed 
 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
Withdrawn 
 
 
 
 
 
 
 
 
Death 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
Adverse Events 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
Withdrawal by patient 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
Physician decision 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
Protocol violation 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
Pregnancy 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
Study terminated by 
Sponsor 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
Lost to follow-up 
 
 
 
 
 
 
 
 
 
Other 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
 
 
 
 
 
 
 
 
 
 
Intent to Treat 
Included 
 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
Completed 
 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
Withdrawn 
 
 
 
 
 
 
 
 
 
Death 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
 
Adverse Events 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
 
Withdrawal by patient 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
 
Physician decision 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
 
Protocol violation 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 


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Pregnancy 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
 
Study terminated by 
Sponsor 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
 
Lost to follow-up 
 
 
 
 
 
 
 
 
Other 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
Per Protocol 
Included 
 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatment groups 
 
 
 
Template T_CM1 
Table   10.2.2 
Summary of Concomitant Medications 
 
Generic Term 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
 
n 
% 
n 
% 
Any medication 
 
 
 
 
 
 
 
 
 
Medication 1 
 
 
 
 
Medication 2 
 
 
 
 
Medication 3 
 
 
 
 
Medication 4 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatment groups 
 
 
 
 
 


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Template T_COMP1 
Table   10.2.2 
Summary of Treatment Compliance 
 
 
 
 
 
 
 
 
 
Variable 
Treatment 
Visit 
n 
Mean 
SD 
Median Min 
Max 
Compliance (%) 
Treatment 1  (N=xx) 
 
 
 
 
 
 
 
 
Programming notes: 
Continued with all treatment groups 
 
 
Template T_MH1 
Table   10.2.2 
Summary of Medical History: Barrett’s Esophagus 
 
Barrett’s mucosa 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
 
n 
% 
n 
% 
Circumferential 
 
 
 
 
 
 
 
 
 
Non-circumferential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Template T_DM1 
Table   14.1 
Summary of Demographic Characteristics 
Variable 
Statistics 
Screen Failures 
(N=xx) 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
Etc 
All Treated Patients 
(N=xx) 
Age (y) 
n 
 
 
 
 
 
Mean 
 
 
 
 
 
SD 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
Gender 
N 
 
 
 
 
 
Female 
 
 
 
 
 
Male 
 
 
 
 
 
Race 
American Indian 
 
 
 
 
 
 
Asian/ Pacific Islander 
 
 
 
 
 
 
Black 
 
 
 
 
 
 
Hispanic 
 
 
 
 
 
 
White 
 
 
 
 
 
 
Other 
 
 
 
 
 
Height (cm) 
n 
 
 
 
 
 
Mean 
 
 
 
 
 
SD 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
Weight (kg) 
n 
 
 
 
 
 
Mean 
 
 
 
 
 
SD 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 


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Variable 
Statistics 
Screen Failures 
(N=xx) 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
Etc 
All Treated Patients 
(N=xx) 
BMI (kg/m2) 
n 
 
 
 
 
 
Mean 
 
 
 
 
 
SD 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
Waist 
circumference 
(cm) 
n 
 
 
 
 
 
Mean 
 
 
 
 
 
SD 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
Cigarettes* 
(daily) 
n 
 
 
 
 
 
Mean 
 
 
 
 
 
SD 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
Alcohol* 
(units/week) 
n 
 
 
 
 
 
Mean 
 
 
 
 
 
SD 
 
 
 
 
 
Median 
 
 
 
 
 
Min 
 
 
 
 
 
Max 
 
 
 
 
 
 
*includes only those patients who smoke/drink alcohol 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatment groups and additional demographic characteristics 
 
 
 


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Template T_AE1 
Table  14.3.3.xx 
Summary of Treatment-Emergent Adverse Events 
 
 
Treatment 1 (N=xx) 
Treatment 2 (N=xx) 
Etc 
System Organ Class 
Preferred Term 
n (%) 
 
n (%) 
 
 
Number of patients with AEs 
 
x (xx.x)  
x (xx.x)  
 
Gastrointestinal disorders 
Total number of patients 
x (xx.x)  
x (xx.x)  
 
 
Abdominal discomfort 
x (xx.x) [xx] 
x (xx.x) [xx] 
 
 
Abdominal pain 
x (xx.x) [xx] 
x (xx.x) [xx] 
 
 
 
 
 
 
 
 
Nervous system disorders 
Total number of patients 
 
 
 
 
 
 
Dizziness 
 
 
 
 
 
 
Headache 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
n = number of patients (patients with 1 adverse event are counted only once per system organ class and preferred term) 
[ ] = number of TEAEs  
Based on MedDRA version xx.x 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatment groups 
 
SOCs and PTs are sorted in decreasing order of frequency 
 
Presented for all applicable MedDRA system organ classes and terms.  


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Template T_LB1 
Table  14.3.4.xx 
Summary of Laboratory Values of Potential Clinical Importance 
 
 
 
 
Laboratory Test (units) 
Treatment 
Visit 
n   (%) 
 
Treatment 1  (N=xx) 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all tests, treatment groups and time points. n = total number of results for that parameter 
 
 
 
 
Template T_LB2 
Table  14.3.5.xx 
Summary of Chemistry Laboratory Values 
 
 
 
 
 
 
 
 
 
Change from Baseline 
Laboratory Test 
(units) 
Treatment 
Visit 
n 
Mean 
SD 
Median Min 
Max 
n 
Mean 
SD 
Median 
Min 
Max 
 
Treatment 1  (N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatments and time points 
For Ki67 Expression data exclude first column 
 
 
 
 


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Template T_UR1 
Table  14.3.5.xx 
Summary of Urinalysis Results 
 
Visit 
Result 
Treatment 1 (N=xx) 
Treatment 2 (N=xx) 
Laboratory Test 
n 
% 
n 
% 
 
Time 1 
Positive 
X 
x 
 
 
 
 
Negative 
X 
X 
 
 
 
 
Not Done 
x 
 
 
 
 
Time 2 
Positive 
 
 
 
 
 
 
Negative 
 
 
 
 
 
 
Not Done 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Results recorded as received, e.g. Negative, Trace, etc; urine pH summarized as <5, 5-8, >8 
Continued with all treatment groups and time points.  The n’s sum to N but the calculated percentages exclude Not Done. 
 
 
Template T_VS1 
Table  14.3.6.xx 
Summary of Vital Signs 
 
 
 
 
Change from Baseline 
Variable (units) 
Treatment 
Visit 
n 
Mean 
SD 
Median 
Min 
Max 
n 
Mean 
SD 
Median Min 
Max 
Systolic BP (mmHg) 
Treatment 1  (N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all variables, treatments and time points 
 
 


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Template T_EG2 
Table  14.3.7.xx 
Summary of ECG Values 
 
 
 
 
Change from Baseline 
Variable (units) 
Treatment 
Visit 
n 
Mean 
SD 
Median 
Min 
Max 
n 
Mean 
SD 
Median 
Min 
Max 
Heart Rate  (bpm) 
Treatment 1 (N=xx)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 2 (N=xx)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PR Interval  (msec) 
Treatment 1 (N=xx)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 2 (N=xx)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatment groups and time points 
 
Do not summarise RR or QRS axis  
 


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Page 33 of 46 
Template T_EG3 
Table  14.3.7.xx 
Summary of ECG Values and Changes in ECG Values of Potential Clinical Importance 
Variable 
Treatment 
Visit 
451 – 480 msec 
481 – 500 msec 
> 500 msec 
>30-60 msec 
Increase 
>60 msec  
Increase 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
QT interval 
Treatment 1 
(N=xx) 
Time 1 
 
 
 
 
 
 
 
 
 
 
Time 2 
 
 
 
 
 
 
 
 
 
 
Time 3 
 
 
 
 
 
 
 
 
 
 
Treatment 2 
(N=xx) 
Time 1 
 
 
 
 
 
 
 
 
 
 
Time 2 
 
 
 
 
 
 
 
 
 
 
Time 3 
 
 
 
 
 
 
 
 
 
 
QTcB interval 
 
Treatment 1 
(N=xx) 
Time 1 
 
 
 
 
 
 
 
 
 
 
Time 2 
 
 
 
 
 
 
 
 
 
 
Time 3 
 
 
 
 
 
 
 
 
 
 
Treatment 2 
(N=xx) 
Time 1 
 
 
 
 
 
 
 
 
 
 
Time 2 
 
 
 
 
 
 
 
 
 
 
Time 3 
 
 
 
 
 
 
 
 
 
 
QTcF interval 
 
Treatment 1 
(N=xx) 
Time 1 
 
 
 
 
 
 
 
 
 
 
Time 2 
 
 
 
 
 
 
 
 
 
 
Time 3 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
Programming notes: 
Continued with all treatments and time points.  n = total number of results for that parameter 
 
 
 
 
 
 
 
 
 
 
 


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Template T_PK1 
Table   14.2.xx 
Summary of Netazepide Plasma Pharmacokinetic Peak and Trough Concentration Data 
Measurement 
(units) 
Treatment 
Visit 
n 
Mean 
SD 
%CVb 
Median 
Min 
Max 
Geom 
Mean 
95% CI 
(Lower,Upper) 
 
 
 
 
 
 
 
 
 
 
 
 
Peak 
Treatment 1 
(N=xx) 
Visit 3 
x 
xxxx.x 
 
xx.x 
xxxx.x 
xxxx 
xxxx 
 
(xxxx.x,xxxx.x) 
 
Visit 4 
x 
xxxx.x 
xx.xx 
xx.x 
xxxx.x 
xxxx 
xxxx 
 
(xxxx.x,xxxx.x) 
 
 
 
 
 
 
 
 
 
 
(xxxx.x,xxxx.x) 
Trough 
Treatment 1 
(N=xx) 
Visit 3 
x 
xxxx.x 
 
xx.x 
xxxx.x 
xxxx 
xxxx 
 
 
 
Visit 4 
x 
xxxx.x 
xx.xx 
xx.x 
xxxx.x 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Listing 16.2.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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19.2.2 Figure Outlines 
 
Template F_PK1 
Figure   14.3.1 
Individual Netazepide Plasma Concentration-Time Plots 
 
Programming notes: 
All patients will be displayed in the same graph on one page. 
 
 
3
Visit
4
Patient
3
1001
4
1002
0
200
400
600
800
1000
1200
1400
1600
YF476 concentration (ng/mL)
Trough
Peak
Trough
Peak


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Template F_PK4 
Figure   14.3.4 
 Mean ± SD serum gastrin – time plot (ITT) 
 
 
 
 
 


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19.2.3 Listing Outlines 
Template L_SD1_PG 
Listing 16.2.x.xx 
Listing of Study Dates 
Treatment 
Patient 
Visit 1 
Visit 2 
Week 6 Visit 
Week 12 Visit 
Follow Up 
 
Programming notes: 
Lists dates for screening, each dosing period and follow up 
 
For crossover studies use Sequence instead of Treatment 
 
Template L_SD2_PG 
Listing 16.2.x.xx 
Listing of Reasons for Withdrawal 
 
Treatment       
 
Patient 
Date of 
Withdrawal     
Study 
Day 
 
Reason 
 
Programming notes: 
Reason for withdrawal is concatenation of reason and details 
 
 
 
Template L_SD3_PG 
Listing 16.2.x.xx 
Listing of Screen Failures 
 
Patient 
Date of 
Screen Failure     
 
Failure Category 
 
Details 
 
 
 


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Template L_DV1_PG 
Listing 16.2.x.xx 
Listing of Patients with Inclusion/Exclusion Criteria Deviations 
Treatment 
Patient 
Type 
Criterion 
 
 
Inclusion 
 
 
 
Exclusion 
 
 
 
Template L_DV2_PG 
Listing 16.2.x.xx 
Listing of Patients with Other Protocol Deviations 
Treatment 
Patient 
Protocol Deviation 
 
 
Template L_AN1_PG 
Listing 16.2.x.xx 
Listing of Analysis Populations 
Treatment 
Patient 
Screened 
Population 
Safety 
Population 
ITT Population 
PP Population 
 


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Template L_DM1_PG 
Listing 16.2.x.xx 
Listing of Demographic Characteristics 
Treatment  
Patient 
Date of visit 
Date of birth 
Age 
(y) 
Gender 
Race 
Ethnic origin 
Height 
(cm) 
Weight 
(kg) 
BMI (kg/m2) 
Etc (units) 
Treatment 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming notes: 
A by-patient listing of demographic characteristics including: 
Treatment 
Patient 
Date of visit 
Date of birth 
Age 
Gender 
Race / Ethnic Origin 
Height (if collected only once during the study) 
Weight (if collected only once during the study) 
Smoking History 
Alcohol Consumption 
Additional study-specific demography characteristics included on the CRF 
 


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Template L_CM1_PG 
Listing 16.2.x.xx 
Listing of Concomitant Medications 
Treatment 
Patient 
Drug Name/ 
Indication 
Dose/ 
Freq/Route 
Date/time Started/ 
Date Stopped 
Time Since Last 
Dose 
Started Pre- 
Trial? 
Ongoing 
Medication? 
 
 
Programming notes: 
Include dose and units (e.g. 5 mg)/Freq/Route 
 
Template L_PP1_PG 
Listing 16.2.x.xx 
Listing of Proton Pump Inhibitor Use 
Treatment 
Patient    
Date/Time 
Is patient taking 
proton pump 
inhibitor? 
Have they been 
taking it for at least 
12 months? 
How often 
does the 
patient 
take the 
PPI? 
Generic 
name 
Dose 
Date Started 
Treatment 1   
1001     
01JAN2002 
Yes 
Yes 
Once daily 
    
    
 
                             
 
 
 
 
 
 
 
 
 
Template L_MH1 
Listing 16.2.x.xx 
Listing of Medical History: Barrett’s Esophagus 
Treatment 
Patient    
Date/Time 
Endoscopy 
Most 
recent 
endoscopy 
date 
Intestinal 
metaplasia 
and no 
dysplasia 
Is Barrett’s 
mucosa 
circumferential 
Maximum 
measurement 
of Barrett’s 
mucosa (cm) 
Treatment 1   
1001     
01JAN2002   
Yes  
 
Yes    
Yes    
 
 
 


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Template L_EX1_PG 
Listing 16.2.x.xx 
Listing of Study Drug Administration 
Treatment 
Patient   
Start Date/  
Start Time of Dose 
Stop Date/  
Stop Time of Dose 
Dur- 
ation 
(days) 
Dose 
Dose 
Unit 
Formulation/ 
Route 
Frequency 
Visit 3 
Compliance 
(%) 
Visit 4 
Compliance 
(%) 
Treatment 1   
1001     
01JAN2002   
15FEB2002  
46  
25     
mg     
Tablet/       
2xday 
 
 
                             
 
23:59        
15:30 
 
 
 
Oral 
 
 
 
 
 
Template L_AE1_PG 
Listing 16.2.x.xx 
Listing of All Adverse Events 
Treatment  
Patient 
System Organ Class / 
Preferred Term/ 
Verbatim Text 
Outcome/  
Onset Date/Time/  
Resolved Date/Time/ 
Duration 
Time Since Last 
Dose 
Severity/ 
Serious/ 
Withdrawal 
Frequency/  
Action Taken (1)/ 
Other Action 
Taken 
Related to Study 
Drug/ 
Treatment 
Emergent? 
Treatment 1 
1001 
Gastrointestinal Disorders / 
Intestinal Spasm / 
Entero-spasm 
Resolved/ 
24SEP2003 13:05/ 
27OCT2003 7:50/ 
34d 4h 5m  
10d 7h 3m 
Mild/ 
No/ 
Yes 
Intermittent/ Dose 
not changed/ 
None  
Possibly/ 
Yes 
(1) Action Taken with Study Treatment 
 
Programming notes:  
For the listing of “other significant AEs” include (from ICH E3) AEs leading to withdrawal, AEs leading to dose reduction (including drug withdrawn, interrupted, 
reduced or similar) and AEs with AEOSE=Y.  If AEOSE has not been collected then use “Otherwise significant” in the CRF. 
 
 
 


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Page 42 of 46 
Template L_LB1_PG 
Listing 16.2.x.xx 
Listing of clinical chemistry abnormalities of potential clinical importance 
Treatment 
Subject 
Laboratory test (units) 
Planned  
Relative  
Time 
Date/Time 
Study 
Day 
 
Value 
Reference Interval 
Clinically 
Significant? 
Treatment 1 
1001  
Alk Phos (U/L) 
Time 1 
01JAN2002 
13:34 
 -1        
 64.00  
 32.0 - 92.0       
Y 
 
 
 
Time 2 
01APR2002 
07:22 
 85       
 84.00  
 32.0 - 92.0       
Y 
 
 
ALT (U/L) 
Time 1 
01JAN2002 
18:56 
 -1         
 29.00  
 10.0 - 40.0       
Y 
 
 
 
Time 2 
01APR2002 
09:22 
 85        
 70.00  
 10.0-  40.0       
Y 
 
 
 
 
 
 
 
 
 
 
Programming notes: 
Lists only Laboratory results identified as ‘clinically significant’ in the CRF 
 
 
 
 
 
 
 
 
 
 


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Template L_LB2_PG 
Listing 16.2.x.xx 
Listing of all clinical chemistry laboratory data for subjects with PCI abnormalities 
Treatment 
Subject 
Planned 
Relative 
Time 
Date/Time 
 
Alkaline Phosphatase (IU/L) 
Alanine Amino Transferase 
(IU/L) 
Aspartate Amino Transferase 
(IU/L) 
Total Bilirubin (UMOL/L) 
Result 
Result 
 
 
Result 
 
 
Result 
 
 
                                                                                                   xx*                                                              x.xx 
Treatment 
Subject 
Planned 
Relative 
Time 
Date/Time 
 
Chloride (MMOL/L) 
Glucose (MMOL/L) 
Potassium (MMOL/L) 
Sodium (MMOL/L) 
Result 
 
 
Result 
 
 
Result 
 
 
Result 
 
 
 
Treatment 
Subject 
Planned 
Relative 
Time 
Date/Time 
 
Calcium (MMOL/L) 
Creatinine (UMOL/L) 
Etc. 
Result 
 
 
Result 
 
 
Result 
 
 
 
* Value of potential clinical significance  
Programming notes: 
Lists only subjects identified as ‘clinically significant’ in the CRF  
Include all parameters for the study following the order from the lab report (above is a guide only) 
 
 
 
 
 
 
 
 


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Template L_EG1_PG 
Listing 16.2.x.xx 
Listing of ECG Values of Potential Clinical Importance 
 
 
 
 
 
QT Int. (msec) 
QTcB (msec) 
QTcF (msec) 
Treatment  
 
Patient 
Planned 
Relative Time 
Date/Time 
Heart 
Rate 
(bpm) 
PR Int. 
(msec) 
QRS 
Dur. 
(msec) 
QRS 
Axis 
(deg) 
Observed 
Change 
from 
Baseline 
Observed 
Change 
from 
Baseline 
Observed 
Change 
from 
Baseline 
 
 
24 H 
26SEP2012:09:57 
63 
148 
78 
50 
390 
32.7 * 
399 
-27.7 
396 
-6.5 
 
* Value of potential clinical importance 
Programming notes: 
Do not list RR 
 
 
Template L_EG2_PG 
Listing 16.2.x.xx 
Listing of Abnormal ECG Findings 
Treatment 
Patient 
 
Planned Relative 
Time 
 
 
Date/Time 
ECG Finding 
 
Comment on Clinical 
Significance  
 
Programming notes: 
Lists only values with Normal variant=’No’ or with comment on ECG result 
 
ECG Finding contains Physician’s Opinion from CRF and relates to whole trace (not individual parameters), e.g. Normal, Abnormal -  NCS or  Abnormal - CS 
 
 


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Page 45 of 46 
Template L_PK1_PG 
Listing 16.2.6.xx 
Listing of Netazepide Plasma Pharmacokinetic Parameters  
 
Treatment 
Patient 
 
 
Date 
Planned 
Relative Time 
 
Concentration (units) 
Peak (Cmax)      Trough (Cmin) 
 
 
 
 
 
 
 
 
 
Template L_PK4_PG 
Listing 16.2.6.xx 
Listing of serum gastrin and plasma CgA data 
 
Treatment 
Patient 
 
 
Date 
Planned 
Relative Time 
 
Serum Gastrin  
Plasma Cg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Page 46 of 46 
Appendix A: Sample Page Layout 
Trio Medicines Ltd : T-016 
Page x of y* 
Population:  [Pop] 
____________________________________________________________________________________________________________________________ 
 
Table [number] [title] 
 
 
Column headers 
 
 
Main body of output 
 
 
 
Source: Listing [16.2.xx] 
 
 
Footnotes about the table or listing text go here. 
 
____________________________________________________________________________________________________________________________ 
Program:  [Prog Name] 
Produced By:[Username] 
[Date] 
HMR 10-505 
 
*y = last page of individual output 
Font size will be Arial 9.5pt. The following margins will be used: Left:  1", Right:  1", Top: 1", Bottom:  1"