Conditions: Diabetes Mellitus Obesity
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 77
Healthy volunteers: yes

Brief summary:
A randomised, placebo controlled Phase I study to investigate investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of Y14 in adult subjects.

Detailed description:
Objectives:

Primary Objective

* To investigate the safety and tolerability of single doses of Y14 in overweight/obese but otherwise healthy male subjects.
* To investigate the safety and tolerability of multiple doses of Y14 in overweight/obese male subjects with normal glucose tolerance, Type 2 diabetes or prediabetes.

Secondary Objectives

* To assess the pharmacokinetic (PK) profile of single doses of Y14 in overweight/obese but otherwise healthy male subjects.
* To assess the PK profile of multiple ascending doses of Y14 in overweight/obese male subjects with normal glucose tolerance, Type 2 diabetes or prediabetes.

Exploratory Objective

* To investigate the effects of multiple doses of Y14 on food consumption, body weight and glucose tolerance in overweight/obese male subjects with normal glucose tolerance, Type 2 diabetes or prediabetes.

Arms:
arm 1: Y14 single dose, subcutaneous arm 2: Y14 single dose, subcutaneous arm 3: Y14 single dose, subcutaneous arm 4: Y14 single dose, subcutaneous arm 5: Y14 single dose, subcutaneous arm 6: Y14 single dose, subcutaneous arm 7: 5 subcutaneous injections of 0.9% saline, over a 4 week treatment period arm 8: Y14 multiple dose, subcutaneous 5 doses over a 4 week treatment period: escalating doses to a max of 26 mg arm 9: Y14 multiple dose, subcutaneous 4 doses over a 4 week treatment period: escalating doses to a max of 36 mg arm 10: Y14 multiple dose, subcutaneous 4 doses over a 4 week treatment period: escalating doses to a max of 36 mg arm 11: Single subcutaneous injection of 0.9% saline arm 12: Y14 single dose, subcutaneous arm 13: Y14 single dose, subcutaneous arm 14: Y14 single dose, subcutaneous arm 15: Y14 single dose, subcutaneous arm 16: Y14 single dose, subcutaneous

Interventions: intervention 1: Y14 intervention 2: Placebo
Intervention descriptions: intervention 1: Gut hormone analogue intervention 2: 0.9% saline

Protocol document:
Prot_SAP_000.pdf: 
 
 
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A randomised, placebo controlled first in human study to investigate the 
safety, tolerability, pharmacokinetics and pharmacodynamics of Y14 in 
adult subjects 
 
 
 
 
 
Protocol Number: 
 
ICIM/2016/Y14-01 
Covance Study Number: 
 
1003346-8313248 
EudraCT Number: 
 
2017-000380-33 
 
Product: 
 
Y14 
Indication: 
 
Obesity 
Clinical Phase: 
 
I 
Sponsor Chief 
Investigator (Imperial 
College) 
Professor Steve Bloom MD, FRCP, DSc, FRCPath 
 
Principal Investigator  
(Covance) 
Dr Jim Bush MBChB, PhD, MRCS, MFPM  
 
Sponsor: 
 
 
Imperial College London 
 
 
 
 
This protocol is the confidential property of Imperial College London, and is 
intended solely for the guidance of this clinical investigation. This protocol may 
not be disclosed to parties not associated with the clinical investigation or used 
for any other purpose without the prior written consent of Imperial College 
London. 
 
 
 
 
 
 
 


 
 
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PROTOCOL REVISION HISTORY 
 
DATE/NA
ME 
DESCRIPTION 
13 Feb 
2017 
First Version of the final protocol 
14 June 
2017 
Non-Substantial Protocol Amendment 1  
 
5th August 
2017 
Protocol Version 2.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ............................................................................ 3 
2 
LIST OF ABBREVIATIONS...................................................................... 5 
3 
INTRODUCTION ....................................................................................... 8 
3.1 
Background Information for Y14 ................................................................ 8 
3.2 
Risk Assessment .......................................................................................... 9 
3.3 
Urgent safety measures .............................................................................. 10 
4 
STUDY OBJECTIVES ............................................................................. 11 
4.1 
Primary Objective ...................................................................................... 11 
4.2 
Secondary Objectives ................................................................................ 11 
4.3 
Exploratory Objective ................................................................................ 11 
5 
INVESTIGATIONAL PLAN .................................................................... 12 
5.1 
Overall Study Design ................................................................................. 12 
5.1.1 
Part A (Single Ascending Dose) ................................................................ 12 
5.1.2 
Part B (Multiple Ascending Dose) ............................................................ 14 
5.1.3 
Safety Committee ...................................................................................... 17 
5.1.4 
Stopping Rules ........................................................................................... 18 
5.1.5 
Discussion of Study Design ....................................................................... 18 
5.2 
Study Population ........................................................................................ 19 
5.2.1 
Subject Inclusion Criteria .......................................................................... 19 
5.2.2 
Subject Exclusion Criteria ......................................................................... 20 
5.2.3 
Restrictions ................................................................................................ 22 
5.2.3.1 
Avoidance of Pregnancy ............................................................................ 23 
5.2.3.2 
Acceptable Forms of Contraception .......................................................... 23 
5.2.3.3 
Time Period for the Collection of Pregnancy Information ........................ 23 
5.2.3.4 
Follow-up in the Event of a Pregnancy ..................................................... 23 
5.2.4 
Subject Withdrawals .................................................................................. 24 
6 
STUDY TREATMENT ............................................................................. 25 
6.1 
Investigational Product(s) .......................................................................... 25 
6.1.1 
Supply, Packaging and Labelling .............................................................. 25 
6.1.2 
Storage and Handling Procedures .............................................................. 25 
6.1.3 
Accountability ............................................................................................ 26 
6.2 
Dosage and Administration ....................................................................... 26 
6.3 
Treatment Strategy ..................................................................................... 26 
6.4 
Warnings and Precautions ......................................................................... 27 
6.5 
Prior and Concomitant Medication ............................................................ 27 
6.6 
Method of Assigning Subjects to Treatment Groups ................................ 27 
6.7 
Randomisation Procedures ........................................................................ 28 
6.8 
Maintenance of Randomisation Codes ...................................................... 28 
6.9 
Blinding ..................................................................................................... 28 


 
 
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7 
STUDY PROCEDURES ........................................................................... 29 
7.1 
Pharmacokinetic Assessments ................................................................... 31 
7.1.1 
Plasma Samples ......................................................................................... 31 
7.2 
Pharmacodynamic/Efficacy Assessments ................................................. 31 
7.2.1 
Visual Analogue Scales ............................................................................. 31 
7.2.2 
Energy Intake ............................................................................................. 31 
7.2.3 
Body Weight .............................................................................................. 32 
7.2.4 
Fluid Intake/Output .................................................................................... 32 
7.2.5 
Immunogenicity ......................................................................................... 32 
7.3 
Safety Assessments .................................................................................... 32 
7.3.1 
Adverse Events .......................................................................................... 32 
7.3.2 
Reporting of Adverse Events ..................................................................... 33 
7.3.3 
Categorisation of Adverse Events ............................................................. 34 
7.3.4 
Causal Relationship Assessment ............................................................... 34 
7.3.5 
Action Taken ............................................................................................. 35 
7.3.6 
Outcome ..................................................................................................... 35 
7.3.7 
Coding of Adverse Events ......................................................................... 35 
7.4 
Clinical Laboratory Safety Tests ............................................................... 36 
7.5 
Clinical Safety Assessments ...................................................................... 37 
7.5.1 
Vital Signs ................................................................................................. 37 
7.5.2 
12-Lead ECG ............................................................................................. 37 
7.5.3 
Medical History ......................................................................................... 37 
7.5.4 
Physical Examination ................................................................................ 37 
7.5.5 
Bedside glucose testing .............................................................................. 37 
7.5.6 
Local Injection Site Reactions ................................................................... 37 
8 
DATA COLLECTION .............................................................................. 39 
9 
EVALUATION OF STUDY DATA ......................................................... 40 
9.1 
Evaluation of Pharmacokinetic Parameters ............................................... 40 
9.2 
Evaluation of Pharmacodynamic Measures ............................................... 40 
9.2.1 
Visual Analogue Scales ............................................................................. 40 
9.2.2 
Energy Intake ............................................................................................. 40 
9.2.3 
Body Weight .............................................................................................. 40 
9.2.4 
Immunogenicity ......................................................................................... 40 
9.3 
Evaluation of Safety .................................................................................. 40 
10 
STATISTICAL METHODS ...................................................................... 41 
10.1 
Primary and Secondary Target Variables .................................................. 41 
10.2 
Sample Size Determination ....................................................................... 41 
10.3 
Subject Population for Analyses ................................................................ 41 
10.4 
Pharmacokinetic Analysis ......................................................................... 42 
10.5 
Pharmacodynamic Analysis....................................................................... 43 
10.6 
Safety Data Analysis .................................................................................. 43 
11 
REGULATORY AND ETHICAL ISSUES .............................................. 44 


 
 
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11.1 
Regulatory and Ethics Review and Approval ............................................ 44 
11.2 
Informed Consent ...................................................................................... 44 
11.3 
Indemnity and Compensation .................................................................... 45 
12 
STUDY MANAGEMENT ........................................................................ 46 
12.1 
Quality Assurance and Quality Control ..................................................... 46 
12.2 
Protocol Adherence ................................................................................... 46 
12.3 
Documents Necessary for Initiation of Study ............................................ 46 
12.4 
Study Monitoring ....................................................................................... 47 
12.5 
Study Closure............................................................................................. 47 
12.6 
Study Record Retention ............................................................................. 47 
12.7 
Publication Policy ...................................................................................... 48 
13 
REFERENCES .......................................................................................... 49 
2 
 LIST OF ABBREVIATIONS  
adm 
ADR 
Administration 
Adverse drug reaction 
AE 
Adverse event 
ALK 
ALS 
Alkaline phosphatase 
Advanced life support 
ALT 
Alanine aminotransferase 
API 
Active pharmaceutical ingredient 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration time curve 
BMI 
Body mass index (kg/m2) 
CI 
Confidence interval 
Cmax 
CNS 
Maximum plasma concentration 
Central Nervous System  
CRF 
CRO 
Case report form 
Contract research organisation  
CRP 
CRU 
C reactive protein 
Clinical research unit 
CV 
DEBQ 
DSM 
Coefficient of variation 
Dutch Eating Behaviour Questionnaire 
Diagnostic and Statistical Manual 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EU  
European Union  
FDA 
Food and Drug Administration 
FIH 
FSH 
First in human 
Follicle-stimulating hormone 
FT4 
Free thyroxine 


 
 
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GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transpeptidase 
GLP 
Good Laboratory Practice 
GLP-1 
Glucagon-like peptide-1 
GMP 
Good Manufacturing Practice 
h 
HbA1c 
Hour 
Haemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HED 
Human equivalent dose 
hERG 
Human ether-a-go-go related gene 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IMP 
Investigational medicinal product 
IMPD 
ISO 
Investigational medicinal product dossier 
International Organisation for Standarisation  
IUD 
Intrauterine device 
IUS 
LC-MS/MS 
Intrauterine system 
Liquid chromatography-tandem mass spectrometry 
LDH 
LH 
Lactate dehydrogenase 
Luteinizing hormone 
MABEL 
Minimum anticipated biological effect level 
MAD 
Multiple ascending dose 
Max 
MedDRA 
Maximum 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
Min 
ml 
mm 
Minimum 
Milliliter 
Millimeter 
MRSD 
Minimum recommended starting dose 
MTD 
ND 
ng 
nM 
Maximum tolerated dose 
Not determined 
Nanogram 
Nanomole 
NOAEL 
OECD 
No observed adverse effect level 
Organisation for Economic Co-operation and Development 
OGTT 
Oral glucose tolerance test 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Pancreatic polypeptide 
PT 
Prothrombin time 
PTFE 
Polytetrafluoroethylene 
PYY 
Peptide YY 
QMS 
Quality management system 
QP 
Qualified person 


 
 
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Ro 
Extent of accumulation in plasma 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SC 
SCOFF 
Subcutaneous 
Sick Control One stone Fat Food questionnaire 
SD 
Standard Deviation 
SEM 
SGLT-2 
Standard Error of the Mean 
Sodium/Glucose cotransporter 2 
SI 
Statutory Instrument 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
TEAE 
Apparent terminal half life 
Treatment Emergent Adverse Event 
tmax 
TP 
Time to maximum plasma concentration 
Treatment period 
TSH 
Thyroid stimulating hormone 
UK 
United Kingdom 
US 
United States of America 
VAS 
Visual analogue scale 
WHO DD 
World Health Organization Drug Dictionary 
Y1r 
Neuropeptide Y subtype 1 receptor 
Y2r 
Neuropeptide Y subtype 2 receptor 
Y4r 
Neuropeptide Y subtype 4 receptor 
Y5r 
Neuropeptide Y subtype 5 receptor 
λz 
Apparent terminal rate constant 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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3 
INTRODUCTION   
A powerful and complex physiological system exists in humans to ensure that adiposity and 
body weight remain constant despite variations in daily food intake and energy expenditure 
[1].  Daily energy intake is determined not only by the composition of the food being eaten but 
also by an individual’s appetite, which can be considered as their drive to eat. The level of 
appetite is controlled predominantly by peptide hormones released in the gut. In particular, 
pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), oxyntomodulin and peptide YY 
(PYY) increase satiety and therefore reduce food intake following a meal [2-7]. However, 
excessive appetite and the easy availability of highly calorific foods with enhanced hedonic 
properties can lead to an increase in body weight and the potential for the development of 
obesity. 
Obesity is defined as a body mass index (BMI) of more than 30 kg/m2. Obesity reduces life 
expectancy and increases the incidence of cardiovascular disease, diabetes, certain cancers and 
depression [8,9]. 
In 2014, about 26% of adults in the United Kingdom were obese [10]. The prevalence of obesity 
is increasing with time and a recent estimate indicated that obesity affects 35% of men and 
40% of women in the US adult population [11]. 
Advice on dietary and lifestyle changes has been ineffective in reducing the incidence of 
obesity.  Currently, two general approaches to treatment are available: first, the use of oral 
medication (orlistat) to reduce fat absorption from the diet, and, second, the use of surgical 
interventions.  However, both approaches are subject to potential problems regarding efficacy 
or safety.  The use of orlistat is limited by side effects and its effect on body weight is relatively 
short-lived [12].  Other drugs, e.g. sibutramine and rimonabant, have recently been withdrawn 
from marketing in Europe due to side effects [13]. Surgical interventions e.g. gastric bypass 
and band surgery can be effective, but also carry a risk of death to the patient, and are 
expensive, being dependent on the availability of specialist surgeons and support facilities.   
3.1 
Background Information for Y14 
Y14 is a human peptide YY (PYY) analogue that is being evaluated by Imperial College 
London as a potential treatment for obesity. 
It was selected from about 1500 PYY analogues that were screened for human neuropeptide 
Y2 receptor (Y2r) binding, mouse Y2r binding and anorectic and weight-reducing effect in 
rodents. The amino acid sequence of Y14 is based on human PYY1-36, with the following 
features: 
• Deletion of the first residue; 
• Substitution of six other residues within the 35-residue peptide with the receptor active 
sequence of PYY being unchanged 
• Composition wholly of natural L-amino acids without derivatisation or cross linking. 


 
 
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For further information please refer to the Investigator's Brochure (IB) [14]. 
3.2 
Risk Assessment 
Y14 has not yet been tested in humans, however the amino acid sequence of Y14 is similar to 
that of PYY. In addition, previous experience was gained with a similar PYY analogue (Y242 
– Imperial College London QLON/2011/Y242-01). Therefore indications of potential safety 
issues related to the administration of Y14 can be obtained from review of the effects of PYY 
and Y242 in humans.  
In a number of published studies when PYY3-36 was administered by IV infusion to healthy 
subjects in doses to achieve normal postprandial values (40-50 pmol/L) no adverse effects were 
reported [6,7]. 
When PYY3-36 was infused at a dose to raise circulating PYY to supraphysiological levels (90 
to 190 pmol/L) nausea, vomiting and abdominal discomfort were reported [16 - 19]. Therefore 
the published data indicate that the therapeutic window for PYY3-36 is narrow. It is possible 
that nausea and vomiting may also be observed in those subjects given Y14. Nausea is a 
common side effect of gut hormone analogues in clinical use, such as the GLP-1 analogues 
exenatide and liraglutide, although this side effect tends to decline with continued use and 
rarely causes discontinuation of the drug [20]. As Y14 has been formulated in ZnCl2, to produce 
a sustained release formulation, the potential for nausea and vomiting to occur is reduced. It 
was also observed that in single doses ranging from 2 to 90 mg, Y242 was well tolerated. 
Subjects receiving multiple doses of Y242 (90 mg) experienced nausea and vomiting as a dose 
related TEAE.  
As nausea and vomiting are expected to be the most common AEs, anti-emetics will be 
available at the clinical unit.  As a precaution, individuals frequently suffering from migraines 
will be excluded from investigational studies with Y14, so that the risk of nausea caused by 
migraines does not interfere with the analysis of adverse events during the study. Volunteers 
with other potential causes of nausea (e.g., gastrointestinal disease) will be ineligible for the 
study at screening.  Nausea will be detected both by adverse event recording and by the use of 
specially designed questionnaires.  Mild to moderate nausea will not be a cause for withdrawal 
from the study.  If eligible subjects suffer from severe and persistent nausea, or severe vomiting 
during this study, which the Investigator believes may be due to the investigational product, 
they will be withdrawn from the study. 
It was also observed in the Y242 study that skin reactions were a common TEAE. Dose levels 
or concentrations may require adjustment accordingly, and the initial doses given during the 
SAD phase of the study will be limited to 20 mg/ml. If necessary, the doses may be divided 
into multiple injections to reduce injection volumes and the amount of Y14 administered per 
injection site. In addition local tolerance and in particular injection site reactions will be 
monitored closely throughout the study. 
PYY is known to cause a 30% increase in urinary sodium output when given to healthy human 
volunteers, but no significant change in urinary volumes [21].  In the Y242 trial, a natriuretic 


 
 
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effect was not observed. In the target clinical population of obese people, hypertension is a 
common co-morbidity, and it is anticipated that, if Y14 does indeed cause a natriuresis, this 
may ameliorate hypertension [21]. GLP-1 has a similar natriuretic effect in humans [22] and 
this effect is thought to underlie its anti-hypertensive action [23]. 
No other safety concerns are anticipated, but monitoring of an extensive list of safety variables 
will take place during this study. 
The proposed study is a single and double-blind, randomised, placebo controlled Phase I FIH 
study to be conducted in 2 parts (Parts A and B);  
As this is a FIH study a sentinel dosing strategy will be used for the first dosing group.  Safety 
data up to and including 24 h postdose will be reviewed by the Investigator prior to dosing the 
remaining subjects at that dose level 48 h later.  Dose escalation will only occur if the previous 
dose level was deemed to be safe and well tolerated.  
Part B will only commence after appropriate and sufficient data from Part A are available to 
enable the determination of a safe starting dose for Part B.  Administration of subsequent dose 
levels will be based on review of available safety, tolerability and PK data from previous doses.  
As with Part A, progression to the next higher dose will only occur if the previous dose level 
was deemed to be safe and well tolerated.  In Part B, dose titration for an individual subject 
may be necessary within a dosing regimen depending on the activity profile and tolerability. 
The study will be conducted in compliance with United Kingdom (UK) regulations and 
guidance, EU and ICH GCP, GMP and current GLP.  The study requires clinical trial 
authorisation by Medicines and Healthcare Products Regulatory Agency (MHRA) and 
National Research Ethics Service approval.  It does not require Ethics Advisory Group 
approval.  
As this is a FIH study involving the administration of a peptide analogue the study will be 
conducted on an in-patient basis, with dosing in a Phase I unit with accreditation from the 
MHRA.  The Principal Investigator and the investigating team will be experienced in the 
administration of novel molecules to man for the first time.   
There is no known antidote for Y14.  Full resuscitation facilities and emergency medication 
will be available at all times. 
3.3 
Urgent safety measures 
In accordance with UK Law (Medicines for Human Use [Clinical Trials] as amended:  
Statutory Instrument [SI] 1031 Part 4 Section 30) the Sponsor and Investigator may take 
appropriate urgent safety measures in order to protect the subjects of a clinical trial against any 
immediate hazard to their health or safety. If such measures are taken the Sponsor shall 
immediately (no later than 3 days from the date the measures are taken) give written notice to 
the licensing authority and the relevant ethics committee of the measures taken and the 
circumstances giving rise to those measures. 
 
 


 
 
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4 
STUDY OBJECTIVES 
4.1 
Primary Objective 
• To investigate the safety and tolerability of single doses of Y14 in overweight/obese but 
otherwise healthy male subjects. 
• To investigate the safety and tolerability of multiple doses of Y14 in overweight/obese 
male subjects with normal glucose tolerance, Type 2 diabetes or prediabetes. 
4.2 
Secondary Objectives 
• To assess the pharmacokinetic (PK) profile of single doses of Y14 in overweight/obese 
but otherwise healthy male subjects.  
• To assess the PK profile of multiple ascending doses of Y14 in overweight/obese male 
subjects with normal glucose tolerance, Type 2 diabetes or prediabetes.  
4.3 
Exploratory Objective 
• To investigate the effects of multiple doses of Y14 on food consumption, body weight, 
enteropancreatic hormone changes and glucose tolerance in overweight/obese male 
subjects with normal glucose tolerance, Type 2 diabetes or prediabetes.  
• To assess the analytical performance of the Imperial College radioimmunoassay for Y14 
compared with the LC-MS/MS assay for Y14. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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5 
INVESTIGATIONAL PLAN 
5.1 
Overall Study Design 
This is a single centre, randomised, placebo controlled Phase I FIH 2 part study:  Part A (single 
ascending dose – SC administration) and Part B (multiple ascending dose – SC administration). 
5.1.1 
Part A (Single Ascending Dose) 
Part A is a double blinded, randomised, placebo controlled, single ascending dose study (SAD). 
The following reflects the plan prior to execution of Part A. Approximately 28 eligible subjects 
will be enrolled in 5 sequential cohorts of overweight but otherwise healthy male subjects (BMI 
range of 25 to 38 kg/m2). No subject will be a member of more than 1 cohort. 
Cohort 1 will comprise 4 subjects (3 active and 1 placebo). In cohort 1, each subject will be 
dosed in three treatment periods (TPs) with three ascending dose levels (proposed doses 1 mg, 
4 mg, 8 mg Y14). The subjects will be randomised to either placebo or active treatment at each 
of these visits, i.e. different subjects will receive placebo in each TP. There will be a minimum 
washout period of 1 week between Day 1 of each TP. If any subject in Cohort 1 drops out 
between doses, they will be replaced. 
Cohort 2 onwards will comprise 6 subjects (5 active and 1 placebo) for each cohort. Each 
volunteer in Cohort 2 onwards will only be dosed once in one TP. Proposed doses for cohorts 
2-5 are 16 mg, 32 mg, 64 mg and 96 mg. All doses, and peptide concentrations are subject to 
change according to safety and PK review. 
Up to eight additional cohorts of up to 6 subjects each (i.e. up to 48 subjects in total) may be 
enrolled if recommended by the Safety Committee (see Section 7.1.4) to increase scientific 
value of this study, e.g. to verify PK data or further characterise PD markers. 
For each dose level, subjects will be randomised to receive a single dose of Y14 or matching 
placebo by SC injection (with fractionation if needed).  A sentinel dosing strategy will be used 
as outlined in Table 5.1.   
Table 5.1  
Dosing Schedule:  Part A 
*May be increased if additional groups are dosed 
 
In Cohort 1, TP1, the first two subjects will be randomised such that 1 subject receives Y14 
and 1 subject receives placebo. This sentinel pair will be dosed first and will be observed for 
at least 48 h before study drug is administered to the remainder of the cohort. Safety (vital 
Cohort 
Treatment 
Periods  
Dosing Session 
Number of Subjects 
 
Y14 
Placebo 
1 
1 
Sentinel subjects 
1 
1 
 
Non-sentinel subjects 
2 
0 
1 
2-3 
Sentinel subjects 
0 
0 
 
 
Non-sentinel subjects 
3 
1 
2 onwards 
1 
Sentinel subjects 
0 
0 
 
Non-sentinel subjects* 
20 
4 


 
 
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signs, ECGs, and clinical laboratory safety tests), and tolerability (adverse event profile) data 
up to and including 24 h postdose will be reviewed by Covance’s clinical team prior to dosing 
the remaining subjects at that dose level. Dosing of the subsequent subjects in cohort 1 will be 
at the discretion of the Principal Investigator. 
Treatments will be administered double blinded (except for Cohort 1, TP1 where it will be 
known that the 3rd and 4th subjects will receive the active dose); subjects will be blinded with 
regard to treatment and clinical staff will remain blinded with regard to treatment until the 
Safety Committee meeting.  
An interval of at least 7 days will separate the dosing of the last subject in one cohort and 
dosing of the first subject in the next cohort to permit a timely review and evaluation of interim 
safety, tolerability and PK data. Safety, tolerability and PK data will be reviewed up to 48 hours 
post-dose prior to the dose escalation decision. If Tmax is significantly later than predicted, PK 
data to a later timepoint may be reviewed prior to the dose escalation decision. The data of up 
to at least 3 subjects receiving Y14 in cohort 1 and 4 subjects, (i.e. a minimum of 3 subjects 
receiving Y14) in cohort 2 onwards will be reviewed before dose escalation.  
Following a 28-day screening period eligible subjects will be admitted to the clinical unit on 
Day -1 (1 day prior to dosing) for eligibility checks and baseline assessments. On Day 1 
subjects will receive a single dose of Y14 or placebo by SC injection, and will remain in the 
clinical unit under medical supervision until 72 h postdose (Day 4) or until Cmax is achieved, 
whichever is the later.  
Safety monitoring will include assessment of adverse events (AEs), physical examination, 12-
lead ECGs, vital signs (blood pressure pulse rate and body temperature) and clinical laboratory 
safety tests (serum biochemistry, haematology, coagulation, thyroid stimulating hormone 
[TSH], FT4 and urinalysis). 
Blood samples for biomarker (tryptase) will be collected immediately after any possible 
allergic or anaphylactic adverse reaction, and 12 hours later. These samples will only be 
analysed if relevant adverse reactions occur. 
The PK evaluation will include measurement of plasma Y14 levels and associated PK 
parameters.  
Exploratory PD evaluation will include evaluation of visual analogue scales (VAS) of nausea 
and satiety. Subjects in Cohort 3 onwards will undergo food intake studies on Day -1 and Day 
1. The timing of the food intake study may be modified according to emerging PK data.  
Blood samples for immunogenicity assays will be collected prior to the first dose (Treatment 
Period 1) and at the final follow-up visit for the volunteers from Cohort 1 only (as these 
volunteers have received multiple doses of Y14). 
All subjects will return for a follow up visit 14 days (± 1 day) after the final dose. 
Following discharge of subjects and depending on emerging PK data, the subjects (except 
cohort 1, dose level 1 and 2) may return to the clinical unit for further outpatient visits. The 


 
 
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number of additional visits per subject will not exceed six and will not extend beyond 8 weeks 
after each final dosing occasion. If additional outpatient visits are scheduled the final outpatient 
visit will be considered to be the final follow up visit where the follow-up visit assessments 
will be performed. 
5.1.2 
Part B (Multiple Ascending Dose) 
Part B will be a double blind, randomised, placebo controlled, multiple ascending dose (MAD) 
study in sequential groups of male subjects (BMI range 25-38 kg/m2). These subjects can either 
have normal glucose tolerance, prediabetes (impaired glucose tolerance or impaired fasting 
glucose) or Type 2 diabetes, defined according to WHO 2006 and 2011 diagnostic criteria. If 
the subject is diagnosed with diabetes or prediabetes, this condition should be stably controlled 
either with:  
i. 
diet only;  
ii. 
monotherapy with a sulphonylurea, metformin, or SGLT-2 inhibitor; 
iii. 
dual therapy with a sulphonylurea, metformin, and/or a SGLT-2 inhibitor; 
iv. 
or triple therapy with a sulphonylurea, metformin, and SGLT-2 inhibitor. 
      Patients treated with other anti-diabetic treatments are excluded. 
      Where subjects have prediabetes or diabetes, their HbA1c at screening should be 6.0–8.5% 
(42–69 mmol/mol) and <±1.0% (±11 mmol/mol) from a previous HbA1c reading within the 
last 6 months, where available. Where a HbA1c reading within the last 6 months is not 
available, the subject should have HbA1c re-measured after at least 4 weeks to assure 
stability of glycaemia before inclusion in the study. This remeasurement may take place any 
time up to and including check in on Day -2.  
For other subjects without known diabetics or pre-diabetes, or in whom the glycaemic status is 
in doubt, they may attend a pre-screening visit no more than 10 weeks before Day 1, where a 
fasting glucose and HbA1c will be measured, and a 75 g oral glucose tolerance test performed 
to classify their diagnosis according to the WHO 2006 and 2011 criteria. 
It is proposed to investigate 3 dose levels of Y14 in up to 3 cohorts of 8 subjects, anticipated 
total of 24 subjects. In each cohort 6 subjects will receive Y14 and 2 subjects will receive 
placebo. Where possible, subjects of a similar glycaemic status (i.e. diabetics, prediabetics or 
normal glucose tolerance) will be grouped in a cohort. 
Up to 3 additional cohorts of 8 patients each, i.e. up to 24 subjects in addition, may be enrolled 
if recommended by the Safety Committee (see Section 7.1.4) to increase scientific value of this 
study, e.g. to assess additional doses of Y14 or further characterise PD markers.  
Part B may commence prior to the completion of Part A (SAD) and the total daily dose will 
not exceed a single dose shown to be safe and well tolerated.  


 
 
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Subjects will receive 5 doses of Y14 or placebo by SC injection (with fractionation if needed), 
each separated by 7 days (i.e., on Days 1, 8, 15, 22, 29). The starting dose level to be 
administered in Part B will be determined from Part A. Administration of subsequent doses 
will be based on review of available data on safety, tolerability and PK up to 48 hours after the 
last dose, gathered from previous doses in a minimum of 6 subjects. The individual doses to be 
given in Part B will not exceed the maximal tolerable dose identified from Part A. Dose titration 
for an individual subject may be necessary within a dosing regimen depending on the activity 
profile and tolerability.  
Subjects are proposed to have 6 inpatient stays in Part B as outlined in Figure 5.1.  


 
 
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Figure 5.1 
Study Overview: Part B 
 
Pre-screening Visit (if required) 
Within 10 weeks prior to Day 1 
 
 
 
 
 
 
 
 
 
 
Screening Visit 
(within 28 days of Day 1) 
 
 
 
 
 
Inpatient Stay 1 
 
 
Day -2 
Admission, acclimatisation & OGTT 
 
 
Day -1 
24 h food intake study 
Day 1 
Standardised breakfast 
Administration of Y14/placebo 
Day 2 
Day 3/4 
24 h food intake study 
Discharge  
 
 
 
Inpatient Stay 2 
 
 
Day 8 
Admission 
Standardised breakfast 
Administration of Y14/placebo 
 
 
Day 9 
Discharge 
 
 
 
Inpatient Stay 3 
 
 
Day 15 
Admission 
Standardised breakfast 
Administration of Y14/placebo 
 
 
Day 16 
Discharge 
 
 
 
Inpatient Stay 4 
 
 
Day 22 
Admission 
Standardised breakfast 
Administration of Y14/placebo 
 
 
Day 23 
Discharge 
 
 
 
Inpatient Stay 5 
 
 
Day 29 
Admission  
Standardised breakfast 
Last dose of Y14/placebo 
 
 
Day 30 
Food intake study 
Day 31 
OGTT, Discharge 
 
 
 
OP visits Day 32, 33, 35 
 
 
 
Inpatient Stay 6 
 
 
Day 36  
Admission  
 
 
Day 37 
OGTT, discharge 
 
 
 
OP visits Days 43, 49, 56, 63 
 
 
 
Last OP visit Day 70-73 
 
 
 
Following a pre-screening visit within 10 weeks of day 1 (if applicable), and a 28-day screening 
period, eligible subjects will be admitted to the clinical unit on the morning of Day -2 (2 days 
prior to first dosing) for the first inpatient stay. At Day -2, the volunteers will undergo an 
OGTT, and therefore will need to attend the visit after an overnight fast.  


 
 
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Subjects will receive a single dose of Y14 or placebo by SC injection(s) on Day 1. Subjects 
will remain in the clinical unit for at least 24 h postdose. It is the intention that subjects will be 
discharged on Day 4, but they may be discharged on Day 3 after the food intake study has been 
completed and if the subject is in good health. If volunteers are discharged on Day 3, they will 
return on Day 4 for collection of a pharmacokinetic sample. 
For most of the subsequent inpatient stays (stays 2 to 4) subjects will be admitted to the clinical 
unit on the day of dosing and will remain in the clinical unit at least until 24 h postdose. In stay 
5 the subjects will be admitted to the clinical unit on the day of dosing and will remain in the 
clinical unit until 48 h postdose. It is proposed that doses will be administered 7 days apart (i.e. 
on Days 1, 8, 15, 22 and 29). 
The proposed duration of the inpatient stays may be altered based on emerging safety, 
tolerability and PK data from Part A (SAD) or previous cohorts in Part B. 
After each inpatient stay, subjects will return to the clinical unit for outpatient visits as 
described in Figure 5.1,  
Safety monitoring will include assessment of adverse events (AEs), physical examination, 12-
lead ECGs, vital signs (blood pressure, pulse rate and body temperature) and clinical laboratory 
safety tests (serum biochemistry, haematology, coagulation, TSH, FT4, and urinalysis). 
Blood samples for biomarker (tryptase) will be collected immediately and 12 hours after any 
possible allergic or anaphylactic adverse reaction. These samples will only be analysed if there 
is a relevant adverse reaction. 
The PK evaluation will include measurement of plasma Y14 levels and associated PK 
parameters.  
Exploratory PD evaluation will include evaluation of the following: glucose tolerance (as 
assessed by a standard 75 g oral glucose tolerance test before and after treatment), energy intake 
at mealtimes, body weight, visual analogue scales (VAS) of nausea and satiety and 
enteropancreatic hormones.  
Blood samples for immunogenicity assays will be collected predose and at the final follow-up 
visit.  
Subjects will attend a final follow-up visit on Day 70-73. If deemed necessary, unblinding will 
be performed as outlined in Section 6.9. 
5.1.3 
Safety Committee 
The Safety Committee’s membership will be composed of a minimum of the Sponsor team 
(Sponsor Senior Physician and Sponsor Senior Scientist or an appropriate delegate) and 
Principal Investigator (or an appropriate delegate). Additional members may be invited as 
needed (e.g. PK scientist, project manager). 
All data reviewed at the dose escalation meeting (safety, tolerability and available PK data) 
will be subjected to a quality control review. 


 
 
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5.1.4 
Stopping Rules 
Dosing for any individual subject will be stopped if the subject experiences a possibly drug-
related serious adverse event or a possibly drug-related significant non serious adverse event, 
which in the opinion of the study physician, Principal Investigator or Chief Investigator 
(Sponsor’s medical representative), warrants discontinuation of the study for that subject’s well 
being.  
In Parts A and B, following consultation with the Sponsor, dose escalation will stop if:  
• Clinically relevant signs or symptoms of similar nature, occur in 2 or more subjects 
within a group/cohort, which in the opinion of the Investigator warrant stopping of dose 
escalation. 
• A serious adverse event (SAE) in one or more subjects thought to be related to the study 
drug or a severe AE in two or more subjects thought to be related to study drug. If this 
criterion is met the study will be halted. If, following internal review, it is deemed 
acceptable to restart the study a substantial amendment will be submitted to the 
Competent Authority. 
• Moderate nausea or vomiting that prevent subjects from eating a meal on 3 or more 
occasions on 2 successive days are seen in 2 or more subjects in a group.  
• Severe diarrhoea, defined as 7 or more episodes, rated as ≥ 5 on the Bristol Stool Chart, 
in 1 day for 2 consecutive days are seen in 2 or more subjects in a group. 
• The mean systemic exposure is predicted to exceed a Cmax of 440 ng/mL and/or AUC(0-
72h) of 28,100 ng·h/mL i.e. systemic exposure will be no greater than that the lowest 
exposure at the NOAEL for male rats (30 mg/kg/dose). This limit is chosen on the basis 
that rats are expected to be the species that will most closely predict toxicity in humans. 
 
5.1.5 
Discussion of Study Design 
This is a double-blinded, randomised, placebo-controlled study in two parts: a single ascending 
dose study and multiple ascending doses, to investigate the effects of Y14. Note, with the 
exception of Cohort 1 TP1 which is partially blinded as this will be a crossover design where 
the volunteers will return for 3 treatment periods. The time interval between each TP should 
be no less than 1 week. As Y14 is intended as an anti-obesity drug, overweight/obese subjects 
have been chosen to provide more clinically relevant PK and PD information. With regards to 
Part B, we propose to recruit patients with Type 2 diabetes or pre-diabetes in order to study the 
impact of Y14 on glycaemia. 
It is the intent of Part B to dose volunteers such that steady-state is achieved and maintained 
for several days. Based on the available pre-clinical data it is expected that this will be achieved 
following 28 days once weekly dosing, however, a full review of all the safety, tolerability and 
pharmacokinetic data from Part A will be performed to confirm the dose regimen for Part B. If 


 
 
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the elimination half-life of Y14 is shorter than anticipated from the pre-clinical data, more 
frequent dosing (e.g. twice weekly) may be appropriate. If the elimination half-life of Y14 is 
longer than anticipated from the pre-clinical data, dosing every two weeks may be more 
appropriate (as steady-state will take longer to achieve). The dose frequency will be no more 
frequent than once a day and no less frequent than once every 14 days. The dosing duration 
will not exceed 29 consecutive days of dosing.  
Details of the dosing regimen and duration used for Part B of the study will be documented in 
the SMF.  
The sample size (approximately 28 subjects in Part A [SAD] and 24 subjects in Part B [MAD]) 
has been chosen to minimise the number of subjects exposed to Y14 whilst obtaining sufficient 
information to assess the safety, tolerability, PK and PD of Y14.  
5.2 
Study Population 
Approximately 28 subjects will be enrolled in Part A (SAD) and 24 subjects will be enrolled 
in Part B (MAD). 
Overweight male volunteers will be entered into this study provided that they satisfy the 
following inclusion/exclusion criteria. 
5.2.1 
Subject Inclusion Criteria 
1. Adult males aged 18 to 65 years inclusive with BMI between 25.0 and 38.0 kg/m2 inclusive; 
2. (PART B only) Subjects who have normal glucose tolerance, Type 2 diabetes, impaired 
glucose tolerance or impaired fasting glucose according to WHO 2006 and 2011 criteria,  
a) In subjects who are identified as being prediabetic or diabetic, they should be stably 
treated either with:  
i. 
diet only;  
ii. 
monotherapy with a sulphonylurea, metformin, or a SGLT-2 inhibitor; 
iii. 
dual therapy with a sulphonylurea, metformin, and/or a SGLT-2 inhibitor; 
iv. 
or triple therapy with a sulphonylurea, metformin, and a SGLT-2 inhibitor. 
Patients treated with other anti-diabetic treatments are excluded. 
b) In subjects who are identified as being prediabetic or diabetic, the HbA1c at screening 
should be 6 - 8.5% (42 - 69 mmol/mol) and <±1.0% (±11 mmol/mol) from a previous 
HbA1c reading within the last 6 months, where available. Where an HbA1c reading 
within the last 6 months is not available, the subject should have HbA1c re-measured 
after at least 4 weeks to assure stability of glycaemia before inclusion in the study. 
This remeasurement may take place any time up to and including check in on Day -2. 
c) To allow assessment of eligibility, subjects without known diabetes or prediabetes, or 
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than 10 weeks before Day 1 for assessment of fasting glucose, HbA1c and glucose 2 
hours after a 75 g oral glucose tolerance test. 
3. Subjects who are otherwise healthy enough to participate, as determined by pre-study 
medical history, physical examination and 12-lead ECG; 
4. Subjects whose clinical laboratory test results are either within the normal range or if 
outside this range the abnormalities are judged to be not clinically relevant and are 
acceptable to the Investigator; 
5. Subjects who are negative for hepatitis B surface antigen (HBsAg), hepatitis C antibody 
and human immunodeficiency virus (HIV) I and II tests at screening; 
6. Subjects who are negative for drugs of abuse and alcohol tests at screening and admissions; 
7. Subjects who are non-smokers for at least 3 months preceding screening; 
8. Subjects who agree to use medically acceptable methods of contraception for at least 3 
months after study drug administration; 
9. Subjects who agree not to donate sperm for at least 3 months after study drug 
administration; 
10. Subjects who are able and willing to give written informed consent. 
Subjects’ medical history must be verified by either a personal physician or medical 
practitioner as appropriate. 
5.2.2 
Subject Exclusion Criteria 
1. Subjects who do not conform to the above inclusion criteria; 
2. Subjects who have a clinically relevant history or presence of gastrointestinal (especially 
associated with vomiting), respiratory, renal, hepatic, haematological, lymphatic, 
neurological (especially if associated with balance disorders or vomiting e.g. migraine or 
labyrinthitis), cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, 
dermatological, connective tissue diseases or disorders; 
3. Subjects who have a clinically relevant surgical history; 
4. Subjects who are currently taking any of the following classes of diabetes medications: 
thiazolidinediones, dipeptidyl peptidase IV inhibitors (‘gliptins’), GLP-1 analogues, and 
insulin; 
5. Subjects who have a history of relevant and severe atopy e.g. asthma, angioedema requiring 
emergency treatment, severe hayfever requiring regular treatment (i.e. taking 
antihistamines and/or glucorticoids more regularly than 3 times a week), severe eczema 
requiring regular treatment (i.e. taking antihistamines and/or glucocorticoids more 
regularly than 3 times a week); 
6. Subjects who have a history of relevant drug hypersensitivity; 


 
 
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7. Subjects who have a history of alcohol abuse or alcohol dependence according to DSM-IV 
criteria within the last 2 years; 
8. Subjects who have a history of drug or substance abuse according to DSM-IV criteria 
within the last 2 years; 
9. Subjects who have a history of clinically significant migraine as judged by the Investigator. 
Subjects can be included if they have not had a migraine for the last 3 years; 
10. Subjects with a history of pancreatitis or pancreatic cancer; 
11. Subjects who consume more than 21 units of alcohol a week (unit = 1 glass of wine (125 
mL) = 1 measure of spirits = ½ pint of beer); 
12. Subjects who have a significant infection or known inflammatory process on screening; 
13. Subjects who have acute gastrointestinal symptoms at the time of screening or admission 
(e.g. nausea, vomiting, diarrhoea, heartburn); 
14. Subjects who have an acute infection such as influenza at the time of screening or 
admission; 
15. Subjects who have used prescription drugs within 2 weeks of first dosing. For Part B, 
patients are allowed to be treated for their diabetes with monotherapy with a sulphonylurea, 
metformin, or a SGLT-2 inhibitor, dual therapy with any two of the following drug types: 
a sulphonylurea, metformin, and/or a SGLT-2 inhibitor; triple therapy with a 
sulphonylurea, metformin, and a SGLT-2 inhibitor. In addition, patients in Part B are 
allowed to take hypolipidaemic and/or antihypertensive treatments, provided that the doses 
have not been altered within the 4 weeks prior to entering the study. Other medications may 
be allowed if the Investigator and Sponsor both agree that they will not affect the outcome 
of the study or the safety of the subject.  
16. Subjects who have used over the counter medication excluding routine vitamins and 
paracetamol but including megadose (intake of 20 to 600 times the recommended daily 
dose) vitamin therapy within 7 days of first dosing, unless agreed as not clinically relevant 
by the Principal Investigator and Sponsor; 
17. Subjects who have donated blood within 3 months prior to screening; 
Subjects who have donated plasma within the 7 days prior to screening; 
Subjects who have donated platelets within the 6 weeks prior to screening 
18. Subjects who have used any investigational drug in any clinical trial within 3 months of 
their first admission date; 
19. Subjects who have received the last dose of investigational drug greater than 3 months ago 
but who are on extended follow-up; 
20. Subjects who have previously received Y14; 


 
 
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21. Subjects who are vegans, vegetarian or have any dietary restriction (unless agreed as not 
clinically relevant by the PI and Sponsors); 
22. Subjects who cannot communicate reliably with the Investigator; 
23. Subjects who are unlikely to co-operate with the requirements of the study; 
24. History or evidence of abnormal eating behaviour, as observed through the Dutch Eating 
Behaviour (DEBQ) and SCOFF questionnaires [24,25] at screening. 
5.2.3 
Restrictions 
In Part A (SAD) subjects will be admitted to the clinical unit on Day -1 and will remain in the 
clinical unit under supervision until discharge on Day 4 (at least 72 h postdose) or when Cmax 
is achieved, whichever is later. Subjects will be required to attend outpatient visits as described 
In Part B (MAD) subjects will be admitted to the clinical unit for 6 inpatient stays: Day -2 
(admission) to Day 4 (discharge), Day 8 (admission) to Day 9 (discharge), Day 15 (admission) 
to Day 16 (discharge), Day 22 (admission) to Day 23 (discharge), Day 29 (admission) to Day 
31 (discharge), and Day 36 (admission) to 37 (discharge). Subjects will return to the clinical 
unit for outpatient visits as described in Table 17.2. 
For both Part A and Part B, the inpatient stays and outpatient visits may be amended upon 
review of safety, tolerability and PK data from previous cohorts or study part. 
Subjects will receive a standard diet whilst resident in the clinical unit and will only consume 
foodstuffs provided by the clinical unit.  Subject's energy intake at each meal, along with fluid 
intake and output will be recorded during the inpatient stays.  For Part B, study participants 
will be provided with a dietary advice sheet providing information with regards to a healthy 
eating diet which they are recommended to follow when they have been discharged from the 
clinical unit. 
For Part A and Part B subjects should refrain from the following: 
• Subjects should refrain from strenuous exercise for 48 h before screening, prior to each 
admission, throughout each inpatient stay and for 48 h prior to each outpatient visit. 
• Subjects should refrain from alcohol and/or xanthine containing products (e.g. caffeine) 
for 48 h prior to screening and admission, during the inpatient stay, and for 48 h prior 
to each outpatient visit.   
• Subjects should refrain from smoking for the duration of the study (until after the final 
follow-up visit). 
• Subjects should refrain from eating foodstuffs that contain poppy seeds for 7 days prior 
to screening and 7 days prior to each admission, as these may result in a positive urine 
test for opiate consumption. 
• Subjects should refrain from taking medications during the study as described in 
Section 6.5. 


 
 
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5.2.3.1 Avoidance of Pregnancy 
Instructions for Male Subjects 
There is no information about effects that Y14 could have on the development of the foetus in 
humans. Therefore, it is important that the partners of male subjects do not become pregnant 
during the study and for a total period of 3 months after the male subject has taken the last dose 
of Y14.   
As a precaution, all male subjects should avoid fathering a child by either true abstinence or 
the use of 2 effective means of contraception (see Section 5.2.3.2).  
As there is no information about Y14 being secreted in the ejaculate, male subjects (including 
men who have had vasectomies) whose partners are currently pregnant should use barrier 
methods for the duration of the study and for a suitable time afterwards (e.g. 1 month).  This is 
to ensure that the foetus is not exposed to the investigational medicinal product (IMP) in the 
ejaculate. 
5.2.3.2 Acceptable Forms of Contraception 
Highly effective methods of birth control are defined as those which result in a low failure rate 
(i.e. less than 1% per year) when used consistently and correctly.  
These include male vasectomy with confirmation of surgical success, female sterilisation (i.e. 
documented bilateral tubal ligation), hormonal methods of contraception (oral, implanted or 
transdermal) or an intrauterine device (IUD).  
Where there is a possibility of pregnancy one of the above highly effective methods should be 
used in combination with male condoms. 
True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the 
subject.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
5.2.3.3 Time Period for the Collection of Pregnancy Information 
All pregnancies in female partners of male subjects receiving at least one dose of IMP will be 
recorded from first dose to 3 months after the final dose. 
5.2.3.4 Follow-up in the Event of a Pregnancy 
If the female partner of a male subject, who has received Y14 becomes pregnant the pregnancy 
will be recorded.  The ethics committee and the Sponsor will be informed.  The subject will be 
asked provide information on the outcome of the pregnancy, including premature termination 
should the case arise.  
Spontaneous miscarriage and congenital abnormalities will be reported as SAEs. 
The follow-up period will be deemed to have ended when the health status of the child has been 
determined on its birth. 


 
 
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5.2.4 
Subject Withdrawals 
A subject may withdraw for any reason.  The Investigator will advise the Sponsor of the 
withdrawal of any subject. 
A subject may be withdrawn in any of the following circumstances: 
• 
Adverse events; 
• 
Protocol violation; 
• 
Withdrawal of consent; 
• 
Termination of the study by the Investigator or Sponsor. 
Subjects who voluntarily withdraw are termed dropouts. Dropouts may be replaced following 
discussion with the Investigator and Sponsor. Subjects withdrawn due to an adverse event 
which is thought to be related to the study drug will not be replaced. This statement will not 
apply to Cohort 1 in the event that a subject is withdrawn prior to dosing in Treatment Periods 
2 or 3. If a subject is withdrawn from Cohort 1, that subject may be replaced in order to allow 
a full cohort of 4 subjects to be dosed in the subsequent treatment period. 
If a subject is withdrawn or withdraws during the inpatient stay the discharge procedures should 
be performed and follow-up assessments completed prior to them leaving. If a subject is 
withdrawn or withdraws after the inpatient stay is completed a follow-up visit should be 
scheduled. 
If a subject is withdrawn due to an adverse event, appropriate medical care should be provided 
and the adverse event should be followed to resolution. Follow-up procedures should be 
conducted as scheduled. 
 
 
 
 
 
 
 
 
 


 
 
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6 
STUDY TREATMENT 
6.1 
Investigational Product(s) 
Y14 is a 35 amino acid linear peptide.  Y14 does not contain any products of human or animal 
origin. 
The bulk drug product (20 mg/vial) is manufactured as a 2 mL ISO clear Type 1 tubular glass 
vial with a 13mm crimp neck.  The vials are sealed with a fluoro-coated lyophilisation stopper 
and an aluminium crimp seal. Y14 will be reconstituted in sterile diluent supplied in a glass 
vial with a fluoro-coated rubber stopper and an aluminium crimp seal. The details of the diluent 
and reconstitution steps will be provided in the IMP Preparation Information.  
The placebo is sterile 0.9% (w/v) saline. 
6.1.1 
Supply, Packaging and Labelling 
Y14 bulk Drug Product and Diluent will be supplied to Covance Clinical Research Unit by 
AMRI (Glasgow). 
A release document signed by a legally authorised Qualified Person (QP) at Covance Clinical 
Research Unit will be placed in the appropriate section of the Trial Master File to document 
labelling and dispensing of the study drug to the subject. A technical agreement between 
Covance Clinical Research Unit and Sponsor will be in place to cover all pharmacy related 
activities, detailing roles and responsibilities prior to receipt of the IMPs at Covance Clinical 
Research Unit. 
These supplies will be packaged in accordance with Annex 13 of “The Rules Governing 
Medicinal Products in European Community, Volume IV Good Manufacturing Practice for 
Medicinal Products”.  
All documents required to perform GMP activities at Covance Clinical Research Unit will be 
supplied as per the Technical Agreement. The Technical Agreement will outline the roles and 
responsibilities between the contract giver and the contract acceptor. 
The placebo (sterile 0.9% [w/v] saline) will be commercially sourced by Covance Clinical 
Research Unit.  
6.1.2 
Storage and Handling Procedures 
The Y14 lyophilised powder will be stored at -15 to -25°C. The diluent will be stored at +2 to 
+8°C. All study medication will be stored in the CRO Pharmacy. 
Details of how the IMP will be prepared for administration will be included in a separate IMP 
Preparation Information document.  
The Sponsor will be permitted upon request to audit the supplies, storage, dispensing 
procedures and records provided that the blind of the study is not compromised.  


 
 
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6.1.3 
Accountability 
In accordance with GCP, the clinical unit will account for all supplies of Y14 and placebo. 
Details of receipt, storage, assembly and return will be recorded.  
All unused supplies of Y14 and placebo will either be destroyed by CRO or returned to the 
study Sponsor at the end of the study in accordance with instructions by the Sponsor. 
6.2 
Dosage and Administration 
Y14 or placebo will be administered by SC injection into the abdomen. The maximum 
individual injection volume will not exceed 1.0 mL, though multiple injections (up to 5) may 
be given for a single dose. The injection site(s) should be circled with indelible marker (or the 
position recorded in some other suitable manner) and inspected at each AE check during Day 
1. Reactions should be described according to the grading table (Table 7.4). Where multiple 
doses of Y14 are given to the volunteer, the injection sites must rotate, i.e. given at different 
sites in the abdomen. 
In the event of injection site reactions thought to be related to the volume of the injection, the 
dose of Y14 or placebo may be fractionated and up to 5 injections may be given.  
Subjects will receive Y14 or placebo, whilst in the supine/semi-supine position, said dose to 
be given 1 hour after the subject has completed eating a standardised breakfast. Subjects will 
remain confined to their beds for a period of 4 h after injection, but will be permitted to visit 
the bathroom to use the toilet if needed. 
In Part A (SAD) the proposed doses are: 1 mg, 4 mg, 8 mg, 16 mg, 32 mg, 64 mg and 96 mg. 
Depending on emerging safety, tolerability and PK data, the doses given may be modified. 
Dose levels administered in Part B (MAD) will be selected following review of the data from 
Part A. In Part B, dose titration for an individual subject may be necessary within a dosing 
regimen depending on the activity profile and tolerability, but will not exceed the maximum 
dose tested in the SAD trial. 
Subjects will not eat for 4 h postdose after which time lunch will be served. Dinner will be 
served 10 h postdose.  
6.3 
Treatment Strategy 
The clinical staff at Covance Clinical Research Unit, Leeds, are responsible for the ongoing 
safety and well-being of the volunteers while they are in the clinical unit. There is a paging 
system to alert the clinical staff to any area in the unit where a subject may need medical 
attention. In the case of an emergency, cardiac resuscitation trolleys are found in the main ward 
areas of the clinical unit. These trolleys contain drugs, equipment for airway insertion, 
circulation lines, defibrillation etc, together with oxygen cylinders and portable suction 
machines. There is a physician on-call 24 hours a day (this can be off site) and all physicians 
are Advanced Life Support (ALS) trained. In addition, the clinical staff can contact further on-
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a serious medical event. Equipment and emergency drugs are available to treat common 
medical emergencies that might occur in a Phase I study.  
6.4 
Warnings and Precautions 
As this is the first administration of Y14 to man, all effects cannot be reliably predicted. The 
preclinical data suggest an acceptable safety margin. Facilities and staff for resuscitation and 
the treatment of other medical emergencies will be provided. 
6.5 
Prior and Concomitant Medication 
The participants are not allowed to take any prescription medication within 2 weeks of first 
dosing apart from those required for treatment of their diabetes, hypercholesterolaemia and 
hypertension.  Subjects are not allowed to take any non-prescription medication (excluding 
paracetamol) or megadose (intake of 20 to 600 times the recommended daily dose) vitamins 
within 7 days of first dosing prior to entrance into the clinical research facility and for the 
duration of the study. 
In the interests of subject safety and acceptable standards of medical care the Investigator will 
be permitted to prescribe treatment(s) at his/her discretion.  All treatments must be recorded in 
the subjects’ case report form (CRF) (medication, dose, treatment duration and indication). 
6.6 
Method of Assigning Subjects to Treatment Groups 
Following confirmation of eligibility, at study drug administration, subjects will be assigned a 
subject number in the order in which they are enrolled in the study, as shown in Table 6.1. The 
subject number will determine the allocation of treatment.  
Table 6.1 
Assignment of Subjects to Treatment 
 
Study Part 
Dose Level(s) 
Subject Numbers 
A 
1, 2, 3 
10001-10004 
 
4 
10005-10010 
 
5 
10011-10016 
 
6 
7 
10017-10022 
10023-10028 
 
Additional1 
10029-10076 
 
 
 
B 
1 
20001-20008 
 
2 
20009-20016 
 
3 
20017-20024 
 
Additional1 
20025-20048 
1 eight additional cohorts of up to 6 subjects in Part A (up to an additional 48 patients) and three additional cohorts of up to 8 subjects in Part 
B (up to an additional 24 patients) may be enrolled in each part if agreed by the Safety Committee. 
 
 
Any replacement subjects will receive the same treatment allocation as those whom they 
replace. 


 
 
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Subjects who are replaced (dropouts or replacements for subjects who are withdrawn from 
Cohort 1) will be allocated the same treatment number with the number 1 in the second digit 
position, e.g., if subject number 10001 is replaced then the replacement subject’s number will 
be 11001. 
6.7 
Randomisation Procedures 
Allocation to treatment will be according to a predetermined random order. Randomisation of 
Y14 or placebo will take place for each group separately. In Part A (SAD), each pair of sentinel 
subjects in Cohort 1 will be randomised such that 1 subject receives Y14 and 1 receives 
placebo. 
The randomisation list will be generated by Covance using the statistical analysis system 
(SAS®) computer package.  
6.8 
Maintenance of Randomisation Codes 
Randomisation codes will be provided to the pharmacist and bioanalyst in a list. Individual 
treatment disclosure envelopes (code break) will also be provided to the clinical unit. The 
pharmacist will use the randomisation code list for preparing subject doses throughout the 
study. The individual disclosure envelopes will be used if it is necessary to break the blind for 
an individual subject. 
6.9 
Blinding 
Part A (SAD) will be conducted double-blind (with the exception of Cohort 1 where the 
volunteers taking the 3rd and 4th injections within a treatment period are guaranteed to be given 
Y14); subjects and clinical staff will remain blinded until the Safety Committee meeting. 
Part B (MAD) will be conducted double-blind. In the event of a medical emergency when 
management of a subject’s condition requires knowledge of the trial medication, the sealed 
“code-break” envelope provided may be opened by personnel authorised by the Principal 
Investigator to determine the nature of the trial medication dispensed. If possible, such 
emergencies should be discussed with the study monitor and the Sponsor’s safety manager 
prior to disclosure of the treatment allocation. Reasons for breaking a code must be clearly 
explained and justified in the CRF. The date on which the code was broken together with the 
identity of the person responsible must also be documented. 
The bioanalyst and the PK scientist who will be unblinded, will be required to provide coded 
data to the Principal Investigator and the Sponsor so that the blind is maintained for all other 
personnel connected with Part B of the study. 
With the exception of the CRO pharmacy department, the statistician preparing the 
randomisation, the bioanalytical assay group and the quality assurance auditors where 
necessary, all clinical and non-clinical staff, with the exception of the PK scientist and PK/PD 
statistician, will remain blinded to the treatment allocation (where applicable) until after the 
database is locked unless there is a medical event that requires code break. 


 
 
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7 
STUDY PROCEDURES 
The blood volumes to be collected from each subject are detailed in Table 7.1 for Part A (SAD) 
and Table 7.2 for Part B (MAD). The total volume to be collected per subject will be no greater 
than 600 mL, staggered over the duration of the study. No more than 15% of the estimated 
blood volume of a subject will be taken on any one occasion as per JPAC guidelines 
(http://www.transfusionguidelines.org/).  
Laboratory sample handling details will be presented in a separate laboratory manual. 
Table 7.1 
Blood Volumes: Part A (SAD)  
 
Cohort 1 
 
Assessment 
Sample 
Volume (mL) 
No. of 
Samples 
Total Volume 
(mL) 
Safety 
 
 
 
 
Serum Biochemistry, Thyroid 
Function 
3.5 
11 
38.5 
 
Serology 
3.5 
1 
3.5 
 
Coagulation 
1.8 
11 
19.8 
 
Haematology 
4.0 
11 
44 
 
Tryptase1 
3.5 
2 
7 
 
Bedside blood glucose 
0.1 
Up to 23 
2.3 
Pharmacokinetic 
 
 
 
 
Y14 
6.0 
 Up to 17 
102 
 
 
 
 
 
Pharmacodynamics 
 
 
 
 
Immunogenicity3 
6.0 
2 
12.0 
 
 
 
 
 
Total2 
 
 
229.1 
1 In the event of an allergic reaction additional samples will be collected.  
2 Sample volumes are based on direct venepuncture 
3Immunogenicity samples from cohort 1 only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Cohort 2 onwards 
 
Assessment 
Sample 
Volume (mL) 
No. of 
Samples 
Total Volume 
(mL) 
Safety 
 
 
 
 
Serum Biochemistry, Thyroid 
Function 
3.5 
5 
17.5 
 
Serology 
3.5 
1 
3.5 
 
Coagulation 
1.8 
5 
9.0 
 
Haematology 
4.0 
5 
20.0 
 
Tryptase1 
3.5 
2 
7 
 
Bedside blood glucose 
0.1 
Up to 11 
1.1 
Pharmacokinetic 
 
 
 
 
Y14 
6.0 
 Up to 17 
102.0 
 
 
 
 
 
 
 
 
 
 
Total2 
 
 
160.1 
1 In the event of an allergic reaction additional samples will be collected.  
2 Sample volumes are based on direct venepuncture. 
 
Table 7.2 
Blood Volumes: Part B (MAD) 
Assessment 
Sample 
Volume (mL) 
No. of 
Samples 
Total Volume 
(mL) 
Safety 
 
 
 
 
Serum 
Biochemistry 
including 
Thyroid function (TSH, FT4) 
3.5 
16 
56.0 
 
Serology 
3.5 
1 
3.5 
 
Coagulation 
1.8 
16 
28.8 
 
Haematology 
4.0 
16 
64.0 
 
 
 
 
 
 
Tryptase1 
3.5 
2 
7.0 
 
Bedside glucose monitoring 
0.1 
54 
5.4 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
Y14 
6.0 
37 
222.0 
 
 
 
 
 
Pharmacodynamics 
 
 
 
 
Immunogenicity 
6.0 
2 
12.0 
 
Oral 
glucose 
tolerance 
test 
glucose and insulin levels 
3.5 
21 
73.5 
 
Enteropancreatic 
hormones 
(GLP-1, PYY, ghrelin, leptin) 
5.0 
21 
105 
 
 
 
 
 
Total2 
 
 
577.2 
1 In the event of an allergic reaction additional samples will be collected.  
2 Sample volumes are based on direct venepuncture 
 
 
 
 


 
 
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7.1 
Pharmacokinetic Assessments  
7.1.1 Plasma Samples 
Blood sample collection times are included in the schedule of events. 
Details of how samples will be collected, processed and stored will be included in a separate 
laboratory manual. 
Bioanalysis 
The bioanalysis will be performed by LGC Ltd. They will be responsible for the GLP validated 
bioanalysis, which will utilise a high performance liquid chromatography-tandem mass 
spectrometry (LC-MS/MS) assay in human plasma. 
Any remaining plasma may be sent to the sponsor for analysis of Y14 using an exploratory 
non-GLP compliant, non-validated radioimmunoassay.  
7.2 
Pharmacodynamic/Efficacy Assessments  
Time points for collection of PD variables are included in the schedule of events. 
7.2.1 Visual Analogue Scales 
Assessments of nausea and satiety will be performed using VAS. Subjects will be requested to 
rate their responses to a series of questions on a VAS from 0 to 100 mm.  
7.2.2 Energy Intake 
Energy intake will be recorded for Part A and Part B.  
A formal 24 h food intake study will be carried out on Part A from Cohort 3 onwards, on Day 
-1 (measuring lunch and dinner on Day -1 and breakfast on Day 1) and Day 1 (measuring lunch 
and dinner on Day 1 and breakfast on Day 2).  
For Part B, the food intake studies will be carried out on Days -1, 2, and 30. The food intake 
study on Day -1 will measure the ad libitum intake of food during breakfast, lunch and dinner 
on Day -1. The food intake study on Day 2 will measure the ad libitum intake of food during 
breakfast, lunch and dinner on Day 2. The food intake study on Day 30 will measure the ad 
libitum intake of food during breakfast, lunch and dinner on Day 30. The timing of the food 
intake study will be altered according to emerging PK data, if the tmax is delayed beyond 24 
hours. If the timing of the food intake studies are changed the times of the OGTT samples may 
also be changed to ensure they do not happen on the same day. 
While resident in the clinical unit during 24 h food intake assessment days, subjects will be 
individually provided meals in a designated area with individual cubicles per subject. Meals 
will be presented with an excess of food and subjects will be asked to eat until they feel 
"comfortably full" within a period of 30 minutes.  Should a volunteer require more time to eat, 
an extra 15 minutes will be allowed, but such an event will be recorded as a deviation from 
protocol. The energy value of each component of the meal will be determined. Food will be 
weighed pre- and post-meal to determine consumption.  


 
 
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For other days in Part A and Part B, energy intake will be carried out semiquantitively i.e. 
clinical research unit staff will record the timing, types and amounts of food eaten by subjects. 
For the semiquantitative measurement, at the end of each meal the percentage of food left will 
be assessed to be either <10%, 10-<25%, 25-<50% or ≥50%. Snack boxes will also be provided 
at certain timepoints whilst resident in the clinical unit (to be specified in the Meal Manual). 
In Part B, subjects will be admitted on Day -2 (2 days prior to dosing) in order to acclimatise 
to the clinical research unit and obtain baseline food consumption measurements. 
7.2.3 Body Weight 
In Part A (SAD) and Part B (MAD), body weight will be recorded AM and PM each day of the 
inpatient stay and once on every outpatient visit (Part B).  
Body weight for each subject should be measured on the same calibrated scale in underwear, 
after voiding urine, before breakfast (AM) and before dinner (PM), with the exception of days 
where subjects are having an OGTT without having breakfast, where they will be weighed 
prior to the OGTT. 
At each timepoint the weight will be measured in triplicate and the mean calculated. The weight 
should be measured in kg to one decimal place.  
7.2.4 
Fluid Intake/Output 
In Part A (SAD) and B (MAD) fluid intake will also be measured on the days when the subjects 
are undergoing food intake studies as per the Study Schedules.  
7.2.5 Immunogenicity 
For assessment of immunogenicity, plain tube serum samples (6 mL blood volume) will be 
collected prior to the first dose and at the final follow-up visit for SAD Cohort 1 and the MAD 
study, as subjects will be receiving multiple doses of the same peptide in these studies. Samples 
will be analysed using a GLP compliant and validated assay method utilising an ELISA 
(bridging assay format) using rabbit positive control antibodies raised against Y14.  
7.3 
Safety Assessments  
7.3.1 
Adverse Events 
Definitions: 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. 
An AE can therefore be any clinically significant sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 


 
 
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Adverse Drug Reaction (ADR) 
Any untoward and unintended response in a subject to an investigational medicinal product 
which is related to any dose administered to that subject. 
Serious Adverse Event (SAE) 
An adverse reaction is ‘serious’ if it: 
25. Results in death; 
26. Is life-threatening; 
27. Requires hospitalisation or prolongation of existing hospitalisation; 
28. Results in persistent or significant disability or incapacity; 
29. Consists of a congenital anomaly or birth defect; 
30. Is a medically important event. 
Unexpected Adverse Reactions 
An adverse reaction is ‘unexpected’ if its nature and severity are not consistent with the 
information about the medicinal product in question set out: 
31. In the case of a product with a marketing authorisation, in the summary of product 
characteristics for that product; 
32. In the case of any other investigational medicinal product, in the Investigator’s Brochure 
relating to the trial in question. 
7.3.2 
Reporting of Adverse Events 
All adverse events must be fully recorded in the adverse event book throughout the entire study 
period and will be transcribed into the subjects’ CRF, whether or not they are considered to be 
drug-related.  Signs and symptoms of each AE should be described in detail: onset time and 
date, offset time and date, description of event, severity, relationship to investigational product, 
action taken and outcome. 
Adverse events should be followed until recovery to the normal state has been achieved. In the 
event of a subject not returning to the clinical unit, the outcome of this event will be recorded 
as lost at follow up. 
Reporting of SAEs and SUSARs 
SAEs occurring on this study will be reported to the Sponsor’s medical representative Dr Tricia 
Tan within agreed timelines.  The Investigator will be requested to complete a separate SAE 
reporting form in addition to the information on the CRF and in the AE book. 
The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory Instrument 1031) 
and subsequent amendments define the following terms: 


 
 
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An adverse reaction is any untoward and unintended response in a subject to an investigational 
medicinal product which is related to any dose administered to that subject. 
A suspected unexpected serious adverse reaction (SUSAR) which is fatal or life-threatening 
must be reported to the competent authority and ethics committee immediately (within 7 days) 
after the Sponsor became aware of the event.  Any additional information must be reported 
within eight days of sending the first report.  
A SUSAR which is not fatal or life-threatening must be reported to the competent authority 
and ethics committee as soon as possible (within 15 days) after the Sponsor becomes aware of 
the event. 
If a clinical trial is being conducted at a trial site in a third country in addition to sites in the 
United Kingdom, the Sponsor of that trial shall ensure that all SUSARs occurring at that site 
are entered into the European database established in accordance with Article 11 of the EU 
Clinical Trials Directive. 
As soon as practicable after the end of the reporting year, a Sponsor shall, in relation to each 
investigational medicinal product tested in clinical trials in the United Kingdom for which he 
is the Sponsor provide the licensing authority and the relevant ethics committees with -  
1. A list of all the suspected serious adverse reactions which have occurred during that year 
in relation to: 
• those trials, whether at trial sites in the United Kingdom or elsewhere;  
• or any other trials relating to that product which are conducted outside the United 
Kingdom and for which he is the Sponsor;  
including those reactions relating to any investigational medicinal product used as a 
placebo or as a reference in those trials; and 
2. A report on the safety of the subjects of those trials. 
7.3.3 
Categorisation of Adverse Events 
The intensity of an AE will be categorised as follows: 
Mild: 
Mild events are those which are easily tolerated with no disruption of 
normal daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to 
interfere with daily activity. 
Severe: 
Severe events are those which incapacitate and prevent usual activity. 
7.3.4 
Causal Relationship Assessment 
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  
To promote consistency, the following guidelines should be taken into considerations along 


 
 
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with good clinical and scientific judgment when determining the relationship of drug 
treatments to an AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in 
a plausible time relationship to the medication administration, and 
which cannot be explained by concurrent disease or other drugs or 
chemicals.  The response to withdrawal of the drug should be 
clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to the medication administration, but which 
could also be explained by concurrent disease or other drugs or 
chemicals.  Information on the drug withdrawal may be lacking or 
unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or 
no temporal relationship to medication administration, and which 
other drugs, chemicals or underlying disease provide plausible 
explanations. 
Not Related: 
A clinical event, including laboratory test abnormality that has no 
temporal relationship to the medication or has more likely alternative 
aetiology. 
7.3.5 
Action Taken 
Action taken will be defined as: 
• 
None; 
• 
Medication given; 
• 
Dosing interrupted (this applies to Part B only as it involves multiple dosing); 
• 
Dosing stopped (this applies to Part B only as it involves multiple dosing). 
7.3.6 
Outcome 
Outcome will be defined as: 
• 
Resolved; 
• 
Ongoing; 
• 
Lost to follow up. 
7.3.7 
Coding of Adverse Events 
All adverse events will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA). 


 
 
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7.4 
Clinical Laboratory Safety Tests 
Sample collection times are included in the schedule of events. 
Additional and repeat testing may be performed at the discretion of the Principal Investigator.  
Safety laboratory variables to be assessed are presented in Table 7.3. 
Table 7.3 
Safety Laboratory Variables 
 
Haematology 
 
White blood cells 
Red blood cells 
Mean corpuscular volume 
Mean corpuscular 
haemoglobin 
Mean corpuscular 
haemoglobin concentration 
Haemoglobin 
Haematocrit  
Neutrophils (absolute and %) 
Lymphocytes (absolute and %) 
Monocytes (absolute and %) 
Eosinophils (absolute and %) 
Basophils (absolute and %) 
Platelets 
Biochemistry  
 
Sodium 
Potassium 
Urea 
Creatinine 
Alkaline phosphatase 
Alanine aminotransferase 
Creatine kinase 
Gamma-glutamyltransferase 
Lactate dehydrogenase 
Aspartate aminotransferase 
Glucose 
Lipase 
Amylase 
Total bilirubin  
Calcium 
Chloride 
Total protein 
Globulin 
Cholesterol 
Triglycerides 
Uric acid 
Phosphate 
Albumin 
Bicarbonate 
C-reactive protein1 
Coagulation 
 
Prothrombin time 
International normalized ratio 
Activated partial thromboplastin 
time 
Thyroid Function 
TSH, FT4 
 
Biomarkers  
Histamine 
Tryptase 
Urinalysis 
 
Protein 
Bilirubin 
Urobilinogen 
Ketones 
Glucose 
Leukocytes 
Red blood cells 
pH 
Nitrite 
Specific gravity 
Urine Microscopy 
Microscopic investigation of sediment in case of pathological 
findings [performed if clinically indicated] 
Viral Serology 
 
HIV I and II 
HBsAg 
Hepatitis C virus 
Drugs of Abuse and Alcohol Screen 
 
Amphetamine / Ecstasy 
Cannabinoids 
Cocaine 
Opiates 
Benzodiazepines 
Methadone metabolites 
Barbiturates 
Cotinine 
Alcohol Screen (Breath test) 
Alcohol 
 
1 At screening only 


 
 
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Unless otherwise specified in the schedule of assessments all clinical laboratory tests will be 
performed by CRO Pathology Lab, which is a GLP Accredited Laboratory. Details of all 
methodology and reference ranges are provided in the Trial Master File.   
7.5 
Clinical Safety Assessments 
Assessment times are included in the schedule of events.  Time points of assessments may be 
amended based on emerging safety, tolerability and PK data. 
7.5.1 
Vital Signs 
Blood pressure and pulse rate will be measured using an automated instrument with the subject 
in the supine position after resting comfortably for 10 minutes.  Body temperature will be 
measured orally in degrees Celsius using an automated thermometer.  Additional vital signs 
measurements may be added for safety of the subjects. 
Measurements will be reported in the subject’s CRF. 
7.5.2 
12-Lead ECG 
Computerised 12-lead ECG recordings will be obtained. after 5 minutes supine rest.  Each lead 
shall be recorded for at least 3 beats at a speed of 25 mm/sec. 
The following parameters will be recorded:  ventricular rate, PR interval, QRS duration, QT 
and QTc. 
7.5.3 
Medical History 
A complete medical history will include evaluation (past or present) of the following:  general, 
head 
and 
neck, 
eyes, 
ears, 
nose 
throat, 
chest/respiratory, 
heart/cardiovascular, 
gastrointestinal/liver, 
gynecological/urogenital, 
musculoskeletal/extremities, 
skin, 
neurological/psychiatric, 
endocrine/metabolic, 
haemotologic/lymphatic, 
allergies/drug 
sensitivities, past surgeries, substance abuse or any other diseases or disorders.  
7.5.4 
Physical Examination 
Physical examinations will be performed by a physician and will include the examination of 
the 
following: 
general 
appearance, 
eyes, 
ears, 
nose, 
throat, 
chest/respiratory, 
heart/cardiovascular, gastrointestinal/liver, musculoskeletal/extremities, dermatological/skin, 
thyroid/neck, lymph nodes, neurological/psychiatric. 
7.5.5 
Bedside glucose testing 
Where indicated in the Study Schedules, bedside glucose testing will be carried out. 
7.5.6 
Local Injection Site Reactions 
Injection sites will be monitored while the subject is resident in the clinical unit for redness, 
swelling, pain, tenderness and bruising.  Reaction grades are provided in Table 7.4. 
In the event that there are injection site reactions thought to be related to the volume of the 
injection, subsequent doses may be split into a maximum of 5 smaller injections. 


 
 
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Injection site reactions with a Grade ≥1 will be recorded as an AE. 
Table 7.4 
Injection Site Reaction Grading Scheme 
 
Reaction 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Redness1 
0–24 mm 
25–50 mm 
51–100 mm 
More than 100 mm 
Requires 
medical 
intervention 
greater than 
analgesia 
Swelling2 
0–24 mm 
25–50 mm and 
does not 
interfere with 
activity 
51–100 mm or 
interferes with 
activity 
More than 100 mm 
and prevents daily 
activity 
Requires 
medical 
intervention 
greater than 
analgesia 
Pain 
None 
Does not 
interfere with 
activity 
Interferes with 
activity or 
repeated use of 
non-narcotic pain 
reliever 
Prevents daily 
activity or repeated 
use of narcotic pain 
reliever 
Requires 
medical 
intervention 
greater than 
analgesia 
Tenderness 
None 
Mild pain to 
touch 
Moderate pain to 
touch 
Severe pain to 
touch 
Requires 
medical 
intervention 
greater than 
analgesia 
Bruising 
None 
Present 
Ulceration 
± tissue 
necrosis 
None  
None 
None 
None 
Present 
1  Assessed by estimating the size of the red patch at the injection site across its widest point 
2  Assessed by estimating the size of the raised area around the injection site across its widest point; also take into account how much it affects 
the subject in their routine daily activities. 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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8 
DATA COLLECTION 
An electronic data capture system will be used in this trial. Data will be captured onto source 
data documents (Workbooks) and will be entered into the Remote Data Capture system by staff 
at the clinical site. Following data entry, the data will undergo quality control checks. Any 
discrepancies will be resolved in the database.  
 
Following all data validation steps, the Principal Investigator, or designee, will electronically 
sign each eCRF prior to database lock. 
 


 
 
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9 
EVALUATION OF STUDY DATA 
9.1 
Evaluation of Pharmacokinetic Parameters 
Pharmacokinetic parameters of Y14 will include: maximum observed concentrations (Cmax), 
time of occurrence of Cmax (Tmax), area under the plasma concentration-time curves (AUC0-, 
AUC0-t, AUC0-), the apparent terminal rate constant (λz), the apparent terminal half-life (t½) 
and the extent of accumulation in plasma (RO).  Pharmacokinetic parameters will be calculated, 
where appropriate, by non-compartmental analysis using WinNonlin Pro Version 5.2.1 (or 
higher version).  Full details of the pharmacokinetic analysis, associated statistics and reporting 
will be documented in a separate Pharmacokinetic Analysis Plan which will be distributed to 
the Sponsor and Principal Investigator for approval. 
9.2 
Evaluation of Pharmacodynamic Measures 
9.2.1 
Visual Analogue Scales 
Change from baseline values will be calculated using Day -1 values as baseline. 
9.2.2 
 Energy Intake 
The energy value per unit of weight will be determined for each individual component of a 
meal.  Each component of the meal will be weighed pre and post-meal and the weight 
consumed will be calculated (i.e. weight pre meal - weight post meal = weight consumed).  
Total energy intake will be calculated from the weight of each component consumed. 
9.2.3 
Body Weight 
Change from baseline values will be calculated using the mean of Day -1 (AM and PM) and Day 
1 (predose) values as baseline. 
9.2.4 
Immunogenicity 
Immunogenicity data will be presented as 'yes/no' based on a cut-off for binding to labelled 
Y14 in the immunogenicity assay (Section 7.2.5). 
9.3 
Evaluation of Safety 
The safety evaluation will include blood pressure, pulse rate, ECG parameters, clinical 
laboratory tests (haematology, serum biochemistry, coagulation, urinalysis and urine 
microscopy).  Histamine and tryptase determinations will only be performed after relevant 
adverse events and analysed retrospectively to inform possible mechanism of AEs. 


 
 
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10 
STATISTICAL METHODS  
10.1 
Primary and Secondary Target Variables  
Primary Target Variables 
• Safety and tolerability as assessed by adverse events, vital signs, physical examination, 
clinical laboratory safety assessments, and ECG parameters. 
Secondary Target Variables 
• Pharmacokinetics of Y14 as measured by plasma concentrations and derived 
pharmacokinetic parameters. 
Exploratory Target Variables  
• The effects of multiple doses of Y14 on food consumption.  
• The effects of multiple doses of Y14 on VAS (nausea and satiety).  
• The effects of multiple doses of Y14 on body weight.  
• The effects of multiple doses of Y14 on enteropancreatic hormone levels. 
• The comparative analytical performance of an Imperial College radioimmunoassay 
versus the LC-MS/MS assay for Y14. 
•  
10.2 
Sample Size Determination 
This is a Phase I study to investigate the safety and tolerability of a novel compound, an 
appropriate sample size cannot be statistically determined and hence the sample size chosen 
was based on previous experience in Phase I studies. 
10.3 
Subject Population for Analyses 
Safety Population 
All subjects who receive study medication (Y14 or placebo) will be included in the safety 
population. 
Pharmacokinetic Population 
All subjects who receive Y14 and have data from at least 1 PK blood draw will be included in 
the PK population.   
Pharmacodynamic Population 
All subjects who receive study medication and have data from at least 1 PD blood draw or 
measurement, as appropriate will be included in the PD population. 


 
 
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10.4 
Pharmacokinetic Analysis 
KinetAssist Limited will be responsible for the pharmacokinetic analysis.  The 
pharmacokinetic analysis will be conducted at a Good Laboratory Practice compliant facility 
which operates a Quality Management System (QMS).  The QMS has been designed to be 
compatible with the Organisation for Economic Co-operation and Development (OECD) 
Principles of GLP and GCP requirements.  The pharmacokinetic analysis will be reported at 
KinetAssist Limited and the report will be included as an appendix to the clinical report. All 
data generated at KinetAssist Limited will be dispatched to the Sponsor and archived according 
to their archiving procedures. 
A review of dosing information will be performed to consider excluding data in any period or 
on any day where a subject was judged to have received <80% or >120% of the scheduled dose 
of the investigational product; resulting exclusions will be documented in advance of issuing 
the draft report and agreed with the Sponsor.  Plasma concentration data will be excluded for 
the affected period or day if concentrations are extremely low relative to other subjects' data; 
in these cases, plasma concentrations will be excluded from all or part of the profile, as 
appropriate. 
PK parameters will be excluded from the analysis and summary statistics, where there are 
insufficient plasma concentration data available.   
Plasma concentration data will be summarised by sampling time, dose level and Day, as 
appropriate; pharmacokinetic parameters (e.g. AUC0-, AUC0-t, AUC0-, Cmax, tmax, t½ and RO) 
will be summarised by dose level and Day, as appropriate. 
All individual plasma and pharmacokinetic parameter estimates will be listed and summarised.  
Mean and individual plasma concentration versus time profiles will be illustrated using both 
linear-linear and logarithmic-linear scales.   
Summary statistics will include number of subjects (n), arithmetic mean and standard deviation 
(SD).  Summaries for the pharmacokinetic parameters will also display the median, minimum 
and maximum.  In addition, the geometric mean and geometric coefficient of variation  
(
100
*
1
)
exp(
2
ln
−
=
SD
CV
, where SDln is the standard deviation of the natural 
logarithmically transformed data) will be reported for all pharmacokinetic parameters except 
tmax. 
Between-subject variability will be based on geometric mean coefficients of variation (CVs). 
A non-linear power model will be used to assess dose-proportionality.  The proportional 
relationship between each parameter and dose is written as a power function:   
y = a×doseb (Equation 1)  
where ‘a’ is a constant, ‘b’ is the proportionality constant and ‘y’ is the parameter of interest 
(AUC0-, AUC0-t, AUC0- or Cmax).  AUC0- (after repeated dosing) AUC0- (or AUC0-t if AUC0-


 
 
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 could not be reliably estimated in all subjects) and Cmax will be each plotted against dose.  
The exponent, b, will be estimated by performing a linear regression of the logged parameter 
on log dose.  The exponent, b, is the estimated slope of the resulting regression line since taking 
logs of Equation (1) gives the linear relationship, log y = log a + b×log dose.  The relationship 
is dose-proportional when b = 1.  The exponents and 95 % confidence intervals (CIs), blower (bl) 
and bupper (bu), are presented.  There would be evidence of non dose-proportionality if this CI 
excludes one.  The estimate of the fold increase in exposure for a doubling in dose (with 95 % 
CI) will also be presented.  The increase in exposure expected for a doubling in dose will be 
calculated as 2b (95 % CI: 2bl, 2bu). 
10.5 
Pharmacodynamic Analysis 
Observed values for all pharmacodynamic parameters will be listed and where appropriate, 
summarised with descriptive statistics.  
Change-from-baseline may be calculated if appropriate. 
Immunogenicity data will be presented as 'yes/no' based on a cut-off of binding to labelled Y14 
in the immunogenicity assay (Section 7.2.5). 
10.6 
Safety Data Analysis 
Safety data analysis will be performed by Covance Clinical Research Unit.  Individual and 
summary blood pressures, pulse rate, ECG parameters and clinical laboratory data 
(haematology, serum biochemistry, urinalysis and coagulation) will be presented in tabular 
form with mean, median, standard deviation and range (min and max) as appropriate.  
Continuous variables will be presented in tabular form with mean, median, standard deviation 
and range (minimum and maximum) as appropriate.  Categorical variables will be summarised 
in frequency tables (frequency and proportion). 
Histamine and tryptase values will be listed if the analysis has been performed and data is 
available. 
For the laboratory safety data, out of range values will be flagged in the data listings and a list 
of clinically significantly abnormal values will be presented. 
Adverse events will be tabulated and summarised according to the current version of Medical 
Dictionary for Regulatory Activities (MedDRA). 


 
 
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11 
REGULATORY AND ETHICAL ISSUES 
11.1 
Regulatory and Ethics Review and Approval 
The study will be submitted to the MHRA (UK) for review and approval and to an Independent 
Ethics Committee for ethical review and approval.  The documents submitted will include but 
are not limited to: 
MHRA: 
3. The final protocol; 
4. The Investigators Brochure (IB); 
5. The Investigational Medicinal Product Dossier (IMPD); and 
6. Annex 1: Clinical Trial Application Form (Request for authorisation of a clinical trial on a 
medicinal product for human use to the competent authorities and for opinion of the ethics 
committees in the community).  
Ethics: 
7. The final protocol; 
8. The Investigators Brochure (IB); 
9. The ethics application form; and  
10. The Informed Consent Form (ICF) 
 
The study will not commence unless the following conditions are satisfied: 
11. An ethics committee has given a favourable opinion in relation to the clinical trial; and 
12. The clinical trial has been authorised by the licensing authority (MHRA). 
 
11.2 
Informed Consent 
Subjects will sign the pre-screening/generic ICF in the presence of a suitably trained CRU 
clinical operations staff member prior to the pre-screening procedures being performed (if 
applicable).  
For the main study, informed consent will be given freely after the subject has been informed 
of the nature, significance, implications and risks of the trial; and consent is evidenced in 
writing, dated and signed, or otherwise marked, by that person so as to indicate his/her consent, 
prior to the start of the study. The nature of the informed consent will comply with the current 
version of the Declaration of Helsinki, the current requirements of GCP (CPMP/ICH/135/95) 
and local regulation (The requirements are set out in Schedule 1 of Statutory Instrument 1031 
and amendments) which ever provides the greater subject protection.  


 
 
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11.3 
Indemnity and Compensation 
In accordance with Statutory Instrument 1031 and amendments section 15 (5i, j) and the EU 
Clinical Trials Directive 2000/20/EC Article 3 (2f), provision is to be made for: 
1. The indemnity or compensation in the event of injury or death attributable to the clinical 
trial; and  
2. Insurance or indemnity to cover the liability of the Investigator or Sponsor. 
Therefore the Sponsor, Imperial College, will indemnify the Investigator, Covance Clinical 
Research Unit, from all and any claims arising out of this study except for their negligence or 
malpractice and providing that the study is conducted according to the standards established 
by the protocol. 
In the event that it can be demonstrated that a subject suffers any significant deterioration in 
health or well-being or any harmful susceptibility or toxicity as a direct result of their 
participation in this study then Imperial College will agree to abide by the current Association 
of the British Pharmaceutical Industry Guidelines with regard to compensation payable to the 
subject.  The amount of compensation will be calculated by reference to the level of damages 
commonly awarded in the UK for similar injuries at the time when such injury occurred. 
The Investigator, Covance Clinical Research Unit, declare to having insurance cover for the 
malpractice and/or negligence of their employees and agents. 


 
 
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12 
STUDY MANAGEMENT  
12.1 
Quality Assurance and Quality Control 
In accordance with the guideline for ICH GCP, the Sponsor has responsibility for implementing 
and maintaining quality assurance and quality control systems, and the ultimate responsibility 
for the quality integrity of the trial data resides with the Sponsor. 
Authorised representatives of the Sponsor may perform audits or inspections during the study.  
The purpose of an audit is to independently assure that the study is conducted and that data is 
collected and reported according to the protocol, Good Clinical Practice (GCP), guidelines of 
the International Conference on Harmonisation (ICH), and any applicable regulatory 
requirements.   
12.2 
Protocol Adherence 
The protocol must be read thoroughly and the instructions followed exactly.  Any deviations 
should be agreed by both the Sponsor and the Investigator, with the appropriate written and 
approved protocol amendments made to reflect the changes agreed upon.  Where the deviation 
occurs for the well-being of the subject, the Sponsor must be informed of the action agreed 
upon. 
12.3 
Documents Necessary for Initiation of Study 
The following documents will be available prior to the first administration of the drug to the 
first subject: 
1. Regulatory authorisation; 
2. Copy of current Investigator’s Brochure; 
3. Risk assessment report; 
4. Completed and signed investigator agreement/contract; 
5. Signed original of the final protocol; 
6. Ethics Committee approval; 
7. Copy of the constitution of the Research Ethics Committee;   
8. A list of members of the Ethics Committee; 
9. A copy of the consent form and subject information to be used; 
10. The curriculum vitae of all Investigators; 
11. The Qualified Person’s certification for the release of each batch of IMP; 
12. A technical agreement between the Sponsor and Covance defining the responsibilities of 
the Sponsor, Covance Clinical Research Unit, and any third parties significantly involved 
in the supply chain of the IMP, where applicable; 


 
 
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13. The product specification file, where applicable; and  
14. A list of laboratory reference range values for parameters measured in the study. 
12.4 
Study Monitoring  
In accordance with ICH GCP, the Sponsor will be responsible for monitoring the conduct of 
the study.  An independent study monitor will be appointed before the study begins. 
The study monitor, will conduct pre-study and start-up meeting site visits and in addition will 
visit the site during the conduct of the study, review the study data and conduct a post-study 
visit.  Study data recorded on source documents will be made available to the study monitor 
for the purpose of source document verification.  The monitor will verify that the: 
• data are authentic, accurate, and complete. 
• safety and rights of subjects are being protected. 
• study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements. 
The Investigator will allow trial-related monitoring audits, IEC review, and regulatory 
inspection allowing direct access to the source data/documents. 
12.5 
Study Closure 
The Sponsor will be responsible for the close out visit which will be conducted on clinical 
completion of the study. 
12.6 
Study Record Retention 
In accordance with SI 1928, the Sponsor and the Principal Investigator shall ensure that the 
documents contained, or which have been contained, in the trial master file are retained for at 
least 15 years after the conclusion of the trial and that during that period are: 
• Readily available to the licensing authority on request; and 
• Complete and legible. 
All data derived from the study will remain the property of the Sponsor.  The study will be the 
subject of a final clinical study report compiled by, or by order of the Sponsor. 
All correspondence (e.g. with the Sponsor, ethics committee) relating to this study should be 
kept in the appropriate file folders. 
Records of subjects' source documents, CRFs, IMP inventory, pertaining to the study must be 
kept on file.  Records must be retained according to the current ICH Guidelines on GCP. 
The Sponsor and Principal Investigator shall ensure that the medical files of trial subjects are 
retained for at least 15 years after the conclusion of the trial.  The Sponsor shall appoint named 
individuals within his organisation to be responsible for archiving the documents which are, or 
have been, contained in the trial master file.  Access to those documents shall be restricted to 


 
 
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those appointed individuals.  If there is transfer of ownership of data or documents connected 
with the clinical trial: 
• The Sponsor shall record the transfer; and 
• The new owner shall be responsible for data retention and archiving in accordance 
Statutory Instrument 1031 and amendments. 
If the Investigator moves, withdraws from an investigation or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept responsibility.  
Notice of transfer must be made to and agreed by the Sponsor. 
12.7 
Publication Policy 
After completion of the study, the Investigator may prepare a joint publication with the 
Sponsor. The Investigator must undertake not to submit any part of the individual data from 
this protocol for publication without prior consent of the Sponsor at a mutually agreed time. 


 
 
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13 
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