Clinical trial NCT02692040
Conditions: Diabetes Mellitus Obesity
Keywords: obesity diabetes mellitus glucagon-like peptide-1
Sponsor: Imperial College London
Start date: 2015-01-01; Completion date: 2019-01-01
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
A randomised, placebo controlled Phase I study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of G3215 in adult subjects.

Detailed description:
Objectives:

Primary Objective

* To investigate the safety and tolerability of single doses of G3215 in overweight but otherwise healthy male subjects.
* To investigate the safety and tolerability of multiple doses of G3215 in overweight male subjects with mild stable Type 2 diabetes or prediabetes.

Secondary Objectives • To assess the pharmacokinetic (PK) profile of single and multiple ascending doses of G3215 in overweight but otherwise healthy male subjects or overweight / obese male subjects with mild stable Type 2 diabetes or prediabetes.

Exploratory Objective

• To investigate the effects of multiple doses of G3215 on food consumption, body weight, enteropancreatic hormone changes and glucose tolerance in overweight male subjects with mild Type 2 diabetes or prediabetes.

Arms: arm 1: G3215 multiple dose, subcutaneous injection:

5 doses over a 4 week treatment period at escalating doses to a max of 24 mg. arm 2: G3215 multiple dose, subcutaneous injection:

5 doses over a 4 week treatment period at escalating doses to a max of 10 mg. arm 3: G3215 multiple dose, subcutaneous injection:

5 doses over a 4 week treatment period at escalating doses to a max of 16 mg. arm 4: G3215 subcutaneous infusion over a 4 day treatment period at escalating doses to a max of 3.2 mg (with either the first or last day administering infusion of placebo \[saline\]). arm 5: 5 subcutaneous injections of 0.9% saline, over a 4 week treatment period arm 6: Single subcutaneous injection of 0.9% saline arm 7: 0.1 mg G3215 single dose, subcutaneous injection arm 8: 0.5 mg G3215 single dose, subcutaneous injection arm 9: 1.5 mg G3215 single dose, subcutaneous injection arm 10: 4 mg G3215 single dose, subcutaneous injection arm 11: 4 mg G3215 single dose, subcutaneous injection arm 12: 4 mg G3215 single dose, subcutaneous injection arm 13: 4 mg G3215 single dose, subcutaneous injection arm 14: 8 mg G3215 single dose, subcutaneous injection arm 15: 10 mg G3215 single dose, subcutaneous injection arm 16: 12 mg G3215 single dose, subcutaneous injection arm 17: 16 mg G3215 single dose, subcutaneous injection arm 18: 32 mg G3215 single dose, subcutaneous injection arm 19: 48 mg G3215 single dose, subcutaneous injection
Interventions: intervention 1: G3215 intervention 2: Placebo
Intervention descriptions: intervention 1: Gut hormone analogue intervention 2: 0.9% saline

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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A randomised, placebo controlled study to investigate the safety, 
tolerability, pharmacokinetics and pharmacodynamics of G3215 in 
adult subjects 
 
 
 
 
 
Protocol Number: 
 
2014/G3215/01 
CRO Study Number: 
 
1003346-8299650 
EudraCT Number: 
 
2014-003672-23 
Product: 
 
G3215 
Indication: 
 
Obesity 
Clinical Phase: 
 
I 
Sponsor Chief 
Investigator  
(Imperial College) 
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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Summary of protocol revision dates and versions 
 
DATE/NAM
E 
DESCRIPTION 
27 Oct 
2014 
 
First Version of the final protocol 
22 Nov 
2014 
 
Non-Substantial Protocol Amendment 1 
 
30 Jan 
2015 
 
Protocol Version 2 – Substantial Protocol Amendment 1 
 
17 Jun 15 
Protocol Version 3 – Substantial Protocol Amendment 2 
8 Feb 2016 
Protocol Version 4.0 
 
21 Dec 
2016 
Protocol Version 5.0 
17 Feb 
2017 
Protocol Version 5.1 
 
31 
May2017 
Protocol Version 6.0 
02 Oct 
2017 
Protocol version 7.0 
 
08 Dec 
2017 
Protocol version 7.1 
09 May 
2018 
Protocol version 8.0 


 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ......................................................................................... 9 
1 
INTRODUCTION ..................................................................................... 11 
1.1 
Background Information for G3215 .......................................................... 11 
1.2 
Risk Assessment ........................................................................................ 12 
1.3 
Urgent safety measures .............................................................................. 14 
STUDY OBJECTIVES ................................................................................................. 15 
1.4 
Primary Objective ...................................................................................... 15 
1.5 
Secondary Objectives ................................................................................ 15 
1.6 
Exploratory Objectives .............................................................................. 15 
2 
INVESTIGATIONAL PLAN .................................................................... 16 
2.1 
Overall Study Design ................................................................................. 16 
2.1.1 
Part A (Single Ascending Dose) ................................................................ 16 
2.1.2 
Part B (Multiple Ascending Dose) ............................................................ 18 
2.1.3 
Part C (Ascending Dose) ........................................................................... 21 
2.1.4 
Dose Escalation Criteria ............................................................................ 24 
2.1.5 
Stopping Rules ........................................................................................... 25 
2.1.6 
Discussion of Study Design ....................................................................... 26 
2.2 
Study Population ........................................................................................ 27 
2.2.1 
Subject Inclusion Criteria .......................................................................... 27 
2.2.2 
Subject Exclusion Criteria ......................................................................... 28 
2.2.3 
Restrictions ................................................................................................ 29 
2.2.3.1 
Avoidance of Pregnancy ............................................................................ 30 
2.2.3.2 
Acceptable Forms of Contraception .......................................................... 31 
2.2.3.3 
Time Period for the Collection of Pregnancy Information ........................ 31 
2.2.3.4 
Follow-up in the Event of a Pregnancy ..................................................... 31 
2.2.4 
Subject Withdrawals .................................................................................. 32 
3 
STUDY TREATMENT ............................................................................. 33 
3.1 
Investigational Product(s) .......................................................................... 33 
3.1.1 
Supply, Packaging and Labelling .............................................................. 33 
3.1.2 
Storage and Handling Procedures .............................................................. 33 
3.1.3 
Accountability ............................................................................................ 34 
3.2 
Dosage and Administration ....................................................................... 34 
3.3 
Treatment Strategy ..................................................................................... 35 
3.4 
Warnings and Precautions ......................................................................... 35 
3.5 
Prior and Concomitant Medication ............................................................ 35 
3.6 
Method of Assigning Subjects to Treatment Groups ................................ 35 
3.7 
Randomisation Procedures ........................................................................ 36 
3.8 
Maintenance of Randomisation Codes ...................................................... 36 
3.9 
Blinding ..................................................................................................... 37 


 
 
 
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4 
STUDY PROCEDURES ........................................................................... 38 
4.1 
Pharmacokinetic Assessments ................................................................... 39 
4.1.1 
Plasma Samples ......................................................................................... 39 
4.2 
Pharmacodynamic/Efficacy Assessments ................................................. 40 
4.2.1 
Visual Analogue Scales ............................................................................. 40 
4.2.2 
Energy Intake ............................................................................................. 40 
4.2.3 
Body Weight .............................................................................................. 41 
4.2.4 
Immunogenicity ......................................................................................... 41 
4.2.5 
Oral glucose tolerance testing and enteropancreatic hormones (Part B) ... 41 
4.3 
Safety Assessments .................................................................................... 42 
4.3.1 
Adverse Events .......................................................................................... 42 
4.3.2 
Reporting of Adverse Events ..................................................................... 43 
4.3.3 
Categorisation of Adverse Events ............................................................. 43 
4.3.4 
Causal Relationship Assessment ............................................................... 43 
4.3.5 
Action Taken ............................................................................................. 44 
4.3.6 
Outcome ..................................................................................................... 44 
4.3.7 
Coding of Adverse Events ......................................................................... 44 
4.4 
Clinical Laboratory Safety Tests ............................................................... 44 
4.5 
Clinical Safety Assessments ...................................................................... 46 
4.5.1 
Vital Signs ................................................................................................. 46 
4.5.2 
Bedside glucose testing .............................................................................. 46 
4.5.3 
12-Lead ECG ............................................................................................. 46 
4.5.4 
Medical History ......................................................................................... 46 
4.5.5 
Physical Examination ................................................................................ 46 
4.5.6 
Local Injection Site Reactions ................................................................... 47 
5 
DATA COLLECTION .............................................................................. 48 
6 
EVALUATION OF STUDY DATA ......................................................... 49 
6.1 
Evaluation of Pharmacokinetic Parameters ............................................... 49 
6.2 
Evaluation of Pharmacodynamic Measures ............................................... 49 
6.2.1 
Visual Analogue Scales ............................................................................. 49 
6.2.2 
Energy Intake ............................................................................................. 49 
6.2.3 
Body Weight .............................................................................................. 49 
6.2.4 
Immunogenicity ......................................................................................... 49 
6.3 
Evaluation of Safety .................................................................................. 49 
7 
STATISTICAL METHODS ...................................................................... 50 
7.1 
Primary and Secondary Target Variables .................................................. 50 
7.2 
Sample Size Determination ....................................................................... 50 
7.3 
Subject Population for Analyses ................................................................ 50 
7.4 
Pharmacokinetic Analysis ......................................................................... 51 
7.5 
Pharmacodynamic Analysis ....................................................................... 52 
7.6 
Safety Data Analysis .................................................................................. 52 


 
 
 
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8 
REGULATORY AND ETHICAL ISSUES .............................................. 54 
8.1 
Regulatory and Ethics Review and Approval ............................................ 54 
8.2 
Informed Consent ...................................................................................... 54 
8.3 
Indemnity and Compensation .................................................................... 55 
9 
STUDY MANAGEMENT ........................................................................ 56 
9.1 
Quality Assurance and Quality Control ..................................................... 56 
9.2 
Protocol Adherence ................................................................................... 56 
9.3 
Documents Necessary for Initiation of Study ............................................ 56 
9.4 
Study Monitoring ....................................................................................... 57 
9.5 
Study Closure ............................................................................................. 57 
9.6 
Study Record Retention ............................................................................. 57 
9.7 
Publication Policy ...................................................................................... 58 
 
 
 


 
 
 
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LIST OF TABLES 
Table 2.1  
Dosing Schedule: Part A .............................................................................. 17 
Table 2.2 
Dosing Schedule: Part C .............................................................................. 23 
Table 3.1 
Assignment of Subjects to Treatment .......................................................... 36 
Table 4.1 
Blood Volumes: Part A (SAD) .................................................................... 38 
Table 4.2 
Blood Volumes: Part B (MAD) ................................................................... 39 
Table 4.3 
Blood Volumes: Part C ................................................................................ 39 
Table 4.4 
Safety Laboratory Variables ........................................................................ 45 
Table 4.5 
Injection Site Reaction Grading Scheme ..................................................... 47 
 
 
 
LIST OF FIGURES 
Figure 2.1 
Study Overview: Part B ............................................................................... 20 
Figure 2.2 
Study Overview: Part C ............................................................................... 23 
 
 
 


 
 
 
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LIST OF ABBREVIATIONS  
adm 
administration 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALK 
Alkaline phosphatase 
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 
Maximum plasma concentration 
CRF 
Case report form 
CRP 
C-reactive protein 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EU  
European Union  
FDA 
Food and Drug Administration 
FIH 
First in human 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transpeptidase 
GLP 
Good Laboratory Practice 
GLP-1 
Glucagon-like peptide-1 
GMP 
Good Manufacturing Practice 
h 
Hour 
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 
Investigational medicinal product dossier 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
LDH 
Lactate dehydrogenase 
MABEL 
Minimum anticipated biological effect level 
MAD 
Multiple ascending dose 


 
 
 
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Max 
Maximum 
MHRA 
Medicines and Healthcare products Regulatory Agency 
Min 
Minimum 
MRSD 
Minimum recommended starting dose 
MTD 
Maximum tolerated dose 
NOAEL 
No observed adverse effect level 
OGTT 
Oral glucose tolerance test 
OXM 
Oxyntomodulin 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Pancreatic polypeptide 
PT 
Prothrombin time 
PTFE 
Polytetrafluoroethylene 
PYY 
Peptide YY 
QMS 
Quality management system 
QP 
Qualified person 
Ro 
Extent of accumulation in plasma 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SD 
Standard Deviation 
SEM 
Standard Error of the Mean 
SGLT-2 
Sodium-Glucose co-transporter 2 
SI 
Statutory Instrument 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Apparent terminal half life 
tmax 
Time to maximum plasma concentration 
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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1 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 (OXM) 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 2008, about 24% of men and 25% of women in the United Kingdom were obese [10]. 
The prevalence of obesity appears to be increasing and a recent estimate indicated that 
obesity would affect up to 33% of 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.  
1.1 Background Information for G3215 
G3125 is an analogue which combines the actions of two important hormones, glucagon, 
which increases energy expenditure, and GLP-1, which inhibits appetite and enhances 
insulin release, similar to the gut peptide oxyntomoduin.  
G3215 was selected from 2,000 G analogues that were screened for human GLP-1 and 
glucagon receptor binding, and for receptor activation via cAMP activity. Bioactivity was 
measured via its anorectic and weight-reducing effect in mice and rats. The amino acid 
sequence of G3215 is based on human Oxyntomodulin, with the following features: 
• 
Deletion of 2 residues; 


 
 
 
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• 
Substitution of 14 other residues within the 35-residue peptide, with the receptor 
active sequence of oxyntomodulin being unchanged; 
• 
Composition wholly of natural L-amino acids without derivatisation or cross linking. 
For further information please refer to the Investigator's Brochure (IB) [14]. 
1.2 Risk Assessment 
The amino acid sequence of G3215 is similar to that of OXM. Therefore indications of 
potential safety issues related to the administration of G3215 can be predicted from review 
of the effects of OXM in humans.  
Oxyntomodulin was infused intravenously into 13 human volunteers at a dose of 3.0 
pmol/kg/min (6.6 ng/kg/min) for 90 minutes (total dose 594 ng/kg). At this dose, there was 
no nausea reported by subjects (4). 
Oxyntomodulin was subsequently studied in healthy overweight and obese volunteers. 
Fourteen volunteers were treated with 400 nmol (1.77 mg, approximately 0.019 mg/kg) of 
oxyntomodulin, administered subcutaneously 3 times a day before meals, for 28 days. 
Transient mild nausea was reported with 3% of oxyntomodulin injections compared to 
0.2% of placebo injections. Although a transient mild discomfort at the injection site was 
reported with 6.9% of oxyntomodulin injections, this was also reported in 6.6% of saline 
injections, and this adverse effect was not considered linked to the oxyntomodulin 
injection. No significant effects on cardiovascular parameters (blood pressure, heart rate) 
were detected when oxyntomodulin was given (22). 
In a placebo-controlled cross-over study in 15 overweight/obese volunteers, the volunteers 
self-administered subcutaneously 400 nmol (1.77 mg or approximately 0.019 mg/kg) of 
oxyntomodulin three times a day before meals for 4 days. Only one subject reported nausea, 
as assessed by visual analogue scales, and this was associated with significantly higher 
plasma levels of oxyntomodulin, implying that nausea is related to drug exposure. No 
statistically significant effects on cardiovascular parameters (blood pressure, heart rate) 
were detected when oxyntomodulin was given (21). 
In a study which examined the effects of the combination of peptide YY and oxyntomodulin 
when given as intravenous infusions for 110 minutes to 12 volunteers, oxyntomodulin alone 
was given in two arms of the study, one arm receiving a low dose (1.5 pmol/kg/min or 6.6 
ng/kg/min, 726 ng/kg total dose) and another arm receiving a high dose (3.0 pmol/kg/min 
or 13.2 ng/kg/min, 1452 ng/kg total dose). Although some reduction in food intake was 
seen in these arms, this was not statistically significant from placebo. One subject receiving 
the high dose of oxyntomodulin reported nausea. The infusion was stopped and the nausea 
settled. No statistically significant effects on cardiovascular parameters (blood pressure, 
heart rate) were detected when oxyntomodulin was given (23). 


 
 
 
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The placebo-controlled Phase I clinical trial sponsored by Merck, Sharp and Dohme 
(Clinicaltrials.gov NCT01373450) reported that of the 12 participants receiving the 
oxytomodulin infusion (3.0 pmol/kg/min for 160 mins, 13.2 ng/kg/min, 1452 ng/kg total 
dose), 0 had serious adverse effects, and 6 had other adverse effects. None reported nausea. 
1/12 participants had a catheter site adverse reaction (versus 2/12 for placebo), 2/12 
reported fatigue (versus 1/12 for placebo), 1/12 reported peripheral oedema (versus 0/12 
for placebo), 1/12 reported rhinitis (versus 0/12 for placebo), 2/12 reported headache 
(versus 3/12 for placebo).  
In summary, most studies examining the effects of oxyntomodulin have investigated its 
effects over a relatively short timespan, the notable exception being (22). The most 
commonly reported adverse effect of oxyntomodulin is that of nausea. The nausea appears 
to be related to drug exposure (Cmax), and transient. There appear to be no significant 
cardiovascular adverse effects noted with oxyntomodulin treatment.  
In view of the testicular findings from the repeat dose toxicology study, all study volunteers 
will have LH, FSH and testosterone monitored pre and post dosing. In Part A, the post dose 
test will be done at the follow up visit. In Part B, the post dose test will be done at Day 15, 
29 and at the final follow up visit. 
As the SAD study (Part A) was a FIH study a sentinel dosing strategy was used for the first 
dosing group. Safety data up to and including 24 h postdose was reviewed by the 
Investigator prior to dosing the remaining subjects at that dose level 48 h later. Dose 
escalation only occurred if the previous dose level was deemed to be safe and well tolerated. 
With the completion of the Part A (SAD) study, G3215 has now been tested in humans, 
and found to be well tolerated in single doses of up to 48 mg. See Section 12 for study 
report from the SAD study. As per Section 12, the MTD was not reached during the Part A 
study where a maximum dose of 48 mg was tested. 
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 
and the single doses have been shown to be safe and well tolerated in Part A. In Part B and 
Part C, dose titration for an individual subject may be necessary within a dosing regimen 
depending on the activity profile and tolerability. The highest doses in Part B and Part C 
will not exceed the maximum dose of 48 mg tested in the SAD study.  
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 and National Research Ethics Service approval.  
The study will be conducted on an in-patient basis, with dosing in a Phase I unit with 
supplementary accreditation from the Medicines and Healthcare Products Regulatory 


 
 
 
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Agency (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 G3215. Full resuscitation facilities and emergency 
medication will be available at all times. 
1.3 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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STUDY OBJECTIVES 
1.4 Primary Objective 
• 
To investigate the safety and tolerability of single doses of G3215 in 
overweight/obese but otherwise healthy male subjects. 
• 
To investigate the safety and tolerability of multiple doses of G3215 in 
overweight/obese male subjects with normal glucose tolerance, Type 2 diabetes or 
prediabetes via weekly subcutaneous injections. 
• 
To investigate the safety and tolerability of sequentially incrementing doses of G3215 
in overweight/obese male subjects with normal glucose tolerance, Type 2 diabetes or 
prediabetes via a three day subcutaneous infusion. 
 
1.5 Secondary Objectives 
• 
To assess the pharmacokinetic (PK) profile of single ascending doses of G3215 in 
overweight/obese but otherwise healthy male subjects via subcutaneous injection. 
• 
To assess the PK profile of multiple ascending doses of G3215 in overweight/obese 
male subjects with normal glucose tolerance, Type 2 diabetes or prediabetes via 
weekly subcutaneous injections. 
• 
To investigate the PK profile of a three day subcutaneous infusion of G3215 in 
overweight/obese male subjects with normal glucose tolerance, Type 2 diabetes or 
prediabetes.  
1.6 Exploratory Objectives 
• 
To investigate the effects of multiple doses of G3215 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 
G3215 compared with the LC-MS/MS assay for G3215. 


 
 
 
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2 INVESTIGATIONAL PLAN 
2.1 Overall Study Design 
This is a single centre, randomised, placebo controlled Phase I first time in human study of 
G3215 in 3 parts: Part A (single ascending dose – SC administration) and Part B (multiple 
ascending dose – weekly SC administration) and Part C (ascending doses – via continuous 
SC infusion). 
2.1.1 Part A (Single Ascending Dose) 
Part A was a double blinded, randomised, placebo controlled, single ascending dose study 
(SAD) and has been completed as of the time of writing of the version of this protocol. 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 volunteer will 
be dosed in three treatment periods (TPs) with three ascending dose levels (proposed doses 
0.1 mg, 0.5 mg, 1.5 mg G3215). 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 TPs. 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 4 mg, 10 mg, 20 mg and 40mg. All doses are subject to change according 
to safety and PK review. 
Up to eight additional cohorts of up to 6 subjects may be enrolled if recommended by the 
Safety Committee (see Section 2.1.4) to increase scientific value of this study, e.g. to verify 
PK data or further characterise PD markers. 
Proposed doses of 0.1 mg, 0.5 mg, 1.5 mg, 4.0 mg, 10 mg and 20 mg and 40mg G3215 will 
be investigated in ascending order. Randomisation for each dose level will be generated 
prior to study start.  
For each dose level, subjects will be randomised to receive a single dose of G3215 or 
matching placebo by SC injection (with fractionation if needed). A sentinel dosing strategy 
will be used as outlined in Table 2.1.  
 
 
 


 
 
 
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Table 2.1  
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 
G3215 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 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. PK data will be reviewed up to 48hours 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 G3215 in cohort 1 and 4 subjects, (i.e. a minimum of 3 
subjects receiving G3215) 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 G3215 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, LH, FSH, testosterone and urinalysis). 
Cohort 
Treatment 
Periods  
Dosing Session 
Number of Subjects 
 
G3215 
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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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 G3215 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 predose and at the final follow-
up visit for the volunteers from Cohort 1 only (as these volunteers have received multiple 
doses of G3215). 
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 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. 
2.1.2 
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: 
1. diet alone; 
2. monotherapy with a sulphonylurea, metformin or SGLT-2 inhibitor; 
3. dual therapy with any two of the following drug classes: sulphonylurea, metformin 
or SGLT-2 inhibitor; 
4. or triple therapy with sulphonylurea/metformin/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 


 
 
 
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Page 19 of 61 
 
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 diabetes 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 an 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 G3215 in up to 3 cohorts of 8 subjects, an 
anticipated total of 24 subjects. In each cohort, 6 subjects will receive G3215 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 2.1.4) to increase scientific 
value of this study, e.g. to assess additional doses of G3215 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.  
Subjects will receive 5 doses of G3215 or placebo by SC injection (with fractionation if 
needed), each separated by 7 days (i.e., on Days 1, 8, 15, 22 and 29). The starting dose level 
to be administered in Part B is 24 mg and the dose frequency weekly. Administration of 
subsequent doses will be based on review of available safety, tolerability and PK data from 
previous doses, and will not exceed a single dose which has been shown to be safe and well 
tolerated. Dose titration for an individual subject may be necessary within a dosing regimen 
depending on the activity profile and tolerability. The highest dose in Part B will not exceed 
the maximum dose of 48 mg tested in the SAD trial.  
Subjects are proposed to have 6 inpatient stays in Part B as outlined in Figure 2.1. 
 


 
 
 
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Figure 2.1 
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 G3215/placebo 
Day 2 
Day 3/4 
24 h food intake study 
Discharge  
 
 
 
Inpatient Stay 2 
 
 
Day 8 
Admission 
Standardised breakfast 
Administration of G3215/placebo 
 
 
Day 9 
Discharge 
 
 
 
Inpatient Stay 3 
 
 
Day 15 
Admission 
Standardised breakfast 
Administration of G3215/placebo 
 
 
Day 16 
Discharge 
 
 
 
Inpatient Stay 4 
 
 
Day 22 
Admission 
Standardised breakfast 
Administration of G3215/placebo 
 
 
Day 23 
Discharge 
 
 
 
Inpatient Stay 5 
 
 
Day 29 
Admission  
Standardised breakfast 
Last dose of G3215/placebo 
 
 
Day 30 
Food intake study 
Day 31 
OGTT, discharge 
 
 
 
OP visits Days 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 prior to 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 


 
 
 
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Page 21 of 61 
 
will undergo an OGTT, and therefore will need to attend the visit after an overnight fast. 
Subjects will receive a single dose of G3215 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 72 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 2.1. 
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, LH, 
FSH, testosterone 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 G3215 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.  
2.1.3 
Part C (Ascending Dose) 
Part C will be a single blind, randomised, placebo controlled, ascending dose study in 
sequential groups of male subjects (BMI range from 25-38 kg/m2). These subjects can 
either have normal glucose tolerance, prediabetes (impaired glucose tolerance or impaired 


 
 
 
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Page 22 of 61 
 
fasting glucose), or Type 2 diabetes, defined according to WHO 2006 and 2011 diagnostic 
criteria.  
It is proposed to investigate 3 sequentially incrementing infusion doses of G3215 in a 
cohort of 4 subjects; and all 4 subjects will receive G3215 and placebo. Within this cohort, 
two subjects will receive placebo on Day 1 and two subjects will receive placebo on Day 4 
(see Table 2.2). Cohort 1 will include normal glucose tolerance subjects only. Up to 3 
additional cohorts of 4 subjects each (up to 12 subjects) may be enrolled if recommended 
by the Safety Committee to increase scientific value of this study (e.g. to assess additional 
doses of G3215 or further characterise PD markers). Where possible, subjects of a similar 
glycaemic status (i.e. diabetics, prediabetics or normal glucose tolerance) will be grouped 
in a cohort.  
Part C may commence prior to the completion of Part B (MAD). 
Subjects will receive 3 doses of G3215 by SC infusion, with a dose increment every 24 
hours. The starting dose will be 0.8 mg/24 hr and if there is no safety and tolerability issues, 
the dose will be increased after 24 hours to 1.6 mg/24 hr and then 3.2 mg/24 hr. Dose 
titration for an individual subject may be necessary within a dosing regimen depending on 
the activity profile and tolerability. The highest total dose given in Part C (over the entire 
dosing interval) will not exceed the maximum dose of 48 mg tested in the SAD trial. 
If applicable, subjects may undergo a pre-screening visit within 10 weeks prior to Day 1 
(see Part B for criteria for pre-screening). After a 28-day screening period eligible subjects 
will be admitted to the clinical unit on Day -1 (1 day prior to the first dosing). This is to 
help them acclimatise to the unit and study procedures. On day 1, after a standardised 
breakfast, the subjects will receive an infusion of G3215 or placebo (0.9% saline) by SC 
infusion pump, at a set infusion dose and rate. The infusion and infusion set will be changed 
on a daily basis, and at this pump change the dose will be escalated. During the infusion, if 
the subject experiences nausea, the infusion rate will be reduced to 50% and the subject 
reviewed hourly by study personnel after that. If the nausea settles, the infusion rate will be 
increased to 75% of the original rate and then again back to the original rate after two hours 
if tolerated. If vomiting occurs, the infusion pump will be stopped and only restart an hour 
later after the nausea has settled. At this point when the infusion is restarted, the infusion 
rate will be 50% of the original rate, and then increased to 75% and then 100% of the 
original rate every two hours if the nausea remains settled.  
If skin irritation/reaction occurs at the infusion site, the infusion set and infusion site will 
be changed.  
Food intake will also be semi-quantitatively measured throughout the admission.  


 
 
 
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It is the intention that subjects will be discharged on Day 5 after the infusion has been 
discontinued. They should remain in the unit for three hours after the infusion pump has 
been disconnected for observations, to check that the subject is stable.  
After the inpatient stay, subjects will return to the clinical unit for one final outpatient visit 
on day 7. Depending on emerging safety and PK data, the subjects may return to the clinical 
unit for further outpatient visits . The 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. 
Safety monitoring will include assessment of adverse events (AEs), physical examination, 
12-lead electrocardiograms (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 are to be analysed only if 
relevant adverse reactions occur.  
The PK evaluation will include measurement of plasma G3215 levels and associated PK 
parameters.  
Exploratory PD evaluation will include evaluation of the following: capillary blood glucose 
monitoring, semi-quantitative energy intake at mealtimes, body weight, visual analogue 
scales (VAS) of nausea and satiety. This assessment will be done during the inpatient stay.  
Blood samples for immunogenicity assays will be collected predose and at the final follow-
up visit.  
In the cohort, each of the 4 healthy volunteers will receive three escalating doses of 
G3215/24 hr. Two volunteers will receive G3215 on day 1 to day 3 and the other two 
volunteers will receive saline/placebo on day 1 and then G3215 on day 2 to 4 (Table 2.2).  
 
Table 2.2 
Dosing Schedule: Part C 
 
N=2 
N=2 
Day 1 
G3215 0.8 mg/24 hr 
Saline/Placebo 
Day 2 
G3215 1.6 mg/24 hr 
G3215 0.8 mg/24 hr 
Day 3 
G3215 3.2 mg/24 hr 
G3215 1.6 mg/24 hr 
Day 4 
Saline/Placebo 
G3215 3.2 mg/24 hr 
 
Figure 2.2 
Study Overview: Part C 
Day -1 
Participants check in to the research facility 
Day 1 
Standardised breakfast to start 2 hours before pump start 


 
 
 
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Page 24 of 61 
 
Start G3215/Placebo infusion pump 
Day 2 
Standardised breakfast to start 2 hours before pump change 
Change G3215/Placebo infusion pump and increase infusion rate as per 
protocol 
Day 3 
As per day 2 
Day 4 
As per day 2 
If the subject received G3215 on day 1 to 3, then on day 4, they will receive 
a placebo infusion. 
If the subject received Placebo on day 1, then on day 4, they will receive 
the next incremental G3215 infusion. 
Day 5 
Infusion completes.  
 
2.1.4 Dose Escalation Criteria 
After each dose level in Part A (SAD) and Part B (MAD) a Safety Committee will review 
and assess the safety, tolerability and PK data to determine the next dose level. This PK 
analysis will utilise data from the GLP-validated LC-MS/MS assay for G3215. For Part C, 
a review by the safety committee will take place to review the safety, tolerability and PK 
data 24 hours after the completion of the infusion within the cohort. The committee will at 
that stage decide if further cohorts infusing similar or different doses of G3215 should be 
done. 
In Part A (SAD), an appropriate 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 data. The committee will review interim safety (vital 
signs, ECGs, and clinical laboratory safety tests), tolerability (adverse event profile) up to 
72 hours post dose, and PK data collected up to at least 48 hours post-dose in at least 3 
subjects receiving G3215 in Cohort 1 and at least 4 subjects (i.e. a minimum of 3 subjects 
receiving G3215) in Cohort 2 onwards. PK data collected from previous dose levels may 
also be reviewed. 
For Part B (MAD) the committee will review interim safety (vital signs, ECGs, and clinical 
laboratory safety tests), tolerability (adverse event profile), and PK data collected up to Day 
31 from a minimum of 6 subjects, such that there will be at least 4 subjects receiving G3215 
at each dose level. 
Progression to the next higher dose level in Part A and Part B will only occur if the previous 
dose level was deemed to be safe and well tolerated by the Safety Committee. When it is 
not appropriate to escalate the dose to the next higher dose level, the Safety Committee 
may decide to administer the same dose (see dose fractionation criteria), a previous dose or 
an intermediate dose to the next cohort of subjects.  


 
 
 
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For Part C, three sequentially incrementing doses per 24 hour infusion of G3215 are 
planned. During the infusion, if the subject experiences nausea, the infusion rate will be 
reduced to 50% and the subject reviewed hourly by study personnel after that. If the nausea 
settles, the infusion rate will be increased to 75% of the original rate and then again back 
to the original rate after two hours if tolerated. If vomiting occurs, the infusion pump will 
be stopped and only restart an hour after the nausea has settled. At this point when the 
infusion is restarted, the infusion rate will be 50% of the original rate, and then increased 
to 75% and then 100% of the original rate every two hours if the nausea remains settled. 
For Part A, Part B, and Part C additional optional cohorts may be enrolled if recommended 
by the Safety Committee to increase scientific value of this study (e.g., to verify PK data 
or further characterise PD markers). The Safety Committee may decide to administer the 
same dose, a previous dose, an intermediate dose or an escalated dose to the optional cohort. 
The optional cohorts may include up to 8 cohorts of 6 subjects each (up to 48 patients) in 
Part A, up to 3 cohorts of 8 subjects each (up to 24 subjects) in Part B and up to 3 cohorts 
of 4 subjects each (up to 12 subjects) in Part C. 
If emerging safety, tolerability and PK data indicate it is appropriate, the Safety Committee 
may vary the dose level providing none of the stopping criteria are met. 
Data will be reviewed unblinded for Part A, B and C as outlined in Section 3.9. 
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. 
2.1.5 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, B, and C, 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. 


 
 
 
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• 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 46.2 ng/mL and/or 
AUC0-72h of 1582 ng·h/mL i.e. systemic exposure will be no greater than that the 
lowest exposure at the NOAEL for cynomolgus monkeys (0.1 mg/kg). This limit is 
chosen on the basis that non-human primates are expected to be the species that will 
most closely predict toxicity in humans. 
2.1.6 Discussion of Study Design 
This is a randomised, placebo-controlled study in three parts: part A, a single ascending 
dose study, part B, multiple ascending dose study (via a weekly SC injection over 28 days) 
and part C multiple ascending dose study via a three day continuous SC infusion. Part A 
and B will be conducted in a double blinded fashion and part C will be single blinded. Note, 
with the exception of Cohort 1 TP1 which is partially blinded, subjects will remain blinded. 
The time interval between each TP should be no less than 1 week. As G3215 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 and Part C, we propose 
to recruit overweight/obese subjects without diabetes, with Type 2 diabetes or pre-diabetes. 
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 the elimination half-life of G3215 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 G3215 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 comprise no less than 28 consecutive days and will 
not exceed 35 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], 24 subjects in Part B [MAD], 
and 4 subjects in Part C) has been chosen to minimise the number of subjects exposed to 
G3215 whilst obtaining sufficient information to assess the safety, tolerability, PK and PD 
of G3215.  


 
 
 
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2.2 Study Population 
Approximately 28 subjects will be enrolled in Part A (SAD), 24 subjects will be enrolled 
in Part B (MAD), and 4 subjects in Part C. 
Overweight male volunteers will be entered into this study provided that they satisfy the 
following inclusion/exclusion criteria. 
2.2.1 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 A and PART C, Cohort 1) Subjects who have normal glucose tolerance; 
3. (PART B and PART C, Cohort 2 onwards) 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: 
(1) diet only; 
(2) monotherapy with a sulphonylurea, metformin, or SGLT-2 inhibitor; 
(3) dual therapy with sulphonylurea/metformin, or sulphonylurea/SGLT-2 
inhibitor; 
(4) or triple therapy with sulphonylurea/metformin/SGLT-2 inhibitor. 
b) Patients treated with other anti-diabetic treatments are excluded; 
c) In subjects who are identified as being prediabetic or diabetic, the 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 
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; 
d) To allow assessment of eligibility, subjects without known diabetes or prediabetes, 
or in whom the glycaemic status is in doubt, may undergo a pre-screening visit no 
more than 10 weeks before Day 1 for assessment of fasting glucose, HbA1c and 
glucose 2 hours after a 75 g oral glucose tolerance test; 
4. Subjects who are otherwise healthy enough to participate, as determined by pre-study 
medical history, physical examination and 12-lead ECG; 
5. 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; 
6. Subjects who are negative for hepatitis B surface antigen (HBsAg), hepatitis C antibody 
and human immunodeficiency virus (HIV) I and II tests at screening; 


 
 
 
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7. Subjects who are negative for drugs of abuse and alcohol tests at screening and 
admissions; 
8. Subjects who are non-smokers for at least 3 months preceding screening; 
9. Subjects who agree to use medically acceptable methods of contraception for at least 3 
months after study drug administration; 
10. Subjects who agree not to donate sperm for at least 3 months after study drug 
administration; 
11. Subjects who are able and willing to give written informed consent. 
12. Subjects’ medical history must be verified by either a personal physician or medical 
practitioner as appropriate. 
2.2.2 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; 
7. Subjects who have a history of alcohol abuse or alcohol dependence according to DSM-
IV criteria within the last two 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; 


 
 
 
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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: monotherapy with sulphonylureas, metformin, or SGLT-2 
inhibitors; dual therapy with any two of the following drug classes: sulphonylureas, 
metformin, or SGLT-2 inhibitor; triple therapy with sulphonylureas/metformin/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 G3215; 
21. Subjects who are vegans or have any dietary restrictions; 
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. 
2.2.3 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. 
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.  


 
 
 
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In Part C, subjects will be admitted to the clinical unit for 1 inpatient stay,  comprising 5 
nights, 6 days: Day -1 (admission) to Day 5 (discharge). They will also attend a final 
outpatient review on Day 7 (± 1 day). Subjects will return to the clinical unit for outpatient 
visits as described in Table 16.4. 
For both Part A, Part B and Part C, 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 will 
be recorded during the inpatient stays.  
For Part A, Part B and Part C subjects should refrain from the following: 
• 
Strenuous exercise for 48 h before screening, 48 h prior to each admission, throughout 
each inpatient stay and for 48 h prior to each outpatient visit. 
• 
Alcohol and/or xanthine containing products (e.g. caffeine) for 48 h prior to screening 
and each admission, during the inpatient stay, and for 48 h prior to each outpatient 
visit.  
• 
Smoking for the duration of the study (until after the final follow-up visit). 
• 
Eating foodstuffs that contain poppy seeds, as these may result in a positive urine test 
for opiate consumption. 
• 
Taking medications during the study as described in Section 3.5. 
2.2.3.1 Avoidance of Pregnancy 
Instructions for Male Subjects 
There is no information about effects that G3215 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 G3215.  
As a precaution, all male subjects should avoid fathering a child by either true abstinence 
or the use of 2 highly effective means of contraception (see Section 2.2.3.2).  
As there is no information about G3215 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. 3 
months). This is to ensure that the foetus is not exposed to the investigational medicinal 
product (IMP) in the ejaculate. 
 
 


 
 
 
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2.2.3.2 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 female sterilisation (i.e. documented bilateral tubal ligation), hormonal 
methods of contraception (oral, implanted or transdermal) or an intrauterine device (IUD) 
in combination with a barrier method (condom, diaphragm).  
Where there is a possibility of pregnancy, 2 effective methods should be used. Effective 
forms of contraception are: 
1. Established use of oral, transdermal, injected or implanted hormonal methods of 
contraception.  
2. Placement of an IUD or intrauterine system (IUS).  
3. Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. The use of 
barrier contraceptives should always be supplemented with the use of a spermicide. The 
following should be noted: 
• Failure rates indicate that, when used alone, the diaphragm and condom are 
not highly effective forms of contraception. Therefore the use of additional 
spermicides does confer additional theoretical contraceptive protection.  
• However, spermicides alone are inefficient at preventing pregnancy when the 
whole ejaculate is spilled. Therefore, spermicides are not a barrier method of 
contraception and should not be used alone. 
4. Male sterilisation (the subject should have received medical assessment to confirm 
surgical success).  
5. True abstinence: 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. 
2.2.3.3 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. 
2.2.3.4 Follow-up in the Event of a Pregnancy 
If the female partner of a male subject who has received G3215 becomes pregnant within 
the time window in Section 2.2.3.3, the pregnancy will be recorded. The ethics committee 
and the Sponsor will be informed. The subject will be asked to 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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2.2.4 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. 
If a subject is withdrawn or withdraws during the inpatient stay, the discharge procedures 
should be performed and a follow-up visit should be scheduled. 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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3 STUDY TREATMENT 
3.1 Investigational Product(s) 
G3215 is a 35 natural amino acid linear peptide. G3215 does not contain any products of 
human or animal origin. 
The bulk drug product (20 mg/vial) is manufactured as a sterile lyophilised powder supplied 
in a clear glass 3 mL vial sealed with a fluoro-coated lyophilisation stopper and an 
aluminium crimp seal. G3215 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 reconstituent steps will be provided in the Study Reference Manual.  
The placebo is sterile 0.9% (w/v) saline. 
3.1.1 Supply, Packaging and Labelling 
G3215 bulk Drug Product and Diluent will be supplied to Clinical CRO by Symbiosis 
Pharmaceutical Services.  
A release document signed by a legally authorised Qualified Person (QP) at CRO 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 CRO and 
Sponsor will be in place to cover all pharmacy related activities, detailing roles and 
responsibilities prior to receipt of the IMPs at CRO. 
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 CRO 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 CRO.  
3.1.2 Storage and Handling Procedures 
The G3215 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 
laboratory manual.  
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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3.1.3 Accountability 
In accordance with GCP, the clinical unit will account for all supplies of G3215 and 
placebo. Details of receipt, storage, assembly and return will be recorded.  
All unused supplies of G3215 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. 
3.2 Dosage and Administration 
G3215 or placebo will be administered by SC injection or continuous infusion 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 maximal SC infusion 
volume will not exceed 20 ml per 24 hr. The injection site(s) should be circled with 
indelible marker and inspected at each AE check during Day 1. Reactions should be 
described according to the grading table (Table 4.5). Where multiple doses or infusions of 
G3215 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 G3215 or placebo may be fractionated and up to 5 injections may be given.  
If skin irritation/reaction occurs at the infusion site, the infusion set and infusion site will 
be changed. Subjects will receive G3215 or placebo after a standardised breakfast, while in 
the supine/semi-supine position. 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: 0.1 mg, 0.5 mg, 1.5 mg, 4.0 mg, 10 mg, 20 mg 
and 40 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 of 48 mg tested in the SAD trial. In Part C, subjects will receive 
a continuous dose of G3215 by SC infusion, with a dose increment every 24 hours. The 
starting dose will be 0.8 mg/24 hr and if there are no safety and tolerability issues, the dose 
will be increased after 24 hr to 1.6 mg/24 hr and then 3.2 mg/24 hr. Dose titration can go 
up or down for an individual subject within a dosing regimen depending on the activity 
profile and tolerability. The highest total dose given in Part C (over the entire dosing 
interval) will not exceed the maximum dose of 48 mg tested in the SAD trial. 
For Parts A and B, subjects will not eat for 4 h postdose after which time lunch will be 
served. Dinner will be served 10 h postdose. Water will be restricted for 1 h pre and 1 h 
postdose. For Part C, subjects will eat a standardised breakfast. For each subject, lunch will 
be served 3 hours after the start of the infusion on each day, and dinner served 8 hours after 
the start of the infusion on each day. There will be no restriction to the amount of water the 


 
 
 
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subjects drink. With regards to eating and drinking when subjects have been discharged 
from the clinical unit during Parts B and C, 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. 
3.3 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-call physicians or public emergency services, including the ambulance service, in the 
event of a serious medical event. Equipment and emergency drugs are available to treat 
common medical emergencies that might occur in a Phase I study.  
3.4 Warnings and Precautions 
As this is the first administration of G3215 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. 
3.5 Prior and Concomitant Medication 
The participants are not allowed to take any prescription medication within 4 weeks of first 
dosing apart from those for diabetes in Part B. 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). 
3.6 Method of Assigning Subjects to Treatment Groups 
At screening, potential study subjects will be assigned a screening number. 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 3.1. The 
subject number will determine the allocation of treatment.  


 
 
 
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Table 3.1 
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 
 
C 
Additional1   
1 
Additional1 
20025-20048 
30001-30004 
30005-30016 
 
1 – Eight additional cohorts of up to 6 subjects in Part A (up to an additional 48 patients), three additional cohorts of up to 8 
subjects in Part B (up to an additional 24 patients), three additional cohorts of up to 4 subjects each in Part C (up to an 
additional 12 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. 
Subjects who are replaced (dropouts) will be allocated the same treatment number with the 
number 1 in the fourth digit position, e.g., if subject number 10001 is replaced then the 
replacement subject’s number will be 11001. 
3.7 Randomisation Procedures 
Allocation to treatment will be according to a predetermined random order. Randomisation 
of G3215 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 G3215 and 
1 receives placebo. 
The randomisation list will be generated by Covance using the statistical analysis system 
(SAS®) computer package.  
3.8 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. 


 
 
 
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3.9 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 G3215); subjects and clinical staff will remain blinded until the Safety Committee 
meeting. 
Part B (MAD) will be conducted double-blind. Treatments will be administered double 
blinded; subjects will be blinded with regard to treatment and clinical staff will remain 
blinded with regard to treatment until the Safety Committee meeting. 
For the purposes of blinding in Parts A and B "clinical staff" refers to staff at the 
investigator site; all sponsor staff will be unblinded to study treatments. 
Part C (Ascending dose study of G3215 via continuous infusion) will be conducted single 
blinded to enable the clinical staff to titrate the dose according to tolerability. 
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 so that the blind is maintained for clinical staff 
connected with 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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4 STUDY PROCEDURES 
The blood volumes to be collected from each subject are detailed in Table 4.1 for Part A 
(SAD), Table 4.2 for Part B (MAD), and Table 4.3 for Part C. The total volume to be 
collected per subject will be no greater than 550 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 4.1 
Blood Volumes: Part A (SAD)  
Cohort 1 
Assessment 
Sample 
Volume (mL) 
No. of 
Samples 
Total Volume 
(mL) 
Safety 
 
 
 
 
Serum Biochemistry, Thyroid 
Function, LH, FSH, testosterone 
3.5 
11 
38.5 
 
Coagulation 
1.8 
11 
19.8 
 
Serology 
3.5 
1 
3.5 
 
Haematology 
4.0 
11 
44 
 
Tryptase1 
3.5 
2 
7 
 
Bedside blood glucose 
0.1 
Up to 23 
2.3ml 
Pharmacokinetic 
 
 
 
 
G3215 
5.0 
 Up to 38 
190 
Pharmacodynamics 
 
 
 
 
Immunogenicity3 
6.0 
2 
12.0 
Total2 
 
 
317.1 
1 In the event of an allergic reaction additional samples will be collected.  
2 Sample volumes are based on direct venepuncture; where a cannula is used, an extra 1 mL will be drawn and discarded. 
3Immunogenicity samples from cohort 1 only. 
 
Cohort 2 onwards 
Assessment 
Sample 
Volume (mL) 
No. of 
Samples 
Total Volume 
(mL) 
Safety 
 
 
 
 
Serum Biochemistry, Thyroid 
Function, LH, FSH, testosterone 
3.5 
5 
17.5 
 
Coagulation 
1.8 
5 
9.0 
 
Serology 
3.5 
1 
3.5 
 
Haematology 
4.0 
5 
20.0 
 
Tryptase1 
3.5 
2 
7 
 
Bedside blood glucose 
0.1 
Up to 11 
1.1ml 
Pharmacokinetic 
 
 
 
 
G3215 
5.0 
 Up to 16 
80.0 
Total2 
 
 
138.1 
1 In the event of an allergic reaction additional samples will be collected.  
2 Sample volumes are based on direct venepuncture; where a cannula is used, an extra 1 mL will be drawn and discarded. 
 


 
 
 
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Table 4.2 
Blood Volumes: Part B (MAD) 
Assessment 
Sample 
Volume (mL) 
No. of 
Samples 
Total Volume 
(mL) 
Safety 
 
 
 
 
Serum 
Biochemistry 
including 
Thyroid function (TSH, FT4), LH, 
FSH, testosterone 
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 
 
 
 
 
G3215 
5.0 
37 
185.0 
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 
 
 
540.2 
1 In the event of an allergic reaction additional samples will be collected.  
2 Sample volumes are based on direct venepuncture; where a cannula is used, an extra 1 mL will be drawn and discarded. 
 
Table 4.3 
Blood Volumes: Part C 
Assessment 
Sample 
Volume (mL) 
No. of 
Samples 
Total Volume 
(mL) 
Safety 
 
 
 
 
Serum 
Biochemistry 
including 
Thyroid function (TSH, FT4), LH, 
FSH, testosterone 
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 
7.0 
 
Bedside glucose monitoring 
0.1 
23 
2.3 
Pharmacokinetic 
 
 
 
 
G32153 
9.0 
26 
234 
Pharmacodynamics 
 
 
 
 
Immunogenicity 
6.0 
2 
12.0 
Total2 
 
 
305.3  
1 In the event of an allergic reaction additional samples will be collected.  
2 Sample volumes are based on direct venepuncture; where a cannula is used, an extra 1 mL will be drawn and discarded. 
3  Two 9ml baseline sample will be collected, and one 9ml PK sample at all other time points 
4.1 Pharmacokinetic Assessments  
4.1.1 Plasma Samples 
Blood sample collection times are included in the schedule of events. 
 


 
 
 
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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 validated 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 G3215 using an 
exploratory non-GLP compliant, non-validated radioimmunoassay. If this analysis is 
performed the results from this analysis will not be reported in the clinical study report for 
this study. 
4.2 Pharmacodynamic/Efficacy Assessments  
Time points for collection of PD variables are included in the schedule of events (see 
Section ). 
4.2.1 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.  
4.2.2 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. 
For Part C, semiquantitative food intake measurements will take place throughout the 
admission. 
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 20 minutes. The energy value of each component of 


 
 
 
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the meal will be determined. Food will be weighed pre- and post-meal to determine 
consumption.  
For other days in Part A and Part B and throughout Part C 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%, 10-24%, 25-49% 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. 
4.2.3 Body Weight 
In Part A (SAD), Part B and Part C, body weight will be recorded AM and PM each day of 
the inpatient stay and once on every outpatient visit (Part B and Part C).  
Body weight for each subject should be measured on the same calibrated scale in light 
clothing, after voiding urine, before breakfast (AM) and before dinner (PM). 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.  
4.2.4 Immunogenicity 
For assessment of immunogenicity, plain tube serum samples (6 mL blood volume) will be 
collected predose and at the final follow-up visit for SAD Group 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 G3215.  
4.2.5 Oral glucose tolerance testing and enteropancreatic hormones (Part B) 
To assess the effect of G3215 on enteropancreatic hormone secretion, a 75 g oral glucose 
tolerance test will be carried out on the designated days as per the schedule of events. 
Subjects will fast for 10 hours before they are given 75 g of glucose to drink. Blood samples 
will be taken for glucose and enteropancreatic hormones (including but not exclusively 
PYY, GLP-1, ghrelin, insulin, glucagon) at the following timepoints: before glucose, 30 
mins, 60 mins, 90 mins, 120 mins, 150 mins, 180 mins. 
 


 
 
 
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4.3 Safety Assessments  
4.3.1 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. 
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: 
1. Results in death; 
2. Is life-threatening; 
3. Requires hospitalisation or prolongation of existing hospitalisation; 
4. Results in persistent or significant disability or incapacity; 
5. Consists of a congenital anomaly or birth defect; 
6. Is a medically important event. 
Pre-planned surgeries and hospitalisations for elective treatment of a pre-existing 
condition do not need reporting as SAEs. 
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: 
1. In the case of a product with a marketing authorisation, in the summary of product 
characteristics for that product; 
2. In the case of any other investigational medicinal product, in the Investigator’s 
Brochure relating to the trial in question. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Any suspected adverse reaction related to an IMP that is both unexpected and serious. 


 
 
 
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4.3.2 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 
An SAE form should be completed and faxed to the Principal Investigator and the Sponsor 
within 24 hours.  
In the case of a SUSAR, the staff at the site should:  
Complete the SAE case report form & send it immediately (within 24 hours, preferably by 
fax or email), signed and dated to the Principal Investigator and Sponsor together with 
relevant treatment forms and anonymised copies of all relevant investigations. 
The delegated site member centre will notify the MHRA, REC and the Sponsor of all 
SUSARs occurring during the study according to the following timelines; fatal and life-
threatening within 7 days of notification and non-life threatening within 15 days. All 
investigators will be informed of all SUSARs occurring throughout the study. 
4.3.3 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. 
4.3.4 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 consideration along 
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, 


 
 
 
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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 for 
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. 
4.3.5 Action Taken 
Action taken will be defined as: 
• 
None; 
• 
Medication given; 
• 
Dosing interrupted (this applies to Parts B and C only); 
• 
Dosing stopped (this applies to Parts B and C). 
4.3.6 Outcome 
Outcome will be defined as: 
• 
Resolved; 
• 
Ongoing; 
• 
Lost to follow up. 
4.3.7 Coding of Adverse Events 
All adverse events will be coded using the current version of Medical Dictionary for 
Regulatory Activities (MedDRA). 
4.4 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 4.4. 


 
 
 
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Table 4.4 
Safety Laboratory Variables 
 
Haematology 
 
White blood cells 
Red blood cells 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
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 
FSH2 
Testosterone2 
Total bilirubin  
Calcium 
Chloride 
Total protein 
Globulin 
Cholesterol 
Triglycerides 
Uric acid 
Phosphate 
Albumin 
Bicarbonate 
C-reactive protein1 
HbA1c1 
LH2 
Coagulation 
 
Prothrombin time 
International normalized ratio 
Activated partial thromboplastin 
time 
Thyroid Function 
TSH, FT4 
 
Biomarkers  
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 
Ethanol 
Cannabinoids 
Cocaine 
Opiates 
Benzodiazepines 
Methadone 
Barbiturates 
Cotinine 
1At pre-screening and screening only, in Parts B and C (cohorts 2 onwards for Part C) HbA1c may be remeasured at any 
time up to and including check in on Day -2 to confirm stability of glycaemia. 
2 At screening and follow up in Part A. At screening, Day 15, Day 29 and follow up in Part B. At screening and follow up in 
Part C. 


 
 
 
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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 GLP Accredited Laboratory. Details of all 
methodology and reference ranges are provided in the Trial Master File.  
4.5 Clinical Safety Assessments 
Assessment times are included in the schedule of events (see Section 16). Time points of 
assessments may be amended based on emerging safety, tolerability and PK data. 
4.5.1 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. 
4.5.2 Bedside glucose testing 
Blood glucose level will be monitored at the times detailed in the schedule of events 
(Section 16). The Investigator may at their discretion vary the number and timing of such 
blood glucose measurements. 
4.5.3 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. 
4.5.4 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, 
gynaecological/urogenital, 
musculoskeletal/extremities, 
skin, 
neurological/psychiatric, endocrine/metabolic, haemotologic/lymphatic, allergies/drug 
sensitivities, past surgeries, substance abuse or any other diseases or disorders.  
4.5.5 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. 


 
 
 
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4.5.6 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 4.5. 
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 (see 
Section 3.2). 
Injection site reactions with a Grade ≥1 will be recorded as an AE. 
Table 4.5 
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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5 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. Covance will perfom 100% QC of the safety data for the 
dose escalation and safety meeting. Any discrepancies will be resolved in the database. The 
sponsor’s independent monitor will perform 100% SDV for 3 subjects at each dose level 
plus 100% SDV of all safety data.  
 
Following all data validation steps, the Principal Investigator, or designee, will 
electronically sign each eCRF prior to database lock. 


 
 
 
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6 EVALUATION OF STUDY DATA 
6.1 Evaluation of Pharmacokinetic Parameters 
Pharmacokinetic (PK) parameters of G3215 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. 
PK parameters will be calculated using the data from the GLP qualified LC-MS/MS assay. 
6.2 Evaluation of Pharmacodynamic Measures 
6.2.1 Visual Analogue Scales 
Change from baseline values will be calculated using Day -1 values as baseline. 
6.2.2  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. 
6.2.3 Body Weight 
Time-matched change from baseline values will be calculated using Day -1 (AM and PM) 
values as baseline. 
6.2.4 Immunogenicity 
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 
G3215.  
6.3 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). Tryptase determinations will only be performed after relevant adverse events 
and analysed retrospectively to inform the determination of the possible mechanism 
underlying AEs. 


 
 
 
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7 STATISTICAL METHODS  
7.1 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 G3215 as measured by plasma concentrations and derived 
pharmacokinetic parameters. 
Exploratory Target Variables  
• 
The effects of multiple doses of G3215 on food consumption. 
• 
The effects of multiple doses of G3215 on VAS (nausea and satiety). 
• 
The effects of multiple doses of G3215 on body weight. 
• 
The effects of multiple doses of G3215 on enteropancreatic hormone levels. 
• 
The effects of a continuous subcutaneous infusion of G3215 on food consumption. 
• 
The effects of a continuous subcutaneous infusion of G3215 on VAS (nausea and 
satiety). 
• 
The effects of a continuous subcutaneous infusion of G3215 on body weight. 
• 
The effects of a continuous subcutaneous infusion of G3215 on enteropancreatic 
hormone levels. 
• 
The comparative analytical performance of an Imperial College radioimmunoassay 
versus the LC-MS/MS assay for G3215. 
7.2 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. 
7.3 Subject Population for Analyses 
Safety Population 
All subjects who receive study medication (G3215 or placebo) will be included in the safety 
population. 


 
 
 
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Pharmacokinetic Population 
All subjects who receive G3215 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. 
7.4 Pharmacokinetic Analysis 
Pharmacokinetic consultancy 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-, AUC0-24, 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  


 
 
 
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(
, 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- 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). 
Full details of the PK analysis and reporting will be included in a PK Analysis Plan. 
7.5 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. 
7.6 Safety Data Analysis 
Safety data analysis will be performed by Covance. 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). 
Tryptase values will be listed if the analysis has been performed and data are available. 
100
*
1
)
exp(
2
ln
−
=
SD
CV


 
 
 
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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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8 REGULATORY AND ETHICAL ISSUES 
8.1 Regulatory and Ethics Review and Approval 
The study will be submitted to the MHRA (UK) for review and approval and to an National 
Research Ethics Service for ethical review and approval. The documents submitted will 
include but are not limited to; 
MHRA: 
1. The final protocol; 
2. The Investigators Brochure (IB); 
3. The Investigational Medicinal Product Dossier (IMPD); and 
4. 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: 
1. The final protocol; 
2. The Investigators Brochure (IB); 
3. The ethics application form; and  
4. The Informed Consent Form (ICF) 
 
The study will not commence unless the following conditions are satisfied: 
1. An ethics committee has given a favourable opinion in relation to the clinical trial; and 
2. The clinical trial has been authorised by the licensing authority (MHRA). 
 
8.2 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 


 
 
 
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1 of Statutory Instrument 1031 and amendments) whichever provides the greater subject 
protection.  
8.3 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, 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, declare to having insurance cover for the malpractice and/or 
negligence of their employees and agents. 


 
 
 
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9 STUDY MANAGEMENT  
9.1 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.  
 
9.2 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. 
9.3 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 bulk IMP; 


 
 
 
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12. A technical agreement between the Sponsor and CRO defining the responsibilities of 
the Sponsor, CRO and any third parties significantly involved in the supply chain of the 
IMP, where applicable; 
9.4 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. 
9.5 Study Closure 
The Sponsor will be responsible for the close out visit which will be conducted on clinical 
completion of the study. 
9.6 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 


 
 
 
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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 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. 
9.7 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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REFERENCES 
1. Wynne K, Stanley S, McGowan B, Bloom S. Appetite control. J Endocrinol. 2005 
Feb;184(2):291-318. 
2. Dakin CL, Gunn I, Small CJ, Edwards CM, Hay DL, Smith DM, et al. Oxyntomodulin 
inhibits food intake in the rat. Endocrinology. 2001 Oct 1;142(10):4244-50. 
3. Dakin CL, Small CJ, Batterham RL, Neary NM, Cohen MA, Patterson M, et al. 
Peripheral oxyntomodulin reduces food intake and body weight gain in rats. 
Endocrinology. 2004 Jun 1;145(6):2687-95. 
4. Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, et al. 
Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin 
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