An Open, One-sequence, Three-period Study in Healthy Subjects to Evaluate Pharmacokinetics and Food Effect After Oral Single Dosing of Two Different Solid Formulations of GS-248
Phase: PHASE1
Conditions: Pharmacokinetic
Sponsor: Gesynta Pharma AB

 
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Clinical Study Protocol 
 
 
EudraCT No. 
2020-000133-41 
 
Investigational Medicinal Product 
GS-248 
 
Sponsor study code 
GS-1002 
 
Protocol Version and Date 
Final version v1.0; 29JAN2020 
 
An open, one-sequence, three-period study in healthy subjects to 
evaluate pharmacokinetics and food effect after oral single dosing of 
two different solid formulations of GS-248 
Phase 
I 
Indication 
Digital ulcers, systemic sclerosis 
Test product and dose 
GS-248 
Sponsor signatory 
Göran Tornling, MD, PhD, MSc 
Gesynta Pharma AB 
Fogdevreten 2 
SE-171 65 Solna, Sweden 
Principal Investigator 
Helena Litorp, MD, PhD 
CTC Clinical Trial Consultants AB 
Uppsala University Hospital, 
Entrance 85, 2nd level  
SE-751 85 Uppsala, Sweden 
Clinical study conduct and management 
CTC Clinical Trial Consultants AB 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
CTC Clinical Trial Consultants AB 
Uppsala University Hospital, 
Entrance 85, 2nd level  
SE-751 85 Uppsala, Sweden 
 
 

 
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1 
STUDY SYNOPSIS 
Study title 
An open, one-sequence, three-period study in healthy subjects to evaluate pharmacokinetics and food 
effect after oral single dosing of two different solid formulations of GS-248 
Study code 
GS-1002 
EudraCT No 
2020-000133-41 
Planned study period 
Q2 2020 
Phase of development 
I 
Principle Investigator  
Helena Litorp, MD, PhD 
CTC Clinical Trial Consultants AB 
Uppsala University Hospital, 
Entrance 85, 2nd level  
SE-751 85 Uppsala, Sweden 
Study design 
This is a Phase I, open, one-sequence, three-period study in healthy volunteers to evaluate 
pharmacokinetics (PK), safety and tolerability of two different solid formulation of GS-248, and the 
food effect on PK and safety of one of these two formulations.    
Objectives 
Primary objectives: 
• 
To evaluate the PK of two different solid formulations of oral GS-248 in healthy subjects. 
• 
To evaluate the effect of food on PK of one of the two formulations of GS-248.  
Secondary objectives: 
• 
To evaluate the safety and tolerability of two different solid formulations of oral GS-248 in 
healthy subjects. 
• 
To evaluate the safety and tolerability of one of the two formulations of oral GS-248 given 
after a standardised high-fat high-calorie breakfast.    
Endpoints 
Primary endpoints: 
• 
The PK parameters of a single dose of two different formulations of GS-248 in fasting 
conditions. The PK parameters to be assessed include, but are not limited to, maximum 
plasma concentration (Cmax), time to Cmax (Tmax),area under the curve from timepoint 0 to 
the last measured timepoint (AUC0-last), AUC from timepoint 0 to infinity (AUC0-inf),  
plasma half-life associated with the terminal elimination phase (T½(z)), volume of 
distribution associated with the terminal elimination phase following non-intravenous 
administration (Vz/F), and total clearance of the drug from plasma following non-intravenous 
administration (CL/F). 
• 
The relative bioavailability of GS-248 after a single dose of Formulation A versus 
Formulation B, and of one of the two formulations in fed versus fasting conditions.  
• 
The PK parameters of a single dose of one of the two formulations of GS-248 in fed 
conditions.  

 
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Secondary endpoints: 
• 
Frequency, intensity and seriousness of adverse events (AEs). 
• 
Clinically significant changes in: 
- Physical examination 
- Vital signs 
- Body temperature 
- Resting 12-lead electrocardiogram (ECG) 
- Safety laboratory parameters 
Number of subjects planned 
Approximately 20 healthy subjects will be screened to achieve a total of 14 dosed subjects, and at 
least 12 evaluable subjects.  
Diagnosis and main eligibility criteria 
• 
Healthy male or female subject, aged ≥ 18 and ≤70 years. 
• 
Subject has provided a signed informed consent and are considered eligible to participate in 
the study. 
• 
Body Mass Index (BMI) ≥ 19 and ≤ 30 kg/m2. 
• 
Willing to use sufficient contraception as defined in this clinical study protocol (CSP). 
• 
Females must not be pregnant, breast feeding or plan to be pregnant until 2 weeks after the 
end-of-study visit.  
• 
Regular use of corticosteroids (inhaled and systemic), Non-Steroidal Anti-Inflammatory 
Drugs (NSAIDs), aspirin or cyclooxygenase inhibitors (coxibs), antacids, proton pump 
inhibitors (PPIs), or any other medication that changes gastric pH within 14 days of study 
drug administration. 
Methodology 
The study is divided in two parts. Part I will evaluate PK, safety and tolerability of a single oral dose 
of two different formulations of GS-248 in fasting conditions. Part II will evaluate PK, safety and 
tolerability of one of the two different formulations of GS-248 in fed conditions.  
Subjects are expected to participate in both Part I and Part II and will come to the clinic for a total of 
7 visits. Screening (Visit 1) will take place from Day -28 to Day -1 and will include an eligibility 
check and a general health assessment.  
In Part I of the study, a single oral dose of GS-248 in two different solid formulations will be 
administered to 14 healthy subjects. All subjects will first receive Formulation A (a lipid-based 
formulation in a capsule) and then Formulation B (a dry powder in a capsule). A wash-out period of 
at least 4 days will be applied between the IMP administrations. Both doses contain 120 mg GS-248. 
For Part I, subjects will come to the clinic for 4 visits. At Visit 2, subjects will be admitted to the 
clinic on the afternoon/evening of Day -1 and will remain at the clinic until Day 2 (24 h post dose) for 
single dose administration of Formulation A and PK and safety assessments. The subjects must fast 
for at least 10 hours before the anticipated dosing time on Day 1. Water, but no other drinks, is 
allowed as desired except for 1 h before and 1 h after dosing. Vital signs and ECG will be checked at 
regular intervals. The subjects will return to the clinic on Day 3 (Visit 3) at 48 h post dose for PK 
blood sampling and safety assessments. Safety assessments include AE reporting, physical 
examination, ECG, vital signs, body temperature, and blood sampling for analysis of safety 
laboratory parameters. 
Visit 4 will be similar to Visit 2, at which subjects will stay overnight at the clinic from Day -1 to 
Day 2 for single dose administration of Formulation B and PK and safety assessments. Visit 5 will be 

 
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similar to Visit 3, at which subjects return to the clinic on Day 3 for PK blood sampling and safety 
assessments.  
After evaluation of the PK profiles of Formulation A and B in Part I of the study, one formulation 
will be selected to be given following intake of a standardised breakfast in Part II of the study. 
Subjects will return to the clinic for a second dose of the selected formulation (Visit 6, similar to Visit 
2), yet now in fed conditions. The assessments during fed conditions will be the same as during 
fasting conditions except that the subjects will consume a high-fat high-calorie breakfast 30 minutes 
prior to IMP administration. At 48 h post dose, subjects will return to the clinic for PK blood 
sampling and final end-of-study safety assessments (Visit 7).  
Investigational Medicinal Product, dosage and mode of administration 
GS-248 is provided in two different solid formulations for oral administration: 
• Formulation A: a lipid-based formulation in size 1 capsules  
• Formulation B: dry powder in size 1 capsules 
Subjects will receive a single dose of each formulation during Part I, and a single dose of one of the 
two formulations during Part II. Each single dose consists of 3 capsules of 40 mg GS-248, 
constituting a total of 120 mg GS-248 per IMP administration.   
Duration of treatment 
Subjects will receive in total 3 single doses of GS-248, with a wash-out period of at least 4 days in 
between each IMP administration.  
Duration of each subject’s involvement in the study 
Each subject is expected to participate in both Part I and Part II of the study, which will take 
approximately 8 weeks including a screening period of up to 4 weeks. 
Pharmacokinetic assessments  
Blood sampling for bioanalysis and subsequent determination of GS-248 PK parameters. 
Safety assessments  
AE reporting, resting 12-lead ECG monitoring, vital signs (blood pressure and pulse), body 
temperature, physical examination, use of concomitant medications, urinalysis and blood sampling 
for haematology, clinical chemistry and coagulation parameters. 
Statistical methods 
No formal sample size calculation has been performed. The proposed sample size is considered 
sufficient to provide adequate information for the study objectives. A statistical analysis plan (SAP) 
will be prepared and signed prior to database lock. PK and safety data will be summarised by 
descriptive statistics as appropriate. 
Study reporting 
After completion of the study, an International Council for Harmonisation (ICH) E3 compliant 
clinical study report (CSR) will be prepared.  
 
 
 
 

 
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2 
TABLE OF CONTENTS 
1 
STUDY SYNOPSIS .................................................................................................. 2 
2 
TABLE OF CONTENTS ......................................................................................... 5 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................... 10 
4 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ................................................................................................... 14 
4.1 
Medical emergencies contacts ........................................................................... 14 
5 
INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE ............ 15 
6 
INTRODUCTION .................................................................................................. 17 
6.1 
Background ......................................................................................................... 17 
 
Systemic sclerosis ............................................................................................. 17 
 
Raynaud’s phenomenon and digital ulcers in systemic sclerosis ..................... 17 
 
Investigational medicinal product characteristics ............................................. 18 
 
Mechanism of action of the investigational medicinal product ........................ 18 
 
Non-clinical summary ...................................................................................... 19 
 
Clinical experience ........................................................................................... 21 
6.2 
Study rationale .................................................................................................... 21 
6.3 
Risk/benefit assessment ...................................................................................... 22 
7 
STUDY OBJECTIVES AND ENDPOINTS ........................................................ 24 
7.1 
Primary objective ............................................................................................... 24 
 
Primary endpoints ............................................................................................. 24 
7.2 
Secondary objective ............................................................................................ 24 
 
Secondary endpoints ......................................................................................... 24 
8 
STUDY DESIGN .................................................................................................... 25 
8.1 
Overall study design and schedule of events .................................................... 25 
 
Part I: Two formulations of GS-248 in fasting conditions ............................... 25 
 
Part II: Food interaction .................................................................................... 26 
8.2 
Rationale for study design ................................................................................. 31 
8.3 
Selection of dose .................................................................................................. 31 
8.4 
Selection of formulation ..................................................................................... 31 
9 
STUDY POPULATION ......................................................................................... 32 
9.1 
Recruitment......................................................................................................... 32 
9.2 
Screening and enrolment log ............................................................................. 32 
9.3 
Number of subjects ............................................................................................. 32 

 
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9.4 
Inclusion criteria ................................................................................................. 32 
9.5 
Exclusion criteria ................................................................................................ 33 
9.6 
Restrictions during the study ............................................................................ 35 
 
General restrictions ........................................................................................... 35 
 
Prior and concomitant therapy .......................................................................... 36 
9.7 
Screen failures ..................................................................................................... 37 
9.8 
Subject withdrawal ............................................................................................. 37 
 
General withdrawal criteria .............................................................................. 37 
 
QTc withdrawal criteria .................................................................................... 38 
 
Liver chemistry withdrawal criteria.................................................................. 38 
 
Procedures for discontinuation of a subject from the study ............................. 38 
 
Subject replacement .......................................................................................... 39 
10 
TREATMENTS ...................................................................................................... 40 
10.1 
Identity of investigational medicinal products................................................. 40 
10.2 
Manufacturing, packaging and labelling and release ..................................... 40 
10.3 
Conditions for storage ........................................................................................ 40 
10.4 
Preparation and accountability ......................................................................... 40 
10.5 
Treatment administration.................................................................................. 41 
10.6 
Continuation of treatment with investigational medicinal product .............. 41 
10.7 
Treatment compliance........................................................................................ 41 
10.8 
Return and destruction of investigational medicinal products ...................... 41 
11 
STUDY ASSESSMENTS ....................................................................................... 42 
11.1 
Recording of data ............................................................................................... 42 
11.2 
Demographics and other baseline characteristics ........................................... 42 
 
Informed consent .............................................................................................. 42 
 
Eligibility criteria .............................................................................................. 42 
 
Demographic information ................................................................................. 42 
 
Weight and height ............................................................................................. 42 
 
Medical/surgical history ................................................................................... 43 
 
Prior and concomitant medication .................................................................... 43 
 
HIV and Hepatitis B/C...................................................................................... 43 
 
Pregnancy test ................................................................................................... 43 
 
Urine drug screen .............................................................................................. 43 
 
Alcohol breath test ............................................................................................ 43 

 
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Baseline symptoms ........................................................................................... 43 
11.3 
Assessments related to primary endpoints ....................................................... 44 
 
Pharmacokinetic sampling and analysis ........................................................... 44 
11.4 
Assessments related to secondary endpoints .................................................... 44 
 
Adverse events .................................................................................................. 44 
 
Physical examination ........................................................................................ 50 
 
Vital signs ......................................................................................................... 50 
 
Body temperature.............................................................................................. 50 
 
Resting 12-lead ECG ........................................................................................ 51 
 
Laboratory safety assessments .......................................................................... 51 
11.5 
Appropriateness of measurements .................................................................... 52 
12 
PROCEDURES FOR BIOLOGICAL SAMPLES .............................................. 53 
12.1 
Sample collection ................................................................................................ 53 
12.2 
Volume of blood .................................................................................................. 53 
12.3 
Handling, storage and destruction of laboratory samples .............................. 53 
12.4 
Chain of custody of biological samples ............................................................. 53 
12.5 
Withdrawal of informed consent for donated biological samples.................. 53 
13 
QUALITY MANAGEMENT, QUALITY ASSURANCE AND QUALITY 
CONTROL .............................................................................................................. 55 
13.1 
Quality management: critical process, system and data identification ......... 55 
13.2 
Quality assurance and quality control .............................................................. 55 
14 
ETHICAL AND REGULATORY REQUIREMENTS ...................................... 56 
14.1 
Ethical conduct of the study .............................................................................. 56 
14.2 
Ethics and regulatory review ............................................................................. 56 
14.3 
Subject information and consent ...................................................................... 56 
14.4 
Subject information card ................................................................................... 57 
14.5 
Subject data protection ...................................................................................... 57 
14.6 
Changes to the approved clinical study protocol ............................................. 58 
14.7 
Audits and inspections ....................................................................................... 58 
14.8 
Insurance ............................................................................................................. 58 
15 
STUDY MANAGEMENT ..................................................................................... 59 
15.1 
Training of study site personnel ........................................................................ 59 
15.2 
Clinical monitoring ............................................................................................. 59 
15.3 
Source data documents ...................................................................................... 60 

 
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15.4 
Study agreements................................................................................................ 60 
15.5 
Study timetable and end of study ...................................................................... 60 
15.6 
Termination of the study.................................................................................... 60 
15.7 
Reporting and publication ................................................................................. 61 
 
Clinical study report ......................................................................................... 61 
 
Annual safety report ......................................................................................... 61 
 
Confidentiality and ownership of study data .................................................... 61 
 
Publication ........................................................................................................ 61 
15.8 
Archiving ............................................................................................................. 61 
16 
DATA MANAGEMENT ....................................................................................... 63 
16.1 
The web-based eCRF ......................................................................................... 63 
16.2 
The entering of data into the eCRF .................................................................. 63 
16.3 
The query process ............................................................................................... 63 
16.4 
Audit trail ............................................................................................................ 64 
16.5 
External data ....................................................................................................... 64 
16.6 
Medical coding .................................................................................................... 64 
16.7 
Database lock ...................................................................................................... 64 
17 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE . 65 
17.1 
General ................................................................................................................ 65 
17.2 
Determination of sample size ............................................................................. 65 
17.3 
Analysis data sets ................................................................................................ 65 
 
Safety analysis set ............................................................................................. 65 
 
PK analysis set - formulation:........................................................................... 65 
 
PK analysis set – food interaction: ................................................................... 66 
17.4 
Description of study population ........................................................................ 66 
 
Demographics and baseline characteristics ...................................................... 66 
 
Medical/surgical history and prior/concomitant medication ............................ 66 
 
Treatment compliance ...................................................................................... 66 
17.5 
Analysis of primary endpoints .......................................................................... 66 
 
Analysis of pharmacokinetics ........................................................................... 66 
17.6 
Analysis of secondary endpoints ....................................................................... 67 
 
Adverse events .................................................................................................. 67 
 
Physical examination ........................................................................................ 67 
 
Vital signs ......................................................................................................... 67 

 
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Body temperature.............................................................................................. 67 
 
Resting 12-lead ECG ........................................................................................ 67 
 
Laboratory safety assessments .......................................................................... 68 
18 
REFERENCES ....................................................................................................... 69 
19 
SIGNATURES ........................................................................................................ 71 
19.1 
Principal Investigator statement ....................................................................... 71 
19.2 
Signature page (approval of the clinical study protocol) ................................ 72 
 
 
List of Tables 
Table 4.1-1 
Medical emergency contacts ............................................................................ 14 
Table 8.1-1 
Schedule of events ............................................................................................ 27 
Table 8.1-2 
Detailed schedule of events for visit 2-7 .......................................................... 29 
Table 11.4-1 Safety laboratory parameters ............................................................................ 52 
 
List of Figures 
Figure 6.1-1 
The pathophysiology of vascular disease in SSc [4] ........................................ 17 
Figure 6.1-2 
Schematic view of arachidonic acid cascade and shunting of the substrate 
PGH2 from PGE2 production to PGI2 formation ...................................................................... 19 
Figure 8.1-1 
Study flow chart ............................................................................................... 25 
 
 
 

 
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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or term                   Explanation 
AA 
Arachidonic acid 
ADL 
Activities of daily living 
AE 
Adverse event 
ADR 
Adverse drug reaction 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical  
AUC0-inf 
Area under the curve from timepoint 0 to infinity 
AUC0-last 
Area under the curve from timepoint 0 to the last 
measured timepoint 
BMI 
Body mass index 
bpm 
Beats per minute 
CA 
Competent authority 
CDC 
Centres for Disease Control and Prevention 
CIOMS 
Council for International Organisations of Medical 
Sciences 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CL/F 
Total clearance of the drug from plasma following 
non-intravenous administration 
COX 
Cyclooxygenase 
Coxib 
Cyclooxygenase inhibitor 
CRP 
C-reactive protein 
CS 
Clinically significant 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTC 
Clinical Trial Consultants AB 
CTCAE 
Common terminology criteria for adverse events 
CTC PV 
CTC’s Pharmacovigilance 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DMP 
Data management plan 
DRF 
Dose range finding  
DSUR 
Development safety update report 
DU 
Digital ulcer 
ECG 
Electrocardiogram 

 
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eCRF 
Electronic CRF 
eGFR 
Estimated glomerular filtration rate 
EDC 
Electronic data capture 
EEA 
European Economic Area 
EMA 
European Medicines Agency 
EUSTAR 
European Scleroderma Trials and Research group 
FDA 
U.S. Food and Drug Administration 
FIH 
First-in-human 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
GDPR 
General data protection regulation 
GMP 
Good manufacturing practice 
h 
hour 
Hb 
Haemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCG 
Human chorionic gonadotropin 
HCVAb 
Hepatitis C virus antibodies 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration  
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
ISF 
Investigator site file 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
LPS 
Lipopolysaccharide 
MAD 
Multiple ascending dose 
MEC 
Molar extinction coefficient  
MedDRA 
Medical dictionary for regulatory activities 
mmHg 
Millimetre of mercury (unit for pressure) 
MPA 
Medical products agency 
MTD 
Maximum tolerated dose 
mPGES-1 
Microsomal Prostaglandin E synthase-1 
NCA 
Non-compartmental analysis 
NCS 
Not clinically significant 
NOAEL 
No observed adverse effect level 

 
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NSAID 
Non-steroidal anti-inflammatory drug 
PDE-5 
Phosphodiesterase type 5  
PG 
Prostaglandin 
PGE2 
Prostaglandin E2 
PGH2 
Prostaglandin H2 
PGI2 
Prostaglandin I2 (prostacyclin) 
pKa 
Negative base-10 logarithm of the acid dissociation 
constant (Ka) of a solution. 
PK 
Pharmacokinetic 
PII 
Personally identifiable information 
pH 
‘Potential of hydrogen’, a measure of acidity or 
alkalinity of a solution 
p.o. 
per os (orally) 
PPI 
Proton pump inhibitor 
PT 
Preferred term 
QC 
Quality control 
RBC 
Red blood cell count 
RBM 
Risk-based monitoring 
RCS 
Raynaud’s Condition Score 
SAD 
Single ascending dose 
SADR 
Serious adverse drug reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDV 
Source data verification 
SmPC 
Summary of product characteristics 
SOC 
System organ class 
SOP 
Standard operating procedure 
SPF 
Sun protection factor 
SSc 
Systemic sclerosis 
SUSAR 
Suspected unexpected serious adverse reaction 
Tmax 
Time to Cmax 
TMF 
Trial master file 
T½(z) 
Plasma half-life associated with the terminal 
elimination phase 
ULN 
Upper limit of normal 
UVA 
Ultraviolet A 
UVB 
Ultraviolet B 

 
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Vz/F   
Volume of distribution associated with the terminal 
elimination phase following non-intravenous 
administration 
WBC 
White blood cell count 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 

 
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4 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR 
4.1 
Medical emergencies contacts 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes a serious adverse event (SAE) and is to be reported as such. Detailed SAE 
reporting procedures are described in Section 11.4.1.13. 
In the case of a medical emergency, the Investigator may contact the Medical Monitor.  
Table 4.1-1 
Medical emergency contacts 
Name 
Function in the study 
Telephone number and e-mail 
Cornelia Lif-Tiberg 
Medical monitor  
Telephone: +46 (0)73 978 94 45 
E-mail: cornelia-lif-tiberg@ctc-ab.se 

 
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5 
INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE  
Sponsor 
Gesynta Pharma AB 
Fogdevreten 2 
SE-171 65 Solna 
Sponsor’s Medical Representative 
Göran Tornling, MD 
Phone: +46 (0)73 096 31 31 
E-mail: goran.tornling@gesynta.se 
 
Sponsor’s Project Manager 
Marie Jansson, CPM  
Phone: +46 (0)72 717 22 21 
E-mail: marie.jansson@gesynta.se 
Clinical conduct 
Clinical Trial Consultants AB (CTC) 
Uppsala University Hospital, 
Entrance 85, 2nd level  
SE-751 85 Uppsala, Sweden 
and 
CTC 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
Principal Investigator 
Helena Litorp, MD, PhD 
Phone: +46 (0)70 254 27 94 
E-mail: helena.litorp@ctc-ab.se 
Study management 
CTC  
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
Clinical Research Manager  
Anna Stendahl, MSc Pharm 
Phone: +46 (0)73 866 48 87 
E-mail: anna.stendahl@ctc-ab.se 
 
Biostatistician 
Fredrik Hansson, MSc 
Phone: +46 (0)72 193 55 01 
E-mail: fredrik.hansson@ctc-ab.se 
 
Medical writer 
Elise Langenkamp, PhD 
Phone: +46 (0)70 330 36 92 
E-mail: elise.langenkamp@ctc-ab.se 
 
Medical monitor 
Cornelia Lif-Tiberg, MD 
Phone: +46 (0)73 978 94 45 
E-mail: cornelia-lif-tiberg@ctc-ab.se 

 
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Laboratory (Safety) 
 
Clinical Microbiology 
Dag Hammarskjölds väg 38 
SE-752 37 Uppsala, Sweden 
Laboratory (Safety) 
 
Clinical Chemistry and Pharmacology 
Uppsala University Hospital 
Entrance 61, 2nd level 
SE-751 85 Uppsala, Sweden 
Laboratory (Bioanalysis) 
 
Lablytica Life Science AB 
Virdings allé 18 
SE-754 50 Uppsala, Sweden 
Investigational medicinal product (IMP) 
manufacturing, packaging, and labelling  
RISE Research Institutes of Sweden AB 
Forskargatan 18 
SE-151 36 Södertälje, Sweden 
Electronic data capture (EDC) system 
provider:  
 
PCG Solutions AB 
S:t Persgatan 6 
SE-753 20 Uppsala, Sweden 
 
 
Signatures are provided in Section 19. 
 
 

 
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6 
INTRODUCTION 
6.1 
Background  
 
Systemic sclerosis 
Systemic Sclerosis (SSc) is an autoimmune disease with microvascular injury and endothelial 
cell activation that results in vascular damage. Pathophysiological consequences of the 
vasculopathy are vasospasm, ischemia-reperfusion injury and coagulation, which manifest as 
Raynaud’s phenomenon in more than 95% of the patients, and around half of patients report a 
history of Digital Ulcers (DUs). DUs are painful, heal slowly and are difficult to treat. In an 
international survey only 16% of those with current or previous use of medications for 
Raynaud’s phenomenon reported at least one medication being effective. Although clinical 
studies have demonstrated phosphodiesterase type 5 (PDE-5) inhibitors and bosentan can 
improve healing and prevent development of new DUs, the efficacy is modest, and more than 
half of the patients with chronic DUs need hospitalisation for intravenous treatment with 
iloprost. 
 
Raynaud’s phenomenon and digital ulcers in systemic sclerosis 
Microvascular injury and endothelial cell activation that results in vascular damage are 
considered to be the earliest, and possibly primary, events in SSc [1]. Changes in capillary 
morphology as investigated with nailfold videocapillaroscopy demonstrate a distinct and 
typical pattern [2] , but also small and medium size arteries are involved [3]. There are four 
pathophysiological components of the vascular disease in SSc (Figure 6.1-1, [4]). 
Figure 6.1-1 The pathophysiology of vascular disease in SSc [4] 
     
 
 
Peripheral blood flow after cold challenge can reliably be assessed also in multi-centre 
clinical studies with laser speckle contrast imaging and thermography [5]. Other methods to 
assess peripheral blood flow in a human experimental setting include microdialysis [6].  
Raynaud’s phenomenon, an episodic painful ischemic event affecting primarily fingers and 
toes in response to cold exposure or to emotional stress, is a very common manifestation of 
SSc. In the large European Scleroderma Trials and Research group (EUSTAR) database, 

 
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including 9182 patients with SSc, more than 95% reported Raynaud’s phenomenon [7]. The 
mean age at onset of Raynaud’s phenomenon, which usually is the first symptom of SSc, was 
42 years and preceded symptoms from other organ manifestations within on average 4 years 
[8]. In an international survey of patients with Raynaud’s phenomenon, most subjects (78%) 
reported making at least one life adjustment due to Raynaud’s phenomenon, and quality of 
life was significantly reduced. Further, of those with current or previous use of medications 
for Raynaud’s phenomenon, only 16% reported at least one medication being effective [9]. 
Raynaud’s Condition Score (RCS), a patient-reported outcome, is a validated method to 
assess and document disease activity and functional status in patients during clinical trials 
[10]. 
DUs are common and disabling manifestations of the underlying vasculopathy in SSc; around 
half of patients report a history of DUs [4], with male sex being associated with higher risk 
[7]. DUs in the course of SSc are painful, heal slowly (3-15 months) and are difficult to treat 
[11]. More than half of the patients with chronic DUs need hospitalisation for intravenous 
treatment with prostacyclin analogues of their ulcers or complications. DU is also a marker 
for a more severe course of SSc with increased frequency of organ manifestations such as 
heart, lung, kidney and the gastrointestinal tract [12].  
Raynaud’s phenomenon and DUs are closely related sharing the same pathophysiology with 
impaired peripheral circulation. Raynaud’s phenomenon in patients with connective tissue 
disease, especially in those with SSc, can sometimes progress to digital ulceration or critical 
ischemia [13]. In line with this, Raynaud’s phenomenon has been demonstrated to be a risk 
factor for the development of DUs [11], and the connection between the 2 conditions is 
further supported by the observation that the RCS is worse in patients with digital ulcers than 
in those without [10].  
 
Investigational medicinal product characteristics 
The IMP, GS-248, is under development for the treatment of DUs. GS-248 is isolated as 
stable, highly crystalline hydrogen sulphate salt. It is an achiral substance with a 
trans-orientation of the 4-trifluoromethylcyclohexyl-group. The parent is a weak base with 
pKa 4.8 (protonation at the benzimidazole moiety) and the water solubility is low and 
pH-dependent. 
 
Mechanism of action of the investigational medicinal product 
GS-248 is a selective and potent inhibitor of the microsomal Prostaglandin E synthase-1 
(mPGES-1). Microsomal PGES-1 is an inducible enzyme that catalyses the second step in the 
prostaglandin E2 (PGE2) formation from arachidonic acid (AA) and is also an anticipated 
drug target to treat inflammation (Figure 6.1-2).  

 
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Figure 6.1-2 Schematic view of arachidonic acid cascade and shunting of the substrate PGH2 from 
PGE2 production to PGI2 formation 
 
 
Selective mPGES-1 inhibitors are suggested to be safer than traditional non-steroidal 
anti-inflammatory drugs (NSAID)s or cyclooxygenase inhibitors (coxibs), which target the 
upstream cyclooxygenases (COX-1 and COX-2, respectively) for general inhibition of 
prostanoid production (Figure 6.1-2). Genetic deletion of mPGES-1, as well as its 
pharmacological inhibition, has been proven to be protective in several models of 
inflammatory disorders such as stroke, multiple sclerosis, atherosclerosis, osteo- and 
rheumatoid arthritis [14]. Prostaglandin I2 (PGI2), another AA metabolite, induces 
vasodilation and inhibits platelet aggregation. PGI2 is formed from common substrate, 
prostaglandin H2 (PGH2), by the enzyme prostacyclin synthase, which is mainly expressed in 
the vascular endothelium. 
The aim of the present project is to achieve an anti-inflammatory effect by reducing 
production of the proinflammatory mediator PGE2 and concomitantly, by substrate shunting, 
so as to elicit a vasodilatory and platelet inhibitory effect through increasing prostacyclin 
(PGI2) production. 
 
Non-clinical summary 
GS-248 inhibits mPGES-1 enzyme with a half maximal inhibitory concentration (IC50) of 
2 nM, while having no effect on COX-1 or COX-2 when tested up to 100 µM. In a human 
whole blood assay (ex vivo measurements of mPGES-1 activity in lipopolysaccharide 
(LPS)-stimulated whole blood), GS-248 inhibited PGE2 synthesis with an IC50 of 0.4 nM. 
Efficacious enzyme inhibition in vivo has been demonstrated in a Thermal Hyperalgesia 
model in the guinea-pig in which GS-248 reversed the (LPS)-induced hyperalgesia in a dose 
dependent manner with maximal effect at 30 mg/kg per os (p.o), 3 h post dose. 

 
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The core battery safety pharmacology studies performed showed that GS-248 had no central 
nervous system (CNS), respiratory or cardiovascular effects after single or repeated 
administration at doses of up to 1000 mg/kg in rats or 80 mg/kg in dogs. 
GS-248 in rat demonstrated an intermediate clearance compound with a large volume of 
distribution, with an oral bioavailability of 37% and a terminal half-life (T½(z)) of 2.5 h in the 
fasted state. The overall steady state toxicokinetic data in the rat and dog showed that the 
exposure increased less than dose proportionally, except for female dogs between the low and 
intermediate doses on test day 1 and between the intermediate and high doses on test day 
18/28, where the increase was dose proportional. The mean exposure (male and female dogs) 
at the no observed adverse effect level (NOAEL) were 2500 nmol/L for maximum plasma 
concentration (Cmax) and 23000 nmol*h/L for area under the curve from timepoint 0 to the last 
timepoint (AUC0-last). No accumulation was observed in the rat, whereas an accumulation was 
observed over the number of treatment days in the dog. 
GS-248 showed a high plasma protein binding in all investigated species, with human serum 
albumin as the major determined protein in human plasma. Radiolabelled GS-248 was 
extensively distributed with the highest concentrations found in the liver, adrenals, brown fat, 
kidneys, salivary glands, and pancreas. After reaching the maximum, radioactivity in tissues 
and organs depleted rapidly within the first 8 h. 
An in vitro metabolism species comparison showed no major difference in metabolic 
pathways between rat, dog, cynomolgus and human hepatocytes. GS-248 has been shown to 
be a potent in vitro inhibitor for cytochrome P450 (CYP) 2C8, 2C9 and 2C19. 
The major part of GS-248 in rats was eliminated in faeces via the bile whereas urinary 
excretion was negligible. Overall, the elimination was fast and almost complete after 48 h. 
Mild increases in serum cholesterol levels were noted in both rats and dogs at all dose levels 
included in the 28-day toxicity studies, but these changes were of a low degree and were 
therefore not considered to be adverse effects. The same applies for mild decreases in serum 
protein levels noted at the low and intermediate dose levels in the dog study. 
Testicular degeneration was noted histopathologically in the 3 male dogs at the highest dose 
level that were necropsied pre-terminally on Day 21 of the 28-day toxicity study. These were 
most probably an exacerbation of effects that can be seen spontaneously in adult dogs, as a 
result of the poor physiological condition of these animals prior to their pre-terminal 
necropsy. Thus, these changes may well be secondary effects and therefore not directly 
related to GS-248 treatment. No such changes were noted at the NOAEL of 20 mg/kg (the 
intermediate dose level). 
Clear adverse effects on the liver and biliary system indicating cholestasis and inflammation 
noted in the dogs in the dose range finding (DRF) and pivotal 28-day toxicity studies are the 
toxicity findings that set the limits for human exposure in the current Phase I study. 
Pronounced and serious effects were seen at the highest dose of 80/40 mg/kg, and thus this 
dose regimen was clearly above the maximum tolerated dose (MTD) for repeated treatment 
with GS-248 in dogs. At the intermediate dose level of 20 mg/kg, a single female showed 
mild to moderate increases in the majority of liver biomarkers, which were followed at regular 
intervals during the study. These changes were primarily observed during the first 2 weeks of 
dosing, subsequently decreased during continued dosing and had finally returned to within the 
normal range at the end of the 28-day dosing period. No treatment-related histopathological 
changes of any type were noted in this animal. Therefore, as the changes in these clinical 

 
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pathology parameters were short-lived (they returned to within the normal range during 
continued and uninterrupted dosing), and no treatment-related histopathological changes were 
noted in these animals, the NOAEL in this study was set at this dose level, i.e. 20 mg/kg. 
This test compound was shown to be negative for genotoxicity in the Ames test and mouse 
lymphoma assay in vitro and the micronucleus test in rats in vivo, following 14 days’ 
treatment at 1000 mg/kg plus an additional 14 days’ treatment at 2000 mg/kg. 
Both the molar extinction coefficient (MEC) value of GS-248 and the fact that it also showed 
a weak and comparatively short-lived potential binding of radioactivity to melanin-containing 
tissues of the ocular bulb indicate a phototoxic potential.  
For details on the non-clinical studies performed, refer to the Investigator’s Brochure (IB) of 
GS-248.  
 
Clinical experience 
A phase 1 first-in-human (FIH) study (GS-1001) has been performed in which GS-248 was 
dosed as an oral solution in fasting conditions. Of this study, the clinical phase has been 
completed (both the single ascending dose [SAD] and multiple ascending dose [MAD] part) 
and the clinical study report (CSR) is under development.  
During the SAD part of this study, 6 cohorts of 8 subjects each were randomised to GS-248 
and placebo at a 3:1 ratio, resulting in a total of 36 subjects being exposed to GS-248. Data 
from this part of the study indicate that GS-248 administered orally as single doses (1 mg to 
300 mg) in healthy volunteers was safe and well tolerated as assessed by reported adverse 
events (AEs), vital signs, electrocardiograms (ECGs), physical examinations and safety 
laboratory parameters. No SAEs, no discontinuations due to AEs, and no other noteworthy 
safety or tolerability findings were reported at any dose level.  
PK analysis demonstrated that GS-248 was rapidly absorbed and reached a maximum plasma 
concentration between 1 and 2.5 hours after single dose administration. The plasma 
concentration profiles exhibited a multi-exponential decline and the shape of the curves 
appeared to be similar between the different dose groups. The apparent total clearance of the 
drug from plasma following non-intravenous administration (CL/F) and apparent volume of 
distribution associated with the terminal elimination phase following non-intravenous 
administration (Vz/F) were both high. The terminal half-life was estimated to approximately 
10 hours. GS-248 exhibited a large variability in exposure and dose proportionality was 
indicated. 
6.2 
Study rationale 
GS-248 is intended to be used for the prevention and treatment of DUs in patients with SSc. 
Current oral therapies for DUs have limited efficacy, and there is a high medical need for new 
therapeutic alternatives. 
The aim of the present project is to achieve an anti-inflammatory effect by reducing 
production of the proinflammatory mediator PGE2 and concomitantly, by substrate shunting, 
to elicit a vasodilatory and platelet inhibitory effect by increased PGI2 production. 

 
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The study will collect information about pharmacokinetics (PK), safety and tolerability 
following a single dose of GS-248 in two different oral solid formulations in capsules to 
healthy subjects.  
The rationale for the study design is outlined in Section 8.2. 
6.3 
Risk/benefit assessment 
The healthy volunteers in this study will, except for thorough health examinations, have no 
medical benefit from participation and their safety and wellbeing are of utmost importance. 
The FIH study with GS-248, in which the SAD part with doses of 1-300 mg is finalised and 
did not reveal any noteworthy safety or tolerability findings at any dose level. The current 
study concerns a single dose of 120 mg in two different formulations, which is well beneath 
the maximum dose level studied in the FIH study. Adverse drug reactions (ADRs) are 
therefore not expected.  
In a pre-clinical study, pronounced and serious effects on the liver and biliary system were 
noted in dogs at the highest dose in the 28-day toxicity study. However, no findings that were 
considered to constitute an adverse effect were noted at the intermediate dose level, primarily 
based on the total lack of treatment-related histopathological findings at this dose level, and 
the NOAEL in this study was therefore set at 20 mg/kg. The liver biomarkers will be closely 
monitored during the present study.  
Subjects will remain in the research clinic for approximately 24 h after the single dose and 
will be closely monitored by medical staff. In addition, subjects will return to the clinic at 
approximately 48 h post dose for safety check-up.  
Overdosing is not likely to occur since all IMP will be administered by site personnel under 
medical surveillance. In cases of accidental overdose, standard supportive measures should be 
adopted as required. For further information regarding overdosing, refer to Section 11.4.1.17. 
The Principal Investigator at the research clinic will ascertain that adequate facilities and 
procedures are available to handle emergency situations should they occur during the study. 
The medical staff at CTC have extensive experience from early Phase I and FIH studies and 
there are adequate procedures in place to handle unexpected and expected adverse reactions in 
the study subjects. CTC has been regularly inspected by the Swedish Medical Products 
Agency (MPA) and is authorised to conduct early phase studies. 
Besides the risks related to the IMP as described above, there may also be risks related to the 
medical devices used in the study, e.g., indwelling venous catheters. However, these are 
devices that are used in routine medical care and the risk associated with their use is 
considered low and ethically justifiable. Study specific evaluations and sampling procedures, 
like blood-pressure measurements using a blood pressure cuff and frequent blood-sampling, 
may cause transient discomfort but the risk is deemed to be low and ethically justifiable.  
Overall, the combined safety data from the pre-clinical studies and the FIH study have not 
revealed any safety issues that would outweigh the expected benefits of the study. While 
keeping the above-mentioned risk factors at a minimum level in order to not expose the 
subjects participating in the study for risks that would not be ethically justifiable, it is 
concluded that the planned study assessments are considered sufficient to meet the scientific 
and medical goals for the study. It is therefore concluded that the potential benefits from the 
study will outweigh the potential risks for the treated subjects. 

 
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More detailed information about the known and expected benefits and risks and reasonably 
expected ADRs of GS-248 is found in the current version of the IB.  

 
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7 
STUDY OBJECTIVES AND ENDPOINTS 
7.1 
Primary objective 
• To evaluate the PK of two different solid formulations of oral GS-248 in healthy 
subjects. 
• To evaluate the effect of food on the PK of one of the two formulations of oral GS-
248.  
 
Primary endpoints 
• The PK parameters of a single dose of two different formulations of GS 248 in fasting 
conditions. The PK parameters to be assessed include, but are not limited to, 
maximum plasma concentration (Cmax), time to Cmax (Tmax),area under the curve from 
timepoint 0 to the last measured timepoint (AUC0-last), AUC from timepoint 0 to 
infinity (AUC0-inf),  plasma half-life associated with the terminal elimination phase 
(T½(z)), volume of distribution associated with the terminal elimination phase 
following non intravenous administration (Vz/F), and total clearance of the drug from 
plasma following non-intravenous administration (CL/F).The relative bioavailability 
of GS-248 after a single dose of Formulation A versus Formulation B, and of one of 
the two formulations in fed versus fasting conditions.  
• The PK parameters of a single dose of one of the two formulations of GS-248 in fed 
conditions.  
7.2 
Secondary objective 
• To evaluate the safety and tolerability of two different solid formulations of oral 
GS-248 in healthy subjects. 
• To evaluate the safety and tolerability of one of the two formulations of oral GS-248 
given after a standardised high-fat high-calorie breakfast.  
 
Secondary endpoints 
• Frequency, intensity and seriousness of AEs. 
• Clinically significant changes in: 
o Physical examination 
o Vital signs 
o Body temperature 
o Resting 12-lead ECG 
o Safety laboratory parameters 
 

 
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8 
STUDY DESIGN 
8.1 
Overall study design and schedule of events 
This is a Phase I, open, one-sequence, three-period study in healthy volunteers to evaluate the 
PK, safety and tolerability of two formulations of GS-248. The study is divided in two parts. 
Part I will evaluate PK, safety and tolerability of a single oral dose of two different 
formulations of GS-248 in fasting conditions (Section 8.1.1). Part II will evaluate PK, safety 
and tolerability of one of the two different formulations of GS-248 in fed conditions 
(Section 8.1.2).  
Subjects are expected to participate in both Part I and Part II and will come to the clinic for a 
total of 7 visits. Screening (Visit 1) will take place from Day -28 to Day -1 and will include 
an eligibility check and a general health assessment, see Table 8.1-1 for details. Each subject 
is expected to participate in the study for approximately 8 weeks including a screening period 
of up to 4 weeks.  
An overview of the study design is shown in Figure 8.1-1.  
Figure 8.1-1 Study flow chart 
 
 
Part I: Two formulations of GS-248 in fasting conditions 
In Part I of the study, a single oral dose of GS-248 in two different solid formulations will be 
administered to 14 healthy subjects. All subjects will first receive Formulation A (a lipid-
based formulation in a capsule) and then Formulation B (a dry powder in a capsule, see 
Section 10.1). A wash-out period of at least 4 days will be applied between the IMP 
administrations. Both doses contain 120 mg GS-248. The rationale for the dose is detailed in 
Section 8.3.  
For Part I, subjects will come to the clinic for 4 visits. At Visit 2, subjects will be admitted to 
the clinic on the afternoon/evening of Day -1 and will remain at the clinic until Day 2 (24 h 
post dose) for single dose administration of Formulation A and PK and safety assessments. 
The subjects must fast for at least 10 hours before the anticipated dosing time on Day 1. 
Water, but no other drinks, is allowed as desired except for 1 h before and 1 h after dosing. 
The subjects will be carefully monitored by clinical staff during and after dosing. Vital signs 
and ECG will be checked at regular intervals as detailed in Table 8.1-2. The subjects will 
return to the clinic on Day 3 (Visit 3) at 48 h post dose for PK blood sampling and safety 
assessments, as outlined in Table 8.1-1. Safety assessments include AE reporting, physical 

 
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examination, ECG, vital signs, body temperature, and blood sampling for analysis of safety 
laboratory parameters.  
Visit 4 will be similar to Visit 2, at which subjects will stay overnight at the clinic from 
Day -1 to Day 2 for single dose administration of Formulation B and PK blood sampling and 
safety assessments. Visit 5 will be similar to Visit 3, at which subjects return to the clinic on 
Day 3 for PK blood sampling and safety assessments.  
The schedule of events for Part I is shown in Table 8.1-1 and detailed for visit 2-7 in 
Table 8.1-2.  
Study assessments are described in Section 11. 
 
Part II: Food interaction 
After evaluation of the PK profiles of Formulation A and B in Part I of the study, one 
formulation will be selected to be given following intake of a standardised breakfast in Part II 
of the study. In this part, any potential food interaction with GS-248 will be investigated.  
After evaluation of the PK results from Part I, subjects will return to the clinic for a second 
dose of the selected formulation (Visit 6, similar to Visit 2), yet this time in fed conditions. 
The assessments during fed conditions will be the same as during fasting conditions (see 
Section 8.1.1), except for the fact that the subjects will consume a high-fat high-calorie 
breakfast 30 minutes prior to IMP administration as detailed in Section 10.5.  
At 48 h post dose, subjects will return to the clinic for PK blood sampling and final 
end-of-study safety assessments (Visit 7). 
The schedule of events for Part II is shown in Table 8.1-1 and detailed for visit 2-7 in 
Table 8.1-2.  
Study assessments are described in Section 11. 

 
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Table 8.1-1 
Schedule of events 
Visit 
Refer to  
CSP  
section 
Screening 
Part I 
Part II 
 
Formulation A 
Wash-out 
>4 days 
Formulation B 
Wash-out 
and  
PK calc 
>14 days 
Formulation A or B fed 
Visit 1 
Visit 21 
Visit 31 
Visit 41 
Visit 51 
Visit 61 
Visit 71 
 
In-clinic 
 
In-clinic 
 
In-clinic 
 
Assessment 
Day -28 to -1 Day -1 to 2 
Day 3 
Day -1 to 2 
Day 3 
Day -1 to 2 
Day 3 
Informed Consent 
14.3 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
9.4, 9.5 
X 
X2 
 
 
 
 
 
 
 
Demographics 
11.2.3 
X 
 
 
 
 
 
 
 
 
Medical/surgical history 
11.2.5 
X 
 
 
 
 
 
 
 
 
HIV, hepatitis B and C 
11.2.7 
X 
 
 
 
 
 
 
 
 
Alcohol breath test 
11.2.10 
X 
X 
 
 
X 
 
 
X 
 
Weight/height (BMI) 
11.2.4 
X 
 
 
 
 
 
 
 
X3 
Pregnancy Test4 
11.2.8 
X 
X 
 
 
X 
 
 
X 
X 
Urine Drug Screen5  
11.2.9 
X5 
X 
X 
 
X 
X 
 
X 
X 
Physical Examination 
11.4.2 
X 
X6 
 
 
X6 
 
 
X6 
X 
Laboratory Safety 
11.4.6 
X 
X 
X 
 
X 
X 
 
X 
X 
Vital Signs 
11.4.3 
X 
X 
X 
 
X 
X 
 
X 
X 
Body temperature 
11.4.4 
 
X 
X 
 
X 
X 
 
X 
X 
12-lead ECG 
11.4.5 
X 
X 
X 
 
X 
X 
 
X 
X 
Baseline symptoms 
11.2.11 
X 
X 
 
 
 
 
 
 
 
IMP administration 
10.5 
 
X 
 
 
X 
 
 
X 
 
PK blood sampling7 
11.3.1 
 
X 
X 
 
X 
X 
 
X 
X 
Breakfast (standardised) 
10.5 
 
 
 
 
 
 
 
X 
 
Other meals (standardised)8 
 
 
X 
 
 
X 
 
 
X 
 
Prior/concomitant med. 
11.2.6 
------------------------------------------------------------------------ X ------------------------------------------------------------------------ 
AEs9 
11.4.1 
 
--------------------------------------------------------------- X --------------------------------------------------------------- 

 
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CSP = Clinical study protocol, HIV= human immunodeficiency virus, BMI = body mass index 
1. Details in separate schedule (Table 8.1-2). 
2. Eligibility check before IMP administration.   
3. Only weight assessments.  
4. Females only. At screening visit: plasma/serum tests; at other visits: urine test.  
5. Drug tests may also be performed at 1 to 2 additional random occasions during the study.  
6. Brief physical examination only 
7. Timing of PK blood sampling is outlined in Table 8.1-2.  
8. At visit 2, 4 and 6, standardised meals are served as outlined in Table 8.1-2. 
9. From first administration of IMP.  
 
 
 
 

 
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Table 8.1-2 
Detailed schedule of events for visit 2-7 
Visit 
Refer to 
CSP  
section 
 
Visit 2, 4, 6 
Visit 
3, 5, 7 
Day -1 
Day 1 
Day 2 
Day 3 
Assessment 
Time1 
 
Pre-
dose 
00:00 
00:15 
00:30 
01:00 
01:30 
02:00 
03:00 
04:00 
06:00 
08:00 
12:00 
16:00 
24:00 
48:00 
Inclusion/exclusion 
criteria 
9.4, 9.5 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
11.2.10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/height (BMI) 
11.2.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3,4 
Pregnancy Test5 
11.2.8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
Urine Drug Screen6 
11.2.9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Physical Examination 
11.4.2 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
Laboratory Safety 
11.4.6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs 
11.4.3 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Body temperature 
11.4.4 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
12-lead ECG 
11.4.5 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Baseline symptoms 
11.2.11 
X2 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration 
10.5 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood sampling8 
11.3.1 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Breakfast 
(standardised)9  
10.5 
 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other meals 
(standardised)10 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant med. 
11.2.6 
--------------------------------------------------------------------------------------------- X --------------------------------------------------------------------------------------------- 
AEs 
11.4.1 
 
 
--------------------------------------------------------------------------------- X --------------------------------------------------------------------------------- 
1. Time is denoted in hh:mm. Time points reflect time in hours and minutes after IMP administration.  

 
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2. Only at Visit 2. 
3. Only weight assessments.  
4. Only at Visit 7 (end-of-study visit) or after early withdrawal.   
5. Females only. Urine test.  
6. Drug tests may also be performed at 1 to 2 additional random occasions during the study.  
7. Brief physical examination only, may be performed on Day -1 or Day 1 pre-dose.  
8. Actual time for PK sampling must not deviate more than ±10% from the planned time. The pre-dose sample may be taken within 60 minutes prior to dose. Refer to 
Section 11.3.1 for more information about timing of PK samples. 
9. Standardised breakfast only at Visit 6, not at Visit 2 and 4. Breakfast should be served 30 min before IMP administration.  
10. Standardised lunch, snack, dinner and evening snack at approximately 4, 7, 9 and 11 hours post breakfast. 

 
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8.2 
Rationale for study design 
The European Medicines Agency (EMA) guideline on strategies to identify and mitigate risks 
for FIH and early clinical trials with IMPs (EMEA/CHMP/SWP/28367/07 Rev. 1) has been 
considered.  
The design of the study is based on the aim to study PK, safety and tolerability of two 
formulations of GS-248 in a limited number of healthy volunteers. The time points for PK 
blood sampling have been selected based on data obtained from pre-clinical studies and the 
FIH study (GS-1001).  
A one-sequence design was chosen for the food interaction part of the study to yield a more 
efficient comparison of treatments than a parallel study design, i.e., fewer subjects might be 
required since each subject will serve as his own control. To avoid carryover effects, a 
washout period of at least 4 days has been incorporated between the three treatment 
administrations. Interim analysis of the FIH study (GS-1001) revealed that none of the 
subjects receiving multiple doses of 180 mg GS-248 had plasma levels over 5% of Cmax at 
48 h after the last dose, which indicates that a 4-day wash-out period should be sufficient. 
The phototoxicity of GS-248 has not been investigated but based on the MEC value obtained 
from absorbance studies and the weak and comparatively short-lived potential binding of 
radioactivity to melanin-containing tissues of the ocular bulb, a phototoxic potential cannot be 
excluded. Thus, sun protection, as defined in Section 9.6.1, should be used during the study. 
GS-248 is a low solubility compound with pH-dependent solubility. A high pH may decrease 
absorption and thus exposure. For this reason, use of antacids, proton pump inhibitors (PPIs) 
or any medication that changes gastric pH is not allowed from 14 days prior to IMP 
administration and until the end-of-study visit.  
Overall, the study will provide important data to support the design of further studies, both in 
healthy volunteers and in patients.  
8.3 
Selection of dose  
A dose of 120 mg is selected to mimic the planned phase IIa study. Provisional data from the 
FIH phase I study (GS-1001) suggest that a dose of 120 mg is safe and tolerable. 
8.4 
Selection of formulation 
After completion of Part I, PK data will be evaluated to determine which of the two 
formulations is to be used in Part II, the food interaction part. The selection will be based on 
PK parameters, e.g., projected AUC and plasma level at the end of dosing intervals in 
repeated dose scenarios. 

 
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9 
STUDY POPULATION  
Prospective approval of protocol deviations to eligibility criteria, also known as protocol 
waivers or exemptions, is not permitted.   
9.1 
Recruitment 
The subjects will be recruited from CTC’s database of healthy volunteers and from 
advertising in media (including social media). 
9.2 
Screening and enrolment log 
Investigators must keep a record of all screened subjects even if they were not subsequently 
included in the study. This information is necessary to verify that subjects were selected 
without bias. The reason for screen failure should be stated for all subjects screened but not 
included. The reason for withdrawal should be stated for all subjects included but not 
completed.  
A screening number will be allocated to each subject in connection to the informed consent 
process at the Screening visit. The screening number is generated automatically in the 
electronic case report form (eCRF). The screening number will allow identification of 
subjects irrespective of their possible eligibility for the study.  
If a subject cannot receive the planned dose of IMP within four weeks after screening (i.e., the 
time interval between signing informed consent until dose administration) the subject should 
be rescreened and assigned a new screening number before proceeding in the study. 
9.3 
Number of subjects 
Approximately 20 healthy subjects will be screened to achieve a total of 14 dosed subjects, 
and at least 12 evaluable subjects. In the event of early withdrawals, subjects may be replaced.  
9.4 
Inclusion criteria 
For inclusion in the study, subjects must fulfil the following criteria:  
1. Willing and able to give written informed consent for participation in the study.  
2. Healthy male or female subject aged ≥ 18 and ≤70 years. 
3. Body Mass Index (BMI) ≥ 19.0 and ≤ 30.0 kg/m2.  
4. Clinically normal medical history, physical findings, vital signs, ECG and laboratory 
values at the time of screening, as judged by the Investigator.  
5. Women of child bearing potential (WOCBP) must practice abstinence from 
heterosexual intercourse (only allowed when this is the preferred and usual lifestyle 
of the subject) or must agree to use a highly effective method of contraception with a 
failure rate of < 1% to prevent pregnancy (combined [oestrogen and progestogen 

 
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containing] hormonal contraception [oral, intravaginal, transdermal], progestogen-
only hormonal contraception associated with inhibition of ovulation [oral, injectable, 
implantable], intrauterine device [IUD]or intrauterine hormone-releasing system 
[IUS]) from at least 4 weeks prior to dose to 4 weeks after last dose. Female subjects 
must refrain from donating eggs from the date of dosing until 3 months after dosing 
with the IMP. Their male partner must agree to use a condom during the same time 
frame if he has not undergone vasectomy. 
Women of non-childbearing potential are defined as pre-menopausal females who 
are sterilised (tubal ligation or permanent bilateral occlusion of fallopian tubes); or 
post-menopausal defined as 12 months of amenorrhea (in questionable cases a 
simultaneous blood sample with simultaneous detection of follicle stimulating 
hormone [FSH] 25-140 IE/L).  
Male subjects must be willing to use condom, be vasectomised or practice abstinence 
from heterosexual intercourse (only allowed when this is the preferred and usual 
lifestyle of the subject) to prevent pregnancy and drug exposure of a partner. Male 
subjects must refrain from donating sperm from the date of dosing until 3 months 
after dosing with the IMP. Their female partner of child-bearing potential must use 
contraceptive methods with a failure rate of < 1% to prevent pregnancy (see above). 
9.5 
Exclusion criteria 
Subjects must not enter the study if any of the following exclusion criteria are fulfilled: 
1. Known allergy to GS-248. 
2. Females who are breast feeding or who plan to become pregnant until 2 weeks after 
the end-of-study visit. 
3. Positive serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of human chorionic gonadotropin [HCG]) at screening and within 24 h prior to 
the first administration of IMP.  
4. Regular use of corticosteroids (inhaled and systemic), NSAIDs, aspirin or coxibs, 
antacids, PPIs, or any other medication that changes gastric pH within 14 days of 
study drug administration. 
5. Regular use of any prescribed or non-prescribed medication including analgesics, 
herbal remedies, vitamins and minerals within 2 weeks prior to the (first) 
administration of IMP, except hormonal contraception and occasional intake of 
paracetamol (maximum 2000 mg/day; and not exceeding 3000 mg/week) and nasal 
decongestants without cortisone, antihistamine or anticholinergics for a maximum of 
10 days, at the discretion of the Investigator. 
6. Presence of inherited or acquired disorders of platelet function, bleeding or 
coagulation, as judged by the investigator.  
7. History or presence of any clinically significant disease or disorder which, in the 
opinion of the Investigator, may either put the subject at risk because of participation 
in the study, or influence the results or the subject’s ability to participate in the study. 

 
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8. After 10 minutes supine rest at the time of screening, any vital signs values outside 
the following ranges: 
• Systolic blood pressure <90 or >140 mmHg, or 
• Diastolic blood pressure <50 or >90 mmHg, or  
• Pulse <40 or >90 bpm 
9. Positive test for serum hepatitis B surface antigen (HBsAg), hepatitis C virus 
antibodies (HCVAb) or HIV 1 and/or 2 antibodies at screening. 
10. Presence or history of drug and/or alcohol abuse and/or excessive intake of alcohol 
and/or history, or current use, of anabolic steroids, as judged by the Investigator. 
11. Positive test for drugs of abuse or alcohol at screening or on admission to the unit 
prior to administration of the IMP.  
12. Participation in other interventional studies within 3 months prior to administration 
of study drug.  
13. Consumption of grapefruit, grapefruit juice, other grapefruit-containing products, or 
Seville oranges within 14 days of first IMP administration.  
14. Any clinically significant illness, medical/surgical procedure or trauma within 4 
weeks of the first administration of IMP.  
15. Malignancy within the past 5 years with the exception of in situ removal of basal cell 
carcinoma. 
16. Any planned major surgery within the duration of the study. 
17. Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant 
abnormalities in the resting ECG, as judged by the Investigator. 
18. Current smokers or users of nicotine products. Irregular use of nicotine (e.g., 
smoking, snuffing, chewing tobacco) less than three times per week is allowed 
before screening visit. 
19. Regular excessive caffeine consumption defined by a daily intake of >5 cups of 
caffeine-containing beverages. 
20. Intake of xanthine- and/or taurine-containing energy drinks within 2 days prior to 
screening and prior to IMP administration.  
21. Plasma donation within one month of screening or blood donation (or corresponding 
blood loss) during three months prior to screening.  
22. Investigator considers the subject unlikely to comply with study procedures, 
restrictions and requirements. 
23. Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2 (determined by the 
revised Lund-Malmö GFR estimating equation). 
24. Subjects with swallowing disorders, which may affect the subject´s capability to 
swallow the IMP.   
25. Subjects who are vegetarian or for other reasons cannot eat the high-fat high-calorie 
breakfast.  

 
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9.6 
Restrictions during the study 
The subjects must be willing to comply to the following restrictions during the entire study 
duration i.e., from screening to the end-of-study visit. 
 
General restrictions 
• Contraception Requirements:  
The male subjects are expected to use condom to prevent pregnancy and drug 
exposure of a partner and refrain from donating sperm from the date of first dosing 
until three months after last dosing of the IMP. Female partners of child-bearing 
potential are expected to use contraceptive methods with a failure rate of < 1% to 
prevent pregnancy (for details, refer to inclusion criterion No 5) during the same 
period.  
Female subjects of child-bearing potential must use effective contraception 
(defined in inclusion criterion No 5) or practice abstinence during the study and for 
30 days after IMP administration. Female subjects must refrain from donating eggs 
from the date of dosing until 3 months after dosing with the IMP. Their male 
partner must agree to use a condom during the same time frame if he has not 
undergone vasectomy. 
• 
Meals and Dietary Restrictions:  
Part I: Subjects should be fasting overnight (10 hours) before IMP administration 
and until 4 hours post dose. IMP will be swallowed together with 240 mL tap 
water.  
Part II: IMP will be administered within 30 minutes after intake of a standardised 
breakfast and swallowed together with 240 mL tap water. 
For details on IMP administration in the fasted and fed state, refer to Section 10.5. 
Part I and Part II: Standardised meals will be served while the study subjects are 
in the research clinic. Lunch will be served 4 hours post dose. Snack, dinner and 
evening snack will be served approximately 7, 9 and 11 hours post dose, 
respectively. Water is allowed ad libitum at the clinic except one hour before dose 
and one hour after dose on dosing days. 
Standardised meals: A menu option (decided by CTC) will be offered while the 
study subjects are in the research clinic. The meal selection is standardised in the 
sense that the nutritional content of the meals should be similar at each time point 
of each treatment day. 
• Alcohol: Consumption of alcohol is not allowed within 48 hours prior to the 
screening visit and prior to and during all subsequent clinic visits, including the 
end-of-study visit.  
• Drugs of abuse: Use of drugs of abuse is not allowed during the study from 
screening to the end-of-study visit. In addition to the urine drug testing described in 
Table 8.1-1, additional random testing can be performed at the clinic visits. 

 
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• Caffeine: Consumption of up to 5 cups of coffee (or equivalent) per day will be 
allowed from 48 h before each visit and during each visit.  
• Xanthine or taurine containing products/beverages: Energy drinks (e.g. Red bull) 
are not allowed during the study from 48 h prior to first IMP administration until 
the end-of-study visit. 
• Nicotine: Smoking or use of nicotine-containing products is not allowed during the 
study from screening until the end-of-study visit. 
• Grapefruit and grapefruit containing products: Consumption of grapefruit and/or 
grapefruit-containing products, Seville oranges is not allowed during the study 
from screening until the end-of-study visit.  
• Blood donation: The subjects must not donate blood or plasma during the study 
from first IMP administration until three months after the end-of-study visit. 
• Participation in other clinical studies: Study subjects are not allowed to participate 
in any other interventional clinical study during the study period. 
• Sun protection: Protection from the sun is required from day of IMP administration 
(Day 1) until 48 h post dose (Day 3) in each sequence. Study subjects are required 
to follow the recommendations given by Centres for Disease Control and 
Prevention (CDC, see [15]): 
o Stay in the shade, especially during peak hours of 10 AM to 4 PM. 
o Wear clothing that covers arms and legs 
o Use a hat or cap that shades the face, head, ears and neck 
o Wear sunglasses that block both ultraviolet A (UVA) and ultraviolet B 
(UVB) rays 
o Proper use of a broad-spectrum sunscreen with a sun protection factor (SPF) 
of 15 or higher. 
o Abstain from use of tanning beds. 
• Exercise: Subjects will abstain from strenuous exercise for 72 h before each blood 
collection for clinical laboratory tests. 
 
Prior and concomitant therapy 
Prohibited medication 
Regular use of corticosteroids (inhaled and systemic), NSAIDs, aspirin, coxibs, antacids, PPIs 
or any other medication that changes gastric pH is prohibited from 14 days prior to first IMP 
administration until the end-of-study visit.  
Use of corticosteroids (inhaled and systemic), NSAIDs, aspirin, coxibs, antacids, PPIs or any 
other medication that changes gastric pH, any other prescribed or non-prescribed medication, 
herbal remedies, vitamin supplements and minerals is prohibited from the first IMP 
administration until the end-of study visit, except as detailed below.  
Allowed medication 
• Paracetamol in doses up to 2000 mg/day for a maximum of 3 consecutive days. If this 
amount of paracetamol is not sufficient for treatment of the subjects, withdrawal 
should be considered. 

 
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• Nasal decongestants without cortisone, antihistamine or anticholinergics for a 
maximum of 10 days.  
• Contraceptives. 
Other medications considered necessary for the subject´s safety and wellbeing may be given 
at the discretion of the Investigator during the residential period. Following consultation with 
the Sponsor, the Investigator will determine whether or not the subject should continue in the 
study.  
9.7 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently dosed in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects. Minimal information includes 
documentation of signed and dated informed consent form (ICF) and reason(s) for screening 
failure. 
Subjects who do not meet the criteria for participation in this study may be rescreened.  
Re-screening can be performed once if any of the following were reasons for screening failure 
or not-dosing (as judged by the Investigator): 
• Practical reasons.  
• Non-significant medical conditions (e.g. influenza, nasopharyngitis).  
• Plasma or blood donation outside allowed time windows. 
For subjects who are re-screened, a new screening number will be assigned and a new, signed 
ICF will be collected. 
9.8 
Subject withdrawal 
 
General withdrawal criteria  
Subjects are free to discontinue their participation in the study at any time and for whatever 
reason without affecting their right to an appropriate follow-up investigation or their future 
care. If possible, the reason for withdrawal of consent should be documented. 
Subjects may be discontinued from the study at any time at the discretion of the Investigator. 
Reasons for discontinuation include:  
• Withdrawal of consent 
• Severe non-compliance to study protocol procedures, as judged by the Investigator 
and/or Sponsor 
• Subject is lost to follow-up.  
• Significant AEs posing a risk for the subject, as judged by the Investigator and/or 
Sponsor 
• Withdrawal of informed consent to the use of biological samples  

 
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• Pregnancy 
• Death 
• Meeting of an exclusion criterion during the study, which, in the opinion of the 
Investigator, may pose a risk for the subject  
 
QTc withdrawal criteria  
A subject meeting the criteria below will be withdrawn from the study. The same QT 
correction formula will be used to determine discontinuation throughout the study. 
• QTcF > 500 msec  
• Change from baseline: QTc > 60 ms 
Withdrawal decisions will be based on an average QTc value of triplicate ECGs. If an ECG 
demonstrated a prolonged QT interval, two more ECGs will be obtained over a brief period 
and the averaged QTc value of the three ECGs used to determine whether the subject should 
be discontinued from the study. 
 
Liver chemistry withdrawal criteria 
Liver chemistry threshold stopping criteria have been designed to assure subject safety and to 
evaluate liver event aetiology. Study treatment will be stopped if any of the following liver 
chemistry stopping criteria, defined in the U.S. Food and Drug Administration (FDA) 
Guidance on Drug-Induced Liver Injury [16], is met: 
• Alanine aminotransferase (ALT) 3 x Upper Limit of Normal (ULN) and total bilirubin 
≥ 2xULN (>35% direct bilirubin); or ALT 3xULN and INR > 1.5) 
NOTE: plasma bilirubin fractionation will be performed. Bilirubin is also measured via 
urine dipstick (a measurement of direct bilirubin, which would suggest liver injury). 
• ALT 5xULN. 
• ALT 3xULN if associated with symptoms (new or worsening) believed to be related to 
hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness or 
jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia). 
• Subjects with ALT 3xULN and < 5xULN and bilirubin < 2xULN, who do not exhibit 
hepatitis symptoms or rash, will be allowed to continue study treatment as long as they 
are monitored weekly for four weeks.  
 
Procedures for discontinuation of a subject from the study 
A subject who prematurely discontinues participation in the study will always be asked about 
the reason(s) for discontinuation and the presence of any AEs. If a subject withdraws consent, 
the Investigator must ask the subject if he/she is willing, as soon as possible, to be assessed 
according to the procedures scheduled for the end-of-study visit. Any ongoing AEs will be 
followed as described in Section 11.4.1.15. The following end-of-study safety assessments 
need to be performed in case of early withdrawal of a subject: weight, pregnancy test (females 
only), physical examination, laboratory safety, vital signs, 12-lead ECG.  

 
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The primary reason for discontinuation/early withdrawal must be specified in the eCRF and 
final drug accountability must be performed. 
 
Subject replacement 
Subjects who are prematurely withdrawn from the study may be replaced during the course of 
the study.  
 

 
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10 
TREATMENTS  
10.1 
Identity of investigational medicinal products  
GS-248 is a selective inhibitor of mPGES-1, developed for the treatment of DUs secondary to 
SSc. 
GS-248 is provided in two different solid formulations: 
• Formulation A: a lipid-based formulation in size 1 capsules  
• Formulation B: dry powder in size 1 capsules 
Each capsule contains 40 mg GS-248.  
Each single dose consists of 3 capsules, constituting a total of 120 mg GS-248 per IMP 
administration.   
10.2 
Manufacturing, packaging and labelling and release 
GS-248 is manufactured, packaged, labelled and released by RISE, Research Institutes of 
Sweden, Södertälje, Sweden. Labels will comply with applicable Good Manufacturing 
Practice (GMP) requirements [17]. The IMP will be shipped to the research clinic (CTC) in 
bottles.  
10.3 
Conditions for storage 
The IMP can be stored in room temperature (15-25oC).  
Temperature logs will be kept for the area where the IMP is stored. The temperature should be 
noted on a daily basis (working days only unless automatic temperature readings are 
available). 
10.4 
Preparation and accountability 
The IMP will be administered by site personnel, i.e., a registered nurse. The IMP, 3 capsules 
of 40 mg GS-248 (a total of 120 mg), will be given to the subject directly from the package. 
Two nurses/site staff will be present at IMP administration, one that provides the IMP to the 
subject, one that checks the procedure. 
CTC and the Investigator will maintain a Storage and Accountability Log as well as a Drug 
Dispensing Log detailing the dates and quantities of study medication received, prepared for 
and used by each subject and study medication returned or destroyed at the end of the study. 
Any discrepancies between prepared and returned IMP must be explained and documented. 
Products deliberately and/or accidentally destroyed by the site or the subject must be 
accounted for. 

 
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10.5 
Treatment administration 
Part I - fasting conditions 
Following an overnight fast of at least 10 hours, subjects will be administered the IMP 
(3 capsules containing 40 mg GS-248 each, constituting a total of 120 mg GS-248 per IMP 
administration) with 240 mL water. No food is allowed for at least 4 h post dose. Water, but 
no other drinks, is allowed as desired except for 1 h before and 1 h after IMP administration.  
Part II - fed conditions  
Following an overnight fast of at least 10 h, subjects will start a high-fat high-calorie 
breakfast 30 min prior to administration of the IMP (for details on the breakfast, see below). 
The subjects should eat this meal in 30 min or less, however, the IMP should be administered 
30 min after start of the meal. The IMP (3 capsules) will be administered with 240 mL water. 
No food is allowed for at least 4 h post dose. Water, but no other drinks, is allowed as desired 
except for 1 h before and 1h after IMP administration (with the exception of the milk that is 
included in the breakfast, see below).  
The high-fat, high-caloric breakfast will consist of the following (or equivalent): 2 eggs fried 
in butter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces hash brown potatoes (113 g) 
and 8 ounces (ca 240 mL) milk 3%. Substitutions in this meal can be made as long as the 
meal provides a similar amount of calories from protein, carbohydrate, and fat and has 
comparable meal volume and viscosity. The test meal should derive approximately 150, 250, 
and 500-600 calories from protein, carbohydrate, and fat, respectively. 
10.6 
Continuation of treatment with investigational medicinal product 
This is a Phase I study in healthy volunteers who will have no medical benefit from the 
treatment and thus there will be no treatment with GS-248 after end of study participation. 
10.7 
Treatment compliance 
All IMP will be administered at the research clinic under medical supervision to ensure 
compliance. 
10.8 
Return and destruction of investigational medicinal products 
Any unused study medication and all empty containers will be destructed at the site upon 
confirmation from the Sponsor. The Monitor will perform final IMP accountability 
reconciliation at the study end to verify that all used and unused IMP is adequately 
documented and destroyed. 
 

 
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11 
STUDY ASSESSMENTS 
The study assessments are described in the sections below and the timing of these assessments 
are detailed in the schedule of events (Table 8.1-1 and Table 8.1-2).   
11.1 
Recording of data 
The Principal Investigator will provide the Sponsor with all data produced during the study 
from the scheduled study assessments. He/she ensures the accuracy, completeness, legibility, 
and timeliness of the data reported to Sponsor in the eCRF and in all required reports. 
It is important that PK blood sampling occurs as close as possible to scheduled time. In order 
to achieve this, the timing priority order at a particular time point is: 
1. Blood samples for PK  
2. Resting 12-lead ECG 
3. Vital signs 
4. Safety laboratory samples 
Time points for PK blood sampling, safety laboratory samples, 12-lead ECG and vital signs 
are outlined in Table 8.1-1 and Table 8.1-2.   
Actual time for PK sampling and other assessments must not deviate more than ±10% from 
the planned time.  
11.2 
Demographics and other baseline characteristics 
 
Informed consent 
Signed informed consent must be obtained before any screening procedures are initiated. The 
informed consent procedure is further described in Section 14.3. 
 
Eligibility criteria 
Eligibility criteria should be checked during screening and verified before IMP 
administration. The criteria are specified in Sections 9.4 and 9.5. 
 
Demographic information 
The following demographic data will be recorded: gender, age, ethnicity and race. 
 
Weight and height 
Weight and height will be measured without shoes. BMI will be calculated in one decimal 
from the height and weight recorded. 
For timing of the assessments, refer to Table 8.1-1 and Table 8.1-2.  

 
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Medical/surgical history  
Medical/surgical history will be obtained by subject interview in order to verify that the 
eligibility criteria are met. 
 
Prior and concomitant medication 
Prior medications taken during the past two weeks will be obtained by subject interview in 
order to verify that the eligibility criteria are met (see also Section 9.6.2). 
Medications are classified as prior if the stop date was before or on the day of the first dose 
administration (pre-dose) and as concomitant if ongoing on the day of the first dose 
administration, stopped after the first dose administration or started after the first dose 
administration. To distinguish between prior and concomitant medications on Day 1, the start 
time of any newly introduced medication or the stop time of any previously ongoing 
medication must be recorded in the eCRF. 
Any use of concomitant medication from screening until the last end-of-study visit must be 
documented appropriately in the subject’s eCRF. Relevant information (i.e. name of 
medication, dose, unit, frequency, dose form, route, start and stop dates, reason for use) must 
be recorded. All changes in medication should be noted in the eCRF. 
 
HIV and Hepatitis B/C 
Subjects will be tested for HBsAg, HCVAb, and HIV prior to inclusion into the study. Any 
positive result will exclude the subject from participating in the study.  
 
Pregnancy test 
All females will do a pregnancy test at screening (blood/serum) and at visits specified in 
Table 8.1-1 and Table 8.1-2 (urine dipstick).   
 
Urine drug screen 
Urine will be screened for drugs of abuse at time points outlined in the schedule of events 
(Table 8.1-1 and Table 8.1-2) using the AlereTM Drug Screen Test Panel. Additional random 
tests can be performed during the study period. 
 
 Alcohol breath test 
An alcohol breath test will be performed at time points outlined in the schedule of events 
(Table 8.1-1 and Table 8.1-2). Additional random tests can be performed during the study 
period. 
 
Baseline symptoms  
A baseline symptom is defined as an event that occurs between the subject’s signing of the ICF 
until the first administration of IMP (i.e. an event that occurs during the screening period). 

 
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Such events are not AEs and will be recorded as baseline symptoms in the Medical History 
Log in the eCRF. 
11.3 
Assessments related to primary endpoints  
 
Pharmacokinetic sampling and analysis  
Venous blood samples (approximately 4 mL) for the determination of plasma concentrations 
of GS-248 after administration of the IMP, will be collected through an indwelling venous 
catheter or by venepuncture at the pre-specified time-points (Table 8.1-2). Actual time for PK 
sampling must not deviate more than ±10% from the planned time. 
Pre-dose sampling may be performed within 60 minutes prior to dosing. 
The date and time of collection of each sample will be recorded in the eCRF.  
The collected blood samples will be centrifuged to separate plasma, which will be divided 
into aliquots after centrifugation for PK analysis. Further collection and handling details will 
be specified in a separate laboratory manual. 
Samples for determination of plasma concentrations of GS-248 will be analysed by Lablytica 
Life Science AB, Uppsala, Sweden, by means of a validated bioanalytical method. The details 
of the analytical method used will be described in a separate bioanalytical report. For details 
on the PK parameters to be determined, refer to Section 17.5.1.  
11.4 
Assessments related to secondary endpoints 
 
Adverse events 
The Principal Investigator is responsible for ensuring that all medical staff involved in the 
study is familiar with the content of this section and the content of the CTC standard 
operating procedures (SOPs) regarding emergencies and Phase I studies.  
11.4.1.1 Definition of adverse event  
An AE is defined as any untoward medical occurrence in a subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
11.4.1.2 Definition of serious adverse event  
An SAE is any AE which: 
• results in death 
• is life-threatening (this refers to a reaction in which the subject was at risk of death 
at the time of the reaction; it does not refer to a reaction that hypothetically might 
had led to death if the reaction was more severe) 
• requires in-patient hospitalisation or prolongation of existing hospitalisation 

 
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• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is an important medical event (IME) (this refers to a reaction that may not be 
immediately life-threatening or result in death or hospitalisation, but may jeopardise 
the subject or may require intervention to prevent any of the other outcomes defined 
above) 
Examples of IMEs are intensive treatment in an emergency room for allergic bronchospasm 
or blood dyscrasias, convulsions that do not result in hospitalisation, development of drug 
dependency, and drug abuse. 
Planned hospitalisations or surgical interventions for a condition that existed before the 
subject signed the ICF and that did not change in intensity are not SAEs. 
If there is any doubt as to whether an AE meets the definition of an SAE, a conservative 
viewpoint must be taken, and the AE must be reported as an SAE. 
11.4.1.3 Definition of adverse drug reaction 
The term ADR is to be used whenever either the Investigator or Sponsor or designee assessed 
the AE as at least possibly related to the IMP. 
11.4.1.4 Definition of serious adverse drug reaction  
The term Serious Adverse Drug Reaction (SADR) is to be used whenever either the 
Investigator or Sponsor or designee assessed the SAE as at least possibly related to the IMP. 
11.4.1.5 Definition of suspected unexpected serious adverse reaction  
A suspected unexpected serious adverse reaction (SUSAR) is any SADR whose nature or 
intensity is not consistent with the current Reference Safety Information (RSI) in the IB or 
summary of product characteristics (SmPC) and therefore is assessed as unexpected. 
11.4.1.6 Time period and frequency for collecting adverse events 
All AEs (including SAEs) will be collected from the start of IMP administration until the 
end-of-study visit. 
Any AE with start date on the day of IMP administration must be recorded with start time. 
At the end-of-study visit, information on new AEs or SAEs, if any, and stop dates for ongoing 
events must be recorded as applicable. 
Investigators are not obliged to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must 
promptly notify the Sponsor. 

 
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11.4.1.7 Assessment of intensity 
The grading of the intensity of AEs will follow the common terminology criteria for adverse 
events (CTCAE) v5.0 [18]. Grade refers to the severity of the AE. The CTCAE displays 
Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this 
general guideline. 
The Investigator must assess the intensity of an AE using the following definitions, and record 
it on the AE Log in the eCRF: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting 
self-care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not being bedridden. 
11.4.1.8  
Assessment of causal relationship 
The Investigator must assess the causal relationship between an AE and the IMP using the 
definitions below and record it the AE Log of the eCRF: 
Probable 
The event has a strong temporal relationship to the IMP or recurs on re-
challenge, and another aetiology is unlikely or significantly less likely. 
Possible 
The event has a suggestive temporal relationship to the IMP, and an 
alternative aetiology is equally or less likely. 
Unlikely 
The event has no temporal relationship to the IMP or is due to 
underlying/concurrent illness or effect of another drug (that is, there is no 
causal relationship between the IMP and the event). 
 
An AE is considered causally related to the use of the IMP when the causality 
assessment is probable or possible. 
11.4.1.9 Assessment of outcome 
The Investigator must assess the outcome of an AE using the definitions below and record 
it on the AE Log of the eCRF: 
Recovered/resolved 
The subject has recovered completely, and no symptoms remain. 
Recovering/resolving  The subject’s condition is improving, but symptoms still remain. 

 
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Recovered/resolved 
with sequelae 
The subject has recovered, but some symptoms remain (for 
example, the subject had a stroke and is functioning normally but 
has some motor impairment). 
Not recovered/not 
resolved 
The subject’s condition has not improved and the symptoms are 
unchanged (for example, an atrial fibrillation has become chronic). 
Fatal 
 
Unknown 
 
11.4.1.10 Reporting of action taken with study treatment 
The Investigator must report the action taken with study treatment using the definitions 
below and record it on the AE Log of the eCRF: 
Dose increased   
Dose not changed 
Dose rate reduced 
Dose reduced 
Drug interrupted 
Drug withdrawn 
Not applicable 
Unknown 
11.4.1.11 Collecting adverse events 
AEs identified using any of the following methods will be recorded: 
• AEs spontaneously reported by the subject 
• AEs observed by the Investigator or medical personnel 
• AEs elicited based on non-leading questions from the Investigator or medical 
personnel 
11.4.1.12 Recording adverse events 
AEs must be recorded in the AE Log of the eCRF. The Investigator must provide 
information on the AE, preferably with a diagnosis or at least with signs and symptoms; 
start and stop dates, start and stop time; intensity; causal relationship to IMP; action taken, 
and outcome. 
If the AE is serious, this must be indicated in the eCRF.  
AEs, including out-of-range clinically significant clinical safety laboratory values, must be 
recorded individually, except when considered manifestations of the same medical condition 
or disease state; in such cases, they must be recorded under a single diagnosis. 

 
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11.4.1.13  Reporting of serious adverse events  
SAE reporting should be performed by the Investigator within 24 hours of awareness via the 
eCRF. All available information regarding the SAE should be entered in the AE Log for the 
specific subject. By saving the event as “serious” in the eCRF and once the Investigator has 
signed-off of the event, an e-mail alert is automatically sent to predefined recipients to 
highlight that an SAE has been registered. The same information is automatically sent to 
sae@ctc-ab.se. 
The SAE report is reviewed by a designated person at CTC’s Pharmacovigilance (CTC PV) 
department to ensure that the report is valid and correct. For fatal or life-threatening SAEs 
where important or relevant information is missing, immediate follow-up is undertaken and 
queries to the site are raised. Investigators or other site personnel should inform CTC PV of 
any follow-up information on a previously reported SAE immediately but no later than within 
24 hours of awareness. 
If the SAE report in the eCRF is updated, a new e-mail alert will be sent.   
If any additional documentation is required (e.g. autopsy report), CTC PV will request this 
information from the study site.  
In case the eCRF cannot be accessed, the SAE should be reported by manual completion of 
the paper SAE Form, provided in the Investigator Site File (ISF). The completed, signed and 
dated paper SAE Form should, within 24 hours, be scanned and e-mailed to:  
Medical monitor: Cornelia Lif-Tiberg 
E-mail: cornelia-lif-tiberg@ctc-ab.se 
Sponsor’s medically representative: Göran Tornling 
E-mail: goran.tornling@gesynta.se and sae@gesynta.se 
A copy of the paper SAE form must also be e-mailed to CTC at: sae@ctc-ab.se. 
The study site should notify the site Monitor via phone or e-mail about the submission of 
the SAE report. As soon as the site personnel have access to the eCRF, the SAE should be 
reported electronically as well. 
The Sponsor or delegate will assume responsibility for reporting SAEs to the competent 
authority (CA) and independent ethics committee (IEC) in accordance with local regulations. 
11.4.1.14 Reporting of SUSARs to EudraVigilance, local CA and IEC 
The term SADR is used whenever either the Investigator or Medical Monitor deems a SAE as 
possibly or probably related to IMP. If an SADR is assessed as unexpected by the Medical 
Monitor, the event is regarded as a SUSAR and the certified EudraVigilance reporter will 
report the SUSAR to the CA, via the EudraVigilance database, and to the IEC in accordance 
with local regulations and CTC SOPs within the following timelines: 
• 7 calendar days if fatal or life-threatening (follow-up information within an additional 8 
days) 
• 15 calendar days if non-fatal and non-life-threatening (follow-up information as soon 
as possible) 

 
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The clock for expedited initial reporting (Day 0) starts as soon as the Sponsor becomes aware 
of an SAE. The date should be documented on an acknowledgement receipt. 
The Medical Monitor is responsible for medical review of the SAE narrative in the Council 
for International Organisations of Medical Sciences (CIOMS) for (or equivalent) prior to 
expedited reporting. 
The Sponsor or delegate is responsible for informing the Investigators concerned of relevant 
information about SUSARs that could adversely affect the safety of subjects.  
The Sponsor or delegate is responsible for once a year throughout the clinical study (or on 
request), submitting a safety report to the CA and the IEC taking into account all new 
available safety information received during the reporting period. 
11.4.1.15 Treatment and follow-up of adverse events 
Subjects with AEs that occur during the study must be treated according to daily clinical 
practice at the discretion of the Investigator. 
AEs must be followed up until resolution or to the end-of-study visit, whichever comes first. 
At the end-of-study visit, information on new AEs, if any, and stop dates for previously 
reported AEs must be recorded (if known). AEs assessed as stable by the Investigator at the 
end-of-study visit will not have to be followed up until resolution. 
It is the responsibility of the Investigator to follow up on all SAEs until the subject has 
recovered, stabilised, or recovered with sequelae, and to report to the Sponsor all relevant new 
information using the same procedures and timelines as those for the initial report. Relevant 
information includes discharge summaries, autopsy reports, and medical consultation. 
11.4.1.16 Procedures in case of pregnancy 
In case of pregnancy or suspicion of possible pregnancy of a female subject, the study 
treatment of that subject must be stopped immediately, and the subject discontinued from 
participation in the study. Pregnancy itself is not regarded as an AE unless there is a suspicion 
that the IMP may have interfered with the effectiveness of the contraceptive medication. 
However, the outcome of all pregnancies (spontaneous abortion, induced abortion, normal 
birth or congenital abnormality) must be followed up and documented even after the subject 
was discontinued from the study. The outcome of all pregnancies of a female partner to a 
male subject must also be followed up and documented, yet the male subject does not need to 
be discontinued from the study.  
All events of congenital abnormalities/birth defects are SAEs. Spontaneous abortions should 
also be reported and handled as AEs. All outcomes of pregnancy must be reported to the 
Sponsor and the Principal Investigator on the pregnancy outcomes report form. 
11.4.1.17 Treatment of overdose 
An overdose is a dose in excess of the dose specified for each cohort in this CSP.   
Over-dosing is not likely to occur in this study since all IMP will be administered by site 
personnel under medical surveillance. In cases of accidental overdose, standard supportive 
measures should be adopted as required. 

 
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An overdose should be documented as follows:  
• An overdose with associated AE is recorded as the AE diagnosis/symptoms in the AE 
Log of the eCRF.  
• 
An overdose without associated symptoms is only reported in the subject’s medical 
records. 
No known antidote is available.  
 
Physical examination 
11.4.2.1 Full physical examination 
A complete physical examination will include assessments of the head, eyes, ears, nose, 
throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph 
nodes and extremities. 
The result of the examination will be documented in the eCRF as normal, abnormal not 
clinically significant (NCS) or abnormal clinically significant (CS). Post-dose physical 
examination judged as abnormal CS will be reported as AE. 
For timing of the assessments, refer to Table 8.1-1 and Table 8.1-2.  
11.4.2.2 Brief physical examination 
A short version of physical examination will include an assessment of selected body systems 
at the judgement of the Investigator but will at least include cardiovascular, lung and 
abdomen.  
The result of the examination will be documented in the eCRF as normal, abnormal NCS or 
abnormal CS. Post-dose physical examination judged as abnormal CS will be reported as AE. 
For timing of the assessments, refer to Table 8.1-1 and Table 8.1-2.  
 
Vital signs 
Systolic and diastolic blood pressure (BP) and pulse will be measured in supine position after 
10 minutes of rest.  
Vital signs will be judged as normal, abnormal NCS or abnormal CS. The assessment will be 
recorded in the eCRF. Post-dose vital signs judged as abnormal CS will be reported as AEs.  
For timing of the assessments, refer to Table 8.1-1 and Table 8.1-2.  
 
Body temperature 
Body temperature will be measured orally using a digital thermometer, and will be judged as 
normal, abnormal NCS or abnormal CS. 
For timing of the assessments, refer to Table 8.1-1 and Table 8.1-2.  

 
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Resting 12-lead ECG 
Single 12-lead ECG will be recorded in supine position after 10 minutes of rest using an ECG 
machine. HR and PR, QRS, QT and QTcF intervals will be recorded.  
Safety ECGs will be reviewed and interpreted on-site by the Investigator. 
Any abnormalities will be specified and documented in the eCRF as NCS or CS. Abnormal 
post-dose findings assessed by the Investigator as CS will be reported as AEs.   
For timing of the assessments, refer to Table 8.1-1 and Table 8.1-2.  
 
 Laboratory safety assessments 
Blood samples for analysis of clinical chemistry and haematology parameters will be 
collected through venepuncture or an indwelling venous catheter and sent to the certified 
clinical chemistry laboratory at Uppsala University Hospital and analysed by routine 
analytical methods.  
Urine analysis will be performed at the research clinic using dip sticks. The assessments will 
be performed at visits specified in Table 8.1-1. 
Urine pregnancy tests will be performed at visits specified in Table 8.1-1. 
The safety laboratory parameters are defined in Table 11.4-1 and will be assessed at 
timepoints detailed in Table 8.1-1. 
Safety laboratory parameters will be judged as normal, abnormal NCS or abnormal CS. 
Abnormal values assessed by the Investigator as CS will be reported as AEs. If an abnormal 
value is associated with corresponding clinical signs or symptoms, the sign/symptom should 
be reported as the AE. 

 
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Table 11.4-1 Safety laboratory parameters 
Category 
Parameter 
Clinical chemistry 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Bilirubin (total and conjugated) 
C-reactive protein (CRP) 
Calcium 
Creatinine 
Cystatin C 
Glucose 
Potassium 
Sodium 
Urea 
Haematology 
Haematocrit 
Haemoglobin (Hb) 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count with differential count 
Urinalysis (dip stick) 
Bilirubin  
Erythrocytes 
Glucose 
Ketones 
Leucocytes 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
FSH-test2  
FSH 
Pregnancy test3  
Serum pregnancy test at screening 
Urine pregnancy test 
1 At screening only 
2 At screening, post-menopausal females only.  
3 Females only. 
11.5 
Appropriateness of measurements 
All methods used for safety assessments are commonly used in standard medical care and in 
Phase I clinical studies. Non-compartmental analysis (NCA) of PK parameters is standard for 
Phase I clinical studies. 

 
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12 
PROCEDURES FOR BIOLOGICAL SAMPLES 
12.1 
Sample collection  
The sample collection procedure for PK analysis is described in Section 11.3.1. 
Safety laboratory samples are collected according to standard procedures. 
12.2 
Volume of blood 
The estimated volume of blood to be collected from each subject during the study will be 
approximately 300 mL in Part I and Part II together. The anticipated volume of blood samples 
collected during the study from each subject will not exceed 450 mL (i.e., less than the 
volume drawn during a regular blood donation). 
12.3 
Handling, storage and destruction of laboratory samples 
All biological samples will be registered in a biobank at CTC (893).  
Any remains from the safety laboratory samples will be disposed of after analyses.  
The samples for analyses of PK parameters will be stored at <-70°C until analysed. The 
samples will be disposed of after the CSR has been finalised. 
12.4 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.  
CTC keeps full traceability of collected biological samples from the subjects while in storage 
at the research clinic until shipment and keeps documentation of receipt of arrival.  
The sample receiver (the analytical laboratory) keeps full traceability of the samples while in 
their storage and during use until used or disposed of.  
The Sponsor keeps oversight of the entire life cycle through internal procedures, monitoring 
of study sites and auditing of external laboratory providers.  
12.5 
Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent to the use of biological samples donated, the samples will be 
disposed of /destroyed, if not already analysed and documented.  
The Principal Investigator will ensure that:  
• Subject withdrawal of informed consent is notified immediately to Sponsor.  
• Biological samples from the subject, if stored at the research clinic, are immediately 
identified, disposed of/destroyed and the action is documented.  

 
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The Sponsor has to ensure that the laboratory(ies) holding the samples is/are informed about 
the withdrawn consent immediately and that samples are disposed of/destroyed or returned to 
the research clinic and the action is documented. 

 
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13 
QUALITY MANAGEMENT, QUALITY ASSURANCE AND QUALITY 
CONTROL 
13.1 
Quality management: critical process, system and data identification 
During CSP development, the Sponsor will identify those processes, systems (facilities, 
computerised systems) and data that are critical to ensure human subject protection and the 
reliability of trial results according to applicable SOPs and International Council for 
Harmonisation (ICH) E6 R2. 
Identified risks will be categorised separately from the CSP. 
13.2 
Quality assurance and quality control 
The Sponsor is responsible for implementing and maintaining quality assurance (QA) and 
quality control (QC) systems with written SOPs with regards to management of identified 
risks, CSP compliance, good clinical practice (GCP) compliance and applicable regulatory 
requirements.  
The Sponsor is responsible for securing agreements with involved subcontractors and to 
perform regular subcontractor oversight to ensure CSP compliance, GCP compliance and 
compliance with applicable regulatory requirements.  
The Sponsor is responsible for implementing a risk-based validated electronic data capture 
system and maintain SOPs for the whole life cycle of the system.  
QC should be applied to each stage of data handling to ensure that all data are reliable and 
have been processed correctly. 
The Sponsor has delegated the responsibilities outlined above to CTC whilst maintaining 
overall study oversight. 

 
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14 
ETHICAL AND REGULATORY REQUIREMENTS  
14.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki [19] and are consistent with ICH GCP E6 (R2), EU Clinical Trials 
Directive, and applicable local regulatory requirements. 
14.2 
Ethics and regulatory review 
The Principal Investigator is responsible for submission of the CSP, the subject information 
and ICF, any other written information to be provided to the subjects and any advertisements 
used for recruitment of subjects to applicable IEC for approval.  
The Sponsor has delegated to CTC the responsibility to submit study documents to the 
applicable CA according to local regulatory requirements. 
Approval must be obtained in writing from both IEC and CA before the first subject can be 
recruited. 
The Sponsor will provide the CA, IEC and Principal Investigators with safety updates/reports 
according to local requirements. Progress reports and notifications of SUSARs will be 
provided to the IEC according to local regulations and guidelines. 
14.3 
Subject information and consent 
It is the responsibility of the Investigator or an authorised associate to give each potential 
study subject adequate verbal and written information before any study specific assessments 
are performed. 
The information will include the objectives and the procedures of the study as well as any 
risks or inconvenience involved. It will be emphasised that participation in the study is 
voluntary and that the subject may withdraw from participation at any time and for any 
reason, without any prejudice. All subjects will be given the opportunity to ask questions 
about the study and will be given sufficient time to consider participation before signing the 
ICF. 
Before performing any study-related procedures the ICF must be signed and personally dated 
by the subject and by the Investigator. A copy of the subject information including the signed 
ICF will be provided to the subject. 
Documentation of the discussion and the date of informed consent must be recorded in the 
source documentation and in the eCRF. The subject information sheet and the signed ICF 
should be filed by the Investigator for possible future audits and/or inspections.  
The final approved version of the subject information and ICF must not be changed without 
approval from the Sponsor and the applicable IEC.  

 
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14.4 
Subject information card  
The subject will be provided with a Subject information card including the following 
information:  
• That he/she is participating in a clinical study 
• Subject study ID  
• That he/she is treated with the IMP 
• The name and phone number of the Investigator  
• Name and address of the Sponsor 
14.5 
Subject data protection 
The ICF includes information that data will be recorded, collected and processed and may be 
transferred to European Economic Area (EEA) or non-EEA countries. In accordance with the 
European Union Data Protection Directive (95/46/EC) and General Data Protection 
Regulation (GDPR), the data will not identify any persons taking part in the study. 
The potential study subject should be informed that by signing the ICF he/she approves that 
authorised representatives from Sponsor and CTC, the concerned IEC and CA have direct 
access to his/her medical records for verification of clinical study procedures. For further 
details on the subject information and ICF process, refer to Section 14.3. 
The subject has the right to request access to his/her personal data and the right to request 
rectification of any data that is not correct and/or complete in accordance with the European 
Union Data Protection Directive (95/46/EC) and the request will be raised to the Principal 
Investigator.  
The Investigator must file a Subject Identification List which includes sufficient information 
to link records, i.e. the eCRF and clinical records. This list should be preserved for possible 
future inspections/audits but must not be made available to the Sponsor except for monitoring 
or auditing purposes. 
Personal data that are collected in the study such as health information and ethnicity are 
considered as sensitive personal data. This data will be pseudoanonymised, i.e. personally 
identifiable information (PII) will be removed and replaced by a unique subject ID and will be 
processed by the Sponsor and other involved parties during the study. After the study end, 
only anonymised data, i.e. aggregated data sets, can be used.  
For this study, the Sponsor Gesynta AB is the data controller of all data processed during the 
study (e.g. Trial Master File [TMF], study reports) and CTC AB is the data processor. Any 
subcontractors used in the study are also data processors.  
For data that are processed at the clinic(s) (e.g. medical records and ISF), CTC AB is the data 
controller.  

 
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14.6 
Changes to the approved clinical study protocol  
Any proposed change to the approved final CSP (including appendices) will be documented 
in a written and numbered clinical protocol amendment. All substantial amendments to the 
protocol must be approved by the appropriate IEC and/or CA before implementation 
according to applicable regulations. 
14.7 
Audits and inspections 
Authorised representatives of Sponsor, a CA, or an IEC may perform audits or inspections at 
the research clinic, including source data verification (SDV). The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, ICH-GCP guidelines and any 
applicable regulatory requirements. The Investigator will contact the Sponsor immediately if 
contacted by a CA about an inspection at the centre. 
14.8 
Insurance 
Subjects will be covered under Gesynta Pharma AB’s liability insurance policy through the 
Swedish Pharmaceutical Insurance (Läkemedelsförsäkringen). The certificate of insurance 
and an information leaflet containing essential information about the insurance coverage can 
be provided upon request. The participating subjects are also protected in accordance with 
national regulations, as applicable. CTC has a company insurance covering services 
performed by CTC. 

 
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15 
STUDY MANAGEMENT 
15.1 
Training of study site personnel 
Before enrolment of the first study subject a Sponsor representative or delegate will perform a 
study initiation visit at the research clinic. The requirements of the CSP and related 
documents will be reviewed and discussed and the investigational staff will be trained in any 
study specific procedures and system(s) utilised. 
It is the responsibility of the Investigator to ensure that all personnel involved in the study are 
fully informed of all relevant aspects of the study and have a detailed knowledge of and 
training in the procedures that are to be executed by them. Any new information of relevance 
to the performance of this study must be forwarded to the staff involved in a timely manner. 
The Investigator will keep a list of all personnel involved in the study together with their 
function and study related duties delegated. A Curriculum Vitae will be available for all staff 
to whom study-specific duties are delegated.  
15.2 
Clinical monitoring  
The Sponsor is responsible for securing agreement from all involved parties to ensure direct 
access to all study related sites, source data/documents, and reports for the purpose of 
monitoring and auditing by the Sponsor, and inspection by domestic and foreign regulatory 
authorities.  
As defined in the risk-based monitoring (RBM) plan, approved by the Sponsor and provided 
separately, the responsible Monitor will periodically visit the study site at times agreed upon 
by the Investigator and the Monitor. At the time of each monitoring visit, the role of the 
Monitor is (but not limited to) to:  
• provide information and support to the investigational team. 
• confirm that facilities and resources remain acceptable. 
• confirm that the investigational team is adhering to the CSP, applicable SOPs, 
guidelines, manuals and regulatory requirements.  
• verify that data are being accurately and timely recorded in the CRFs and that IMP 
accountability checks are being performed. 
• verify that data in the eCRF are consistent with the clinical records (SDV) in 
accordance with the RBM plan.  
• verify that the correct informed consent procedure has been adhered to for participating 
subjects.  
• ensure that withdrawal of informed consent to the use of the subject’s biological 
samples will be reported and biological samples are identified and disposed 
of/destructed accordingly, and that this action is documented and reported to the 
subject. 
• verify that AEs are recorded and reported in a timely manner and according to the CSP. 

 
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• raise and escalate any serious quality issues, serious GCP breach and any data privacy 
breach to the Sponsor.  
Centralised monitoring will also be performed continuously by study team members at CTC 
in accordance with the RBM plan.  
When the study has been completed and all queries have been resolved and the database has 
been locked, the Monitor will perform a close-out visit. 
15.3 
Source data documents 
A separate Origin of Source Data List will be generated for each site before start of 
enrolment, specifying the location of the source of derived information appearing in the CRF. 
This document must be signed by the Principal Investigator and the Monitor to confirm 
agreement before start of recruitment. 
Source documents are all documents used by the Investigator or hospital that relate to the 
subject’s medical history, that verifies the existence of the subject, the inclusion and exclusion 
criteria, and all records covering the subject’s participation in the trial. They include 
laboratory notes, memoranda, material dispensing records, subject files, etc. The eCRF may 
constitute source data if clearly defined in the Origin of Source Data List.  
The Investigator should guarantee access to source documents to the Monitor, CAs and the 
IECs, if required. 
15.4 
Study agreements 
The Principal Investigator must comply with all the terms, conditions, and obligations of the 
Clinical Study Agreement for this study. 
Agreements between Sponsor and CTC must be in place before any study-related procedures 
can take place, or subjects be enrolled. 
15.5 
Study timetable and end of study 
The study is expected to start in and be completed by Q2 2020. 
A subject considered to have completed the study if he/she has completed all visits in the 
study including the End-of-Study visit. 
The end of the clinical part of the study is defined as the last visit of the last subject 
participating in the study. 
15.6 
Termination of the study 
The Investigator or the Sponsor may terminate this study prematurely for any reasonable 
cause. The IEC and CA should be informed promptly. Conditions that may warrant study 
termination include, but are not limited to: 

 
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• The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study or potential study subjects; or 
• A decision by the Sponsor to suspend or discontinue development of the IMP. 
• If the CA obtains information that raises doubts about the safety or scientific validity 
of the clinical study, the CA can suspend or prohibit the study. Before the CA reaches 
its decision, it shall, except where there is imminent risk, ask the Sponsor and/or the 
Investigator for their opinion, to be delivered within one week (Directive 2001/20/EC, 
Article 12, Section 1).  
If the study is prematurely terminated or suspended for any reason, the Investigator/institution 
should promptly inform the study subjects and should assure appropriate follow-up for the 
subjects. 
15.7 
Reporting and publication 
 
Clinical study report  
A summarising report must be submitted to the applicable CA and IEC within 12 months after 
completion of the study (in accordance with LVFS 2011:19, Chapter 9). 
A CSR, in compliance with ICH-E3, describing the conduct of the study, any statistical 
analyses performed and the results obtained, will be prepared by CTC AB. The report will be 
reviewed and approved by, as a minimum, the Principal Investigator, the Statistician and the 
Sponsor. The study results will be reported in the EudraCT database per applicable 
regulations within 12 months after completion of the study. 
 
Annual safety report 
If the study duration exceeds one year, the Sponsor must submit development safety update 
report (DSUR) to the CA and to the IEC. The report shall summarise all pertinent safety 
information collected during the reporting period and contain an update of the risk-benefit 
evaluation if there has been any change since the approval of the clinical study. 
 
Confidentiality and ownership of study data 
Any confidential information relating to the IMP or the study, including any data and results 
from the study, will be the exclusive property of the Sponsor. The Investigator and any other 
persons involved in the study are responsible for protecting the confidentiality of this 
proprietary information belonging to the Sponsor.   
 
Publication 
The results from this study may be submitted for publication at the discretion of the Sponsor.  
15.8 
Archiving  
The Principal Investigator is responsible for maintaining essential documents, (as defined in 
ICH E6 GCP, Section 8) for 10 years after finalisation of the CSR. This includes any original 

 
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source documents related to the study, the Subject Identification List (providing the sole link 
between named subject source records and anonymous eCRF data), the original signed ICFs 
and detailed records of disposition of IMP.  
It is the responsibility of the Sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained. 
The Sponsor will archive the TMF in accordance with ICH E6 GCP, Section 8 and applicable 
regulatory requirements. 
The data from the eCRFs will be sent to the Sponsor and a copy will be sent to the clinic and 
filed in the ISF for archiving for 10 years after finalisation of the CSR. 
The completed eCRFs are the sole property of the Sponsor and should not be made available 
in any form to third parties, except for authorised representatives of appropriate 
Health/Regulatory Authorities, without written permission from the Sponsor.  

 
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16 
DATA MANAGEMENT 
The data management routines include procedures for handling of the eCRF, database set-up 
and management, data entry and verification, data validation, QC of the database, and 
documentation of the performed activities including information of discrepancies in the 
process. The database, data entry screens, and program will be designed in accordance with 
the CSP. 
Data validation/data cleaning procedures are designed to assure validity and accuracy of 
clinical data. These procedures consist of computerised online edit checks identifying e.g. 
data values that are outside the allowed range and SAS-programmed batch checks on data 
exports. All study-specific and standard data validation programming will be tested in a 
separate testing environment prior to use on production data. 
Detailed information on data management will be described in a study-specific Data 
Management Plan (DMP). 
16.1 
The web-based eCRF 
Clinical data will be entered into a 21 CFR Part 11-compliant eCRF (Viedoc™) provided by 
PCG Solutions AB. The eCRF includes password protection and internal quality checks, such 
as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents or at bedside (if the eCRF 
data constitutes source data). Source data are to be defined at the site before inclusion of the 
first subject (Section 15.3). 
Authorised site personnel designated by the Investigator will complete data collection. 
Appropriate training and security measures will be completed with the Investigator and all 
authorised trial site personnel prior to the trial being initiated and any data being entered into 
the system for any study subject. 
16.2 
The entering of data into the eCRF 
All entries, corrections, and alterations are to be made by the Investigator or designee. Neither 
the Monitor nor any other study team member besides site staff can enter data in the eCRF. 
All data should be entered in English. The eCRFs should be completed as soon as possible 
during or after the subject’s visit. The Investigator must verify that all data entries in the 
eCRFs are accurate and correct. If some assessments are not done, or if certain information is 
not available, not applicable or unknown, the Investigator or assigned clinical staff should 
record such information in the eCRF. The Investigator will be required to electronically sign 
off the clinical data. This will be performed by means of the Investigator’s unique User ID 
and password; date and time stamps will be added automatically at time of electronic 
signature. 
16.3 
The query process 
The Monitor will review the eCRFs and evaluate them for completeness and consistency. 
Data in the eCRF will be compared with the respective source documents to ensure that there 

 
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are no discrepancies for critical data as described in the RBM plan. All entries, corrections, 
and alterations are to be made by the Investigator or designee. Neither the Monitor nor any 
other study team member besides site staff can enter data in the eCRF.  
If corrections are needed, queries will be raised within the eCRF, either as a result of built-in 
edit checks or manually raised by the monitor. An appropriate member of the site staff will 
answer the queries in the eCRF either by correcting the data or by entering a response to the 
query. The monitor will either approve the answer/correction or re-issue the query. 
16.4 
Audit trail 
All entries in the eCRF will be fully recorded in a protected audit trail. Once clinical data 
have been saved, corrections to the data fields will be audit trailed, meaning that the reason 
for change, the name of the person who made the change, together with time and date will be 
logged. 
16.5 
External data 
External data consists of data that are not recorded in the eCRF. Data may be received in 
electronic format or as a paper printout. Key variables are defined in order to uniquely 
identify each sample record. File and data formats are agreed with the external data provider.  
16.6 
Medical coding 
Medical coding will be performed by trained personnel at CTC. AEs and medical/surgical 
history verbatim terms will be coded using the Medical Dictionary of Regulatory Activities 
(MedDRA; latest version available at start of coding). Prior and concomitant medications will 
be coded according to the World Health Organisation (WHO) Anatomic Therapeutic 
Chemical (ATC) classification system. All coding will be approved by Sponsor prior to 
database lock. 
16.7 
Database lock 
When all data have been entered and discrepancies solved, clean file will be declared, the 
database will be locked and the data will be analysed.  

 
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17 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE  
The principal features of the statistical analysis to be performed are described in this section. 
A more technical and detailed elaboration of the principal features will be presented in a 
separate Statistical Analysis Plan (SAP), which will be signed and approved prior to database 
lock. 
Analyses of the primary and secondary endpoints will be performed by CTC. 
17.1 
General 
Continuous data will be presented in terms of evaluable and missing observations, arithmetic 
mean, standard deviation (SD), median, minimum and maximum value. In addition, for the 
parameters AUC and Cmax the geometric mean and coefficient of variation (CV) will be 
presented.  
Categorical data will be presented as counts and percentages. When applicable, summary data 
will be presented by treatment, and by assessment time. Individual subject data will be listed 
by subject number, treatment, and, where applicable, by assessment time. 
All descriptive summaries and statistical analyses will be performed using SAS Version 9.4 or 
later (SAS Institute, Inc., Cary, NC). 
Baseline will be defined as the last data collection point prior to each administration of IMP. 
All hypothesis testing will use a significance level of 5%.  
No imputation of missing data will be performed. 
17.2 
Determination of sample size 
No formal sample size calculation has been performed for this study. The proposed sample 
size is considered sufficient to provide adequate information for the study objectives. 
Approximately 14 subjects will be dosed to achieve a total of at least 12 evaluable subjects 
that completed the study. Subjects will be evaluable for safety analysis after receiving 1 dose 
of the study drug.  
17.3 
Analysis data sets 
 
Safety analysis set 
The Safety Analysis Set will consist of all subjects who received at least one dose of the IMP.  
 
PK analysis set - formulation:  
The PK analysis set – formulation will consist of all subjects who received a single dose of 
both Formulation A and Formulation B, from whom PK blood samples were collected after 
IMP dosing, and for whom there were no AEs or protocol deviations judged to affect the 
analysis of the data.  

 
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PK analysis set – food interaction:  
The PK analysis set – food interaction will consist of all subjects who received all three IMP 
doses, from whom PK blood samples were collected after IMP dosing, and for whom there 
were no AEs or protocol deviations judged to affect the analysis of the data.  
17.4 
Description of study population 
 
Demographics and baseline characteristics 
Descriptive statistics for demographics, weight and height will be presented. 
 
Medical/surgical history and prior/concomitant medication 
Medical/surgical history will be presented by system organ class (SOC) and preferred term 
(PT). Prior/concomitant medications will be presented by ATC level 1, 3 and 5 as applicable. 
All data will be listed by subject.  
 
Treatment compliance 
The number of subjects treated in each treatment period and their individual dose will be 
listed. 
17.5 
Analysis of primary endpoints 
 
Analysis of pharmacokinetics  
The PK analysis will be based on the PK analysis set and performed by CTC. The PK 
parameters will be calculated by NCA using the software Phoenix WinNonlin® version 8.1 or 
later (Certara, U.S.A.).  
The NCA PK parameters to be assessed include, but are not limited to: 
• AUC0-inf 
• AUC0-last  
• Cmax 
• Tmax 
• T½(z) 
• CL/F 
• Vz/F  
• Relative bioavailability for Formulation A versus B and for one of the two 
formulations in fed versus fasting conditions. 
• Comparisons of all relevant PK parameters (e.g., AUC, Tmax, Cmax) for Formulation A 
versus B and for one of the two formulations in fed versus fasting conditions.  

 
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Summary statistics for the PK parameters will be presented with number of measurements, 
arithmetic mean, SD, CV, median, minimum, maximum, geometric mean, geometric CV%, 
except for Tmax for which only median, minimum and maximum will be presented. 
The relative bioavailability of GS-248 will be analysed with a 90% confidence interval for the 
ratio of Formulation A and B, and for the ratio of the selected formulation in fed and fasting 
conditions using a mixed model approach with treatment, period and subject in the model.  
Further details will be specified in the SAP. 
All data will be listed by subject. 
17.6 
Analysis of secondary endpoints 
 
Adverse events  
An overview of all AEs, including SAEs, intensity, relationship to IMP, and deaths will be 
presented by SOC and PT. 
Incidence of AEs and SAEs will be summarised by SOC and PT.   
All AE data will be listed subject and include the verbatim term entered by the Investigator. 
 
Physical examination 
Clinically significant and non-clinically significant abnormal findings will be specified and 
presented by subject and summarised. 
Changes over time will be presented using shift tables, if considered applicable.  
All data will be listed by subject. 
 
Vital signs 
Vital signs (systolic/diastolic BP, pulse) will be summarised. Data will be presented with 
absolute and percent change from baseline at each visit. Clinical evaluation of vital signs will 
be summarised in frequency tables.  
All data will be listed by subject. 
 
Body temperature 
Body temperature will be summarised. Data will be presented with absolute and percent 
change from baseline at each visit.  
All data will be listed by subject. 
 
Resting 12-lead ECG 
All ECGs will be categorised as ”normal”, ”abnormal, not clinically significant”, or 
”abnormal, clinically significant” (as judged by the Investigator) and summarised using 
frequency tables.  
Changes over time will be presented using shift tables, if considered applicable. 

 
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All data will be listed by subject. 
 
Laboratory safety assessments 
Safety laboratory data will be summarised with absolute and percent change from baseline at 
each visit. 
Abnormal, clinically significant values will be summarised separately if considered 
appropriate.  
All data will be listed by subject. 
 
 

 
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18 
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16. FDA Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical 
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