A Phase I, Placebo-controlled, Double-blind, First-in-human Study to Investigate Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GS-248 Solution in Healthy Subjects and Patients With Systemic Sclerosis (SSc)
Phase: PHASE1
Conditions: Healthy
Sponsor: Gesynta Pharma AB

 
 
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Clinical Study Protocol 
 
 
EudraCT No. 
2019-000815-98 
 
Investigational Medicinal Product 
GS-248 
 
Sponsor study code 
GS-1001 
 
CTC study code 
225-45-2018 
 
Protocol Version and Date 
Final Version 2.0, 29MAY2019 
 
 
A Phase I, placebo-controlled, double-blind, first-in-human study to 
investigate safety, tolerability, pharmacokinetics (PK) and 
pharmacodynamics (PD) of GS-248 solution in healthy subjects and patients 
with systemic sclerosis (SSc) 
 
Phase 
I, first-in-human (FIH) 
Indication 
Digital ulcers, Systemic sclerosis 
Test product  
GS-248 
Reference product  
Celecoxib  
Sponsor signatory 
Göran Tornling, MD, PhD, MSc 
Gesynta Pharma AB 
Fogdevreten 2 
SE-171 65 Solna, Sweden 
Principal Investigator 
Folke Sjöberg, MD, PhD, Professor 
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 
Uppsala University Hospital, 
Entrance. 85, 2nd level  
SE-751 85 Uppsala, Sweden 
CTC Clinical Trial Consultants AB 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
 
 
 

 
 
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1 
STUDY SYNOPSIS 
Study title 
A Phase I, placebo-controlled, double-blind, first-in-human (FIH) study to investigate safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of GS-248 solution in healthy 
subjects and patients with systemic sclerosis (SSc) 
Study code 
GS-1001 
EudraCT No 
2019-000815-98 
Planned study period 
Q2 2019 to Q2 2020 
Phase of development 
I, FIH 
Principal Investigator  
Folke Sjöberg, MD, PhD, Professor 
CTC Clinical Trial Consultants AB 
Uppsala University Hospital, 
Entrance. 85, 2nd level  
SE-751 85 Uppsala, Sweden 
Study design 
This is a FIH, double-blind, parallel-group, randomised, placebo-controlled study designed to 
evaluate the safety, tolerability, PK and PD of single and multiple ascending oral doses of GS-248 in 
healthy subjects and in patients with SSc. In addition, an exploratory comparison of the PD effects 
between celecoxib and GS-248 will be performed.  
The study will be conducted in 4 parts: 
Part I (single ascending dose [SAD]): safety, tolerability, PK and PD of single ascending oral doses 
of GS-248 in healthy male and female subjects.  
Part II (multiple ascending dose [MAD]): safety, tolerability, PK and PD of multiple ascending oral 
doses of GS-248 in healthy male and female subjects during 10 days administration. 
Part III (SSc patients): safety, tolerability, PK and PD of multiple oral doses of GS-248 in patients 
with SSc during 10 days administration. 
Part IV (celecoxib): PD of multiple oral doses of celecoxib (200 mg BID) in healthy males and 
females during 10 days administration.  
Objectives  
Primary objective 
• 
To determine the safety and tolerability following oral single and multiple ascending doses of 
GS-248 (solution) in healthy subjects and patients with SSc  
Secondary objectives  
• 
To evaluate the PK of GS-248 in healthy subjects and patients with SSc 
Exploratory objectives 
• 
To evaluate the PD effects of GS-248 and celecoxib by determination of microsomal 
Prostaglandin E synthase-1 (mPGES-1) activity (Prostaglandin E2 [PGE2] levels) in a whole 
blood assay (WBA) 

 
 
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• 
To explore the PD effects of GS-248 in plasma (asymmetric dimethylarginine [ADMA]) and 
urine (arachidonic acid [AA] metabolites) and additional exploratory inflammatory 
biomarkers in healthy subjects and patients with SSc 
• 
To explore the PD effects of celecoxib in plasma (ADMA) and urine (AA metabolites) and 
additional exploratory inflammatory biomarkers in healthy subjects after 10 days twice daily 
dosing to enable exploratory comparisons with GS-248 treated subjects  
• 
To explore potential metabolites of GS-248 in plasma and urine (including metabolites in 
safety testing [MIST]) 
Endpoints 
Primary endpoints  
• 
Frequency, severity and seriousness of adverse events (AEs) 
• 
Clinically significant changes in: 
o 12-lead electrocardiogram (ECG) 
o Vital signs 
o Safety laboratory parameters 
o Physical examinations   
Secondary endpoints  
• 
PK parameters: 
o Part I: area under the curve from time 0 to time t (AUC0-t), AUC from time 0 to 
infinity (AUC0-), terminal half-life (T½), maximum plasma concentration (Cmax), 
time to Cmax (Tmax), dose proportionality (based on AUC and Cmax), apparent total 
body clearance following extravascular administration (CL/F) and apparent volume 
of distribution following extravascular administration (Vz/F) 
o Part II and III after first dose interval: AUC0-t, T½, Tmax, Cmax, dose proportionality 
(based on AUC and Cmax)  
o Part II and III after last dose interval: AUC0-t, AUC at steady state (AUCss), T½, Tmax, 
Cmax, observed concentration at the end of a dosing interval, immediately before next 
administration (Ctrough from the 2 doses preceding the last dose), dose proportionality 
(based on AUCss and Cmax), CL/F, Vz/F and accumulation ratio 
Exploratory endpoints  
• 
Ex vivo determination of mPGES-1 activity (PGE2 levels) in a WBA  
• 
AA metabolites in urine captured pre-dose administration and during 24 h post-dose: 
o 11-alfa-hydroxy-9,15-dioxo-13,14-dihydro-2,3,4,5, tetranor-prostan-1,20-dioic acid 
(PGEM) 
o 2, 3-dinor-6-ketoprostaglandin F1α (PGIM) 
o 11-dehydro-thromboxane B2 (TXM) 
• 
ADMA in plasma  
• 
Collection of plasma and urine for future analysis of potential metabolites after single and 
multiple dosing with GS-248  

 
 
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• 
Plasma and urine samples will be saved for future biomarker analyses e.g. further AA 
metabolite profiling in plasma and urine and inflammatory biomarkers in plasma and urine 
The outcome of the WBA will be reported in the clinical study report (CSR) whereas the other 
exploratory endpoints may be reported separately from the CSR. 
Number of subjects/patients planned 
Part I (SAD): 48 subjects will be randomised and dosed (6 cohorts, each of 8 subjects with 6 subjects 
receiving GS-248 and 2 receiving placebo). 
Part II (MAD): 32 subjects will be randomised and dosed (4 cohorts, each of 8 subjects with 
6 subjects receiving GS-248 and 2 receiving placebo). 
Part III (SSc patients): 10 SSc patients will be randomised and dosed (1 cohort with 10 subjects of 
which 8 will receive GS-248 and 2 will receive placebo). 
Part IV (celecoxib): 8 subjects will be randomised and dosed (1 cohort with 8 subjects receiving 
celecoxib). 
If indicated by emerging data and recommended by the internal safety review committee (iSRC), 
2 additional cohorts (8+8 subjects) may be added to Part I, 1 cohort (8 subjects) may be added to 
Part II and 1 cohort (10 patients) may be added to Part III. 
Diagnosis and main eligibility criteria 
Part I (SAD), II (MAD) and IV (celecoxib):  
• 
Healthy male and female subjects aged 18-70 years inclusive (Part I) and 40-75 years 
inclusive (Part II and IV).  
• 
Has provided a signed informed consent and are considered eligible to participate in the 
study. 
• 
Body Mass Index (BMI) ≥ 19 and ≤ 30 kg/m2. 
• 
Agree to use sufficient contraception as defined in this clinical study protocol (CSP). 
• 
Females must not be pregnant, breast feeding or plan to be pregnant.  
• 
Use of corticosteroids (inhaled and systemic), non-steroidal anti-inflammatory drugs 
(NSAIDs including e.g. coxibs and aspirin), antacids, proton pump inhibitors (PPIs) or any 
medication that changes gastric pH is prohibited within 14 days of the first IMP 
administration until the end-of study visit of each part.  
Part IV (celecoxib) only: 
• 
Subjects with a history of salicylate hypersensitivity or NSAID hypersensitivity or subjects 
who have experienced asthma, urticaria or other allergic reactions after taking aspirin or other 
NSAIDs will be excluded from study participation. 
Part III (SSc patients):  
• 
Male and female SSc patients aged 40-75 years inclusive diagnosed according to the 
European League Against Rheumatism (EULAR)/American College of Rheumatology 
(ACR) criteria. Patients must not satisfy more than one set of ACR criteria for rheumatic 
disease. 
• 
SSc disease duration less than 60 months based on the time from the first non-Raynaud 
phenomenon manifestation.  
• 
Raynaud’s Phenomenon with a typical frequency of attacks during the winter months of on 
average 5 per week.  

 
 
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• 
Has provided a signed informed consent and are considered eligible to participate in the 
study. 
• 
Agree to use sufficient contraception as defined in this CSP. 
• 
Females must not be pregnant, breast feeding or plan to be pregnant.  
• 
Use of iloprost or corticosteroids (inhaled and systemic) or other immunosuppressive 
therapies including, but not restricted to cyclophosphamide, azathioprine, mycophenolic acid, 
methotrexate, or cyclosporine is prohibited within 4 weeks of the first IMP administration 
until the end-of study visit. 
• 
Use of NSAIDs (including e.g. coxibs and aspirin), antacids, PPIs or any medication that 
changes gastric pH is prohibited within 14 days of the first IMP administration until the end-
of study visit.  
Methodology 
Part I (SAD) 
In the SAD part of the study, single oral doses of GS-248 will be administered in 6 sequential cohorts, 
each of 8 subjects. Within each cohort, subjects will be randomised in a 3:1 ratio to receive either 
GS-248 (n=6) or placebo (n=2) in a blinded fashion. The proposed starting dose is 1 mg. Up to 
2 additional dose cohorts can be explored based on the safety, tolerability and PK of the drug if 
recommended by the iSRC. 
Subjects will come for 3 visits to the clinic. Screening (Visit 1) will take place from Day -28 to 
Day -1. At Visit 2, subjects will be admitted to the clinic on Day -1 and will remain at the clinic until 
Day 3 for single dose IMP administration, safety, PK and PD (PD from cohort 3) assessments. The 
subjects must fast for at least 10 h 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 first 2 subjects in each 
cohort will be dosed in a sentinel fashion; 1 subject will receive GS-248 and the other will receive 
placebo as randomised. The subjects will be carefully monitored by clinical staff during and after 
dosing. Vital signs and ECG will be checked at regular intervals. There is immediate access to 
equipment, qualified staff and an intensive care unit (ICU) in case of an acute emergency. To give 
sufficient time for observation of any reactions, there will be at least 24 h before dosing of the third 
and fourth subject, who will be dosed on the same day approximately 2 h apart. The remaining 
4 subjects will also be dosed 2 by 2, i.e. 2 subjects will be dosed on the same day approximately 2 h 
apart. A final end-of-study visit (Visit 3) will take place on Day 8 (±2 days) or after early withdrawal.  
In all cohorts, safety and PK will be assessed before and after dose. Exploratory blood sampling for 
WBA and potential future metabolite analysis will be performed before and after dose from cohort 3 
and onwards. 
Before initiating a new cohort, all subjects in the previous cohort must have been treated and 48 h 
safety, tolerability and PK data for all treated subjects must have been evaluated by the iSRC. Once 
Day 3 safety, tolerability and PK data for the last subject in each cohort has been collected, there will 
be at least 1week between dose escalations.  
Part II (MAD) 
Part II of the study will explore multiple ascending dosing of GS-248. The initial dose, dose 
escalation and dosing schedule will be based on emerging knowledge of safety, tolerability and PK of 
GS-248 observed in the SAD part of the study (Part I). The proposed starting dose is 25 mg/day. 
GS-248 is planned to be administered once daily for 10 days. Each dose level during the MAD part 
will be selected such that the predicted maximum exposure will not exceed the maximum exposure 
(based on AUC and Cmax) in previously evaluated SAD cohorts. The starting dose, subsequent dose 
levels and time points and visits for PK sampling may be adjusted based on safety and PK evaluation 
in the SAD and MAD part.  

 
 
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GS-248 will be administered in 4 sequential cohorts, each of 8 subjects. Within each cohort, subjects 
will be randomised in a 3:1 ratio to receive GS-248 (n=6) or placebo (n=2) in a blinded fashion. Up to 
1 additional dose cohort can be explored based on the safety, tolerability and PK of the drug if 
recommended by the iSRC.   
Subjects will come for 9 visits to the clinic. Screening (Visit 1) will take place from Day -28 to 
Day -2. At Visit 2, subjects will be admitted to the clinic in the morning of Day -1 for pre-dose 
assessments including a 24 h baseline urine collection and will remain at the clinic until Day 3 for 
IMP administration and safety, PK and PD assessments. Up to 4 subjects will be dosed on the same 
day. There will be at least 30 minutes between the dosing of each subject. The subjects will be 
carefully monitored by clinical staff during and after dosing. Vital signs and ECG will be checked at 
regular intervals. There is immediate access to equipment, qualified staff and an ICU in case of an 
acute emergency.  
Outpatient visits for IMP administration, safety and PK assessments are planned for Day 4 to Day 8. 
(Visit 3 to Visit 7). On Day 9 (Visit 8), subjects will come to the unit in the morning for IMP 
administration and PK sampling and will return again in the evening for admission. For practical 
reasons, and if preferred by the subject, he or she may remain at the clinic during the whole Day 9. 
Subjects will be admitted to the clinic between Day 9 and Day 12 (Visit 8) for IMP administration, 
safety, PK and exploratory PD assessments. The last dosing day is Day 10. Urine collection for 
exploratory PD analysis will be performed during 24 h after the last dose. A final end-of-study visit 
(Visit 9) is planned to take place on Day 19 (±2 days) or after early withdrawal. 
Before initiating a new cohort, all subjects in the previous cohort must have been treated and 11 days 
safety, tolerability and PK data (i.e. data up to and including 24 h post last dose) for all treated 
subjects must have been evaluated by the iSRC. Once Day 11 safety, tolerability and PK data for the 
last subject in each cohort has been collected, there will be at least 1 week between dose escalations. 
Part III (SSc patients) 
Part III of the study will explore multiple dosing of GS-248 in SSc patients with Raynaud’s 
Phenomenon. The dose will be based on emerging knowledge of safety, tolerability and PK of GS-
248 observed in the preceding SAD and MAD parts of the study (Part I and II).  
GS-248 is planned to be administered once daily for 10 days. The dose level in part III will be 
selected such that the predicted maximum exposure will not exceed the maximum exposure (based on 
AUC and Cmax) in previously evaluated cohorts in healthy volunteers (Part I and Part II). The dose 
and time points and visits for PK sampling may be adjusted based on PK evaluation in the SAD and 
MAD parts.  
Ten SSc patients will be included in Part III of the study. The patients will be randomised in a 4:1 
ratio to receive GS-248 (n=8) or placebo (n=2) in a blinded fashion. One additional cohort may be 
added as needed to test e.g. additional doses or dosing schemes.   
Patients will come for 9 visits to the clinic. Screening (Visit 1) will take place from Day -42 to 
Day -2. At Visit 2, patients will be admitted to the clinic in the morning of Day -1 for pre-dose 
assessments including a 24 h baseline urine collection and will remain at the clinic until Day 3 for 
IMP administration and safety, PK and PD assessments. Up to 2 subjects will be dosed on the same 
day. The patients will be carefully monitored by clinical staff during and after dosing. Vital signs and 
ECG will be checked at regular intervals. There is access to equipment, qualified staff and an ICU in 
case of an acute emergency.  
Outpatient visits for IMP administration, safety and PK assessments are planned for Day 4 to Day 8 
(Visit 3 to Visit 7). On Day 9 (Visit 8), patients will come to the unit in the morning for IMP 
administration and PK sampling and will return again in the evening for admission. For practical 
reasons, and if preferred by the patient, he or she may remain at the clinic during the whole Day 9. 
Subjects will be residential at the clinic between Day 9 and Day 12 (Visit 8) for IMP administration, 

 
 
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safety, PK and exploratory PD assessments. The last dosing day is Day 10. Urine collection for 
exploratory PD analysis will be performed during 24 h after the last dose. A final end-of-study visit 
(Visit 9) is planned to take place on Day 19 (±2 days) or after early withdrawal. 
Part IV (celecoxib) 
In Part IV of the study, 200 mg celecoxib will be administered to 8 healthy volunteers twice daily for 
10 days (i.e. 400 mg/day for 10 days).  
Subjects will come for 5 visits to the clinic. Screening (Visit 1) will take place from Day -28 to 
Day -2. At Visit 2, subjects will be admitted to the clinic in the morning of Day -1 for pre-dose 
assessments including a 24 h baseline urine collection and will remain at the clinic until Day 2 for 
IMP administration and PD assessments. Subjects will be discharged from the clinic after the 
morning dose on Day 2.  
From the evening of Day 2 to the evening of Day 8, subjects will self-administer celecoxib at home 
twice daily (morning and evening) and register each administration in an electronic diary 
(ViedocMe). Any reactions or use of concomitant medication will also be registered in ViedocMe. On 
Day 5 (Visit 3), the subjects will be contacted by phone for a drug accountability and AE check-up.  
Subjects will again be residential at the clinic between Day 9 and Day 11 (Visit 4) for IMP 
administration and exploratory PD assessments. The last dosing day is Day 10. Urine collection for 
exploratory PD analysis will be performed during 24 h after the last morning dose on Day 10. A final 
end-of-study visit (Visit 5) will take place on Day 19 (±2 days) or after early withdrawal. 
Investigational Medicinal Product (IMP), dosage, mode of administration and duration of 
treatment 
GS-248 is an oral solution of pH 3. Placebo contains the same components as the GS-248 solution 
except the active substance.  
Part I (SAD), planned dosage: single doses of 1 mg, 5 mg, 25 mg, 75 mg, 225 mg and 450 mg 
GS-248 
Part II (MAD), planned dosage: once daily dosing of 25 mg, 75 mg, 225 mg and 450 mg GS-248 
for 10 days 
Part III (SSc patients), planned dosage: the dose in Part III will be based on safety, tolerability and 
PK data collected during Part I and II of the study and will be documented in a substantial 
amendment, which must be approved by the regulatory authorities and the ethics committee prior to 
start of Part III. The dose is planned to be administered once daily for 10 days. 
Reference product, dosage, mode of administration and duration of treatment 
Celecoxib is a registered product provided as oral capsules (200 mg).  
Part IV (celecoxib) dosage: 200 mg twice daily for 10 days.   
Duration of each subject’s/patient’s involvement in the study 
Part I (SAD: Each subject is expected to participate in the study for approximately 36 days including 
a 28-day screening period. 
Part II (MAD): Each subject is expected to participate in the study for approximately 47 days 
including a 27-day screening period. 
Part III (SSc patients): Each patient is expected to participate in the study for approximately 61 days 
including a 41-day screening period. 
Part IV (celecoxib): Each subject is expected to participate in the study for approximately 47 days 
including a 27-day screening period. 

 
 
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Safety assessments (Part I, II and III) 
AE reporting, 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. 
Pharmacokinetic (PK) assessments (Part I, II and III) 
Blood sampling for bioanalysis and subsequent determination of GS-248 PK parameters 
Exploratory assessments 
• 
Blood sampling for analysis of mPGES-1 activity (PGE2 levels) in an ex vivo WBA (all parts, 
Part I from cohort 3) 
• 
Blood and urine sampling for analysis of ADMA in plasma and AA metabolites in urine 
(Part II, III and IV) 
• 
Blood and urine sampling for future analysis of GS-248 metabolites (Part I [plasma only] and 
Part II, Part II includes MIST). 
• 
Blood and urine sampling to be saved for future biomarker analyses e.g. further AA 
metabolite profiling in plasma and urine and inflammatory biomarkers in plasma (all parts, 
Part I from cohort 3) and urine (Part II, III and IV).  
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 the first database lock which will take place after completion of 
Part I, II and IV. Safety, PK and PD data will be summarised by descriptive statistics as appropriate. 
Study reporting 
After completion of the study, an ICH-E3 compliant CSR will be prepared.  

 
 
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2 
TABLE OF CONTENTS 
1 
STUDY SYNOPSIS ............................................................................................... 2 
2 
TABLE OF CONTENTS ...................................................................................... 9 
3 
LIST OF ABBREVIATIONS AND DEFINTIONS OF TERMS ...................... 16 
4 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ............................................................................................... 20 
4.1 
Medical emergencies contacts ......................................................................... 20 
5 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .......... 20 
6 
INTRODUCTION ............................................................................................... 22 
6.1 
Background ..................................................................................................... 22 
 
Systemic Sclerosis ......................................................................................... 22 
 
Raynaud’s phenomenon and digital ulcers in Systemic sclerosis .................... 22 
6.2 
Product characteristics .................................................................................... 23 
6.3 
Mechanism of action ........................................................................................ 23 
6.4 
Non-clinical summary ..................................................................................... 24 
6.5 
Clinical experience .......................................................................................... 26 
6.6 
Study rationale ................................................................................................ 26 
6.7 
Risk/benefit assessment ................................................................................... 27 
7 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 30 
7.1 
Primary objective ............................................................................................ 30 
 
Primary endpoints .......................................................................................... 30 
7.2 
Secondary objective ......................................................................................... 30 
 
Secondary endpoints ...................................................................................... 30 
7.3 
Exploratory objectives .................................................................................... 30 
 
Exploratory endpoints .................................................................................... 31 
8 
STUDY DESIGN ................................................................................................. 32 
8.1 
Overall study design and schedule of events .................................................. 32 
 
Part I: Single Ascending Dose (SAD) ............................................................ 32 
 
Part II: Multiple Ascending Dose (MAD) ...................................................... 37 
 
Part III: Patients with Systemic Sclerosis and Raynaud’s Phenomenon .......... 43 
 
Part IV: Celecoxib – open cohort with healthy volunteers .............................. 48 
8.2 
Rationale for study design ............................................................................... 51 
8.3 
Selection of starting dose and rationale for planned dose escalation............. 51 

 
 
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Selection of starting dose in the SAD part ...................................................... 51 
 
Rationale for dose escalation in the SAD part ................................................ 53 
 
Selection of starting dose and dose escalation in the MAD part ...................... 53 
 
Maximum exposure and dose ......................................................................... 54 
 
From single to multiple dosing ....................................................................... 54 
 
From healthy volunteers to patients ................................................................ 54 
 
Stopping criteria for dose escalation ............................................................... 55 
 
Internal safety review committee ................................................................... 57 
9 
STUDY POPULATION ...................................................................................... 59 
9.1 
Recruitment ..................................................................................................... 59 
9.2 
Screening and enrolment log ........................................................................... 59 
9.3 
Number of subjects/patients ............................................................................ 59 
9.4 
Eligibility criteria ............................................................................................ 60 
 
Inclusion criteria Part I, II and IV: SAD, MAD and celecoxib in healthy 
volunteers...................................................................................................................... 60 
 
Exclusion criteria Part I, II and IV: SAD, MAD and celecoxib in healthy 
volunteers...................................................................................................................... 60 
 
Inclusion criteria Part III: SSc patients ........................................................... 62 
 
Exclusion criteria part III: SSc patients .......................................................... 63 
9.5 
Restrictions during the study .......................................................................... 64 
 
Restrictions all parts....................................................................................... 64 
 
Restrictions Part I, II and III ........................................................................... 66 
 
Prior and concomitant therapy ....................................................................... 66 
9.5.3.1 
Prohibited medication Part I, II and IV ....................................................... 66 
9.5.3.2 
Prohibited medication Part III..................................................................... 66 
9.5.3.3 
Allowed medication (all parts) ................................................................... 66 
9.6 
Screening failures ............................................................................................ 67 
9.7 
Subject/patient withdrawal ............................................................................. 67 
 
General withdrawal criteria ............................................................................ 67 
 
QTc withdrawal criteria ................................................................................. 68 
 
Liver chemistry withdrawal criteria ................................................................ 68 
 
Procedures for discontinuation of a subject/patient from the study ................. 68 
 
Subject/patient replacement ........................................................................... 69 
9.8 
Randomisation ................................................................................................. 69 

 
 
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9.9 
Blinding ............................................................................................................ 69 
9.10 
Emergency unblinding during the study ........................................................ 69 
10 
TREATMENTS .................................................................................................. 70 
10.1 
Identity of investigational medicinal products ............................................... 70 
10.2 
Identity of reference product .......................................................................... 70 
10.3 
Manufacturing, packaging and labelling ........................................................ 70 
10.4 
Conditions for storage ..................................................................................... 70 
10.5 
Dispensing and accountability ........................................................................ 71 
10.6 
Treatment administration ............................................................................... 71 
10.7 
Continuation of treatment with Investigational Medicinal Product ............. 71 
10.8 
Treatment compliance ..................................................................................... 72 
10.9 
Return and destruction of investigational medicinal products ...................... 72 
11 
STUDY ASSESSMENTS .................................................................................... 73 
11.1 
Recording of data ............................................................................................ 73 
11.2 
Demographics and other baseline characteristics .......................................... 73 
 
Informed consent ........................................................................................... 73 
 
Eligibility criteria ........................................................................................... 73 
 
Demographic information .............................................................................. 73 
 
Weight and height .......................................................................................... 74 
 
Medical/surgical history ................................................................................. 74 
 
Prior and concomitant medication .................................................................. 74 
 
HIV and Hepatitis B/C ................................................................................... 74 
 
Pregnancy test ................................................................................................ 74 
 
Urine drug screen ........................................................................................... 74 
 Alcohol breath test ......................................................................................... 75 
 Baseline symptoms ........................................................................................ 75 
11.3 
Assessments related to primary endpoints: safety and tolerability ............... 75 
 
Adverse events............................................................................................... 75 
11.3.1.1 Definition of adverse event......................................................................... 75 
11.3.1.2 Definition of serious adverse event ............................................................. 75 
11.3.1.3 Definition of adverse drug reaction............................................................. 76 
11.3.1.4 Definition of serious adverse drug reaction ................................................. 76 
11.3.1.5 Definition of suspected unexpected serious adverse reaction ...................... 76 
11.3.1.6 Time period and frequency for collecting adverse events ............................ 76 

 
 
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11.3.1.7 Assessment of intensity .............................................................................. 76 
11.3.1.8 Assessment of causal relationship............................................................... 77 
11.3.1.9 Assessment of outcome .............................................................................. 77 
11.3.1.10 Collecting adverse events ........................................................................... 78 
11.3.1.11 Recording adverse events ........................................................................... 78 
11.3.1.12 Reporting of serious adverse events ............................................................ 78 
11.3.1.13 Reporting of SUSARs to EudraVigilance, CA and IEC .............................. 79 
11.3.1.14 Treatment and follow-up of adverse events ................................................ 79 
11.3.1.15 Treatment of overdose ................................................................................ 80 
11.3.1.16 Procedures in case of pregnancy ................................................................. 80 
 
Physical examination ..................................................................................... 80 
 
Vital signs and body temperature ................................................................... 80 
 
Resting 12-lead ECG ..................................................................................... 81 
 
Telemetry ...................................................................................................... 81 
 
Clinical laboratory profile .............................................................................. 81 
11.4 
Assessments related to secondary endpoints: pharmacokinetics and 
pharmacodynamics.......................................................................................... 84 
 
Pharmacokinetic sampling and analysis ......................................................... 84 
11.5 
Assessments related to exploratory endpoints ................................................ 84 
 
Blood sampling for ex-vivo whole blood assay (WBA) .................................. 84 
 
Urine sampling for analysis of AA metabolites, GS-248 metabolites and future 
biomarker analysis ........................................................................................................ 85 
 
Blood sampling for ADMA analysis .............................................................. 85 
 
Blood sampling for GS-248 metabolites (including MIST) ............................ 85 
 
Blood sampling for future biomarker analysis ................................................ 85 
 
Open question, Raynaud’s (Part III only) ....................................................... 86 
11.6 
Appropriateness of measurements .................................................................. 86 
12 
PROCEDURES FOR BIOLOGICAL SAMPLES............................................. 86 
12.1 
Sample collection ............................................................................................. 86 
12.2 
Volume of blood ............................................................................................... 86 
12.3 
Handling, storage and destruction of laboratory samples ............................. 86 
12.4 
Chain of custody of biological samples ........................................................... 87 
12.5 
Withdrawal of informed consent for donated biological samples ................. 87 

 
 
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13 
QUALITY MANAGEMENT, QUALITY ASSURANCE AND QUALITY 
CONTROL .......................................................................................................... 88 
13.1 
Quality management: critical process, system and data identification ......... 88 
13.2 
Quality assurance and quality control ............................................................ 88 
14 
ETHICAL AND REGULATORY REQUIREMENTS ..................................... 88 
14.1 
Ethical conduct of the study ............................................................................ 88 
14.2 
Ethics and regulatory review .......................................................................... 88 
14.3 
Subject/Patient information and consent ....................................................... 89 
14.4 
Subject/Patient information card.................................................................... 89 
14.5 
Subject/Patient data protection....................................................................... 89 
14.6 
Changes to the approved clinical study protocol............................................ 90 
14.7 
Audits and inspections ..................................................................................... 90 
14.8 
Insurance ......................................................................................................... 91 
15 
STUDY MANAGEMENT .................................................................................. 91 
15.1 
Training of study site personnel ...................................................................... 91 
15.2 
Clinical monitoring .......................................................................................... 91 
15.3 
Source data documents.................................................................................... 92 
15.4 
Study agreements ............................................................................................ 92 
15.5 
Study timetable and end of study .................................................................... 92 
15.6 
Termination of the of the study ....................................................................... 93 
15.7 
Reporting and publication .............................................................................. 93 
 
Clinical study report....................................................................................... 93 
 
Annual safety report....................................................................................... 93 
 
Confidentiality and ownership of study data................................................... 93 
 
Publication ..................................................................................................... 93 
15.8 
Archiving ......................................................................................................... 93 
16 
DATA MANAGEMENT .................................................................................... 94 
16.1 
The web-based eCRF....................................................................................... 94 
16.2 
The entering of data into the eCRF ................................................................ 95 
16.3 
Electronic patient reported outcome .............................................................. 95 
16.4 
The query process ............................................................................................ 95 
16.5 
Audit trail ........................................................................................................ 95 
16.6 
External data ................................................................................................... 95 
16.7 
Medical coding ................................................................................................. 95 

 
 
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16.8 
Database lock ................................................................................................... 96 
17 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE .. 96 
17.1 
General............................................................................................................. 96 
17.2 
Determination of sample size .......................................................................... 96 
17.3 
Analysis data sets ............................................................................................. 97 
 
Safety analysis set .......................................................................................... 97 
 
Full analysis set ............................................................................................. 97 
 
Per protocol set .............................................................................................. 97 
 
PK analysis set ............................................................................................... 97 
17.4 
Description of study population ...................................................................... 97 
 
Demographics and baseline characteristics ..................................................... 97 
 
Medical/surgical history and prior/concomitant medication ............................ 97 
 
Treatment compliance .................................................................................... 97 
17.5 
Analysis of primary endpoints ........................................................................ 98 
 
Adverse events............................................................................................... 98 
 
Physical examination ..................................................................................... 98 
 
Vital signs and body temperature ................................................................... 98 
 
12-lead ECG .................................................................................................. 98 
 
Safety laboratory analyses.............................................................................. 98 
17.6 
Analysis of secondary endpoints ..................................................................... 99 
 
Analysis of pharmacokinetics ........................................................................ 99 
17.7 
Analysis of exploratory endpoints................................................................. 100 
 
Analysis of mPGES-1 activity (PGE2 levels) levels using whole blood assay ..... 
 
 .................................................................................................................... 100 
 
ADMA and AA metabolites in plasma and urine.......................................... 100 
 
Metabolites in safety testing (MIST) ............................................................ 100 
 
Future exploratory analyses of biomarkers and GS-248 metabolites ............. 100 
 
Raynaud’s questioning ................................................................................. 100 
18 
REFERENCES.................................................................................................. 101 
19 
SIGNATURES .................................................................................................. 103 
19.1 
Principal Investigator statement ................................................................... 103 
19.2 
Signature page (approval of the clinical study protocol) ............................. 104 
 
 
 

 
 
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List of Tables 
Table 8.1-1 
Schedule of events Part I (SAD) .................................................................... 34 
Table 8.1-2 
Detailed schedule of events for Visit 2, Part I (SAD) ..................................... 35 
Table 8.1-3 
Schedule of events Part II (MAD).................................................................. 39 
Table 8.1-4 
Detailed schedule of events for Visit 2 and Visit 8, Part II (MAD) ................. 41 
Table 8.1-5 
Schedule of events Part III (SSc patients) ...................................................... 44 
Table 8.1-6 
Detailed schedule of events for Visit 2 and Visit 8, Part III (SSc patients) ..... 46 
Table 8.1-7 
Part IV Schedule of events, celecoxib ............................................................ 49 
Table 8.3-1 
Exposure margins for mean Cmax and AUClast values between GS-248-treated 
animals in the pivotal 28-day toxicity studies and the predicted values in humans in the SAD . 
 
 ...................................................................................................................... 52 
Table 8.3-2 
Tentative dose escalation schedule SAD ........................................................ 53 
Table 8.3-3 
Tentative dose escalation schedule MAD....................................................... 54 
Table 8.3-4 
Dose escalation and stopping rules, Part I and Part II ..................................... 56 
Table 11.3-1 
Safety laboratory parameters Part I, II and III ............................................ 82 
Table 11.3-2 
Safety laboratory parameters Part IV ......................................................... 83 
 
List of Figures 
Figure 6.1-1 
The pathophysiology of vascular disease in SSc (Hughes & Herrik, 2017) .... 22 
Figure 6.3-1 
Schematic view of arachidonic acid cascade and shunting of the substrate 
PGH2 from PGE2 production to PGI2 formation .................................................................... 24 
Figure 8.1-1 
Overview of the study design ........................................................................ 32 
 
 
 

 
 
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3 
LIST OF ABBREVIATIONS AND DEFINTIONS OF TERMS 
Abbreviation or term                   
Explanation 
AA 
Arachidonic acid 
ADL 
Activities of daily living 
AE 
Adverse event 
ACE 
Angiotensin Converting Enzyme 
ACR 
American College of Rheumatology 
ADMA 
Asymmetric dimethylarginine 
ADR 
Adverse drug reaction 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical  
AUC0-t 
Area under the curve from time 0 to time t 
AUC0-∞ 
Area under the curve from time 0 to infinity 
AUCss 
Area under the curve at steady state 
AUE 
Area under the effect curve 
BMI 
Body mass index 
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 
COX 
Cyclooxygenase 
CRM 
Clinical research manger  
CRP 
C-reactive protein 
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 
Ctrough 
Observed concentration at the end of a dosing 
interval, immediately before next administration  
CV 
Coefficient of variation 
DBL 
Database lock 
DMP 
Data management plan 
DRF 
Dose range finding  

 
 
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DSUR 
Development safety update report 
DU 
Digital ulcer 
ECG 
Electrocardiogram 
eCRF 
Electronic CRF 
eGFR 
Estimated glomerular filtration rate 
EDC 
Electronic data capture 
EEA 
European Economic Area 
ePRO 
Electronic patient reported outcome 
EULAR 
European League Against Rheumatism 
FAS 
Full analysis set 
FDA 
U.S. Food and Drug Administration 
FIH 
First-in-human 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
GDPR 
General data protection regulation 
gGT 
Gamma glutamyl transferase 
GI 
Gastrointestinal 
GMP 
Good manufacturing practice 
h 
hour 
Hb 
Haemoglobin 
HBsAG 
Hepatitis B surface antigen 
HCG 
Human chorionic gonadotropin 
HCVAb 
Hepatitis C virus antibodies 
HED 
Human Equivalent Dose  
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
IC50 
Half maximal inhibitory concentration  
ICF 
Informed consent form 
ICH 
International conference on harmonisation 
ICU 
Intensive care unit 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
ISF 
Investigator site file 
iSRC 
Internal safety review committee 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
LD 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantification 
LPS 
Lipopolysaccharide 

 
 
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MABEL 
Minimum Anticipated Biological Effect Level 
MAD 
Multiple ascending dose 
MCV 
Mean corpuscular volume 
MEC 
Molar extinction coefficient  
MedDRA 
Medical dictionary for regulatory activities 
min 
minute 
MIST 
Metabolites in Safety Testing 
MPA 
Medical products agency 
MTD 
Maximum tolerated dose 
mPGES-1 
Microsomal Prostaglandin E synthase-1 
N 
number 
NCA 
Non-compartmental analysis 
NCI 
National Cancer Institute 
NIH 
National Institute of Health 
NOAEL 
No observed adverse effect level 
NSAID 
Non-steroidal anti-inflammatory drug 
OTC 
Over the counter 
PD 
Pharmacodynamic(s) 
PDE-5 
Phosphodiesterase type 5  
PG 
Prostaglandin 
PGE2 
Prostaglandin E2 
PGH2 
Prostaglandin H2 
PGI2 
Prostaglandin I2 (prostacyclin) 
PGEM 
11-alfa-hydroxy-9,15-dioxo-13,14-dihydro-2,3,4,5, 
tetranor-prostan-1,20-dioic acid  
PGIM 
2, 3-dinor-6-ketoprostaglandin F1α 
PK 
Pharmacokinetic 
PK(INR) 
Prothrombin complex international normalised ratio 
PII 
Personally identifiable information 
PPS 
Per protocol set 
PPI 
Proton pump inhibitor 
PT 
Preferred term 
QC 
Quality control 
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 

 
 
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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 
TPC 
Thrombocyte particle concentration 
TSH 
Thyroid Stimulating hormone 
TXM 
11-dehydro-thromboxane B2 
T½ 
Terminal half life 
ULN 
Upper limit of normal 
UVA 
Ultraviolet A 
UVB 
Ultraviolet B 
WBA 
Whole blood assay, ex vivo measurements of 
mPGES-1 activity in LPS-stimulated whole blood 
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 11.3.1.12. 
In the case of a medical emergency the Investigator may contact the Medical Monitor.  
Name 
Function in the study 
Telephone number and e-mail 
Cornelia Lif-
Tiberg 
Medical monitor and adjunct 
member of the internal Safety 
Review Committee (iSRC) 
Telephone: +46 (0)73 978 94 45 
E-mail: cornelia-lif-tiberg@ctc-ab.se 
5 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE  
Sponsor 
Gesynta Pharma AB 
Fogdevreten 2 
SE-171 65 Solna 
Sponsor’s Medical Representative 
Name, title: Göran Tornling, MD 
Phone: +46 (0)73 096 3131 
E-mail: goran.tornling@gesynta.se 
 
Clinical conduct 
CTC Clinical Trial Consultants AB (CTC) 
Uppsala University Hospital, 
Entrance 85, 2nd level  
SE-751 85 Uppsala, Sweden 
 
CTC Clinical Trial Consultants AB 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
 
Part I and II will be conducted at the FIH 
Uppsala University Hospital clinic. Part III 
and IV may be conducted either at the clinic 
at Uppsala University Hospital or at the 
clinic on Dag Hammarskjölds väg 10B.   
Principal Investigator 
Folke Sjöberg, MD, PhD, Professor 
Phone: +46 (0)70 557 18 20 
E-mail: folke.sjoberg@ ctc-ab.se 
 
 
Study management 
CTC Clinical Trial Consultants AB 
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 

 
 
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Biostatistician 
Fredrik Hansson, MSc 
Phone: +46 (0)72 193 55 01 
E-mail: fredrik.hansson@ctc-ab.se 
 
Medical writer 
Sandra Kuusk, PhD 
Phone: +46 (0)70 330 42 74 
E-mail: sandra.kuusk@ctc-ab.se 
 
Medical monitor  
Cornelia Lif-Tiberg, MD 
Phone: +46 (0)73 978 94 45 
E-mail: cornelia-lif-tiberg@ctc-ab.se 
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, ADMA in plasma, 
AA metabolites in urine) 
 
Recipharm OT Chemistry AB 
Virdings allé 18 
SE-754 50 Uppsala, Sweden 
Laboratory (ex vivo WBA, MIST and other 
exploratory analyses) 
To be decided.  
Investigational medicinal product (IMP) 
manufacturing, packaging and labelling 
RISE Research Institutes of Sweden AB 
Forskargatan 18 
SE-151 36 Södertälje, Sweden.  
Pharmacy 
 
Apoteket Clinical Trial Unit 
Dag Hammarskjölds väg 18 
SE-751 85 Uppsala, 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). Most subjects make at least one life adjustment due to 
Raynaud’s Phenomenon, and quality of life is significantly reduced. 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 (Hughes & Herrik, 2017) 
 
 
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 

 
 
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SSc. In the large EUSTAR database, including 9,182 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 mean 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 a common and disabling manifestation 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]. DU 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].  
6.2 
Product characteristics 
The Drug Substance, 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-dependant. 
The Drug Product to be used in the study is an oral solution where GS-248 is dissolved in an 
acidic vehicle at pH 3.0. 
6.3 
Mechanism of action 
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 6.3-1).  

 
 
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Figure 6.3-1 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 Coxibs, which target the upstream cyclooxygenases 
(COX-1 and COX-2, respectively) for general inhibition in prostanoid production 
(Figure 6.3-1). 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 vasodilatation 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, 
elicit a vasodilatory and platelet inhibitory effect by increased prostacyclin (PGI2) production. 
6.4 
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 uM. In a human 
whole blood assay (WBA), 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 lipopolysaccharide (LPS)-induced 
hyperalgesia in a dose dependent manner with maximal effect at 30 mg/kg p.o., 3 h post-dose. 
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)  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 

 
 
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concentration (Cmax) and 23000 nmol*h/L for AUC(0-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 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 
pathology parameters were short-lived, 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.  

 
 
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For details on the non-clinical studies performed, refer to the Investigator’s Brochure (IB) of 
GS-248.  
6.5 
Clinical experience 
The present study is a first-in-human (FIH) study, hence there is no clinical experience of 
GS-248 administration to humans. However, substances targeting the same enzyme have 
previously been investigated in Phase I studies; no target related toxicity was observed in the 
study with LY3023703 [15], but the development was discontinued due to liver toxicity 
related to formation of reactive metabolites formed from those compounds [16]. Similar 
metabolites have not been observed from GS-248 and are unlikely to be formed based on the 
chemical structure of the molecule.  
6.6 
Study rationale 
GS-248 is intended to be used for the prevention and treatment of DUs in patients with 
systemic sclerosis. Current oral therapies for DUs have limited efficacy, and there is a high 
medical need for new therapeutic alternatives. 
This is a FIH study including healthy volunteers and patients with SSc. It is not expected that 
the healthy volunteers will gain any benefit from GS-248. However, should patients included 
in the cohort(s) with systemic sclerosis potentially experience improvement of symptoms 
related to Raynaud’s phenomenon, this will be captured by posing relevant questions to the 
patients during the study. 
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. 
The study will collect information about safety, tolerability and pharmacokinetics (PK) 
following single and multiple administration of GS-248 to healthy subjects and patients with 
SSc. In addition, an exploratory comparison of the pharmacodynamic (PD) effects between 
celecoxib and GS-248 will be performed.   
It is considered desirable to obtain safety and tolerability data in the target SSc patient 
population early in the clinical program. In addition, specific reasons to include patient 
cohort(s) are: 
• More than 50% of patients with SSc have gastrointestinal involvement, which may 
influence uptake of study drug 
• Inclusion of patients will allow early assessment of PD effects based on ex vivo whole 
blood PGE2 synthesis. The mPGES enzyme is upregulated in inflammatory tissues 
such as in patients with SSc. Thus, the levels of active prostaglandin (PG)-metabolite 
may differ between healthy subjects and patients with SSc. 
The rationale for the study design is outlined in Section 8.2. 

 
 
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6.7 
Risk/benefit assessment 
Part I, II and III 
The healthy volunteers in Part I and II (single ascending dose [SAD] and multiple ascending 
dose [MAD], respectively) in this study will, except for thorough health examinations, have 
no medical benefit from participation and their safety and wellbeing are of outmost 
importance. The study involves the first administration of GS-248 to humans, and there are no 
previous data on the effects of the drug in humans. It is therefore difficult to make predictions 
about possible adverse drug reactions (ADRs).  
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, providing the 
possibility to stop dosing in individuals with signs on emerging liver toxicity. The medical 
monitor will continuously review individual subjects to decide if dosing should be 
discontinued. An internal safety review committee (iSRC) will review both individual 
subjects and trends between dosing groups as recommended in the U.S. Food and Drug 
Administration (FDA) Guidance on Drug-Induced Liver Injury [25] to decide if dosing should 
be continued, and in that case at which dose level, see Section 9.7.3. Stopping of further 
dosing or adjustments from the intended dosing scheme can be considered also if the stopping 
rules recommended in the Guidance are not fulfilled. 
Mild increases in serum cholesterol levels have been noted in both rats and dogs at all dose 
levels included in the 28-day toxicity studies. However, these changes were of a low degree 
and were therefore not considered to be adverse effects. The likelihood of any clinically 
relevant increases in serum cholesterol in the present study is low, but serum cholesterol will 
be monitored throughout the study in order to discern any evolving effects. 
Testicular degeneration was noted histopathologically in the 3 male dogs at the highest dose 
level in the 28-day study that were necropsied pre-terminally on Day 21. These changes were 
interpreted as most probably being secondary effects as a result of the poor physiological 
condition of these animals, and therefore not directly related to GS-248 treatment. 
Furthermore, as no such changes were noted at the NOAEL (the intermediate dose level) in 
this study, there will be sufficient safety margins to such effects in the present study.   
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 9.5.2, should be used during the study. 
The selection of starting-dose and dose-escalation steps represents a careful approach to 
administer GS-248 for the first time in humans (see Section 8.3). Sentinel dosing will apply 
for the first 2 subjects in each SAD cohort. 
SSc patients participating in the study may experience some symptom relief. The risks for SSc 
patients are considered to be comparable to those identified for the healthy volunteers 
participating in Part I and Part II of the study with the exception that patients may experience 

 
 
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discomfort following withdrawal of e.g. proton pump inhibitors (PPIs) and other medications 
(see below).  
In Part I, II and III, use of antacids, PPIs or any medication that changes gastric pH is 
disallowed from 14 days prior to IMP administration and during the study since GS-248 is a 
low solubility compound with pH dependent solubility. A high pH may decrease exposure.  
Use of NSAIDs, coxibs and aspirin is prohibited from 14 days prior to IMP administration 
and during the study to avoid interference with the GS-248 signal transduction pathway and 
evaluation of study results.  
The iSRC will monitor emerging safety and PK data over the course of the study and must 
give a favourable recommendation prior to any dose escalation, see Section 8.3.7 and Section 
8.3.8 for stopping criteria for dose escalation and for further information about the iSRC. 
Subjects will remain in the research clinic for approximately 48 h after the single dose in Part 
I (SAD) and will be closely monitored by medical staff. In Part II (MAD) and Part III (SSc 
patients), subjects/patients will be residential at the clinic for approximately 48 h after the first 
dose (Day 1) and the last dose (Day 10) for safety surveillance and PK/PD sampling. In 
addition, subjects will visit the clinic in the morning of each day in between the residential 
stays for IMP administration and safety check-up. The duration of the residential periods may 
be amended if indicated by PK and/or safety data, see Section 8.3.8.  
Part IV 
The healthy volunteers in Part IV will receive the registered product celecoxib. Subjects with 
a history of salicylate hypersensitivity or NSAID hypersensitivity or subjects who have 
experienced asthma, urticaria or other allergic reactions after taking aspirin or other NSAIDs 
will not be included in Part IV of the study. 
No specific safety surveillance following intake of celecoxib is considered necessary, but 
subjects will stay at the clinic for 24 h following the first and last dose of celecoxib, for PD 
assessments. On the remaining dosing days (from the evening dose on Day 2 until the evening 
dose on Day 8), subjects will self-administer celecoxib at home. The intake, and the time for 
intake, of celecoxib as well as any reactions or use of concomitant medications will be 
registered in an electronic diary (ViedocMe), see Section 16.3.  
All parts 
In all parts, subjects/patients will be admitted to the clinic the day before each residential stay. 
Visits at the clinic may be prolonged in case the Investigator finds it medically warranted for 
safety reasons. Each volunteer will be provided with a subject information card with 
information detailed in Section 14.4. 
Overdosing of GS-248 is not likely to occur since GS-248 will be administered by site 
personnel under medical surveillance. In cases of accidental overdose, appropriate supportive 
medical care should be provided, see Section 11.3.1.15. In the event of suspected overdose of 
celecoxib, which will be self-administered by the subjects from the evening of Day 2 to the 
evening of Day 8, appropriate supportive medical care should be provided, see Section 
11.3.1.15. The maximum recommended total daily dose is 400 mg, which corresponds to the 
intended dose in this study (2x200 mg/day).  
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. 

 
 
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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. The research clinic is located adjacent and on the same floor as the 
Intensive Care Unit (ICU) at the University Hospital in Uppsala. CTC has a separate 
agreement with the ICU for support in case of emergencies. CTC has been regularly inspected 
by the Swedish Medical Products Agency (MPA) and is authorised to conduct FIH studies. 
Besides the risks related to the IMPs 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, 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 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/patients. 
More detailed information about the known and expected benefits and risks and reasonably 
expected ADRs of GS-248 and celecoxib is found in the IB of GS-248 and in the Summary of 
Product Characteristics (SmPC) of celecoxib (Celebra, Pfizer) respectively.  

 
 
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7 
STUDY OBJECTIVES AND ENDPOINTS 
7.1 
Primary objective 
• To determine the safety and tolerability following oral single and multiple ascending 
doses of GS-248 (solution) in healthy subjects and patients with SSc 
 Primary endpoints 
• Frequency, severity and seriousness of adverse events (AEs) 
• Clinically significant changes in: 
o 12-lead electrocardiogram (ECG) 
o Vital signs 
o Safety laboratory parameters 
o Physical examinations   
7.2 
Secondary objective 
• To evaluate the PK of GS-248 in healthy subjects and patients with SSc 
 Secondary endpoints 
• PK parameters: 
o Part I: area under the curve from time 0 to time t (AUC0-t), AUC from time 0 
to infinity (AUC0-), T½, Cmax, time to Cmax (Tmax), dose proportionality (based 
on AUC and Cmax), apparent total body clearance following extravascular 
administration (CL/F) and apparent volume of distribution following 
extravascular administration (Vz/F) 
o Part II and III after first dose interval: AUC0-t, T½, Tmax, Cmax, dose 
proportionality (based on AUC and Cmax)  
o Part II and III after last dose interval: AUC0-t, AUC at steady state (AUCss), 
T½, Tmax, Cmax, observed concentration at the end of a dosing interval, 
immediately before next administration (Ctrough from the 2 doses preceding the 
last dose), dose proportionality (based on AUCss and Cmax), CL/F, Vz/F and 
accumulation ratio 
7.3 
Exploratory objectives 
• To evaluate the PD effects of GS-248 and celecoxib by determination of mPGES-1 
activity (PGE2 levels) in a WBA 
• To explore the PD effects of GS-248 in plasma (asymmetric dimethylarginine 
[ADMA]) and urine (AA metabolites) and additional exploratory inflammatory 
biomarkers in healthy subjects and patients with SSc 

 
 
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• To explore the PD effects of celecoxib in plasma (ADMA) and urine (AA metabolites) 
and additional exploratory inflammatory biomarkers in healthy subjects after 10 days 
twice daily dosing to enable exploratory comparisons with GS-248 treated subjects  
• To explore potential metabolites of GS-248 in plasma and urine (including metabolites 
in safety testing [MIST]) 
 Exploratory endpoints 
• Ex vivo determination of mPGES-1 activity (PGE2 levels) in a WBA  
• AA metabolites in urine captured pre-dose administration and during 24 h post-dose: 
o 11-alfa-hydroxy-9,15-dioxo-13,14-dihydro-2,3,4,5, tetranor-prostan-1,20-dioic 
acid (PGEM) 
o 2, 3-dinor-6-ketoprostaglandin F1α (PGIM) 
o 11-dehydro-thromboxane B2 (TXM) 
• ADMA in plasma 
• Collection of plasma and urine for future analysis of potential metabolites after single 
and multiple dosing with GS-248  
• Plasma and urine samples will be saved for future biomarker analyses e.g. further 
AA metabolite profiling in plasma and urine and inflammatory biomarkers in plasma 
and urine 
The outcome of the WBA will be reported in the clinical study report (CSR) whereas the 
other exploratory endpoints may be reported separately from the CSR.

 
 
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8 
STUDY DESIGN 
8.1 
Overall study design and schedule of events 
This is a FIH, double-blind, parallel-group, randomised, placebo-controlled study designed to 
evaluate the safety, tolerability, PK and PD of single and multiple ascending oral doses of 
GS-248 in healthy subjects and in patients with SSc. In addition, an exploratory comparison 
of the PD effects between celecoxib and GS-248 will be performed. 
The study will be conducted in 4 parts: 
Part I (SAD): safety, tolerability, PK and PD (PD from cohort 3) of single ascending oral 
doses of GS-248 in healthy male and female subjects (Section 8.1.1).  
Part II (MAD): safety, tolerability, PK and PD of multiple ascending oral doses of GS-248 in 
healthy male and female subjects during 10 days administration (Section 8.1.2). 
Part III (SSc patients): safety, tolerability, PK and PD of multiple oral doses of GS-248 in 
patients with SSc during 10 days administration (Section 8.1.3)  
Part IV (celecoxib): PD of multiple oral doses of celecoxib (200 mg BID) in healthy males 
and females during 10 days administration (Section 8.1.4).  
An overview of the study design is shown in Figure 8.1-1.  
Figure 8.1-1 Overview of the study design 
 
1. 
Tentative dose levels (grey). Final doses will be set based on emerging data.  
2. 
Optional cohort. The dose may be set to between 450 mg and 800 mg, may be a repeated dose or another 
intermediate dose. 
3. 
Optional cohort. 800 mg corresponds to the maximum dose to be administered in the study. 
4. 
Optional cohort.  
5. 
Dose in Part III to be set based on emerging data and will be documented in a substantial amendment, which must 
be approved prior to start of the cohort.  
6. 
Optional cohort.  
 Part I: Single Ascending Dose (SAD)  
In the SAD part of the study, single oral doses of GS-248 will be administered in 6 sequential 
cohorts, each of 8 subjects. Within each cohort, subjects will be randomised in a 3:1 ratio to 
receive either GS-248 (n=6) or placebo (n=2) in a blinded fashion. The proposed starting dose 
is 1 mg. The rationale for the starting dose and the planned dose escalation is detailed in 
1 mg
5 mg1
25 mg1
75 mg1
225 mg1
450 mg1
25 mg1
75 mg1
225 mg1
XX mg5
Part I: HV SAD
Part II: HV MAD
10 days
Part III: SSc patients
10 days
Part IV: HV 10 days
XX mg2
≤800 mg3
450 mg1
XX mg4
XX mg6
Celecoxib 
200 mg BID

 
 
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Section 8.3. Up to 2 additional dose cohorts can be explored based on the safety, tolerability 
and PK of the drug if recommended by the iSRC. 
Subjects will come for 3 visits to the clinic. Screening (Visit 1) will take place from Day -28 
to Day -1. For details on assessments, refer to Table 8.1-1. At Visit 2, subjects will be 
admitted to the clinic on Day -1 and will remain at the clinic until Day 3 for single dose IMP 
administration, safety, PK and PD (PD from cohort 3) assessments (Table 8.1-1 and 
Table 8.1-2). The subjects must fast for at least 10 h 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 first 2 subjects in each cohort will be dosed in a sentinel fashion; 1 subject will 
receive GS-248 and the other will receive placebo as randomised. 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. There is immediate access to 
equipment, qualified staff and an ICU in case of an acute emergency. To give sufficient time 
for observation of any reactions, there will be at least 24 h before dosing of the third and 
fourth subject, who will be dosed on the same day approximately 2 h apart. The remaining 
4 subjects will also be dosed 2 by 2, i.e. 2 subjects will be dosed on the same day 
approximately 2 h apart. A final end-of-study visit (Visit 3) will take place on Day 8 (±2 
days) or after early withdrawal.  
In all cohorts, safety and PK will be assessed before and after dose as outlined in Table 8.1-1 
and detailed in Table 8.1-2. Exploratory blood sampling for WBA and future biomarker 
analysis (from cohort 3 and onwards) and potential future metabolite analysis will be 
performed before and after dose (Table 8.1-1 and Table 8.1-2). 
Before initiating a new cohort, all subjects in the previous cohort must have been treated and 
48 h safety, tolerability and PK data for all treated subjects must have been evaluated by the 
iSRC, see Section 8.3.8. Once Day 3 safety, tolerability and PK data for the last subject in 
each cohort has been collected, there will be at least 1week between dose escalations.  
Each subject is expected to participate in the study for approximately 36 days including a 
28-day screening period. 
The schedule of events for Part I is shown in Table 8.1-1 and detailed for Visit 2 in 
Table 8.1-2. Study assessments are described in Section 11.  
Safety assessments include: AE reporting, 12-lead ECG monitoring, vital signs (blood 
pressure and pulse), body temperature, physical examination, use of concomitant medications 
and blood sampling for haematology, clinical chemistry and coagulation parameters, see 
Section 11.3. 
PK assessments include: blood sampling for bioanalysis and subsequent determination of PK 
parameters, see Section 11.4.  
Exploratory assessments include: blood sampling for analysis of mPGES-1 activity (PGE2 
levels) in an ex vivo WBA, for future biomarker analysis (from cohort 3 and onwards) and for 
future exploratory analysis of metabolites, see Section 11.5. 

 
 
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Table 8.1-1 
Schedule of events Part I (SAD) 
 
Screening 
Residential period 
End-of-study 
Visit 
Visit 1 
Visit 21 
Visit 3 
Assessment 
Day -28 to  
Day -12 
Admission  
Day -12 
Day 1 
Day 2 
Day 3 
Day 8 (±2 days) 
Informed Consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X3 
 
 
 
Weight/height/BMI 
X 
 
 
 
 
X4 
Medical/surgical history 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
HIV, hepatitis B and C 
X 
 
 
 
 
 
Urine Drug Screen5 
X 
X 
 
 
 
X 
Alcohol breath test 
X 
X 
 
 
 
X 
Pregnancy Test (WOCBP)6 
X 
X 
 
 
 
X 
Physical Examination 
X 
 
X7, 8 
 
 
X 
Clinical Laboratory Profile9 
X 
X 
 
 
X 
X 
Vital signs10  
X 
X 
X11 
X 
X 
X 
Body temperature 
 
 
X8 
 
 
 
12-lead ECG 
X 
 
X8, 11 
X 
X 
X 
Telemetry  
 
 
X12 
 
 
Randomisation 
 
 
X 
 
 
 
IMP administration13 
 
 
X 
 
 
 
PK blood sampling14 
 
 
X11 
X11 
X11 
Blood sampling for WBA15 
 
 
X15 
X15 
 
 
Blood sampling for future 
biomarker analyses15  
 
 
X15 
X15 
 
 
Meals16 
 
X 
X 
X 
X 
 
Baseline symptoms 
X 
X 
 
 
 
 
AEs and SAEs 
 
 
X17 
Prior and concomitant 
medications 
X 
1. Details in separate flow chart (Table 8.1-2). The duration of the residential period may be amended following review of 
data from earlier cohorts.  
2. Screening and admission to the clinic may be conducted on the same day.  
3. Confirmation of eligibility prior to randomisation. Day -1 or Day 1.  
4. Weight only.  
5. Random drug screening test may also be performed at the discretion of the investigator. 
6. Screening: plasma/serum tests, other visits: urine test.  
7. Short version of physical examination on Day 1.  
8. Pre-dose assessments may be performed pre-dose Day 1 or on Day -1.  
9. Clinical chemistry, haematology, coagulation, urinalysis (dip-stick), see Section 11.3.6. 
10. Blood pressure and pulse, see Section 11.3.3.  
11. For timing of assessments, refer to Table 8.1-2. 
12. Ambulatory ECG telemetry for up to 24 h after IMP administration. 
13. Administered under fasting conditions, i.e. fasting for 10 h before IMP administration until 4 h post administration. 
14. Includes sampling for future exploratory analyses of potential GS-248 metabolites.  
15. Sampling for WBA analysis and for future biomarker analyses starts at cohort 3. For timing of assessments, refer to 
Table 8.1-2. 
16. Breakfast, lunch, snack, dinner and evening snack. Standardised meals during 24 h after dose. For timing of meals, 
refer to Table 8.1-2. No breakfast on Day 1. Breakfast only on Day 3.  
17. From administration of IMP.  

 
 
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Table 8.1-2 
Detailed schedule of events for Visit 2, Part I (SAD) 
 
Day -1 
Day 1 
Day 2 
Day 3 
Assessment/time-point 
Admission 
Pre-
dose 
0 
0.25h 
0.5h 
1h 
1.5h 
2h 
3h 
4h 
6h 
8h 
12h 
16h 
24h 
36h 
48 h 
Inclusion/exclusion criteria 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X1,2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory profile 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital signs  
X 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
Body temperature 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
 
X1 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
Telemetry 
 
 
X 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood sampling4 
 
X3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
 
X 
Blood sampling for WBA6 
 
X3 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Blood sampling for future 
biomarker analyses6 
 
X3 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Breakfast7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Meals 
X9 
 
 
 
 
 
 
 
 
X8, 9 
 
 
 
 
X9 
 
X9 
Baseline symptoms 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs and SAEs 
 
 
X 
Prior and concomitant medications 
X 
1. 
Day -1 or pre-dose Day 1 prior to randomisation. 
2. 
Short version of physical examination. 
3. 
Within 60 minutes prior to dose. 
4. 
Includes sampling for future exploratory analyses of potential GS-248 metabolites. 

 
 
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5. 
The 24 h PK sample is taken pre-dose Day 2 within 10 minutes of the of the nominal time for the dosage interval. For details regarding time windows for PK sampling, refer to Section 
11.4.1. 
6. 
From cohort 3 and onwards.  
7. 
Fasting on Day 1. Breakfast on Day 2 and Day 3 after PK blood sampling.  
8. 
Standardised lunch at least 4 h post-dose.  
9. 
Standardised lunch, snack, dinner and evening snack at approximately 4, 7 and 9 and 11 h post-dose on Day 1 until 24 h after dose. Non-standardised lunch, snack, dinner and evening 
snack at approximately 4, 7 and 9 and 11 h post breakfast on Day 2. Dinner and evening snack on Day -1. Breakfast only on Day 3.  

 
 
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 Part II: Multiple Ascending Dose (MAD)  
Part II of the study will explore multiple ascending dosing of GS-248. The initial dose, dose 
escalation and dosing schedule will be based on emerging knowledge of safety, tolerability 
and PK of GS-248 observed in the SAD part of the study (Part I). The proposed starting dose 
is 25 mg/day. The rationale for the starting dose and the planned dose escalation is detailed in 
Section 8.3. 
GS-248 is planned to be administered once daily for 10 days. Each dose level during the 
MAD part will be selected such that the predicted maximum exposure will not exceed the 
maximum exposure (AUC and Cmax) in previously evaluated SAD cohorts. The starting dose, 
subsequent dose levels and time points and visits for PK sampling may be adjusted based on 
safety and PK evaluation in the SAD and MAD part as outlined in Section 8.3.8.  
GS-248 will be administered in 4 sequential cohorts, each of 8 subjects. Within each cohort, 
subjects will be randomised in a 3:1 ratio to receive GS-248 (n=6) or placebo (n=2) in a 
blinded fashion. Up to 1 additional dose cohort can be explored based on the safety, 
tolerability and PK of the drug if recommended by the iSRC. 
Subjects will come for 9 visits to the clinic. Screening (Visit 1) will take place from Day -28 
to Day -2. For details on assessments, refer to Table 8.1-3. At Visit 2, subjects will be 
admitted to the clinic in the morning of Day -1 for pre-dose assessments including a 24 h 
baseline urine collection and will remain at the clinic until Day 3 for IMP administration and 
safety, PK and exploratory PD assessments (Table 8.1-3 and Table 8.1-4). Up to 4 subjects 
will be dosed on the same day. There will be at least 30 minutes between the dosing of each 
subject. 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 8.1-4. There is 
immediate access to equipment, qualified staff and an ICU in case of an acute emergency.  
Outpatient visits for IMP administration, safety and PK assessments are planned for Day 4 to 
Day 8. (Visit 3 to Visit 7), see Table 8.1-3 and Table 8.1-4. On Day 9 (Visit 8), subjects will 
come to the unit in the morning for IMP administration and PK sampling and will return again 
in the evening for admission. For practical reasons, and if preferred by the subject, he or she 
may remain at the clinic during the whole Day 9. 
Subjects will be admitted to the clinic between Day 9 and Day 12 (Visit 8) for IMP 
administration, safety, PK and exploratory PD assessments. The last dosing day is Day 10. 
Urine collection for exploratory PD analysis will be performed during 24 h after the last dose. 
A final end-of-study visit (Visit 9) is planned to take place on Day 19 (±2 days) or after early 
withdrawal. 
Before initiating a new cohort, all subjects in the previous cohort must have been treated and 
11 days safety, tolerability and PK data (i.e. data up to and including 24 h post last dose) for 
all treated subjects must have been evaluated by the iSRC, see Section 8.3.8. Once Day 11 
safety, tolerability and PK data for the last subject in each cohort has been collected, there 
will be at least 1 week between dose escalations.  
Each subject is expected to participate in the study for approximately 47 days including a 
27-day screening period.  
The schedule of events for Part II is shown in Table 8.1-3 and is detailed for Visit 2 and 
Visit 9 in Table 8.1-4. Study assessments are described in Section 11. 

 
 
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Safety assessments include: AE reporting, 12-lead ECG monitoring, vital signs (blood 
pressure and pulse), body temperature, physical examination, use of concomitant medications 
and blood sampling for haematology, clinical chemistry and coagulation parameters, see 
Section 11.3. 
PK assessments include: blood sampling for bioanalysis and subsequent determination of 
GS-248 PK parameters, see Section 11.4.  
Exploratory assessments include: blood sampling for analysis of mPGES-1 activity (PGE2 
levels) in an ex vivo WBA, blood and urine sampling for analysis of ADMA in plasma and 
AA metabolites in urine, blood and urine sampling for future exploratory analysis of GS-248 
metabolites and for future exploratory biomarker analyses, see Section 11.5. 
 
 
 

 
 
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Table 8.1-3 
Schedule of events Part II (MAD) 
 
Screening 
Residential period 
Daily 
visits 
Residential period 
End-of-
study 
Visit 
Visit 1 
Visit 21 
Visit 3 to 7 
Visit 81 
Visit 9 
Assessment 
Day -28 to 
Day -2 
Admission  
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 to 8 
Admission 
Day 9 
Day 10 
Day 11 
Day 12 
Day 19 
(±2 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X2 
 
 
 
 
 
 
 
 
Weight/height/BMI 
X 
 
 
 
 
 
 
 
 
 
X3 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
HIV, hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen4 
X 
X 
 
 
 
 
X 
 
 
 
X 
Alcohol breath test 
X 
X 
 
 
 
 
X 
 
 
 
X 
Pregnancy Test (WOCBP)5 
X 
X 
 
 
 
 
X 
 
 
 
X 
Physical Examination 
X 
 
X 6, 7 
 
 
 
 
 
 
X6 
X 
Clinical Laboratory Profile8 
X 
X 
 
X9 
X 
X9 
X 
 
 
X 
X 
Vital signs10 
X 
X 
X11 
X11 
X 
 
X 
X11 
X11 
X 
X 
Body temperature 
 
 
X7 
 
 
 
 
X7 
 
 
 
12-lead ECG 
X 
 
X7, 11 
X 
X 
 
 
X7,11 
 
X 
X 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
IMP administration12 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
PK blood sampling 
 
 
X11 
X11 
 
X14 
X11, 14 
X11, 14 
X 
X 
 
Blood sampling for GS-248 
MIST13  
 
 
X11 
X11 
 
 
 
X11 
X11 
 
 
Blood sampling for WBA 
 
 
X11 
X11 
 
 
 
X11 
X11 
 
 
Blood sampling for ADMA 
analysis 
 
 
X11 
X11 
 
 
 
X11 
X11 
 
 
Blood sampling for future 
biomarker analyses15 
 
 
X11 
X11 
 
 
 
X11 
X11 
 
 

 
 
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Screening 
Residential period 
Daily 
visits 
Residential period 
End-of-
study 
Visit 
Visit 1 
Visit 21 
Visit 3 to 7 
Visit 81 
Visit 9 
Assessment 
Day -28 to 
Day -2 
Admission  
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 to 8 
Admission 
Day 9 
Day 10 
Day 11 
Day 12 
Day 19 
(±2 
Urine collection 
 
X16 
 
 
 
X16 
 
 
Meals17 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Baseline symptoms 
X 
X 
 
 
 
 
 
 
 
 
 
AEs and SAEs 
 
 
X18 
Prior and concomitant 
medications 
X 
1. Details in separate flow chart (Table 8.1-4). The duration of the residential period may be amended following review of data from earlier cohorts.  
2. Confirmation of eligibility prior to randomisation. Day -1 or Day 1. 
3. Weight only.  
4. Random drug screening test may also be performed at the discretion of the investigator. 
5. WOCBP only. Screening: plasma/serum tests, other visits: urine test.  
6. Short version of physical examination on Day 1 and Day 12.  
7. Pre-dose assessments may be performed pre-dose Day 1/Day 10 or on Day -1/Day 9.  
8. Clinical chemistry, haematology, coagulation, urinalysis (dip-stick), see Section 11.3.6. 
9. Clinical chemistry only on Day 2 and Day 6. Approximately 8 h post-dose on Day 2 and pre-dose on Day 6. No clinical laboratory sampling on Day 4, 5, 7 and 8.  
10. Blood pressure and pulse, see Section 11.3.3.  
11. For timing of assessments, refer to Table 8.1-4. 
12. Once daily administration of IMP. On Day 1 and Day 10, administration under fasting conditions, i.e. fasting for 10 h before IMP administration until 4 h post administration. On Days 2 
to 9, administration prior to breakfast at the same time each morning (±1 h).  
13. Includes sampling for future exploratory analyses of potential GS-248 metabolites.  
14. Pre-dose PK samples on Day 8, 9 and 10 must be taken within 5 minutes before dose.  
15. Future exploratory analyses of biomarkers e.g. inflammatory biomarkers.  
16. Urine for analysis of AA metabolites and for future analysis of GS-248 metabolites and biomarkers will be collected at the following intervals: 0 to 6 h, 6 to 12 h and 12-24 h post 
administration of study drug on Day 1 and Day 10. In addition, baseline urine is collected -24 h to -12 h and -12 h to 0 h prior to the first IMP administration on Day -1/Day 1.  
17. Breakfast, lunch, snack, dinner and evening snack. Standardised meals during 24 h after dose on Day 1 and Day 10. For timing of meals, refer to Table 8.1-4. No breakfast on Day 1 and 
Day 10. Breakfast only on Day 3 and Day 12.  
18. From administration of IMP.  

 
 
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Table 8.1-4 
Detailed schedule of events for Visit 2 and Visit 8, Part II (MAD) 
 
Day 
-1 
Day 9 
Day 1/Day 10 
Day 2/Day 11 
Day 3/ 
Day 12 
Assessment/time-point 
Admission 
Pre-
dose 
0 
0.25h 
0.5h 
1h 
2h 
4h 
6h 
8h 
12h 
16h 
24h 
36h 
48 h 
Inclusion/exclusion criteria 
 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
X1,2 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
Clinical laboratory profile 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X5 
 
X 
Vital signs6 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Body temperature 
 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
 
 
X4 
 
 
 
 
X 
 
 
X 
 
 
X7 
 
X 
Randomisation 
 
 
X8 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X9 
 
X9 
PK blood sampling 
 
X11 
X10,11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
 
X13 
Blood sampling for GS-248 
MIST14 
 
 
X11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
 
 
Blood sampling for WBA 
 
 
X10 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Blood sampling for ADMA 
analysis 
 
 
X10 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Blood sampling for future 
biomarker analyses 
 
 
X10 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Urine collection15 
X 
 
 
X 
X 
X 
 
 
Breakfast16 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Meals 
X17 
X17, 
 
 
 
 
 
 
X17,18 
 
 
 
 
X17 
 
X17 
Baseline symptoms 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs and SAEs 
 
 
 
X 
Prior and concomitant 
medications 
X 

 
 
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1. 
Day -1 or pre-dose Day 1 prior to randomisation. Not Day 10.  
2. 
Short version of physical examination. 
3. 
Physical examination Day 12, not Day 3. 
4. 
Day -1/Day 9 or pre-dose Day 1/Day 10 
5. 
Day 2; clinical chemistry only. Approximately 8 h post-dose. Not Day 11.  
6. 
Day 1 at time points indicated, Day 2, Day 3 and Day 10 (approximately 2 h post-dose only) and Day 12 prior to departure. Not Day 11. 
7. 
ECG on Day 2, not Day 11.  
8. 
Randomisation on Day 1.  
9. 
IMP administration on Day 2 and Day 3, not Day 11 or Day 12.  
10. Pre-dose sample on Day 1 should be taken within 60 minutes prior to dose.  
11. Pre-dose samples on Day 8, 9 and 10 must be taken within 5 minutes before dose.  
12. The 24 h PK sample is taken pre-dose Day 2 or 24 h post last dose on Day 11 within 10 minutes of the of the nominal time for the dosage interval. For details regarding time windows 
for PK sampling on Days 2, 8, 9 and 10, refer to Section 11.4.1. 
13. 48 h after last dose on Day 12. Not Day 3. 
14. Day 1 and Day 10 during 24 h in association with PK sampling. Includes sampling for future exploratory analyses of potential GS-248 metabolites. 
15. Urine for analysis of AA metabolites and for future analysis of GS-248 metabolites and biomarkers will be collected at the following intervals: 0 to 6 h, 6 to 12 h and 12-24 h post 
administration of study drug on Day 1 and Day 10. In addition, baseline urine is collected -24 h to -12 h and -12 h to 0 h prior to the first IMP administration on Day -1/Day 1. 
16. Fasting on Day 1 and Day 10. Non-standardised breakfast on Day 2, Day 3, Day 9, Day 11 and Day 12 after PK blood sampling.  
17. Standardised lunch, snack, dinner and evening snack at approximately 4, 7 and 9 and 11 h post breakfast. Breakfast only on Day 3 and Day 12. 
18. Standardised lunch at least 4 h post-dose.  
 
 

 
 
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 Part III: Patients with Systemic Sclerosis and Raynaud’s Phenomenon  
Part III of the study will explore multiple dosing of GS-248 in SSc patients with Raynaud’s 
Phenomenon. The dose will be based on emerging knowledge of safety, tolerability and PK of 
GS-248 observed in the preceding SAD and MAD parts of the study (Part I and II).  
GS-248 is planned to be administered once daily for 10 days. The dose level in part III will be 
selected such that the predicted maximum exposure will not exceed the maximum exposure 
(based on AUC and Cmax) in previously evaluated cohorts in healthy volunteers (Part I and 
Part II). The dose and time points and visits for PK sampling may be adjusted based on PK 
evaluation in the SAD and MAD parts.  
Ten SSc patients will be included in Part III of the study. The patients will be randomised in a 
4:1 ratio to receive GS-248 (n=8) or placebo (n=2) in a blinded fashion. One additional cohort 
may be added as needed to e.g. repeat the dose or to test additional doses or dosing schemes.   
Patients will come for 9 visits to the clinic. Screening (Visit 1) will take place from Day -42 to 
Day -2 (for details on assessments, refer to Table 8.1-5). At Visit 2, patients will be admitted 
to the clinic in the morning of Day -1 for pre-dose assessments including a 24 h baseline urine 
collection and will remain at the clinic until Day 3 for IMP administration and safety, PK and 
exploratory PD assessments (Table 8.1-5 and Table 8.1-6). Up to 2 subjects will be dosed on 
the same day. The patients 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 8.1-5. 
There is access to equipment, qualified staff and an ICU in case of an acute emergency.  
Outpatient visits for IMP administration, safety and PK assessments are planned for Day 4 to 
Day 8 (Visit 3 to Visit 7), see Table 8.1-5 and Table 8.1-6. On Day 9 (Visit 8), patients will 
come to the unit in the morning for IMP administration and PK sampling and will return again 
in the evening for admission. For practical reasons, and if preferred by the patient, he or she 
may remain at the clinic during the whole Day 9. Subjects will be residential at the clinic 
between Day 9 and Day 12 (Visit 8) for IMP administration, safety, PK and exploratory PD 
assessments. The last dosing day is Day 10. Urine collection for exploratory PD analysis will 
be performed during 24 h after the last dose. A final end-of-study visit (Visit 9) is planned to 
take place on Day 19 (±2 days) or after early withdrawal. 
Each patient is expected to participate in the study for approximately 61 days including a 
41-day screening period.  
The schedule of events for Part III is shown in Table 8.1-5 and is detailed for Visit 2 and 
Visit 9 in Table 8.1-6. Study assessments are described in Section 11. 
Safety assessments include: AE reporting, 12-lead ECG monitoring, vital signs (blood 
pressure and pulse), body temperature, physical examination, use of concomitant medications 
and blood sampling for haematology, clinical chemistry and coagulation parameters, see 
Section 11.3. 
PK assessments include: blood sampling for bioanalysis and subsequent determination of PK 
parameters, see Section 11.4.  
Exploratory assessments include: blood sampling for analysis of mPGES-1 activity (PGE2 
levels) in an ex vivo WBA, blood and urine sampling for analysis of ADMA in plasma and 
AA metabolites in urine, and blood and urine sampling for future exploratory biomarker 
analyses, see Section 11.5. 

 
 
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Table 8.1-5 
Schedule of events Part III (SSc patients)  
 
Screening 
Residential period 
Daily 
visits 
Residential period 
End-of-
study 
Visit 
Visit 1 
Visit 22 
Visit 3 to 7 
Visit 82 
Visit 9 
Assessment/time point  
Day -42 to 
Day -2 
Admission  
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 to 8 
Admission 
Day 9 
Day 10 
Day 11 
Day 12 
Day 19 
(±2 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X3 
 
 
 
 
 
 
 
 
Weight/height 
X 
 
 
 
 
 
 
 
 
 
X4 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
HIV, hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
X 
 
 
 
X 
Pregnancy Test (WOCBP)5 
X 
X 
 
 
 
 
X 
 
 
 
X 
Physical Examination 
X 
 
X6, 7 
 
 
 
 
 
 
X6 
X 
Clinical Laboratory Profile8 
X 
X 
 
X9 
X 
X9 
X 
 
 
X 
X 
Vital signs10 
X 
X 
X11 
X11 
X 
 
X 
X11 
X11 
X 
X 
Body temperature 
 
 
X7 
 
 
 
 
X7 
 
 
 
12-lead ECG 
X 
 
X7, 11 
X 
X 
 
 
X7, 11 
 
X 
X 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
IMP administration12 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
PK blood sampling 
 
 
X11 
X11 
X13 
X11, 13 
X11, 13 
X 
X 
Blood sampling for WBA 
 
 
X11 
X11 
 
 
 
X11 
X11 
 
 
Blood sampling for ADMA 
analysis 
 
 
X11 
X11 
 
 
 
X11 
X11 
 
 
Blood sampling for future 
biomarker analyses14 
 
 
X11 
X11 
 
 
 
X11 
X11 
 
 
Urine collection 
 
X15 
 
 
 
X15 
 
 
Raynaud’s questioning 
 
 
 
 
 
 
 
 
X 
 
 
Meals16 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 

 
 
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Screening 
Residential period 
Daily 
visits 
Residential period 
End-of-
study 
Visit 
Visit 1 
Visit 22 
Visit 3 to 7 
Visit 82 
Visit 9 
Assessment/time point  
Day -42 to 
Day -2 
Admission  
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 to 8 
Admission 
Day 9 
Day 10 
Day 11 
Day 12 
Day 19 
(±2 days) 
Baseline symptoms 
X 
X 
 
 
 
 
 
 
 
 
 
AEs 
 
 
X17 
SAEs 
X 
Prior and concomitant 
medications 
X 
1. The screening visits may be conducted as a single visit.  
2. Details in separate flow chart (Table 8.1-6). The duration of the residential period may be amended following review of data from earlier cohorts.  
3. Confirmation of eligibility prior to randomisation. Day -1 or Day 1. 
4. Weight only.  
5. Screening: plasma/serum tests, other visits: urine test.  
6. Short version of physical examination on Day 1 and Day 12.  
7. Pre-dose assessments may be performed pre-dose Day 1/Day 10 or on Day -1/Day 9.  
8. Clinical chemistry, haematology, coagulation, urinalysis (dip-stick), see Section 11.3.6. 
9. Clinical chemistry only on Day 2 and Day 6. Approximately 8 h post-dose on Day 2 and pre-dose on Day 6. No clinical laboratory sampling on Day 4, 5, 7 and 8.  
10. Blood pressure and pulse, see Section 11.3.3.  
11. For timing of assessments, refer to Table 8.1-6. 
12. Once daily administration of IMP. On Day 1 and Day 10, administration under fasting conditions, i.e. fasting for 10 h before IMP administration until 4 h post administration. On Day 2 to 
Day 9, administration prior to breakfast at the same time each morning (±1 h).  
13. Pre-dose PK samples on Day 8, 9 and 10 must be taken within 5 minutes before dose.  
14. Future exploratory analyses of biomarkers e.g. further AA metabolite profiling and inflammatory biomarkers.  
15. Urine for analysis of AA metabolites and for future analysis of biomarkers will be collected at the following intervals: 0 to 6 h, 6 to 12 h and 12-24 h post administration of study drug on 
Day 1 and Day 10. In addition, baseline urine is collected -24 h to -12 h and -12 h to 0 h prior to the first IMP administration on Day -1/Day 1.  
16. Standardised breakfast, lunch, snack, dinner and evening snack. For timing of meals, refer to Table 8.1-6. No breakfast on Day 1 and Day 10. Breakfast only on Day 3 and 12.  
17. From administration of IMP.  

 
 
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Table 8.1-6 
Detailed schedule of events for Visit 2 and Visit 8, Part III (SSc patients) 
 
Day -1 
Day 9 
Day 1/Day 10 
Day 2/ Day 11 
Day 3/ 
Day 12 
Assessment/time-point 
Admission 
Pre-
dose 
0 
0.25h 
0.5h 
1h 
2h 
4h 
6h 
8h 
12h 
16h 
24h 
36h 
48h 
Inclusion/exclusion criteria 
 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
X1,2 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
Clinical laboratory profile 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X5 
 
X 
Vital signs6 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Body temperature 
 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
 
 
X4 
 
 
 
 
X 
 
 
X 
 
 
X7 
 
X 
Randomisation 
 
 
X8 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X9 
 
X9 
PK blood sampling 
 
X11 
X10, 11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
 
X13 
Blood sampling for WBA 
 
 
X10 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Blood sampling for 
ADMA analysis 
 
 
X10 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Blood sampling for future 
biomarker analyses 
 
 
X10 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Urine collection14 
X 
 
X 
X 
X 
 
 
Raynaud’s questioning 
 
 
 
 
 
 
 
 
 
 
 
 
 
X15 
 
 
Breakfast16 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Meals17 
X17 
X17 
 
 
 
 
 
 
X17,18 
 
 
 
 
X17 
 
X17 
Baseline symptoms  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
 
X 
 
X 
SAEs 
X 
Prior and concomitant 
medications 
X 

 
 
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1. 
Day -1 or pre-dose Day 1 before randomisation. Not Day 10.  
2. 
Short version of physical examination. 
3. 
Physical examination on Day 12, not Day 3.  
4. 
Day -1/Day 9 or pre-dose Day 1/Day 10 
5. 
Day 2; clinical chemistry only. Approximately 8 h post-dose. Not Day 11. 
6. 
Day 1 at time points indicated, Day 2, Day 3 and Day 10 (approximately 2 h post-dose only) and Day 12 prior to departure. Not Day 11. 
7. 
ECG on Day 2, not Day 11. 
8. 
Randomisation on Day 1.  
9. 
IMP administration on Day 2 and Day 3, not Day 11 or Day 12. 
10. Pre-dose sample on Day 1 should be taken within 60 minutes prior to dose. 
11. Pre-dose PK samples on Day 8, 9 and 10 must be taken within 5 minutes before dose.  
12. The 24 h sample is taken pre-dose Day 2 or 24 h post last dose on Day 11 within 10 minutes of the of the nominal time for the dosage interval. For details regarding time windows for 
PK sampling on Days 2, 8, 9 and 10, refer to Section 11.4.1. 
13. 48 h after last dose on Day 12. Not Day 3. 
14. Urine for analysis of AA metabolites and for future analysis of biomarkers will be collected at the following intervals: 0 to 6 h, 6 to 12 h and 12-24 h post administration of study drug 
on Day 1 and Day 10. In addition, baseline urine is collected -24 h to -12 h and -12 h to 0 h prior to the first IMP administration on Day -1/Day 1. 
15. Day 11, not Day 2.  
16. Fasting on Day 1 and Day 10. Standardised breakfast on Day 2, Day 3 and Day 9 after PK blood sampling.  
17. Standardised lunch, snack, dinner and evening snack at approximately 4, 7 and 9 and 11 h post breakfast. Breakfast only on Day 3 and Day 12. 
18. Standardised lunch at least 4 h post-dose.  
 

 
 
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 Part IV: Celecoxib – open cohort with healthy volunteers 
In Part IV of the study, 200 mg celecoxib will be administered to 8 healthy volunteers twice 
daily for 10 days (i.e. 400 mg/day for 10 days).  
Subjects will come for 5 visits to the clinic. Screening (Visit 1) will take place from Day -28 
to Day -2. For details on assessments, refer to Table 8.1-7. At Visit 2, subjects will be 
admitted to the clinic in the morning of Day -1 for pre-dose assessments including a 24 h 
baseline urine collection and will remain at the clinic until Day 2 for IMP administration and 
PD assessments (Table 8.1-7). Subjects will be discharged from the clinic after the morning 
dose on Day 2.  
From the evening of Day 2 to the evening of Day 8, subjects will self-administer celecoxib at 
home twice daily (morning and evening) and register each administration in an electronic 
diary (ViedocMe). Any reactions or use of concomitant medication will also be registered in 
ViedocMe. On Day 5 (Visit 3), the subjects will be contacted by phone for a drug 
accountability and AE check-up.  
Subjects will again be residential at the clinic between Day 9 and Day 11 (Visit 4) for IMP 
administration and exploratory PD assessments. The last dosing day is Day 10. Urine 
collection for exploratory PD analysis will be performed during 24 h after the last morning 
dose on Day 10. A final end-of-study visit (Visit 5) will take place on Day 19 (±2 days) or 
after early withdrawal.  
Each subject is expected to participate in the study for approximately 47 days including a 
27-day screening period. 
The schedule of events for Part IV is shown in Table 8.1-7. 
Study assessments are described in Section 11. 
Safety assessments include: AE reporting and use of concomitant medications, see 
Section 11.3. 
Exploratory assessments include: blood sampling for analysis of mPGES-1 activity (PGE2 
levels) in an ex vivo WBA, blood and urine sampling for analysis of ADMA in plasma and 
AA metabolites in urine, and blood and urine sampling for future exploratory biomarker 
analysis, see Section 11.5. 
 
 

 
 
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Table 8.1-7 
Part IV Schedule of events, celecoxib 
 
Screening
Residential 
At home 
Telephone 
call 
At 
home 
Residential 
End-of-
study 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Assessment 
Day -28 
to Day -2 
Day -1 
Day 1 
Day 2 
Day 3 & 4 
Day 5 
Day 6, 
7 & 8 
Day 9 
Day 10 
Day 11 
Day 19 (±2 
days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X1 
 
 
 
 
 
 
 
 
Weight/height/BMI 
X 
 
 
 
 
 
 
 
 
 
X2 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
HIV, hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen3 
X 
X 
 
 
 
 
 
X 
 
 
X 
Alcohol breath test 
X 
X 
 
 
 
 
 
X 
 
 
X 
Pregnancy Test4 
X 
X 
 
 
 
 
 
X 
 
 
X 
Physical Examination 
X 
 
 
 
 
 
 
 
 
X 
Clinical Laboratory Profile5 
X 
 
 
 
 
 
 
 
 
X 
Vital signs  
X 
 
 
 
 
 
 
X 
12-lead paper ECG 
X 
 
 
 
 
 
 
 
X 
Celecoxib administration BID6 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood sampling for WBA7 
 
 
X 
X 
 
 
 
 
X 
X 
 
Blood sampling for ADMA analysis7 
 
 
X 
X 
 
 
 
 
X 
X 
 
Blood sampling for future biomarker  
analyses7 
 
 
X 
X 
 
 
 
 
X 
X 
 
Urine collection8 
 
X 
X 
X 
 
 
 
 
X 
X 
 
Meals9 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
Baseline symptoms 
X 
X 
 
 
 
 
 
 
 
 
 
AEs and SAEs10 
 
 
X 
Prior and concomitant medications 
X 

 
 
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1. Confirmation of eligibility prior to randomisation. Day -1 or Day 1. 
2. Weight only.  
3. Random drug screening test may also be performed at the discretion of the investigator. 
4. WOCBP only. Screening: plasma/serum tests, other visits: urine test.  
5. Clinical chemistry, haematology, coagulation, urinalysis (dip-stick), see Section 11.3.6. 
6. To be taken each morning and evening at the same time (±1 h). Self-administration at home from the evening of Day 2 to the evening of Day 8. 
7. Blood samples for WBA, ADMA and future biomarker analyses are drawn 0 h (within 60 min pre-dose) and 2 h, 8 h and 24 h post administration of celecoxib on Day 1 and Day 10 (24 h 
samples taken pre-dose on Day 2 and 24 h post last dose on Day 11, respectively). 
8. Urine for PD analysis will be collected at the following intervals: 0 to 6 h, 6 to 12 h and 12-24 h post administration of celecoxib on Day 1 and Day 10. In addition, baseline urine is 
collected -24 h to -12 h and -12 h to 0 h prior to the first celecoxib administration on Day -1/Day 1.  
9. Breakfast, lunch, snack, dinner and evening snack. Breakfast only on Day 2 and 11.  
10. From administration of IMP.  

 
 
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8.2 
Rationale for study design 
The design of the study is based on the aim to study safety, tolerability, PK and PD of 
selected doses of GS-248 in a limited number of healthy volunteers and patients. The design 
is adaptive, to allow for flexible dose escalation and involves careful monitoring of the 
subjects’ well-being. The time points for PK blood sampling have been selected based on data 
obtained from pre-clinical studies but may be changed based on emerging data. Time points 
for PD sampling (blood and urine) is based on previous experience with selective inhibition of 
the mPGES-1 in a human Phase I study [15] and on predicted human PK.  
A placebo control will be used in Parts I, II and III to establish the frequency and magnitude 
of changes in endpoints that may occur in the absence of active treatment.  
Randomisation will be used in Part I, II and III to minimise bias in the assignment of subjects 
to dose groups and to increase the likelihood that known and unknown subject attributes (e.g., 
demographic and baseline characteristics) are evenly balanced across treatment groups.  
Blinded treatment will be used in Part I, II and III to reduce potential bias during data 
collection and evaluation of endpoints. 
Part IV will be non-placebo controlled, non-randomised and open. The purpose of Part IV is 
to collect PD data for comparison with GS-248.   
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 starting dose and rationale for planned dose escalation  
 Selection of starting dose in the SAD part 
A single oral dose of 1 mg is proposed for the first cohort, since it is estimated that this will 
yield a pharmacological response close to the Minimum Anticipated Biological Effect Level 
(MABEL), which corresponds to 20% of the maximum attainable area under the effect (AUE; 
i.e. inhibition) curve 0-24 h as described in the IB. 
In assessment of the pharmacological response in terms of mPGES-1 inhibition, one must 
consider both the duration and the magnitude of such inhibition, i.e. the AUE. In view of a 
target human dosing interval of at most 24 h and the projected PK of GS-248, it appears 
reasonable to apply the AUE from 0 to 24 h [AUE(0-24)] as a function of dose in order to 
define MABEL. In this context, 20% of maximum attainable AUE(0-24) is chosen to constitute 
MABEL, and is projected to be achieved by a single oral dose of GS-248 between 0.9 and 
1.7 mg, based on allometric scaling from dog and cynomolgus monkey, respectively.  
The NOAEL in the 28-day dog toxicity study was set at 20 mg/kg, with mean Cmax and 
AUC0-24 h values at this dose level of 2500 nmol/L and 23000 h*nmol/L (in males and females 
combined), respectively. These values set the maximum limits for exposure in humans in this 
Phase I study. 
The predicted exposure at the chosen starting dose in the SAD phase results in exposure 
margins for Cmax and AUC0-24 h of 250- and 290-fold, respectively, compared to the exposure 
at the lowest dose level in the dog study, and 450- and 740-fold, respectively, compared to the 

 
 
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exposure at the NOAEL (Table 8.3-1). All these margins are considered to constitute good 
safety margins between animals and man. However, it should be realised that the human 
exposure values used in these calculations are, of necessity, only estimated values.  
Table 8.3-1 
Exposure margins for mean Cmax and AUClast values between GS-248-treated 
animals in the pivotal 28-day toxicity studies and the predicted values in humans 
in the SAD  
Species 
Study 
No. 
Dose level 
Duration 
Sex 
Cmax 
AUCa 
Exposure 
margin 
 
(mg/kg 
animals) 
(days) 
 
(nmol/L) 
(h*nmol/L) 
animals:mane 
(X-fold) 
 
 
(mg 
humans) 
 
 
 
 
Cmax 
AUCa 
Rats 
36325 
150/400/1000 
(< NOAEL) 
28 
Fb 
ca. 2100c 
ca. 30000c 
- 
- 
 
 
 
 
 
 
 
 
 
Dogs 
36327 
5 
28 
M+
F 
1400 
9000 
- 
- 
 
 
20 NOAEL 
28 
M+
F 
2500 
23000 
- 
- 
 
 
 
 
 
 
 
 
 
Humans 
Pre-
dicted 
1 
Starting dose 
SADd 
1 
- 
4.6-5.6 
19-31 
250f 
290f 
450g 
740g 
NOAEL = No observed adverse effect level 
a 
AUC0-24 h in rats and dogs; AUC0-∞ in humans 
b 
Exposure was clearly higher in female rats than in males. Therefore, values in females only are included exposure 
c 
Exposure was equivalent at all 3 dose levels in rats. Therefore, approximate mean values from all females combined are 
given 
d 
See above in Section 8.3.1 for the rationale for the starting dose in the SAD phase of the study 
e 
All exposure margins are calculated against the highest predicted exposure values in man 
f 
Exposure margins based on the lowest dose level in the 28-day dog study 
g 
Exposure margins based on NOAEL (the intermediate dose level) in the 28-day dog study 
 
Additionally, an approximate comparison of the given doses in the preclinical repeat-dose 
studies expressed as mg/m2 body surface area can be used to supplement comparison based on 
kinetic data. The mg/kg doses are converted to mg/m2 body surface area by multiplying by a 
factor 20 for dogs and 37 for a 60 kg human in terms of Human Equivalent Dose (HED), as 
per FDA guideline on estimation of maximum safe starting dose in initial clinical trials [17]. 
This gives 0.62 mg/m2 for the starting dose in the SAD part (1 mg) 100 mg/m2 for the lowest 
dose level (5 mg/kg) and 400 mg/m2 for NOAEL (20 mg/kg) in the 28-day dog study, with 
dose margins of 160- and 650-fold, respectively. 
In view of the sizable margin against NOAEL in the 28-day dog study in terms of predicted 
human AUC(0-inf) (740-fold) and also in terms of HED (650-fold), together with the fact that 
the target, mPGES-1, has previously been subject to pharmacological intervention in clinical 
trials with no reported overt target-related side-effects [15] it was deemed reasonable not to 
apply any additional margins against MABEL in the first cohort. Furthermore, mPGES-1 -/- 
mice are viable and fertile and develop normally compared with wild-type controls [18], 

 
 
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hence have no specific phenotype under normal conditions, while being protected in various 
inflammatory disease models [14]. 
 Rationale for dose escalation in the SAD part 
The desired pharmacological effect of GS-248 in humans includes i) blocking the production 
of PGE2 via mPGES-1, and ii) increased production of the vasodilatory and platelet-inhibitory 
PGI2 via substrate shunting. The latter aspect calls for a pronounced level of inhibition of 
mPGES-1 over 24 h, to optimise for the desired shunting effect and intravascular PGI2 
synthesis. 
A PK/exposure-driven dose escalation strategy will be applied such that the first cohort is 
expected to yield a systemic exposure corresponding to MABEL and the last cohort will 
achieve exposures close to the maximum exposure limits, as established by the 28-day dog 
toxicity study, unless safety or tolerability has previously limited escalation. The escalation 
steps will be smaller when the maximum exposure limits are approached.  
Pharmacokinetics will be evaluated following each cohort and the escalation scheme can be 
modified based on the totality of acquired PK, safety and tolerability data. In case of sings of 
unpredictable PK (i.e. highly variable or non-linear PK) escalation steps will be decreased. In 
case the systemic exposure following the first cohort is appreciably smaller than predicted or 
below the lower limit of quantification (LLOQ), multiple maximum 8-fold dose escalations 
will be allowed until the exposure is within the predicted range of the study. If the systemic 
exposure following the first cohort is appreciably larger than projected, escalation steps will 
be decreased or, in case of limiting safety or tolerability, de-escalation may be performed. The 
decision on dose selection will be made by the iSRC, which will have access to all safety, 
tolerability and PK data (8.3.8).  
A tentative dose escalation scheme based on target systemic exposures is shown in 
Table 8.3-2 where the first and last cohorts are determined by MABEL and maximum 
exposure limits, and the mid-range of maximum attainable AUE(0-24) is expected to be 
achieved between cohort 2 and 3. 
Table 8.3-2 
Tentative dose escalation schedule SAD 
Cohort: 
1 
2 
3 
4 
5 
6 
(7) 
Tentative 
dose (mg) 
1 
5 
25 
75 
225 
450 
 800 
Predicted 
AUC0-inf 
19-31 
97-150 
480 – 770 
1500 – 
2300 
4400 – 
6900 
8700 – 
14000 
16000- 
25000 
 
For details on the prerequisites for the transition from single to multiple dosing, refer to 
Section 8.3.5. 
 Selection of starting dose and dose escalation in the MAD part 
The starting dose in the MAD part of the study will be selected with the aim to achieve an 
exposure similar to that observed in the third cohort in the SAD part, and is tentatively set to 
25 mg. The doses in the second and third MAD cohorts will be selected to achieve an 

 
 
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escalation of exposure of approximately 3 times of what was observed in the previous cohort. 
The dose in the fourth (and potential fifth) MAD cohort will be selected to achieve an 
exposure twice of what was observed in the previous cohort. Tentative doses are displayed in 
Table 8.3-3.  
Table 8.3-3 
Tentative dose escalation schedule MAD 
Cohort: 
1 
2 
3 
4 
Maximum exposure escalation steps 
 
3x 
3x 
2x 
Tentative doses (mg) 
251 
75 
225 
4502 
1. 
Aimed to achieve an exposure similar to that in the third cohort of the SAD part. 
2. 
Projected exposure not exceeding what was achieved by the study maximum dose given in the SAD part in 
terms of AUC0-∞. 
If the systemic exposure following any of the first 3 cohorts is appreciably larger than 
projected, escalation steps will be decreased. In case of limiting safety or tolerability, de-
escalation may be performed. The decision on dose selection will be made by the iSRC, 
which will have access to all safety, tolerability and PK data as outlined in Section 8.3.8.  
PK information from the SAD part will give the terminal T½ of the drug, which in turn, will 
indicate potential accumulation of GS-248. The dose, or dosing interval, will be adjusted 
accordingly if such is identified. If safety and tolerability allows, the aim is to, in the last 
MAD cohort, reach a maximum exposure in terms of AUC0-tau not exceeding what was 
achieved by the study maximum dose given in the SAD part in terms of AUC0-∞. 
 Maximum exposure and dose 
The maximum dose to be given is 800 mg/day. The maximum exposure in the study may not 
exceed 2500 nmol/L or 23 000 h*nmol/L in terms of Cmax and AUC, respectively, based on 
Cmax and AUC0-24 at the dog NOAEL (males and females combined). 
 From single to multiple dosing 
Following completion of cohort 4 of Part I (SAD), the iSRC will evaluate all available safety, 
tolerability and PK data up until and including at least 48 h data from SAD cohort 4 and, if 
necessary, suggest adjustments to dose levels, dosing regimens or dosing duration in a written 
recommendation to the Sponsor. If no safety or tolerability concerns are identified, and 
provided that the PK of GS-248 is linear, cohort 1 of Part II (MAD) will be initiated 
approximately in parallel with cohort 5 of Part I (SAD) as decided by the Sponsor. The 
predicted exposure in the MAD will not exceed the maximum exposure (based on AUC and 
Cmax) in any previously evaluated SAD cohort. The iSRC recommendation, as well as 
Sponsor’s decision, will be documented in a non-substantial amendment to the clinical study 
protocol (CSP). 
 From healthy volunteers to patients 
Prior to start of Part III (SSc patients), a substantial amendment containing a summary of 
blinded Part I and Part II safety, tolerability and PK data (all cohorts), the intended Part III 
dose, a dose rationale, the dosing duration and a request to start Part III, will be submitted to 

 
 
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the competent authority (CA) and an independent ethics committee (IEC). In case the 
systemic exposure of GS-248 is considered sufficiently high already after 3 MAD cohorts, or 
if indicated by safety and tolerability data, the fourth (and fifth) cohort(s) will not be 
conducted and the substantial amendment prior to start of Part III will be submitted following 
completion of the third MAD cohort. Part III will not start until after approval from the CA 
and IEC. 
 Stopping criteria for dose escalation 
The iSRC (including the Principal Investigator; Section 8.3.8) will follow the 
recommendations and grading system of Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0 [19] see Section 11.3.1.7 but also take into account the recommendations 
published by Sibille et al. 2010 [20]  which is an adaptation to FIH studies of the grading 
systems previously proposed by National Cancer Institute (NCI) [19], World Health 
Organization (WHO) [21], National Institute of Health (NIH) [22] and the FDA [23]. The 
grade, the frequency of AEs and the blindness will be considered. 
A rolling review of emerging safety data will be performed throughout the study taking into 
account any AEs (in particular moderate AEs assessed as at least possibly related to the IMP 
administration), the number of subjects in whom they occur, concurrency of more than one 
event within the same subject and any trends. Changes from baseline measurements will also 
be considered and not just absolute cut-off based on upper- or lower limits of normal that 
might apply for healthy volunteers. 
Trends or safety signals described above, which are not necessarily covered by the stopping 
criteria in Table 8.3-4 may warrant the scheduling of ad hoc iSRC meetings after which the 
iSRC will make recommendations to sponsor on e.g. whether to terminate the study or to stop 
dosing in individual subjects or a certain cohort.  
Additional study specific withdrawal criteria are summarised in Section 9.7. 

 
 
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Table 8.3-4 
Dose escalation and stopping rules, Part I and Part II 
Stop criterion 
Action taken 
At individual and dose group level 
If no subject has an SAE 
considered at least 
possibly related to the IMP 
administration, i.e. a 
serious adverse drug 
reaction (SADR) 
Escalate to the next higher dose level. 
If 1 subject on active 
treatment has an SAE 
assessed as at least 
possibly related to IMP 
administration 
1. Stop dosing of subject with a potential SADR. Withdrawal of subject. 
2. Unblinding of subject with potential SADR. Only voting members of 
the iSRC will be unblinded.  
3. Evaluation by iSRC. The iSRC makes recommendation to Sponsor. 
4. Sponsor decides how to proceed: 
Subject met stop criterion: stop further dosing at this dose level for all 
subjects. Sponsor decides if the study will be terminated or if dosing 
will commence at a lower dose level or at an intermediate dose level.  
If 2 subjects on active 
treatment have severe, 
non-serious AEs assessed 
at least possibly related to 
the IMP administration 
(independent of within or 
not within the same 
System organ class [SOC])  
1. Stop dosing of subjects with severe, non-serious potential ADRs. 
2. Unblinding of the subjects with potential ADRs. Only voting members 
of the iSRC will be unblinded. 
3. Evaluation by iSRC. The iSRC makes recommendation to Sponsor. 
4. Sponsor decides how to proceed: 
Both subjects meet stop criterion: stop further dosing at this dose level 
for all subjects. Sponsor decides if the study will be terminated or if 
dosing should commence at a lower dose level or at an intermediate 
dose level.  
If 1 subject has an AUC0-∞ 
(single dose) or AUC0-tau 
(repeated dose)  higher 
than 23 000 h*nmol/L 
(corresponding to the 
NOAEL in male and 
female dogs)1 
1. Evaluation by iSRC. The iSRC makes recommendation to Sponsor. 
2. Sponsor decides if the study will be terminated or if dosing in the next 
cohort should commence at a lower dose level or at an intermediate 
dose level.  
If 1 subject has a Cmax 
higher than 2500 nmol/L 
(corresponding to the 
NOAEL in male and 
female dogs) 1 
1. Evaluation by iSRC. The iSRC makes recommendation to Sponsor 
2.  Sponsor decides if dosing in the next cohort should commence at a 
lower dose level or at an intermediate dose level. 
Final dosing stop and termination of study 
If 2 subjects on active 
treatment in different 
cohorts have SAEs 
assessed as at least 
possibly related to IMP 
administration 
1. Stop dosing of subjects with potential SADR. Withdrawal of subjects. 
2. Unblinding of subjects with potential SADRs. Only voting members of 
the iSRC will be unblinded.  
3. Evaluation by iSRC. The iSRC makes recommendation to Sponsor. 
4. Subjects meet stop criterion: Termination of study.  
1. When reviewing emerging data in relation to this criterion, the maximum exposure observed in individual 
subjects within a cohort rather than the mean exposure should be taken into account 

 
 
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 Internal safety review committee  
Before initiating a new cohort, all subjects in the previous cohort must have been treated and 
safety, tolerability and PK data (at least 48 h data in Part I [SAD] and data up until and 
including 24 h post last dose in Part II [MAD]) for all treated subjects must have been 
evaluated by the iSRC.  
If GS-248 is considered safe and tolerable, a written recommendation on the next dose level 
based on the predicted exposure will be provided to the Sponsor. Likewise, the iSRC will 
recommend dose levels for Part II and III, respectively, based on review of data from earlier 
cohorts/study parts.   
Details regarding timing of iSRC review and the data to be reviewed will be provided in a 
separate iSRC charter. Based on emerging safety and PK information, the amount of safety 
and PK data to be reviewed after a completed cohort might be adjusted.  
The voting members of the iSRC will consist of the Principal Investigator and the Sponsor’s 
medically responsible person or delegate. In addition, the study clinical research manager 
(CRM), the study pharmacokineticist, additional Sponsor representatives and further internal 
or external experts will be invited and consulted as appropriate.  
An adaptive dosing strategy will be applied to allow for a flexible and safe dose escalation. 
The planned dose escalation is outlined in Section 8.3.2 and Section 8.3.3. The actual doses 
given in each cohort will be guided by the iSRC recommendations based on available safety, 
tolerability and PK data. Every dose step is thus adjustable and the recommendation to the 
Sponsor may be to continue with a higher or lower dose than the intended dose, repeat the 
same dose level, continue with an intermediate dose level or to stop dosing.  
The recommendation of the iSRC on the next dose level will be taken in consensus between 
the iSRC members and documented as appropriate. In case there is disagreement between the 
2 voting members, the most conservative approach will be recommended. It is not acceptable 
to repeat a dose level where any of the dose escalation stopping rules have been met. 
In Part I and Part II, 2 or 1 additional cohort(s), respectively, may be added as needed to test 
additional doses or dosing schemes, repeat the dose given in a previous cohort, to establish the 
target dose for Part III and subsequent studies and/or to reach steady state. In Part III, 
1 additional cohort (10 patients) may be added.  
The duration of the residential periods in each part may be amended following review of data 
from earlier cohorts. The predicted T½ of GS-248 is between 2 and 13 h, based on allometric 
scaling of preclinical data. A significantly shorter T½ than expected, as determined following 
analysis of PK data in the study, may warrant a shortening of the residential period provided 
that no safety issues are indicated. Conversely, if indicated by safety and or PK data, the 
duration of the residential periods may be prolonged. Should the duration of any residential 
period change, subsequent changes to the timing of safety and PK assessments will be done as 
necessary. A significantly shorter T½ than expected may also require a change in the dosing 
interval, i.e. twice daily GS-248 dosing rather than once daily dosing might be required in 
order to reach sufficient exposure. Such changes to the CSP (Part I, II or IV with healthy 
volunteers) will be documented in non-substantial amendments. A substantial amendment will 
be submitted to both the CA and the IEC prior to start of Part III (SSc patients) of the study, 
see Section 8.3.6. 

 
 
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The treatment code may be broken by the iSRC during the assessment process (partial un-
blinding) in accordance with stopping criteria described in Table 8.3-4. The medical staff and 
the subjects will still be blinded for the treatments (active drug or placebo) to be administered 
in the subsequent dose groups/cohorts in order to minimise bias. If unblinding was considered 
necessary, the iSRC meeting will consist of a closed part and an open part. 

 
 
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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 
Fort Part I, II and IV, the subjects will be recruited from CTC’s database of healthy volunteers 
and from advertising in media (including social media). 
Subjects may participate in more than one part of the study provided that the eligibility 
criteria for each part are met.  
The patients for Part III will be identified by referring rheumatologists.  
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 screening 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.  
Subjects included and randomised will be assigned a randomisation number (1101, 1102 etc. 
in the Part I, cohort 1; 2101, 2102 etc. in the Part II, cohort 1 and so on). The first digit will 
correspond to the study part, the second digit will correspond to the cohort and the 3rd and 4th 
digits correspond to the subject number.  
If a subject/patient cannot receive the planned dose of IMP within 27 days/41 days after 
screening (i.e., the time interval between signing informed consent until dose administration) 
the subject should be re-screened before proceeding in the study. 
9.3 
Number of subjects/patients  
Part I (SAD): 48 subjects will be randomised and dosed (6 cohorts, each of 8 subjects: 
6 GS-248, 2 placebo). 
Part II (MAD): 32 subjects will be randomised and dosed (4 cohorts, each of 8 subjects: 
6 GS-248, 2 placebo). 
Part III (SSc patients): 10 SSc patients will be randomised and dosed (1 cohort with 
10 subjects: 8 GS-248, 2 placebo). 
Part IV (celecoxib): 8 subjects will be randomised and dosed (1 cohort with 8 subjects 
receiving celecoxib). 

 
 
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If indicated by emerging data and recommended by the iSRC, 2 additional cohorts 
(8+8 subjects) may be added to Part I, 1 cohorts (8 subjects) may be added to Part II and 
1 cohort (10 patients) may be added to Part III. In such cases, and to account for potential 
drop-outs, additional subjects might be included in the study. 
For replacements of subjects who discontinue from the study, see Section 9.7.5. 
9.4 
Eligibility criteria 
 Inclusion criteria Part I, II and IV: SAD, MAD and celecoxib in healthy volunteers 
For inclusion in Part I, II and IV of the study, subjects must fulfil the following criteria:  
1. Willing and able to give written informed consent for participation in the study.  
2. Male and female healthy subjects aged 18-70 years inclusive (Part I [SAD]) and 40-
75 years inclusive (Part II [MAD] and Part IV [celecoxib])  
3. Women of child bearing potential (WOCBP) must practice abstinence (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 containing] hormonal contraception 
associated with inhibition of ovulation [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. Their male 
partner must agree to use a condom during the same time frame. 
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 blood 
sample with simultaneous detection of follicle stimulating hormone [FSH] 25-140 
IE/L and oestradiol <183 pmol/l is confirmatory).  
Male subjects must be willing to use condom or be vasectomised or practice sexual 
abstinence to prevent pregnancy and drug exposure of a partner and 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). 
4. Body mass index (BMI) ≥ 19 and ≤ 30 kg/m2.  
5. Subjects must be in good health as determined by medical history, physical 
examination, vital signs, 12-lead ECG and clinical laboratory assessments at the time 
of screening, as judged by the Investigator.  
 Exclusion criteria Part I, II and IV: SAD, MAD and celecoxib in healthy volunteers 
Subjects must not enter the study if any of the following exclusion criteria are fulfilled: 
1. Known allergy to any components of the GS-248 formulation. 
2. Females who are breast feeding or plan to be pregnant.  

 
 
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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. Use of corticosteroids (inhaled and systemic), NSAIDs (including e.g. coxibs and 
aspirin), antacids, PPIs or any medication that changes gastric pH within 2 weeks prior 
to the (first) administration of IMP. 
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. Inherited or acquired disorders of platelet function, bleeding or coagulation.  
7. Presence of any clinically relevant acute or chronic disease that could interfere with 
the subject’s safety during the clinical study or expose the subject to undue risk.  
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. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), 
hepatitis C virus antibodies (HCVAb) or human immunodeficiency virus (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. Any positive result for drug abuse and/or alcohol at screening or on admission to the 
unit prior to administration of the IMP. 
12. Participation in another clinical study with an experimental drug within 3 months 
before the administration of IMP.  
13. Consumption of grapefruit or grapefruit juice within 14 days of study drug 
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 or resected benign colonic polyps. 
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 at the time of screening, as judged by the 
Investigator. 

 
 
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18. Current smokers or users of nicotine products. Irregular use of nicotine (e.g. smoking, 
snuffing, chewing tobacco) less than 3 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. 
21. Plasma donation within one month of screening or blood donation (or corresponding 
blood loss) during the three months prior to screening.   
22. Investigator considers the subject unlikely to comply with study procedures, 
restrictions and requirements. 
Part IV, celecoxib only: 
History of salicylate hypersensitivity or NSAID hypersensitivity or subjects who have 
experienced asthma, urticaria or other allergic reactions after taking aspirin or other NSAIDs.  
 Inclusion criteria Part III: SSc patients 
1. Willing and able to give written informed consent for participation in the study. 
2. Male and female SSc patients aged 40-75 years inclusive. 
3. SSc disease duration less than 60 months based on the time from the first 
non-Raynaud phenomenon manifestation. 
4. Systemic Sclerosis diagnosed according to European League Against Rheumatism 
(EULAR)/American College of Rheumatology (ACR) criteria [24]. 
5. Raynaud’s Phenomenon as determined by the investigator, and with a typical 
frequency of attacks during the winter months of on average 5 per week (re-confirmed 
on admission to the study unit Day-1). 
6. WOCBP must practice abstinence (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 containing] hormonal contraception associated with inhibition of 
ovulation [oral, intravaginal, transdermal], progestogen-only hormonal contraception 
associated with inhibition of ovulation [oral, injectable, implantable], IUD or IUS) 
from at least 4 weeks prior to dose to 4 weeks after last dose. Their male partner must 
agree to use a condom during the same time frame. 
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 blood 
sample with simultaneous detection of FSH 25-140 IE/L and oestradiol <183 pmol/l is 
confirmatory). 
Male subjects must be willing to use condom or be vasectomised or practice sexual 
abstinence to prevent pregnancy and drug exposure of a partner and refrain from 
donating sperm from the date of dosing until 3 months after dosing with the IMP. 

 
 
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Their female partner of child-bearing potential must use contraceptive methods with a 
failure rate of < 1% to prevent pregnancy (see above). 
 Exclusion criteria part III: SSc patients 
1. Females who are breast feeding or plan to be pregnant. 
2. Positive serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of HCG) at screening and within 24 h prior to the first administration of IMP.  
3. Mixed connective tissue disease or "overlap" (i.e. those who satisfy more than one set 
of ACR criteria for a rheumatic disease). 
4. Ongoing treatment with immunosuppressive therapies including, but not restricted to; 
cyclophosphamide, azathioprine, mycophenolic acid, methotrexate, or cyclosporine, or 
use of those medications within 4 weeks prior to first dose. 
5. Use of inhaled or systemic corticosteroids within 4 weeks prior to first dose.   
6. Use of iloprost within 4 weeks prior to first dose.  
7. Concurrent serious medical condition which in the opinion of the investigator makes 
the patient inappropriate for this study such as uncontrollable Congestive heart failure, 
significant arrhythmia, severe pulmonary or systemic hypertension, severe 
gastrointestinal (GI) involvement, significant hepatic impairment, serum creatinine of 
greater than 2.0, active infection, severe diabetes, unstable atherosclerotic 
cardiovascular disease, malignancy, or severe peripheral vascular disease. Ongoing 
DUs are allowed at the discretion of the Investigator but must not need iloprost 
treatment and should not be infected. 
8. Have known allergies to any components of the GS-248 formulation. 
9. Use of NSAIDs (including e.g. coxibs and aspirin), antacids, PPIs or any medication 
that changes gastric pH within 2 weeks prior to the (first) administration of IMP. 
10. 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. 
11. Any positive result on screening for HBsAg, HCVAb or HIV 1 and/or 2 antibodies. 
12. Presence or history of drug or alcohol abuse or excessive intake of alcohol, as judged 
by the Investigator. 
13. Any positive result for drug abuse and/or alcohol at screening or on admission to the 
unit prior to administration of the IMP. 
14. Participation in another clinical study with an experimental drug within 3 months 
before the administration of IMP.  
15. Consumption of grapefruit or grapefruit juice within 14 days of study drug 
administration. 

 
 
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16. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks 
of the first administration of IMP. 
17. Malignancy within the past 5 years with the exception of in situ removal of basal cell 
carcinoma or resected benign colonic polyps. 
18. Any planned major surgery within the duration of the study. 
19. Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant 
abnormalities in the resting ECG at the time of screening, as judged by the 
Investigator. 
20. Current smokers or users of nicotine products. Irregular use of nicotine (e.g. smoking, 
snuffing, chewing tobacco) less than 3 times per week is allowed before screening 
visit. 
21. Unable or unwilling to reduce caffeine consumption to a daily intake of >5 cups of 
caffeine containing beverages. 
22. Intake of xanthine and/or taurine containing energy drinks within 2 days prior to 
screening. 
23. Plasma donation within one month of screening or blood donation (or corresponding 
blood loss) during the three months prior to screening.   
24. Investigator considers the subject unlikely to comply with study procedures, 
restrictions and requirements. 
9.5 
Restrictions during the study 
The subjects must be willing to comply to the below restrictions during the entire study 
duration i.e., from screening to the end-of-study visit (or longer if specified). 
 Restrictions all parts 
Contraception Requirements: All WOCBP must use effective contraception (defined in 
inclusion criterion No 3) or practice abstinence (only allowed when this is the preferred and 
usual lifestyle of the subject) from at least 4 weeks prior to dose until 4 weeks after last dose. 
Their male partners must agree to use a condom during the same time frame. 
The male volunteers are expected to use condom and their female partner of child-bearing 
potential must use a contraceptive method with a failure rate of < 1% to prevent pregnancy 
(for details, refer to inclusion criterion No 3) and drug exposure of a partner and refrain from 
donating sperm from the date of dosing until 3 months after the last IMP administration. 

 
 
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Meals and Dietary Restrictions:  
Part I: The IMP will be administered in the fasted state (at least 10 h of fasting) together with 
240 mL of tap water. 
Part II and Part III: On Day 1 and Day 10, the IMP will be administered in the fasted state 
(at least 10 h of fasting) together with 240 mL of tap water. On other dosing days, the IMP 
will be administered at the clinic just prior to breakfast.  
Part IV: On Day 1 and Day 10, the morning dose will be administered in the fasted state (at 
least 10 h of fasting) together with 240 mL of tap water. From Day 2 (evening dose) to Day 9 
(evening dose) there are no food restrictions in relation to intake of celecoxib. However, the 
IMP should be taken at approximately the same time (±1 h) each morning and evening. 
During residential stays, standardised meals will be served on PK/PD sampling days (24 h 
after dose on Day 1 [Part I], Day 1 and Day 10 [Part II, III and IV]). Breakfast will be served 
just after dose (except on Day 1 and Day 10 of Part II, III and IV) and lunch will be served 4 h 
post-dose. Snack, dinner and evening snack will be served approximately 7, 9 and 11 h post-
dose, respectively. Water is allowed ad libitum at the clinic except 1 h before dose and 1 h 
after dose on PK and PD sampling days. 
For details on IMP administration in terms of food restrictions, refer to Section 10.6. 
Fasting: The subjects should be fasting overnight (10 h) before Day 1 of Part I and before 
Day 1 and Day 10 of Part II, III and IV until 4 h post-dose. 
Alcohol: Consumption of alcohol is not allowed within 48 h prior to the screening visit and 
all subsequent visits to the clinic including the end-of-study visit of each part. In addition, 
consumption of alcohol is disallowed during residential stays. 
Coffee: Not more than 5 cups of coffee per day is allowed during the study from screening to 
end-of-study visit of each part. 
Xanthine or taurine containing products/beverages: Energy drinks (e.g. Redbull) are not 
allowed during the study from screening until the end-of-study visit of each part. 
Nicotine: Smoking or use of nicotine-containing products is not allowed during the study 
from screening until the end-of-study visit of each part. 
Grapefruit and grapefruit containing products: Consumption of grapefruit and/or 
grapefruit containing products, Seville oranges is not allowed during the study from 14 days 
prior to IMP administration until the end-of-study visit of each part. 
Blood donation: The subjects must not donate blood or plasma during the study until 
3 months after the final medical examination at the end-of-study visit of each part. 
Participation in other clinical studies: Study subjects are not allowed to participate in any 
other interventional clinical study during the study period. 
Exercise: Subjects will abstain from strenuous exercise for 72 h before each blood collection 
for clinical laboratory tests. 
 

 
 
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 Restrictions Part I, II and III 
Sun protection is required in Part I, Part II and Part III from the first administration of IMP 
until the end-of-study visit of each part to follow the recommendations given by Centres for 
Disease Control and Prevention (CDC): https://www.cdc.gov/cancer/skin/basic_info/sun-
safety.htm: 
• Stay in the shade, especially during peak hours of 10 AM to 4 PM. 
• Wear clothing that covers arms and legs 
• Use a hat or cap that shades the face, head, ears and neck 
• Wear sunglasses that block both ultraviolet A (UVA) and ultraviolet B (UVB) rays 
• Proper use of a broad-spectrum sunscreen with a sun protection factor (SPF) of 15 or 
higher. 
• Abstain from use of tanning beds. 
 Prior and concomitant therapy 
9.5.3.1 
Prohibited medication Part I, II and IV 
Use of any prescribed or non-prescribed medication including corticosteroids (inhaled and 
systemic), NSAIDs (including e.g. coxibs and aspirin), antacids, PPIs or any medication that 
changes gastric pH, herbal remedies, vitamin supplements and minerals and other over-the 
counter (OTC) medicines is prohibited within 14 days of IMP administration until the end-of 
study visit of each part. 
9.5.3.2 
Prohibited medication Part III 
Use of iloprost or corticosteroids (inhaled and systemic) is disallowed from 4 weeks prior to 
the first IMP administration until the end-of study visit as are treatment with other 
immunosuppressive therapies including, but not restricted to, cyclophosphamide, 
azathioprine, mycophenolic acid, methotrexate, or cyclosporine. 
Use of any prescribed or non-prescribed medication including NSAIDs (including e.g. coxibs 
and aspirin), antacids, PPIs or any medication that changes gastric pH, herbal remedies, 
vitamin supplements and minerals and other OTC medicines is prohibited within 14 days of 
IMP administration until the end-of study visit of each part. 
9.5.3.3 
Allowed medication (all parts) 
• Paracetamol in doses up to 4000 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. 
• Nasal decongestants without cortisone, antihistamine or anticholinergics for a 
maximum of 10 days.  
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 

 
 
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the Sponsor, the Investigator will determine whether or not the subject should continue in the 
study.  
9.6 
Screening failures 
Screening failures are defined as subjects who consent to participate in the clinical study but 
are not subsequently randomised in the study. A minimal set of screening failure information 
is required to ensure transparent reporting of screening failure subjects. Minimal information 
includes documentation of signed and dated ICF and reason(s) for screening failure. 
Subjects/patients who do not meet the criteria for participation in this study may be re-
screened.  
Re-screening can be performed once if any of the following were reasons for screening failure 
or non-randomisation (as judged by the Investigator): 
• Practical reasons.  
• No significant medical conditions (e.g. influenza, nasopharyngitis).  
• Reserve subject in previous cohort. 
• 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. 
9.7 
Subject/patient withdrawal 
 General withdrawal criteria  
Subjects/patients 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/patients may be discontinued from the study at any time at the discretion of the 
Investigator for any of the following reasons:  
• Severe non-compliance to study protocol procedures, as judged by the Investigator 
and/or Sponsor 
• Subject/patient is lost to follow-up  
• Significant AEs posing a risk for the subject/patient, as judged by the Investigator 
and/or Sponsor 
• Withdrawal of informed consent to the use of biological samples  
• Pregnancy 
Meeting of an exclusion criterion during the study, which, in the opinion of the Investigator, 
may pose a risk for the subject/patient.  

 
 
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 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 ms  
• Change from baseline (i.e. the last measurement prior to the first dose) 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 values 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 FDA Guidance on Drug-Induced Liver Injury [25], 
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/patient 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 in each part. Any ongoing 
AEs will be followed as described in Section 11.3.1.14.  
The primary reason for discontinuation/early withdrawal must be specified in the eCRF and 
final drug accountability must be performed. 

 
 
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 Subject/patient replacement 
Part I: Based on recommendations given by the iSRC and as decided by the Sponsor, 
subjects who were randomised but not dosed may be replaced.  
Part II, III and IV: Based on recommendations given by the iSRC and as decided by the 
Sponsor, subjects/patients who were randomised but not dosed may be replaced as may 
subjects who were prematurely withdrawn from the study for any reason except the 
occurrence of AEs assessed at least possibly related to the IMP.  
9.8 
Randomisation 
Part I, II and III: On Day 1, subjects in each cohort will be randomised in a 3:1 ratio to 
receive either GS-248 (n=6) or placebo (n=2). The first 2 subjects in a cohort will be 
randomised to GS-248 (n=1) or placebo (n=1). A computer-generated randomisation list will 
be created using SAS Proc Plan, SAS Version 9.4. The randomisation list will contain subject 
number and treatment and will be kept by the randomiser in a sealed envelope until database 
lock. A copy of the randomisation list will be kept by an unblinded pharmacist at the site.  
Sealed individual, treatment code envelopes will be kept in a locked and restricted area at the 
clinic in case of need for emergency unblinding 
Sealed individual, treatment code envelopes will also be kept at CTC’s Pharmacovigilance 
(CTC PV) department in a locked and restricted area. 
Part IV of the study is open and non-randomised. All subjects will receive celecoxib.  
9.9 
Blinding 
Part I, II and III of the study will be conducted in double-blind fashion and the allocation of 
treatments will not be disclosed until clean file has been declared and the database has been 
locked, see Section 16.8.  
GS-248 and the placebo are identical in appearance, taste and smell.  
Part IV of the study is open. All subjects will receive celecoxib.  
9.10 Emergency unblinding during the study 
The treatment code may only be broken by the Principal Investigator or delegate in case of 
emergency when knowledge of the treatment received is necessary for the proper medical 
management of the subject/patient. The code breaking procedure should be carefully 
documented. 
The randomisation code may be broken by the iSRC during the assessment process (partial 
un-blinding) to enable their decision on continued dosing of further cohorts or to stop the dose 
escalation, see Section 8.3.7. The medical staff and the subjects will still be blinded for the 
treatments (active drug or placebo) to be administered in the subsequent cohorts in order to 
minimise bias (see Section 8.3.8). 
For unblinding procedures in case of a potential suspected unexpected serious adverse 
reaction (SUSAR), refer to Section 11.3.1.13. 

 
 
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10 TREATMENTS  
10.1 Identity of investigational medicinal products  
The Drug Substance, GS-248 SU, 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-dependant. 
The Drug Product to be used in the study is an oral solution where GS-248 is dissolved in an 
acidic vehicle at pH 3.0. 
GS-248 is a low solubility compound with pH dependent solubility and therefore an aqueous, 
acidic solution was developed for the formulation.  
Placebo has the same composition as the GS-248 solution but without the active substance 
and will be provided as a frozen stock solution of pH 3.  
GS-248 and placebo will be used in Part I, II and III of the study.  
10.2 Identity of reference product 
Celecoxib will be used as a reference product in Part IV of the study. Oral capsules, 200 mg 
for twice daily dosing will be used. Celecoxib will be purchased from the Swedish market 
(Celebra, Pfizer). For details on celecoxib, refer to the product’s SmPC. 
10.3 Manufacturing, packaging and labelling  
GS-248 and placebo are manufactured, packaged, labelled and released by RISE, Research 
Institutes of Sweden, Södertälje, Sweden. Labels will comply with applicable Good 
Manufacturing Practice (GMP) requirements [26]. The IMP (GS-248 and placebo) will be 
shipped to the research clinic (CTC) in brown bottles. GS-248 will be provided in 2 different 
strengths; 1 mg/mL and 10 mg/mL with respect to the GS-248 parent.  
CTC will add a subject specific label to the bottle or syringe with dispensed IMP. CTC staff 
present during dispensing will thus be unblinded. 
Celecoxib (Celebra, Pfizer) will be labelled by the Hospital Pharmacy, Akademiska 
Sjukhuset, Uppsala, Sweden. Once labelled, the Hospital Pharmacy will provide celecoxib to 
CTC.  
10.4 Conditions for storage 
GS-248 and placebo will be stored frozen at -20ºC ±5 °C in an access-controlled storage area 
at CTC. The GS-248 solutions are sensitive to light. Prior to dispensing, the solutions will be 
thawed. Details regarding thawing conditions and storage of the thawed and dispensed 
solution, will be specified in a separate Pharmacy manual.  
Celecoxib should not be stored above 30°C.  

 
 
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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).  
10.5 Dispensing and accountability 
IMP dispensing will be done by trained personnel, i.e. a site pharmacist or a registered nurse, 
in a dedicated room at CTC. There will be two unblinded persons working together, one 
person will handle the IMP and perform the dispensing according to the randomisation list 
and the other person will supervise the process.  
Dispensing details will be specified in a separate Pharmacy manual. No dilution steps are 
required, for each dose level a different volume will be dispensed.  
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, dispensed to 
and used by each subject and study medication returned or destroyed at the end of the study. 
Any discrepancies between dispensed and returned IMP must be explained and documented. 
Products deliberately and/or accidentally destroyed by the site or the subject must be 
accounted for. 
10.6 Treatment administration 
Part I (SAD): Subjects in the SAD part will be administered a single oral dose of either 
GS-248 or placebo as randomised. 
The IMP will be administered with 240 mL of water following an overnight fast of at least 
10 h. No food is allowed until 4 h post-dose. Water, but no other drinks, is allowed as desired 
except for 1 h before and after IMP administration.  
Part II (MAD) and Part III (SSc patients): Subjects in the MAD part and in the SSc part 
will be administered single oral doses of GS-248 or placebo as randomised for 10 consecutive 
days.  
On Day 1 and Day 10, the IMP will be administered with 240 mL of water following an 
overnight fast of at least 10 h. No food is allowed until 4 h post-dose. Water, but no other 
drinks, is allowed as desired except for 1 h before and after IMP administration. 
On other treatment days (Day 2 to Day 9), the IMP will be administered at the clinic before 
breakfast each morning at approximately the same time each day (±1 h).  
Part IV (celecoxib): Subjects in the celecoxib cohort will receive twice daily oral doses of 
celecoxib (200 mg) for 10 consecutive days. Doses on Day 1, Day 2 (morning dose), Day 9 
and Day 10 will be administered at the clinic. Other study days (Day 2 [evening dose] and 
Day 3 to Day 8) will be self-administered by the subjects at home at 12 h intervals (with or 
without food). An electronic diary (ViedocMe) will be used to document the time of 
administration and any deviations each day.  
10.7 Continuation of treatment with Investigational Medicinal Product 
No subject or patient will continue treatment with GS-248 after the end-of-study participation.  

 
 
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10.8 Treatment compliance 
Part I, SAD: all IMP will be administered at the research clinic under medical supervision to 
ensure compliance. 
Part II, MAD: all IMP will be administered at the research clinic under medical supervision 
to ensure compliance. 
Part III, SSc patients: all IMP will be administered at the research clinic under medical 
supervision to ensure compliance. 
Part IV, celecoxib: celecoxib will be administered at the research clinic under medical 
supervision On Day 1, Day 2 (morning dose), Day 9 and Day 10. On other study days, 
subjects will self-administer celecoxib twice daily and document the time of administration 
and any deviations in an electronic diary (ViedocMe). Compliance will also be confirmed by 
a telephone call at Visit 5 and by counting any unused celecoxib on Day 9.  
In all parts, the administration of IMP will be documented in the eCRF. ViedocMe data is an 
integrated part of the eCRF.   
10.9 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: 
Part I (SAD): Table 8.1-1 and Table 8.1-2. 
Part I (MAD): Table 8.1-3 and Table 8.1-4.  
Part III (SSc patients): Table 8.1-5 and Table 8.1-6. 
Part IV (celecoxib): Table 8.1-7. 
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 and PD blood sampling occurs as close as possible to the scheduled 
time. In order to achieve this, the timing priority order at a particular time point is: 
1. Blood samples for PK and explorative GS-248 metabolite analysis 
(includes MIST in Part II) 
2. Blood samples for PD (WBA, ADMA, future analyses) 
3. Standard 12-lead ECG 
4. Safety laboratory samples 
5. Vital signs 
Time points for PK and PD blood sampling, PD urine sampling, safety laboratory samples, 
standard 12-lead ECG and vital signs are outlined in Table 8.1-2 for Part I, Table 8.1-4 for 
Part II, Table 8.1-6 for Part III and Table 8.1-7 for Part IV (PD only).   
Actual time for PK/PD sampling must not deviate more than ±10% from the planned time. 
For further details regarding time windows for PK sampling, refer to Section 11.4.1. 
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 randomisation and 
IMP administration. The criteria are specified in Section 9.4. 
 Demographic information 
The following demographic data will be recorded: gender, age, ethnicity and race. 

 
 
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 Weight and height 
Weight and height will be measured without shoes at screening. BMI will be calculated from 
the height and weight recorded. Weight will also be measured at the end-of-study visit of each 
part.  
 Medical/surgical history  
Medical/surgical history will be obtained by subject interview in order to verify that the 
eligibility criteria are met. 
The date (month) for onset of SSc will be documented in the eCRF as will the typical 
frequency of Raynaud’s Phenomenon attacks.  
 Prior and concomitant medication 
Prior medications taken will be obtained by subject interview in order to verify that the 
eligibility criteria are met (see also Section 9.5.3). 
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 in each 
part (i.e. the first dosing day), 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 2 weeks before the first IMP administration until the 
end-of-study visit of each part must be documented appropriately in the subject’s/patient’s 
eCRF. Relevant information (i.e. name of medication, dose, unit, frequency, 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 HIV and hepatitis B/C prior to inclusion into the study. Any 
positive result will exclude the patient from participating in the study.  
 Pregnancy test 
All WOCBP will do a pregnancy test at screening (blood/serum) and at visits specified in 
Table 8.1-1, to Table 8.1-7 (urine dipstick).   
FSH and oestradiol levels will be determined as needed to confirm postmenopausal females. 
 Urine drug screen 
Urine will be screened for drugs of abuse at time points in Part I, II and IV as outlined in the 
schedule of events (Table 8.1-1 to Table 8.1-4 and Table 8.1-7) using the AlereTM Drug 

 
 
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Screen Test Panel. Random drug tests can be performed during the study period in all parts of 
the study including Part III. 
 Alcohol breath test 
An alcohol breath test will be performed at time points outlined in the schedule of events 
(Table 8.1-1 to Table 8.1-7). 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/patient’s signing 
of the ICF until the first administration of IMP (i.e. an event that occurs during the screening 
period). 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: safety and tolerability 
 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 CTC’s standard operating 
procedures (SOPs) regarding emergencies and FIH studies.  
11.3.1.1 
Definition of adverse event  
An AE is defined as any untoward medical occurrence in a subject/patient who has received 
an IMP. The event does not necessarily need to have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including clinically 
significant abnormal values from relevant tests, such as clinical safety laboratory tests, 
ECGs, vital signs), symptom, or disease temporally associated with the use of an IMP, 
regardless of whether it is considered related to the IMP. 
11.3.1.2 
Definition of serious adverse event  
An SAE is any AE that: 
• results in death 
• is life-threatening (this refers to an event in which the subject/patient was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death had it been more severe) 
• requires inpatient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is medically important (this refers to an event that may not be immediately life-
threatening or result in death or hospitalisation, but may jeopardise the 
subject/patient or may require intervention to prevent any of the SAEs defined 
above) 

 
 
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Examples of medically important events 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/patient 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. 
11.3.1.3 
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. 
11.3.1.4 
Definition of serious adverse drug reaction  
The term SADR is to be used whenever either the Investigator or Sponsor or designee 
assessed the SAE as possibly or probably related to the IMP. 
11.3.1.5 
Definition of suspected unexpected serious adverse reaction  
A SUSAR is any SADR whose nature or intensity is not consistent with the current version of 
the IB. 
11.3.1.6 
Time period and frequency for collecting adverse events 
Part I, II and IV: All AEs (including SAEs) will be collected from the start of IMP 
administration until the end-of-study visit of each part. 
Part III: SAEs will be collected from the time of signing the informed consent whereas AEs 
will be collected from the start of IMP administration. Both AEs and SAEs will be collected 
until the end-of-study visit.  
Any AE with start date on the day IMP administration must be recorded with start time. 
At the end-of-study visit, new information regarding AEs or SAEs, if any, including status of 
ongoing events must be recorded as applicable. 
Investigators are not obligated 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. 
11.3.1.7 
Assessment of intensity 
The grading of the intensity of AEs will follow the CTCAE v5.0 [1]. 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 CRF: 

 
 
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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 bedridden. 
11.3.1.8 
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. 
11.3.1.9 
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/patient has recovered completely, and no symptoms 
remain. 
Recovering/resolving  The subject’s/patient’s condition is improving, but symptoms still 
remain. 
Recovered/resolved 
with sequelae 
The subject/patient has recovered, but some symptoms remain (for 
example, the subject/patient had a stroke and is functioning 
normally but has some motor impairment). 
Not recovered/not 
resolved 
The subject’s/patient’s condition has not improved and the 
symptoms are unchanged (for example, an atrial fibrillation has 
become chronic). 
Fatal 
 
Unknown 
 

 
 
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11.3.1.10 Collecting adverse events 
AEs identified using any of the following methods will be recorded: 
• AEs spontaneously reported by the subject/patient 
• AEs observed by the Investigator or medical personnel 
• AEs elicited based on non-leading questions from the Investigator or medical 
personnel 
11.3.1.11 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. 
11.3.1.12  Reporting of serious adverse events  
SAE reporting should be performed by the Investigator within 24 h 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 the 
end of the next business day of when he or she becomes aware of it.  
If the SAE report in eCRF is updated, a new e-mail alert is sent to the predefined recipients.   
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 manually completing the 
paper SAE Form, provided in the Investigator Site File (ISF). The completed, signed and 
dated paper SAE Form should, within 24 h, 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 

 
 
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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 CA and IEC in 
accordance with local regulations. 
11.3.1.13 Reporting of SUSARs to EudraVigilance, CA and IEC 
The term SADR is used whenever either the Investigator or medical monitor deems a blinded 
SAE as possibly or probably related to IMP. If an SADR is assessed as unexpected by the 
medical monitor, it is a potential SUSAR and under such circumstances an EudraVigilance 
reporter will be unblinded. In case the subject had received active treatment, 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) 
The clock for expedited initial reporting (Day 0) starts as soon as the Sponsor has received the 
information containing the minimum reporting criteria. 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 patients.  
The Sponsor or delegate is responsible for once a year throughout the clinical study (or on 
request), submit a safety report to the CA and the IEC taking into account all new available 
safety information received during the reporting period. 
11.3.1.14 Treatment and follow-up of adverse events 
Subjects/patients 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/patient 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. 

 
 
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11.3.1.15 Treatment of overdose 
An overdose is a dose in excess of the dose specified for each cohort in this CSP.   
Overdosing of GS-248 is not likely to occur in this study since all IMP will be administered 
by site personnel under medical surveillance. Overdosing of celecoxib may occur during the 
period when subjects self-administer celecoxib at home. In the event of suspected overdose, 
appropriate supportive medical care should be provided. Reactions will be treated 
symptomatically.  
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/patient’s 
medical records. 
No known antidote is available.  
11.3.1.16 Procedures in case of pregnancy 
In case of pregnancy or suspicion of possible pregnancy of any female subjects or female 
partners of male subjects, the study treatment 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 miscarriage, 
elective termination, normal birth or congenital abnormality) must be followed up and 
documented even after the subject was discontinued from the study. 
All events of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages 
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. 
 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. 
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. 
For timing of assessments, refer to Table 8.1-1 to Table 8.1-7.  
 Vital signs and body temperature 
All parts: Systolic and diastolic blood pressure and pulse will be measured in supine position 
after 10 minutes of rest. Body temperature will be measured orally using a digital 
thermometer.  
Abnormal post-dose findings assessed by the Investigator as clinically significant will be 
reported as AEs.  

 
 
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For timing of assessments, refer to Table 8.1-1 to Table 8.1-7. 
 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 PQ/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 as clinically significant or not clinically 
significant. Abnormal post-dose findings assessed by the Investigator as clinically significant 
will be reported as AEs.   
For timing of assessments, refer to Table 8.1-1 to Table 8.1-7. 
 Telemetry 
Ambulatory ECG telemetry will be used for cardiac surveillance up to 24 h after IMP 
administration in the Part I of the study.  
Telemetry will be reviewed on-site by the Investigator. Any abnormalities will be specified 
and documented as clinically significant or not clinically significant. Abnormal post-dose 
findings assessed by the Investigator as clinically significant will be reported as AEs. 
 Clinical laboratory profile 
Blood samples for analysis of clinical chemistry, haematology and coagulation 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 at visits specified in Table 8.1-1 to Table 8.1-7..  
Urinalysis will be performed at the research clinic using dip sticks.  
Serum/urine pregnancy tests will be performed at visits specified in Table 8.1-1 to 
Table 8.1-7. 
The safety laboratory parameters are defined in Table 11.3-1. 
Abnormal values assessed by the Investigator as clinically significant 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 11.3-1 Safety laboratory parameters Part I, II and III 
Category 
Parameter 
Clinical chemistry 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Bilirubin (total and conjugated) 
Calcium, total 
Creatinine 
Estimated glomerular filtration rate (eGFR) calculated according 
to the revised Lund-Malmö GFR estimating equation 
Cholesterol  
C-reactive protein (CRP) 
Cystatin C 
Gamma Glutamyl Transferase (gGT) 
Glucose 
Lactate dehydrogenase (LD) 
Osmolality 
Phosphate 
Potassium 
Sodium 
Urea nitrogen 
Haematology 
Erythrocyte count  
Haematocrit (Erythrocyte volume fraction) 
Haemoglobin (Hb) 
Leucocyte count  
Leucocyte differential, absolute count (lymphocytes, monocytes, 
neutrophil-, eosinophil-, and basophil-granulocytes) 
Mean Corpuscular Volume (MCV) 
Platelet count (Thrombocyte particle concentration [TPC]) 
Coagulation 
Activated Partial Thromboplastin Time (APTT) 
Prothrombin Complex International Normalised Ratio 
Urinalysis (dip stick) 
Bilirubin 
Erythrocytes 
Glucose 
Ketone 
Leucocytes 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Urine creatinine1 
 
Hormone analysis (at screening 
only) 
Thyroid Stimulating hormone (TSH) 

 
 
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Category 
Parameter 
FSH-test (at screening, 
postmenopausal females only) 
FSH 
Oestradiol 
Pregnancy test 
Serum pregnancy test at screening, urine pregnancy test at other 
visits 
1. Part II and III. Urine creatinine is not regarded as a safety parameter but is taken in order to normalise the PD 
urine analysis. 
Table 11.3-2 Safety laboratory parameters Part IV 
Category 
Parameter 
Clinical chemistry 
ALT 
Albumin 
ALP 
AST 
Bilirubin (total and conjugated) 
Creatinine 
eGFR calculated according to the revised Lund-Malmö GFR 
estimating equation 
CRP 
gGT 
LD 
Haematology 
Erythrocyte count  
Haematocrit (Erythrocyte volume fraction) 
Hb 
Leucocyte count  
MCV 
Platelet count (TPC) 
Urinalysis (dip stick) 
Bilirubin 
Erythrocytes 
Glucose 
Ketone 
Leucocytes 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Urine creatinine1 
 
Hormone analysis (at screening 
only) 
TSH 
FSH-test (at screening, 
postmenopausal females only) 
FSH 
Oestradiol 
Pregnancy test 
Serum pregnancy test at screening, urine pregnancy test at other 
visits 
1. Urine creatinine is not regarded as a safety parameter but is taken in order to normalise the PD urine analysis 

 
 
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11.4 Assessments related to secondary endpoints: pharmacokinetics and 
pharmacodynamics 
 Pharmacokinetic sampling and analysis 
Blood samples for PK analysis will be drawn in Part I (SAD), Part II (MAD) and Part III 
(SSc patients).  
Venous blood samples (approximately 5 mL) for the determination of plasma concentrations 
of GS-248 will be collected through venepuncture or an indwelling venous catheter at the pre-
specified time-points (Part I, SAD: Table 8.1-1 and Table 8.1-2, Part II, MAD: Table 8.1-3 
Table 8.1-4, and Part III, SSc patients: Table 8.1-5 and Table 8.1-6). Actual time for PK blood 
sampling must not deviate more than ±10% from the planned time except as detailed below.  
Pre-dose PK sampling before the first dose may be performed within 60 minutes prior to 
dosing. 
Pre-dose PK sampling on Day 8, Day 9 and Day 10 in Part II (MAD) and Part III 
(SSc patients) must be performed immediately before dosing (within 5 minutes). 
The 24 h sample to be taken on Day 2 in Part I (SAD) must be taken within 10 minutes of the 
nominal time for the dosage interval.  
The 24 h samples to be taken pre-dose on Day 2 and on Day 11, respectively, in Part II 
(MAD) and Part III (SSc patients) must be taken within 10 minutes of the nominal time for 
the dosage interval.  
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, MIST (Part II) and further metabolite 
analysis (Part I and II). 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 
Recipharm, Uppsala, Sweden by means of a validated bioanalytical method. The details of the 
analytical method used will be described in a separate bioanalytical report. Both the 
bioanalytical laboratory and the pharmacokineticist will be blinded to treatment. For details 
on the PK parameters to be determined, refer to Section 17.6.1.  
Samples for determination of GS-248 metabolites will be analysed under a separate protocol, 
see Section 11.5.4.  
11.5 Assessments related to exploratory endpoints 
 Blood sampling for ex-vivo whole blood assay (WBA) 
Blood samples (approximately 3 mL) to determine mPGES activity (PGE2 levels) will be 
drawn in Part I (SAD, from cohort 3 and onwards), Part II (MAD), Part III (SSc patients) and 
in Part IV (celecoxib) at visits and time points detailed in Table 8.1-1 to Table 8.1-7.  
The date and time of collection of each sample will be recorded in the eCRF. Collection and 
handling details will be specified in a separate laboratory manual.  

 
 
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Samples for determination of PGE2 levels, will be analysed by means of a validated method. 
The details of the analytical method used will be described in a separate bioanalytical report. 
Both the bioanalytical laboratory and the evaluator will be blinded to treatment. 
 Urine sampling for analysis of AA metabolites, GS-248 metabolites and future 
biomarker analysis 
Urine collection for exploratory analysis of AA metabolites and for future biomarker analysis 
will be performed in Part II (MAD), Part III (SSc patients) and in Part IV (celecoxib) whereas 
urine collection for future exploratory analysis of GS-248 metabolites will be performed in 
Part II (MAD) only.  
Urine will be collected at visits and time intervals presented in Table 8.1-3 (Part II, MAD), 
Table 8.1-5 (Part III, SSc patients) and Table 8.1-7 (Part IV, celecoxib). The volume of urine 
will be determined by total weight and documented in the eCRF. The date and time interval of 
each collection (start and stop time) will be recorded in the eCRF. 
Three urine aliquots (5 mL) from each collection interval will be transferred to pre-labelled 
polypropylene cryotubes and will thereafter immediately be frozen at -70°C. Urine samples 
for future analysis will be stored for retention in a biobank, see Section 12.3. 
Details on sample collection and handling will be provided in a separate laboratory manual. 
 Blood sampling for ADMA analysis  
Blood collection for exploratory analysis of ADMA in plasma will be performed in Part II 
(MAD), Part III (SSc patients) and in Part IV (celecoxib). 
Blood will be collected at visits presented in Table 8.1-3 (Part II, MAD), Table 8.1-5 (Part III, 
SSc patients) and Table 8.1-7 (Part IV, celecoxib). The date and time of collection of each 
sample will be recorded in the eCRF. 
Venous blood samples (approximately 5 mL) will be collected through venepuncture or an 
indwelling venous catheter. The separated plasma from each blood sample will be divided 
into aliquots and frozen at -70°C within 1 h after centrifugation.  
Collection and handling details will be provided in a separate laboratory manual. 
 Blood sampling for GS-248 metabolites (including MIST) 
Blood sampling for future analysis of GS-248 metabolites will be performed in Part I and 
Part II. The collection and handling of these samples are described in Section 11.4.1 since the 
samples constitute an aliquot of the plasma generated from each PK sample. Metabolite 
sampling will be performed at visits presented in Table 8.1-1 (Part I, SAD) Table 8.1-3 
(Part II, MAD). 
The results will be analysed under a separate protocol and reported separately. 
 Blood sampling for future biomarker analysis  
Blood sampling for future exploratory analysis of biomarkers e.g. inflammatory biomarkers 
will be performed in all parts. Blood will be collected at visits presented in Table 8.1-1 (Part I, 

 
 
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SAD) Table 8.1-3 (Part II, MAD), Table 8.1-5 (Part III, SSc patients) and Table 8.1-7 (Part 
IV, celecoxib). The date and time of collection of each sample will be recorded in the eCRF. 
Venous blood samples (approximately 5 mL) analysis will be collected through venepuncture 
or an indwelling venous catheter. The separated plasma from each blood sample will be 
divided into aliquots after centrifugation. Collection and handling details will be provided in a 
separate laboratory manual. 
Plasma samples for future analysis will be stored for retention in a biobank, see Section 12.3. 
 Open question, Raynaud’s (Part III only) 
On Day 11, approximately 24 h post last dose in Part III of the study, an open question will be 
raised to each participating patient:  
“Did you experience any change in your Raynaud’s status during the treatment period 
(Y/N)?” 
If the answer was yes, the patient will be asked to specify the change. The response to both 
questions will be documented in the eCRF.   
11.6 Appropriateness of measurements 
The stopping rules for dose escalation used (see Section 8.3.7) follows the recommendations 
and grading system of CTCAE v4.03 [1] but also take into account the recommendations 
published by Sibille et al 2010 [20], which is an adaptation to FIH studies of the grading 
systems previously proposed by NCI [1], WHO [21], NIH [22] and FDA [23].  
All other methods used for safety assessments are commonly used in standard medical care 
and in Phase I clinical studies. Non-compartmental analysis of PK parameters is also standard 
for Phase I clinical studies. 
12 PROCEDURES FOR BIOLOGICAL SAMPLES 
12.1 Sample collection  
The sample collection procedures for PK, PD and metabolite analysis are briefly described in 
Section 11.4.1 and are detailed in a separate laboratory manual. 
Safety laboratory samples will be collected according to standard procedures. 
12.2 Volume of blood 
The estimated volume of blood to be collected from each subject/patient during the study will 
be approximately 150 mL in Part I, 300 mL in Part II and III and 130 mL in in Part IV, which 
is less than 450 mL, i.e. 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).  

 
 
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Any remains from the safety laboratory samples will be disposed of after analyses.  
The samples for analysis of GS-248 plasma concentration, WBA and ADMA in plasma and 
AA metabolites in urine will be stored at -70°C until analysed. The samples will be disposed 
of once the exploratory analyses have been documented in addendum to the CSR. The 
samples will not be retained for longer than 15 years after study completion.  
Bulk urine samples will be discarded immediately after collection of aliquots for analysis 
(including future analysis).  
Exploratory GS-248 metabolite samples may be retained for up to 15 years after study 
completion for future analysis. Exploratory plasma and urine samples for potential future 
biomarker analysis may also be retained for up to 15 years after study completion. 
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. The Sponsor has delegated to 
CTC the responsibility to monitor study sites and to audit any external laboratory provider.  
Remaining samples collected for analysis of GS-248 plasma concentrations and exploratory 
biological samples will be transferred to Gesynta AB or designee at an agreed timepoint and 
stored for up to 15 years after study completion. 
12.5 Withdrawal of informed consent for donated biological samples 
If a subject/patient 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/patient withdrawal of informed consent is notified immediately to Sponsor.  
• Biological samples from the subject/patient, if stored at the research clinic, are 
immediately identified, disposed of/destroyed and the action is documented.  
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 protocol 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 conference on 
Harmonisation (ICH) E6 R2. 
Identified risks will be categorised separately from the CSP and will be discussed/addressed 
between CTC and the Sponsor. Specific mitigation and contingency plans will be put into 
place. 
13.2 Quality assurance and quality control 
The Sponsor is responsible for implementing and maintaining quality assurance and quality 
control 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 EDC system and maintain 
SOPs for the whole life- cycle of the system.  
The Sponsor has delegated the responsibilities mentioned above whilst maintaining overall 
study oversight.  
Quality control should be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly. 
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 [27] 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 patient information 
and ICF, any other written information to be provided to the subjects/patients and any 
advertisements used for recruitment of subjects/patients to applicable IEC for approval.  
The Sponsor has delegated to CTC the responsibility for submission of study documents to 
the applicable CA according to local regulatory requirements. 

 
 
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Approval must be obtained in writing from both IEC and CA before the first subject/patient 
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/Patient information and consent 
It is the responsibility of the Investigator or an authorised associate to give each potential 
study subject/patient 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/patient may withdraw from participation at any time and for 
any reason, without any prejudice. All subjects/patients will be given the opportunity to ask 
questions about the study and will be given sufficient time to consider participation before 
signing the ICF. 
The informed consent must be signed by the subject and by the person who conducted the 
informed consent discussion before any study-related information is recorded or procedures 
performed. A copy of the subject/patient information including the signed ICF will be 
provided to the subject/patient.  
Documentation of the discussion and the date of informed consent must be recorded in the 
source documentation and in the CRF. The subject/patient information sheet and the signed 
ICF should be filed by the Investigator for possible future audits and/or inspections.  
The final approved versions (one per part) of the subject/patient information and ICF must not 
be changed without approval from the Sponsor and the applicable IEC.  
14.4 Subject/Patient information card  
The subject/patient will be provided with a Subject/Patient 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/celecoxib  
• The name and phone number of the Investigator  
• Name and address of the Sponsor 
14.5 Subject/Patient 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 

 
 
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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/patient (or the subject’s/patient’s legally acceptable representative 
and/or witness, as applicable) 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. This agreement 
is to be substantiated in a separate document, according to local requirements. 
The subject/patient 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/Patient Identification List which includes sufficient 
information to link records, i.e. the CRF 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.  
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 

 
 
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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/patients 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/patients are also protected 
in accordance with national regulations, as applicable. CTC has a company insurance 
covering services performed by CTC. 
15 STUDY MANAGEMENT 
15.1 Training of study site personnel 
Before screening 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 
delegated study-specific duties. 
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. 

 
 
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• 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/patient’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. 
• 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 ay 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 screening, 
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/patient’s medical history, that verifies the existence of the subject, the inclusion and 
exclusion criteria, and all records covering the subject’s/patient’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/patients be enrolled. 
15.5 Study timetable and end of study 
The study is expected to start in Q2, 2019 and to be completed by Q2, 2020. 
A subject/patient is considered to have completed the study if he/she has completed all visits 
in the study including the last scheduled procedure at the end-of-study visit of each part. 

 
 
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The end of the study is defined as the date of last scheduled visit/procedure shown in the 
Schedules of Events (Table 8.1-1 to Table 8.1-7) for the last subject/patient in study.  
15.6 Termination of the of the study 
The Sponsor reserves the right to discontinue the study at any time but intends only to 
exercise this right for valid scientific or administrative reasons. 
After such a decision, the Investigator must inform all participating subjects/patients and 
perform relevant assessments, preferably according to the scheme for the final assessments. 
All delivered and unused study products and other study materials must be returned and all 
eCRFs completed as far as possible. 
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. 
The data obtained from any exploratory analyses may be reported separately from the CSR. 
 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 15 years after finalisation of the CSR. This includes any original 

 
 
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source documents related to the study, the Patient/Subject Identification List (providing the 
sole link between named subject/patient source records and anonymous CRF 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 Trial Master File 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 Investigator Study File for archiving for 15 years after finalisation of the CSR. 
The completed original 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.  
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, quality control (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 offline 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/patient. 

 
 
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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/patient’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 UserID and password; date and time stamps will be added automatically at time of 
electronic signature. 
16.3 Electronic patient reported outcome  
The subjects in Part IV (celecoxib) of the study will record data (celecoxib intake twice daily 
and AEs) using a web-based electronic patient reported outcomes (ePRO) system 
(ViedocMe) linked to the eCRF. The ePRO system includes password protection and 
internal quality checks. Mobile phone text reminders can be sent to the subject through the 
ePRO. All data registered in ViedocMe are stored together with the eCRF data.  
16.4 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 
are no discrepancies for critical data as described in the risk-based monitoring plan.  
If corrections are needed, queries will be raised within the eCRF. 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. 
16.5 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. 
16.6 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.  
16.7 Medical coding 
Medical coding will be performed by trained personnel at CTC. AEs and medical/surgical 
history verbatim terms are coded using the Medical Dictionary of Regulatory Activities 

 
 
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(MedDRA; latest version available at start of coding). Prior and concomitant medications will 
be coded according to the WHO Anatomic Therapeutic Chemical (ATC) classification 
system. All coding will be approved by Sponsor prior to database locks. 
16.8 Database lock 
When all data have been entered and discrepancies solved, clean file will be declared, the 
database will be locked, the code will be broken and the data will be analysed.  
There will be two database locks (DBLs), one following completion of Part I, II and IV and 
one following completion of Part III.   
One ICH-E3 compliant CSR will be written following the final DBL.  
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 prepared and signed prior to the first 
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 visit with last data collection point prior to the first 
administration of IMP. 
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. 

 
 
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17.3 Analysis data sets 
 Safety analysis set 
The safety analysis set of each part will consist of all subjects/patients who have been 
randomised and received at least one dose of IMP.  
 Full analysis set 
The Full Analysis Set (FAS) of each part will consist of all subjects/patients who have been 
randomised and received at least one dose of IMP and who has at least one post-baseline 
assessment of efficacy data.  
 Per protocol set 
The Per Protocol Set (PPS) of each part will consist of all subjects who have been randomised 
and completed the study without any major protocol deviations that are judged to compromise 
the analysis of the data. All protocol violations will be judged as major or minor prior to 
database lock. 
 PK analysis set 
The PK analysis set will consist of all subjects who received at least one dose of the study 
drug and provided evaluable plasma concentration data and who have no AEs or protocol 
deviations judged to affect the PK analysis.  
17.4 Description of study population 
 Demographics and baseline characteristics 
Descriptive statistics for demographics, weight and height will be presented by part, treatment 
and cohort/dose group. 
 Medical/surgical history and prior/concomitant medication 
Medical/surgical history and prior/concomitant medications will be presented by part, 
treatment, cohort/dose group and overall using descriptive statistics and listings. 
 Treatment compliance 
The number of subjects/patients treated in each cohort and part and their individual dose will 
be listed. 

 
 
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17.5 Analysis of primary endpoints 
 Adverse events  
An overview of all AEs, including SAEs, intensity, relationship to IMP, and deaths will be 
presented by SOC and preferred term (PT). 
Incidence of AEs and SAEs will be summarised by SOC and PT by part, treatment, 
cohort/dose group and overall.   
All AE data will be listed by part, cohort, treatment and subject/patient 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/patient and summarised by part, treatment and cohort/dose group. 
Changes over time will be presented using shift tables.  
All data will be listed by part, cohort, treatment and subject/patient. 
 Vital signs and body temperature 
Vital signs (systolic/diastolic blood pressure and pulse) and body temperature will be 
summarised by part, treatment and cohort/dose group. Data will be presented with absolute 
and percent change from baseline at each visit.  
All data will be listed by part, cohort, treatment and subject/patient. 
 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 by part, 
treatment and cohort/dose group using frequency tables.  
Changes over time will be presented using shift tables. 
All data will be listed by part, cohort, treatment and subject/patient. 
 Safety laboratory analyses 
Safety laboratory data will be summarised by part, treatment and cohort/dose group 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 part, cohort, treatment and subject/patient. 

 
 
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17.6 Analysis of secondary 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 non-compartmental analysis (NCA) using the software 
Phoenix WinNonlin® version 6.3 or later (Pharsight Corporation, U.S.A.).  
The following non-compartmental PK parameters will be assessed in Part I (SAD): 
• AUC0-t,  
• AUC0-,  
• T½,  
• Tmax,  
• Cmax,  
• Dose proportionality after a single dose based on AUC and Cmax 
• Vz/F 
• CL/F 
The following non-compartmental PK parameters will be assessed after the first dose interval 
in Part II (MAD) and Part III (SSc patients): 
• AUC0-t  
• T½  
• Tmax 
• Cmax 
• Dose proportionality after the first dose interval based on AUC and Cmax 
The following non-compartmental PK parameters will be assessed after the last dose interval 
in Part II (MAD) and Part III (SSc patients):  
• AUC0-t 
• AUCss 
• T½ 
• Tmax 
• Cmax 
• Ctrough from the 2 doses preceding the last dose 
• Dose proportionality after the last dose interval based on AUCss and Cmax 
• Vz/F 
• CL/F 
• Accumulation ratio  
Summary statistics for the PK parameters will be presented by part, treatment and cohort with 
number of measurements, arithmetic mean, SD, CV, median, minimum, maximum, geometric 
mean, geometric CV%. Additional PK parameters may be determined if deemed appropriate.  
All data will be listed by part, cohort, treatment and subject/patient. 

 
 
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17.7 Analysis of exploratory endpoints 
 Analysis of mPGES-1 activity (PGE2 levels) levels using whole blood assay 
PGE2 levels will be summarised by part, treatment and cohort with absolute and percent 
change from baseline at each visit. 
All data will be listed by part, cohort, treatment and subject/patient. 
 ADMA and AA metabolites in plasma and urine  
Each parameter will be summarised by part, treatment and cohort with absolute and percent 
change from baseline at each visit.  
All data will be listed by part, cohort, treatment and subject/patient. 
 Metabolites in safety testing (MIST) 
Details will be specified elsewhere.  
 Future exploratory analyses of biomarkers and GS-248 metabolites 
Details will be specified elsewhere.  
 Raynaud’s questioning 
Data will be listed by treatment and patient.  
 
 

 
 
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