A Phase 2, Single-center, Randomised, Double-blind, Placebo-controlled, Cross-over Cold Challenge Study Investigating the Effect of C21 on Cold-induced Vasoconstriction in Subjects With Raynaud's Phenomenon (RP) Secondary to Systemic Sclerosis (SSc)
Phase: PHASE2
Conditions: Raynaud Phenomenon, Systemic Sclerosis
Sponsor: Vicore Pharma AB

 
Clinical Trial Protocol 
 
Title: 
A Phase 2, single-center, randomised, double-blind, placebo-controlled, 
cross-over, cold challenge study investigating the effect of C21 on cold-
induced vasoconstriction in subjects with Raynaud’s Phenomenon (RP) 
secondary to systemic sclerosis (SSc) 
 
Short Title:  
Cold challenge with C21 in RP  
 
Sponsor: 
 
Vicore Pharma AB 
Kronhusgatan 11 
SE-411 05 Göteborg 
Sweden 
 
Trial ID: 
 
VP-C21-004 
 
NCT No.: 
 
NCT04388176 
 
EudraCT No.: 
2019-003203-35  
 
Investigational  
Medicinal Product: 
C21 
 
Indication: 
 
RP secondary to SSc  
 
Phase: 
 
2 
 
Version: 
 
4.0 
 
Date: 
 
22-OCT-2020 
 
 
 
 
 
 
 
 
 
This Clinical Trial Protocol is the property of Vicore Pharma AB and is a confidential document. It is not to 
be copied or distributed to other parties without written approval from Vicore Pharma AB. 

 
Clinical Trial Protocol 
Vicore Pharma AB 
Version: 4.0  
Trial ID: VP-C21-004 
Date: 22-OCT-2020 
 
 
Confidential 
Page 1 of 45 
 
 
 
 
 
 
 
 
 
Clinical Trial Protocol 
 
Title: 
A Phase 2, single-center, randomised, double-blind, placebo-controlled, 
cross-over, cold challenge study investigating the effect of C21 on cold-
induced vasoconstriction in subjects with Raynaud’s Phenomenon (RP) 
secondary to systemic sclerosis (SSc) 
Short Title: 
Cold challenge with C21 in RP  
Sponsor: 
Vicore Pharma AB 
Kronhusgatan 11 
SE-411 05 Göteborg 
Sweden 
Trial ID: 
VP-C21-004 
EudraCT No.: 
2019-003203-35  
Investigational 
Medicinal Product: 
C21 
Indication: 
RP secondary to SSc  
Phase: 
2 
Version: 
4.0 
Date: 
22-OCT-2020 
 
 
 
 
 
 
 
 
 
This Clinical Trial Protocol is the property of Vicore Pharma AB and is a confidential document. It is not 
to be copied or distributed to other parties without written approval from Vicore Pharma AB. 

 
Clinical Trial Protocol 
Vicore Pharma AB 
Version: 4.0  
Trial ID: VP-C21-004 
Date: 22-OCT-2020 
 
 
Confidential 
Page 2 of 45 
 
 
 
 
 
 
Sponsor’s Approval of Clinical Trial Protocol 
 
This trial will be conducted in compliance with the protocol, GCP, and applicable regulatory 
requirements. 
 
 
 
 
Sponsor’s Medical Expert: 
___________________ 
______________ 
Rohit Batta, MBBS MRCGP FFPM.,   
Signature 
 
Date 
Vicore Pharma AB 
Telephone: +44 7950670515 
 
 
 
 
Sponsor’s Statistical Expert: 
___________________ 
______________ 
Thomas Bengtsson, M.Sc.,    
Signature 
 
Date 
StatMind AB 
 
 
 
Senior Director,  
Head of Clinical Operations: 
___________________ 
______________ 
Anne Katrine Cohrt, 
 
Signature 
 
Date 
Vicore Pharma AB 
 
 
 
 
 
 

 
Clinical Trial Protocol 
Vicore Pharma AB 
Version: 4.0  
Trial ID: VP-C21-004 
Date: 22-OCT-2020 
 
 
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Signatory Investigator’s Approval of Clinical Trial Protocol 
 
This trial will be conducted in compliance with the protocol, GCP, and the applicable regulatory 
requirements. 
 
I confirm, that I agree to conduct this study in compliance with the Declaration of Helsinki, the 
International Conference on Harmonisation (ICH) Guideline for GCP and applicable regulatory 
requirements. 
 
Furthermore, I confirm that I have read and understood the present clinical trial protocol and agree 
to conduct the study in compliance with this. I fully understand that any changes from the protocol 
constitute a deviation which will be notified to the Sponsor. 
 
 
 
 
Coordinating 
Investigator: 
 
___________________ 
______________ 
Ariane Herrick, MD, FRCP 
Signature 
 
Date 
 
Faculty of Biology, Medicine and Health  
Division of Musculoskeletal and Dermatological Sciences  
The University of Manchester 
Salford Royal NHS Foundation Trust 
Salford, M6 8HD, UK 
 
 
 

 
Clinical Trial Protocol 
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Date: 22-OCT-2020 
 
 
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TABLE OF CONTENTS 
SPONSOR’S APPROVAL OF CLINICAL TRIAL PROTOCOL ............................................. 2 
SIGNATORY INVESTIGATOR’S APPROVAL OF CLINICAL TRIAL PROTOCOL ......... 3 
1 
PROTOCOL SUMMARY ........................................................................................... 6 
2 
FLOW CHARTS ......................................................................................................... 8 
3 
BACKGROUND AND RATIONALE ...................................................................... 11 
3.1 
Indication Raynaud’s phenomenon in Systemic sclerosis ................................... 11 
3.2 
Current Treatment for Raynaud’s phenomenon in Systemic sclerosis .............. 11 
3.3 
Investigational Medicinal Product ....................................................................... 11 
3.4 
Pre-Clinical Safety ................................................................................................ 11 
3.5 
Clinical Safety ....................................................................................................... 12 
3.6 
Rationale for Trial ................................................................................................ 14 
3.7 
Rationale for Trial Design .................................................................................... 15 
3.8 
Rationale for Dose and Dosing Regimen .............................................................. 15 
3.9 
Risk-Benefit Assessment ....................................................................................... 15 
4 
OBJECTIVES AND ENDPOINTS ........................................................................... 16 
4.1 
Primary Objective ................................................................................................ 16 
4.2 
Secondary Objectives ............................................................................................ 16 
4.3 
Exploratory Objectives ......................................................................................... 16 
4.4 
Primary Endpoint ................................................................................................. 16 
4.5 
Secondary Endpoints ............................................................................................ 16 
4.6 
Exploratory Endpoints ......................................................................................... 16 
5 
TRIAL POPULATION ............................................................................................. 16 
5.1 
Inclusion Criteria .................................................................................................. 16 
5.2 
Exclusion Criteria ................................................................................................. 17 
5.3 
Restrictions during the study ............................................................................... 18 
5.4 
Withdrawal Criteria ............................................................................................. 19 
6 
TRIAL DESIGN ........................................................................................................ 20 
6.1 
Overall Trial Design ............................................................................................. 20 
6.2 
Number of Subjects .............................................................................................. 20 
6.3 
Trial Diagram ....................................................................................................... 21 
6.4 
Trial Duration and Participating Centers............................................................ 21 
6.5 
Schedule of Events ................................................................................................ 21 
7 
TRIAL TREATMENT .............................................................................................. 24 
7.1 
Investigational Medicinal Products ...................................................................... 24 
7.1.1         Active Treatment ................................................................................................... 24 
7.1.2         Reference Treatment (Placebo) ............................................................................ 24 
7.2 
Packaging, Labeling and Storage ......................................................................... 24 
7.3 
Treatment Assignment ......................................................................................... 25 
7.4 
Administration of Investigational Medicinal Products........................................ 25 
7.5 
Compliance Check and Drug Accountability ...................................................... 25 
7.6 
Blinding of the Trial ............................................................................................. 25 
7.7 
Procedures for Unblinding ................................................................................... 26 
7.8 
Prior and Concomitant Medications .................................................................... 26 

 
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8 
ASSESSMENTS......................................................................................................... 27 
8.1 
Efficacy Assessments ............................................................................................ 27 
8.2 
Safety Assessments ................................................................................................ 28 
8.3 
Other Assessments ................................................................................................ 29 
9 
ADVERSE EVENTS ................................................................................................. 30 
9.1 
Adverse Event Definitions .................................................................................... 30 
9.2 
Adverse Event Assessment Definitions................................................................. 31 
9.3 
Reporting of Adverse Events ................................................................................ 32 
9.4 
Follow-up on Adverse Events ............................................................................... 32 
9.5 
Pregnancies ........................................................................................................... 33 
10 
CHANGES TO TRIAL CONDUCT ......................................................................... 33 
10.1 
Protocol Amendments........................................................................................... 33 
10.2 
Premature Termination of the Trial .................................................................... 33 
10.3 
Premature Termination of a Trial Site ................................................................ 33 
11 
DATA HANDLING AND RECORD KEEPING ...................................................... 33 
11.1 
Data from Clinical Trial Sites .............................................................................. 33 
11.2 
Source Data ........................................................................................................... 34 
11.3 
Coding of Data ...................................................................................................... 35 
11.4 
Subject Confidentiality ......................................................................................... 35 
12 
RETENTION OF DOCUMENTS ............................................................................. 35 
13 
STATISTICAL METHODS ...................................................................................... 35 
13.1 
Sample Size and Power Considerations ............................................................... 36 
13.2 
Analysis Data Sets ................................................................................................. 36 
13.3 
Subject Disposition ............................................................................................... 36 
13.4 
Efficacy Analysis ................................................................................................... 36 
13.5 
Safety Analysis ...................................................................................................... 37 
14 
GOOD CLINICAL PRACTICE ............................................................................... 38 
15 
ETHICS...................................................................................................................... 38 
15.1 
Independent Ethics Committees / Health Authorities ......................................... 38 
15.2 
Informed Consent ................................................................................................. 38 
16 
AUDITS AND INSPECTIONS ................................................................................. 38 
17 
MONITORING .......................................................................................................... 39 
18 
REPORTING OF RESULTS .................................................................................... 39 
18.1 
Integrated Clinical Trial Report .......................................................................... 39 
18.2 
Use of Information ................................................................................................ 39 
18.3 
Publication of Results ........................................................................................... 39 
19 
INSURANCE AND LIABILITY ............................................................................... 40 
20 
REFERENCES .......................................................................................................... 41 
21 
ABBREVIATIONS .................................................................................................... 44 
 

 
Clinical Trial Protocol 
Vicore Pharma AB 
Version: 4.0  
Trial ID: VP-C21-004 
Date: 22-OCT-2020 
 
 
Confidential 
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1 
PROTOCOL SUMMARY   
Trial Title 
 
A Phase 2, single-center, randomised, double-blind, placebo-controlled, cross-over study 
investigating the effect of C21 on cold-induced vasoconstriction in subjects with Raynaud’s 
Phenomenon (RP) secondary to systemic sclerosis (SSc) 
Trial ID 
VP-C21-004 
Trial Phase 
2 
Objectives 
 
Primary 
To evaluate the effect of a single dose C21 200 mg o.d. on cold-induced vasoconstriction in 
subjects with Raynaud’s Phenomenon (RP) secondary to systemic sclerosis (SSc). 
 
Secondary 
• To evaluate the safety of a single dose C21 200 mg o.d. in subjects with RP secondary to 
SSc. 
• To evaluate the effect of a single dose C21 200 mg o.d. on finger temperature in subjects 
with RP secondary to SSc 
 
Exploratory 
To evaluate the effect of a single dose C21 200 mg o.d. on relevant biomarkers. 
Endpoints 
 
Primary 
Area under the curve for rewarming of each finger after cold challenge (AUC) as measured 
by thermography. 
 
Secondary 
To evaluate the safety of a single dose C21 200 mg o.d. in subjects with RP secondary to 
SSc. 
To evaluate the effect of a single dose C21 200 mg o.d. on finger temperature in subjects 
with RP secondary to SSc. 
 
Exploratory 
• Change in hand temperature from intake of IMP to start of cold challenge  
• Nailfold capillaroscopy  
• Potential analyses of biomarkers related to endothelium and platelets  
Trial Design 
 
This is a randomised, double-blind, placebo-controlled, cross-over, cold challenge study  
The subjects will come to the clinic for four visits: 
• Visit 1: Screening 
• Visit 2: IMP administration and cold challenge (3-21 days after Visit 1)  
• Visit 3: IMP administration and cold challenge (3-7 days after Visit 2)  
• Visit 4: End of trial (3-15 days after Visit 3 or after withdrawal from trial)  
Inclusion Criteria 
 
1) Written informed consent must be obtained before any trial related procedures are 
performed 
2) Subjects diagnosed with SSc according to European League Against Rheumatism 
(EULAR)/American College of Rheumatology (ACR) criteria [van den Hoogen et al 
2013]  
3) Age 19-75 years inclusive  
4) RP secondary to SSc as determined by the investigator, and with a typical frequency of 
attacks during the winter months (November-March) of on average at least 5 per week 
Exclusion Criteria 
 
1) Smoking (including E-cigarettes) or use of nicotine replacement therapy for three months 
prior to Visit 1 and during the trial 

 
Clinical Trial Protocol 
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2) BMI >35 
3) Mixed connective tissue disease or "overlap" (i.e. those who satisfy more than one set of 
ACR criteria for a rheumatic disease)  
4) Concurrent serious medical condition with special attention to cardiac or ophthalmic 
conditions which in the opinion of the investigator makes the patient inappropriate for this 
study  
5) Malignancy within the past 5 years with the exception of in situ removal of basal cell 
carcinoma and cervical intraepithelial neoplasia grade I  
6) Planned major surgery within the duration of the study 
7) Subjects who forsake any alcohol intake or have known uncontrolled allergic conditions 
or allergy/hypersensitivity to any components of the trial drug or placebo excipients (see 
Section 7.1) 
8) Blood donation (or corresponding blood loss) within three months prior to Visit 1  
9) Treatment with any of the medications listed below within 4 weeks prior to Visit 1: 
• 
Any dose-change or initiation of vasoactive substances), and not able or 
willing to withhold these medications for 3 days preceding Visit 2 and Visit 3, 
respectively  
• 
Iloprost  
• 
Any treatment with CYP3A4 inducers (e.g. rifampicin, phenytoin, St John’s Wort) 
• 
Any treatment with CYP3A4 inhibitors (e.g. clarithromycin, ketoconazole, 
nefazodone, itraconazole, ritonavir) 
• 
Any treatment with medicines that are substrates of CYP1A2, CYP3A4 or CYP2C9 
with a narrow therapeutic range 
• 
Any experimental drug 
• 
Any systemic immunosuppressive therapy other than: 
o Inhaled corticosteroids which can be used throughout the trial period 
oThe continuation of stable doses of <10 mg prednisolone  
o Mycophenolate mofetil (MMF) which must be withheld for 3 days preceding 
   Visit 2 and Visit 3  
10) Any of the following findings at the time of screening: 
• Finger temperature below 27°C after acclimatising at an ambient temperature of 23°C 
for a period of 20 minutes 
• Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant 
abnormalities in the resting ECG, as judged by the Investigator 
• Positive results for HBsAg, HCVAb or HIV 1+2 Ag/Ab 
• Positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 
HCG)  
• Clinically significant abnormal laboratory value at Visit 1 indicating a potential risk for 
the subject if enrolled in the trial as evaluated by the Investigator 
11) Pregnant or breast-feeding female subjects.  
12) Female subjects of childbearing potential not willing to use contraceptive methods  
described in Section 5.3.1  
13) Male subjects not willing to use contraceptive methods described in Section 5.3.1.  
14 )Participation in any other interventional trial during the trial period 
15) Subjects known or suspected of not being able to comply with this trial protocol (e.g. 
due to alcoholism, drug dependency or psychological disorder) 
 
 

 
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2 
FLOW CHARTS 
Table 1. Flow Chart for Trial Procedures  
 
Screening 
Treatment 
Treatment 
End-of-Trial 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4* 
Visit Window (days allowed from 
previous visit) 
 
3–21 Days 
3–7 Days 
3–15 Days 
Clinical assessments 
Informed consent 
X 
 
 
 
In- & exclusion criteria  
X 
 
 
 
Randomisation 
 
X 
 
 
Withdrawal criteria 
 
X 
X 
 
Demographics 
X 
 
 
 
Medical history & concomitant illness 
X 
 
 
 
Weight, height and BMI 
X 
 
 
 
Physical examination  
X 
X1) 
X1) 
X 
Vital signs 
X 
X 
X 
X 
Nailfold Capillaroscopy 
X 
X 
X 
 
Thermal probe2) 
X 
 
 
 
Modified Rodnan Skin Score 
X 
 
 
 
Raynaud’s Condition Score 
X 
X 
X 
 
Thermography 3) 
 
X 
X 
 
Cold challenge 
 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
12-lead ECG  
X 
 
 
X 
Holter ECG 
 
X4) 
X4) 
 
IMP administration 5) 
 
X 
X6) 
 
Adverse events 7) 
X 
X 
X 
X 
* Visit 4: End-of-Trial Visit for all randomised subjects must be performed no later than 30 days after Visit 2 
(randomisation). Visit 4 must also be performed if a randomised subject is withdrawn from the trial for any 
reason 
1) Brief examination according to Investigator’s judgement  
2) Application of thermal probe for check of finger temperature not being below 27°C (exclusion criterion 
10)  
3) Please refer to Section 6.5.2 for details 
4) Holter ECG from 30 mins prior to IMP administration and until 180 mins after  
5) Withdrawal criteria must be checked prior to IMP administration (see Section 5.4) 
6) Subjects will cross-over to opposite IMP (either C21 or placebo) compared to Visit 2  
7) AEs will be reported from signing of informed consent until End of Trial participation (Visit 4) 
 
 

 
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Table 2. Laboratory Parameters 
 
 
 
Screening 
Treatment Treatment 
End-of-
 
Visit 1 
Visit 2 
Visit 3 
Visit 4* 
Time tolerance from previous visit 
 
3–21 Days 
3–7 Days 
3–15 Days 
Laboratory Assessments 
Haematology1) 
X 
 
 
X 
Biochemistry2) 
X 
 
 
X 
Urinanalysis3) 
X 
 
 
X 
HIV and Hepatitis B/C4) 
X 
 
 
 
Thyroid Stimulating hormone (TSH) 
X 
 
 
 
Blood samples for potential analyses of 
exploratory biomarkers  
X 
X5) 
X5) 
X 
Blood sample for potential analysis of 
exposure to C21 
 
X6) 
X6) 
 
Pregnancy tests 
(WOCBP) 
beta-HCG for WOCBP. 
Follicular Stimulating 
Hormone (FSH), 
oestradiol for confirmation 
of WONCBP 
X 
 
 
X 
Urine dip-stick 
 
X 
X 
 
 
 
* Visit 4: End-of-Trial Visit for all randomised subjects.  
Visit 4 must be performed if a randomized subject is withdrawn from trial treatment for any reason 
 
1) Haemoglobin (Hb), haematocrit (Erythrocyte volume fraction), platelet count (Trombocyte particle 
concentration [TPC]), leucocyte count, Mean Corpuscular Volume (MCV) 
2) Albumin, alanine transferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase 
Gamma (ALP), bilirubin, Blood Urea Nitrogen (BUN), calcium, creatinine, C-Reactive Protein 
(CRP), Gamma Glutamyl Transferase (gGT), glucose, Lactate dehydrogenase (LD), potassium, 
sodium 
3) PH, glucose, protein/albumin and Hb 
4) HBsAg, HCVAb and HIV 1+ 2 AgAb 
5) Samples to be obtained before IMP administration, before cold challenge, immediately after cold 
challenge, 15 min after cold challenge 
6) Samples to be collected 15 min after cold challenge 
 
 
 

 
Clinical Trial Protocol 
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Table 3. Procedures and Assessments Visit 2 and Visit 3 
 
Time 
Procedure/Assessments (to be done in the following order) 
≥ 20 min 
• 
Subjects arrive at the department after overnight fasting (minimum 4 hours fasting - allowed 
to drink water and take usual medicine) and being requested to refrain from various activities 
(e.g. vigorous exercise, caffeine, and alcohol prior to any trial related assessments) see 
Section 5.4 
• 
Withdrawal criteria controlled (see Section 5.4) 
• 
Pregnancy test (WOCBP) – urine dip stick 
• 
Brief physical examination according to Investigator’s judgement 
• 
Randomisation (Visit 2 only) 
• 
Adverse Event questions reflecting the time from the previous visit 
• 
Concomitant medication 
• 
Raynaud’s Condition Score 
• 
Capillaroscopy 
• 
Application of intravenous cannula for blood sampling (before IMP administration, before 
cold challenge, immediately after cold challenge, 15 minutes after cold challenge)  
• 
Application of Holter ECG from 30 mins prior to IMP administration until 180 min after  
 
0 min 
• 
Capillaroscopy immediately before IMP administration 
• 
IMP administration (definition of the time 0 min) 
• 
Thermography image every 10 minutes 
 
40 min 
• 
Last thermography image before cold challenge test 
• 
Capillaroscopy immediately before cold challenge test 
• 
Immersion of both hands up to the metacarpophalangeal joints for 1 minute into cooled water 
(15°C) 
• 
Thermography images every 15 sec for 15 min 
• 
Capillaroscopy after thermography measurements have been completed 
 
120 min 
• 
Meal 
180 min  
• 
Removal of Holter ECG  
• 
Questions on Adverse Events during the day 
• 
Discharge 
 
 
 

 
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3 
BACKGROUND AND RATIONALE 
3.1 
Indication Raynaud’s phenomenon in Systemic sclerosis 
Systemic sclerosis (SSc) is an autoimmune disease characterised by dysregulation of innate and 
adaptive immunity, vasculopathy and fibrosis, which could affect several organ systems. Skin 
fibrosis (scleroderma) is the distinguishing hallmark of SSc, and microvascular injury and 
endothelial cell activation that results in vascular damage are considered to be the earliest, and 
possibly primary, events in SSc [Allanore et al 2015]. Changes in capillary morphology as 
investigated with nailfold videocapillaroscopy demonstrate a distinct and typical pattern [Ruaro et 
al 2017], but also small and medium size arteries are involved [Aïssou et al 2016]. There are four 
pathophysiological components of the vascular disease in SSc; vasospasm, vasculopathy, ischemia 
reperfusion injury and coagulation [Hughes & Herrick 2017].  
Raynaud’s phenomenon (RP), an episodic painful ischemic event affecting primarily fingers and 
toes in response to cold exposure or to emotional stress, is a very common manifestation of SSc. 
In the large EUSTAR database, including 9,182 patients with SSc, more than 95% reported RP 
[Elhai et al 2016]. The mean age at onset of RP, which usually is the first symptom of SSc, was 42 
years and preceded symptoms from other organ manifestations with an average of 4 years [Meier 
et al 2012]. In an international survey of patients with RP, most subjects (78%) reported making 
at least one life adjustment due to RP, and quality of life was significantly reduced. Further, of 
those with current or previous use of medications for RP, only 16% reported at least one medication 
being effective [Hughes et al 2015], and hence a substantial unmet medical need for efficient 
treatment of RP exists. 
3.2 
Current Treatment for Raynaud’s phenomenon in Systemic sclerosis 
Non-pharmacological therapies involve reducing stress, avoiding cold temperatures and stopping 
smoking. EULAR recommends dihydropyridine calcium channel blockers as first-line 
pharmacological therapy for SSc-RP, but PDE-5 inhibitors should also be considered, and 
fluoxetine could be a useful alternative for patients who cannot tolerate or do not respond to 
vasodilators [Kowal-Bielecka et al 2017]. Other therapies used for RP include topical 
nitroglycerine. 
3.3 
Investigational Medicinal Product 
The Investigational Medicinal Product (C21) is a selective angiotensin II type 2 receptor (AT2R) 
agonist presented as a solution for oral administration. 
3.4 
Pre-Clinical Safety 
The toxicity of C21 has been evaluated in single and repeated dose oral gavage studies of up to 13 
weeks duration in rats, dogs and NHP, as well as in genotoxicity studies. Safety pharmacology 
studies on respiratory function, cardiovascular system and behavior/CNS activity have been 
performed in rats and dogs.  
In a 13-week repeated dose study in rats with three different dose levels of C21 (6, 20 and 60 
mg/kg/day) ophthalmology examinations showed that the 20 and 60 mg doses caused unilateral or 
bilateral lens opacity (clinical signs observed from week 7 and onwards) and with signs of 
progression following a 28-day recovery. There were also indications of a similar effect in the 4-

 
Clinical Trial Protocol 
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week rat study at 60 mg/kg/day. In the dog, no lens opacity was observed and in a subsequent 
ophthalmology specific 13 week NHP study doses up to 30 mg/kg/day was clinically well tolerated 
without any in-vivo or morphological ophthalmic findings. Thus, the no observed adverse effect 
level (NOAEL) was determined to be 30 mg/kg/day in the NHP. As in man, the eye is the primary 
sensory organ in the NHP and therefore the overall anatomy and function of the eye is close to 
humans. Also, based on the phylogenetic similarities between NHP and humans, it is reasonable 
to assume that NHP represent the most appropriate translational model for ocular changes. Thus, 
it is very unlikely that a single dose of C21 could cause lens opacity in humans. 
No irreversible effects were detected in the dog. The main findings were increase in blood pressure 
at 1 mg/kg and evidence of ECG aberrations from 10 mg/kg in a telemetry study. In a 4-week 
general toxicity study increase in systolic and diastolic pressure was first noted at 25 mg/kg/day. 
In contrast, no blood pressure changes were seen in the 13-week repeated exposure study in doses 
up to 15 mg/kg/day. In the telemetry study ECG changes with PR- and QT/QTcR prolongations, 
AV-block I and II and isolated premature ventricular contractions were observed. Most of these 
findings could indicate a cardiac membrane stabilizing effect. The NOAEL in dogs based on data 
after exposure for 13 weeks was determined to 15 mg/kg/day. No NOAEL could be established 
for the effects on arterial blood pressure. 
An IC50 value of 53.3 µM was determined for hERG inhibition by C21 in recombinant HEK-293 
cells. This indicates low risk for QTc prolongation in humans at expected plasma concentrations 
of C21. 
Other findings in rats with up to 60 mg/kg of C21 daily for 12 weeks, were associated with 
reversible organ weight and/or histopathological findings within the pituitary, adrenal glands, 
ovary, thyroid gland and liver and also reversible changes in some hematological and blood 
chemistry parameters. None of these findings could be associated with any observed effect on 
organ function. Other findings in dogs with doses of 15/25 mg/kg/day of C21 for up to 13 weeks 
were associated with reversible changes in faecal consistency food consumption and consequently 
a change in body weight gain, mild haemoconcentration (both sexes), slightly elevated monocyte 
count (males) and fibrinogen levels (both sexes), increased overnight urine volumes and an 
associated reduction in urine specific gravity (females). 
There were no indications of any mutagenic or genotoxic potential of C21. 
For further details on the non-clinical studies performed with C21, please refer to the current 
Investigator’s Brochure (IB). 
 
3.5 
Clinical Safety 
Phase I clinical safety, tolerability and PK properties of C21 has been evaluated in single and 
repeated dose oral studies of up to 8 days’ duration in healthy male volunteers (Table 4). 
 
 
 

 
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Table 4. 
List of completed Clinical Phase I Studies with C21 
Study ID 
Objectives 
Study Design 
Population 
Total N 
Dose Regimens 
C21-001-16 
EudraCT: 
2015-005718-32 
Safety, 
tolerability, 
PK 
Placebo-
controlled single 
dose 
Healthy male 
volunteers 
48 
0.3, 1, 3, 10, 30, 100 
mg 
Oral solution 
C21-002-16 
EudraCT 
2015-005719-33 
Safety, 
tolerability, 
PK 
Placebo-
controlled 
multiple doses 
Healthy male 
volunteers 
24 
25, 50, 100 
mg/day 
Oral solution 
Overweight 
male 
volunteers 
16 
100 
mg/day 
oral solution 
 
In the single ascending dose (SAD) and multiple ascending dose (MAD) studies, C21 was rapidly 
absorbed, with a median tmax ranging from 20 to 40 min after dosing both after single dose and 
repeated dosing. Indications of multiphasic elimination was evident, with a very fast first 
distribution phase seen at lower doses of C21 (t½ of about 0.5 hours). A second slower phase, due 
to the elimination of C21, was observed at higher doses with a t½ of 5.37 hours. There was no 
accumulation of C21 at any of the investigated dose levels. Based on the SAD and MAD data, C21 
seems to have a more than dose-proportional increase of Cmax and AUC. 
No serious adverse events (SAE) were observed in any of the clinical investigations, and 
generally the observed adverse event (AE) profile was comparable between the C21 and placebo 
groups. However, a single subject receiving a single low dose (3 mg) showed a prolonged PR 
interval one hour post dose. This was not seen or replicated in any other subject within the same 
dose group or at higher doses. The subject was excluded from the trial and examination weeks 
after the last dose revealed 1st and 2nd degree AV block, suggesting that predisposition for longer 
PR intervals/AV blocks may have been the reason for the observation during the study. Within 
the MAD study, one subject experienced a syncope on the first day of treatment (100 mg dose), 
shortly after the 20-minute blood sample collection. It was managed by the Investigator as a 
vasovagal reaction as the subject swiftly returned to consciousness with elevation of the legs. 
Vasovagal syncope is a common phenomenon in Phase 1 studies of young healthy volunteers, 
and this event could have been provoked by the blood sampling and apprehension on the first 
day of dosing. The AE was recorded as a syncope, was rated as moderate in severity and related 
to IMP intake. During the syncope a sinus arrest was observed, which is also described in the 
literature in connection with vasovagal syncope [Palmert and Kahn 1996]. The subject continued 
with the study and completed dosing on 7 consecutive days with no further untoward effects or 
ECG abnormalities. 
A Phase 1, randomised, double blind, placebo-controlled SAD study is currently ongoing in 
healthy volunteers to test higher doses of C21 than previously investigated. So far, ten male and 
female subjects (8 active, 2 placebo) per dose group have been administered single doses of either 
100 mg BID, 200 mg QD or 200 mg BID for assessments of safety, tolerability and PK of C21.  
No SAEs were reported in either of the three dose groups tested. Furthermore, no clinically 
significant findings were observed in ECG, telemetry, vital signs or safety laboratory analyses. In 

 
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conclusion, the tested C21 doses were found to be well-tolerated and have an appropriate safety 
profile.  
Furthermore, 10 male and female subjects (8 on active and 2 on placebo) received  C21 doses of 
either 100 mg BID or 200 mg BID for 8 consecutive days. All doses in this multiple ascending 
dose (MAD) study were also found to have a good safety profile, no SAEs were reported and there 
were no clinical significant findings in ECG, telemetry, vital signs or safety laboratory. However, 
5 of the 8 subjects exposed to 200 mg BID reported alopecia between 7 and 14 days after the 8 
days treatment period was completed. Hair loss of different intensity was seen on all body parts 
This observation was assessed as probably related to IMP. The majority of subjects have reported 
regrowth of hair after one month and are presently being followed to assess the quality of the 
regrowing hair. For further details on the clinical experience with C21, please refer to the current 
Investigator’s Brochure (IB) including addendum 1.0 dated 26-September-2019. 
 
3.6 
Rationale for Trial 
C21 is intended to be used for the prevention and treatment of RP in patients with SSc. Current 
oral therapies for RP have limited efficacy, and there is a high medical need for new therapeutic 
alternatives. The aim of the present project is to achieve a vasodilatory effect by stimulation of the 
AT2R. 
Although the renin-angiotensin system (RAS) is best known as a major physiological regulator of 
blood pressure and fluid homeostasis, a number of other physiological functions including cell 
growth and differentiation, cell adhesion, inflammation and fibrosis are also regulated by the RAS. 
Angiotensin II (Ang II) is the major effector peptide of the RAS system. 
Ang II has potent vasoconstrictor effects mediated by the angiotensin II type 1 receptor (AT1R) 
[Forrester et al 2018]. The angiotensin II type 2 receptor (AT2R) is described as a central 
component of the “protective arm” of the renin-angiotensin system [Unger et al., 2015]. In a study 
using micro-dialysis to assess vascular tone, Ang II infusion caused a dose dependent 
vasoconstriction; AT2R inhibition with PD-123319 increased the vasoconstriction response, 
indicating a counterregulatory role of the receptor [Lang & Krajek 2019]. 
In adult human skin a complete RAS is present [Stecklings et al 2004], and it is upregulated with 
increased AT2R expression under pathophysiological status such as SSc [Kawaguchi et al 2004]. 
The AT2R is also upregulated in both vessels and septal areas in lungs from patients with SSc 
[Parra et al 2014]. 
Intra-arterial infusion of an AT2R agonist in healthy volunteers mediates vasodilation in the 
forearm [Schinzari et al 2011]. Further, the AT2R contributes to angiotensin II mediated 
vasodilation in resistance arteries of hypertensive diabetic patients treated with AT1R blocker for 
one year [Savoia et al 2007].  
In a pre-clinical study on human heart micro-coronaries, it was demonstrated that endothelial cells 
expressed the AT2R, and that exposure to C21 caused relaxation of the vessels mediated through 
nitric oxide (NO) [Batenburg et al 2004]. AT2R stimulation in human endothelial cells increases 
endothelial nitric oxide synthase (eNOS) activity through phosphorylation of activating eNOS 
residues and dephosphorylation of inactivating eNOS residues, thus increasing NO release [Peluso 
et al 2018]. 

 
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3.7 
Rationale for Trial Design 
This is a randomised, double-blind, placebo controlled cold challenge study. A cross-over design 
is applied to control for inter-individual variability in response to cold challenge.  
Randomisation is applied to minimise bias in the assignment of subjects. Double-blinded treatment 
is applied to reduce potential bias during data collection and evaluation of endpoints. 
Time points for IMP administration, cold challenge and thermography is based on the 
pharmacokinetic properties of C21.  
Overall, the study will provide important data to support the design of further studies.  
3.8 
Rationale for Dose and Dosing Regimen 
The dose of C21 (200 mg) is selected to achieve sufficient coverage of the receptor during the 
warm-up phase after the cold challenge.  
3.9 
Risk-Benefit Assessment  
The subjects’ safety and wellbeing are of outmost importance. The risk to subjects will be 
minimised by compliance with the eligibility criteria and by close clinical monitoring. Cold 
challenge is a well-established test for the diagnosis of RP and will be conducted with a standard 
procedure, which is used routinely in clinical practise. The subjects may experience discomfort 
following withdrawal of concomitant vasodilatory medication.  However, this is an important pre-
requisite for an objective evaluation of the study results, and hence the Investigator must exclude 
any subject considered unlikely to comply with the specified restrictions (see exclusion criterion 
17). 
The subjects may experience transient discomforts during the cold challenge test and in relation 
with the use of medical devices for study specific evaluations (e.g. indwelling venous catheters) 
and blood-pressure measurements using a blood pressure cuff. These procedures and devices are 
however used routinely in clinical practise, and part of the regular and well-established 
assessments of this patient population. Hence, the risks associated with are deemed to be low and 
considered ethically justifiable. 
All subjects are carefully monitored while receiving active compound and placebo. The C21 dose 
tested in the present trial has been evaluated in Part A of an ongoing Phase 1 study. Please refer to 
section 3.5 for further details. Overdosing of C21 is not likely to occur since the IMP will be 
administered by site personnel under medical surveillance.  
Except for thorough health examinations, the subjects participating in the present study are not 
expected to experience any medical benefits, but their participation provides important data, which 
will be used for a thorough assessment of the efficacy, safety and tolerability of C21. This 
information may form the basis for improved future treatment of patients suffering from RP and 
SSc. 
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 of the 
study. It is therefore concluded that the benefits from the study will outweigh the potential and 
minimal risks for the treated subjects. 

 
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4 
OBJECTIVES AND ENDPOINTS 
4.1 
Primary Objective 
To evaluate the effect of a single dose C21 200 mg o.d. on cold-induced vasoconstriction in 
subjects with Raynaud’s Phenomenon (RP) secondary to systemic sclerosis (SSc). 
4.2 
Secondary Objectives 
To evaluate the safety of a single dose C21 200 mg o.d. in subjects with RP secondary to SSc. 
To evaluate the effect of a single dose C21 200 mg o.d. on finger temperature in subjects with RP 
secondary to SSc. 
4.3 
Exploratory Objectives 
To evaluate the effect of a single dose C21 200 mg o.d. on relevant biomarkers 
4.4 
Primary Endpoint 
Area under the curve for rewarming of each finger after cold challenge (AUC) as measured by 
thermography. 
4.5 
Secondary Endpoints 
• Maximum skin temperature after rewarming (MAX) 
• The distal dorsal difference, defined as the difference in temperature between the dorsum and 
the finger (DDD) 
• Gradient of rewarming in the first 2 minutes post–cold challenge (GRAD) 
• Adverse events (AEs)  
4.6 
Exploratory Endpoints1 
• Change in hand temperature from intake of IMP to start of cold challenge  
• Nailfold capillaroscopy (including red blood cell velocity measurements) 
• Potential analyses of biomarkers related to endothelium and platelets 
 
5 
TRIAL POPULATION 
5.1 
Inclusion Criteria 
1) Written informed consent must be obtained before any trial related procedures are 
performed. 
2) Subjects diagnosed with SSc according to European League Against Rheumatism 
(EULAR)/American College of Rheumatology (ACR) criteria [van den Hoogen et al 
2013].  
 
1 The results on exploratory endpoints may not be included in the CSR 
 

 
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3) Age 19-75 years inclusive  
4) RP secondary to SSc as determined by the investigator, and with a typical frequency of 
attacks during the winter months (November-March) of on average at least 5 per week. 
5.2 
Exclusion Criteria 
1) Smoking (including E-cigarettes) or use of nicotine replacement therapy for three months 
prior to Visit 1 and during the trial. 
2) BMI >35 
3) Mixed connective tissue disease or "overlap" (i.e. those who satisfy more than one set of 
ACR criteria for a rheumatic disease).  
4) Concurrent serious medical condition with special attention to cardiac or ophthalmic 
conditions which in the opinion of the investigator makes the patient inappropriate for this 
study  
5) Malignancy within the past 5 years with the exception of in situ removal of basal cell 
carcinoma and cervical intraepithelial neoplasia grade I  
6) Planned major surgery within the duration of the study 
7) Subjects who forsake any alcohol intake or have known uncontrolled allergic conditions or 
allergy/hypersensitivity to any components of the trial drug or placebo excipients (see 
Section 7.1) 
8) Blood donation (or corresponding blood loss) within three months prior to Visit 1  
9) Treatment with any of the medications listed below within 4 weeks prior to Visit 1: 
• Any dose-change or initiation of vasoactive substances2), and not able or willing to 
withhold these medications for 3 days preceding Visit 2 and Visit 3, respectively  
• Iloprost  
• Any treatment with CYP3A4 inducers (e.g. rifampicin, phenytoin, St John’s Wort) 
• Any treatment with CYP3A4 inhibitors (e.g. clarithromycin, ketoconazole, 
nefazodone, itraconazole, ritonavir) 
• Any treatment with medicines that are substrates of CYP1A2, CYP3A4 or CYP2C9 
with a narrow therapeutic range3 
• Any experimental drug 
• Any systemic immunosuppressive therapy other than: 
o  Inhaled corticosteroids which can be used throughout the trial period 
 
2) Calcium channel blockers, Nitrates or nitric oxide donors, PDE5 inhibitors, Angiotensin receptor blockers 
(ARBs), ERA's, Alpha-blockers or Fluoxetine, Antithrombotic agents, Beta-blockers or Clonidine  
 
3 e.g. alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, phenytoin, pimozide, quinidine, 
sirolimus, tacrolimus, theophylline, pirfenidone, celecoxib and warfarin. Investigators will need to consult the product 
information of a concomitant drug as these lists may not be exhaustive. 

 
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o  The continuation of stable doses of <10 mg prednisolone  
o  Mycophenolate mofetil (MMF) which must be withheld for 3 days 
preceding Visit 2 and Visit 3 
10) Any of the following findings at the time of screening: 
• Finger temperature below 27°C after acclimatising at an ambient temperature of 
23°C for a period of 20 minutes 
• Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant 
abnormalities in the resting ECG, as judged by the Investigator 
• Positive results for HBsAg, HCVAb or HIV 1+2 Ag/Ab 
• Positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 
HCG)  
• Clinically significant abnormal laboratory value at Visit 1 indicating a potential risk 
for the subject if enrolled in the trial as evaluated by the Investigator 
11) Pregnant or breast-feeding female subjects.  
12) Female subjects of childbearing potential not willing to use contraceptive methods 
described in Section 5.3.1.  
13) Male subjects not willing to use contraceptive methods described in Section 5.3.1.  
14) Participation in any other interventional trial during the trial period 
15) Subjects known or suspected of not being able to comply with this trial protocol (e.g. due 
to alcoholism, drug dependency or psychological disorder) 
5.3 
Restrictions during the study 
5.3.1 
Contraception Requirements 
Women of child bearing potential (WOCBP) must practice abstinence (if that is their preferred 
lifestyle) from Visit 1 to Visit 4, 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, unless he has had a demonstrated successful vasectomy more 
than 6 months ago 
Males should use condom and their female partner of child-bearing potential must use a 
contraceptive method with a failure rate of <1% to prevent pregnancy (see above) 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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5.3.2 
Meals and Dietary Restrictions  
IMP should be administrated after overnight fasting. Subjects will be allowed to drink water and 
take his/her usual medication (e.g. proton pump inhibitor) with water on the morning of the visits. 
The following is not allowed prior to Visit 2 and Visit 3: 
• Within 10 days: Consumption of grapefruit and/or grapefruit containing products  
• Within 12 hours: Smoking or use of nicotine-containing products such as e-
cigarettes, vaping, chewing tobacco, snuff or smoking cessation compounds  
• Within 4 hours: Food, coffee, caffeine, xanthine and taurine (e.g. energy drinks 
such as Redbull) or alcohol  
5.3.3 
Exercise  
Subjects should abstain from strenuous exercise for 4 hours before Visit 2 and Visit 3. 
5.4 
Withdrawal Criteria 
5.4.1 
Withhold requirements at Visits 2 and 3 
The below requirements must be evaluated prior to performing the cold challenge test at Visit 2 
and Visit 3. Subjects violating any of the requirements can be re-scheduled for a new Visit < 10 
days later. Re-scheduling can only occur once per visit.  
 
Table 5. Overview of substances to be withheld before performing cold challenge test at Visit 2 & 3 
Time to withhold 
Substances 
4 weeks before 
Visit 1 
• 
Systemic immunosuppressive therapies1) with the exception of inhaled 
corticosteroids and MMF (see later in this table) 
• 
Iloprost  
• 
CYP3A4 inducers (e.g. rifampicin, phenytoin, St John’s Wort) 
• 
CYP3A4 inhibitors (e.g. clarithromycin, ketoconazole, nefazodone, 
itraconazole, ritonavir) 
• 
CYP2C9, CYP3A4 and CYP1A2 substrates with a narrow therapeutic 
range2) 
10 days  
• 
Acetylsalicylic acid  
• 
Clopidogrel  
• 
Grapefruit and/or grapefruit containing products 
3 days  
• 
Vasoactive substances3) 
• 
Mycophenalate mofetil (MMF) 
12 hours 
• 
Smoking or use of nicotine-containing products such as e-
cigarettes, vaping, chewing tobacco, snuff or smoking cessation 
compounds 
4 hours 
• 
Food 
• 
Coffee, Caffeine 
• 
Energy drinks 
• 
Alcohol 
• 
Rigorous exercise 

 
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1) e.g. cyclophosphamide, azathioprine, methotrexate, cyclosporine or systemic corticosteroids other than 
mycophenale mofetil (MFF) and continuation of stable doses of < 10 mg predniosolone 
2) e.g. alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, phenytoin, 
pimozide, quinidine, sirolimus, tacrolimus, theophylline, pirfenidone, celecoxib and warfarin. Investigators will 
need to consult the product information of a concomitant drug as these lists may not be exhaustive. 
3) Calcium channel blockers, Nitrates or nitric oxide donors, PDE5 inhibitors, Angiotensin receptor blockers 
(ARBs), ERA's, Alpha-blockers or Fluoxetine, Antithrombotic agents, Beta-blockers or Clonidine  
5.4.2 
Withdrawal from Trial  
• The subject receives disallowed treatment during the study period (see Section 
7.8.2) 
• Failure to comply with withhold requirements in the table in Section 5.4.1 
• The Investigator judges it necessary due to medical reasons 
• The subject experiences a serious adverse event evaluated as related to trial 
medication 
• It is the wish if the subject for any reason 
• Pregnancy 
• Un-blinding of treatment 
An End-of-Trial Visit (Visit 4) must be completed for all randomised subjects withdrawn from the 
trial  
Subjects withdrawn due to pregnancy will be followed – as consented to – until termination or 
delivery and the infant must be followed at least until the age of one month. 
 
6 
TRIAL DESIGN 
6.1 
Overall Trial Design 
This is a randomised, double-blind, placebo-controlled, cross-over cold challenge study  
The subjects will come to the clinic for four visits: 
• Visit 1: Screening 
• Visit 2: IMP administration and cold challenge (3-21 days after Visit 1)  
• Visit 3: IMP administration and cold challenge (3-7 days after Visit 2)  
• Visit 4: End of trial (3-15 days after Visit 3 or after withdrawal from trial)  
Each subject is expected to participate in the study for 11-51 days including a 3-21 days screening 
period. 
6.2 
Number of Subjects 
The study will include 16 randomised subjects. 

 
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6.3 
Trial Diagram 
  
 
 
 
 
 
 
 
 
 
6.4 
Trial Duration and Participating Centers 
Planned first subject screened: 
Q4 2019 
Planned last subject randomised: 
Q3 2020 
Planned last subject last visit: 
Q4 2020 
 
The end of trial is defined as the date of last subject last visit. 
 
6.5 
Schedule of Events 
6.5.1 
Screening (Visit 1) 
Prior and no later than at start of screening (Visit 1) i.e. before any trial related activity takes place, 
the Investigator or a qualified designee will explain the nature of the trial, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved and any 
discomfort it may entail. All explanations shall be in layman’s language. The subject will be 
provided with a copy of the information sheet. The subject must be given sufficient time to 
consider the trial before deciding whether to participate or not. 
After signed informed consent is obtained from the subject, the screening procedures can be 
initiated. 
All subjects giving informed consent to participate in the trial will receive a screening number. 
During the screening visit, the subject is evaluated for eligibility (please refer to Section 5.1 and 
5.2). 
The following procedures are performed: 
• Informed consent to be obtained 
• Assignment of screening number 
• Pregnancy testing (beta-HCG) 
Figure 1. Trial Design 

 
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• Check of in- & exclusion criteria 
• Application of thermal probe for check of finger temperature not being below 27°C 
(exclusion criterion 10)  
• Assessment of eligibility which includes review of demographics, medical history, 
concomitant illnesses and medication, physical examination, height, weight, BMI and 
measurement of blood pressure and pulse 
• Medical history and concomitant medication 
• Raynaud’s Condition Score 
• Modified Rodnan skin score 
• Application of thermal probe 
• Nailfold capillaroscopy 
• 12-lead ECG 
• Blood sampling for safety and biomarker assessments (See Table 2 and Section 8) 
• Information on restrictions prior to IMP administration at Visit 2 and Visit 3 (see Section 
5.4.1) 
• Reporting of AEs 
6.5.2 
Treatment (Visits 2 and 3) 
Visit 2 can be scheduled as soon as the relevant screening assessments are available, and the 
subject has been found to be eligible. Visit 2 must occur 3- 21 days from Visit 1 (screening), to 
ensure that no eligibility assessments are older than 21 days when treatment is initiated. 
Visit 3 can be scheduled 3-7 days days after Visit 2 
The following procedures are performed: 
 
Visit 2 only 
a) Randomisation and assignment of randomisation number 
  
Visit 2 and 3 
 
1) Before IMP administration: 
a) Concomitant medication 
b) Withdrawal criteria to be checked (see Section 5.4)  
c) Pregnancy test (urine dip stick) 
d) Vital signs 
e) Physical examination (See Table 1 and Section 8.2.4) 
f) Raynaud’s Condition Score 
g) Nailfold capillaroscopy 
h) Adverse events since last Visit  
i) Application of Holter ECG from 30 mins prior to IMP administration until 180 mins after 
time 0 
 
 
 

 
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Administration of IMP (time 0) 
a) Capillaroscopy immediately before IMP administration 
b) IMP administration (definition of the time 0 min) 
c) Thermography image every 10 minutes 
 
2) 40 min. after IMP (time 0) (Cold Challenge Test4)  
a) Last thermography image before cold challenge test 
b) Capillaroscopy immediately before cold challenge 
c) Immersion of both hands up to the metacarpophalangeal joints for 1 minute into cooled 
water (15°C) 
d) Thermography images every 15 sec for 15 min  
e) Capillaroscopy after thermography measurements have been completed 
 
3) 55-60 min after IMP (time 0): 
a) Blood sampling for potential analysis of C21 exposure (55 min after time 0) 
b) Removal of temperature probe (60 min after time 0) 
 
4) 120 min after IMP (time 0) 
a) Meal 
 
5) 180 min after IMP (time 0): 
a) Removal of Holter ECG  
b) Questions on Adverse Events during the day 
For traceability purposes and to verify the subjects’ existence, the Investigator must maintain an 
Identification List of all subjects who receive treatment. The list must contain full name, initials 
and date of birth.  
6.5.3 
Follow-up (Visit 4) 
Visit 4 is performed 3 days after Visit 3. The visit must be performed no later than 30 days after 
Visit 2 (randomisation) 
The following procedures are performed: 
a) Recording of concomitant medication 
b) Blood sampling for safety and biomarker assessments (See Table 2 and Section 8) 
c) Urinanalysis 
d) Pregnancy test (bloodsample) 
e) Physical examination (See Table 1 and Section 8.2.4) 
f) Vital signs 
g) Reporting of AEs 
h) 12-lead ECG 
If a subject is withdrawn from treatment (see Section 5.3.2), a Visit 4 (End-of-Trial Visit) must be 
performed. 
 
4 According to standard protocol [Wilkinson et al 2018] 

 
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7 
TRIAL TREATMENT 
7.1 
Investigational Medicinal Products 
7.1.1    Active Treatment 
Active substance: C21 is presented as a solution for oral administration. It is a solution of the 
sodium salt of C21 (3-[4-(1H-imidazol-1- ylmethyl)phenyl]- 5-(2- methylpropyl)t hiophene-2-
[(N-butyloxylcarbamate)-sulphonamide] sodium salt). The concentration is 5.2 mg/mL of the 
sodium salt, equivalent to a 5 mg/mL of the parent acid.  
Excipients: 
Name of ingredient 
Reference to standard 
Sodium carbonate, anhydrous 
Ph.Eur. 
Sodium hydrogen carbonate 
Ph.Eur. 
Water, purified 
Ph.Eur. 
 
7.1.2        Reference Treatment (Placebo) 
Active substance: None 
Excipients: 
Name of ingredient 
Reference to standard 
Citric acid monohydrate 
Ph.Eur. 
Denatonium benzoate 
USP-NF 
Ethanol (96 %) 
Ph.Eur. 
Hydrochloric acid 
Ph.Eur. 
Sodium hydroxide 
Ph.Eur. 
Water, purified 
Ph.Eur. 
 
7.2 
Packaging, Labeling and Storage 
IMP will be delivered in 50 mL vials containing 20 mL solutions of 100 mg C21 or placebo, and 
must be stored in a freezer (below -15°C). The IMP could however be stored in  refrigerator (+2 
to +8°C) for a maximum of 1 month prior to being administered to the patient. Details regarding 

 
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thawing conditions and storage of the thawed solution, will be specified in a separate trial specific 
document. 
The study drug will be labelled according to applicable regulatory requirements including unique 
vial-numbers and a placeholder for the patient ID to clearly identify the vials given to the subjects. 
At the trial site, IMP must be stored seperately from normal clinic stocks in a securely locked area 
only accessible to authorized trial personnel. Storage temperature must be monitored. 
Labeling of the IMP will be done in compliance with GMP Annex 13 [GMP 2003] and local 
regulatory requirements. 
 
7.3 
Treatment Assignment 
Eligible subjects will be randomised to receive either C21 or placebo in a random order at Visit 2 
and the opposite medication at Visit 3.  The doses administered to each subject is: 
• Placebo  
• C21 200 mg 
Each subject will be assigned a randomisation code number. 
Authorised trial staff will document the randomisation code number assigned in the subject’s 
medical record and in the relevant electronic Case Report Forms (eCRFs). 
7.4 
Administration of Investigational Medicinal Products 
At Visit 2, a single dose of either 200 mg C21 or placebo will be administered orally to subjects 
in fasted state together with 200 mL of water. At Visit 3 each subject will cross-over and receive 
the opposite medication. Subjects must stay fasted for minimum 4 hours before and minimum 1 
hour after IMP intake. 
IMP will be administered by the site staff and a trial staff member will oversee that the IMP is 
actually swallowed. The IMP must be administered 40 minutes before initiation of the Cold 
Challenge Test, at time 0 min. 
7.5 
Compliance Check and Drug Accountability 
All IMP will be administered at the research clinic under medical supervision to ensure 
compliance. 
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 . All details will be recorded in the eCRF. 
After completed drug accountability, all unused and partly used IMP will be returned to Sponsor 
or Sponsor’s designee for destruction. All returned IMP will be reconciled. 
7.6 
Blinding of the Trial 
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.  

 
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The packaging and labeling of IMP will reveal no evidence of IMP identity. C21 and the placebo 
are identical in appearance.. No difference can be sensed regarding smell. The placebo formulation 
contains an additive giving a bitter taste to obtain a medicinal taste. Hence, it is expected that 
subjects, Investigator and other trial personnel will remain unaware of treatment allocation. 
7.7 
Procedures for Unblinding 
The Sponsor or Sponsor’s designee will provide trial sites with one randomisation code envelope 
per each randomised subject (together with the IMP). 
The treatment code may only be broken in case of a medical emergency. The Investigator shall 
only un-blind the treatment allocation of a subject in the course of a clinical trial, if un-blinding is 
relevant for the safety of the subject.  
For expedited reporting purposes the Sponsor or Sponsor’s designee will be able to perform un-
blinding.  
Whenever a randomisation code is broken at the site, the person breaking the code must record the 
time, date and reason as well as her/his initials in the subject’s medical records. 
The subject must be withdrawn immediately after code break. 
7.8 
Prior and Concomitant Medications 
Concomitant medications are all medications being continued by the subject at trial entry and all 
medications 4 weeks prior to screening and received in addition to IMP during the trial period. 
At each visit, the Investigator or qualified designee will ask the subject about concomitant 
medication. All concomitant medications will be documented in the subject’s medical records and 
in the eCRF. Any changes in concomitant medications (e.g. new treatment, discontinuation of 
treatment or change in dosage) during the trial period must be documented in the subject’s medical 
records and in the eCRF. 
The following information will be recorded in the eCRF: 
• Generic name (preferred) or trade name 
• Reason for prescription 
• Dose unit and frequency 
• Route of administration 
• Start date (if started > 3 months prior to Visit 1, then this can be stated instead of recording 
a date) 
• Stop date (unless ongoing at trial termination) 
 
7.8.1 
Allowed Concomitant Medication 
If considered unlikely to interfere with IMP or the outcome of the trial results, concomitant 
medication may be given according to local standard of care.  
 

 
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7.8.2 
Disallowed Concomitant Medication 
The following treatments are not allowed: 
4 weeks before Visit 1  
• 
Immunosuppressive therapies 1) 
• 
Iloprost  
• 
CYP3A4 inducers (e.g. rifampicin, phenytoin, St John’s 
Wort) 
• CYP3A4 inhibitors (e.g. clarithromycin, 
ketoconazole, nefazodone, itraconazole, ritonavir) 
• Treatment with medicines that are substrates of 
CYP1A2, CYP3A4 or CYP2C9 with a narrow 
therapeutic range 
 
10 days before Visit 2 and Visit 3 
• Acetylsalicylic acid  
• Clopidogrel 
  
3 days before Visit 2 and Visit 3 
• Vasoactive substances 2) 
• Mycophenolate mofetil (MFF) 
 
 
1) e.g. cyclophosphamide, azathioprine, methotrexate, cyclosporine or systemic corticosteroids other than 
Mycophenolate mofetil (MMF) and continuation of stable doses of <10 mg prednisolone 
2) e.g. alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, phenytoin, 
pimozide, quinidine, sirolimus, tacrolimus, theophylline, pirfenidone, celecoxib and warfarin. Investigators will 
need to consult the product information of a concomitant drug as these lists may not be exhaustive. 
3)  
Calcium channel blockers, Nitrates or nitric oxide donors, PDE5 inhibitors, Angiotensin receptor blockers 
(ARBs), ERA's, Alpha-blockers or Fluoxetine, Antithrombotic agents, Beta-blockers or Clonidine 
 
8 
ASSESSMENTS 
8.1 
Efficacy Assessments 
8.1.1 
Cold challenge 
Cold challenge will be performed following a standard protocol [Wilkinson et al 2018]. A baseline 
thermography will be performed, and a temperature probe will be attached to a finger before IMP 
is administrated.  
Thermography will be initiated immediately prior to IMP intake (time 0). Images will be obtained 
every 10 minutes until immediately prior to cold challenge (40 minutes after time 0), where both 
hands will be immersed up to the metacarpophalangeal joints for 1 minute into cooled water 
(temperature of 15°C ±1°C). Reperfusion/rewarming will be imaged by thermography every 15 
seconds at 4 frames per minute, for 15 minutes. Analysis of the images will be performed using 
Research IR Max (version 4.2; FLIR).  

 
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8.1.2 
Biomarkers  
 Blood samples (plasma) for potential analysis of biomarkers related to platelet activation and 
endothelium will be obtained at the following timepoints:  
• Visit 1 
• Visit 2 and Visit 3: 
▪ Before IMP administration  
▪ Within 5 minutes before cold challenge  
▪ Within 1 minute after cold challenge   
▪ 15 minutes after cold challenge  
• Visit 4 
8.1.3 
C21 Exposure 
Blood sample for potential analysis of C21 plasma concentration will be obtained 15 min after 
cold challenge at Visit 2 and Visit 3 to check if subjects have been exposed to active treatment, if 
relevant.  
 
8.2 
Safety Assessments 
8.2.1 
Adverse Events 
Adverse Events (AEs) will be reported from signing of informed consent until End of Trial 
participation (Visit 4) 
AEs concerning cardiac or ophthalmic conditions are of special interest and must be reported to 
the Sponsor within 24 hours of obtaining knowledge of the event.  
8.2.2 
Medical History and Concomitant Illnesses 
The medical history and concomitant illness will be obtained by interviewing the patient or by 
inspecting his/her medical records. 
8.2.3 
Pregnancy Test 
Women of childbearing potential will undergo pregnancy tests at all visits 1).  
• Visit 1 and Visit 4: Blood sample  
• Visit 2 and Visit 3: Urine dip-stick 
1) 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). 
8.2.4 
Physical Examination 
A complete physical examination including assessments of the head, eyes, ears, nose, throat, skin, 
thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and 
extremities will be performed at Visit 1 and Visit 4. 

 
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A short version of physical examination including assessments of selected body systems at the 
judgement of the Investigator will be performed at Visit 2 and Visit 3 and must include cardiac 
examination. 
8.2.5 
Vital Signs  
Systolic and diastolic blood pressure, pulse and body temperature will be measured in supine 
position after 10 minutes of rest. 
8.2.6 
Electrocardiogram 
12-lead ECG will be recorded at Visit 1 and Visit 4.  
Holter ECG will be recorded at Visit 2 and Visit 3 from 30 mins prior to IMP administration until 
180 mins after.  
ECG evaluation will be performed by a centralised reader. 
8.2.7 
Safety Laboratory Parameters 
Safety laboratory parameters will be taken at Visit 1 and Visit 4: 
 
• Haematology: Haemoglobin (Hb), haematocrit (Erythrocyte volume fraction), platelet 
count (Trombocyte particle concentration [TPC]), leucocyte count, Mean Corpuscular 
Volume (MCV).  
• Biochemistry: Albumin, alanine transferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase Gamma (ALP), bilirubin, Blood Urea Nitrogen (BUN), calcium, 
creatinine, C-Reactive Protein (CRP), Gamma Glutamyl Transferase (gGT), glucose, 
Lactate dehydrogenase (LD), potassium, sodium 
 
Any laboratory abnormality, judged by the Investigator to be a clinically relevant worsening since 
Visit 1, should be reported as AEs if the laboratory abnormality required clinical intervention or 
further investigation, unless the laboratory abnormality is associated with an already reported 
event. 
8.3 
Other Assessments 
8.3.1 
Demographics and other Baseline Characteristics 
Demographic and baseline characteristics include but are not limited to age at screening, sex, 
height, weight, date of first diagnosis of disease under study, and disease-specific scoring. 
8.3.2 
Raynaud’s Condition Score 
Subjects will complete the Raynaud’s Condition Score (RCS), at Visit 1, Visit 2 and Visit 3 to 
assess the severity and impact of their RP for that day (Merkel et al 2002). 
8.3.3 
Nailfold Capillaroscopy 
Capillaroscopy, including measurement of red blood cell velocity, will be performed at Visit 1 to 
assess the degree of vasculopathy as a baseline descriptor [Herrick & Murray 2018]. Exploratory 

 
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capillaroscopy will be performed at Visit 2 and 3 before IMP administration and before and after 
cold challenge (See Section 6.5.2) 
8.3.4 
Modified Rodnan Skin Score (mRSS) 
The modified Rodnan skin score (mRSS) is a measure of skin involvement (Khanna et al 2017) 
and will be assessed at Visit 1 as a baseline descriptor. 
8.3.5 
Prior and concomitant medication 
Prior medications taken will be obtained by subject interview in order to verify that the eligibility 
criteria are met. 
Any use of concomitant medication from screening until the end-of-study visit 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. 
 
9 
ADVERSE EVENTS 
9.1 
Adverse Event Definitions 
An Adverse Event (AE), an Adverse Drug Reaction (ADR) and a Serious Adverse Event (SAE) 
are defined according to ICH Guideline E2A [ICH 1994]. 
An AE is any untoward medical occurrence in a subject administered the IMP and which does not 
necessarily have to have a causal relationship with this IMP. An AE can therefore be any 
unfavorable and unintended sign (e.g. a significant abnormal laboratory finding, , symptom, or 
disease temporally associated with the use of the IMP, whether or not considered related to the 
IMP. 
An ADR is any noxious and unintended response to an IMP related to any dose of the IMP.  
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (this refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it was more severe) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is judged medically important (this refers to an event that may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed) 
A non-SAE is any AE that does not meet the definition of an SAE. 
The following will not be considered an AE: 

 
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• Pre-planned procedure (documented at Visit 1) unless the condition for which the 
procedure was planned has worsened from the first trial related activity after the subject 
has signed the informed consent form 
• Concomitant illness identified as a result of screening procedures. However, if symptoms 
are worsened and/or become serious as defined in Section 9.1, this must be reported as a 
SAE. 
9.2 
Adverse Event Assessment Definitions 
9.2.1 
Severity 
The investigator should assess the severity of all AEs according to the following definitions: 
• Mild: awareness of sign or symptom, but easily tolerated (acceptable). 
• Moderate: discomfort to interfere with usual activities (disturbing). 
• Severe: incapacity to work or to perform usual activities (unacceptable).  
Note the distinction between seriousness and severity: The term severe is used to describe the 
intensity of the event and a severe event is not necessarily serious. The seriousness criteria serve 
as a guide for defining regulatory reporting obligations. 
9.2.2 
Relationship to IMP 
Assessment of causality is based on the following considerations: associative connections (time 
and/or place), pharmacological explanations, previous knowledge of the drug, presence of 
characteristic clinical or pathological phenomena, exclusion of other causes, and/or absence of 
alternative explanations. 
The investigator will be asked to assess causal relationship to the trial treatment according to the 
following classifications: 
Related:  
• Time relationship exists; and previous knowledge of the trial product supports a causal 
relationship although another cause cannot be ruled out; and/or improvement on dechallenge 
or dose reduction has occurred (if performed); and/or recurrence of symptoms on rechallenge 
has occurred (if performed); and/or a specific laboratory test supports a causal relationship. 
 
Not related:  
• No time relationship between administration of the trial product and occurrence or worsening 
of the AE exists; and/or another cause is confirmed and no indication for involvement of the 
trial product in the occurrence/worsening of the AE exists. The alternative, most likely other 
cause(s) should be indicated.   
9.2.3 
Outcome 
The investigator will be asked to record the most appropriate outcome of the following: 
• Recovered 

 
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• Ongoing  
• Not recovered 
• Recovered with sequelae 
• 
Death 
• 
Unknown 
9.3 
Reporting of Adverse Events 
All events meeting the definition of an AE must be reported in the period from the subject has 
signed the informed consent form until the end of trial participation (Visit 4). 
At each visit the subject will be asked about AEs in an objective manner, e.g.: “Have you 
experienced any problems since the last visit?” 
Only medically qualified personnel (investigators) must assess AEs. 
AEs must be reported on the AE form. The diagnosis should be recorded, if available. If no 
diagnosis is available each sign and symptom should be recorded as individual AEs. 
AEs concerning cardiac or ophthalmic conditions are of special interest and must be reported to 
the Sponsor within 24 hours of obtaining knowledge of the event.  
SAEs, in addition, must be reported within 24 hours of obtaining knowledge of the event. The 
information to be reported will include assessment of severity, causal relationship to IMP or trial 
procedures, action taken, outcome, and a narrative description of the course of the event. 
Additional information may be subsequently provided. 
All other relevant documents supporting the reported SAE (e.g. diagnostic procedures, hospital 
records, autopsy reports) must be faxed or scanned/emailed to Sponsor or Sponsor’s designee.  
The independent ethics committees (IEC) and regulatory authorities will be notified of SAEs 
according to current regulation and local requirements. 
All Suspected, Unexpected Serious Adverse Reactions (SUSARs) are subject to expedited 
reporting to regulatory authorities. Pharmacovigilance will unblind such cases prior to reporting. 
Investigators, the Sponsor and local IECs (if applicable) will remain blinded. 
The expectedness of a SUSAR will be assessed against the reference safety information. Any 
SUSARs will be reported by the CRO to the relevant Competent Authority. SUSARS will also be 
reported to the Ethics Committee by the site/CRO. Fatal and life threatening SUSARs will be 
reported as soon as possible and no later than seven calendar days from the date of first knowledge 
of the event. Relevant follow-up information will subsequently be expedited within an additional 
eight days. All other SUSARs will be expedited no later than 15 calendar days of first knowledge 
of the event. 
9.4 
Follow-up on Adverse Events 
All AEs should be followed until they are resolved or the subject’s participation in the trial ends, 
whichever comes first. 
SAEs and severe, non-serious AEs considered related to trial drug should be followed on a regular 
basis according to the investigator’s clinical judgment until a final outcome has been established. 

 
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9.5 
Pregnancies 
Any pregnancy that occurs during trial participation must be reported and administration of trial 
drug must be terminated immediately. A pregnancy must be reported to Sponsor or designee within 
2 weeks of learning of its occurrence. The pregnancy must be followed up to determine outcome 
(including premature termination) and status of mother and infant. Pregnancy complications and 
elective terminations for medical reasons must be reported as AEs or SAEs, as applicable. 
Spontaneous abortion must be reported as an SAE. 
In addition, the investigator must attempt to collect pregnancy information on any female partners 
of male trial participants who become pregnant while the participant is enrolled in the trial. 
Pregnancy information must be reported to Sponsor as described above. 
 
10 
CHANGES TO TRIAL CONDUCT 
10.1 
Protocol Amendments 
Before implementation of substantial changes (as defined in EU guidance documents [European 
Commission 2006, 2010]) unless considered an urgent safety measure, approval / favorable 
opinion must be obtained from the appropriate regulatory authority(ies) and IEC(s)  
10.2 
Premature Termination of the Trial 
In case of premature termination of the trial, health authorities and IECs will be notified in writing, 
including the reason for premature termination. 
Conditions that may warrant premature termination of the trial include, but are not limited to the 
following: 
• The discovery of an unexpected and significant or unacceptable risk to the subjects enrolled in 
the trial 
• A decision of the Sponsor to discontinue development of the drug 
10.3 
Premature Termination of a Trial Site 
The Sponsor can decide to prematurely terminate a site. Conditions that may warrant termination 
include, but are not limited to: 
• Insufficient adherence to protocol requirements 
• Failure to enrol subjects at an acceptable rate 
 
11 
DATA HANDLING AND RECORD KEEPING  
11.1 
Data from Clinical Trial Sites 
Data from clinical trial sites will be entered in an eCRF. 
The Investigator will sign relevant eCRF sections by use of an electronic signature. Only the 
Investigator (i.e. medically qualified personnel) can sign data on medical assessments. Any 
corrections made by the Investigator or authorised staff to the eCRF after original entry will 
document in an audit trail. The person making the change and the date, time and reason for the 

 
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change will be identified in the audit trail. Changes to the data already approved/signed by an 
Investigator will require re-signature by the Investigator. The Investigator (principal Investigator 
or sub-Investigator) will sign all patient data in the eCRF by an electronic signature. 
Subject data will be recorded anonymously and the subjects will be identified only by a screening 
number. 
The monitor will check the eCRF for accuracy and completion and perform source data 
verification. Data entered in the eCRF will be verified against source data. The level of source data 
verification is described in Section 11.2. 
11.2 
Source Data 
All data entered in the eCRF should be verifiable by source data in the subject’s medical record 
or other records at the trial site, as applicable: 
• Details of the trial (trial ID and subject screening and randomisation number) 
• Date(s) of informed consent of the subject 
• Data of each trial visit including signature and /or initials of person(s) conducting the visit 
• Data and information of any relevant telephone contact with the subject and signature and/or 
initials of person(s) conducting or receiving the call 
• Subject’s date of birth 
• Diagnosis of SSc including start date 
• Medical history and concomitant illness including start and stop dates 
• Concomitant medication including start and stop dates 
• Overall conslusion of the subject’s eligibility 
• Conclusion for each in-/exclusion criterion with respect to fulfillment of trial eligibility or 
not 
• Physical examination 
• Height, body weight and BMI 
• Blood pressure and pulse 
• Laboratory data, including date and time of blood sampling 
• Investigator’s evaluation of haematology and biochemistry results being out of range 
• Date and times of blood sampling 
• Nailfold capilloscopy 
• Modified Rodnan Skin Score 
• Raynaud’s Condition Score 
• Thermography 

 
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• Cold challenge 
• All AEs, SAEs and pregnancies described in details 
• Fasting before IMP administration 
• IMP dispensed including time of dispensing 
• Premature withdrawal of subject from the trial including reason and withdrawal criteria 
fullfilled 
11.3 
Coding of Data 
Medical history and AEs will be coded using the lastest version of Medical Dictionary for 
Regulatory Activities (MedDRA). 
Concomitant medication will be coded using the latest version of World Health Organisation 
(WHO) Drug Reference List. 
11.4 
Subject Confidentiality 
The confidentiality of the subject data and subject records shall be protected, respecting the 
privacy and confidentiality rules in accordance with applicable regulatory requirements. 
 
12 
RETENTION OF DOCUMENTS 
The monitor will instruct the investigator to maintain source documents and the signed informed 
consent form for each subject. 
Furthermore, the monitor will instruct the investigator to archive essential documents for the 
duration defined in the ICH Guideline E6 (Note for Guidance on Good Clinical Practice [ICH 
1997] or for 15 years, whichever comes first. 
The duration of archiving defined in the ICH Guideline E6 is as follows: 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a longer 
period however if required by the applicable regulatory requirements or by an agreement with the 
Sponsor. 
The Sponsor will notify the investigator when retention of the trial-related records is no longer 
required. 
13 
STATISTICAL METHODS 
The principal features of the statistical analysis to be performed are described in this section. A 
more technical and detailed elaboration of the principal features will be presented in a separate 
Statistical Analysis Plan (SAP), which will be signed and approved prior to the database lock. 

 
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13.1 
Sample Size and Power Considerations 
A Total of 16 subjects will be included. With 14 subjects a difference of 0.104 in the primary 
endpoint (log(AUC)) could be detected with a power of 90% (and alpha=0.1) based on variability 
previously reported, intra-individual standard deviation of the differences of 0.126 (Wilkinson et 
al 2018). Two additional subjects will be included to compensate for potential drop-outs. 
13.2 
Analysis Data Sets 
The Full Analysis Set (FAS) will consist of all subjects/subjects who have been randomised and 
received at least one dose of IMP and who has at least one post-baseline assessment of efficacy 
data allowing endpoint computation from each of the 2 treatment periods.  
The Per Protocol Analysis Set (PPAS) will be a subset of FAS and 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. 
The Safety Analysis Set (SAS) will consist of all subjects who have been randomised and received 
at least one dose of IMP. 
 
13.3 
Subject Disposition 
13.3.1 
Baseline Characteristics 
Demographics, medical history, baseline characteristics, and prior medications will be listed and 
summarized in terms of descriptive statistics: mean, SD, median and range for continuous 
outcomes and frequencies and percentages for categorical outcomes. 
13.4 
Efficacy Analysis 
Rewarming after cold challenge will be assessed by thermography, and the following endpoints 
will be calculated: 
• Area under the curve for reperfusion/rewarming in each finger (AUC) – Primary variable 
• Maximum skin temperature after rewarming (MAX) 
• The distal dorsal difference, defined as the difference in temperature between the dorsum and 
the finger (DDD) 
• Gradient of rewarming in the first 2 minutes post–cold challenge (GRAD) 
In addition, change in finger temperature during the first 60 minutes after administration of IMP 
will be assessed by temperature probe. 
13.4.1 
Efficacy Endpoint Analysis 
Treatments will be compared using an analysis of (co)variance model (AN(C)OVA) adjusting for 
patient, period and treatment and including the baseline value of the period as a covariate if 
appropriate. Model for AUC will be multiplicative, with data being logged prior to analysis. Model 
estimates will be back-transformed giving the treatment contrast as a geometric mean ratio with 
90% confidence intervals and associated, 2-sided p-value. 

 
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Secondary efficacy endpoints will be compared between treatment groups using similar  
AN(C)OVA models , multiplicative for MAX and GRAD and additive for other endpoints. 
13.4.2 
Statistical/Analytical Issues 
13.4.2.1 Missing Data 
Procedures for dealing with missing data will be described in the statistical analysis plan. 
13.4.2.2 Examination of Subgroups 
Important demographic and baseline value-defined subgroups will be examined and the results 
presented, e.g., comparison of effects by smoking status, age, sex and baseline disease severity. A 
detailed description will be provided in the Statistical Analysis Plan. 
 
13.5 
Safety Analysis 
13.5.1 
Adverse Events 
An overview of all treatment-emerging AEs including severity, relationship to IMP, serious AEs 
(SAEs) and AEs leading to withdrawals or death will be presented by treatment group. 
AEs will be summarized by treatment group, system organ class (according to MedDRA) and 
preferred term (according to MedDRA) displaying number of subjects in treatment group, number 
and percentage of subjects having the AE as well as number of AEs. Furthermore, AEs will be 
summarized according to severity, relationship, outcome and seriousness. 
SAEs and AEs leading to withdrawal will be listed and tabulated, if appropriate. 
13.5.2 
Electrocardiogram 
Overall assesssment of 12-lead ECG at Visit 1 and Visit 4 will be summarized by visit.  
Change from baseline (before IMP administration) of continuous HolterECG at Visit 2 and Visit 
3 (treatment visits) will be systematically analysed and summarised by treatment group. 
13.5.3 
Vital Signs 
Change from baseline (before IMP administration) of blood pressure and pulse will be summarized 
at Visit 2 and Visit 3 by treatment group. 
13.5.4 
Laboratory Safety Assessments 
Changes in laboratory parameters over the study (Visit 1 to Visit 4) will be presented by descriptive 
statistics and by shift tables  showing baseline values against values at end-of-study. Laboratory 
parameters will be categorised as ‘low’, ‘normal’ or ‘high’ (i.e. below, within, or above the 
reference ranges, respectively). 
13.5.5 
Physical examination 
Results of full physical examination will be summarised for Visit 1 and Visit 4 
 

 
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14 
GOOD CLINICAL PRACTICE 
This trial will be carried out in compliance with the protocol, GCP, Standard Operating Procedures 
(SOPs) of the CROs and applicable regulatory requirements. 
The investigator agrees, when signing this protocol, to adhere to the instructions and procedures 
described in it, to the principles of the Declaration of Helsinki, GCP and applicable regulatory 
requirements.  
15 
ETHICS 
15.1 
Independent Ethics Committees / Health Authorities 
Before implementing this trial, the protocol, the proposed subject information and subject consent 
form, and other documents as required, will be reviewed by properly constituted Independent 
Ethics Committees (IECs) and by the national regulatory authorities. 
A signed and dated statement that the protocol and subject information and subject consent form 
have been approved by the IECs and regulatory authorities will be obtained before trial initiation. 
For each individual IEC the name and occupation of the chairman and the members of the IEC 
will be collected as well as a statement that the IEC works in accordance with ICH GCP. 
IECs will receive updates on trial progress according to local regulations. 
15.2 
Informed Consent 
The subject’s signed and dated informed consent to participate in the trial will be obtained prior to 
any trial related procedure being carried out. 
Before any trial related procedure the investigator will explain to the potential subject the aims, 
methods, reasonably expected benefits and potential hazards of the trial and any discomfort 
participation in the trial may entail. Subjects will be informed that participation in the trial is 
voluntary and that the subject may withdraw from the trial at any time and for any reason. Subjects 
will be informed that if they choose not to participate, this will not affect the care the subject will 
receive for the treatment of his or her disease. Finally, subjects will be informed that their records 
may be accessed by health authorities and authorized Sponsor staff without violating the 
confidentiality of the subject, to the extent permitted by the applicable laws or regulations. 
All subjects will be given opportunity to ask questions and will be given sufficient time to consider 
before consenting. The subjects may choose to be accompanied, e.g. by a family member, during 
the information process. After having consented, a copy of the informed consent form will be 
given to the subject. 
 
16 
AUDITS AND INSPECTIONS 
A representative of the Sponsor may visit the trial site(s) at any time during the trial or after 
completion of the trial to conduct an audit of the trial. These audits will require access to all trial 
records, including source documents, for inspection and comparison with the CRFs. Subject 
privacy will, however, be respected. The investigator and other trial personnel will be responsible 

 
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for being present and available for consultation during routinely scheduled site audit visits 
conducted by the Sponsor’s representative. 
Similar auditing procedures (inspections) may also be conducted by agents of regulatory health 
authorities, either as part of a national GCP compliance program or to review the results of this 
trial in support of a regulatory submission. The investigator should notify the Sponsor’s 
representative or Sponsor immediately, if he/she has been contacted by a regulatory agency 
concerning an upcoming inspection. 
 
17 
MONITORING 
Before trial initiation a monitor from Sponsor’s representative will review the protocol and the 
CRF with the investigators and their trial personnel. During the trial the monitor will visit the trial 
site regularly to check the completeness of subject records, the accuracy of entries in CRFs, the 
adherence to the protocol and to GCP, the progress of enrolment and the handling and accounting 
of IMP. Key trial personnel must be available to assist the monitor during these visits. 
The investigator must give the monitor direct access to source data/documents (e.g. relevant 
hospital or medical records) to confirm their consistency with the entries in CRFs. No information 
in these records about the identity of the subjects must leave the trial site. 
 
18 
REPORTING OF RESULTS 
18.1 
Integrated Clinical Trial Report 
Data will be reported in an integrated clinical trial report in compliance with the requirements of 
the current version of ICH E3: Structure and Content of Clinical Study Report [ICH 1995]. The 
signatory investigator will review and sign the integrated clinical trial report. 
18.2 
Use of Information 
All unpublished information relating to this trial and/or to the trial drug is considered confidential 
by the Sponsor and shall remain the sole property of the SSponsor. 
The investigator must accept that the Sponsor may use the information from this clinical trial in 
connection with the development of the IMP, and therefore, may disclose it as required to other 
investigators, to government licensing authorities, to regulatory agencies of other governments, 
stock exchange market, and commercial partners. 
18.3 
Publication of Results 
Basic information of this trial will be posted by the Sponsor on the website: www.clinicaltrials.gov 
before the first subject enters the trial. 
The Sponsor is committed to publishing the trial results, whether positive or negative, in a peer-
reviewed journal [Wager, 2003; Graf 2009]. 

 
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The criteria for authorship as set out by the Committee of Medical Journal Editors 
(www.icmje.org) will be applied. 
The contributorship model will be applied and contributors who do not meet the criteria for 
authorship will be listed in an acknowledgments section with descriptions of the role of each 
contributor in order to ensure indexation in the National Library of Medicine. 
Publications are subject to the following conditions: 
• Data are the property of the Sponsor and cannot be published without prior authorization from 
the Sponsor. 
• Publications should be drafted with protection of individual privacy, intellectual property and 
contract rights in mind, and also conform to legislation and current national practices in patent 
and other laws. 
• The primary publication (i.e. the results from all centers) should be published before, or in 
parallel with, any secondary publications.  
• Publications shall not disclose any Sponsor confidential information or property. 
 
19 
INSURANCE AND LIABILITY 
The Sponsor has subscribed to an insurance policy covering, in its terms and provision, its legal 
liability for injuries caused to participating subjects and arising out of trial procedures performed 
in accordance this protocol, in accordance with applicable law and with the ICH Guideline E6 
(Note for Guidance on Good Clinical Practice) [ICH 1997]. 
 
 

 
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20 
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21 
ABBREVIATIONS 
ACR 
American College of Rheumatology 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
Ang II 
Angiotensin II 
ANOVA 
Analysis of Variance 
AP 
Anterior-Posterior 
ARB 
Angiotensin receptor blocker 
AST 
Aspartate Aminotransferase 
AT1R 
Angiotensin II type 1 receptor 
AT2R 
Angiotensin II type 2 receptor 
AUC 
Area under the curve 
AV 
Atrioventricular 
BMI 
Body mass index 
BUN 
Blood Urea Nitrogen 
cAMP 
cyclic Adenosine Monophosphate 
Cmax 
Maximum plasma concentration 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CSR 
Ckinical study report 
DDD 
Distal dorsal difference 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiography 
EoT 
End of Treatment 
EMA 
European Medicines Agency 
eNOS  
Endothelial nitric oxide synthase 
ERA 
Endothelin receptor antagonist 
EU 
European Union 
EULAR 
European League Against Rheumatism 
FAS 
Full Analysis Set 
FSH 
Follicle-stimulating Hormone 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GDF15 
Growth Differentiation Factor 15 
gGT 
Gamma Glutamyl Transferase 
GMP 
Good manufacturing practise 
GRAD 
Gradient of rewarming 
Hb 
Haemoglobin 
HBsAg 
Hepatitis B virus s-antigen  
HCG 
Human chorionic gonadotropin 
HCVAb 
Hepatitis C virus antibodies 
HEK 
Human embryonic kidney 
HIV 
Human Immunodeficiency Virus 
HDL 
High-density Lipoprotein 
hERG 
Human Ether-a-go-go-related Gene 
hs-CRP 
High-sensitivity C-Reactive Protein 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 

 
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IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
ITT 
Intention to Treat 
IUD 
Intrauterine device [IUD 
IUS 
Intrauterine hormone-releasing system 
LD 
Lactate dehydrogenase 
LDL 
Low-density Lipoprotein 
LFT 
Liver Function Test 
MAD 
Multiple ascending dose 
MAX 
Maximum skin temperature after rewarming 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities  
MMF 
Mycophenolate mofetil 
mRSS 
Modified Rodnan skin score 
NHP 
Non-Human Primate 
NO 
Nitric oxide 
NOAEL 
No Observed Adverse Effect Level 
PDE-5 
Phosphodiesterase 5 
PK 
Pharmacokinetic 
PPAS 
Per Protocol Analysis Set 
QTcF 
QT interval with Fridericia's correction 
QTcR 
QT interval with Rautaharju’s correction 
RAS 
Renin-angiotensin system 
RCS 
Raynaud’s Condition Score 
RP 
Raynaud’s Phenomenon 
SAD 
Single ascending dose 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SAS 
Safety Analysis Set 
SSc 
Systemic Sclerosis 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TPC 
Trombocyte particle concentration 
TSH 
Thyroid Stimulating hormone 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential