Conditions: Raynaud Phenomenon Systemic Sclerosis
Keywords: Systemic sclerosis Raynaud's phenomenon Vasoconstriction
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 20
Healthy volunteers: no

Brief summary:
This is a randomised, double-blind, placebo-controlled, cross-over phase 2 trial investigating the effect of C21 on cold-induced vasoconstriction in subjects with Raynaud's phenomenon secondary to systemic sclerosis. The purpose of the trial is to achieve a vasodilatory effect in subjects with Raynaud's phenomenon by stimulation of the AT2R (angiotensin II type 2 receptor) with C21.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: C21 intervention 2: C21 intervention 3: Placebo intervention 4: Placebo
Intervention descriptions: intervention 1: C21 as first treatment intervention 2: C21 as second treatment intervention 3: Placebo as second treatment intervention 4: Placebo as first treatment

Protocol document:
Prot_000.pdf: 
 
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 
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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 
 
 
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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 


 
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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 
 
 
 


 
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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-


 
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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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Trial ID: VP-C21-004 
Date: 22-OCT-2020 
 
 
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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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Trial ID: VP-C21-004 
Date: 22-OCT-2020 
 
 
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20 
REFERENCES 
Aïssou L, Meune C, Avouac J, Meunier M, Elhaïd M, Sorbets E, Kahan A, Allanore Y. Small, 
medium but not large arteries are involved in digital ulcers associated with systemic sclerosis. Joint 
Bone Spine 83: 444–447, 2016 
Allanore Y, Simms R, Distler O, Trojanowska M, Pope J, Denton CP, Varga J. Systemic sclerosis. 
Nature Reviews Disease Primers 1: 15002, 2015 
Batenburg WW, Garrelds IM, Bernasconi CC, Juillerat-Jeanneret L, van Kats JP, Saxena PR, 
Danser AHJ. Angiotensin II Type 2 Receptor–Mediated Vasodilation in Human Coronary 
Microarteries. Circulation 109:2 296-2301, 2004 
Elhai M, Avouac J, Walker UA, Matucci-Cerinic M, Riemekasten G, Airò P, Hachulla E, Valentini 
G, Carreira PE, Cozzi F, Balbir Gurman A, Braun-Moscovici Y, Damjanov N, Ananieva LP, 
Scorza R, Jimenez S, Busquets J, Li M, Müller-Ladner U, Kahan A, Distler O, Allanore Y, 
EUSTAR co-authors. A gender gap in primary and secondary heart dysfunctions in systemic 
sclerosis: a EUSTAR prospective study. Ann Rheum Dis 75: 163–169, 2016 
European Commission. Detailed guidance for the request for authorization of a clinical trial on a 
medicinal product for human use to the competent authorities, notification of substantial 
amendments and declaration of the end of the trial (CT1), 2010. 
European Commission. Detailed guidance on the application format and documentation to be 
submitted in an application for an Ethics Committee opinion on the clinical trial on medicinal 
products for human use (CT2), 2006. 
Forrester SJ, Booz GW, Sigmund CD, Coffman TM, Kawai T, Rizzo V, Scalia R, Eguchi S. 
Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology. 
Physiol Rev 98: 1627–1738, 2018 
Graf C, Battista WP, Bridges D, Bruce-Winkler V, Conaty JM, Ellison JM, et al. Good publication 
practise for community company sponsored medical reasearch: the GPP2 guidelines. Bmj 
2009;339(Nov27 1):b4330-b 
Good Manufacturing Practises, Annex 13, Manufacture of Investigational medicinal products, 
2003 
Herrick AL & Murray A. The role of capillaroscopy and thermography in the assessment and 
management of Raynaud's phenomenon. Autoimmunity Reviews 17: 465–472, 2018 
Hughes M & Herrick AL. Digital ulcers in systemic sclerosis. Rheumatology 56: 14-25, 2017 
Hughes M, Snapir A, Wilkinson J, Snapir D, Wigley FM, Herrick AL. Prediction and impact of 
attacks of Raynaud’s phenomenon, as judged by patient perception. Rheumatology (Oxford) 54: 
1443-7, 2015 
ICH E3 Harmonized Tripartite Guideline, E3: Structure and Content of Clinical Study Reports. 
Step 5, 1995. 
ICH Harmonized Tripartite Guideline E2A, Step 5: Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting, October 1994. 


 
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Trial ID: VP-C21-004 
Date: 22-OCT-2020 
 
 
Confidential 
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ICH Harmonized Tripartite Guideline E6 (R1), Step 5: Guideline for Good Clinical Practice. 
Adopted by CPMP July 1996 and by FDA May 1997. 
Kawaguchi Y, Takagi K, Hara M, Fukasawa C, Sugiura T, Nishimagi E, Harigai M, Kamatani N. 
Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via 
angiotensin II type 1 receptor. Arth Rheum 50: 216-26, 2004 
Khanna D, Furst DE, Clements PJ, Allanore Y, Baron M, Czirjak L, Distler O, Foeldvari I, 
Kuwana M, Matucci-Cerinic M, Mayes M, Medsger T Jr, Merkel1 PA, Pope JE, Seibold JR, Steen 
V, Stevens W, Denton CP on behalf of the Scleroderma Clinical Trials Consortium and the World 
Scleroderma Foundation. Standardization of the modified Rodnan skin score for use in clinical 
trials of systemic sclerosis. J Scleroderma Relat Disord 2: 11–18, 2017 
Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, Distler O, Clements P, 
Cutolo M, Czirjak L, Damjanov N, del Galdo F, Denton CP, Distler JHW, Foeldvari I, Figelstone 
K, Frerix M, Furst DE, Guiducci S, Hunzelmann N, Khanna D, Matucci-Cerinic M, Herrick AL, 
van den Hoogen F, van Laar JM, Riemekasten G, Silver R, Smith V, Sulli A, Tarner I, Tyndall A, 
Welling J, Wigley F, Valentini G, Walker UA, Zulian F, Müller-Ladner U, EUSTAR Coauthors. 
Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis 76: 
1327-1339, 2017 
Lang JA & Krajek AC. Age-related differences in the cutaneous vascular response to exogenous 
angiotensin II. Am J Physiol Heart Circ Physiol 316: H516–H521, 2019 
Meier FMP, Frommer KW, Dinser R, Walker UA, Czirjak L, Denton CP, Allanore Y, Distler O, 
Riemekasten G, Valentini G, Müller-Ladner U, EUSTAR Co-authors. Update on the profile of the 
EUSTAR cohort: ananalysis of the EULAR Scleroderma Trials andResearch group database. Ann 
Rheum 71: 1355–1360, 2012 
Merkel PA, Herlyn K, Martin RW, Anderson JJ, Mayes MD, Bell P, Korn JH, Simms RW, Csuka 
ME, Medsger TA Jr, Rothfield NF, Ellman MH, Collier DH, Weinstein A, Furst DE, Jiménez SA, 
White B, Seibold JR, Wigley FM, for the Scleroderma Clinical Trials Consortium. Measuring 
Disease Activity and Functional Status in Patients With Scleroderma and Raynaud’s Phenomenon. 
Arthritis & Rheumatism 46: 2410–2420, 2002 
Palmert MR., Kahn, J.A. 1996. CaseReport. A 15-year-old young man with syncope and transient 
sinus arrest. Curr. Opin. Pediatrics. 261-265 
Parra ER, Ruppert AD, Capelozzi VL. Angiotensin II type 1 and 2 receptors and lymphatic vessels 
modulate lung remodeling and fibrosis in systemic sclerosis and idiopathic pulmonary fibrosis. 
Clinics 69 :47-54, 2014 
Peluso AA, Bertelsen JB, Andersen K, Mortsensen TP, Hansen PD, Sumners C, Bader M, Santos 
RA, Steckelings UM. Identification of protein phosphatase involvement in the AT2 receptor-
induced activation of endothelial nitric oxide synthase. Clinical Science 132: 777–790, 2018 
Ruaro B, Sulli A, Smith V, Pizzorni C,  Paolino S, Alessandri E, Cutolo M. Microvascular damage 
evaluation in systemic sclerosis: the role of nailfold videocapillaroscopy and laser techniques. 
Reumatismo 69: 147-155, 2017 
Savoia C, Touyz RM, Volpe M, Schiffrin ET. Angiotensin Type 2 Receptor in Resistance Arteries 
of Type 2 Diabetic Hypertensive Patients. Hypertension 49: 341-346, 2007 


 
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Version: 4.0  
Trial ID: VP-C21-004 
Date: 22-OCT-2020 
 
 
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Schinzari F, Tesauro M, Rovella V, Adamo A, Mores N, Cardillo C. Coexistence of functional 
angiotensin II type 2 receptors mediating both vasoconstriction and vasodilation in humans. J 
Hypertens 29: 1743–1748, 2011 
Steckelings UM. Wollschläger T, Peters J, Henz BM, Hermes B, Artuc M. Human skin: source of 
and target organ for angiotensin II. Experimental Dermatology 13: 148–154, 2004 
Unger T, Steckelings UM, dos Santos RAS Eds. The Protective Arm of the Renin–Angiotensin 
System - Functional Aspects and Therapeutic Implications. Elsevier 2015 
van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, 
Naden RP, Medsger Jr. TA, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, 
Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, 
Inanc M, Kowal-Bielecka O, Müller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, 
Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh 
B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE. 2013 classification 
criteria for systemic sclerosis: an American College of Rheumatology/European League against 
Rheumatism collaborative initiative. Arthritis Rheum 65: 2737–47, 2013 
Wager E, Field EA, Grossman L. Good publication practise for pharmaceutical companies, 
Current Medical Research amd Opnion, 2003;19(3):149-54 
Wilkinson JD, Leggett SA, Marjanovic EJ, Moore TL, Allen J, Anderson ME, Britton J, Buch 
MH, Del Galdo F, Denton CP, Dinsdale G, Griffiths B, Hall F, Howell K, MacDonald A, Neil J. 
McHugh NJ, Manning JB, Pauling JD, Roberts C, Shipley JA, Herrick AL, Murray AK. A 
Multicenter Study of the Validity and Reliability of Responses to Hand Cold Challenge as 
Measured by Laser Speckle Contrast Imaging and Thermography - Outcome Measures for 
Systemic Sclerosis–Related Raynaud’s Phenomenon. Arthritis & Rheumatology 70: 903–911, 
2018 
 


 
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Trial ID: VP-C21-004 
Date: 22-OCT-2020 
 
 
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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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Trial ID: VP-C21-004 
Date: 22-OCT-2020 
 
 
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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  
 
 
 
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
 
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: 
 
Final 1.0 
 
Date: 
 
01-Feb-2021 
 
 
 
 
 
 
 
 
 
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. 


 
 
 
Page 1 of 37 
 
STATISTICAL ANALYSIS PLAN 
 
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) 
 
Protocol: VP-C21-004 
SGS LS number: BE-80-1903115 
Development phase: II 
Sponsor: Vicore Pharma AB 
Analysis purpose: Final analysis 
SAP version number: Final 1.0 
SAP version date: 01FEB2021 
 
 


Statistical Analysis Plan 
 
VP-C21-004 
Final analysis 
Final 1.0 
 of 01FEB2021 
 
Page 2 of 37 
SIGNATURE PAGE 
Name and function 
Date 
(ddMMMyyyy) 
Signature 
SGS LS author(s) and reviewer(s): 
Jie Yang, Junior 
Biostatistician 
 
 
 
 
Bastiaan Jansen, 
Biostatistical 
Coordinator-Senior 
Biostatistician 
 
 
 
 
Sponsor’s approval: 
The approver agrees the statistical analysis will be performed according to this 
statistical analysis plan. 
Thomas Bengtsson, 
Statistical Expert,  
 
 
 
 
Kamilla Overbeck 
Nygaard, Clinical Trial 
Manager 
 
 
 
 
 
 
 
01-Feb-2021 | 13:53 CET
01-Feb-2021 | 14:16 CET
01-Feb-2021 | 05:22 PST
01-Feb-2021 | 12:01 PST


Statistical Analysis Plan 
 
VP-C21-004 
Final analysis 
Final 1.0 
 of 01FEB2021 
 
Page 3 of 37 
TABLE OF CONTENTS 
Signature page .............................................................................................................. 2 
Table of contents .......................................................................................................... 3 
Protocol history ............................................................................................................ 6 
List of abbreviations .................................................................................................... 7 
Definition of terms ....................................................................................................... 9 
1. 
Introduction ....................................................................................................... 10 
1.1 
Study objectives............................................................................................. 10 
1.2 
Study design .................................................................................................. 10 
1.3 
Expected sample size ..................................................................................... 11 
1.4 
Randomisation and blinding .......................................................................... 11 
1.5 
Interim analysis ............................................................................................. 11 
1.6 
Software ......................................................................................................... 11 
1.7 
Validation model ........................................................................................... 11 
2. 
Efficacy, pharmacokinetic and pharmacodynamic analyses ......................... 13 
2.1 
Efficacy.......................................................................................................... 13 
2.1.1 
Available data .................................................................................. 13 
2.1.2.1 Primary endpoint ............................................................................................. 13 
2.1.2.2 Secondary endpoints ....................................................................................... 13 
2.1.2.3 Exploratory endpoints ..................................................................................... 13 
2.1.2 
Inferential statistics ......................................................................... 14 
2.1.3 
Presentation of results ..................................................................... 14 
2.1.3.1 
Primary endpoint ...................................................................................... 15 
2.1.3.2 
Secondary endpoints................................................................................. 15 
2.1.3.3 
Exploratory endpoints .............................................................................. 15 
3. 
Safety analyses ................................................................................................... 16 
3.1 
Adverse events............................................................................................... 16 
3.1.1 
Available data .................................................................................. 16 
3.1.2 
Derivation rules ............................................................................... 16 
3.1.3 
Presentation of results ..................................................................... 17 
3.2 
Clinical laboratory evaluation ....................................................................... 17 
3.2.1 
Available data .................................................................................. 17 
3.2.2 
Derivation rules ............................................................................... 17 
3.2.3 
Presentation of results ..................................................................... 18 
3.3 
Vital signs ...................................................................................................... 18 


Statistical Analysis Plan 
 
VP-C21-004 
Final analysis 
Final 1.0 
 of 01FEB2021 
 
Page 4 of 37 
3.3.1 
Available data .................................................................................. 18 
3.3.2 
Derivation rules ............................................................................... 18 
3.3.3 
Presentation of results ..................................................................... 18 
3.4 
Electrocardiograms ........................................................................................ 19 
3.4.1 
Available data .................................................................................. 19 
3.4.2 
Derivation rules ............................................................................... 19 
3.4.3 
Presentation of results ..................................................................... 20 
3.5 
Physical examinations ................................................................................... 20 
4. 
General characteristics analyses ...................................................................... 21 
4.1 
Subject disposition......................................................................................... 21 
4.2 
Protocol deviations and eligibility ................................................................. 21 
4.3 
Demographic and other baseline characteristics ........................................... 21 
4.3.1 
Available data .................................................................................. 21 
4.3.2 
Derivation rules ............................................................................... 22 
4.3.3 
Presentation of results ..................................................................... 22 
4.4 
Medical history and concomitant diseases .................................................... 22 
4.4.1 
Available data .................................................................................. 22 
4.4.2 
Derivation rules ............................................................................... 22 
4.4.3 
Presentation of results ..................................................................... 22 
4.5 
Prior and concomitant therapies .................................................................... 23 
4.5.1 
Available data .................................................................................. 23 
4.5.2 
Derivation rules ............................................................................... 23 
4.5.3 
Presentation of results ..................................................................... 23 
4.6 
Exposure to study drug .................................................................................. 23 
4.6.1 
Available data .................................................................................. 23 
4.6.2 
Derivation rules ............................................................................... 23 
4.6.3 
Not applicable. Presentation of results ............................................ 23 
5. 
General methodology......................................................................................... 24 
5.1 
Analysis sets .................................................................................................. 24 
5.1.1 
Analysis sets .................................................................................... 24 
5.1.2 
As planned versus as actual analysis ............................................... 24 
5.2 
Phases, periods and time points ..................................................................... 25 
5.2.1 
Phases and periods .......................................................................... 25 
5.2.2 
Baseline and change from baseline ................................................. 25 


Statistical Analysis Plan 
 
VP-C21-004 
Final analysis 
Final 1.0 
 of 01FEB2021 
 
Page 5 of 37 
5.2.3 
Relative day ..................................................................................... 25 
5.2.4 
Analysis visits ................................................................................. 25 
5.3 
Imputation and rounding rules ....................................................................... 26 
5.3.1 
Missing values ................................................................................. 26 
5.3.2 
Handling partially or completely missing dates in calculations ...... 26 
5.3.3 
Rounding of derived variables ........................................................ 26 
5.3.4 
Outliers ............................................................................................ 26 
5.4 
Presentation of results.................................................................................... 27 
5.4.1 
Calculation of descriptive statistics and percentages ...................... 27 
5.4.2 
Presentation of treatments ............................................................... 27 
5.4.3 
Ordering in tables, figures and listings ............................................ 27 
6. 
Changes to the planned analysis ....................................................................... 28 
6.1 
Changes not covered by protocol amendments before database lock ........... 28 
6.2 
Changes not covered by protocol amendments after database lock .............. 28 
6.3 
Changes to the final statistical analysis plan ................................................. 28 
7. 
References ........................................................................................................... 29 
8. 
List of tables, listings and figures ..................................................................... 30 
8.1 
Tables ............................................................................................................ 30 
8.2 
Listings .......................................................................................................... 31 
8.3 
Figures ........................................................................................................... 32 
9. 
Appendices ......................................................................................................... 33 
9.1 
SAS code ....................................................................................................... 33 
9.2 
Schedule of assessments ................................................................................ 34 
 


Statistical Analysis Plan 
 
VP-C21-004 
Final analysis 
Final 1.0 
 of 01FEB2021 
 
Page 6 of 37 
PROTOCOL HISTORY 
 
Protocol: 
Version or ID 
Date 
(ddMMMyyyy) 
Impact of the changes on the statistical 
analysis 
Final 1.0 
20AUG2019 
NAP 
Final 2.0 
27AUG2019 
NAP 
Final 3.0 
11OCT2019 
NAP 
Final 4.0 
22OCT2020 
NAP 
 
Protocol amendments: 
Version or ID 
Date 
(ddMMMyyyy) 
Impact of the amendment on the 
statistical analysis 
NAP 
 
 
 
 
 
This statistical analysis plan (SAP) only considers the last version of the protocol, and 
of the protocol amendments, as listed above. 
 
 


Statistical Analysis Plan 
 
VP-C21-004 
Final analysis 
Final 1.0 
 of 01FEB2021 
 
Page 7 of 37 
LIST OF ABBREVIATIONS 
 
ADaM 
analysis data model 
AE 
ALP 
ALT 
ANOVA 
ANCOVA 
AST 
adverse event 
alkaline phosphatase 
alanine transaminase 
analysis of variance 
analysis of covariance 
aspartate transaminase 
bpm 
beats per minute 
CI 
confidence interval 
CRF 
case report form 
DBP 
diastolic blood pressure 
DSMB 
data safety monitoring board 
DY 
relative day 
ECG 
electrocardiogram 
FAS 
GGT 
full analysis set 
gamma-glutamyl transferase 
GMR 
geometric mean ratio 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAP 
not applicable 
PP 
per protocol 
QTc 
corrected QT interval 
QTcB 
Bazett’s corrected QT interval 
QTcF 
Fridericia’s corrected QT interval 
RND 
all randomised subjects analysis set 
SAP 
statistical analysis plan 
SAF 
safety analysis set 
SBP 
systolic blood pressure 


Statistical Analysis Plan 
 
VP-C21-004 
Final analysis 
Final 1.0 
 of 01FEB2021 
 
Page 8 of 37 
SCR 
all screened subjects analysis set 
SD 
standard deviation 
SE 
standard error 
SGS LS 
SGS Life Sciences 
SOP 
standard operating procedure 
TEAE 
TLF 
treatment-emergent adverse event 
tables, listings and figures 
VS 
vital signs 
WHO 
World Health Organisation 


Statistical Analysis Plan 
 
VP-C21-004 
Final analysis 
Final 1.0 
 of 01FEB2021 
 
Page 9 of 37 
DEFINITION OF TERMS 
 
bias 
The systematic tendency of any factors associated with the design, 
conduct, analysis and evaluation of the results of a clinical trial to 
make the estimate of a treatment effect deviate from its true value. 
Bias introduced through deviations in conduct is referred to as 
‘operational’ bias. The other sources of bias listed above are 
referred to as ‘statistical’. 
 
 
case report 
form (CRF) 
A printed, optical, or electronic document designed to record 
protocol required information to be reported to the sponsor for each 
trial subject. 
 
 
display 
Analysis table, listing or figure 
 
 
phase 
Interval of time in the planned conduct of a study associated with a 
specific purpose: for example, screening, treatment, follow-up. 
 
 
round half to 
even tie-
breaking 
rule 
Convention to round values ending with 5 to the nearest even digit. 
This method treats positive and negative values symmetrically, and 
is therefore free of sign bias, which is not the case for the round half 
up tie-breaking rule. The round half to even rule is implemented in 
the SAS® ROUNDE function. 
Examples: 
Database value 
Rounded value 
-1.35 
-1.4 
-1.25 
-1.2 
 1.25 
 1.2 
 1.35 
 1.4 
significant 
digit 
All digits of a number used to express it to the required degree of 
accuracy, starting from the first non-zero digit. 
 
 
study drug 
Pharmaceutical form of an active ingredient or placebo, being tested 
or used as a reference in a clinical study. 
 
 
 
 
 


Statistical Analysis Plan 
 
VP-C21-004 
Final analysis 
Final 1.0 
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1. 
INTRODUCTION 
This SAP describes the final statistical analysis to be performed for the VP-C21-004 
(BE-80-1903115) study. 
This SAP covers the efficacy, safety, and general characteristics parts of the statistical 
analysis. It specifies the analysis displays to be presented and describes the methods 
and procedures in a more elaborated way than in the statistical methods section of the 
protocol. 
The interim / DSMB / other analysis is / are not in the scope of this SAP. 
The statistical analysis will process and present the results following the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) standards, in particular the ICH-E3, ICH-E6, and ICH-E9 
guidelines. 
1.1 
STUDY OBJECTIVES 
The primary objective of this study is: 
• 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). 
The secondary objectives of this study are: 
• 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. 
The exploratory objective of this study is: 
• To evaluate the effect of a single dose C21 200 mg o.d. on relevant 
biomarkers. 
1.2 
STUDY DESIGN 
This is a randomised, double-blind, placebo-controlled, cross-over cold challenge 
study. As shown in Figure 1, the subjects are divided into 2 groups randomly, for 
different treatment sequence (C21-Placebo or Placebo-C21). 
They will come to the clinic for four visits: 
• Visit 1: Screening 
• Visit 2: study drug administration and cold challenge (3-21 days after Visit 
1) 
• Visit 3: study drug 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. 


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Figure 1. Trial Design 
The schedule of assessments is in appendix 9.2. 
1.3 
EXPECTED SAMPLE SIZE 
A total of 16 subjects was planned to 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 dropouts. 
1.4 
RANDOMISATION AND BLINDING 
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. 
The study will be conducted in double-blind fashion and the allocation of treatment 
sequences will not be disclosed until the database has been locked. 
1.5 
INTERIM ANALYSIS 
No interim analyses are foreseen. 
1.6 
SOFTWARE 
SAS version 9.4 will be used for programming. 
1.7 
VALIDATION MODEL 
SGS Life Sciences (SGS LS) – Clinical Research Statistics (STAT) standard 
operating procedures (SOPs) and work instructions (WIs) as effective at the project 


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start will be followed throughout the project, provided the applicable regulatory 
requirements are still met. 
The primary endpoint tables/figures/listings will be validated according to Model C: 
review by an independent person and independent programming of the parameters 
indicated in this SAP. All other analysis tables/figures/listings will be validated 
according to Model B: review by an independent person (see SOP.STAT.020). 


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2. 
EFFICACY, PHARMACOKINETIC AND 
PHARMACODYNAMIC ANALYSES 
2.1 
EFFICACY 
2.1.1 
Available data 
The efficacy parameters are collected by thermography and capillaroscopy. The 
following parameters are available: Temperature (of each finger), Area Under the 
Curve (of each finger and the mean for all 8 fingers), Maximum skin temperature 
after rewarming (of each finger and the mean for all 8 fingers), Distal Dorsal 
Difference (of each finger and the mean for all 8 fingers), Gradient of rewarming (of 
each finger and the mean for all 8 fingers), Mean Velocity, Mean Width, Mean 
Shape, Mean Orientation, and Mean Density. 
2.1.2.1 PRIMARY ENDPOINT 
The primary endpoint is defined as the area under the curve for rewarming of each 
finger after cold challenge (AUC) which is measured by thermography and available 
in the clinical database provided by a third-party vendor as specified in the data 
transfer agreement. 
AUC is calculated using the linear trapezoidal rule, by summing all individual 
trapezoids: 
𝐴𝑈𝐶𝑡𝑖−𝑡𝑖+1 = 
1
2 (𝑇𝑒𝑚𝑝𝑖+ 𝑇𝑒𝑚𝑝𝑖+1) ∗(𝑡𝑖−𝑡𝑖+1) 
Log-transformation will be applied.  
2.1.2.2 SECONDARY ENDPOINTS 
The following secondary endpoints are available in the clinical database provided by 
a third-party vendor as specified in the data transfer agreement: 
• Maximum skin temperature after rewarming post-cold challenge (MAX) 
o Pre-cold challenge time points are not considered. 
• Distal dorsal difference (DDD): the mean difference in temperature between 
the dorsum and the finger for different time points 
• Gradient of rewarming in the first 2 minutes post-cold challenge (GRAD): 
o 𝐺𝑟𝑎𝑑𝑖𝑒𝑛𝑡𝑡𝑖−𝑡𝑖+1 = 
𝑇𝑒𝑚𝑝𝑖−𝑇𝑒𝑚𝑝𝑖+1
𝑡𝑖−𝑡𝑖+1
 
Log-transformation will be applied, except for DDD. 
2.1.2.3 EXPLORATORY ENDPOINTS 
Nailfold capillaroscopy exploratory endpoints (red blood cell Mean Width, Mean 
Shape, Mean Orientation, Mean Density, and Mean Velocity) are available in the 
clinical database provided by a third-party vendor as specified in the data transfer 
agreement. 
Change in finger temperature from intake of IMP to start of cold challenge will be 
derived. 


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Potential analyses of biomarkers related to endothelium and platelets are not in scope 
of this SAP. 
2.1.2 
Inferential statistics 
All statistical comparisons will be made using two-sided tests at the 0.1 significance 
level unless specifically stated otherwise. As this is a proof-of-concept study, no 
correction method for multiple testing is foreseen. P-values should thus be interpreted 
accordingly. 
Different from the definition of baseline value in section 5.2.2, the baseline value of 
the period is defined uniquely for each endpoint in this section. The baseline values 
for the endpoints AUC, MAX, GRAD and change in finger temperature are the last 
thermography temperature per finger before IMP administration in each period. For 
the endpoint DDD, the baseline is the thermography DDD value before IMP 
administration in each period. Similarly, the Mean Velocity value before IMP 
administration is treated as baseline for the exploratory endpoint capillaroscopy Mean 
Velocity. 
The modelling of the primary endpoint is based on the log-transformed value of 
AUC. Multiplicative ANCOVA model will be used, with patient (sequence), 
sequence, period, treatment and baseline value of the period as covariates. Treatment, 
sequence and period will be modelled as fixed effects and patient nested in sequence 
will be modelled as random effect. The default standard Variance Components 
covariance structure is preferred in the analysis.  
The secondary efficacy endpoints will be compared between treatment groups using 
similar multiplicative ANCOVA models for MAX and GRAD, with the same 
covariates mentioned above. Therefore, log-transformation will also be applied for 
the endpoints MAX and GRAD respectively. For the endpoint DDD, a similar 
additive ANCOVA model with the same covariates will be used. Since the DDD data 
is collected every 10 mins before cold challenge test, we would model DDD at each 
measurement time point separately. The selection principle of covariance structure 
remains the same for the additive and multiplicative models of secondary endpoints. 
Similar additive ANCOVA models will be used for the exploratory endpoints change 
in finger temperature and capillaroscopy Mean Velocity, with the same covariates 
from ANCOVA model of AUC. For capillaroscopy Mean Velocity, the data would be 
collected multiple times at different time points. More specifically, the before-cold-
challenge and post-recovery value in each period will be treated as the response 
variables for 2 separate ANCOVA models of capillaroscopy Mean Velocity. The 
selection principle of covariance structure remains the same for all the models of 
exploratory endpoints. 
SAS code can be found in section 9.1. 
2.1.3 
Presentation of results 
A listing will be prepared showing all derived parameters for different efficacy 
endpoints. 


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2.1.3.1 
PRIMARY ENDPOINT 
For primary endpoint, descriptive statistics (n, mean, the standard error (SE), median, 
interquartile range, minimum, and maximum) will be calculated per treatment group 
in each period.  
For multiplicative AN(C)OVA model, the model estimates will be back-transformed. 
A table will report the back-transformed least square means per treatment group with 
90% CI, and geometric mean ratio with 90% confidence intervals and 2-sided p-
value. 
2.1.3.2 
SECONDARY ENDPOINTS 
All the secondary endpoints will be summarised by means of descriptive statistics (n, 
mean, the standard error (SE), median, interquartile range, minimum, and maximum) 
per treatment group per treatment and period. The results will also be presented at 
each time point for DDD.  
Secondary endpoints will be analysed based on the same multiplicative AN(C)OVA 
model as for the primary endpoint described above except for the DDD endpoint. The 
results will also be back-transformed and reported in a similar way as mentioned 
above.  
For DDD, separate tables will report the results of the respective AN(C)OVA models 
for each measurement time point, including the least square means per treatment 
group with 90% CI, least square mean differences (C21 - placebo) with 90% CI and 
2-sided p-value for testing differences between treatment groups. 
  
2.1.3.3 
EXPLORATORY ENDPOINTS 
The following parameters of Nailfold capillaroscopy will be listed: Mean Width, 
Mean Shape, Mean Orientation, and Mean Density. 
For Mean Velocity, descriptive statistics (n, mean, the standard error (SE), median, 
interquartile range, minimum, and maximum) per treatment group will be reported at 
different time points in each period. A table will report the results of the additive 
ANCOVA models, including the least square means per treatment group with 90% 
CI, least square mean differences (C21 - placebo) with 90% CI and 2-sided p-value 
for testing differences between treatment groups. 
 


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3. 
SAFETY ANALYSES 
3.1 
ADVERSE EVENTS 
3.1.1 
Available data 
Adverse events (AEs) are coded into system organ classes and preferred terms using 
the medical dictionary for regulatory activities (MedDRA). For each AE, start and 
stop datetimes are collected as well as severity, a seriousness flag, treatment-
relationship, action taken towards the study drug and outcome. 
3.1.2 
Derivation rules 
Treatment-emergent adverse events (TEAE) are defined as AEs starting on or after 
first administration of any study drug. 
Based on their start datetime, AEs will be allocated to the phase and period during 
which they started. Each AE will therefore be reported in only one phase and period. 
Phases and periods are defined in section 5.2.1. In case the AE start datetime is 
incomplete or missing and the AE could consequently be allocated to more than one 
phase or period, a worst-case allocation will be done as detailed below: 
• Treatment phase vs. non-treatment phase: AE will be allocated to the 
treatment phase unless the available parts of the AE start or stop datetime 
provide evidence for allocating to the non-treatment phase. 
• Multiple treatment periods: AE will be allocated to the last treatment period 
unless the available parts of the AE start or stop datetime provide evidence 
the AE did not occur during that period or unless the period is a placebo 
period. 
A fatal AE is defined as an AE with outcome ‘fatal’. 
An AE for which the study drug was discontinued is defined as an AE with action 
taken ‘drug withdrawn’.  
AE onset and duration will be calculated as follows when start and stop dates are 
fully known: 
• AE onset day (vs. first administration) = 
o AE start date ≥ date of first administration: AE start date – date of first 
administration + 1 day 
o AE start date < date of first administration: AE start date – date of first 
administration  
• AE onset day (vs. start of phase / period) = AE start date – analysis phase / 
period start date + 1 day 
• AE duration (days) =  
o AE end date – AE start date + 1 day 
o date of last contact – AE start date + 1 day (when the AE start date is 
fully known but the AE is not resolved at the end of the study) 
In this case the duration will be presented as “>x days”. 


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3.1.3 
Presentation of results 
Tables will present TEAEs only. Pre-treatment AEs will only be listed.  
An overview table by period will show the number and percentage of subjects with at 
least one event and the number of events for the following: 
• TEAEs 
• Serious TEAEs 
• TEAEs by severity 
• Fatal TEAEs 
• Treatment-related TEAEs 
• Serious treatment-related TEAEs 
• TEAEs for which the study was discontinued  
Summary tables by MedDRA system organ class and preferred term will show the 
number and percentage of subjects with at least one event. The table of TEAEs will 
additionally show the number of events. Each AE record in the clinical database is 
considered as a distinct adverse event and is counted as such. 
Separate tables will be prepared for the following: 
• TEAEs 
• TEAEs by worst severity 
• TEAEs by worst relationship to study drug 
All AEs will be listed. Separate listings will be prepared for serious AEs, AEs for 
which the study was discontinued and fatal AEs.  
3.2 
CLINICAL LABORATORY EVALUATION 
3.2.1 
Available data 
Per protocol, the following laboratory parameters are expected: 
• Haematology: Haemoglobin (Hb), haematocrit (Erythrocyte volume 
fraction), platelet count (Thrombocyte 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 
• Urinalysis: PH, glucose, protein/albumin and Hb 
For each laboratory record, laboratory test, test result in standardised unit, sample 
datetimes, fasting status (if available), and clinical significance as assessed by the 
investigator are collected. Normal ranges are available as provided by the laboratory. 
3.2.2 
Derivation rules 
The following abnormality categories will be defined: 


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• Low: value < lower limit of normal range 
• Normal: lower limit of normal range ≤ value ≤ upper limit of normal range 
• High: value > upper limit of normal range 
Note: 
• Classification will be done in standardised units, using non-imputed values 
and limits. 
3.2.3 
Presentation of results 
The statistical analysis will present results in standardised units. 
Continuous laboratory parameters will be summarised by means of descriptive 
statistics at baseline and at each scheduled post-baseline visit. Actual values and 
changes from baseline will be tabulated separately. Categorical parameters will be 
listed only. 
Laboratory abnormalities will be presented as cross-tabulations of the abnormality at 
each scheduled post-baseline visit versus the baseline abnormality. 
All laboratory data will be listed. 
3.3 
VITAL SIGNS 
3.3.1 
Available data 
The following vital signs parameters are collected: pulse rate in supine position, 
systolic (SBP) and diastolic blood pressure (DBP) in supine position, body 
temperature (after 10 mins of rest). 
For each vital sign record, parameter name, test result and unit, assessment datetimes 
and clinical significance as assessed by the investigator are collected. 
3.3.2 
Derivation rules 
Abnormalities are defined in below table. 
 
Pulse rate 
(bpm) 
SBP (mmHg) DBP 
(mmHg) 
Temp (°C) 
Low 
<50 
<90 
<60 
<35.5 
Normal 
50-100 
90-140 
60-90 
35.5- 37.5 
High 
>100  
>140 
>90 
>37.5 
3.3.3 
Presentation of results 
Vital signs parameters will be summarised by means of descriptive statistics at each 
visit as collected in the CRF (visit 1, 2, 3, and 4).  
Abnormalities will be presented as cross-tabulations of the abnormality at the 
scheduled post-baseline visit 4 versus the visit 1 abnormality.   
All vital signs data will be listed. 


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3.4 
ELECTROCARDIOGRAMS 
3.4.1 
Available data 
The following electrocardiogram (ECG) parameters will be collected: heart rate (HR), 
RR interval, QRS interval, PR interval, QT interval and corrected QT interval (Bazett 
/ Fridericia). 
For each ECG record, parameter name, test result and unit, assessment datetimes and 
clinical significance as assessed by the investigator are collected. 
3.4.2 
Derivation rules 
In case triplicates value are available, mean values of the triplicates will be calculated 
per time point and rounded as detailed in section 5.3.3. Throughout the analysis, 
including the derivation of baseline and abnormalities, the mean values will be used. 
Individual triplicate values will only be listed. 
If needed, HR can be calculated from the RR interval as follows: HR = 60 / (RR (in 
sec)). 
If not available in the database, corrected QT intervals (QTc) will be calculated using 
Fridericia’s (QTcF) and Bazett’s (QTcB) formula specified below and rounded as 
detailed in section 5.3.3: 
• QTcB (ms) = QT (ms) * 
60
)
(bpm
HR
 
• QTcF (ms) = QT (ms) * 
3
60
)
(bpm
HR
 
Abnormalities for HR, QRS and PR parameters are defined in below table. 
 
HR (bpm) 
PR (ms) 
QRS (ms) 
Low 
<50 
<120 
<60 
Normal 
50-100 
120-200 
60-109 
High 
>100 
>200 
>109 
For QTc interval (ms), the following categories are defined: 
• Actual values: 
o ≤ 320 (Low) 
o ]320; 450] 
o > 450 (High) 


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• Changes: 
o  ≤ 30 (normal) 
o ]30; 60] 
o > 60 
 
3.4.3 
Presentation of results 
Uncorrected QT interval will only be listed, RR interval will not be displayed. 
Continuous ECG parameters will be summarised by means of descriptive statistics at 
baseline and at each scheduled post-baseline visit. Actual values and changes from 
baseline will be tabulated separately. 
Abnormalities of the actual values will be presented as cross-tabulations of the 
abnormality at each scheduled post-baseline visit versus the baseline abnormality. 
Abnormalities of the QTc changes will be presented as tabulations of the change 
abnormality at each scheduled post-baseline visit. 
All ECG data will be listed. 
3.5 
PHYSICAL EXAMINATIONS 
Abnormal physical examination findings will be listed. 


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4. 
GENERAL CHARACTERISTICS ANALYSES 
4.1 
SUBJECT DISPOSITION 
The following subject data will be tabulated: 
• The number of subjects in each analysis set 
• Dates of first signed informed consent, last visit and last contact (overall 
only) 
• The number and percentage of subjects who completed or discontinued the 
study as documented on the study termination page and the number and 
percentage of subjects for each study discontinuation reason by actual 
treatment 
All information collected in the CRF concerning allocation, code breaking, study 
discontinuation will be listed. 
4.2 
PROTOCOL DEVIATIONS AND ELIGIBILITY 
All available information concerning major protocol deviations, violations on 
eligibility criteria and subjects not treated will be listed. 
4.3 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
4.3.1 
Available data 
The following parameters will be available: 
• Demographics: sex, age, height, body weight at screening, date of birth, 
date of signing informed consent form (ICF), date of first diagnosis of 
disease under study, and disease-specific scoring 
• Screening tests: serology (HBsAg, HCVAb and HIV 1+ 2 AgAb), Thyroid 
Stimulating hormone (TSH), ethanol and urine drug screen, pregnancy tests, 
finger temperature 
• Baseline disease characteristics: date of first diagnosis of systemic sclerosis 
(SSc) and disease-specific scoring (modified Rodnan skin score) 


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4.3.2 
Derivation rules 
The following parameters will be derived: 
• Body mass index (BMI) at screening (kg/m²) = (body weight at screening 
(kg)) / (height (m))² 
Note: The BMI will be recalculated and rounded as detailed in section 5.3.3, 
even when already available in the database. 
• Age category: < 65 years / ≥ 65 years  
• Baseline disease severity:  <median of Raynaud’s Condition score / ≥
median of Raynaud’s Condition score  
• Time since diagnosis (years): (date of ICF – date of diagnosis)/365.25 
Note: Partially missing dates will be imputed as specified in section 5.3.2 
4.3.3 
Presentation of results 
Demographics will be presented using descriptive statistics for age, height, body 
weight and BMI and frequency tabulations for sex, age category and baseline disease 
severity. 
Baseline disease characteristics will be presented using descriptive statistics for time 
since diagnosis and disease-specific scoring. 
All demographic data and baseline disease characteristics will be listed. Listings will 
also be created for screening tests and pregnancy tests. 
4.4 
MEDICAL HISTORY AND CONCOMITANT DISEASES 
4.4.1 
Available data 
Medical history findings are coded using the medical dictionary for regulatory 
activities (MedDRA) into system organ classes and preferred terms. For each finding 
(MH.MHCAT is ‘MEDICAL HISTORY’), a start and stop date or ongoing flag is 
collected. 
4.4.2 
Derivation rules 
The following parameters will be derived: 
• Medical history finding: not ongoing at screening (MH.MHENRTPT is 
‘BEFORE’) 
• Concomitant disease finding: still ongoing at screening (MH.MHENRTPT 
is ‘ONGOING’ or missing) 
4.4.3 
Presentation of results 
Medical history and concomitant diseases will be tabulated separately. Each table will 
show: 
• The number and percentage of subjects with and without findings 
• The number and percentage of subjects with findings by system organ class 
and coded term 


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Medical history and concomitant diseases will be presented by treatment sequence 
and overall. 
All medical history and concomitant diseases data will be listed separately. 
4.5 
PRIOR AND CONCOMITANT THERAPIES 
4.5.1 
Available data 
Concomitant medication will be coded using the latest version of World Health 
Organisation (WHO) Drug Reference List. ATC selection is performed. ATC coding 
up to level 5 is available in the clinical database. For each therapy, a start date or prior 
flag and stop date or ongoing flag are collected. 
4.5.2 
Derivation rules 
Therapies will be allocated into one of the following categories: 
- 
Prior therapies: the therapy ended before the first study drug administration 
- 
Concomitant therapies: the therapy was taken after the first study drug 
administration 
Based on their start and stop datetime, concomitant therapies will be allocated to each 
period during which they were administered. A therapy can therefore be reported in 
more than one period. 
Phases and periods are defined in section 5.2.1. Concomitant therapies with (partially) 
missing dates will be allocated to each period unless the available parts of the therapy 
start or stop datetime provide evidence the therapy was not taken during that period. 
4.5.3 
Presentation of results 
Prior and concomitant therapies will be tabulated by ATC class (level 5) and generic 
term.  
All prior and concomitant therapies data will be listed with detailed information about 
ATC classes. All prior and concomitant therapies data will be listed. 
4.6 
EXPOSURE TO STUDY DRUG  
4.6.1 
Available data 
For each study drug administration, the start datetimes, dose, administration route and 
fasting status will be recorded. 
4.6.2 
Derivation rules 
4.6.3 
Not applicable. Presentation of results 
All exposure data will be listed. 


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5. 
GENERAL METHODOLOGY 
5.1 
ANALYSIS SETS 
5.1.1 
Analysis sets 
The following analysis sets will be considered in the statistical analysis: 
All screened subjects set 
(SCR): 
subjects who signed an informed consent to participate 
in this study 
All randomised subjects 
set (RND): 
subjects who were randomised into this study 
Safety analysis set 
(SAF): 
randomised subjects who were exposed to the study 
drug 
Full analysis set (FAS): 
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. 
Per protocol (PP) 
analysis set: 
a subset of FAS and consists of all subjects in FAS 
without any major protocol deviations that are judged to 
compromise the analysis of the data. All protocol 
deviations will be judged as major or minor prior to 
database lock. 
Notes: 
• Having signed an informed consent is defined as having a complete 
informed consent signature date in the database. 
• Randomised is defined as having a complete randomisation date in the 
database or any information to confirm randomisation. 
• Being exposed to the study drug is defined as having an exposure date or 
any information confirming exposure present in the database. 
Unless stated otherwise, the SAF will be used for the general characteristics and 
safety tables, listings and figures. The FAS will be used for the efficacy tables, 
listings and figures. In case the population differs by more than 2 patients from the 
safety population, demographic data table will be repeated for the FAS. The PP 
analysis set will be used for the sensitivity analysis of the primary efficacy endpoint.  
5.1.2 
As planned versus as actual analysis 
For analyses done on the safety analysis set, the actual treatment sequence of the 
subject will be considered. 
For all other analyses, the planned treatment sequence will be used. 


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5.2 
PHASES, PERIODS AND TIME POINTS 
5.2.1 
Phases and periods 
 
Phase 
Period 
Start 
End 
Screening 
 
Date of signing the 
informed consent form 
(ICF), with 00:00 added as 
time part 
First administration 
datetime in period 1 – 1 
minute 
Treatment Period 1 First administration 
datetime in period 1 
First administration 
datetime in period 2 – 1 
minute 
Period 2 First administration 
datetime in period 2 
Date of last contact, with 
23:59 added as time part 
Per definition, and for each subject, the first phase starts on the date of the earliest 
available ICF signature with 00:00 added as time part, and the last available phase 
ends on the date of last contact, with 23:59 added as time part. 
All tables, figures and listings will present treatments rather than periods. 
AEs and concomitant therapies will be allocated to phases and periods as described in 
sections 3.1.2 and 4.5.2 respectively.  
5.2.2 
Baseline and change from baseline 
For baseline disease characteristics, clinical laboratory evaluation, and 
electrocardiograms, the baseline value is the last available and non-missing value 
before the first administration of study drug. This definition does not apply in the 
efficacy part, which has its own baseline definition in part 2.1.2. 
Change from baseline is defined as: 
Change from baseline at time point t = value at time point t – baseline value. 
5.2.3 
Relative day 
Relative days (DY) will be calculated according to the following rule: 
• Concerned date < reference date: DY = concerned date – reference date 
• Concerned date ≥ reference date: DY = concerned date – reference date + 1 
The reference date is the date of first administration of study drug.  
5.2.4 
Analysis visits 
For clinical laboratory evaluation and electrocardiograms, the baseline value is the 
last available and non-missing value before the first administration of study drug. 
This value corresponds to Visit 1, except in case of retesting. Reason for this 
approach is the use of retest results for subject eligibility assessment. 


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For all other assessments after the reference date, the analysis will use the visits and 
time points indicated on the subject’s case report form (CRF). Unscheduled 
assessments after the reference date will only be listed. 
Baseline is defined in section 5.2.2. 
5.3 
IMPUTATION AND ROUNDING RULES 
5.3.1 
Missing values 
No imputation will be done of missing values (i.e. observed cases analysis). 
5.3.2 
Handling partially or completely missing dates in 
calculations 
No imputation will be done of missing values (i.e. observed cases analysis). If 
missing date information causes a conflict for phase allocation, a worst 
case/conservative approach will be implemented. 
5.3.3 
 Rounding of derived variables 
Derived variables will be rounded to the appropriate number of significant digits (see 
Definition of terms):  
• Corrected QT intervals will be rounded to integer. 
• Mean of triplicates, mean scores and BMI will be rounded to 1 decimal. 
• Log-transformed values will not be rounded. 
• Ratios will be rounded to the number of significant digits of the parameter 
with the least number of significant digits. 
• When converting values to different units, the converted value will have the 
same number of significant digits as the original value, limiting the number 
of decimals to 3. 
Examples: 
Parameter Database value 
Converted value 
GFR 
52 mL/min 
0.87 mL/s 
Creatinine 
0.71 mg/dL 
63 µmol/L 
Urate 
4.7 mg/dL 
280 µmol/L 
All derivations will be done before rounding. Rounding will be done using the round 
half to even tie-breaking rule (see Definition of terms). 
5.3.4 
Outliers 
There will be no outlier detection. All measured values will be included in the 
analyses. 


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Final 1.0 
 of 01FEB2021 
 
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5.4 
PRESENTATION OF RESULTS 
5.4.1 
Calculation of descriptive statistics and percentages 
For continuous parameters, full descriptive statistics will only be presented if there 
are at least 2 non-missing observations. Alternatively, only the number of non-
missing data points and mean are shown. 
Descriptive statistics will include the number of non-missing data points, the 
arithmetic mean, the standard deviation (SD) and standard error (SE), the median, 
minimum and maximum.  
Mean, median, SE, SD and CI will be presented with one more decimal place than the 
individual values. Minimum and maximum will be presented with the same number 
of decimal places than the individual values. 
For frequency tabulations and cross-tabulations, missing values will not be included 
in the denominator count when computing percentages. For cross-tabulations of post-
baseline results versus baseline results, a ‘missing’ category will be shown for 
baseline results if applicable. 
Percentages will be shown with one decimal place. 
5.4.2 
Presentation of treatments 
The following treatment labels will be used in the tables, listings and figures: 
• C21: C21 200mg 
• PLA: Placebo 
When presented by treatment sequence: 
• C21-PLA 
• PLA-C21 
If possible, the long labels (i.e. C21 200mg or Placebo) should be used for tables, 
listings and figures presented by treatment. If needed for layout purposes, the short 
labels (C21 or PLA) will be used instead.  
Treatment sequences will be presented using the short labels for tables and listings 
(e.g. C21-PLA). 
In the general characteristics’ analysis, a grand total will be added to summarise all 
subjects over sequences / treatments. Grand totals will be shown last. 
5.4.3 
Ordering in tables, figures and listings 
In the analysis of general characteristics, results will be presented by sequence except 
where stated otherwise. For efficacy and adverse events, results will be presented by 
treatment. 
All listings will be ordered by treatment sequence, subject, analysis visit and time 
point, unless specified otherwise.  
In tables and figures showing several parameters, each parameter will begin on a new 
page and parameters will be sorted alphabetically, within the parameter category if 
applicable. 
 
 


Statistical Analysis Plan 
 
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Final analysis 
Final 1.0 
 of 01FEB2021 
 
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6. 
CHANGES TO THE PLANNED ANALYSIS 
6.1 
CHANGES NOT COVERED BY PROTOCOL AMENDMENTS BEFORE 
DATABASE LOCK 
6.2 
CHANGES NOT COVERED BY PROTOCOL AMENDMENTS AFTER 
DATABASE LOCK 
6.3 
CHANGES TO THE FINAL STATISTICAL ANALYSIS PLAN 
 
SAP version 
number 
SAP version Date 
(ddMMMyyyy) 
Changes 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
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 of 01FEB2021 
 
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7. 
REFERENCES 
ICH Topic E6(R2) Guideline for Good Clinical Practice – Step 4, 9 November 2016. 
An analysis of the time-relations of electrocardiogram. Bazett HC Heart 1920 7:353–
370. 
Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei 
Herzkranken. Fridericia LS Acta Med Scand 1920 15:469–485. 
Which QT correction formulae to use for QT monitoring? Vandenberk B, Vandael E, 
Robyns T et al. J Am Heart Assoc. 2016;5:e003264. 
ICH guideline E14: the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs (R3) – questions and answers, 
January 2016. 
ICH Topic E9 Statistical Principles for Clinical Trials – Step 5 – Note for Guidance 
on Statistical Principles for Clinical Trials (CPMP/ICH/363/96), September 1998. 
Hughes M, Snapir A, Wilkinson J, Snapir D, Wigley FM, Herrick AL. Prediction and 
impact of attacks of Raynaud’s phenomenon, as judged by patient perception. 
Rheumatology (Oxford) 54:1443-7, 2015 
 


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8. 
LIST OF TABLES, LISTINGS AND FIGURES 
8.1 
TABLES 
 
GENERAL CHARACTERISTICS 
 
14.1.1.1 
Analysis Sets 
SCR 
 
14.1.1.2 
First and Last Contact in the Study 
SCR 
 
14.1.1.3 
Study Discontinuation 
SAF 
 
14.1.2.1 
Demographic Data 
SAF 
 
14.1.2.2 
Baseline Disease Characteristics 
SAF 
 
14.1.2.3 
Medical History 
SAF 
 
14.1.2.4 
Concomitant Diseases 
SAF 
 
14.1.2.5 
Prior Therapies by ATC Class (Level 5) and Generic Term 
SAF 
 
14.1.2.6 
Concomitant Therapies by ATC Class (Level 5) and Generic Term 
SAF 
 
EFFICACY 
 
14.2.1.1 
Descriptive Statistics of Primary Endpoint Thermography AUC  
FAS 
 
14.2.1.2 
Primary Endpoint Thermography AUC per Finger ANCOVA Model    
FAS 
 
14.2.1.3 
Primary Endpoint Thermography AUC per Finger ANCOVA Model    
PP 
 
14.2.2.1 
Descriptive Statistics of the Secondary Endpoint Thermography MAX 
FAS 
 
14.2.2.2 
Secondary Endpoint Thermography MAX ANCOVA Model   
FAS 
 
14.2.3.1 
Descriptive Statistics of the Secondary Endpoint Thermography DDD 
FAS 
 
14.2.3.2 
Secondary Endpoint Thermography DDD ANCOVA Model   
FAS 
 
14.2.4.1 
Descriptive Statistics of the Secondary Endpoint Thermography GRAD 
FAS 
 
14.2.4.2 
Secondary Endpoint Thermography GRAD ANCOVA Model   
FAS 
 
14.2.5.1 
Descriptive Statistics of the Exploratory Endpoint Change in Finger 
Temperature 
FAS 
 
14.2.5.2 
Exploratory Endpoint Change in Finger Temperature ANCOVA Model 
FAS 
 
14.2.6.1 
Descriptive Statistics of the Exploratory Endpoint Capillaroscopy Mean 
Velocity 
FAS 
 
14.2.6.2 
Exploratory Endpoint Capillaroscopy Mean Velocity ANCOVA Model 
FAS 
 
SAFETY 
 
ADVERSE EVENTS 
 
14.3.1.1 
Adverse Events Overview 
SAF 
 
14.3.1.2 
Treatment-Emergent Adverse Events by MedDRA System Organ Class and 
Preferred Term 
SAF 
 
14.3.1.3 
Treatment-Emergent Adverse Events by MedDRA System Organ Class, 
Preferred Term and Worst Severity 
SAF 
 
14.3.1.4 
Treatment-Emergent Adverse Events by MedDRA System Organ Class, 
Preferred Term and Worst Relationship to Study Drug 
SAF 
 


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LABORATORY DATA 
 
14.3.2.1 
Descriptive Statistics of Laboratory Test Actual Values 
SAF 
 
14.3.2.2 
Descriptive Statistics of Changes From Baseline in Laboratory Test Results 
SAF 
 
14.3.2.3 
Cross-Tabulation of Laboratory Abnormalities Versus Baseline 
SAF 
 
VITAL SIGNS 
 
14.3.3.1 
Descriptive Statistics of Vital Signs Actual Values 
SAF 
 
14.3.3.2 
Cross-Tabulation of Vital Signs Abnormalities Versus Visit 1 
SAF 
 
ECG 
 
14.3.4.1 
Descriptive Statistics of 12-lead ECG Actual Values 
SAF 
 
14.3.4.2 
Descriptive Statistics of Changes From Baseline in 12-lead ECG 
SAF 
 
14.3.4.3 
Cross-Tabulation of 12-lead ECG Abnormalities Versus Baseline 
SAF 
 
14.3.4.4 
Cross-Tabulation of 12-lead ECG QTc Change Abnormalities Versus 
Corresponding Actual Value 
SAF 
 
14.3.4.5 
Tabulation of Holter ECG Results 
SAF 
 
8.2 
LISTINGS 
GENERAL CHARACTERISTICS 
16.2.1.1 
Allocation 
RND 
16.2.1.2 
Code Breaking Information 
RND 
16.2.1.3 
Analysis Phases and Periods  
SAF 
16.2.1.4 
Study Discontinuation  
SAF 
16.2.2.1 
Protocol Deviations 
SAF 
16.2.2.2 
Violations on Eligibility Criteria 
SAF 
16.2.2.3 
No-Treatment Subjects 
SCR 
minus 
SAF 
16.2.4.1 
Demographic Data 
SAF 
16.2.4.2 
Baseline Disease Characteristics 
SAF 
16.2.4.3 
Screening Tests 
SAF 
16.2.4.4 
Pregnancy Tests 
SAF 
16.2.4.5 
Medical History 
SAF 
16.2.4.6 
Concomitant Diseases 
SAF 
16.2.4.7 
Prior and Concomitant Therapies  
SAF 
16.2.4.8 
Comments 
SAF 
16.2.5.1 
16.2.5.2  
Exposure to Study Drug 
Cold Challenge 
SAF 
SAF 
EFFICACY 
16.2.6.1 
Efficacy: Thermography Endpoints 
FAS 
16.2.6.2 
Efficacy: Nailfold Capillaroscopy Endpoints 
FAS 


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SAFETY 
ADVERSE EVENTS 
16.2.7.1 
Adverse Events 
SAF 
16.2.7.2 
Serious Adverse Events 
SAF 
16.2.7.3 
Fatal Adverse Events  
SAF 
16.2.7.4 
Treatment-Emergent Adverse Events Resulting in Study Discontinuation  
SAF 
PHYSICAL EXAMINATIONS 
16.2.7.5 
Physical Examinations Abnormalities 
SAF 
LABORATORY DATA 
16.2.8.1 
Laboratory Test Results  
SAF 
VITAL SIGNS 
16.2.9.1 
Vital Signs Results  
SAF 
ECG 
16.2.10.1 
12-lead ECG Results 
SAF 
16.2.10.2 
12-lead ECG Interpretation and Morphology 
SAF 
16.2.10.3 
Holter ECG Interpretation and Morphology 
SAF 
8.3 
FIGURES 
14.2.1.1 
Histogram of Primary Endpoint Thermography AUC  
FAS 
 
14.2.1.2 
Histogram of Primary Endpoint Thermography AUC 
PP 
 
14.2.1.3 
Scatter Plot of Primary Endpoint Thermography AUC 
FAS 
 
14.2.1.4 
Scatter Plot of Primary Endpoint Thermography AUC 
PP 
 
14.2.1.5 
Mean (± SE) Plots of the Thermography Temperature Values Over Time 
FAS 
 
14.2.1.6 
Mean (± SE) Plots of the Thermography Temperature Values Over Time 
PP 
 
14.2.2.1 
Histogram of the Secondary Endpoint Thermography MAX 
FAS 
 
14.2.2.2 
Scatter Plot of the Secondary Endpoint Thermography MAX 
FAS 
 
14.2.3.1 
Histogram of the Secondary Endpoint Thermography DDD 
FAS 
 
14.2.3.2 
Scatter Plot of the Secondary Endpoint Thermography DDD 
FAS 
 
14.2.4.1 
Histogram of the Secondary Endpoint Thermography GRAD 
FAS 
 
14.2.4.2 
Scatter Plot of the Secondary Endpoint Thermography GRAD 
FAS 
 


Statistical Analysis Plan 
 
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9. 
APPENDICES 
9.1 
SAS CODE 
ANCOVA model 
PROC MIXED data=test_proc;  
   CLASS sequence subject period treatment;  
   MODEL log_AUC = baseline sequence period treatment / ddfm=kenwardroger;  
   RANDOM subject(seq) / subject=subject type=VC;  
   LSMEANS trt /pdiff cl alpha=0.1;  
run; 
 
The above are sample codes and can be adapted to the study as needed.


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9.2 
SCHEDULE OF ASSESSMENTS 
 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 
 


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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-Trial 
 
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 
 
 
 
Plasma and whole blood samples for potential analyses of exploratory 
biomarkers  
X 
X5) 
X5) 
X 
Plasma 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 
 
 
 


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* 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