Cold Challenge With C21 in RP

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Raynaud Phenomenon, Systemic Sclerosis

Intervention / Treatment
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* Drug: C21
* Drug: C21
* Drug: Placebo
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent must be obtained before any trial related procedures are performed. Subjects diagnosed with SSc according to European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria Age 19-75 years inclusive 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: Smoking (including E-cigarettes) or use of nicotine replacement therapy for three months prior to Visit 1 and during the trial. BMI >30 Mixed connective tissue disease or overlap (i.e. those who satisfy more than one set of ACR criteria for a rheumatic disease). 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 Malignancy within the past 5 years with the exception of in situ removal of basal cell carcinoma and cervical intraepithelial neoplasia grade I Planned major surgery within the duration of the study 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) Blood donation (or corresponding blood loss) within three months prior to Visit 1 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: Inhaled corticosteroids which can be used throughout the trial period The continuation of stable doses of <10 mg prednisolone Mycophenolate mofetil (MMF) which must be withheld for 3 days preceding Visit 2 and Visit 3 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 Pregnant or breast-feeding female subjects. Female subjects of childbearing potential not willing to use contraceptive methods described in Section 5.3.1. Male subjects not willing to use contraceptive methods described in Section 5.3.1. Participation in any other interventional trial during the trial period Subjects known or suspected of not being able to comply with this trial protocol (e.g. due to alcoholism, drug dependency or psychological disorder)

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: 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.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: C21 followed by placebo<br> | Drug: C21<br>* C21 as first treatment<br>Drug: Placebo<br>* Placebo as second treatment<br>|
| Experimental: Placebo followed by C21<br> | Drug: C21<br>* C21 as second treatment<br>Drug: Placebo<br>* Placebo as first treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve for Rewarming of Each Finger After Cold Challenge (AUC) as Measured by Thermography | Area under the curve for rewarming of each finger after cold challenge as measured by thermography for 15 min | For 15 min after cold challenge (40-55 min after IMP [investigational manufacturing product] administration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Skin Temperature After Rewarming (MAX) | Maximum skin temperature after rewarming within 15 min after cold challenge | For 15 min after cold challenge (40-55 min after IMP administration) | 
| The Distal Dorsal Difference, Defined as the Difference in Temperature Between the Dorsum and the Finger (DDD) | The distal dorsal difference, defined as the difference in temperature between the dorsum and the finger (DDD), from administration of IMP until before cold challenge (0 to 40 min) | Baseline, 10, 20, 30 and 40 min | 
| Gradient of Rewarming in the First 2 Minutes Post-cold Challenge (GRAD) |  | 2 min after cold challenge (40-42 min after IMP administration) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic sclerosis, Raynaud's phenomenon, Vasoconstriction