Raynaud Phenomenon, Systemic Sclerosis
Conditions
Keywords
Systemic sclerosis, Raynaud's phenomenon, Vasoconstriction
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.
Interventions
DRUGC21
C21 as first treatment
DRUGPlacebo
Placebo as second treatment
Sponsors
SGS Life Sciences, a division of SGS Belgium NV
Vicore Pharma AB
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
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.
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
19 Years to 75 Years
Healthy volunteers
No
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 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. 2. BMI \>30 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: * 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 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve for Rewarming of Each Finger After Cold Challenge (AUC) as Measured by Thermography | For 15 min after cold challenge (40-55 min after IMP [investigational manufacturing product] administration) | Area under the curve for rewarming of each finger after cold challenge as measured by thermography for 15 min |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Skin Temperature After Rewarming (MAX) | For 15 min after cold challenge (40-55 min after IMP administration) | Maximum skin temperature after rewarming within 15 min after cold challenge |
| The Distal Dorsal Difference, Defined as the Difference in Temperature Between the Dorsum and the Finger (DDD) | Baseline, 10, 20, 30 and 40 min | 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) |
| Gradient of Rewarming in the First 2 Minutes Post-cold Challenge (GRAD) | 2 min after cold challenge (40-42 min after IMP administration) | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Finger Temperature From Intake of IMP to Start of Cold Challenge | From intake of IMP to start of cold challenge (0-40 min) | — |
| Nailfold Capillaroscopy (Including Red Blood Cell Velocity Measurements) | Before cold challenge (at 40 min) and post-recovery (at 55 min) | Nailfold capillaroscopy mean velocity was measured as red blood cell velocity before cold challenge and post recovery |
Countries
United Kingdom
Participant flow
Recruitment details
The trial planned to include 16 subjects, however as recruitment was challenging during the COVID-19 (coronavirus disease 2019) pandemic, enrolment was stopped prematurely when 12 subjects were randomised. This ensured that trial results could be available in a timely manner.
Pre-assignment details
A total of 20 unique subjects provided informed consent and were enrolled in the trial. Seven of these were screening failures. In addition, 2 subjects were not randomised; 1 subject due to the COVID-19 pandemic and 1 subject due technical issues with the Holter ECG. The latter subject was re-screened. A total of 12 subjects were randomised.
Participants by arm
| Arm | Count |
|---|---|
| C21 Followed by Placebo C21: C21 as first treatment
Placebo: Placebo as second treatment | 6 |
| Placebo Followed by C21 C21: C21 as second treatment
Placebo: Placebo as first treatment | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | C21 Followed by Placebo | Placebo Followed by C21 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 4 Participants | 9 Participants |
| Age, Continuous | 59.5 years | 51.5 years | 55.5 years |
| BMI | 25.6 kg/m^2 | 24.2 kg/m^2 | 24.9 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 163.1 cm | 164.3 cm | 163.7 cm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 6 Participants | 12 Participants |
| Region of Enrollment United Kingdom | 6 participants | 6 participants | 12 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Weight | 68.3 kg | 64.9 kg | 66.6 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 3 / 12 | 5 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
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
Time frame: For 15 min after cold challenge (40-55 min after IMP [investigational manufacturing product] administration)
Population: Full analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Curve for Rewarming of Each Finger After Cold Challenge (AUC) as Measured by Thermography | 19558.43 C*sec | Geometric Coefficient of Variation 4.36 |
| C21 200 mg | Area Under the Curve for Rewarming of Each Finger After Cold Challenge (AUC) as Measured by Thermography | 20045.96 C*sec | Geometric Coefficient of Variation 7.68 |
p-value: =0.380190% CI: [0.9859, 1.0442]ANCOVA
Secondary
Gradient of Rewarming in the First 2 Minutes Post-cold Challenge (GRAD)
Time frame: 2 min after cold challenge (40-42 min after IMP administration)
Population: The full analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Gradient of Rewarming in the First 2 Minutes Post-cold Challenge (GRAD) | 0.5412 °C/min | Geometric Coefficient of Variation 42.26 |
| C21 200 mg | Gradient of Rewarming in the First 2 Minutes Post-cold Challenge (GRAD) | 0.4482 °C/min | Geometric Coefficient of Variation 39.35 |
p-value: =0.28290% CI: [0.6206, 1.1102]ANCOVA
Secondary
Maximum Skin Temperature After Rewarming (MAX)
Maximum skin temperature after rewarming within 15 min after cold challenge
Time frame: For 15 min after cold challenge (40-55 min after IMP administration)
Population: Full analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Skin Temperature After Rewarming (MAX) | 22.5043 °C | Geometric Coefficient of Variation 3.73 |
| C21 200 mg | Maximum Skin Temperature After Rewarming (MAX) | 23.5336 °C | Geometric Coefficient of Variation 8.49 |
p-value: =0.035690% CI: [1.0086, 1.0613]ANCOVA
Secondary
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)
Time frame: Baseline, 10, 20, 30 and 40 min
Population: The full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | The Distal Dorsal Difference, Defined as the Difference in Temperature Between the Dorsum and the Finger (DDD) | 10 min | -3.2378 °C | Standard Error 0.3045 |
| Placebo | The Distal Dorsal Difference, Defined as the Difference in Temperature Between the Dorsum and the Finger (DDD) | 30 min | -3.1005 °C | Standard Error 0.1903 |
| Placebo | The Distal Dorsal Difference, Defined as the Difference in Temperature Between the Dorsum and the Finger (DDD) | 20 min | -3.0596 °C | Standard Error 0.2323 |
| Placebo | The Distal Dorsal Difference, Defined as the Difference in Temperature Between the Dorsum and the Finger (DDD) | 40 min | -2.7921 °C | Standard Error 0.1918 |
| Placebo | The Distal Dorsal Difference, Defined as the Difference in Temperature Between the Dorsum and the Finger (DDD) | Baseline | -2.810 °C | Standard Error 0.3375 |
| C21 200 mg | The Distal Dorsal Difference, Defined as the Difference in Temperature Between the Dorsum and the Finger (DDD) | 40 min | -2.9448 °C | Standard Error 0.333 |
| C21 200 mg | The Distal Dorsal Difference, Defined as the Difference in Temperature Between the Dorsum and the Finger (DDD) | Baseline | -2.4215 °C | Standard Error 0.495 |
| C21 200 mg | The Distal Dorsal Difference, Defined as the Difference in Temperature Between the Dorsum and the Finger (DDD) | 10 min | -3.395 °C | Standard Error 0.458 |
| C21 200 mg | The Distal Dorsal Difference, Defined as the Difference in Temperature Between the Dorsum and the Finger (DDD) | 20 min | -3.1419 °C | Standard Error 0.4792 |
| C21 200 mg | The Distal Dorsal Difference, Defined as the Difference in Temperature Between the Dorsum and the Finger (DDD) | 30 min | -3.0347 °C | Standard Error 0.4037 |
Comparison: Analysis at the 10 min pointp-value: =0.015490% CI: [-0.8234, -0.1749]ANCOVA
Other Pre-specified
Change in Finger Temperature From Intake of IMP to Start of Cold Challenge
Time frame: From intake of IMP to start of cold challenge (0-40 min)
Population: The full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Finger Temperature From Intake of IMP to Start of Cold Challenge | -0.697 °C | Standard Error 0.471 |
| C21 200 mg | Change in Finger Temperature From Intake of IMP to Start of Cold Challenge | -1.347 °C | Standard Error 0.343 |
p-value: =0.372290% CI: [-1.1718, 0.3739]ANCOVA
Other Pre-specified
Nailfold Capillaroscopy (Including Red Blood Cell Velocity Measurements)
Nailfold capillaroscopy mean velocity was measured as red blood cell velocity before cold challenge and post recovery
Time frame: Before cold challenge (at 40 min) and post-recovery (at 55 min)
Population: The full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Nailfold Capillaroscopy (Including Red Blood Cell Velocity Measurements) | Baseline | 0.122 mm/sec | Standard Error 0.042 |
| Placebo | Nailfold Capillaroscopy (Including Red Blood Cell Velocity Measurements) | Before cold | 0.302 mm/sec | Standard Error 0.175 |
| Placebo | Nailfold Capillaroscopy (Including Red Blood Cell Velocity Measurements) | Post recovery | 0.318 mm/sec | Standard Error 0.14 |
| C21 200 mg | Nailfold Capillaroscopy (Including Red Blood Cell Velocity Measurements) | Baseline | 0.369 mm/sec | Standard Error 0.193 |
| C21 200 mg | Nailfold Capillaroscopy (Including Red Blood Cell Velocity Measurements) | Before cold | 0.207 mm/sec | Standard Error 0.054 |
| C21 200 mg | Nailfold Capillaroscopy (Including Red Blood Cell Velocity Measurements) | Post recovery | 0.323 mm/sec | Standard Error 0.149 |
Comparison: Analysis of capillaroscopy before coldp-value: =0.498290% CI: [-0.4074, 0.1895]ANCOVA
Comparison: Analysis of capillaroscopy post recoveryp-value: =0.621990% CI: [-0.3037, 0.1763]ANCOVA