OA07 A Phase 2 randomised placebo-controlled trial investigating the effect of the angiotensin II type 2 receptor agonist C21 on cold-induced vasoconstriction in patients with Raynaud's phenomenon secondary to systemic sclerosis
Authors: Herrick Ariane L , Batta Rohit , Overbeck Kamilla , Raud Johan , Manning Joanne , Dinsdale Graham , Murray Andrea , Tornling Goran 
Published: April 2022

Abstract

Background/Aims
Safe, effective treatments for systemic sclerosis (SSc)-related Raynaud’s phenomenon (RP) are badly needed. The aim of this trial was to investigate the effect of a single oral dose of C21, a selective angiotensin II type 2 receptor (AT2R) agonist, on cold-induced vasoconstriction in SSc-RP. The AT2R is considered a key component of the ‘protective arm’ of the renin-angiotensin system and contributes to vasodilation.

Methods
Twelve female patients with SSc (median age 58.5 years [range 35-69], median duration of RP 19.0 years [range 0.4-41.0], median duration of SSc 6.9 years [range 0.2-39.0]) were randomised. To be included, patients had to experience at least 5 attacks of RP/week. Patients attended on four occasions: screening, treatments visits 1 and 2 (separated by 3-7 days), and follow-up. At the first treatment visit, patients were randomised to receive a single oral dose of either C21 (200mg) or placebo: at the second treatment visit they received the opposite treatment. Forty minutes after each treatment, each patient underwent a standard cold challenge of the hands (15°C for one minute) with temperature response over the subsequent 15 minutes measured by infrared thermography. The primary end point was the area under the curve (AUC) for rewarming for each finger (8 fingers). Secondary endpoints included the maximum finger temperature after rewarming (MAX), and the gradient of the rewarming curve in the first two minutes post-cold challenge (GRAD). Statistical analyses were performed by multiplicative ANCOVA models.

Results
All patients completed the study. Mean AUC for rewarming for all 8 fingers combined was numerically higher after treatment with C21 than after placebo (geometric mean 20046°C*sec vs 19558°C*sec), but the difference was not statistically significant (p = 0.380). MAX (at 15 minutes) was higher after C21 than after placebo (geometric mean 23.5°C versus 22.5°C): for all 8 fingers combined, the geometric mean ratio (C21 vs placebo) was 1.035 (90% confidence interval: 1.009, 1.061; p = 0.036). Mean temperature difference between the treatment periods gradually increased over time. There was no statistically significant difference in GRAD between treatment arms. C21 was well tolerated with the majority of adverse events being non-related to treatment and of mild severity.

Conclusion
Although the primary endpoint was not met, AUC for rewarming after a cold challenge was numerically higher after C21 than after placebo, and MAX was significantly higher after C21. For both treatments, finger temperature was still increasing after 15 minutes’ observation, suggesting that the full effect of C21 was not captured: future trials should include a longer observation period post-cold challenge. Despite the small trial size, a signal emerged suggesting that even in patients with established SSc (and therefore with structural digital vascular disease) C21 may confer benefit for RP and deserves further investigation.

Disclosure
A.L. Herrick: Other; Principal Investigator in study sponsored by Vicore. R. Batta: Corporate appointments; Vicore Pharma. Shareholder/stock ownership; Vicore Pharma. K. Overbeck: Corporate appointments; Vicore Pharma. Shareholder/stock ownership; Vicore Pharma. J. Raud: Corporate appointments; Vicore Pharma. Shareholder/stock ownership; Vicore Pharma. J. Manning: None. G. Dinsdale: None. A. Murray: None. G. Tornling: Consultancies; Vicore Pharma. Shareholder/stock ownership; Vicore Pharma.