A double-blind, randomized, placebo-controlled crossover trial of the  2C-adrenoceptor antagonist ORM-12741 for prevention of cold-induced vasospasm in patients with systemic sclerosis

Abstract

OBJECTIVES: Our primary purpose was to evaluate the efficacy of the high-potency α2C-adrenoceptor antagonist ORM-12741 in the attenuation of a cold-induced reduction in finger blood flow and temperature in patients with RP secondary to SSc. Secondary objectives were to assess safety and tolerability. METHODS: This was a phase IIa, randomized, double-blind, crossover, single-dose, placebo-controlled, single-centre study. Patients attended five times: initial screening, treatment visits 1-3 (each at least 1 week apart) and 1-2 weeks after the last treatment. At each treatment visit, each subject received a single oral dose of 30 mg or 100 mg of ORM-12741 or placebo. Thirty minutes later the subject underwent a cold challenge. Blood flow to the fingers was assessed by three methods [temperature by probe, laser Doppler imaging (LDI) and infrared thermography] performed before, during and after the cold challenge. RESULTS: Twelve patients (10 female, mean age 58 years) were included. The area under the rewarming curve (LDI) of the right index finger (arbitrary flux units × time) was lower for both 30 mg (P = 0.043) and 100 mg (P = 0.025) of ORM-12741 compared with placebo, indicating delayed reperfusion. The time to 70% temperature recovery (middle finger probe) was longer with active than placebo treatment: mean (s.d.) values for placebo, 30 mg of ORM-12741 and 100 mg of ORM-12741 were 21.4 min (12.4), 25.7 min (12.2) and 26.9 min (13.9), respectively. Overall ORM-12741 was well tolerated. CONCLUSION: ORM-12741 did not expedite recovery from a cold challenge in the fingers of patients with SSc. TRIAL REGISTRATION: https://www.clinicaltrialsregister.eu/; no. 2010-024005-13.