Background/Purpose:

The alpha-_2C adrenoceptor is thought to play a key role in mediating cold-induced vasospasm in the digits. A previous study suggested that in patients with systemic sclerosis (SSc), treatment with the alpha-_2C adrenoceptor antagonist OPC-23826 improved recovery of finger skin perfusion following a cold challenge. Our primary purpose was to evaluate the efficacy of the high potency alpha-_2Cadrenoceptor antagonist ORM-12741 in the attenuation of a cold-induced reduction in finger blood flow and temperature in patients with Raynaud’s phenomenon secondary to SSc. Secondary objectives were to assess safety and tolerability.

Methods:

This was a phase IIa, randomised, double-blind, crossover, single-dose placebo-controlled, single-centre study. Patients attended 5 times: screen, treatment visits 1-3 (each at least one week apart), and an end of study visit 1-2 weeks after the last treatment. At each treatment visit, each subject after acclimatisation received a single oral dose of 30mg or 100mg of ORM-12741 or placebo. 30 minutes later s/he underwent a cold challenge (the hand was placed in a cold chamber cooled to -18⁰C until the finger temperature reached 12⁰C or until the subject could no longer tolerate the cold). Blood flow to the fingers was assessed by 3 methods (temperature by probe, laser Doppler imaging [LDI] and infrared thermography) performed before, during and after the cold challenge, until 70% of the drop in skin temperature had been recovered (but no longer than 45 minutes).

Results:

12 patients (10 female, mean age 58 years) were included. Recovery from cold challenge was faster after placebo treatment than with either dose of ORM-12741 as measured by temperature probe and LDI (Table 1). In 10 out of 12 subjects the area under the time-LDI curve was greater with placebo than with either ORM-12741 dose. Overall ORM-12741 was well tolerated. Headache was the most common adverse effect with 8 events (3 placebo, 5 active treatment) in 4 patients.

 

Table 1 – Mean (standard deviation) blood flow results by the 3 different methods

	Placebo	ORM-12741 30mg	ORM-12741 100mg
Time to 70% temperature recovery (by probe) (minutes)	21.4 (12.4)	25.7 (12.2)	26.9 (13.9)
LDI (Area under the curve, right index finger) (arbitrary flux units x time)	20.5 (13.7)	11.2 (10.6)1	9.6 (7.0)2
Thermography (area under the curve) (oC x time)	288.4 (172.2)	280.0 (108.8)	305.8 (136.3)

1. P= 0.045 versus placebo
2. P = 0.023 versus placebo

Conclusion:

ORM-12741 did not expedite recovery from a cold challenge in the fingers of patients with SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-double-blind-placebo-controlled-crossover-trial-of-the-alpha-2c-adrenoceptor-antagonist-orm-12741-for-prevention-of-cold-induced-vasospasm-in-patients-with-systemic-sclerosis/