A double-blind, randomized, placebo-controlled crossover trial of the α2C-adrenoceptor antagonist ORM-12741 for prevention of cold-induced vasospasm in patients with systemic sclerosis.
OBJECTIVE
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.


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


BACKGROUND
https://www.clinicaltrialsregister.eu/; no. 2010-024005-13.
Clinical Sciences Building, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK. ariane.herrick@manchester.ac.uk.
Ariane L
AL
Herrick
Andrea K
AK
Murray
Angela
A
Ruck
Juha
J
Rouru
Tonia L
TL
Moore
John
J
Whiteside
Pasi
P
Hakulinen
Fredrick
F
Wigley
Amir
A
Snapir
D058669:Adrenergic alpha-2 Receptor Antagonists / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D001572:Benzofurans / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D003080:Cold Temperature / Q000009:adverse effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004837:Epinephrine / Q000097:blood; D005260:Female; D005385:Fingers / Q000098:blood supply; D006801:Humans; D017078:Laser-Doppler Flowmetry; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000097:blood; D054837:Quinolizidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011928:Raynaud Disease / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012595:Scleroderma, Systemic / Q000150:complications*; D013817:Thermography; D016896:Treatment Outcome
D058669:Adrenergic alpha-2 Receptor Antagonists; D001572:Benzofurans; C000588919:ORM-12741; D054837:Quinolizidines; D018341:Receptors, Adrenergic, alpha-2; D009638:Norepinephrine; D004837:Epinephrine
Raynaud’s phenomenon; randomized controlled trial; systemic sclerosis; α2C-adrenoceptor antagonism