The patients were assigned in a 1:1:1 ratio to receive 30?mg orvepitant, 10?mg orvepitant or placebo tablets once daily (in the evening before bedtime) for 4 weeks. primary endpoint was change from baseline in mean patient-recorded numerical rating scale (NRS) score (over the last three recordings) at week 4. Secondary outcome measures were NRS score, verbal rating scale score, Skindex-16 and Leeds Sleep Evaluation Questionnaire at each study visit (baseline, weeks 1, 4, 8); rescue medication use; EGFRI dose reduction; and study withdrawal because of intense uncontrolled pruritus. Results The trial was terminated early because of recruitment challenges; only 44 of the planned 90 patients were randomised. All patients were analysed for efficacy AT101 acetic acid and safety. Mean NRS score change from baseline to week 4 was ?2.78 (SD: 2.64) points in the 30?mg group, ?3.04 (SD: 3.06) points in the 10?mg group and ?3.21 (SD: 1.77) points in the placebo group; the difference between orvepitant and placebo was not AT101 acetic acid statistically significant. No safety signal was detected. Adverse events related to orvepitant (asthenia, dizziness, dry mouth, hyperhidrosis) were all of moderate or moderate severity. Conclusions Orvepitant was safe and well tolerated. No difference in NRS score between the orvepitant and placebo groups was observed at the week 4 primary endpoint. A number of explanations for this outcome are possible. Trial registration number EudraCT2013-002763-25. reported that pruritus occurs in approximately half of all patients treated with EGFRIs.4 Finally, in a review of interviews conducted with 100 patients taking mainly EGFR mAbs, 72% of patients reported experiencing pruritus.13 A safe and effective cancer-supportive care therapy to ameliorate the itching burden these patients experience is urgently needed. Neurokinin-1 (NK1) receptors are 7-transmembrane receptors with a preferred peptide agonist ligand of material P (SP).14 SP produced by peripheral skin sensory nerve fibres is thought to promote itching via activation of NK1 receptors on keratinocytes and mast cells causing local inflammatory and vasodilatory effects.15 Interestingly, Gerber reported that mast cells significantly accumulate in the lesional skin of patients treated with EGFRIs and suggested that this antipruritic activity of the NK1 receptor antagonist aprepitant in this population is achieved by blocking the activation of mast cell NK1 receptors by SP, thereby preventing the release of mast cell histamine and other proinflammatory/pruritogenic mediators.16C18 Recently, another receptor, the Mas-related G-protein coupled receptor member X2, has been shown to be activated in humans by SP, and this conversation may contribute additionally to the proinflammatory effects mediated by mast cell degranulation.19 SP and the NK1 receptor are also widely expressed centrally and have a role in transmission of the peripheral itch signal via the spinal superficial dorsal horn to higher brain centres for processing.20 In rodents scratching behaviour can be blocked by neurotoxic destruction of spinal NK1 receptor-expressing AT101 acetic acid neurons,21 22 and (the gene encoding SP)-expressing spinal neurons have also Rabbit Polyclonal to EXO1 been linked to the promotion of scratching behaviour.23 Intradermal injection of SP in humans causes pruritus, erythema and oedema.24C26 Scratching behaviour induced by intradermal injection of either SP or an NK1 agonist or topical administration of a hapten in animals can all be profoundly reduced by NK1 antagonist treatment, including both orvepitant and aprepitant.27C30 These data suggest that the NK1 receptor system is involved in itch signalling and therefore blockade of these pathways with NK1 receptor antagonists represents a potentially promising therapy for pruritic conditions, including EGFRI-induced pruritus.31 32 Aprepitant (Emend, formerly MK-869) is the first commercially available drug of a new class of NK1 receptor antagonists for the prevention of chemotherapy-induced and postoperative nausea and vomiting. It has been evaluated in numerous open-label clinical studies of patients suffering from treatment-refractory pruritus, including a large number of patients suffering with acute EGFRI-induced pruritus.33C49 In these uncontrolled studies, aprepitant AT101 acetic acid acted as a rapid and highly effective antipruritic medication that also significantly improved patients quality of life, leading to advocacy for clinical assessment of aprepitant and other emerging NK1 receptor antagonists in patients receiving agents with a high risk of pruritus.50 Like aprepitant, orvepitant is an orally active, potent, brain-penetrant and selective.