Rationale and design of the multicentric, double-blind, double-placebo, randomized trial APrepitant versus HYdroxyzine in association with cytoreductive treatments for patients with myeloproliferative neoplasia suffering from Persistent Aquagenic Pruritus. Trial acronym: APHYPAP

Abstract

Background Aquagenic pruritus (AP), an intense sensation of scratching induced after water contact, is the most troublesome aspect of BCR-ABL1-negative myeloproliferative neoplasms (MPNs). Mostly described in polycythemia vera (PV, ~ 40%), it is also present in essential thrombocythemia (ET) and primary myelofibrosis (PMF) (10%). Even if this symptom can decrease or disappear under cytoreductive treatments, 30% of treated MPN patients still persist with a real impact on the quality of life (QoL). Because its pathophysiology is poorly understood, efficient symptomatic treatments of AP are missing. The neuropeptide substance P (SP) plays a crucial role in the induction of pruritus. Several studies showed the efficacy of aprepitant, an antagonist of SP receptor (NK-1R), in the treatment of chronic pruritus but never evaluated in AP. The objectives of APHYPAP are twofold: a clinical aim with the evaluation of the efficacy of two drugs in the treatment of a persistent AP for MPN patients and a biological aim to find clues to elucidate AP pathophysiology. Methods/design A multicentric, double-blind, double-placebo, randomized study will include 80 patients with MPN (PV or ET or PMF) treated since at least 6 months for their hemopathy but suffering from a persistent AP (VAS intensity ≥6/10). Patients will be randomized between aprepitant (80 mg daily) + placebo to match to hydroxyzine OR hydroxyzine (25 mg daily) + placebo to match to aprepitant for 14 days. At D0, baseline information will be collected and drugs dispense. Outcome measures will be assessed at D15, D30, D45, and D60. The primary study endpoint will be the reduction of pruritus intensity below (or equal) at 3/10 on VAS at D15. Secondary outcome measures will include the number of patients with a reduction or cessation of AP at D15 or D60; evaluation of QoL and AP characteristics at D0, D15, D30, D45, and D60 with MPN-SAF and AP questionnaires, respectively; modification of plasmatic concentrations of cytokines and neuropeptides at D0, D15, D30, and D60; and modification of epidermal innervation density and pruriceptor expression at D0 and D15. Discussion The APHYPAP trial will examine the efficacy of aprepitant vs hydroxyzine (reference treatment for AP) to treat persistent AP in MPN patients. The primary objective is to demonstrate the superiority of aprepitant vs hydroxyzine to treat persistent AP of MPN patients. The treatment received will be considered efficient if the AP intensity will be reduced at 3/10 or below on VAS after 14 days of treatment. The results of this study may provide a new treatment option for this troublesome symptom and also give us more insights in the pathophysiology understanding of AP. Trial registration APHYPAP. NCT03808805, first posted: January 18, 2019; last update posted: June 10, 2021. EudraCT 2018-090426-66

Differences between aquagenic and non‐aquagenic pruritus in myeloproliferative neoplasms: An observational study of 500 patients

“…30 In order to find an efficient therapeutic alternative to treat AP in MPN, we are conducting a prospective trial comparing hydroxyzine to aprepitant in patients with severe AP resistant to cytoreductive drugs (acronym: APHYPAP, NCT03808805). 31 Aprepitant is an anti-NK-1R substance P receptor that has been identified as active on dermatological and lymphoid-related pruritus. 32 Furthermore, we also retrospectively studied patient outcomes and found that our patients with pruritus had a higher risk of phenotypical evolution (secondary MF or AcPh/AML).…”

“…38,39 To assess the impact of cytokines in these situations, we are waiting for the results of the APHYPAP prospective trial, in which cytokines will be explored deeply. 31 A non-mutually exclusive explanation for the difference between AP and non-AP groups could be the presence of additional mutations that might be associated with pruritus and a higher risk of evolution. The classic mutations carried by MPN patients can also acquire additional mutations that can modify the initial mutation and the evolutive profile of the patients.…”

“…However, the improvement observed in AP was assimilated by this group of experts to a placebo effect 30 . In order to find an efficient therapeutic alternative to treat AP in MPN, we are conducting a prospective trial comparing hydroxyzine to aprepitant in patients with severe AP resistant to cytoreductive drugs (acronym: APHYPAP, NCT03808805) 31 . Aprepitant is an anti‐NK‐1R substance P receptor that has been identified as active on dermatological and lymphoid‐related pruritus 32 …”

“…However, with the exceptions of Gangemi's study in 2012 showing no correlation between IL‐10, Il‐22 and Il‐23 expression and the presence of AP in PV patients and Ishii's 2009 study evoking the role of IL‐31, there has been no systematic study exploring the cytokine profile of MPN patients in relation to the presence or absence of pruritus 38,39 . To assess the impact of cytokines in these situations, we are waiting for the results of the APHYPAP prospective trial, in which cytokines will be explored deeply 31 . A non‐mutually exclusive explanation for the difference between AP and non‐AP groups could be the presence of additional mutations that might be associated with pruritus and a higher risk of evolution.…”

Aquagenic pruritus indicates increased risks in patients with myeloproliferative neoplasms

“…Thus, in addition to cytoreductive drugs, it is necessary to employ symptomatic antipruritic drugs to relieve pruritus and restore Qol in AP patients. In this respect, a prospective trial (acronym: APHYPAP, NCT03808805) comparing hydroxyzine with aprepitant, a neurokinin‐1 inhibitor, in patients with severe AP resistant to cytoreductive drugs is ongoing, and the results are eagerly awaited 8 . Especially because this trial will also involve a study of the potentially involved cytokines, it will hopefully lead to new insights in AP pathophysiology.…”