A Phase 3 Active-Controlled Study of Maribavir (MBV) for the Treatment (Tx) of Transplant Recipients with Refractory/Resistant (RR) Cytomegalovirus (CMV): Study Design

Abstract

Introduction In transplant recipients, CMV infection RR to prior antiviral Tx is associated with significant morbidity and mortality. Existing antivirals are not approved for RR CMV infection and are limited by their toxicities. A prior Phase 2 dose-ranging study of MBV for RR CMV (67% of patients [pts] achieved undetectable CMV DNA within 6 wks) motivated initiation of a Phase 3 trial with the concept of an investigator-assigned (IA) Tx comparator arm. Objective To assess the efficacy and safety of MBV compared with IA anti-CMV therapies in HSCT/SOT recipients with RR CMV infection. Methods In this Phase 3, randomized, open-label, multicenter, active-controlled study (NCT02931539), HSCT/SOT recipients (≥12 years old) with RR CMV infection are randomized 2:1 to MBV (400 mg BID) or IA Tx (ganciclovir [GCV], valganciclovir [VGC], foscarnet [FSC], cidofovir [CDV]) for 8 wks. Pts in the IA Tx group discontinuing Tx early (lack of response and/or intolerance; investigator discretion) are assessed Wks 3–7 to enter MBV rescue arm. Pts are followed for 12 wks after the 8-wk Tx period. Inclusion criteria include: documented CMV infection with screening value ≥2730 IU/mL / ≥910 IU/mL (whole blood / plasma) in 2 consecutive tests ≥1 day apart; current refractory CMV infection: documented failure to achieve >1 log10 decrease in CMV DNA after ≥14 days of the same anti-CMV Tx. Pts with ≥1 genetic mutation associated with GCV/VGC, FSC or CDV resistance must also meet refractory criteria. Pts with tissue invasive CMV disease with CNS involvement including the retina, eg CMV retinitis, are excluded. A central specialty laboratory quantifies plasma CMV DNA (COBAS ‘AmpliPrep/TaqMan' CMV test). The primary efficacy endpoint is confirmed CMV viremia clearance (defined as plasma CMV DNA concentrations Results Planned enrollment is 351 pts across ∼140 sites (North America, Europe, Asia Pacific). Study start, Dec 2016; completion ∼Sep 2020. Conclusions The comparator arm of this Phase 3 study is valid for evaluating efficacy and safety of MBV for RR CMV compared with available anti-CMV Tx, whilst allowing for personalized Tx for pts in the comparator group.