Treatment for First Cytomegalovirus Infection Post–Hematopoietic Cell Transplant in the AURORA Trial: A Multicenter, Double-Blind, Randomized, Phase 3 Trial Comparing Maribavir With Valganciclovir
Authors: Papanicolaou Genovefa A , Avery Robin K , Cordonnier Catherine , Duarte Rafael F , Haider Shariq , Maertens Johan , Peggs Karl S , Solano Carlos , Young Jo-Anne H , Fournier Martha , Murray Rose Ann , Wu Jingyang , Winston Drew J ,   AURORA Trial Investigators, Singhal Deepak , Sasadeusz Joe , Maertans Johan , Georgala Aspasia , Selleslag Dominik , Verlinden Anke , Kerre Tessa , De Becker Ann , Haider Shariq , Wright Alissa , Wu Depei , Vrhovac Radovan , Cordonnier Catherine , Berceanu Ana , Francois Sylvie , Michonneau David , Huynh Anne , Bethge Wolfgang , Kaufmann Martin , Stelljes Matthias , Franke Georg-Nikolaus , Schmitt Timo , Müller Lutz , Ahlgrimm Manfred , Niederland Judith , Tsirigotis Panagiotis , Ram Ron , Shemtov Noga , Rosenvald-Zuckerman Tsila , Cutini Ilaria , Busca Alessandro , Onida Francesco , Tecchio Cristina , Browett Peter , Do Young Rok , Kim Sung Hyun , Ho Aloysius , Koh Liang Piu , Lopez Maria Lourdes Vazquez , Jimenez Javier Lopez , Coll Christelle Ferra , De la Camara Rafael , Solano Carlos , Mussetti Alberto , Llamas Juan Carlos Vallejo , Suñol Pere Barba , Chacón Manuel Jurado , Duarte Rafael F , Rodríguez María Aranzazu Bermúdez , Mueller Nicolas , Ozdogu Hakan , Gurman Gunhan , Bloor Adrian , Kishore Bhuvan , Peggs Kari S , Milojkovic Dragana , Orchard Kim , Toth Arpad Gabor , Koh Mickey , Avery Robin K , Pisano Jennifer , Alangaden George , Winston Drew J , Papanicolau Genovefa , Gewurz Benjamin , Marty Francisco M , Young Jo-Anne H , Hagen Patrick , Reshef Ran , Abedin Sameem , Shaughnessy Paul , Gibson Laura , Shore Joan Tsiporah , Bachier Carlos R , Yared Jean , Malinis Maricar 
Published: November 2023

Abstract

Background
Neutropenia may limit the use of valganciclovir treatment for cytomegalovirus (CMV) infection following hematopoietic cell transplant (HCT). A phase 2 study indicated efficacy of maribavir with fewer treatment-limiting toxicities than valganciclovir.

Methods
In this multicenter, double-blind, phase 3 study, patients with first asymptomatic CMV infection post-HCT were stratified and randomized 1:1 to maribavir 400 mg twice daily or valganciclovir (dose-adjusted for renal clearance) for 8 weeks with 12 weeks of follow-up. The primary endpoint was confirmed CMV viremia clearance at week 8 (primary hypothesis of noninferiority margin of 7.0%). The key secondary endpoint was a composite of the primary endpoint with no findings of CMV tissue-invasive disease at week 8 through week 16. Treatment-emergent adverse events (TEAEs) were assessed.

Results
Among patients treated (273 maribavir; 274 valganciclovir), the primary endpoint of noninferiority of maribavir was not met (maribavir, 69.6%; valganciclovir, 77.4%; adjusted difference: −7.7%; 95% confidence interval [CI]: −14.98, −.36; lower limit of 95% CI of treatment difference exceeded −7.0%). At week 16, 52.7% and 48.5% of patients treated (maribavir and valganciclovir, respectively) maintained CMV viremia clearance without tissue-invasive disease (adjusted difference: 4.4%; 95% CI: −3.91, 12.76). With maribavir (vs valganciclovir), fewer patients experienced neutropenia (16.1% and 52.9%) or discontinued due to TEAEs (27.8% and 41.2%). Discontinuations were mostly due to neutropenia (maribavir, 4.0%; valganciclovir, 17.5%).

Conclusions
Although noninferiority of maribavir to valganciclovir for the primary endpoint was not achieved based on the prespecified noninferiority margin, maribavir demonstrated comparable CMV viremia clearance during post-treatment follow-up, with fewer discontinuations due to neutropenia.
Clinical Trials Registration. NCT02927067 [AURORA].