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].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].Noninferiority of maribavir to valganciclovir was not met for the primary endpoint of CMV viremia clearance at study week 8. However, maribavir had comparable post-treatment CMV viremia clearance to valganciclovir, and was associated with a lower incidence of treatment-limiting neutropenia.Graphical Abstract
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 / G.A. Papanicolaou, R.K. Avery, C. Cordonnier, R.F. Duarte, S. Haider, J. Maertens, K.S. Peggs, C. Solano, J.H. Young, M. Fournier, R.A. Murray, J. Wu, D.J. Winston, D. Singhal, J. Sasadeusz, J. Maertans, A. Georgala, D. Selleslag, A. Verlinden, T. Kerre, A. De Becker, S. Haider, A. Wright, D. Wu, R. Vrhovac, C. Cordonnier, A. Berceanu, S. Francois, D. Michonneau, A. Huynh, W. Bethge, M. Kaufmann, M. Stelljes, G. Franke, T. Schmitt, L. Müller, M. Ahlgrimm, J. Niederland, P. Tsirigotis, R. Ram, N. Shemtov, T. Rosenvald-Zuckerman, I. Cutini, A. Busca, F. Onida, C. Tecchio, P. Browett, Y.R. Do, S.H. Kim, A. Ho, L.P. Koh, M.L.V. Lopez, J.L. Jimenez, C.F. Coll, R. De la Camara, C. Solano, A. Mussetti, J.C.V. Llamas, P.B. Suñol, M.J. Chacón, R.F. Duarte, M.A.B. Rodríguez, N. Mueller, H. Ozdogu, G. Gurman, A. Bloor, B. Kishore, K.S. Peggs, D. Milojkovic, K. Orchard, A.G. Toth, M. Koh, R.K. Avery, J. Pisano, G. Alangaden, D.J. Winston, G. Papanicolau, B. Gewurz, F.M. Marty, J.H. Young, P. Hagen, R. Reshef, S. Abedin, P. Shaughnessy, L. Gibson, J.T. Shore, C.R. Bachier, J. Yared, M. Malinis. - In: CLINICAL INFECTIOUS DISEASES. - ISSN 1058-4838. - 78:3(2024 Mar 15), pp. 562-572. [10.1093/cid/ciad709]
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
F. Onida;
2024
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].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].Noninferiority of maribavir to valganciclovir was not met for the primary endpoint of CMV viremia clearance at study week 8. However, maribavir had comparable post-treatment CMV viremia clearance to valganciclovir, and was associated with a lower incidence of treatment-limiting neutropenia.Graphical Abstract
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