A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation

Abstract

Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (HCT). In this trial, we randomized adult CMV-seropositive HCT recipients without CMV viremia at screening 2:1 to receive brincidofovir or placebo until week 14 post-HCT. Randomization was stratified by center and risk of CMV infection. Patients were assessed weekly through week 15 and every third week thereafter through week 24 post-HCT. Patients who developed clinically significant CMV infection (CS-CMVi; CMV viremia requiring preemptive therapy or CMV disease) discontinued the study drug and began anti-CMV treatment. The primary endpoint was the proportion of patients with CS-CMVi through week 24 post-HCT; patients who discontinued the trial or with missing data were imputed as primary endpoint events. Between August 2013 and June 2015, 452 patients were randomized at a median of 15 days after HCT and received study drug. The proportion of patients who developed CS-CMVi or were imputed as having a primary endpoint event through week 24 was similar between brincidofovir-treated patients and placebo recipients (155 of 303 [51.2%] versus 78 of 149 [52.3%]; odds ratio, .95 [95% confidence interval, .64 to 1.41]; P = .805); fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients (41.6%; P < .001). Serious adverse events were more frequent among brincidofovir recipients (57.1% versus 37.6%), driven by acute graft-versus-host disease (32.3% versus 6.0%) and diarrhea (6.9% versus 2.7%). Week 24 all-cause mortality was 15.5% among brincidofovir recipients and 10.1% among placebo recipients. Brincidofovir did not reduce CS-CMVi by week 24 post-HCT and was associated with gastrointestinal toxicity.

Keywords: Allogeneic hematopoietic cell transplantation; Antiviral; Brincidofovir; CMX001; Cytomegalovirus; Prophylaxis.

Figure 1.

Consent, screening, enrollment, randomization, and follow-up.

Figure 2.

Time to clinically significant CMV infection (A) and time to all-cause mortality (B) from day of transplantation through week 24 post-transplantation, intention-to-treat population. Patients without a clinically significant CMV infection were censored at the end-of-study visit or at 24 weeks (+2-week window) after transplantation, whichever was earlier. For mortality through week 24, patients who died after week 24 post-transplantation were censored at the end-of-study visit or week 24, whichever was earlier.

Figure 3.

Time to clinically significant CMV infection according to several subgroups. (A and B) Results by randomization strata groups of higher and lower risk of CMV disease progression. (C and D) Post hoc results according to use of T cell depletion strategies (ATG, alemtuzumab, or ex vivo T cell depletion) (C) and all other patients (D). (E and F) Post hoc results according to conditioning regimen, either reduced-intensity (E) or myeloablative (F) conditioning.

Figure 4.

(A) Brincidofovir exposure and risk of diarrhea, Common Terminology Criteria for Adverse Events grade ≥2 or gastrointestinal GVHD stage ≥1. The solid line indicates calculated risk; dotted lines, 95% CIs of calculated risk; X, individual patients who experienced the adverse event if on 1.0 on the y-axis, who did not experience the adverse event if on 0 on the y-axis. (B) Impact of SMMP patient management on clinically significant CMV infection and all-cause mortality from week 8 through week 24 among brincidofovir-treated patients. BCV, brincidofovir; primary endpoint event, clinically significant CMV infection. Footnote: AUC, area under the curve; BCV, brincidofovir; primary endpoint event, clinically-significant CMV infection. Panel A: solid line, calculated risk; dotted lines, 95% confidence intervals of calculated risk; X, individual patients who experienced the adverse event if on 1.0 on the y axis, who did not experience the adverse event if on 0.0 on the y axis.