A Phase 2, Randomized, Double-blind, Placebo-Controlled Trial of Presatovir for the Treatment of Respiratory Syncytial Virus Upper Respiratory Tract Infection in Hematopoietic-Cell Transplant Recipients

Roy F Chemaly, Sanjeet S Dadwal, Anne Bergeron, Per Ljungman, Yae-Jean Kim, Guang-Shing Cheng, Sudhakar N Pipavath, Ajit P Limaye, Elodie Blanchard, Drew J Winston, Patrick J Stiff, Tsila Zuckerman, Silvy Lachance, Galia Rahav, Catherine B Small, Kathleen M Mullane, Roberto L Patron, Dong-Gun Lee, Hans H Hirsch, Alpana Waghmare, Matt McKevitt, Robert Jordan, Ying Guo, Polina German, Danielle P Porter, David L Gossage, Timothy R Watkins, Francisco M Marty, Jason W Chien, Michael Boeckh, Roy F Chemaly, Sanjeet S Dadwal, Anne Bergeron, Per Ljungman, Yae-Jean Kim, Guang-Shing Cheng, Sudhakar N Pipavath, Ajit P Limaye, Elodie Blanchard, Drew J Winston, Patrick J Stiff, Tsila Zuckerman, Silvy Lachance, Galia Rahav, Catherine B Small, Kathleen M Mullane, Roberto L Patron, Dong-Gun Lee, Hans H Hirsch, Alpana Waghmare, Matt McKevitt, Robert Jordan, Ying Guo, Polina German, Danielle P Porter, David L Gossage, Timothy R Watkins, Francisco M Marty, Jason W Chien, Michael Boeckh

Abstract

Background: Hematopoietic-cell transplant (HCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. We evaluated the RSV fusion inhibitor presatovir in a randomized, double-blind, Phase II trial in HCT recipients with RSV upper respiratory tract infections.

Methods: Patients were stratified by lymphopenia (<200/µL) and ribavirin use; were randomized, stratified by lymphopenia (<200/μL) and ribavirin use, to receive oral presatovir at 200 mg or a placebo on Days 1, 5, 9, 13, and 17, and were followed through Day 28. The coprimary efficacy endpoints were the time-weighted average change in the nasal RSV viral load between Days 1 and 9 and the proportion of patients developing lower respiratory tract complications (LRTCs) through Day 28.

Results: From 23 January 2015 to 16 June 2017, 189 patients were randomly assigned to treatment (96 to presatovir and 93 to the placebo). Presatovir treatment, compared with the placebo treatment, did not significantly affect (prespecified α = 0.01) a time-weighted average decline in the RSV viral load from Day 1 to 9 (treatment difference, -0.33 log10 copies/mL; 95% confidence interval [CI] -.64 to -.02 log10 copies/mL; P = .040) or the progression to LRTC (11.2% vs 19.5%, respectively; odds ratio, 0.50; 95% CI, .22-1.18; P = .11). In a post hoc analysis among patients with lymphopenia, presatovir decreased LRTC development by Day 28 (2/15 [13.3%] vs 9/14 [64.3%], respectively; P = .008), compared with the placebo. Adverse events were similar for patients receiving presatovir and the placebo.

Conclusions: Presatovir had a favorable safety profile in adult HCT recipients with RSV but did not achieve the coprimary endpoints. Exploratory analyses suggest an antiviral effect among patients with lymphopenia.

Clinical trials registration: NCT02254408; EUDRA-CT#2014-002474-36.

Keywords: presatovir; hematopoietic cell transplant; respiratory syncytial virus.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Patient disposition from enrollment through analysis. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; RSV, respiratory syncytial virus; URT, upper respiratory tract.
Figure 2.
Figure 2.
Nasal respiratory syncytial virus (RSV) RNA at each study visit in the efficacy population. A, The median nasal RSV RNA. B, The median change from baseline in nasal RSV RNA at each study visit in patients treated with presatovir (closed circles, solid line) versus placebo (open circles, dashed line). Error bars represent the interquartile range.
Figure 3.
Figure 3.
Development of lower respiratory tract complications (LRTC) in the efficacy population. The LRTC rate at each study visit in patients treated with presatovir (solid line) versus placebo (dashed line) is shown.
Figure 4.
Figure 4.
Occurrence of death or respiratory failure requiring mechanical ventilation in the efficacy population. The event rate at each study visit in patients receiving presatovir (solid line) versus placebo (dashed line) is shown.

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