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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
Chemaly, R. F., Dadwal, S. S., Bergeron, A., Ljungman, P., Kim, Y. J., Cheng, G. S., Pipavath, S. N., Limaye, A. P., Blanchard, E., Winston, D. J., et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019
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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 2 trial in HCT recipients with RSV upper respiratory tract infection (URTI). METHODS Patients were randomized, stratified by lymphopenia (<200/microL) and ribavirin use, to receive oral presatovir 200 mg or placebo on days 1, 5, 9, 13, and 17, and followed through day 28. The coprimary efficacy endpoints were time-weighted average change in nasal RSV viral load between days 1 and 9, and proportion of patients developing lower respiratory tract complications (LRTC) through day 28. RESULTS From January 23, 2015, to June 16, 2017, 189 patients were randomized (96 presatovir, 93 placebo). Presatovir vs placebo treatment did not significantly affect (prespecified alpha = 0.01) time-weighted average decline in RSV viral load from day 1 to 9 (treatment difference: -0.33 log10 copies/mL; 95% CI: -0.64, -0.02 log10 copies/mL; p = 0.040) or progression to LRTC (11.2% vs 19.5%; odds ratio [95% CI], 0.50 [0.22, 1.18]; p = 0.11). In post hoc analysis among patients with lymphopenia, presatovir vs placebo treatment decreased LRTC development by day 28 (2/15 [13.3%] vs 9/14 [64.3%], p = 0.008). Adverse events were similar for patients receiving presatovir vs 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.
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A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus (RSV) Infection of the Lower Respiratory Tract
Marty, F. M., Chemaly, R. F., Mullane, K. M., Lee, D. G., Hirsch, H. H., Small, C. B., Bergeron, A., Shoham, S., Ljungman, P., Waghmare, A., et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019
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Abstract
BACKGROUND Presatovir significantly reduced nasal viral load, signs, and symptoms of respiratory syncytial virus (RSV) infection in a human challenge study. We evaluated presatovir in hematopoietic-cell transplant (HCT) recipients with RSV lower respiratory tract infection (LRTI). METHODS Patients with confirmed RSV in upper and lower respiratory tract and new chest X-ray abnormalities were randomized (1:1), stratified by supplemental oxygen and ribavirin use, to receive oral presatovir 200 mg or placebo every 4 days for 5 doses. The primary endpoint was time-weighted average change in nasal RSV viral load through day 9. Secondary endpoints included supplemental oxygen-free days, incident respiratory failure requiring mechanical ventilation, and all-cause mortality. RESULTS From January 31, 2015, to March 20, 2017, 60 patients from 17 centers were randomized (31 presatovir, 29 placebo); 59 received study treatment (50 allogeneic, 9 autologous HCT). In the efficacy population (29 presatovir, 28 placebo), presatovir treatment did not significantly reduce time-weighted average change in viral load (-1.12 vs -1.09 log10 copies/mL; treatment difference -0.02 log10 copies/mL, 95% confidence interval: -.62, .57; P = .94), median supplemental oxygen-free days (26 vs 28 days, P = .84), incident respiratory failure (10.3 vs 10.7%, P = .98), or all-cause mortality (0 vs 7.1%, P = .19) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients. CONCLUSIONS Presatovir treatment was well tolerated in HCT patients with RSV LRTI but did not improve virologic or clinical outcomes versus placebo. CLINICAL TRIALS REGISTRATION www.clinicaltrials.gov, NCT02254421; EudraCT, #2014-002475-29.
PICO Summary
Population
Hematopoietic-cell transplant (HCT) recipients with confirmed RSV lower respiratory tract infection (n=60)
Intervention
Oral presatovir 200 mg every 4 days for 5 doses (n=29)
Comparison
Placebo (n=28)
Outcome
In the efficacy population, presatovir treatment did not significantly reduce time-weighted average change in viral load (-1.12 vs -1.09 log10 copies/mL; treatment difference -0.02 log10 copies/mL), median supplemental oxygen-free days (26 vs 28 days), incident respiratory failure (10.3 vs 10.7%), or all-cause mortality (0 vs 7.1%) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients.
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Supplemental Oxygen-Free Days in Hematopoietic Cell Transplant Recipients With Respiratory Syncytial Virus
Waghmare, A., Xie, H., Kimball, L., Yi, J., Ozkok, S., Leisenring, W., Cheng, G. S., Englund, J. A., Watkins, T. R., Chien, J. W., et al
Journal of Infectious Diseases. 2017;216(10):1235-1244
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Abstract
Background: Clinically meaningful endpoints for respiratory syncytial virus (RSV) treatment trials are lacking for hematopoietic cell transplant (HCT) recipients. We evaluated supplemental oxygen use among HCT recipients with RSV infection. Methods: Subjects were grouped according to the presence of upper respiratory tract infection (URTI) without lower respiratory tract infection (LRTI), URTI progressing to LRTI, and LRTI at presentation. LRTI was defined as a positive lower respiratory tract sample with or without radiographic abnormality (defined as proven or probable LRTI, respectively) or a positive upper respiratory tract sample with radiographic abnormality (possible LRTI). Supplemental oxygen-free days were defined as any day while alive after diagnosis of RSV infection during which <=2 L of supplemental oxygen per minute was received. Results: Among 230 patients, supplemental oxygen use by day 28 after the first diagnosis of RSV infection was lowest in patients presenting with URTI (31 of 197 [16%]). Supplemental oxygen use was lower in patients with possible LRTI (12 of 45 [27%]) than in those with proven/probable LRTI (29 of 42 [69%]). Patients presenting with proven/probable LRTI had a median of 16 fewer supplemental oxygen-free days than those presenting with URTI (P < .0001). Death only occurred among patients with proven/probable LRTI (11 of 42 [26%]). Conclusions: Confirmation of RSV infection in the lower respiratory tract provides prognostic information that may help prioritize therapies. Supplemental oxygen-free days as a clinical endpoint may allow smaller sample sizes for trials evaluating RSV antivirals.