DAS181 Treatment of Severe Lower Respiratory Tract Parainfluenza Virus Infection in Immunocompromised Patients: A Phase 2 Randomized, Placebo-Controlled Study

Roy F Chemaly, Francisco M Marty, Cameron R Wolfe, Steven J Lawrence, Sanjeet Dadwal, Rosemary Soave, Jason Farthing, Stephen Hawley, Paul Montanez, Jimmy Hwang, Jennifer Hui-Chun Ho, Stanley Lewis, George Wang, Michael Boeckh, Roy F Chemaly, Francisco M Marty, Cameron R Wolfe, Steven J Lawrence, Sanjeet Dadwal, Rosemary Soave, Jason Farthing, Stephen Hawley, Paul Montanez, Jimmy Hwang, Jennifer Hui-Chun Ho, Stanley Lewis, George Wang, Michael Boeckh

Abstract

Background: There are no antiviral therapies for parainfluenza virus (PIV) infections. DAS181, a sialidase fusion protein, has demonstrated activity in in vitro and in animal models of PIV.

Methods: Adult immunocompromised patients diagnosed with PIV lower respiratory tract infection (LRTI) who required oxygen supplementation were randomized 2:1 to nebulized DAS181 (4.5 mg/day) or matching placebo for up to 10 days. Randomization was stratified by need for mechanical ventilation (MV) or supplemental oxygen (SO). The primary endpoint was the proportion of patients reaching clinical stability survival (CSS) defined as returning to room air (RTRA), normalization of vital signs for at least 24 hours, and survival up to day 45 from enrollment.

Results: A total of 111 patients were randomized to DAS181 (n = 74) or placebo (n = 37). CSS was achieved by 45.0% DAS181-treated patients in the SO stratum compared with 31.0% for placebo (P = .15), whereas patients on MV had no benefit from DAS181. The proportion of patients achieving RTRA was numerically higher for SO stratum DAS181 patients (51.7%) compared with placebo (34.5%) at day 28 (P = .17). In a post hoc analysis of solid organ transplant, hematopoietic cell transplantation within 1 year, or chemotherapy within 1 year, more SO stratum patients achieved RTRA on DAS181 (51.8%) compared with placebo (15.8%) by day 28 (P = .012).

Conclusions: The primary endpoint was not met, but post hoc analysis of the RTRA component suggests DAS181 may have clinical activity in improving oxygenation in select severely immunocompromised patients with PIV LRTI who are not on mechanical ventilation. Clinical Trials Registration. NCT01644877.

Keywords: DAS181; immunocompromised; lower respiratory tract infections; parainfluenza virus; supplemental oxygen.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Clinical trial design timeline. Abbreviation: RTRA, return to room air.
Figure 2.
Figure 2.
Patient population. A total of 111 patients were randomized to DAS181 or placebo treatment groups. The FAS consisted of 110 randomized patients that received at least 1 dose of study drug (DAS181, n = 74; placebo, n = 36). The mITT data set was 109 patients because of the exclusion of 1 patient that did not meet all inclusion criteria. Abbreviations: I/E, inclusion/exclusion criteria; FAS, full analysis set; mITT, modified intent-to-treat; MV, mechanically ventilated; SO, supplemental oxygen.
Figure 3.
Figure 3.
Time to clinical stability survival (SO and MV strata, mITT population). (A) Subjects within the NIPPV/O2 supplemental oxygen stratum. (B) Subjects within the mechanical ventilation stratum. Abbreviations: mITT, modified intent-to-treat; MV, mechanically ventilated; NIPPV, noninvasive positive pressure ventilation; SO, supplemental oxygen.
Figure 4.
Figure 4.
Time to subject RTRA (SO stratum, mITT population). Time to subject return to room air for DAS181 and placebo groups showing a trend toward improved time to RTRA with DAS181 treatment. Two patients were excluded from this analysis because they had achieved RTRA before receiving the first treatment dose. Abbreviations: mITT, modified intent-to-treat; RTRA, return to room air; SO, supplemental oxygen.
Figure 5.
Figure 5.
Strata and subgroup populations. Strata and subgroups for analysis of treatment effect using RTRA endpoint. Two patients that achieved RTRA before receiving treatment are not evaluable for this endpoint. Both of these patients were contained within the SO stratum and were removed for all RTRA and related endpoint analyses. The SO stratum consists of 2 subgroups: severely immunocompromised and mildly immunocompromised. Abbreviations: mITT, modified intent-to-treat; RTRA, return to room air; SO, supplemental oxygen.
Figure 6.
Figure 6.
Time to subject RTRA (SO stratum, severely immunocompromised patient subgroup, N = 68). Abbreviations: RTRA, return to room air; SO, supplemental oxygen.
Figure 7.
Figure 7.
Absolute change from baseline FEV1% predicted. Subjects had FEV1% predicted determined daily for 10 days starting at treatment day 1, and at day 14 posttreatment. (A) SO strata patients. (B) Severely immunocompromised SO subgroup. *P < .05. Abbreviations: FEV1%, forced expiratory volume percent; SO, supplemental oxygen.

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Source: PubMed

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