A Multicenter, Open-Label Study to Assess the Safety of Nebulized Tissue Plasminogen Activator for the Acute Treatment of Pediatric Plastic Bronchitis: The PLATyPuS Trial.

Abstract

Introduction: Pediatric plastic bronchitis (PB) is a rare complication of surgically palliated congenital heart disease (CHD). Fibrin casts obstruct airways and can cause respiratory distress. There are no therapeutics approved by the United States Food and Drug Administration to treat PB, but inhaled tissue plasminogen activator (tPA) has been anecdotally used to relieve symptoms. We conducted a phase II open-label clinical trial to test the safety of inhaled tPA in pediatric PB.

Methods: Patients with an acute exacerbation of PB requiring hospitalization were enrolled to test the safety of an inhaled tPA regimen (5 mg every 6 h). The primary end point was to assess the safety and tolerability of repeated doses of nebulized, inhaled tPA in pediatric patients with acute PB. Safety parameters consisted of clinical laboratories to assess bleeding, which were measured prior to, during, and after tPA treatment. To benchmark efficacy using spirometry and oxygen saturation, children with Fontan-palliated CHD without a history of PB, with and without protein losing enteropathy (PLE), and healthy children were enrolled in a control arm that did not receive tPA.

Results: Of the 10 patients with PB screened for enrollment, eight qualified for immediate treatment with inhaled tPA. A total of 29 non-PB participants (PLE, n = 8 [10-18 yo]; CHD, n = 9 [8-17 yo]; and healthy, n = 12 [7-16 yo]) were enrolled. There were no differences in pretreatment clinical blood laboratory values of hemostasis and those during and after treatment with the study drug (primary safety outcome). However, there were four episodes of self-limiting epistaxis related to the study drug. Inhaled tPA statistically improved oxygen saturation although this was moderate and likely not clinically significant; inhaled tPA did not alter spirometry values.

Conclusion: In this small, phase II study, repeated doses of inhaled tPA in patients with an acute exacerbation of PB did not result in disrupted systemic coagulation or hematological homeostasis or serious bleeding. However, patients should be monitored for localized bleeding. Larger, randomized trials are needed to provide more comprehensive assessments of bleeding risk and to further assess efficacy.

Trial registration: ClinicalTrials.gov identifier: NCT02315898.