Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection

Summary

The global pandemic COVID-19 has overwhelmed the medical capacity to accommodate a large surge of patients with acute respiratory distress syndrome (ARDS). In the United States, the number of cases of COVID-19 ARDS is projected to exceed the number of available ventilators. Reports from China and Italy indicate that 22-64% of critically ill COVID-19 patients with ARDS will die. ARDS currently has no evidence-based treatments other than low tidal ventilation to limit mechanical stress on the lung and prone positioning. A new therapeutic approach capable of rapidly treating and attenuating ARDS secondary to COVID-19 is urgently needed.

The dominant pathologic feature of viral-induced ARDS is fibrin accumulation in the microvasculature and airspaces. Substantial preclinical work suggests antifibrinolytic therapy attenuates infection provoked ARDS. In 2001, a phase I trial 7 demonstrated the urokinase and streptokinase were effective in patients with terminal ARDS, markedly improving oxygen delivery and reducing an expected mortality in that specific patient cohort from 100% to 70%. A more contemporary approach to thrombolytic therapy is tissue plasminogen activator (tPA) due to its higher efficacy of clot lysis with comparable bleeding risk 8. We therefore propose a phase IIa clinical trial with two intravenous (IV) tPA treatment arms and a control arm to test the efficacy and safety of IV tPA in improving respiratory function and oxygenation, and consequently, successful extubation, duration of mechanical ventilation and survival.

Conditions

• Severe Acute Respiratory Syndrome
• Respiratory Failure
• Acute Respiratory Distress Syndrome

Interventions

DRUG

Alteplase 50 MG [Activase]

Patients randomized to Alteplase-50 group will receive 50 mg of Alteplase intravenous bolus administration over 2 hours, given as a 10 mg push followed by the remaining 40 mgs over a total time of 2 hrs. Immediately following the Alteplase infusion, 5000 units (U) of unfractionated heparin (UFH) will be delivered and the heparin drip will be continued to maintain the activated partial thromboplastin time (aPTT) at 60-80sec (2.0 to 2.5 times the upper limit of normal). Re-bolusing of Alteplase, at the same dose, is permitted in the Alteplase-50 intervention group in those patients who show an initial transient response (\>20% improvement of PaO2/FiO2 over pre-infusion of Alteplase at any of the measurements at 2, 6, 12 or 18 hours, but \<50% improvement of PaO2/FiO2 at 24 hours after randomization); the repeat dose will be given between 24 and 36 hours after the initial Alteplase administration.

DRUG

Alteplase 50 MG [Activase]

wed by the remaining 40 mgs over a total time of 2 hrs. Immediately following this initial Alteplase infusion, we will initiate a drip of 2 mg/hr Alteplase over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of 500 units per hour (U/hr) heparin during the Alteplase drip. After this, heparin dose will be increased slowly to maintain aPTT between 60 and 80 sec, titrated per attending's discretion.

Sponsors & Collaborators

• Genentech, Inc.

  collaborator INDUSTRY

• University of Colorado, Denver

  collaborator OTHER

• National Jewish Health

  collaborator OTHER

• Beth Israel Deaconess Medical Center

  collaborator OTHER

• Long Island Jewish Medical Center

  collaborator OTHER

• Scripps Health

  collaborator OTHER

• St. Mary's Medical Center

  collaborator OTHER

• University of Miami

  collaborator OTHER

• Ben Taub Hospital

  collaborator OTHER

• The Methodist Hospital Research Institute

  collaborator OTHER

• Denver Health and Hospital Authority

  lead OTHER

Principal Investigators

• Ernest E Moore, MD · Denver Health Medical Center (DHMC)

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SEQUENTIAL

Eligibility

Min Age

18 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-05-14

Primary Completion

2021-03-21

Completion

2021-09-30

FDA Drug

Yes

Countries

• United States

Study Locations