Enrollment challenges; new batch of drug is being manufactured and there may be additional impetus to reactivate after the analogous Phase 2 study in Japan is completed and those results are made available

This is a single-center, randomized double blind placebo controlled trial to evaluate the efficacy and safety of novel PAI-1 inhibitor (TM5614) for high-risk patients hospitalized with severe COVID-19 at Northwestern Memorial Hospital. The patients will be randomized in a 1:1 ratio to receive standard of care plus TM5614 or standard of care plus placebo.

This project will evaluate the efficacy and safety of a novel small molecule therapy targeting PAI-1 (TM5614) for patients with severe COVID-19. This is a randomized (1:1), double-blinded trial that will enroll adult patients (> 65 years OR <65 years with at least one major cardiometabolic comorbidity [diabetes, hypertension, or cardiovascular disease]) with COVID-19 requiring supplemental oxygen. The study intervention will be a small molecule inhibitor of PAI-1, TM5614, up to 180 mg, compared to matching placebo for up to 7 days.

Research blood samples for PAI-1 and C-reactive protein (CRP) will be collected at time of enrollment, 48 hours after 1st dose of medication and at day 7 or discharge, whichever comes first.

These objectives will allow for the planning of subsequent phase 3 study, and strengthen implementation of a multi-center randomized trial should this study confirm safety, and suggest efficacy of therapy.

Inclusion Criteria:

1. Adults ≥65 years old or < 65 years old AND at least one major cardiometabolic comorbidity (diabetes, hypertension, or cardiovascular disease)
2. Established diagnosis of COVID-19 as evidenced by a positive nasopharyngeal or bronchoalveolar lavage viral PCR for SARS-CoV2
3. Requiring supplemental oxygen

Exclusion Criteria:

1. Age <18 years old

2. Pregnancy or breast-feeding

3. Known contraindication to tissue plasminogen activator (tPA), including

   1. Active internal bleeding
   2. History of cerebrovascular accident
   3. Recent intracranial or intraspinal surgery or trauma
   4. Intracranial neoplasm, arteriovenous malformation or aneurysm
   5. Known bleeding diathesis
   6. Severe uncontrolled hypertension (SBP>200 persistently >12 hours)

4. Currently receiving therapeutic dose anticoagulation (specifically will exclude those with potential drug-drug interaction such as heparin, apixaban, warfarin)

5. Platelets <50,000

6. Hematocrit <30%

7. Not hemodynamically stable in the preceding 4 hours (symptomatic hypotension or systolic BP <95 mmHg at 2 out of 3 measurements)

8. Concomitant illness, physical impairment or mental condition which in the opinion of the study team / primary care physician could interfere with the conduct of the study including outcome assessment

9. Other patient characteristics (not thought to be related to COVID-19) that portend a very poor prognosis (e.g., severe liver failure, metastatic malignancy)

10. Participation in a concurrent interventional medical investigation or pharmacologic clinical trial. Patients in observational, natural history or epidemiological studies not involving an intervention are eligible.

11. Participant's responsible attending physician believes it is not appropriate for participant to participate in the study.

12. Inability or unwillingness to provide written informed consent

13. Involvement in the planning and/or conduct of the study

14. Previous randomization in the present study

15. Unable to complete study procedures.

16. Patients with active venothromboembolic disease

17. Patients who are receiving other investigational agents for COVID-19.

double-blind, randomized (1:1)