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.
Drug: TM5614
TM5614 is provided in 30 mg tablets and 6 tablets (180 mg) will be taken in the evening for up to 7 days.
Other Name: Plasminogen activator inhibitor-1 (PAI-1)
Other: Placebo
Matching placebo will be provided and participants will take 6 tablets in the evening for up to 7 days.
Other Name: TM5614 Placebo
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.
Northwestern University
Chicago, Illinois, United States
Sanjiv Shah, MD, Principal Investigator
Northwestern University