Study To antagOnize Plasminogen Activator Inhibitor-1 in Severe COVID-19

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Study To antagOnize Plasminogen Activator Inhibitor-1 in Severe COVID-19 (STOP Severe COVID-19)

Conditions
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Covid19

Intervention / Treatment
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* Drug: TM5614
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults ≥65 years old or < 65 years old AND at least one major cardiometabolic comorbidity (diabetes, hypertension, or cardiovascular disease) Established diagnosis of COVID-19 as evidenced by a positive nasopharyngeal or bronchoalveolar lavage viral PCR for SARS-CoV2 Requiring supplemental oxygen Exclusion Criteria: Age <18 years old Pregnancy or breast-feeding Known contraindication to tissue plasminogen activator (tPA), including Active internal bleeding History of cerebrovascular accident Recent intracranial or intraspinal surgery or trauma Intracranial neoplasm, arteriovenous malformation or aneurysm Known bleeding diathesis Severe uncontrolled hypertension (SBP>200 persistently >12 hours) Currently receiving therapeutic dose anticoagulation (specifically will exclude those with potential drug-drug interaction such as heparin, apixaban, warfarin) Platelets <50,000 Hematocrit <30% Not hemodynamically stable in the preceding 4 hours (symptomatic hypotension or systolic BP <95 mmHg at 2 out of 3 measurements) 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 Other patient characteristics (not thought to be related to COVID-19) that portend a very poor prognosis (e.g., severe liver failure, metastatic malignancy) 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. Participant's responsible attending physician believes it is not appropriate for participant to participate in the study. Inability or unwillingness to provide written informed consent Involvement in the planning and/or conduct of the study Previous randomization in the present study Unable to complete study procedures. Patients with active venothromboembolic disease Patients who are receiving other investigational agents for COVID-19.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: TM5614<br>TM5614 30 mg tablets. 6 tablets (180 mg) taken by mouth, once daily for up to 7 days | Drug: TM5614<br>* TM5614 is provided in 30 mg tablets and 6 tablets (180 mg) will be taken in the evening for up to 7 days.<br>* Other names: Plasminogen activator inhibitor-1 (PAI-1);|
| Placebo Comparator: Placebo<br>Placebo tablets. 6 tablets taken by mouth, once daily for up to 7 days | Other: Placebo<br>* Matching placebo will be provided and participants will take 6 tablets in the evening for up to 7 days.<br>* Other names: TM5614 Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical improvement | Change of at least 2 points in the NIAID-defined ordinal scale (higher scores indicate improved outcome),: Death Hospitalized, receiving invasive mechanical ventilation or ECMO Hospitalized, receiving noninvasive ventilation or high-flow oxygen devices Hospitalized, requiring low-flow supplemental oxygen Hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or not related to Covid-19) Hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that specified in the protocol) Not hospitalized | 7 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sequential organ failure assessment (SOFA) score change | Change in degree of organ dysfunction as defined by the Sequential Organ Failure Assessment (SOFA) Score. The SOFA score ranges from 0 to 24 (higher scores indicate more severe organ failure), with 0 to 4 points assigned for each of 6 organ dysfunctions (ie, central nervous system, cardiovascular, respiratory, renal, coagulation, and liver). | 7 Days | 
| PAI-1 Levels | Change in circulating levels | 48 hours | 
| Ventilator free days | For subjects who received mechanical ventilation, total number of days the subject was not on mechanical or non invasive mechanical ventilation while in the hospital | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PAI-1, TM5614, Plasminogen Activator Inhibitor