Study to AntagOnize Plasminogen Activator Inhibitor-1 in Severe COVID-19

Study to AntagOnize Plasminogen Activator Inhibitor-1 in Severe COVID-19 (STOP Severe COVID-19)

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.

Study Overview

• Status: Suspended
• Conditions: Covid19
• Intervention / Treatment: Drug: TM5614; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Northwestern University
• Investigators: Principal Investigator: Sanjiv Shah, MD, Northwestern University

Publications and helpful links

General Publications

• Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30.
• Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
• Chang D, Lin M, Wei L, Xie L, Zhu G, Dela Cruz CS, Sharma L. Epidemiologic and Clinical Characteristics of Novel Coronavirus Infections Involving 13 Patients Outside Wuhan, China. JAMA. 2020 Mar 17;323(11):1092-1093. doi: 10.1001/jama.2020.1623.
• Liu YC, Liao CH, Chang CF, Chou CC, Lin YR. A Locally Transmitted Case of SARS-CoV-2 Infection in Taiwan. N Engl J Med. 2020 Mar 12;382(11):1070-1072. doi: 10.1056/NEJMc2001573. Epub 2020 Feb 12. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2021
• Primary Completion (Estimated): April 23, 2025
• Study Completion (Estimated): May 30, 2025

Study Registration Dates

• First Submitted: November 17, 2020
• First Submitted That Met QC Criteria: November 17, 2020
• First Posted (Actual): November 18, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 27, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: PAI-1; TM5614; Plasminogen Activator Inhibitor
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Fibrin Modulating Agents; Fibrinolytic Agents; Serine Proteinase Inhibitors; Plasminogen; Plasminogen Inactivators; Plasminogen Activator Inhibitor 1
• Other Study ID Numbers: STU00213262

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No