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

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ClinicalTrials.gov Identifier: NCT04634799
Recruitment Status : Recruiting
First Posted : November 18, 2020
Last Update Posted : January 22, 2021
Sponsor:
Information provided by (Responsible Party):
Sanjiv Shah, Northwestern University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Covid19 Drug: TM5614 Other: Placebo Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: double-blind, randomized (1:1)
Primary Purpose: Treatment
Official Title: Study To antagOnize Plasminogen Activator Inhibitor-1 in Severe COVID-19 (STOP Severe COVID-19)
Actual Study Start Date : January 8, 2021
Estimated Primary Completion Date : November 30, 2021
Estimated Study Completion Date : June 30, 2022

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 Name: 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 Name: TM5614 Placebo




Primary Outcome Measures :
  1. Clinical improvement [ Time Frame: 7 Days ]

    Change of at least 2 points in the NIAID-defined ordinal scale (higher scores indicate improved outcome),:

    1. Death
    2. Hospitalized, receiving invasive mechanical ventilation or ECMO
    3. Hospitalized, receiving noninvasive ventilation or high-flow oxygen devices
    4. Hospitalized, requiring low-flow supplemental oxygen
    5. Hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or not related to Covid-19)
    6. Hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that specified in the protocol)
    7. Not hospitalized


Secondary Outcome Measures :
  1. Sequential organ failure assessment (SOFA) score change [ Time Frame: 7 Days ]

    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).


  2. PAI-1 Levels [ Time Frame: 48 hours ]
    Change in circulating levels

  3. Ventilator free days [ Time Frame: 14 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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04634799


Contacts
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Contact: Sanjiv J Shah, MD 312 695 0993 sanjiv.shah@northwestern.edu
Contact: Douglas E Vaughan, MD 312-926-9436 d-vaughan@northwestern.edu

Locations
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United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Lyndsay Christensen, MSN    312-694-0661    lyndsay.christensen@nm.org   
Contact: Anna Huskin, RN    312.695.4067    anna.huskin@nm.org   
Sponsors and Collaborators
Northwestern University
Investigators
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Principal Investigator: Sanjiv Shah, MD Northwestern University
Publications:
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Responsible Party: Sanjiv Shah, Director of Research, Bluhm Cardiovascular Institute, Northwestern University
ClinicalTrials.gov Identifier: NCT04634799    
Other Study ID Numbers: STU00213262
First Posted: November 18, 2020    Key Record Dates
Last Update Posted: January 22, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sanjiv Shah, Northwestern University:
PAI-1
TM5614
Plasminogen Activator Inhibitor
Additional relevant MeSH terms:
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Plasminogen
Plasminogen Activator Inhibitor 1
Plasminogen Inactivators
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors