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

Primary Purpose

Covid19

Status

Suspended

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

TM5614

Placebo

About this trial

This is an interventional treatment trial for Covid19 focused on measuring PAI-1, TM5614, Plasminogen Activator Inhibitor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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
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)
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.

Sites / Locations

Northwestern University

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

TM5614

Placebo

Arm Description

TM5614 30 mg tablets. 6 tablets (180 mg) taken by mouth, once daily for up to 7 days

Placebo tablets. 6 tablets taken by mouth, once daily for up to 7 days

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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).

PAI-1 Levels

Change in circulating levels

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

Full Information

NCT ID

NCT04634799

First Posted

November 17, 2020

Last Updated

May 15, 2023

Sponsor

Northwestern University

1. Study Identification

Unique Protocol Identification Number

NCT04634799

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Suspended

Why Stopped

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

Study Start Date

January 8, 2021 (Actual)

Primary Completion Date

April 23, 2025 (Anticipated)

Study Completion Date

May 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Northwestern University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Covid19

Keywords

PAI-1, TM5614, Plasminogen Activator Inhibitor

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Masking Description

double-blind, randomized (1:1)

Allocation

Randomized

Enrollment

9 (Actual)

8. Arms, Groups, and Interventions

Arm Title

TM5614

Arm Type

Active Comparator

Arm Description

TM5614 30 mg tablets. 6 tablets (180 mg) taken by mouth, once daily for up to 7 days

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo tablets. 6 tablets taken by mouth, once daily for up to 7 days

Intervention Type

Drug

Intervention Name(s)

TM5614

Other Intervention Name(s)

Plasminogen activator inhibitor-1 (PAI-1)

Intervention Description

TM5614 is provided in 30 mg tablets and 6 tablets (180 mg) will be taken in the evening for up to 7 days.

Intervention Type

Other

Intervention Name(s)

Placebo

Other Intervention Name(s)

TM5614 Placebo

Intervention Description

Matching placebo will be provided and participants will take 6 tablets in the evening for up to 7 days.

Primary Outcome Measure Information:

Title

Clinical improvement

Description

Time Frame

7 Days

Secondary Outcome Measure Information:

Title

Sequential organ failure assessment (SOFA) score change

Description

Time Frame

7 Days

Title

PAI-1 Levels

Description

Change in circulating levels

Time Frame

48 hours

Title

Ventilator free days

Description

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

Time Frame

14 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sanjiv Shah, MD

Organizational Affiliation

Northwestern University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Northwestern University

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

32031568

Citation

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.

Results Reference

background

PubMed Identifier

32007143

Citation

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.

Results Reference

background

PubMed Identifier

32109013

Citation

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.

Results Reference

background

PubMed Identifier

32050059

Citation

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.

Results Reference

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

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