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

Sponsor

Northwestern University (Other)

Overall Status

Suspended

CT.gov ID

NCT04634799

Collaborator

(none)

Enrollment

Location

Arms

28.6

Anticipated Duration (Months)

0.3

Patients Per Site Per Month

Study Details

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.

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

9 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 :

Jan 8, 2021

Anticipated Primary Completion Date :

Apr 23, 2023

Anticipated Study Completion Date :

May 30, 2023

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Clinical improvement [7 Days]
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 [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).
PAI-1 Levels [48 hours]
Change in circulating levels
Ventilator free days [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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
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.