Clinical trial NCT04634799: 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
Overall status: SUSPENDED
Phase: PHASE1
PHASE2
Conditions: Covid19
Keywords: PAI-1
TM5614
Plasminogen Activator Inhibitor
Lead sponsor: Northwestern University
Sponsor class: OTHER
First posted: 2020-11-18
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Clinical improvement
timeFrame: 7 Days
Secondary outcomes:
measure: Sequential organ failure assessment (SOFA) score change
timeFrame: 7 Days
measure: PAI-1 Levels
timeFrame: 48 hours
measure: Ventilator free days
timeFrame: 14 days
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
Study officials:
affiliation: Northwestern University
name: Sanjiv Shah, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.