Clinical trial NCT04357730: Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection
Official title: Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection: A Phase 2a Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Severe Acute Respiratory Syndrome
Respiratory Failure
Acute Respiratory Distress Syndrome
Keywords: COVID-19
ARDS
SARS-CoV-2
Betacoronavirus
Lead sponsor: Denver Health and Hospital Authority
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
name: University of Colorado, Denver
name: National Jewish Health
name: Beth Israel Deaconess Medical Center
name: Long Island Jewish Medical Center
name: Scripps Health
name: St. Mary's Medical Center
name: University of Miami
name: Ben Taub Hospital
name: The Methodist Hospital Research Institute
First posted: 2020-04-22
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This is a Phase IIa clinical trial, open label, with a modified stepped-wedge design, testing systemic administration of fibrinolytic therapy with alteplase (tPA) versus standard of care for patients infected with COVID-19 resulting in severe respiratory failure. The design is a rapidly adaptive, pragmatic clinical trial, with 3 interim analyses and 1 final look at the data.
Primary purpose: TREATMENT

Brief summary: The global pandemic COVID-19 has overwhelmed the medical capacity to accommodate a large surge of patients with acute respiratory distress syndrome (ARDS). In the United States, the number of cases of COVID-19 ARDS is projected to exceed the number of available ventilators. Reports from China and Italy indicate that 22-64% of critically ill COVID-19 patients with ARDS will die. ARDS currently has no evidence-based treatments other than low tidal ventilation to limit mechanical stress on the lung and prone positioning. A new therapeutic approach capable of rapidly treating and attenuating ARDS secondary to COVID-19 is urgently needed.

The dominant pathologic feature of viral-induced ARDS is fibrin accumulation in the microvasculature and airspaces. Substantial preclinical work suggests antifibrinolytic therapy attenuates infection provoked ARDS. In 2001, a phase I trial 7 demonstrated the urokinase and streptokinase were effective in patients with terminal ARDS, markedly improving oxygen delivery and reducing an expected mortality in that specific patient cohort from 100% to 70%. A more contemporary approach to thrombolytic therapy is tissue plasminogen activator (tPA) due to its higher efficacy of clot lysis with comparable bleeding risk 8. We therefore propose a phase IIa clinical trial with two intravenous (IV) tPA treatment arms and a control arm to test the efficacy and safety of IV tPA in improving respiratory function and oxygenation, and consequently, successful extubation, duration of mechanical ventilation and survival.

Detailed description: As the COVID-19 pandemic accelerates, cases have grown exponentially around the world. Other countries' experience suggests that 5-16% of COVID-19 in-patients will undergo prolonged intensive care with 50-70% needing mechanical ventilation(MV) threatening to overwhelm hospital capacity. ARDS has no effective treatment besides supportive care, the use of ventilation strategies encompassing low tidal volumes that limit trans-pulmonary pressures, and prone positioning in severe disease. Most current trials in clinicaltrials.gov for COVID-19-induced ARDS aim at modulating the inflammatory response or test anti-viral drugs. Sarilumab and tocilizumab that block IL-6 effects are being tested in RCT for patients hospitalized with severe COVID-19 (NCT04317092, NCT04322773, NCT04327388). The World Health Organization international trial SOLIDARITY will test remdesivir; chloroquine + hydroxychloroquine; lopinavir + ritonavir; and lopinavir + ritonavir and interferon-beta (NCT04321616). Yet studies targeting the coagulation system, which is intrinsically intertwined with the inflammatory response are lacking.

A consistent finding in ARDS is the deposition of fibrin in the airspaces and lung parenchyma, along with fibrin-platelet microthrombi in the pulmonary vasculature, which contribute to the development of progressive respiratory dysfunction and right heart failure. Similar to pathologic findings of ARDS, microthrombi have now been observed in lung specimens from patients infected with COVID-19.

Inappropriate activation of the clotting system in ARDS results from enhanced activation and propagation of clot formation as well as suppression of fibrinolysis. Our group has shown that low fibrinolysis is associated with ARDS. Studies starting decades ago have demonstrated the systemic and local effects of dysfunctional coagulation in ARDS, specifically related to fibrin. This occurs largely because of excessive amounts of tissue factor that is produced by alveolar epithelial cells and activated alveolar macrophages, and high levels of plasminogen activator inhibitor-1 (PAI-1) produced and released by endothelial cells. Consistent with this, generalized derangements of the hemostatic system with prolongation of the prothrombin time, elevated D-dimer and fibrin degradation products have been reported in severely ill COVID-19 patients, particularly in non-survivors. These laboratory findings, in combination with the large clot burden seen in the pulmonary microvasculature, mirrors what is seen in human sepsis, experimental endotoxemia, and massive tissue trauma. Targeting the coagulation and fibrinolytic systems to improve the treatment of ARDS has been proposed for at least the past two decades. In particular, the use of plasminogen activators to limit ARDS progression and reduce ARDS-induced death has received strong support from animal models, and a phase 1 human clinical trial. In 2001, Hardaway and colleagues showed that administration of either urokinase or streptokinase to patients with terminal ARDS reduced the expected mortality from 100% to 70% with no adverse bleeding events. Importantly, the majority of patients who ultimately succumbed died from renal or hepatic failure, rather than pulmonary failure.

Consideration of therapies that are widely available but not recognized for this indication and traditionally considered "high-risk" such as fibrinolytic agents is warranted in this unprecedented public health emergency, since the risk of adverse events from tPA is far outweighed by the extremely high risk of death in the patient's meeting the eligibility criteria for this trial. While the prior studies by Hardaway et al evaluating fibrinolytic therapy for treatment of ARDS used urokinase and streptokinase, the more contemporary approach to thrombolytic therapy involves the use of tissue-type plasminogen activator (tPA) due to higher efficacy of clot lysis with comparable bleeding risk to the other fibrinolytic agents.

Eligibility criteria: Inclusion Criteria: We will include adult patients ages 18-75 years old with known or suspected COVID-19 infection with a PaO2/FiO2 ratio \< 150 or inferred PaO2/FiO2 ratio from SpO2 if ABG is unavailable (Table) persisting for \> 4 hours despite optimal mechanical ventilation management according to each institution's ventilation protocols, and a neurological exam without focal signs or new deficits at time of enrollment (if patient is on paralytics, patient has been aroused sufficiently to allow a neurological examination to exclude new focal deficits or has MRI/CT scan in the last 4.5 hours with no evidence of stroke. Finally, patients must be on the ventilator for \<=10 days to be eligible. Based on experience with critically ill patients, longer ventilation time may be associated with increased risk of bleeding. Patients will be enrolled based on clinical features, without consideration of language (using hospital interpreters and translated consent), race/ethnicity, or gender. A neurological exam or CT/MRI scan to demonstrate no evidence of an acute stroke is needed due to a recent case-report of large-vessel stroke as a presenting feature of COVID-19 in young individuals.

Exclusion Criteria:

* Active bleeding
* Acute myocardial infarction or history of myocardial infarction within the past 3 weeks or cardiac arrest during hospitalization
* Hemodynamic instability with Noradrenaline \>0.2mcg/Kg/min
* Acute renal failure requiring dialysis
* Liver failure (escalating liver failure with total Bilirubin \> 3 mg/dL)
* Suspicion of cirrhosis due to history of cirrhosis diagnosis, hepatic encephalopathy, documentation of portal hypertension, bleeding from esophageal varices, ascites, imaging or operative finding suggestive of liver cirrhosis, or constellation of abnormal laboratory test results suggestive of depressed hepatic function
* Cardiac tamponade
* Bacterial endocarditis
* Severe uncontrolled hypertension defined as SBP\>185mmHg or DBP\>110mmHg
* CVA (stroke), history of severe head injury within prior 3 months, or prior history of intracranial hemorrhage
* Seizure during pre-hospital course or during hospitalization for COVID-19
* Diagnosis of brain tumor, arterio-venous malformation (AVM) or ruptured aneurysm
* Currently on ECMO
* Major surgery or major trauma within the past 2 weeks
* GI or GU bleed within the past 3 weeks
* Known bleeding disorder
* P2Y12 receptor inhibitor medication (anti-platelet) within 5 days of enrollment
* Arterial puncture at a non-compressible site within the past 7 days
* Lumbar puncture within past 7 days
* Pregnancy
* INR \> 1.7 (with or without concurrent use of warfarin)
* Platelet count \< 100 x 109/L or history of HITT
* Fibrinogen \< 300mg/dL
* Known abdominal or thoracic aneurysm
* History of CNS malignancy or CNS metastasis within past 5 years
* History of non-CNS malignancy within the past 5 years that commonly metastasizes to the brain (lung, breast, melanoma)
* Prisoner status

Primary outcomes:
measure: PaO2/FiO2 Change (Increase) From Pre-to-post Intervention
timeFrame: at 48 hours post randomization
Secondary outcomes:
measure: Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2
timeFrame: at 48 hours post randomization
measure: National Early Warning Score 2 (NEWS2)
timeFrame: at 48 hours post randomization
measure: 28 Days In-hospital Mortality
timeFrame: 28 days post randomization
measure: ICU-free Days
timeFrame: 28 days of hospital stay or until hospital discharge (whichever comes first)
measure: Ventilator-free Days
timeFrame: 28 days of hospital stay or until hospital discharge (whichever comes first)
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Scripps Memorial Hospital La Jolla
state: California
city: Aurora
country: United States
facility: University of Colorado, Denver
state: Colorado
city: Denver
country: United States
facility: Denver Health Medical Center
state: Colorado
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: West Palm Beach
country: United States
facility: St. Mary's Medical Center
state: Florida
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: New York
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: Dallas
country: United States
facility: Methodist Dallas Medical Center
state: Texas
city: Houston
country: United States
facility: Ben Taub Hospital
state: Texas
Study officials:
affiliation: Denver Health Medical Center (DHMC)
name: Ernest E Moore, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Barrett CD, Moore HB, Moore EE, Wang J, Hajizadeh N, Biffl WL, Lottenberg L, Patel PR, Truitt MS, McIntyre RC Jr, Bull TM, Ammons LA, Ghasabyan A, Chandler J, Douglas IS, Schmidt EP, Moore PK, Wright FL, Ramdeo R, Borrego R, Rueda M, Dhupa A, McCaul DS, Dandan T, Sarkar PK, Khan B, Sreevidya C, McDaniel C, Grossman Verner HM, Pearcy C, Anez-Bustillos L, Baedorf-Kassis EN, Jhunjhunwala R, Shaefi S, Capers K, Banner-Goodspeed V, Talmor DS, Sauaia A, Yaffe MB. Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19: A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized Controlled Trial. Chest. 2022 Mar;161(3):710-727. doi: 10.1016/j.chest.2021.09.024. Epub 2021 Sep 27.
citation: Moore HB, Barrett CD, Moore EE, Jhunjhunwala R, McIntyre RC, Moore PK, Wang J, Hajizadeh N, Talmor DS, Sauaia A, Yaffe MB. Study of alteplase for respiratory failure in severe acute respiratory syndrome coronavirus 2/COVID-19: Study design of the phase IIa STARS trial. Res Pract Thromb Haemost. 2020 Aug 19;4(6):984-996. doi: 10.1002/rth2.12395. eCollection 2020 Aug.