Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection

NCT ID: NCT04357730

Last Updated: 2022-01-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-05-14
• Study Completion Date: 2021-09-30

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.

Conditions

Severe Acute Respiratory Syndrome; Respiratory Failure; Acute Respiratory Distress Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Control

Patients randomized to Control arm will receive no study medication; the treatment will be standard of care according to the institution's protocol for ARDS.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Alteplase-50 bolus

Patients randomized to Alteplase-50 group will receive 50 mg of Alteplase intravenous bolus administration over 2 hours. Re-bolusing of Alteplase, at the same dose, is permitted in those patients who show an initial transient response. The repeat dose will be given between 24 and 36 hours after the initial Alteplase administration.

Group Type: EXPERIMENTAL

Alteplase 50 MG [Activase]

Intervention Type: DRUG

Patients randomized to Alteplase-50 group will receive 50 mg of Alteplase intravenous bolus administration over 2 hours, given as a 10 mg push followed by the remaining 40 mgs over a total time of 2 hrs. Immediately following the Alteplase infusion, 5000 units (U) of unfractionated heparin (UFH) will be delivered and the heparin drip will be continued to maintain the activated partial thromboplastin time (aPTT) at 60-80sec (2.0 to 2.5 times the upper limit of normal). Re-bolusing of Alteplase, at the same dose, is permitted in the Alteplase-50 intervention group in those patients who show an initial transient response (\>20% improvement of PaO2/FiO2 over pre-infusion of Alteplase at any of the measurements at 2, 6, 12 or 18 hours, but \<50% improvement of PaO2/FiO2 at 24 hours after randomization); the repeat dose will be given between 24 and 36 hours after the initial Alteplase administration.

Alteplase-50 bolus plus drip

Patients randomized to Alteplase-50 plus drip group will receive 50 mg of Alteplase intravenous bolus administration over 2 hours. Immediately following this initial Alteplase infusion, a drip of 2 mg/hr of Alteplase will be initiated over the ensuing 24 hours (total 48 mg infusion).

Group Type: EXPERIMENTAL

Alteplase 50 MG [Activase]

Intervention Type: DRUG

wed by the remaining 40 mgs over a total time of 2 hrs. Immediately following this initial Alteplase infusion, we will initiate a drip of 2 mg/hr Alteplase over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of 500 units per hour (U/hr) heparin during the Alteplase drip. After this, heparin dose will be increased slowly to maintain aPTT between 60 and 80 sec, titrated per attending's discretion.

Interventions

Alteplase 50 MG [Activase]

Patients randomized to Alteplase-50 group will receive 50 mg of Alteplase intravenous bolus administration over 2 hours, given as a 10 mg push followed by the remaining 40 mgs over a total time of 2 hrs. Immediately following the Alteplase infusion, 5000 units (U) of unfractionated heparin (UFH) will be delivered and the heparin drip will be continued to maintain the activated partial thromboplastin time (aPTT) at 60-80sec (2.0 to 2.5 times the upper limit of normal). Re-bolusing of Alteplase, at the same dose, is permitted in the Alteplase-50 intervention group in those patients who show an initial transient response (\>20% improvement of PaO2/FiO2 over pre-infusion of Alteplase at any of the measurements at 2, 6, 12 or 18 hours, but \<50% improvement of PaO2/FiO2 at 24 hours after randomization); the repeat dose will be given between 24 and 36 hours after the initial Alteplase administration.

Intervention Type: DRUG

Alteplase 50 MG [Activase]

wed by the remaining 40 mgs over a total time of 2 hrs. Immediately following this initial Alteplase infusion, we will initiate a drip of 2 mg/hr Alteplase over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of 500 units per hour (U/hr) heparin during the Alteplase drip. After this, heparin dose will be increased slowly to maintain aPTT between 60 and 80 sec, titrated per attending's discretion.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: collaborator

National Jewish Health

OTHER

Sponsor Role: collaborator

Beth Israel Deaconess Medical Center

OTHER

Sponsor Role: collaborator

Long Island Jewish Medical Center

OTHER

Sponsor Role: collaborator

Scripps Health

OTHER

Sponsor Role: collaborator

St. Mary's Medical Center

OTHER

Sponsor Role: collaborator

University of Miami

OTHER

Sponsor Role: collaborator

Ben Taub Hospital

OTHER

Sponsor Role: collaborator

The Methodist Hospital Research Institute

OTHER

Sponsor Role: collaborator

Denver Health and Hospital Authority

OTHER

Sponsor Role: lead

Responsible Party

Ernest E. Moore, MD

Director of Surgical Research, Ernest E Moore Shock Trauma Center at Denver Health

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ernest E Moore, MD

Role: PRINCIPAL_INVESTIGATOR

Denver Health Medical Center (DHMC)

Locations

Scripps Memorial Hospital La Jolla

La Jolla, California, United States

University of Colorado, Denver

Aurora, Colorado, United States

Denver Health Medical Center

Denver, Colorado, United States

National Jewish Health

Denver, Colorado, United States

St. Mary's Medical Center

West Palm Beach, Florida, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Long Island Jewish Medical Center

New York, New York, United States

Methodist Dallas Medical Center

Dallas, Texas, United States

Ben Taub Hospital

Houston, Texas, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 34592318 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32838109 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

20-0880

Identifier Type: -

Identifier Source: org_study_id