NCT04357730

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
50

participants targeted

Target at P25-P50 for phase_2

Timeline
Completed

Started May 2020

Shorter than P25 for phase_2

Geographic Reach
1 country

9 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

April 18, 2020

Completed
4 days until next milestone

First Posted

Study publicly available on registry

April 22, 2020

Completed
22 days until next milestone

Study Start

First participant enrolled

May 14, 2020

Completed
10 months until next milestone

Primary Completion

Last participant's last visit for primary outcome

March 21, 2021

Completed
6 months until next milestone

Study Completion

Last participant's last visit for all outcomes

September 30, 2021

Completed
4 months until next milestone

Results Posted

Study results publicly available

January 20, 2022

Completed
Last Updated

January 20, 2022

Status Verified

January 1, 2022

Enrollment Period

10 months

First QC Date

April 18, 2020

Results QC Date

November 7, 2021

Last Update Submit

January 18, 2022

Conditions

Severe Acute Respiratory SyndromeRespiratory FailureAcute Respiratory Distress Syndrome

Keywords

COVID-19ARDSSARS-CoV-2Betacoronavirus

Outcome Measures

Primary Outcomes (1)

  • PaO2/FiO2 Change (Increase) From Pre-to-post Intervention

    PaO2/FiO2 change (increase) from pre-to-post intervention at 48 hours post randomization. Ideally, the PaO2/FiO2 will be measured with the patient in the same prone/supine position as in baseline, as change in positions may artificially reduce the change (increase) attributable to the study drug. However, given the pragmatic nature of the trial, the prone/supine position will be determined by the attending physician, in which case, we will use as an outcome the PaO2/FiO2 closest to the 48 hours obtained prior to the change in position as the outcome.

    at 48 hours post randomization

Secondary Outcomes (5)

  • Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2

    at 48 hours post randomization

  • National Early Warning Score 2 (NEWS2)

    at 48 hours post randomization

  • 28 Days In-hospital Mortality

    28 days post randomization

  • ICU-free Days

    28 days of hospital stay or until hospital discharge (whichever comes first)

  • Ventilator-free Days

    28 days of hospital stay or until hospital discharge (whichever comes first)

Study Arms (3)

Control

NO INTERVENTION

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.

Alteplase-50 bolus

EXPERIMENTAL

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.

Drug: Alteplase 50 MG [Activase]

Alteplase-50 bolus plus drip

EXPERIMENTAL

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).

Drug: Alteplase 50 MG [Activase]

Interventions

Alteplase 50 MG [Activase]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

Eligibility Criteria

Age18 Years - 75 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may not qualify if:

  • 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
  • +12 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (9)

Scripps Memorial Hospital La Jolla

La Jolla, California, 92037, United States

Location

University of Colorado, Denver

Aurora, Colorado, 80045, United States

Location

Denver Health Medical Center

Denver, Colorado, 80204, United States

Location

National Jewish Health

Denver, Colorado, 80206, United States

Location

St. Mary's Medical Center

West Palm Beach, Florida, 33407, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Long Island Jewish Medical Center

New York, New York, 11040, United States

Location

Methodist Dallas Medical Center

Dallas, Texas, 75203, United States

Location

Ben Taub Hospital

Houston, Texas, 77030, United States

Location

Related Publications (2)

  • 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.

    PMID: 34592318DERIVED

  • 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.

    PMID: 32838109DERIVED

MeSH Terms

Conditions

Severe Acute Respiratory SyndromeRespiratory InsufficiencyRespiratory Distress SyndromeCOVID-19

Interventions

Tissue Plasminogen Activator

Condition Hierarchy (Ancestors)

Respiratory Tract InfectionsInfectionsCoronavirus InfectionsCoronaviridae InfectionsNidovirales InfectionsRNA Virus InfectionsVirus DiseasesRespiratory Tract DiseasesRespiration DisordersLung DiseasesPneumonia, ViralPneumonia

Intervention Hierarchy (Ancestors)

Serine EndopeptidasesEndopeptidasesPeptide HydrolasesHydrolasesEnzymesEnzymes and CoenzymesSerine ProteasesPlasminogen ActivatorsBlood Coagulation FactorsBlood ProteinsProteinsAmino Acids, Peptides, and ProteinsBiological Factors

Results Point of Contact

Title
Dr. Ernest Moore, Director of Surgical Research
Organization
Denver Health Medical Center
ernest.moore@dhha.org
3036021820

Study Officials

  • Ernest E Moore, MD

    Denver Health Medical Center (DHMC)

    PRINCIPAL INVESTIGATOR

Publication Agreements

PI is Sponsor Employee
No
Restrictive Agreement
No

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
SEQUENTIAL
Model Details: 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.
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Director of Surgical Research, Ernest E Moore Shock Trauma Center at Denver Health

Study Record Dates

First Submitted

April 18, 2020

First Posted

April 22, 2020

Study Start

May 14, 2020

Primary Completion

March 21, 2021

Study Completion

September 30, 2021

Last Updated

January 20, 2022

Results First Posted

January 20, 2022

Record last verified: 2022-01

Data Sharing

IPD Sharing
Will share

A de-identified dataset will be made available to other investigators who may submit proposals to the PI for additional analyses or validation.

Shared Documents
STUDY PROTOCOL, SAP, ICF

Locations

US(9)