Severe Acute Respiratory SyndromePhase 2NCT04357730
Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection
A Phase 2 study testing Alteplase 50 MG [Activase] in people with Severe Acute Respiratory Syndrome and Respiratory Failure, run by Denver Health and Hospital Authority at 9 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Severe Acute Respiratory Syndrome, Respiratory Failure, Acute Respiratory Distress Syndrome
- What is being tested?
- Alteplase 50 MG [Activase]
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 9 sitesUnited States
- Study dates
- 14 May 2020to 30 Sep 2021
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
None listed.
Who cannot join
- 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
Show all 27Show fewer
- 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
Trial locations and contacts
9 sites in 1 country.
9 sites in 1 country
United States9 sites
University of Colorado, Denver
Aurora, Colorado, 80045
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Methodist Dallas Medical Center
Dallas, Texas, 75203
Denver Health Medical Center
Denver, Colorado, 80204
National Jewish Health
Denver, Colorado, 80206
Ben Taub Hospital
Houston, Texas, 77030
Scripps Memorial Hospital La Jolla
La Jolla, California, 92037
Long Island Jewish Medical Center
New York, New York, 11040
St. Mary's Medical Center
West Palm Beach, Florida, 33407
About this study
Official title: Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection: A Phase 2a Clinical Trial
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.
Read the 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
- Being tested
- Alteplase 50 MG [Activase]
- Keywords
- COVID-19, ARDS, SARS-CoV-2, Betacoronavirus
- Medical subject headings
- Severe Acute Respiratory Syndrome, Respiratory Insufficiency, Respiratory Distress Syndrome, COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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 MG [Activase]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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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). Receives: Drug: Alteplase 50 MG [Activase] |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: at 48 hours post randomization
Secondary outcomes (5)
Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2
Number of Participants with Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2 (whatever is lower)
Measured: at 48 hours post randomization
National Early Warning Score 2 (NEWS2)
NEWS2 is a standardised clinical scoring system developed to improve detection of deterioration in acutely ill patients. It is based on aggregate scoring of six physiological parameters; respiratory rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness or new confusion, and body temperature. A NEWS2 score of 5 or 6 is considered a key threshold that may indicate clinical deterioration and should prompt urgent response by a clinician or a team with competence in assessment and treatment of acutely ill patients.The total score range is 0 to 20.
Measured: at 48 hours post randomization
28 Days In-hospital Mortality
28 days mortality for hospitalized patients
Measured: 28 days post randomization
ICU-free Days
ICU-free days will be calculated based on (28 - number of days spent in the ICU) formula
Measured: 28 days of hospital stay or until hospital discharge (whichever comes first)
Ventilator-free Days
Ventilator-free days will be calculated based on (28 - number of days on mechanical ventilation) formula.
Measured: 28 days of hospital stay or until hospital discharge (whichever comes first)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Apr 2020
- Study start14 May 2020
- Primary completion21 Mar 2021
- Study completion30 Sep 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Severe Acute Respiratory SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- 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.
- Masking
- None (open label)
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- Denver Health and Hospital Authority
- Sponsor type
- University, hospital or other
- Collaborators
- Genentech, Inc., University of Colorado, Denver, National Jewish Health, Beth Israel Deaconess Medical Center, Long Island Jewish Medical Center, Scripps Health, St. Mary's Medical Center, University of Miami, Ben Taub Hospital, The Methodist Hospital Research Institute
- Responsible party
- Principal investigator, Ernest E. Moore, MD, Denver Health and Hospital Authority
- Investigators
- Ernest E Moore, MD, Principal investigator, Denver Health Medical Center (DHMC)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04357730
- Sponsor's protocol ID
- 20-0880
- Status last verified
- Jan 2022
- First submitted
- 18 Apr 2020
- Last updated
- 20 Jan 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: A de-identified dataset will be made available to other investigators who may submit proposals to the PI for additional analyses or validation.
Publications
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.
PubMed 34592318Moore 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.
PubMed 32838109
Study at a glance
From the registry record, last updated by the sponsor on 20 Jan 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection: A Phase 2a Clinical Trial
- ClinicalTrials.gov ID
- NCT04357730
- Acronym / sponsor ID
- 20-0880
- Conditions
- Severe Acute Respiratory Syndrome, Respiratory Failure, Acute Respiratory Distress Syndrome
- Keywords
- COVID-19, ARDS, SARS-CoV-2, Betacoronavirus
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- Denver Health and Hospital AuthorityUniversity, hospital or other
- Collaborators
- Genentech, Inc., University of Colorado, Denver, National Jewish Health, Beth Israel Deaconess Medical Center, Long Island Jewish Medical Center, Scripps Health, St. Mary's Medical Center, University of Miami, Ben Taub Hospital, The Methodist Hospital Research Institute
- Study start
- 14 May 2020 (actual)
- Primary completion
- 21 Mar 2021 (actual)
- Study completion
- 30 Sep 2021 (actual)
- First posted
- 22 Apr 2020 (actual)
- Results
- Posted 20 Jan 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
- 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.
| Arm | Type | Receives |
|---|---|---|
| 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 | Drug: Alteplase 50 MG [Activase]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. |
| Alteplase-50 bolus plus drip | Experimental | Drug: Alteplase 50 MG [Activase]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). |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (0 listed)
Key exclusion criteria (27 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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. | Drug | Alteplase-50 bolus |
| 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. | Drug | Alteplase-50 bolus plus drip |
Primary outcome
PaO2/FiO2 Change (Increase) From Pre-to-post Intervention
Time frame: at 48 hours post randomization
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.
5 secondary outcomes
Achievement of PaO2/FiO2 ≥ 200 or 50% Increase in PaO2/FiO2
Time frame: at 48 hours post randomization
National Early Warning Score 2 (NEWS2)
Time frame: at 48 hours post randomization
28 Days In-hospital Mortality
Time frame: 28 days post randomization
ICU-free Days
Time frame: 28 days of hospital stay or until hospital discharge (whichever comes first)
Ventilator-free Days
Time frame: 28 days of hospital stay or until hospital discharge (whichever comes first)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Jan 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34592318Barrett 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.
- Derived from this study: PubMed 32838109Moore 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.
- Individual participant dataSharing planned: Yes. A de-identified dataset will be made available to other investigators who may submit proposals to the PI for additional analyses or validation.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ernest E Moore, MD principal investigator
Denver Health Medical Center (DHMC)
9 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Alteplase 50 MG [Activase] in people with Severe Acute Respiratory Syndrome and Respiratory Failure, run by Denver Health and Hospital Authority at 9 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 0 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Jan 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
PaO2/FiO2 Change (Increase) From Pre-to-post Intervention (time frame: at 48 hours post randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04357730, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Jan 2022.