COVID-19 Pneumonia
Conditions
Keywords
Uproleselan, Selectin Inhibitor
Brief summary
The purpose of this study is to find out whether the drug uproleselan can help patients with severe COVID-19 pneumonia. Investigators will study both the side effects of the drug and assess if the drug will help patients recover more quickly and slow down the progression of acute respiratory failure.
Detailed description
Soluble E-selectin is a significant biomarker for adult respiratory distress syndrome (ARDS). Soluble E-selectin also has pro-inflammatory properties further releasing cytokines and promoting its synthesis and the continued influx of neutrophils. Small molecule glycomimetic antagonists of E-selectin (rivipansel and uproleselan) are 500- to 1000-fold more potent inhibitors of E-selectin and have shown activity and no measurable toxicity in human clinical trials for other indications. Treatment with these E-selectin inhibitors reduced the levels of soluble E-selectin in the bloodstream which occurs during recovery of ARDS. Thus, antagonists of E-selectin which include glycomimetic antagonists and more specifically, rivipansel (GMI-1070) and uproleselan (GMI-1271), may be used to treat COVID-19 patients with respiratory symptoms that may lead to ARDS Primary Objective: Safety of uproleselan in patients with severe COVID-19 pneumonia. Secondary Objectives: To evaluate if treatment with uproleselan administered intravenously in addition to the best available therapy according to institutional guidelines is able to reduce the progression of acute respiratory failure, in patients with severe COVID-19 pneumonia. * To evaluate proportion of patients alive and free of respiratory failure through Day 28 * To evaluate overall survival and all-cause mortality at day 15 and 28. * To evaluate changes in the COVID ordinal outcomes scale. * To assess adverse events to evaluate the safety of uproleselan. * To assess ventilator-free days, ICU-free days, oxygen, vasopressor free days. * To evaluate changes in D-dimer. Exploratory Objectives: * To examine the correlation of plasma soluble E-selectin concentrations with clinical outcomes. * To examine the correlations of other biomarkers of interest with clinical outcome. Previous versions of this record mistakenly suggested the trial would assess the number of participants who experienced a Grade 3-5 hemorrhagic event. The outcome title has been corrected to state the number of participants with a Grade 3-4 hemorrhagic event were assessed, as the scale used does not go to Grade 5.
Interventions
DRUGUproleselan
Uproleselan 20 mg/kg BID up to maximum dose of 2500 mg, infused IV over 20 minutes on days 1-7 or until hospital discharge. It should be administered intravenously (IV) into a peripheral line, a central catheter, or a peripherally inserted central line catheter (PICC). Infusion should take place at a steady rate over a period of 20 minutes ±2 minutes using a syringe pump or IV pump.
Sponsors
Lena Napolitano, MD
GlycoMimetics Incorporated
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a prospective, interventional, single-arm, open label trial, with 1:1 matched de-identified retrospective control cohort.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Documented COVID-19 pneumonia: defined as upper respiratory tract specimen (nasopharyngeal swab (NPS) or viral throat swab) positive for COVID-19 and/or imaging at computed tomography scan suggestive of COVID-19 pneumonia. * Confirmed coronavirus (SARS-CoV-2) (positive real-time reverse transcription polymerase chain reaction test (RT-PCR) for SARS-CoV-2 within 72 hours) enrolled ≤ 48 hours of need for supplemental oxygen. * Currently hospitalized requiring supplemental oxygen. * Have severe COVID-19 according to the World Health Organization (WHO) Interim Guidance with confirmation by real-time RT-PCR assay. The enrollment criteria with one of the following: respiratory distress, respiratory rate (RR) ≥30 beats/min; oxygen saturation level less than 93% in resting state; or partial pressure of oxygen (PaO2)/oxygen concentration (FiO2) ≤ 300 mmHg. * Willing and able to participate in all required evaluations and procedures.
Exclusion criteria
* In the opinion of at least two investigators, unlikely to survive for \>48 hours from screening. * Severe chronic respiratory disease (e.g. Chronic obstructive pulmonary disease or other) requiring supplemental oxygen and/or having required mechanical ventilation pre-COVID-19 infection. * Concurrent enrollment in a COVID related interventional drug trial. Use of remdesivir, steroids, and convalescent plasma are permitted along with other standard of care therapies for COVID.37 * Currently on invasive mechanical ventilation. * Hypotension defined as systolic blood pressure \< 90 mmHg on two sequential readings at least 4 hours apart. * Total Bilirubin ≤ 3 x upper limit of normal (ULN), Creatinine Clearance ≥ 30 mL/min/1.73m2. * Pregnant or breastfeeding. * Known diagnosis of an acute thrombosis on admission. * Concurrent dual antithrombotic therapy (aspirin or P2Y12 inhibitor plus anticoagulation to treat deep venous thrombosis or pulmonary embolism (single antiplatelet or anticoagulant agent at prophylactic dose is permitted). * Concomitant use of thrombolytic therapy. * Concomitant therapeutic systemic anticoagulant therapy (e.g. heparin, warfarin, direct thrombin inhibitors and direct factor Xa inhibitors). As per NIH Guidelines: Hospitalized adults with COVID-19 should receive Venous thromboembolism (VTE) prophylaxis per the standard of care for other hospitalized adults (AIII). Anticoagulant or antiplatelet therapy should not be used to prevent arterial thrombosis outside of the usual standard of care for patients without COVID-19 (AIII); https://www.covid19treatmentguidelines.nih.gov/therapeutic-management/ * History of recent major bleeding, defined in accordance with the criteria of the International Society on Thrombosis and Hemostasis (ISTH). * History of bleeding disorder thought to impose excessive bleeding risk as per investigator discretion * Hemodynamic instability, defined as inability to maintain mean arterial pressure. * Hypersensitivity to the active substance or to any of the excipients of uproleselan. * Any physical examination findings and/or history of any illness that, in the opinion of the investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Uproleselan - as Measured by Serious Adverse Events | Up to 28 days | Descriptive statistics will be calculated for quantitative safety data |
| Safety of Uproleselan- as Measured by Frequency of Serious Adverse Events | Up to 28 days | Frequency counts will be compiled for classification of qualitative safety data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality | Up to 28 days | All-cause hospital mortality |
| Time to Change Oxygenation | during hospitalization; hospital stay ranged from 2 to 10 days | Number of days it took to reduce their oxygen requirements |
| Number of Patients Requiring Mechanical Ventilation | Up to 28 days | Number of patients requiring mechanical ventilation |
| Change in the World Health Organization (WHO) COVID-19, 8-point Ordinal Scale as Shown by Presenting Selected Time Points Through Day 28 | Enrollment, day 28 | WHO COVID-19, 8-point ordinal scale has a range of 1-8 with higher numbers indicating a more severe disease. |
| Actual Duration of Hospitalization | Up to 28 days | Duration of hospitalization - number of inpatient hospital days. Participants were planned to be followed for up to 28 days, although the longest actual hospital stay for a participant was 10 days. |
| Change in the Progression to Acute Respiratory Failure for Patients With a Baseline PaO2/FiO2 >= 200 | Enrollment, 15 days | Patients with a baseline PaO2/FiO2 \>= 200: progression of respiratory failure is defined by: 1. severe gas transfer deficit (PaO2/FiO2 \< 200); 2. persistent respiratory distress while receiving oxygen (persistent marked dyspnea, use of accessory respiratory muscles, paradoxical respiratory movements); The rate will be calculated as the proportion of patients who experienced at least one of the events above by day+15 from treatment start. |
| Participants Who Experienced Grade 3-4 Hemorrhagic Events | Up to 28 days | Number of participants who experienced a Grade 3 or Grade 4 hemorrhagic event based on the World Health Organization's (WHO) Bleeding Scale. On the scale, a Grade 3 event means gross blood loss, and a Grade 4 event means debilitating blood loss. |
| Change in E-selectin Plasma Concentrations, as Shown by Values for Each of Those Days | 6 Days | Changes in E-selectin plasma concentrations measured each day for 6 days. |
| Participants Who Experienced Venous Thromboembolism (Deep Venous Thrombosis or Pulmonary Embolism) | Enrollment, up to day 28 | Venous thromboembolism - DVT or PE |
| Number of Mechanical Ventilation and Vasopressor Days | Up to Day 28 | Days of mechanical ventilation and days of vasopressors |
| Actual Duration of ICU Care | Up to 28 days | Duration of ICU stay - number of ICU days. Participants were planned to be followed for up to 28 days, although the longest actual hospital stay for a participant was 10 days. |
| Number of Patients Alive Who Are Free of Respiratory Failure | Up to 28 days | Number of patients alive and free of acute respiratory failure which required initiation of mechanical ventilation |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Uproleselan Uproleselan injection is a sterile solution for IV administration, supplied in single-dose vials at a concentration of 50 mg/mL.
Uproleselan: Uproleselan 20 mg/kg BID up to maximum dose of 2500 mg, infused IV over 20 minutes on days 1-7 or until hospital discharge. It should be administered intravenously (IV) into a peripheral line, a central catheter, or a peripherally inserted central line catheter (PICC). Infusion should take place at a steady rate over a period of 20 minutes ±2 minutes using a syringe pump or IV pump. | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Uproleselan | — |
|---|---|---|
| Age, Continuous | 56.5 years STANDARD_DEVIATION 13.7 | — |
| Body Mass Index (BMI | 37.21 Kg/m^2 STANDARD_DEVIATION 10.36 | — |
| E-selectin Plasma Concentrations | 15.83 nanograms divided by milliliters STANDARD_DEVIATION 6.479 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 6 participants | — |
| Sex: Female, Male Female | 2 Participants | — |
| Sex: Female, Male Male | 4 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 3 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
Safety of Uproleselan- as Measured by Frequency of Serious Adverse Events
Frequency counts will be compiled for classification of qualitative safety data.
Time frame: Up to 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Uproleselan | Safety of Uproleselan- as Measured by Frequency of Serious Adverse Events | 0 daily events |
Primary
Safety of Uproleselan - as Measured by Serious Adverse Events
Descriptive statistics will be calculated for quantitative safety data
Time frame: Up to 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Uproleselan | Safety of Uproleselan - as Measured by Serious Adverse Events | 0 Serious Adverse Events |
Secondary
Actual Duration of Hospitalization
Duration of hospitalization - number of inpatient hospital days. Participants were planned to be followed for up to 28 days, although the longest actual hospital stay for a participant was 10 days.
Time frame: Up to 28 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Uproleselan | Actual Duration of Hospitalization | 4.67 days | Standard Deviation 2.56 |
Secondary
Actual Duration of ICU Care
Duration of ICU stay - number of ICU days. Participants were planned to be followed for up to 28 days, although the longest actual hospital stay for a participant was 10 days.
Time frame: Up to 28 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Uproleselan | Actual Duration of ICU Care | 1.33 days | Standard Deviation 1.89 |
Secondary
All-cause Mortality
All-cause hospital mortality
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Uproleselan | All-cause Mortality | 0 Participants |
Secondary
Change in E-selectin Plasma Concentrations, as Shown by Values for Each of Those Days
Changes in E-selectin plasma concentrations measured each day for 6 days.
Time frame: 6 Days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Uproleselan | Change in E-selectin Plasma Concentrations, as Shown by Values for Each of Those Days | Day 1 | 19.19 Nanograms divided by milliliter | Standard Deviation 9.783 |
| Uproleselan | Change in E-selectin Plasma Concentrations, as Shown by Values for Each of Those Days | Day 2 | 15.15 Nanograms divided by milliliter | Standard Deviation 6.524 |
| Uproleselan | Change in E-selectin Plasma Concentrations, as Shown by Values for Each of Those Days | Day 3 | 18.15 Nanograms divided by milliliter | Standard Deviation 9.66 |
| Uproleselan | Change in E-selectin Plasma Concentrations, as Shown by Values for Each of Those Days | Day 4 | 18.09 Nanograms divided by milliliter | Standard Deviation 7.239 |
| Uproleselan | Change in E-selectin Plasma Concentrations, as Shown by Values for Each of Those Days | Day 5 | 27.04 Nanograms divided by milliliter | Standard Deviation 0 |
| Uproleselan | Change in E-selectin Plasma Concentrations, as Shown by Values for Each of Those Days | Day 6 | 26.85 Nanograms divided by milliliter | Standard Deviation 0 |
Secondary
Change in the Progression to Acute Respiratory Failure for Patients With a Baseline PaO2/FiO2 >= 200
Patients with a baseline PaO2/FiO2 \>= 200: progression of respiratory failure is defined by: 1. severe gas transfer deficit (PaO2/FiO2 \< 200); 2. persistent respiratory distress while receiving oxygen (persistent marked dyspnea, use of accessory respiratory muscles, paradoxical respiratory movements); The rate will be calculated as the proportion of patients who experienced at least one of the events above by day+15 from treatment start.
Time frame: Enrollment, 15 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Uproleselan | Change in the Progression to Acute Respiratory Failure for Patients With a Baseline PaO2/FiO2 >= 200 | 0 Participants |
Secondary
Change in the World Health Organization (WHO) COVID-19, 8-point Ordinal Scale as Shown by Presenting Selected Time Points Through Day 28
WHO COVID-19, 8-point ordinal scale has a range of 1-8 with higher numbers indicating a more severe disease.
Time frame: Enrollment, day 28
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Uproleselan | Change in the World Health Organization (WHO) COVID-19, 8-point Ordinal Scale as Shown by Presenting Selected Time Points Through Day 28 | Day 1 | 4.67 score on a scale | Standard Deviation 0.42 |
| Uproleselan | Change in the World Health Organization (WHO) COVID-19, 8-point Ordinal Scale as Shown by Presenting Selected Time Points Through Day 28 | Day 3 | 2.8 score on a scale | Standard Deviation 0.74 |
| Uproleselan | Change in the World Health Organization (WHO) COVID-19, 8-point Ordinal Scale as Shown by Presenting Selected Time Points Through Day 28 | Day 15 | 1.17 score on a scale | Standard Deviation 0.16 |
| Uproleselan | Change in the World Health Organization (WHO) COVID-19, 8-point Ordinal Scale as Shown by Presenting Selected Time Points Through Day 28 | Day 28 | 1.20 score on a scale | Standard Deviation 0.2 |
Secondary
Number of Mechanical Ventilation and Vasopressor Days
Days of mechanical ventilation and days of vasopressors
Time frame: Up to Day 28
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Uproleselan | Number of Mechanical Ventilation and Vasopressor Days | Days of mechanical ventilation | 0 days |
| Uproleselan | Number of Mechanical Ventilation and Vasopressor Days | vasopressor days | 0 days |
Secondary
Number of Patients Alive Who Are Free of Respiratory Failure
Number of patients alive and free of acute respiratory failure which required initiation of mechanical ventilation
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Uproleselan | Number of Patients Alive Who Are Free of Respiratory Failure | 6 Participants |
Secondary
Number of Patients Requiring Mechanical Ventilation
Number of patients requiring mechanical ventilation
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Uproleselan | Number of Patients Requiring Mechanical Ventilation | 0 Participants |
Secondary
Participants Who Experienced Grade 3-4 Hemorrhagic Events
Number of participants who experienced a Grade 3 or Grade 4 hemorrhagic event based on the World Health Organization's (WHO) Bleeding Scale. On the scale, a Grade 3 event means gross blood loss, and a Grade 4 event means debilitating blood loss.
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Uproleselan | Participants Who Experienced Grade 3-4 Hemorrhagic Events | 0 Participants |
Secondary
Participants Who Experienced Venous Thromboembolism (Deep Venous Thrombosis or Pulmonary Embolism)
Venous thromboembolism - DVT or PE
Time frame: Enrollment, up to day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Uproleselan | Participants Who Experienced Venous Thromboembolism (Deep Venous Thrombosis or Pulmonary Embolism) | 0 Participants |
Secondary
Time to Change Oxygenation
Number of days it took to reduce their oxygen requirements
Time frame: during hospitalization; hospital stay ranged from 2 to 10 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Uproleselan | Time to Change Oxygenation | 2 Days | Standard Deviation 1 |