Clinical trial NCT05057221: Safety, Tolerability and Efficacy of Uproleselan (GMI-1271) in Patients With COVID-19 Pneumonia
Official title: A Pilot Study to Assess the Safety, Tolerability and Efficacy of Selectin Inhibitor Uproleselan (GMI-1271) in Patients With COVID-19 Pneumonia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: COVID-19 Pneumonia
Keywords: Uproleselan
Selectin Inhibitor
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: GlycoMimetics Incorporated
First posted: 2021-09-27
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a prospective, interventional, single-arm, open label trial, with 1:1 matched de-identified retrospective control cohort.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Safety of Uproleselan - as Measured by Serious Adverse Events
timeFrame: Up to 28 days
measure: Safety of Uproleselan- as Measured by Frequency of Serious Adverse Events
timeFrame: Up to 28 days
Secondary outcomes:
measure: Change in the Progression to Acute Respiratory Failure for Patients With a Baseline PaO2/FiO2 >= 200
timeFrame: Enrollment, 15 days
measure: Number of Patients Alive Who Are Free of Respiratory Failure
timeFrame: Up to 28 days
measure: All-cause Mortality
timeFrame: Up to 28 days
measure: Time to Change Oxygenation
timeFrame: during hospitalization; hospital stay ranged from 2 to 10 days
measure: Number of Patients Requiring Mechanical Ventilation
timeFrame: Up to 28 days
measure: Change in the World Health Organization (WHO) COVID-19, "8-point Ordinal Scale" as Shown by Presenting Selected Time Points Through Day 28
timeFrame: Enrollment, day 28
measure: Actual Duration of Hospitalization
timeFrame: Up to 28 days
measure: Actual Duration of ICU Care
timeFrame: Up to 28 days
measure: Participants Who Experienced Grade 3-4 Hemorrhagic Events
timeFrame: Up to 28 days
measure: Change in E-selectin Plasma Concentrations, as Shown by Values for Each of Those Days
timeFrame: 6 Days
measure: Participants Who Experienced Venous Thromboembolism (Deep Venous Thrombosis or Pulmonary Embolism)
timeFrame: Enrollment, up to day 28
measure: Number of Mechanical Ventilation and Vasopressor Days
timeFrame: Up to Day 28
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: The University of Michigan
state: Michigan
Study officials:
affiliation: University of Michigan
name: Lena Napolitano, MD
role: PRINCIPAL_INVESTIGATOR
References: