Dociparstat for the Treatment of Severe COVID-19 in Adults at High Risk of Respiratory Failure

Study Overview
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Brief Summary
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This was a randomized, double-blind, placebo-controlled Phase 2/3 study to evaluate the safety and efficacy of dociparstat sodium in adult patients with acute lung injury (ALI) due to Coronavirus Disease 2019 (COVID-19). This study was designed to determine if dociparstat sodium could accelerate recovery and prevent progression to mechanical ventilation in patients severely affected by COVID-19.

Detailed Description
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This was a randomized, double-blind, placebo-controlled, Phase 2/3 trial to evaluate the safety and efficacy of dociparsat sodium in adults patients with severe COVID-19 who were at high risk of respiratory failure. Eligible subjects were with confirmed COVID-19 and required hospitalization and supplemental oxygen therapy. This study was designed to determine if dociparstat sodium could accelerate recovery and prevent progression to mechanical ventilation in patients severely affected by COVID-19.

Official Title
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A Phase 2/3 Study to Evaluate the Safety and Efficacy of Dociparstat Sodium for the Treatment of Severe COVID-19 in Adults at High Risk of Respiratory Failure

Conditions
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Coronavirus Disease 2019 (COVID-19), Acute Lung Injury, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Intervention / Treatment
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* Drug: Dociparstat sodium
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A potential participant must have met all the following criteria to be included in the study: Was hospitalized for laboratory-documented Coronavirus Disease 2019 (COVID-19) (e.g., positive for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] via nasopharyngeal swab real time polymerase chain reaction [RT-PCR; or other commercial or public health assay]). Was aged ≥18 years and ≤85 years. Had a resting oxygen saturation (SaO2) of <94% while breathing ambient air. Had a score of 3 or 4 on the National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale (required supplemental oxygen or non-invasive ventilation). Had provided informed consent to participate in the study (by participant or legally-acceptable representative). Exclusion Criteria: A potential participant who met any of the following criteria was not eligible to participate in the study: Was currently receiving invasive mechanical ventilation (e.g., via an endotracheal tube) (score of 2 on NIAID ordinal scale). Had severe chronic respiratory disease, defined by any oxygen requirement prior to incident COVID-19. Had active or uncontrolled bleeding at the time of randomization; a bleeding disorder, either inherited or caused by disease; history of known arterial-venous malformation, intracranial hemorrhage, or suspected or known cerebral aneurysm; or clinically significant (in the judgment of the Investigator) gastrointestinal bleeding within the 3 weeks prior to randomization. Was receiving any other investigational (non-approved) therapy for the treatment of COVID-19 or participating in the treatment period of any other therapeutic intervention clinical study. Participating in the follow-up period of an interventional study may be permitted with prior medical monitor approval; participation in an observational study is permitted. Was receiving systemic corticosteroids for a chronic condition. Was receiving chronic anticoagulation with warfarin or direct oral anticoagulants (e.g., rivaroxaban, dabigatran, apixaban, edoxaban). Was receiving or anticipated to require other systemic anticoagulation dosing at a therapeutic intensity. Prophylaxis of venous thromboembolism (VTE) using subcutaneous (SC) unfractionated heparin or enoxaparin was permitted with appropriate monitoring of coagulation status and within the guidelines described in the protocol. Was receiving antiplatelet therapy, alone or in combination, including aspirin and other antiplatelet agents (e.g., clopidogrel, ticagrelor, and prasugrel), unless able to discontinue these agents at the time of randomization and was able to remain off these agents throughout the duration of the study intervention infusion period. Had treatment with systemic (non-steroid) immunomodulators or immunosuppressant medications, including but not limited to tumor necrosis factor (TNF) inhibitors, anti-interleukin-1 agents and Janus kinase (JAK) inhibitors within 5 half-lives or 30 days (whichever was longer) prior to randomization. Had a history of congestive heart failure requiring hospitalization. Had active pericarditis (based on clinical assessment). Had malignancy or other irreversible disease or condition for which 6-month mortality was estimated ≥50%. Had a corrected QT interval (QTc) >500 msec (or >530-550 msec in participants with QRS greater than >120 msec). Had a Tisdale risk score ≥11 without the ability to monitor with serial electrocardiograms (ECGs) or telemetry. Had severe renal impairment, as determined by calculated creatinine clearance <30 mL/min or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2. Had alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values >5x upper limit of normal (ULN). Had activated partial thromboplastin time (aPTT) >42 seconds. Had thrombocytopenia with a platelet count <80,000/mm3. Had severe chronic liver disease (Child-Pugh Score of 10 to 15). Had received dociparstat in a different clinical study. Woman of childbearing potential who was pregnant, breastfeeding, and/or not using a highly-effective method of contraception (consistent with local regulations regarding the methods of contraception for those participating in clinical studies). Had evidence of clinical improvement in COVID-19 status including, but not limited to, a sustained reduction in oxygen requirements over the previous 48 hours, or extubated and/or no longer requiring mechanical ventilation following intubation for COVID-19. Had any other condition, including abnormal laboratory values, that, in the judgment of the Investigator, could have put the participant at increased risk, or would have interfered with the conduct or planned analysis of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The first 12 subjects were to be randomized 1:1 (dociparstat:placebo) All other subjects were to be randomized 2:1 (dociparstat:placebo)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 dociparstat<br>Subjects received 4 mg/kg of dociparstat administered as an intravenous (IV) bolus on Day 1, followed by 0.25 mg/kg/hr dociparstat by continuous IV infusion for 24 hours daily for up to 7 days (starting on Day 1 and ending on Day 8 [168 hours]). | Drug: Dociparstat sodium<br>* Dociparstat is a glycosaminoglycan derived from porcine heparin.<br>* Other names: ODSH;|
| Placebo Comparator: Cohort 1 placebo<br>Placebo IV bolus on Day 1, followed by Placebo by continuous IV infusion for 24 hours daily for up to 7 days (starting on Day 1 and ending on Day 8 [168 hours]) | Drug: Placebo<br>* 0.9% Normal Saline<br>* Other names: 0.9% Normal Saline;|
| Experimental: Cohort 2 dociparstat<br>Subjects received 4 mg/kg of dociparstat administered as an intravenous (IV) bolus on Day 1, followed by 0.325 mg/kg/hr dociparstat by continuous IV infusion for 24 hours daily for up to 7 days (starting on Day 1 and ending on Day 8 [168 hours]). | Drug: Dociparstat sodium<br>* Dociparstat is a glycosaminoglycan derived from porcine heparin.<br>* Other names: ODSH;|
| Placebo Comparator: Cohort 2 placebo<br>Subjects received placebo IV bolus on Day 1, followed by placebo by continuous IV infusion for 24 hours daily for up to 7 days (starting on Day 1 and ending on Day 8 [168 hours]). | Drug: Placebo<br>* 0.9% Normal Saline<br>* Other names: 0.9% Normal Saline;|
| Experimental: Cohort 3 dociparstat<br>Subjects received 4 mg/kg of dociparstat administered as an intravenous (IV) bolus on Day 1, followed by 0.325 mg/kg/hr dociparstat by continuous IV infusion for 24 hours daily for up to 7 days (starting on Day 1 and ending on Day 8 [168 hours]). | Drug: Dociparstat sodium<br>* Dociparstat is a glycosaminoglycan derived from porcine heparin.<br>* Other names: ODSH;|
| Placebo Comparator: Cohort 3 placebo<br>Subjects received placebo IV bolus on Day 1, followed by placebo by continuous IV infusion for 24 hours daily for up to 7 days (starting on Day 1 and ending on Day 8 [168 hours]). | Drug: Placebo<br>* 0.9% Normal Saline<br>* Other names: 0.9% Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Are Alive and Free of Invasive Mechanical Ventilation or ECMO Through Day 28 | The primary efficacy endpoint was to be the proportion of participants who were alive and free of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) through Day 28. Data also shows proportion of participants with invasive mechanical ventilation or ECMO, all-cause mortality, or early study discontinuation (<Day 25), whichever occurred first, by Day 28. | Day 1 to Day 28 (28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, ALI, SARS-CoV-2