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

• ClinicalTrials.gov Identifier: NCT04389840
• Recruitment Status: Terminated
• First Posted: May 15, 2020
• Results First Posted: August 30, 2022
• Last Update Posted: August 30, 2022
• Sponsor: Chimerix
• Information provided by (Responsible Party): Chimerix

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Coronavirus Disease 2019 (COVID-19); Acute Lung Injury; Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)	Drug: Dociparstat sodium; Drug: Placebo	Phase 2; Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double-blind
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: July 8, 2020
• Actual Primary Completion Date: May 20, 2021
• Actual Study Completion Date: May 20, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1 dociparstat; 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; Dociparstat is a glycosaminoglycan derived from porcine heparin.; Other Names: DSTAT; CX-01; 2-0,3-0 desulfated heparin; ODSH
Placebo Comparator: Cohort 1 placebo; 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; 0.9% Normal Saline; Other Names: Normal saline; Sodium chloride 0.9%; 0.9% Normal Saline
Experimental: Cohort 2 dociparstat; 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; Dociparstat is a glycosaminoglycan derived from porcine heparin.; Other Names: DSTAT; CX-01; 2-0,3-0 desulfated heparin; ODSH
Placebo Comparator: Cohort 2 placebo; 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; 0.9% Normal Saline; Other Names: Normal saline; Sodium chloride 0.9%; 0.9% Normal Saline
Experimental: Cohort 3 dociparstat; 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; Dociparstat is a glycosaminoglycan derived from porcine heparin.; Other Names: DSTAT; CX-01; 2-0,3-0 desulfated heparin; ODSH
Placebo Comparator: Cohort 3 placebo; 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; 0.9% Normal Saline; Other Names: Normal saline; Sodium chloride 0.9%; 0.9% Normal Saline

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Who Are Alive and Free of Invasive Mechanical Ventilation or ECMO Through Day 28 [ Time Frame: Day 1 to Day 28 (28 days) ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

A potential participant must have met all the following criteria to be included in the study:

1. 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]).
2. Was aged ≥18 years and ≤85 years.
3. Had a resting oxygen saturation (SaO2) of <94% while breathing ambient air.
4. 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).
5. 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:

1. Was currently receiving invasive mechanical ventilation (e.g., via an endotracheal tube) (score of 2 on NIAID ordinal scale).
2. Had severe chronic respiratory disease, defined by any oxygen requirement prior to incident COVID-19.
3. 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.
4. 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.
5. Was receiving systemic corticosteroids for a chronic condition.
6. Was receiving chronic anticoagulation with warfarin or direct oral anticoagulants (e.g., rivaroxaban, dabigatran, apixaban, edoxaban).
7. 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.
8. 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.
9. 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.
10. Had a history of congestive heart failure requiring hospitalization.
11. Had active pericarditis (based on clinical assessment).
12. Had malignancy or other irreversible disease or condition for which 6-month mortality was estimated ≥50%.
13. Had a corrected QT interval (QTc) >500 msec (or >530-550 msec in participants with QRS greater than >120 msec).
14. Had a Tisdale risk score ≥11 without the ability to monitor with serial electrocardiograms (ECGs) or telemetry.
15. 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.
16. Had alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values >5x upper limit of normal (ULN).
17. Had activated partial thromboplastin time (aPTT) >42 seconds.
18. Had thrombocytopenia with a platelet count <80,000/mm3.
19. Had severe chronic liver disease (Child-Pugh Score of 10 to 15).
20. Had received dociparstat in a different clinical study.
21. 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).
22. 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.
23. 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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35294

United States, Florida

Advanced Pulmonary Research Institute/Wellington Regional Medical Center

Loxahatchee Groves, Florida, United States, 33470

United States, Georgia

Augusta University

Augusta, Georgia, United States, 30912

United States, Louisiana

Our Lady of the Lake

Baton Rouge, Louisiana, United States, 70808

Tulane University

New Orleans, Louisiana, United States, 70112

University Medical Center

New Orleans, Louisiana, United States, 70112

United States, Michigan

William Beaumont Hospital

Royal Oak, Michigan, United States, 48073

Ascension Macomb-Oakland Cardiovascular Research

Warren, Michigan, United States, 48072

United States, North Carolina

Wake Forest Baptist Health

Winston-Salem, North Carolina, United States, 27157

United States, Texas

Texas Health Harris Methodist Hospital Fort Worth

Dallas, Texas, United States, 76104

United States, Wisconsin

Ascension St. Francis Hospital

Milwaukee, Wisconsin, United States, 53215

Ascension All Saints Hospital

Racine, Wisconsin, United States, 53405

Sponsors and Collaborators

Chimerix

  Study Documents (Full-Text)

Documents provided by Chimerix:

Study Protocol  [PDF] November 6, 2020

Statistical Analysis Plan  [PDF] March 12, 2021

More Information

Publications:

Lasky JA, Fuloria J, Morrison ME, Lanier R, Naderer O, Brundage T, Melemed A. Design and Rationale of a Randomized, Double-Blind, Placebo-Controlled, Phase 2/3 Study Evaluating Dociparstat in Acute Lung Injury Associated with Severe COVID-19. Adv Ther. 2021 Jan;38(1):782-791. doi: 10.1007/s12325-020-01539-z. Epub 2020 Oct 27.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.

• Responsible Party: Chimerix
• ClinicalTrials.gov Identifier: NCT04389840
• Other Study ID Numbers: CMX-DS-004
• First Posted: May 15, 2020
• Results First Posted: August 30, 2022
• Last Update Posted: August 30, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Chimerix:

COVID-19; ALI; SARS-CoV-2

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Severe Acute Respiratory Syndrome; Respiratory Insufficiency; Lung Injury; Acute Lung Injury; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Thoracic Injuries; Wounds and Injuries; Heparin; Anticoagulants; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action