Acute Lung Injury, Coronavirus Disease 2019 (COVID-19), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Conditions
Keywords
COVID-19, ALI, SARS-CoV-2
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.
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.
Interventions
Dociparstat is a glycosaminoglycan derived from porcine heparin.
DRUGPlacebo
0.9% Normal Saline
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind
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)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Are Alive and Free of Invasive Mechanical Ventilation or ECMO Through Day 28 | 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. |
Countries
United States
Participant flow
Pre-assignment details
Study enrollment was terminated on 20 May 2021 due to improvement in the Coronavirus Disease 2019 (COVID-19) pandemic and low subject accrual. At the time of termination, a total of 27 subjects of the planned 75 subjects had been enrolled, of which 26 subjects were treated and 22 subjects had completed the study across Cohorts 1, 2, and 3 (partial) of the Phase 2 portion of the study.
Participants by arm
| Arm | Count |
|---|---|
| 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 \[168 hours\]). | 6 |
| Cohort 1 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 \[168 hours\]). | 6 |
| 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 \[168 hours\]). | 8 |
| 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 \[168 hours\]). | 3 |
| 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 \[168 hours\]). | 2 |
| 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 \[168 hours\]). | 1 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Death | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Subject request and prohibited concomitant medication | 2 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort 3 Placebo | Cohort 3 Dociparstat | Cohort 2 Placebo | Cohort 2 Dociparstat | Cohort 1 Dociparstat | Cohort 1 Placebo |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 57.0 years | 41 years | 39.5 years | 62.0 years | 62.0 years | 50.5 years | 63.0 years |
| Body mass index | 33.0 kg/m^2 STANDARD_DEVIATION 6.85 | 45.4 kg/m^2 | 28.6 kg/m^2 STANDARD_DEVIATION 5.05 | 36.4 kg/m^2 STANDARD_DEVIATION 12.34 | 31.0 kg/m^2 STANDARD_DEVIATION 6.17 | 32.5 kg/m^2 STANDARD_DEVIATION 6.57 | 33.9 kg/m^2 STANDARD_DEVIATION 5.85 |
| NIAID Score (actual) 3 | 12 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 2 Participants | 5 Participants |
| NIAID Score (actual) 4 | 14 Participants | 0 Participants | 0 Participants | 3 Participants | 6 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 0 Participants | 1 Participants | 1 Participants | 4 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Female | 15 Participants | 0 Participants | 0 Participants | 3 Participants | 2 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 11 Participants | 1 Participants | 2 Participants | 0 Participants | 6 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 1 / 6 | 0 / 8 | 0 / 3 | 0 / 2 | 0 / 1 |
| other Total, other adverse events | 5 / 6 | 6 / 6 | 5 / 8 | 2 / 3 | 1 / 2 | 1 / 1 |
| serious Total, serious adverse events | 2 / 6 | 3 / 6 | 1 / 8 | 0 / 3 | 0 / 2 | 0 / 1 |
Outcome results
Primary
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.
Time frame: Day 1 to Day 28 (28 days)
Population: Note: This outcome measure was analyzed using the Intent-to-Treat (ITT) Analysis Set. In the ITT Analysis Set included 4 placebo-treated subjects for Cohort 2; however, only 3 placebo-treated subjects from Cohort 2 were included in the Safety Analysis Set. This subject was randomized to receive placebo but never received treatment due to consent withdrawal.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 Dociparstat | Number of Participants Who Are Alive and Free of Invasive Mechanical Ventilation or ECMO Through Day 28 | 3 Participants |
| Cohort 1 Placebo | Number of Participants Who Are Alive and Free of Invasive Mechanical Ventilation or ECMO Through Day 28 | 4 Participants |
| Cohort 2 Dociparstat | Number of Participants Who Are Alive and Free of Invasive Mechanical Ventilation or ECMO Through Day 28 | 7 Participants |
| Cohort 2 Placebo | Number of Participants Who Are Alive and Free of Invasive Mechanical Ventilation or ECMO Through Day 28 | 3 Participants |
| Cohort 3 Dociparstat | Number of Participants Who Are Alive and Free of Invasive Mechanical Ventilation or ECMO Through Day 28 | 2 Participants |
| Cohort 3 Placebo | Number of Participants Who Are Alive and Free of Invasive Mechanical Ventilation or ECMO Through Day 28 | 1 Participants |