Assessing Safety, Hospitalization and Efficacy of rNAPc2 in COVID-19

Study Overview
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Brief Summary
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Sequential randomized, multicenter, active comparator study to evaluate the hypothesis that rNAPc2 (AB201), a novel, potent and highly selective tissue factor inhibitor with anticoagulant, anti-inflammatory and potential antiviral properties, shortens time to recovery compared to heparin in hospitalized patients with COVID-19 and elevated D-dimer levels.

Detailed Description
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Sequential randomized, multicenter, active comparator study to evaluate the hypothesis that rNAPc2, a novel, potent and highly selective tissue factor inhibitor with anticoagulant, anti-inflammatory and potential antiviral properties, shortens time to recovery compared to heparin in hospitalized patients with COVID-19 and elevated D-dimer levels. Study participants and Clinical Endpoint Committee (CEC) members assessing the clinical endpoints will be blinded to treatment assignment. The protocol comprises sequential Phase 2b and Phase 3 studies. Analysis of Phase 2b data could lead to study discontinuation, adjustment of eligibility criteria or sample size, and will inform the rNAPc2 dose level to be studied in Phase 3.

Official Title
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Assessing Safety, Hospitalization and Efficacy of rNAPc2 in COVID-19 (ASPEN-COVID-19)

Conditions
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Covid19

Intervention / Treatment
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* Drug: rNAPc2
* Drug: Heparin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years and ≤ 90 years at the Screening assessment Weight ≥ 50 kg at randomization Hospitalized with a diagnosis of COVID-19 and in need of inpatient medical care Positive for SARS-CoV-2 on nasopharyngeal, oropharyngeal or other tissue/body fluid samples by PCR or validated other test of ongoing infection (not an antibody test for prior exposure), within seven (7) days of hospitalization or screening assessment D-dimer level > upper limit of normal at screening Provided electronic or written informed consent, either personally or through a legally authorized representative (LAR) Must agree not to participate in a concurrent interventional study involving anticoagulation or anti-platelet therapy Female patients of reproductive or child-bearing potential must be willing to use an effective method of contraception for the duration of the study, and male patients must be willing to use an effective method of contraception to avoid partner pregnancy and abstain from sperm donation for at least 90 days after last dose Exclusion Criteria: High bleeding risk, e.g. major surgery within prior 1 month, history of a major bleed while receiving anticoagulation, recent hemorrhagic stroke, current or planned (during current hospitalization) dual anti-platelet therapy, platelet count <25,000/uL, current therapeutic anticoagulation for a medical indication other than COVID-19, e.g. atrial fibrillation, known thrombosis, hereditary or acquired coagulopathy treated with therapeutic anticoagulation. Patients receiving prophylactic anticoagulation are eligible if they are willing to discontinue current anticoagulation. Sustained systolic blood pressure < 90 mmHg considered to be clinically significant Persistent eGFR <20 ml/min/1.73m2 Known severe liver disease (e.g. bilirubin >3.5 mg/dL (60 umol/L)) Life expectancy estimated to be < 72 hours based on current clinical condition Anticipated hospital discharge or transfer within 5 days based on current clinical condition Known anti-phospholipid syndrome Unable to receive heparin, e.g. history of heparin-induced thrombocytopenia and thrombosis (HITT) Participation in any interventional clinical study with an investigational product within seven (7) days of the Screening assessment or within 5 half-lives of the investigational agent, whichever is longer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: investigational product compared to active comparator
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rNAPc2 Higher Dose<br>loading dose of 7.5 μg/kg SC on Day 1 followed by 5 μg/kg SC on Days 3 and 5 | Drug: rNAPc2<br>* two dose levels of rNAPc2<br>* Other names: Recombinant Nematode Anticoagulant Protein c2;|
| Experimental: rNAPc2 Lower Dose<br>loading dose of 5 ug/kg SC on Day 1 followed by 3 ug/kg SC on Days 3 and 5 | Drug: rNAPc2<br>* two dose levels of rNAPc2<br>* Other names: Recombinant Nematode Anticoagulant Protein c2;|
| Active Comparator: Heparin<br>heparin at either prophylactic or therapeutic doses per Standard of Care at Institution | Drug: Heparin<br>* standard of care heparin per institution (therapeutic or prophylactic regimen)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportional Change in D-dimer Level From Baseline to Day 8, or Day of Discharge if Prior to Day 8 (Phase 2b) | Proportional change is represented as percent change, and is defined as: 100 × (D-Dimer level at Day 8 or early discharge - D-Dimer level at baseline) / D-Dimer level at baseline. Baseline and post-baseline D-Dimer results are tested in the same laboratory, i.e. both from central laboratory, or local laboratory paired samples if the central laboratory values are not available. | 8 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportional Change in D-dimer Level From Baseline to 24 Hours Post-dose (Day 2) and Day 3 (Phase 2b) | Proportional change is represented as percent change, and is defined as: 100 × (D-Dimer level at Day 2/3 or early discharge - D-Dimer level at baseline)/D-Dimer level at baseline. Baseline and post-baseline D-Dimer results are tested in the same laboratory. | 2 days and 3 days | 
| Number of Major or Non-major Clinically Relevant Bleeding Events Within Eight (8) Days of Randomization as Compared to Heparin (Phase 2b) | Clinical events as reported by site. ISTH= International Society on Thrombosis and Haemostasis, TIMI= Thrombolysis in Myocardial Infarction. Heparin Dosing Strategy as indicated by Investigator. Where subjects have more than one bleeding event recorded, only the highest level of severity was summarized. | 8 days | 
| Number of Major or Non-major Clinically Relevant Bleeding Events With rNAPc2 vs. Heparin Through Day 30 (Phase 2b) | Clinical events as reported by site. ISTH= International Society on Thrombosis and Haemostasis, TIMI= Thrombolysis in Myocardial Infarction. Heparin Dosing Strategy as indicated by Investigator. Where subjects have more than one bleeding event recorded, only the highest level of severity was summarized. | 30 days | 
| Change in High Sensitivity C-reactive Protein Laboratory Values From Baseline Through Day 8 (Phase 2b) | Central lab samples collected per protocol. Proportional change is represented as percent change, and is defined as: 100 × (Biomarker level at Day 8 or early discharge - Biomarker level at baseline)/Biomarker level at baseline. | 8 days | 
| Change in Interleukin-6 Laboratory Values From Baseline Through Day 8 (Phase 2b) | Central lab samples collected per protocol. Proportional change is represented as percent change, and is defined as: 100 × (Biomarker level at Day 8 or early discharge - Biomarker level at baseline)/Biomarker level at baseline. | 8 days | 
| Change in Tissue Factor Laboratory Values From Baseline Through Day 8 (Phase 2b) | Central lab samples collected per protocol. Proportional change is represented as percent change, and is defined as: 100 × (Biomarker level at Day 8 or early discharge - Biomarker level at baseline)/Biomarker level at baseline. | 8 days | 
| Change in Antiphospholipid Antibodies Laboratory Values From Baseline Through Day 8 (Anti-Beta 2 Glycoprotein IgG) (Phase 2b) | Proportional change is represented as percent change, and is defined as: 100 × (Biomarker level at Day 8 or early discharge - Biomarker level at baseline)/Biomarker level at baseline. | 8 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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D-dimer, Thromboprophylaxis, Anti-coagulant, Thrombotic Events, Coagulation, Inflammation, Heparin