Chimerix protocol CMX-DS-004 is a randomized, double-blind, placebo-controlled, Phase 2/3 study to determine the safety and efficacy of dociparstat versus placebo in adults receiving standard of care for acute lung injury associated with severe COVID-19 who are at high risk of respiratory failure.
This trial is designed in accord with the consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines; applicable International Council of Harmonization (ICH) Good Clinical Practices (GCP) Guidelines; and applicable laws and regulations. All documents are initially approved by a central institutional review board (Advarra) and/or by the individual site IRB if required. Written informed consent is obtained from all participants before any study-related procedures are implemented. When available, the results will be published in a peer-reviewed journal.
Participants are randomized 1:1 in three sequential Phase 2 cohorts, followed by the Phase 3 portion of this pivotal study (Figure 2). Randomization of participants in Phase 2/Cohort 3 and Phase 3 will be stratified by baseline score on the National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale (3 or 4) and by age (<60 or ≥60 years) . Randomization of participants in Phase 3 will additionally be stratified by baseline BMI (<34 or ≥34 kg/m2).
The primary objective of Phase 3 is to assess the effect of dociparstat on disease progression in participants with severe COVID-19. Approximately 15 U.S. clinical sites are to be engaged in Phase 2 to enroll a total of 74 participants. Phase 3 is expected to include approximately 75 clinical sites to enroll 452 participants.
All participants receive randomized treatment for 7 days and are followed through Day 28. Phase 2, Cohort 2 and Cohort 3 continuous infusion dose will be confirmed after review of data by an independent Data Monitoring Committee (DMC) from prior cohort(s). Phase 3 continuous infusion dose will be the same as administered in Phase 2, Cohort 3.
Eligible participants must be adults between the ages of 18 and 85 years, who are hospitalized for laboratory-documented COVID-19 (e.g., positive SARS-CoV-2 nasopharyngeal swab by reverse transcriptase polymerase chain reaction [RT-PCR]), with a resting oxygen saturation on room air of ≤93%, and have a score of 3 or 4 on the NIAID ordinal scale (i.e., hospitalized requiring supplemental oxygen).
Key exclusion criteria include the requirement for invasive mechanical ventilation or ECMO (extracorporeal membrane oxygenation), acute pericarditis, severe renal impairment (calculated creatinine clearance < 30 mL/min), an irreversible disease or condition with a mortality of ≥50% within 6 months, active or uncontrolled bleeding, or a pre-existing history of severe chronic respiratory disease, severe chronic liver disease, or congestive heart failure requiring hospitalization. Eligible participants must not be receiving chronic anticoagulation, treatment with non-steroid immunomodulators or immunosuppressant medications, or other investigational or non-approved therapies for COVID-19. Laboratory exclusion criteria include an activated partial thromboplastin time (aPTT) greater than 42 seconds, alanine aminotransferase or aspartate aminotransferase greater than 5 times the upper limit of normal, or a platelet count of less than 80,000/mm3.
Importantly, due to the risk of thromboembolic events in COVID-19, participants are permitted to receive prophylaxis for deep venous thrombosis with subcutaneous administration of enoxaparin or unfractionated heparin up to intermediate intensity, with dosing based on body mass index (BMI) and creatinine clearance.
Participants will receive blinded study intervention consisting of either dociparstat or normal saline as a placebo control for up to 7 days. Both groups will also receive best supportive care, as determined by the investigator. All participants will be followed through Day 28.
Based on DSTAT’s relationship to heparin with its pharmacologically-mediated effect on coagulation, and results of nonclinical and clinical studies possible risks of particular interest with dociparstat therapy include prolonged aPTT (with a potential associated risk of bleeding/hemorrhagic events) and an increase in serum aminotransferase concentrations. In previous studies in which higher doses of DSTAT have been administered, mild to modest aPTT elevations have been observed which were manageable with monitoring, and dociparstat dose adjustment, if needed. The transient elevation of liver enzymes is considered a non-adverse class effect for all heparins, heparin derivatives, low molecular weight heparins, and heparinoids . Nevertheless, in the interest of subject safety, eligibility criteria have been designed to ensure appropriate subject selection and specific safety monitoring and management guidelines have been incorporated into the protocol, which include interruption or discontinuation of study drug dosing.
Notably, both unfractionated and low molecular weight heparins have been associated with heparin-induced thrombocytopenia (HIT). In contrast, dociparstat suppresses heparin-induced thrombocytopenia-related platelet activation in vitro and may disrupt formation of heparin/PF4 multimolecular complexes .
Efficacy will be evaluated through clinical examinations, oxygen requirements, and laboratory tests.
Safety will be monitored through collection of adverse event data and laboratory samples.
Plasma samples will be collected for analysis of dociparstat concentrations and biomarkers to further elucidate the mechanism of action of DSTAT, and sputum samples will be collected for virology testing.
The primary efficacy endpoint is the proportion of participants who are alive and do not require invasive mechanical ventilation through Day 28. Secondary efficacy endpoints include all-cause mortality, time to clinical improvement defined as at least a 2-grade improvement on the NIAID ordinal scale, number of ventilator-free days, time to hospital discharge, and average daily corticosteroid use. Dociparstat plasma concentrations and pharmacokinetic parameters will be summarized, as will biomarkers related to the pathophysiology of severe COVID-19, including HMGB1, soluble RAGE, IL-6, and TNFα.
Safety endpoints include incidence of adverse events, changes from baseline in clinical laboratory parameters, and distribution of graded clinical laboratory results.
Sample size and power calculations
Approximately 600 potential participants are expected to be screened to achieve a total of approximately 74 participants randomized in Phase 2 and 452 participants randomized in Phase 3.
The sample size of 6 participants per treatment group for Cohorts 1 and 2 was selected to assess any safety signals in a limited number of participants. The sample size for Cohort 3 was selected to provide a reasonable level of precision to assess the treatment effect for the primary endpoint.
For Phase 3, the sample size of 226 participants per group was selected to detect the difference between a control failure rate of 20% and a dociparstat failure rate of 10% at a two-sided 0.05 alpha level with >80% power. This sample size also accounts for a futility analysis after 50% of the Phase 3 participants are enrolled using a Pocock beta spending function. Participants enrolled in Phase 2 will not contribute to the inferential Phase 3 analysis.
The primary Phase 3 analysis will utilize the intent-to-treat analysis set and a Cochran-Mantel-Haenszel test stratified by each of the actual stratification factors at the 0.05 alpha level. Participants will be counted as failures once they go on a ventilator or die. Number and percentage of failures will be presented for each treatment arm. Cochran-Mantel-Haenszel p-values, estimated common odds ratios, estimated common risk differences, and corresponding approximate two-sided 95% CIs will be presented. The Breslow-Day test will be used to test the homogeneity of the odds ratios across strata. Although missing data are expected to be limited, any such cases will be imputed as failure. A supportive analysis using multiple imputation will be done in order to assess the sensitivity of the inference to the approach to missing data.
In the event the primary endpoint is met, the key secondary analysis of all-cause mortality at Day 28 will be tested sequentially at the 0.05 alpha level, using the same method used for the primary endpoint.
Data Monitoring Committee
An independent unblinded data monitoring committee (DMC) will review safety data from Cohort 1 to make a recommendation on dose escalation in Cohort 2 and review safety data from both Cohorts 1 and 2 to make a recommendation on dosing in Cohort 3. After completion of Phase 2, all data will be unblinded to the DMC and sponsor to determine whether the study should proceed. During Phase 3, the DMC will convene to periodically review safety data, as well as to review the pre-specified futility interim analysis.
Importantly, ensuring feasibility of study conduct in the setting of the current COVID-19 pandemic was considered during study design and led to multiple features to accommodate changing institutional practices to limit patient contact in order to protect medical staff, conserve personal protective equipment, and decrease transmission of infection. This included allowing alternative means of collecting informed consent from potential subjects, limiting the number of blood draws and flexible scheduling, and even permitting longer intravenous (IV) lines to allow the location of IV pumps outside of patient rooms.