ACTIV-4 trials to zero in on best agents and disease stages for addressing blood clots in COVID-19
NIH’s trio of adaptive ACTIV-4 Antithrombotics studies are going beyond identifying which drugs most effectively prevent blood clots in individuals infected with SARS-CoV-2 to figuring out when in the course of COVID-19 the drugs will be beneficial.
The National Heart, Lung and Blood Institute (NHLBI) announced Thursday the launch of the first two Phase III studies to prevent blood clots in COVID-19 patients: the open-label ACTIV-4-Antithrombotics Inpatient trial and the double-blind ACTIV-4-Antithrombotics Outpatient trial.
The third study will enroll patients discharged from the hospital after moderate to severe disease, who, NHLBI director Gary Gibbons said on a conference call Thursday, have residual risk of developing blood clots.
On the call, Gibbons and NIH director Francis Collins noted that although blood clots were identified early in the pandemic as a complication of COVID-19, optimal medications and their dosages remain to be defined.
Gibbons added that many COVID-19 patients have elevated levels of D-dimer proteins, a biomarker of coagulation, and that through ACTIV-4 “we’ll be able to characterize that more systematically in the study; and indeed that may be used to derive who’s at greatest risk for a clot, and who should we treat most intensively to prevent the clot.”
Blood samples collected from subjects in the outpatient study may also enable researchers to identify new drug targets and biomarkers of other complications.
ACTIV-4-Antithrombotics Outpatient will enroll about 7,000 newly diagnosed COVID-19 patients who will receive low or high dose Eliquis apixaban from Bristol Myers Squibb Co. (NYSE:BMY), aspirin or placebo. The primary endpoint is a composite of need for hospitalization due to cardiovascular or pulmonary events, symptomatic deep venous thrombosis, pulmonary embolism, arterial thromboembolism, myocardial infarction, ischemic stroke and all-cause mortality over 45 days.
ACTIV-4-Antithrombotics Inpatient is comparing a low, prophylactic dose of heparin with a high dose in about 7,000 patients. Gibbons said that it’s fairly standard in the inpatient setting for COVID-19 patients to receive low doses of anticoagulants, and that in the ACTIV-4 inpatient study the prophylactic heparin dose will be the comparator for the high, therapeutic dose.
The primary endpoint is the number of days free of supplemental oxygen, invasive or non-invasive ventilation, or vasopressor therapy over the first 21 days, according to ClinicalTrials.gov. The key secondary endpoint is a composite of death, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction or ischemic stroke at hospital discharge or 28 days.
According to the registry, the estimated primary completion dates for the outpatient and inpatient studies are January 2021 and March 2021, respectively.
ACTIV-4 is one of five ACTIV clinical trial programs being funded by Operation Warp Speed to identify effective treatments among different classes of therapy. ACTIV-1 is testing immune modulators; ACTIV-2 and ACTIV-3 are testing antiviral mAbs in inpatient and outpatient settings; and ACTIV-5 will evaluate promising agents, such as antivirals, that haven’t been investigated elsewhere (see “ACTIV Coming Into Focus”).
Rather than focusing on single drug classes, other COVID-19 master protocol trials — including REMAP-CAP, which has a heparin arm — are evaluating a mix of therapies with different mechanisms (see “Master Protocols Should Not Be A One-off Phenomenon Confined to COVID-19”).