Ultomiris (Ravulizumab), is a monoclonal antibody that specifically targets terminalcomplement products and is proposed for the treatment of COVID-19 inducedmicrovasculature injury and endothelial damage leading to thrombotic microangiopathy(TMA) causing acute kidney injury (AKI). Ravulizumab is to be used for participants witha confirmed diagnosis of COVID-19 who clinically or diagnostically present withdeteriorating renal function. Ravulizumab causes immediate and sustained inhibition ofthe terminal complement cascade. The use of ravulizumab could ameliorate COVID-19 inducedkidney injury due to TMA, shorten hospital stay, and improve the overall survival.
The novel coronavirus (COVID 19) is responsible for the current pandemic with the numbers
of diagnoses and fatalities rising daily. It is reported that of those requiring medical
intensive care almost 49% will expire prior hospital discharge. The initial peak of
hospitalized patients in Boston, MA occurred on April 15, 2020 however new presentations
continue to manifest at a local and national level.
The exact pathophysiology is still not clear. There are various theories that explain the
pathophysiology which includes but is not limited to direct viral damage via the
angiotensin-converting enzyme 2 receptor, systemic inflammatory response with cytokine
storm, and aggravated hypoxia.
Recently, it has been observed that signs and symptoms of severe COVID 19 describe
complement-mediated TMA rather than the sepsis induced coagulopathy. This strengthens the
hypothesis that complement inhibition by C5a inhibitor, Ultomiris (ravulizumab) could
ameliorate COVID 19 induced TMA, improve renal function, shorten the hospital stay and
reduce the overall mortality.
In those affected with severe or fatal COVID-19, there is evidence of end-organ damage
with acute kidney injury which has heightened the interest in studying the excessive
cytokine release and its overall effect in the form of multi-organ failure.
Ultomiris (Ravulizumab) is a long acting second generation monoclonal antibody against a
terminal complement product C5a and is FDA approved for the treatment of Paroxysmal
Nocturnal Hemoglobinuria (PNH) and atypical hemolytic uremic syndrome.The benefit of
Ultomiris has not been clinically evaluated in COVID 19 induced TMA.
Recently, ravulizumab has been utilized in the setting of a phase 3 clinical trial for
the treatment of COVID 19 induced pneumonia, acute lung injury and acute respiratory
distress. As it binds to C5 and impedes the cleavage of C5 by C5 convertase to generate
C5a and membrane attack complex, ravulizumab could possibly improve the renal function in
COVID 19 induced TMA and potentially improve overall survival, due to similar
pathophysiology in the microvasculature of the kidney. More so, studies are being
conducted to determine renal and cardiovascular sequelae of COVID-19 infection, which
further enhances the interest to closely examine and evaluate those patients presenting
30-60 days after COVID-19 infection with signs of renal failure. There remains an unmet
clinical need to investigate this approach with a randomized controlled trial to
determine if complement cascade inhibition can improve the clinical outcome for COVID 19
induced acute kidney injury as measured by improvement of renal function and decline in
the overall morbidity and mortality.
Drug: Ravulizumab
Patients will receive weight-based dosing of ravulizumab on Days 1, 5, 10, and 15 along
with the standard care.
Inclusion Criteria:
1. Males or Females 18 years of age or above and weighing 40kg or above at the time of
providing informed consent.
2. A clinical diagnosis of thrombotic microangiopathy will then be applied to include
the following criteria: i) D-dimer > 100% the upper limit of the reference range and
ii) serum creatinine >25% of the normal range or iii) >25% increase from patient's
baseline serum creatinine.
3. Diagnosis of SARS-CoV-2 infection within 90 days prior to enrollment
Exclusion Criteria:
1. Participant is not expected to survive more than 24 hours.
2. Participant has an unresolved Neisseria Meningitides infection.
3. Hypersensitivity to murine proteins or to one of the excipients of ravulizumab.
Brigham and Women's Hospital
Boston, Massachusetts, United States