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Ravulizumab and COVID-19

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ClinicalTrials.gov Identifier: NCT04570397
Recruitment Status : Recruiting
First Posted : September 30, 2020
Last Update Posted : January 14, 2021
Sponsor:
Information provided by (Responsible Party):
Andrew Michael Siedlecki, Brigham and Women's Hospital

Study Description
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Brief Summary:
Ultomiris (Ravulizumab), is a monoclonal antibody that specifically targets terminal complement products and is proposed for the treatment of COVID-19 induced microvasculature injury and endothelial damage leading to thrombotic microangiopathy (TMA) causing acute kidney injury (AKI). Ravulizumab is to be used for participants with a confirmed diagnosis of COVID-19 who clinically or diagnostically present with deteriorating renal function. Ravulizumab causes immediate and sustained inhibition of the terminal complement cascade. The use of ravulizumab could ameliorate COVID-19 induced kidney injury due to TMA, shorten hospital stay, and improve the overall survival.

Condition or disease Intervention/treatment Phase
Covid19 Thrombotic Microangiopathies Acute Kidney Injury Drug: Ravulizumab Phase 3

Detailed Description:

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: C5 Complement Inhbition Using Ravulizumab for the Treatment of COVID-19 Induced Thrombotic Microangiopathy
Actual Study Start Date : December 18, 2020
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : November 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Ravulizumab

Arms and Interventions
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Arm Intervention/treatment
Experimental: Interventional arm
ravulizumab
 Drug: Ravulizumab
Patients will receive weight-based dosing of ravulizumab on Days 1, 5, 10, and 15 along with the standard care.
No Intervention: Control arm
patients in this arm will recieve standard care


Outcome Measures
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Primary Outcome Measures :
  1. Assess the efficacy of ravulizumab to ameliorate SARS-CoV-2 (COVID-19)-induced acute kidney injury manifesting as thrombotic microangiopathy. [ Time Frame: 30 days ]
    50% improvement in estimated glomerular filtration rate compared to conventional therapy within 30 days of treatment for COVID-19-induced acute kidney injury.


Secondary Outcome Measures :
  1. Evaluation of pharmacokinetics of ravulizumab in participants with COVID-19 [ Time Frame: 120 days ]
    Evaluation of pharmacokinetics of ravulizumab in participants with COVID-19 Changes in ravulizumab concentration in plasma


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04570397


Contacts
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Contact: Andrew M Siedlecki, M.D 13148092879 asiedlecki@partners.org
Contact: Aliza Anwar Memon, M.B.B.S 3479824073 aamemon@bwh.harvard.edu

Locations
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United States, Massachusetts
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Andrew M Siedlecki, M.D    314-809-2879    asiedlecki@partners.org   
Contact: Aliza Anwar Memon, M.B.B.S    3479824073    aamemon@bwh.harvard.edu   
Principal Investigator: Andrew M Siedlecki, M.D         
Sub-Investigator: Aliza Anwar Memon, M.B.B.S         
Sponsors and Collaborators
Brigham and Women's Hospital
More Information
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Responsible Party: Andrew Michael Siedlecki, asistant professor, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT04570397    
Other Study ID Numbers: 092420
First Posted: September 30, 2020    Key Record Dates
Last Update Posted: January 14, 2021
Last Verified: January 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Acute Kidney Injury
Thrombotic Microangiopathies
Renal Insufficiency
Kidney Diseases
Urologic Diseases
Thrombocytopenia
Blood Platelet Disorders
 Hematologic Diseases
Ravulizumab
Complement Inactivating Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs