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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

Tracking Information
First Submitted Date  ICMJE September 29, 2020
First Posted Date  ICMJE September 30, 2020
Last Update Posted Date January 14, 2021
Actual Study Start Date  ICMJE December 18, 2020
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 29, 2020)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 29, 2020)
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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ravulizumab and COVID-19
Official Title  ICMJE C5 Complement Inhbition Using Ravulizumab for the Treatment of COVID-19 Induced Thrombotic Microangiopathy
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Covid19
  • Thrombotic Microangiopathies
  • Acute Kidney Injury
Intervention  ICMJE Drug: Ravulizumab
Patients will receive weight-based dosing of ravulizumab on Days 1, 5, 10, and 15 along with the standard care.
Study Arms  ICMJE
  • Experimental: Interventional arm
    ravulizumab
    Intervention: Drug: Ravulizumab
  • No Intervention: Control arm
    patients in this arm will recieve standard care
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 29, 2020)
32
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2021
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Andrew M Siedlecki, M.D 13148092879 asiedlecki@partners.org
Contact: Aliza Anwar Memon, M.B.B.S 3479824073 aamemon@bwh.harvard.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04570397
Other Study ID Numbers  ICMJE 092420
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Andrew Michael Siedlecki, Brigham and Women's Hospital
Study Sponsor  ICMJE Brigham and Women's Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Brigham and Women's Hospital
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP