Study for the Use of the IL-6 Inhibitor Clazakizumab in Patients With Life-threatening COVID-19 Infection

Study Overview
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Brief Summary
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In this study, the investigators propose to administer clazakizumab to patients with life-threatening Coronavirus Disease 2019 (COVID-19) infection manifest by pulmonary failure and a clinical picture consistent with a cytokine storm syndrome. This is a single-center randomized, double-blind, placebo-controlled trial in which 30 patients will be enrolled and randomly assigned in a 1:1 ratio to two study arms and receive clazakizumab at a dose of 25 mg or placebo.

Detailed Description
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The limited understanding of the clinical behavior of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (the viral organism responsible for COVID-19 disease) is evolving on a daily basis. Reports from China indicate that a subset of patients with the worst clinical outcomes may manifest cytokine storm syndrome. Hypotheses that excess cytokines may trigger a secondary hemophagocytic lymphohistiocytosis (sHLH) have been proposed. Indeed, cytokine profiles consistent with this picture were observed in Chinese patients with severe pulmonary involvement. Specifically, elevated ferritin and interleukin-6 (IL-6) were associated with fatalities among the infected patients. A role for targeted anti-inflammatory and anti-cytokine therapies in the treatment of pulmonary hyperinflammation has been proposed. Clazakizumab is a genetically engineered humanized immunoglobulin-1 (IgG1) monoclonal antibody (mAb) that binds with high affinity to human IL-6. This investigational agent is currently being studied as a treatment for chronic active antibody mediated rejection of renal allografts. In this study investigators propose to administer clazakizumab to patients with life-threatening pulmonary failure secondary to COVID-19 disease.

Official Title
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A Randomized Placebo-Controlled Safety and Dose-Finding Study for the Use of the IL-6 Inhibitor Clazakizumab in Patients With Life-threatening COVID-19 Infection

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Clazakizumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be eligible to participate in this study, the patients must meet all of the following criteria: At least 18 years of age Confirmed COVID-19 disease (by Cobas SARS-CoV-2 real time reverse transcription polymerase chain reaction (RT-PCR) using nasopharyngeal swab sample, or equivalent test available to be performed by the Columbia University Irving Medical Center (CUIMC)/New York Presbyterian (NYP) clinical laboratory). Effort will be made to have the confirmatory test result <72 hours prior to enrollment however given overall clinical demand this may not be feasible in all cases. Respiratory failure manifesting as: Acute Respiratory Distress Syndrome (defined by a P/F ratio of <200), OR oxygen saturation (SpO2) < 90% on 4 liters (L) (actual or expected given higher O2 requirement) OR increasing O2 requirements over 24 hours, plus 2 or more of the following predictors for severe disease: CRP > 35 mg/L Ferritin > 500 ng/mL D-dimer > 1 mcg/L Neutrophil-Lymphocyte Ratio > 4 Lactate dehydrogenase (LDH) > 200 U/L Increase in troponin in patient w/out known cardiac disease Has a consent designee willing to provide informed consent on behalf of the patient (this assumes that a mechanically ventilated patients lacks capacity to consent on his/her own behalf. Should it be deemed that the patient has capacity to consent, consent may be obtained from the patient.) Women of childbearing potential must be willing and able to use at least one highly effective contraceptive method for a period of 5 months following the study drug administration. In the context of this study, an effective method is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly such as: combined (estrogen and progestogen containing) hormonal contraception combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, or transdermal) progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) intrauterine device (IUD) intrauterine hormone-releasing system (IUS) vasectomized partner bilateral tubal occlusion true abstinence. when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence, such as calendar, ovulation, symptothermal, postovulation methods, and withdrawal are not acceptable methods of contraception. Men must be willing to use a double-barrier contraception from enrollment until at 5 months after the last dose of study drug, if not abstinent. Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: Evidence of irreversible injury deemed non-survivable even if the pulmonary failure recovers (for example severe anoxic brain injury) Known active inflammatory bowel disease Known active, untreated diverticulitis Known untreated bacteremia Pregnancy. (The protocol will exclude pregnant subjects given the lack of overall data on use of clazakizumab in pregnancy however the study team would consider a protocol revision should more than 3 potential pregnant study subjects be excluded on this basis). Known hypersensitivity to the clazakizumab

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized, double-blind, placebo-controlled, adaptive seamless Phase II/III design (ASD). The investigators propose the administration of an investigational drug in patients with high predicted short-term mortality secondary to COVID-19 disease. Patients will be enrolled and randomly assigned in a 1:1 ratio to two study arms that will receive clazakizumab at a dose of 25 mg or placebo.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clazakizumab 25 mg<br>The first dose will be administered as soon as possible after the patient is enrolled and randomized into the Clazakizumab 25 mg arm. The route of administration will be intravenous. Each dose will be administered as an infusion that is run over 30 minutes. Serum C-reactive protein (CRP) will be evaluated at baseline and on days 1 and 2 following clazakizumab administration. If the CRP does not decrease by 50% within 36-48 hours after the first dose, a second dose of 25 mg clazakizumab will be given no later than day 3. | Drug: Clazakizumab<br>* Dose is 25mg intravenously over 30 minutes.<br>* Other names: Clazakizumab solution;|
| Placebo Comparator: Placebo<br>The first dose will be administered as soon as possible after the patient is enrolled and randomized into the Placebo arm. The route of administration will be intravenous. Each dose will be administered as an infusion that is run over 30 minutes. Serum CRP will be evaluated at baseline and on days 1 and 2 following clazakizumab administration. If the CRP does not decrease by 50% within 36-48 hours after the first dose, a second dose of placebo will be given no later than day 3. | Other: Placebo<br>* Intravenously administered over 30 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of Serious Adverse Events Associated With Clazakizumab or Placebo |  | 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of Intubation |  | 14 days | 
| Time to Extubation |  | 14 days | 
| Length of Intensive Care Unit (ICU) Stay |  | 14 days | 
| Number of Patients Who Present a Decrease in C-reactive Protein (CRP) |  | 14 days | 
| Number of Patients With Acute Kidney Injury (AKI) |  | 14 days | 
| Number of Patients With a Need for Renal Replacement Therapy (RRT) |  | 14 days | 
| Duration of Renal Replacement Therapy (RRT) |  | 60 days | 
| Patient Survival | Number of participants alive at day 28. | 28 days | 
| Patient Survival | Number of participants alive at day 60, end of study. | 60 days | 
| Number of Patients With Hemodialysis |  | 60 days | 
| Number of Patients With Continuous Renal Replacement Therapies (CRRT) |  | 60 days | 
| Number of Patients With Peritoneal Dialysis |  | 60 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronavirus, SARS-COVID-2