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
Condition: COVID-19
MeSH terms: COVID-19
Intervention: Clazakizumab 25 mg; Clazakizumab 12.5 mg; Placebo
Intervention description: 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 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.; The first dose will be administered as soon as possible after the patient is enrolled and randomized into the Clazakizumab 12.5 mg 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 12.5 mg clazakizumab will be given no later than day 3.; 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a randomized, double-blind, placebo-controlled, adaptive seamless Phase II/III design (ASD). We propose the administration of an investigational drug in patients with high predicted short-term mortality secondary to COVID-19 disease. 80 patients were randomly assigned in a 1:1:1 ratio to three study arms that will receive clazakizumab at a dose of 12.5 mg, 25 mg or placebo. Interim analyses occurred every 7 days since the enrollment of the first 30 patients. Based on week 4 interim analysis the DSMB has recommendation discontinuing the low-dose 12.5 mg of clazakizumab arm. The DSMB has advised continuing enrollment in the placebo and high-dose 25mg of clazakizumab arms in a 1:1 randomization.
Masking: Double (Participant, Investigator)
Masking description: This study is double-blind and therefore neither the Investigator, the subject, the Sponsor and its representatives, nor other designated study site personnel involved in running of the study will be aware of the identification of the investigational drug administered to each subject.
Enrollment: 178.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      In this study invetigators propose to administer clazakizumab to patients with
      life-threatening COVID-19 infection manifest by pulmonary failure and a clinical picture
      consistent with a cytokine storm syndrome. This is a double-blinded randomized multi-center
      trial designed as a phase II dose-finding three arm trial with seamless adaptive transition
      to a phase III efficacy trial. For phase II, patients were randomized 1:1:1 ratio to three
      study arms and received clazakizumab at a dose of 12.5 mg, 25 mg or placebo.

      Based on interim analysis, the low dose arm was dropped and the phase III portion of the
      study continued to enroll patients randomized 1:1 to high dose clazakizumab or placebo.

      Based on interim analysis, the remaining 10 subjects at NYU will be randomly assigned to a
      1:1 ratio to two arms that will receive clazakizumab at a dose of 25 mg or placebo. The NYU
      site will serve as the central data management site for other centers who undertake this
      protocol. Other sites will enroll patients based on the two arm 1:1 randomization. 60
      patients at outside sites are expected to enroll.
    

Eligibility criteria:

        Inclusion Criteria:

        In order to be eligible to participate in this study, the patients must meet all of the
        following criteria:

          1. At least 18 years of age

          2. Confirmed COVID-19 disease (by Cobas SARS-CoV-2 real time RT-PCR using nasopharyngeal
             swab sample, or equivalent test available to be performed by the NYU Langone 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.

          3. Respiratory failure manifesting as: Acute Respiratory Distress Syndrome (defined by a
             P/F ratio of <200), OR SpO2 < 90% on 4L (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 > 1000 mg/mL Neutrophil-Lymphocyte Ratio >
             4 LDH > 200 U/L Increase in troponin in patient w/out known cardiac disease

          4. 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.)

          5. 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:

               1. combined (estrogen and progestogen containing) hormonal contraception combined
                  (estrogen and progestogen containing) hormonal contraception (oral, intravaginal,
                  or transdermal)

               2. progestogen-only hormonal contraception associated with inhibition of ovulation
                  (oral, injectable, implantable)

               3. intrauterine device (IUD)

               4. intrauterine hormone-releasing system (IUS)

               5. vasectomized partner

               6. bilateral tubal occlusion

               7. 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.

          6. 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:

          1. Evidence of irreversible injury deemed non-survivable even if the pulmonary failure
             recovers (for example severe anoxic brain injury)

          2. Known active inflammatory bowel disease

          3. Known active, untreated diverticulitis

          4. Known untreated bacteremia

          5. 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).

          6. Known hypersensitivity to the clazakizumab