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.
The limited understanding of the clinical behavior of patients infected with 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 lymphhistiocytosis (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 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.
Drug: Clazakizumab 25 mg
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.
Drug: Clazakizumab 12.5 mg
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.
Other: Placebo
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.
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
Mayo Clinic
Phoenix, Arizona, United States
The Johns Hopkins Hospital
Baltimore, Maryland, United States
New York University School of Medicine
New York, New York, United States
Bonnie Lonze, MD, Principal Investigator
NYU Langone Health