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.
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.
Drug: Clazakizumab
Dose is 25mg intravenously over 30 minutes.
Other Name: Clazakizumab solution
Other: Placebo
Intravenously administered over 30 minutes.
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 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.
3. 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
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
Columbia University Medical Center / New York Presbyerian Hospital
New York, New York, United States
David J. Cohen, MD, Principal Investigator
Columbia University