Clazakizumab vs Placebo (RCT)

Hospitalized patients

On March 18th, 2021, we published results of the living systematic review on IL-6 blocking agents which included all preprints and published trials published online up to February 11th, 2021.

We updated the the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19. On June 1, 2023, an update of the systematic review on IL-6 blocking agents was published. It included all preprints and published trials published online up to June 7, 2022.FOREST PLOTS -2022-05-29

Studies description

Trial NCT04348500
Publication Jordan S, Unpublished (2021) (results posted on registry)
Dates: 2020-04-28 to 2020-07-30
Funding: Private (Vitaeris Inc.)
Conflict of interest: *

Methods
RCT
Blinding: quadruple blinding
Location : Single center / USA
Follow-up duration (days): 60
Inclusion criteria
  • Age >18 at the time of screening
  • Subject must be able to understand and provide informed consent
  • Hospitalized with COVID-19 (+) disease (confirmed by polymerase chain reaction (PCR) assay from any specimen (e.g. respiratory, blood, urine, stool, other bodily fluid))
  • Not on mechanical ventilation and/or ECMO
  • Evidence of pulmonary involvement with at least 2 of the following: 1. Oxygen saturation (SpO2) at rest in ambient air with SpO2 ≤ 94%, 2 Tachypnea with resting respiration rate > 25 breaths/minute, 3 Partial pressure of oxygen (PaO2) / fraction of inspired oxygen (FiO2) ≤ 300 mmHg, 4 Chest imaging (radiograph, CT scan, or lung ultrasound) with abnormalities consistent COVID-19 pneumonia, 5 C-reactive protein (CRP) >35 mg/L
Exclusion criteria
  • Previous hypersensitivity or allergic reactions to clazakizumab
  • Lactating or pregnant females
  • Subjects with latent Tuberculosis (TB) and who are not receiving treatment
  • Subjects with active TB
  • A significantly abnormal general serum screening lab result defined as a White Blood Count (WBC) < 3.0 X 103/ml, a Hgb < 8.0 g/dL, a platelet count < 50 X 103/ml, a serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) > 5x upper limit normal
  • Participation in another clinical trial investigating COVID-19 aimed agents
Interventions
Treatment
Clazakizumab
25 mg in 50 mL of 0.9% saline intravenously single dose. A second dose could be given after 24 hours up to day 14.
Control
Placebo

Participants
Randomized
participants :
Clazakizumab =8
Placebo=9
Characteristics of participants
N= 17
Mean age : NR
10 males
Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
In the register
Safety of Clazakizumab for the Treatment of Patients With COVID-19 Disease [ Time Frame: 14 days ]
In the report
NR
Documents
avalaible

Protocol

Yes. In English

Statistical plan

Yes

Data-sharing willing stated in the publication:

Not reported
Risk of bias
Overall
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
Some concerns
General comment The trial registry, protocol and statistical analysis plan were used in data extraction and assessment of risk of bias. This is an unpublished study whose results have been reported in ClinicalTrials.gov. The trial was registered prospectively and no important changes were made to primary or secondary outcomes after recruitment start. The trial (n = 17) did not achieve its target sample size (n = 60) and is underpowered to assess statistical significance between the treatment and placebo group.

Trial NCT04343989
Publication Lonze B, Crit Care Med (2022) (published paper)
Dates: 2020-04-01 to 2020-12-03
Funding: Mixed (This study was funded by a grant from the Jack Rudin Family Foundation to Dr. Lonze. Clazakizumab was provided at no cost to the investigators by Vitaeris, recently acquired by CSL Behring. No corporate monetary support was provided. Vitaeris provided advice on the study design but had no role in conduct of the study, data collection, analysis, or interpretation. CSL Behring had no role in the study design, study conduct, data collection, analysis, or interpretation.)
Conflict of interest: Yes

Methods
RCT
Blinding: double blinding
Location : Multicenter / USA
Follow-up duration (days): 60
Inclusion criteria
  • Confirmed SARS-CoV-2 infection by reverse transcriptase-quantitative polymerase chain reaction testing and hypoxemia indicated by any of the following: Pao2/Fio2 ratio less than 200, saturation of less than 90% on at least 4 L supplemental oxygen, or increasing oxygen requirements over 24 hours preceding enrollment
  • Two or more indicators of hyperinflammation were required: C-reactive protein (CRP) greater than 35 mg/L, ferritin greater than 500 mg/mL, d-dimer greater than 1,000 ng/mL, neutrophil:lymphocyte ratio greater than 4, lactate dehydrogenase greater than 200 U/L, or elevated troponin absent cardiac disease
  • Subjects with capacity provided written consent, consent was otherwise obtained from legally authorized representatives
Exclusion criteria
  • Irreversible conditions deemed nonsurvivable
  • Active inflammatory bowel disease
  • Active untreated diverticulitis
  • Untreated bacteremia
  • Pregnancy
  • Known hypersensitivity to clazakizumab
Interventions
Treatment
Clazakizumab 12.5
12.5 mg IV single dose. 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.

Clazakizumab
25 mg IV single dose. 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.
Control
Placebo

Participants
Randomized
participants :
Placebo=74
Clazakizumab 12.5=26
Clazakizumab=78
Characteristics of participants
N= 178
Mean age : NR
123 males
Severity : Mild: n=0 / Moderate: n=25 / Severe: n=90 Critical: n=37
Primary outcome
In the register
1) Ventilator Free Survival [ Time Frame: 28 days ] Ventilator Free Survival is defined as the total number of patients who were alive and ventilator free at 28 days; 2) Number of Serious Adverse Events Associated With High and Low Dose of Clazakizumab [ Time Frame: 60 days ]
In the report
28-day ventilator free survival
Documents
avalaible

Protocol

Yes. In English

Statistical plan

Yes

Data-sharing willing stated in the publication:

Not reported
Risk of bias
Overall
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
Some concerns
General comment In addition to the published article, the study registry, protocol/SAP were used in data extraction and risk of bias assesment. The study achieved the target sample size specified in the trial registry. There is no change from the trial registration in the intervention and control treatments. The registry original primary outcome does not reflect the current primary outcome. This study reports on the results of the high-dose clazakizumab only since the Safety and Monitoring Board (DSMB) recommended dropping of the low-dose arm after interim analysis.