Covid-19 living Data

Canakinumab vs Placebo (RCT)

Hospitalized patients

On Jan 26th, 2022, we published results of the Are medicines that block interleukin‐1 (a protein involved in immune responses) effective treatments for COVID‐19 and do they cause unwanted effects? which included all preprints and published trials published online up to November 5, 2021.

Studies included but not extracted/included in the analysis: Hepprich M, EClinicalMedicine, 2022

FOREST PLOTS -2022-10-07

Studies description

Trial NCT04362813; EudraCT 2020-001370-30
Publication CAN-COVID - Caricchio R, JAMA (2021) (published paper)
Dates: 2020-04-30 to 2020-08-17
Funding: Private (Novartis Pharma AG )
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / France, Italy, Russia, Spain, UK and USA Follow-up duration (days): 28
Inclusion criteria	Hospitalized patients with severe COVID-19 at least 12 years old (United States) or 18 years old (Europe) hypoxemia but did not require IMV diagnosis of infection with SARS- CoV-2 within 7 days prior to randomization diagnosis of pneumonia with pulmonary infiltrates on chest x-ray or computed tomographic scan within 5 days prior to randomization peripheral capillary oxygen saturation of 93% or less on room air or arterial oxygen partial pressure/fraction of inspired oxy- gen less than 300 mm Hg, blood levels of CRP of 20 mg/L or greater or ferritin of 600 μg/L or greater.
Exclusion criteria	Treated with therapies targeting IL-1 or IL-6 suspected or known untreated active infection due to another pathogen if progression to death was imminent within 24 hours according to the investigator.
Interventions
	Treatment Canakinumab Single dose infused IV over 2 hours: 450 mg for body weight 40-<60 kg, 600 mg for 60-80 kg, 750 mg for >80 kg in 250 mL of 5% dextrose.
	Control Placebo
Participants
	Randomized participants : Canakinumab=227 Placebo=227
	Characteristics of participants N= 454 Mean age : NR 267 males Severity : Mild: n=26 / Moderate: n=321 / Severe: n=104 Critical: n=0
Primary outcome
	In the register Patients who survived without requiring invasive mechanical ventilation from Day 3 to Day 29
	In the report The proportion of patients who survived without ever requiring IMV from day 3 to day 29 (inclusive).
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
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	Low
General comment	In addition to the published article, the trial registry, protocol, statistical analysis plan and supplementary appendices were used in data extraction and assessment of risk of bias. There were no substantive differences between the published article and the registry in population, procedures, interventions or outcomes. The report describes the participants as having severe COVID-19, and chest x-ray or CT scan and blood oxygen inclusion criteria indicate severe disease. However, assessments at baseline on the WHO ordinal scale range from Mild (Hospitalized, no oxygen therapy) to Severe (Noninvasive ventilation or high-flow oxygen). And this scale has been used to categorize patients for this extraction. The study achieved its target sample size. The study reports an interim analysis including data up to day 29. This study was updated on October 25th, 2021 with data from contact with authors. This study was updated on September 28th, 2022 with data extracted from the registry.

Trial NCT04365153
Publication The three C study - Cremer P, Eur Heart J (2021) (published paper)
Dates: 2020-04-28 to 2020-08-25
Funding: Private (Novartis )
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Multicenter / USA Follow-up duration (days): 150
Inclusion criteria	>= 18 years-old hospitalized for COVID-19 infection with a documented upper respiratory tract specimen positive for SARS-CoV2 RNA had a troponin T >99th percentile upper reference range NT-proBNP greater than the age-adjusted upper reference limit C-reactive protein (CRP) >50 mg/L
Exclusion criteria	Alternative explanation for troponin elevation Chronic Systolic Heart Failure with EF < 35% Age < 18 years-old Uncontrolled systemic bacterial or fungal infection Concomitant viral infection (eg, Influenza or other respiratory virus) Pregnant On mechanical circulatory support On mechanical ventilation for greater than 48 hours Resuscitated cardiac arrest known hypersensitivity to canakinumab or any of its excipients Neutrophil count <1000/mm3 history of myeloproliferative disorder or active malignancy receiving chemotherapy known active tuberculosis or history of incompletely treated tuberculosis Current treatment with immunosuppressive agents Chronic prednisone use >10 mg/daily (for more than 3 weeks prior to admission) Has a history of solid-organ or bone marrow transplant Severe preexisting liver disease with clinically significant portal hypertension End-stage renal disease on chronic renal replacement therapy Enrollment in another investigational study using immunosuppressive therapy In the opinion of the investigator and clinical team, should not participate in the study If male and sexually active, must have documented vasectomy or must practice birth control and not donate sperm during the study and for 3 months after study drug administration Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of investigational drug
Interventions
	Treatment Canakinumab 600 mg IV single dose Canakinumab 300 300 mg IV single dose Canakinumab 600 600 mg IV single dose
	Control Placebo
Participants
	Randomized participants : Canakinumab =29 Placebo=16 Canakinumab 300=14 Canakinumab 600=15
	Characteristics of participants N= 74 Mean age : NR 44 males Severity : Mild: n=6 / Moderate: n=25 / Severe: n=14 Critical: n=15
Primary outcome
	In the register Clinical Improvement at Day 14 [ Time Frame: Up to day 14 ] (Number of patients with either an improvement of two points on a seven category ordinal scale or discharge from the hospital)
	In the report Time to clinical improvement up to day 14, defined as the time in days from randomization to either an improvement of two points on a seven category ordinal scale or discharge from the hospital, whichever occurred first
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 two published articles, the study registry (with outcome data posted online) and the protocol were used in data extraction and risk of bias assessment. The study achieved the target sample size specified in the trial registry. There is no change from the trial registration in the population, intervention and control treatments, or in the primary outcomes. On 10th of August, 2021, this study was updated based on the published report in European Heart Journal.